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'Acid-base pHysiology' by Kerry Brandis

Contents Chapter 1 : Introduction 1.1 Overview 1.2 Acids and Bases 1.3 The Hydrogen Ion Chapter 2 : Control of Acid-Base Balance 2.1 Acid'Base Ba#ance 2.2 Buffering 2.3 )es iratory )egu#ation Chapter 3 : Acid-Base isorders 3.1 Termino#ogy of Acid'Base .isorders 3.2 Anion /a 3.3 The .e#ta )atio Chapter ! : "espiratory Acidosis 4.1 .efinition 4.2 "auses 4.3 Maintenance 4.4 Meta$o#ic 1ffects Chapter # : $etabolic Acidosis !.1 .efinition !.2 "auses !.3 Maintenance !.4 Meta$o#ic 1ffects Chapter % : "espiratory Al&alosis %.1 .efinition %.2 "auses %.3 Maintenance %.4 Meta$o#ic 1ffects Chapter ' : $etabolic Al&alosis %.! "om ensation %.% "orrection %.2 Assessment %.3 4revention 3.4 0rinary Anion /a 3.! Osmo#ar /a 2.4 )ena# )egu#ation 2.! The Acid'Base )o#e of the *iver 2.% )egu#ation of Intrace##u#ar +H,1.4 Measurement of H 1.! Im ortance of H in "e##u#ar Meta$o#ism 1.% Imida&o#e A# ha'(tat Hy othesis

4.! "om ensation 4.% "orrection 4.2 Assessment 4.3 4revention

!.! "om ensation !.% "orrection !.2 Assessment !.3 4revention

2.1 .efinition 2.2 "auses 2.3 Maintenance 2.4 Meta$o#ic 1ffects

2.! "om ensation 2.% "orrection 2.2 Assessment 2.3 4revention

Chapter ( : $a)or *ypes of $etabolic Acidosis 3.1 *actic Acidosis 3.2 5etoacidosis 3.3 Acidosis and )ena# 6ai#ure 3.4 Hy erch#oraemic Acidosis 3.! )ena# Tu$u#ar Acidosis 3.% Acidosis due to .rugs and To7ins 3.2 0se of Bicar$onate in Meta$o#ic Acidosis

Chapter + : Assess,ent of Acid-Base isorders 8.1 (tructured A roach to Assessment 8.2 (ystematic 1va#uation 8.3 Bedside )u#es to Assess "om ensation 8.4 The )ationa#e 8.! The /reat Trans'At#antic Acid'Base .e$ate 8.% "#inica# 17am #es "ase History Inde7 for wor9ed e7am #es Chapter 1- : .uantitati/e Acid-Base Analysis 1:.1 The (ystem 1:.2 The Bac9ground 1:.3 The ;aria$#es 1:.4 The 1<uations 1:.! The (o#utions 1:.% The Im #ications

Chapter 11 : 0pecial Aspects of Acid-Base 1hysiology 11.1 4regnancy 11.2 "hi#dren 11.3 Acid'Base .isorders due to .rugs and To7ins

Acid-base 1hysiology 121 - 3/er/ie4 12121 Approaches to understanding acid-base physiology

*raditional Approach The discussion of acid'$ase hysio#ogy out#ined in most of this $oo9 is the =traditiona#> em irica# a roach. The conce ts and e7 #anations of this a roach are sti## the most common way that acid'$ase hysio#ogy is taught and understood $y many c#inicians. But this is not the on#y a roach. 1hysico-che,ical Approach An a#ternative a roach derived from hysico'chemica# rinci #es was ro osed $y a "anadian hysio#ogist? 4eter (tewart in 1831. A#ternative names for this a roach are the @(tewart a roach@ and @Auantitative Acid'$ase Ana#ysis@ The two a roaches are very simi#ar in the way that acid'$ase disorders are c#assified and measured. The maBor difference is in the e7 #anation and inter retation of acid'$ase disorders and contro# mechanisms. )ecent research has #arge#y confirmed the correctness of the (tewart a roach $ut it must $e admitted that it wi## ta9e <uite some time for main'stream acid'$ase hysio#ogy teaching to catch u . Indeed? there has $een some vitrio#ic resistance from the traditiona#ists. The rest of this cha ter discusses some introductory conce ts. 12122 5hat to e6pect in this boo& "ha ter 1 rovides an introduction to $asic conce ts of acids C $ases and the hydrogen ion . The reason why the e7treme#y #ow hydrogen ion concentrations in the $ody have such maBor effects on $ody rocesses is discussed. The fina# art of this cha ter is a$out the imida&o#e a# ha'stat hy othesis and the H'stat hy othesis. "ha ter 2 considers the contro# of acid'$ase $a#ance? inc#udingD The acids roduced $y the $ody and the conce t of $a#ance? $oth interna# and e7terna# Buffering and other as ects of the $odyEs res onse to acid'$ase stress The maBor ro#es of the #ungs and the 9idneys in acid'$ase regu#ation The im ortance of the #iver )egu#ation of intrace##u#ar H.

"ha ters 3 discusses the termino#ogy of acid'$ase disorders. A distinction is made $etween rimary rocesses which generate an acid'$ase disorder and the $odyEs com ensatory res onses. The conce ts of anion ga ? de#ta ratio? urinary anion ga and osmo#ar ga are usefu# in ana#ysis of some acid'$ase disorders. The 4 ty es of acid'$ase disorder ' "ha ter 4D )es iratory acidosis? "ha ter !D Meta$o#ic acidosis? "ha ter %D )es iratory a#9a#osis? "ha ter 2D Meta$o#ic a#9a#osis ' are each covered in a systematic wayD definition? causes? maintenance? meta$o#ic effects? com ensation? correction? assessment? revention. "ha ter 3 covers some of the maBor ty es of meta$o#ic acidosis in more detai#. In articu#ar? attention is focussed on #actic acidosis? 9etoacidosis? acidosis with rena# fai#ure? hy erch#oraemic acidosis? rena# tu$u#ar acidosis?and acidosis occurring with drugs and to7ins. The #ace of sodium $icar$onate thera y is discussed. "ha ter 8 e7 #ains a structured a roach to the assessment of acid'$ase disorders C inc#udes numerous wor9ed c#inica# e7am #es. Fou can wor9 through these e7am #es yourse#f? then com are your resu#ts with my ana#ysis. The a roach to ana#ysis used in this $oo9 is $ased on the EBoston a roachE so an

introduction to the E/reat transat#antic acid'$ase de$ateE discusses why this a roach is $est. "ha ter 1: introduces <uantitative acid'$ase ana#ysis G or @the ( tewart a roach@ H. This is on#y an introductory treatment $ut wi## $e enhanced as this method of ana#ysis $ecomes more common in c#inica# use. 4eter (tewart introduced an a roach that #eads to an im roved understanding of acid'$ase contro# in the $ody. His #andmar9 1831 $oo9 G@Ho4 to 7nderstand Acid-Base@H has recent#y $een #aced on'#ine at htt DIIwww.AcidBase.org . "ha ter 11 considers severa# s ecia# areas inc#uding chi#dren C regnancy . The $est way to #earn ana#ysis of acid'$ase resu#ts is to fre<uent#y ractice what you have #earnt. As a neo hyte to acid'$ase ana#ysis? you wi## genera##y consider this a retty daunting to ic. Fou wi## notice that arteria# $#ood gas resu#ts are fre<uent#y ordered on i## atients $ut #itt#e comment is made on these in the atient record. It is certain that a #ot of re#evant c#inica# information is #ost $ecause of a #ac9 of understanding of acid $ase ana#ysis. A articu#ar aim of this $oo9 is to deve#o the su$Bect gradua##y and systematica##y? and to #ead you to a ractica# structured a roach to ana#ysis of $#ood gas resu#ts which you can use in your c#inica# ractice. Because of the interaction of acid'$ase hysio#ogy with res iratory? cardiovascu#ar? and rena# systems and su$strate meta$o#ism in articu#ar? a set of $#ood'gas resu#ts can $e a very usefu# teaching aid. The B#ood /as Archive contains a set of si7 Gho efu##y entertainingH simu#ated teaching e7ercisesJ this is constructed as a dia#ogue $etween a consu#tant and a registrar. (ome of the difficu#ties in #earning acid'$ase hysio#ogy are out#ined in the fo##owing <uote. 4ertinent Auote @AcidI$ase homeostasis is argua$#y one of the most difficu#t of the su$disci #ines of hysio#ogy for veterinary and human medica# students to master. There are severa# reasons for this. Ty ica##y? the a roach to this materia# is high#y <uantitative and $ased on the hysica# characteristics and fundamenta# $ehaviors of acids and $ases? which can $e off' utting to veterinary and human medica# students.@ @Keo hyte students are a#so often intimidated $y acidI$ase hysio#ogy? $ecause it is atent#y integrative. (tudents <uic9#y rea#i&e that understanding the data in a $#ood gas ane# re<uires an a reciation for not on#y acids and $ases? $ut a#so venti#ation? gas e7change? dynamics of e#ectro#yte and water movement? #asma com osition? res iratory contro#? and rena# mechanisms of hydrogen ion? e#ectro#yte? and water e7cretion.@ @In addition? it is essentia# that the student deve#o an understanding of a host of other organ? meta$o#ic? and structura# dysfunctions that can otentia##y contri$ute acid or $ase #oads to the e7trace##u#ar f#uid.@ from: Rawson RE & Quinlan KM, Adv Physiol Educ 2002; 26: !"#$

Acid-base 1hysiology 122 Acids 8 Bases 12221 5hat is an acid9 The term is derived from the *atin word =acidus> which means sour. 1ar#y chemists had a #ist of ro erties that were common to the su$stances that they considered to $e acids or $ases +eg acids had a sour taste? turned #itmus red? reacted with some meta#s to roduce a f#amma$#e gas GhydrogenH ..etc.. -. They wou#d assess a new su$stance as an acid or as a $ase Gor as neitherH $y com aring the ro erties of the new su$stance against the #ist of ro erties. *he Arrhenius *heory The first modern a roach to acid'$ase chemistry was $y Arrhenius in 1332. He defined an acid as a su$stance which was ca a$#e of dissociating in water so#ution to roduce hydrogen ions. This definition identified most of the su$stances which were considered to $e acids at that time. A $ase was defined as a su$stance which dissociated in water so#ution to roduce hydro7ide ions. The theory was not tota##y satisfactory for severa# reasons. 6or e7am #e? some su$stances which had acidic ro erties did not contain hydrogen and some $ases did not contain hydro7ide ions. The theory a#so a #ied on#y to a<ueous so#utions. *he Bronsted-:o4ry *heory The ne7t deve#o ment was the Bronsted'*owry Theory G1823H and this is the a roach which is genera##y acce ted in $io#ogica# and medica# fie#ds. An acid is defined as a su$stance which donates a hydrogen ion to another su$stance. This does not re<uire an a<ueous so#ution or dissociation into ions as in the Arrhenius definition. The su$stance which acce ts the H, from the acid is ca##ed the =conBugate $ase>. This idea of conBugate acid'$ase airs is an im ortant art of the Bronsted'*owry a roach. Acid strength is defined in terms of the strength of the tendency to donate the hydrogen ion to the so#vent Gie water in $io#ogica# systemsH. A strong acid has a high tendency to donate a roton to waterJ so the +H3O,- is high. 3ther Approaches: :e4is 8 7sano/ich A more genera# definition of acids and $ases is the a roach of *ewis in 1823. The im etus here was the ro$#em of su$stances which e7hi$ited acidic ro erties in so#ution Geg "O2H $ut did not contain a H,. *ewis defined an acid as any com ound that was a otentia# e#ectron air acce tor and a $ase as any com ound that was a otentia# e#ectron air donor. In the *ewis scheme? H, itse#f is an acid. 0sanovich G1838H deve#o ed an even more genera# a roach to acid'$ase theory that conso#idated the differing a roaches of the revious theories. 12222 5hat Approach 0hould 5e 7se9 6rom the medica# and $io#ogica# ers ective? the Bronsted'*owry theory is easy to understand and encom asses a## the $io#ogica# acids and $ases encountered in a<ueous so#utions. It is the referred a roach.G"O2 is not strict#y an acid in the Bronsted'*owry system as it has no hydrogen ion $ut it can

$e accommodated $y considering car$onic acid G H2"O3 H as the acid.H In rea#ity? most hysicians have a $asic 9now#edge of acids and $ases which is somewhat of an com$ination of the Arrhenius a roach GacidD H, in so#utionH? the Bronsted'*owry a roach Gacid L roton donorH and even the *ewis a roach Geg "O2 as an acidH. This #eve# of understanding is genera##y satisfactory for c#inica# ur oses. The ta$#e $e#ow summarises the different a roaches. Basic 1rinciples of the ;arious *heories of Acids and Bases Traditiona# a roach AcidD a su$stance that has certain ro erties Geg sour taste? turns #itmus redH Acid D H, in a<ueous so#ution Base D OH' in a<ueous so#ution At neutra#ityD +H,- L +OH'Acid D H, donor Base D H, acce tor "onBugate acid'$ase airs Ko conce t of neutra#ity Acid D a otentia# e#ectron' air acce tor Base D a otentia# e#ectron' air donor AcidD a su$stance that donates a cation? or acce ts an anion or an e#ectron BaseD a su$stance that donates an anion? or acce ts a cation.

Arrhenius

Bronsted'*owry

*ewis

0sanovich

Acid-Base 1hysiology 123 - *he Hydrogen Ion 12321 Hydrogen Ion in 0olution Bare rotons Gie H,H do not e7ist in so#ution. 4rotons are associated and react with surrounding water mo#ecu#es. This is sometimes re resented as H3O, Gthe hydronium ionH $ut this one'to'one re#ationshi is a#so inaccurate. (tewart suggests that the most accurate re resentation is MHDGH2OHnN, to i##ustrate the reaction or interaction of H, with water mo#ecu#es. This wou#d $e e7treme#y inconvenient to use c#inica##y so we continue to s ea9 of the hydrogen ion GH,H sim #y out of convenience. This is an acce ta$#e convention $ut remem$er that H, is a =sym$o# for a meta hor> G(tewartH and does not e7ist

in so#utions in that form. This @meta horica# H,@ is e7tensive#y used and this convention is continued here. 12322 Hydrogen Ion Acti/ity "hemists s ea9 of =idea# so#utions> which have certain redicta$#e hysicochemica# ro erties. However? rea# so#utions e7hi$it various degrees of =non'idea#> $ehaviour. This deviation from idea# $ehaviour is due to interactions $etween the mo#ecu#es in the so#ution and inc#udes $oth so#vent'so#ute interactions and so#ute'so#ute interactions. The magnitude of this interaction Gand the deviation from idea# $ehaviourH is higher with higher artic#e concentration in the so#ution and with ions as com ared to non'charged s ecies. The idea of Eeffective concentrationE or EactivityE was introduced $y *ewis to dea# with this ro$#em. Activity indicates how many artic#es seem to $e resent in the so#ution and is different from how many actua##y are resent. Activity can $e thought of as a #ying a correction factor to the concentration. Activity is re#ated to concentration $y the activity coefficientD efinition of Acti/ity a7 L g . +7whereD a7 L activity of su$stance 7 in the so#ution g L activity coefficient of 7 +7- L concentration of su$stance 7 in the so#ution The activity coefficient of a so#ute is constant in any articu#ar given so#ution $ut its va#ue can change if the ro erties of the so#ution are changed Geg $y changing the ionic strength or the tem eratureH. If the re#ationshi $etween concentration and activity is #otted on a gra h? it is not #inear. It de ends on the ty e of so#vent and the ty e and concentration of the various so#utes resent in the so#ution. In an idea# so#ution? the activity coefficient is one. The activity coefficient a#so a roaches unity as non'idea# so#utions $ecome more and more di#ute. It is usua# in discussions of acid'$ase $a#ance to assume the activity coefficient of so#utes is e<ua# to one and use concentrations nstead of activities. This is o$vious#y not correct $ut the errors introduced are usua##y sma## and not c#inica##y re#evant. (ome measurement techni<ues Gsuch as ion se#ective e#ectrodesH measure activities and others measure concentration. 12323 pH The g#ass e#ectrode for H, is an ion'se#ective e#ectrode GI(1H wide#y used in c#inica# medicine. The otentia# that deve#o s in this e#ectrode is ro ortiona# to the #og of the hydrogen ion activity in the test so#ution. The term used is = H> which is now defined asD efinition of pH H L ' #og1: aH, GorD aH, L 1: G'
HH

where aH, is activity of H, The term pH Gin that e7act form ' #owercase ? u ercase HH was first used $y OM "#ar9 Ginventor of the "#ar9 o7ygen e#ectrodeH in 182:. GseeD "om act O7ford 1ng#ish .ictionaryH However the conce t was invented $y the .anish chemist? (oren 4eter (orensen in 18:8 to refer to the negative #og of hydrogen ion concentrationJ he used the term 1H in his origina# a er. He ca##ed it the 5asserstoffionene6ponent G/erman for hydrogen ion e7 onent as hydrogen is @wasserstoff@ in /ermanH. There are severa# versions of what the E E means. In the common version? the refers to the /erman word = oten&> G ower in the sense of $eing an e7 onentH so H means E ower of hydrogenE. The ower referred to is the ower of 1: used as the $ase for the #og and not to the acid strength of the so#ution. )ecent research suggests the E E was used as a resu#t of how he ar$itrari#y #a$e##ed the 2 e#ectrodes used in his e7 eriment as E E and E<E? and the measurements derived from these e#ectrodes inc#uded the #etters and <. Kote that the sym$o# = > is used in two conte7ts in acid'$ase discussionsD meaning =the negative #og of> as in H? 5? OH meaning = artia# ressure> as in "O2

H is regarded as a Edimension#ess re resentation of the +H,-E G5e##um? 2:::H and is not itse#f a concentration. Because of this? H does not have any unitsD it is Bust a num$er. There is a #oose use of the term = H units> as a device to assist e7 #anation of some conce ts. 6or e7am #e? the ma7ima# H gradient across the gastric mucosa is % H units G ie 2.4 minus 1.4 H re resenting a hydrogen ion concentration gradient of 1:% Gie 1?:::?:::H. By contrast? the hydrogen ion gradient across the rena# co##ecting duct when ma7ima##y acidic urine G H 4.!H is roduced is a$out 3 H units Gie gradient of 1:3 H. The term = H unit> is considered to mean =unit change in H> in most conte7ts. The term = H concentration> is sim #y wrong and shou#d never $e used. %h&or&'ically? va#ues of H cou#d range from 'infinity to ,infinity $ut the ractica# #imits in a<ueous so#utions are from '1.2 to ,1! ref#ecting +H,- varying from 1! to 1:'1! mo#esI#itre. "oncentrated hydroch#oric acid used $y chemists has a H of '1.1. ;a#ues in human f#uids range from e7treme#y acid G H :.32 for H"# secretion into the intrace##u#ar cana#icu#us of gastric arieta# ce##sH to the a#9a#ine va#ues of $i#e and ancreatic Buice. The reference range for arteria# H is 2.3% to 2.44 and the #imits of surviva# cover a ten fo#d range of H, G from 1%: to 1% nmo#esI# which is H %.3 to 2.3H. 1232! 5hich is Best: pH or <H=> 9 There is a continuing discussion a$out the most a ro riate sym$o# to re resent the acidity of $ody f#uidsD H or +H,-. In ractica# terms it is $est to $e most fami#iar with what is used in your #oca# atho#ogy #a$oratory. The current recommendation of the re#evant internationa# $ody Gthe I0""H is to use H. The advantages of H com ared to +H,- areD It is the traditiona# sym$o# and remains in wide use It is re#ated to the activity of H, Grather than concentrationH or more s ecifica##y the #og of H, activity and this is what hysio#ogica# systems seem to res ond to. It is what is measured $y the H e#ectrode Gie activity of H,H

The a#ternative +H,- is not correct $ecause the activity coefficient is ignored 6ree H, Gie $are rotonsH are not the form rea##y resent in so#ution anyway. The disadvantages of H areD It is a contrived sym$o# which re resents a dou$#e non'#inear transformation of +H,- Gie the #og of a reci roca#H It is difficu#t to #earn and understand It disguises the magnitude of changes in +H,1232# A 0i,ple 5ay to Con/ert bet4een pH and <H=> "hanges in the +H,- $y a factor of 2 cause a H change of :.3 'this rovides us with a sim #e way to determine various H'+H,- airs of va#ues if we 9now that H 2.4 is 4: nmo#esI#. 6or e7am #eD a +H,of 3: nmo#esI# is a H of 2.1 ' ins ection of the ta$#e a$ove shows a va#ue of 28 so this sim #e method is retty accurate. This usefu# re#ationshi ho#ds $ecause #og 2 is :.3 so a dou$#ing or a ha#ving of +H,means a change in H $y :.3 either u or down. "elationship bet4een pH 8 <H=> pH %.3 %.8 2.: 2.1 2.2 2.3 2.4 2.! 2.% 2.2 2.3 <H=> ?nano,oles@lA 1!3 12! 1:: 28 %3 !: 4: 31 2! 2: 1!

This doesnEt a##ow you to menta##y ca#cu#ate every H and +H,- va#ue $ut the 4 $asic airs which are usefu# and easy to memorise areD H 2.4 is 4: nM H 2.: is 1:: nM H 2.3% is 44 nM H 2.44 is 3% nM

The #ast two va#ues a$ove are the norma# range of H va#ues which is easy to remem$er $ecause the re#ationshi $etween the +H,- and the decima# art of the H Gie the norma# range of 2.3% to 2.44 is a +H,- range of 44 to 3% nM. Kow you can wor9 out that a H of 2.:% has a +H,- va#ue of 33nm as this is dou$#e that at 2.3% Gie 44nMH ' and so on.

"eferences 1. Kor$y P. The origin and meaning of the #itt#e in H. Trends in Biochemica# (ciences 2:::J 2!D 3%' 32. EAcid'$ase Hysio#ogyE $y 5erry Brandis ' from htt DIIwww.anaesthesiaM"A.com Acid-Base 1hysiology 12!: *he $easure,ent of pH 12!21 $ethods The hydrogen gas #atinum e#ectrode was origina##y used for measuring +H,- $ut is not usefu# for c#inica# H ana#ysis. The sam #e had to $e fu##y saturated with hydrogen gas and a## the o7ygen e#iminated. The method is not suita$#e for ra id automated ana#ysis of $#ood sam #es. "urrent methods of H measurement inc#udeD "o#orimetric methods. *itmus a er is used to decide $etween acid or $ase $ut a ers incor orating H'sensitive dyes have $een $een designed to measure finer gradations of H Geg urine H is estimated $y use of indicator dyes in di stic9sH. 4rogress in co#orimetric H methods using indicator dyes Ginc#. f#uorescent dyesH has #ead to the deve#o ment of accurate intravascu#ar methods of H measurement. The 4aratrend 2, is a commercia##y avai#a$#e system for measuring intra'arteria# H and $#ood gases. /#ass e#ectrodes. These are wide#y used in medica# a #ications eg $#ood'gas machines. I(61T e#ectrodes ' using EIon'se#ective fie#d effect transistorsE. These are used most#y in industry $ut have $een deve#o ed for intravascu#ar use.

12!22 *he Blass pH Clectrode "remer in 18:% discovered that a e#ectrica# otentia# deve#o ed across a g#ass mem$rane which was ro ortiona# to the H difference across the mem$rane. 5erridge in 182! deve#o ed the first g#ass e#ectrode for ana#ysis of $#ood sam #es. MacInnes C .o#e in 1828 e7 erimented with different ty es of g#ass to find the one which was most sensitive. This MacInnes'.o#e g#ass G9nown as "orning :1! g#assH consists of 22Q si#icon dio7ide? %Q ca#cium o7ide and 22Q disodium o7ide GKa2OH. < iagra, to be added> The H e#ectrode consists of 2 ha#f ce##sD the g#ass e#ectrode and a reference e#ectrode Geg ca#ome# e#ectrodeH. This unit deve#o s an e#ectrica# otentia# across the g#ass which is de endent on the difference in aH, across the g#ass mem$rane. This effective#y a##ows measurement of the H of the test so#ution $ecause the H in the so#ution on the other side of the mem$rane is constant. Other otentia#s deve#o in the H e#ectrode Geg #i<uid Bunction otentia#? asymmetry otentia# C diffusion otentia#sH and these are usua##y not <uantified in a articu#ar e#ectrode. The ro$#em is overcome $y standardisation and ca#i$ration. (tandardisation refers to the rocess of re<uiring that these otentia#s are the same when measuring the sam #e so#ution and when measuring the ca#i$rating so#utions. In articu#ar? the #i<uid Bunction otentia# must remain unchanged. The ca#i$rating so#utions are chemica# standard $uffer so#utions with a 9nown H. Many of the com onents of the e#ectrode Geg the ca#ome# reference ce##H are very tem erature sensitive. The tem erature of the measurement must $e recise#y contro##edD usua##y at 32R".

12!23 *e,perature Correction If re<uired? modern $#ood gas machines wi## re ort the H va#ue for actua# atient tem erature $ut this =corrected va#ue> is ca#cu#ated mathematica##y from the H measured at 32R" in the machine. The change in H with tem erature is a#most #inear and Eanaero$ic coo#ingE of a $#ood sam #e Gie coo#ing in a c#osed systemH causes the H to rise. The )osentha# correction factor is recommended for c#inica# use. )osentha# "orrection 6actor "hange in H L :.:1! H units er degree " change in tem erature C6a,ple If the measured H is 2.3%: at a $#ood gas e#ectrode tem erature of 32R"? then the H at a atient tem erature of 34R" is ca#cu#ated as fo##owsD H L +2.3%: , G32'34HG:.:1!H- L 2.4:!. The otentia# generated in the H e#ectrode is a$out %1.! m;I H unit. The e#ectrode has a high interna# resistance so the measuring a aratus has to have a very high G1:11 OhmsH im edance to avoid drawing current from the ce## and changing the otentia#. 4revious S Inde7 S To of age S Ke7t EAcid'$ase Hysio#ogyE $y 5erry Brandis 'from htt DIIwww.anaesthesiaM"A.com

Acid-Base 1hysiology 12#: pH 8 Cellular $etabolis, 12#21 5hy is pH so i,portant9 *he a/is Hypothesis 8 Ion trapping Ohat is the ro#e of H in the $ody and why does H, have an im ortance which seems out of 9ee ing with its incredi$#y #ow concentrationT An insight can $e gained from the findings of .avis G18!3H. He surveyed a## 9nown meta$o#ic athways and #oo9ed at the structura# features of the com ounds in each of these athways. He found that near#y every =$iosynthetic intermediate has at #east one grou that wou#d $e #arge#y ionised at hysio#ogica# H? whether it is an acid or a $ase>. The on#y few e7ce tions he cou#d find amongst hundreds of com ounds were some macromo#ecu#es? some water'inso#u$#e #i ids and end' roducts of meta$o#ism Geg waste com oundsH. In summary? he found thatD =all 'h& (nown low mol&cular w&i)h' and wa'&r solu*l& *iosyn'h&'ic in'&rm&dia'&s +oss&ss )rou+s 'ha' ar& &ss&n'ially com+l&'&ly ionis&d a' n&u'ral +,-. These grou s are hos hate? ammonium and car$o7y#ic acid grou s. *he a/is hypothesis is that the ad/antage to the cell of this pH-dependent ionisation 4as the efficient trapping of these ionised co,pounds 4ithin the cell and its organelles2

12#22 5hat about the e6ceptions to this generalisation9 There are some com ounds that are seeming e7ce tions to the genera#isation. (o we need to as9 this <uestionD .oes the e7istence of the e7ce tions that .avis found render his who#e theory of ion tra ing inva#idT *ets #oo9 at the 3 grou s of ossi$#e e7ce tionsD 0o,e ,acro,olecules It cou#d $e argued that these #arge mo#ecu#es do not need to $e charged for their distri$ution to $e restricted to the intrace##u#ar environment. They cou#d $e tra ed within the ce## $ecause of their si&e. However? si&e'tra ing is not articu#ar#y effective if the macromo#ecu#e is very hydro ho$ic as such mo#ecu#es wou#d tend to move into #i id mem$ranes. But most macromo#ecu#es in ther ce## Geg roteinsH are charged or are o#ar mo#ecu#es and it is this that effective#y tra s them within the ce## Gun#ess there is a s ecific athway for their e7cretion from the ce##H. :ipids *i ids are not ionised and cross ce## mem$ranes easi#y. But some #i ids are Etra edE within the ce## des ite not $eing ionised. These #i ids which are not charged are tra ed within the ce## $y another mechanismD $y $eing rotein'$ound. (o #i ids that are necessary for intrace##u#ar ur oses are tra ed

$y an a#ternative means. $etabolic precursors 8 4aste products These com ounds need to $e a$#e to cross the mem$rane for ease of u ta9e G recursors #i9e g#ucoseH or e7cretion Gwaste roductsH from the ce##. It is an advantage if they are not charged and not tra ed. The first reaction that recursors undergo when they enter a ce## is a reaction that #aces a charged grou on the mo#ecu#e. An e7am #e is g#ucose which is converted to g#ucose'%' hos hate which is charged at intrace##u#ar H and there$y tra ed within the ce##. "#ear#y any reaction athway that had noncharged or non'$ound intermediates wou#d have strong evo#utionary ressures against it $ecause of the diffusiona# #oss of these intermediates from the ce##. (o these e7ce tions do not inva#idate the .avis hy othesis $ut instead add to it. The im ortance of H, is c#ear#y not re#ated to its concentration er se $ecause this is incredi$#y sma##. Its im ortance derives from the fact even though its concentration is e7treme#y #ow? an a#teration in this concentration has maBor effects on the re#ative concentrations of every conBugate acid and $ase of a## the wea9 e#ectro#ytes. One maBor conse<uence as discussed a$ove is that at Eneutra# HE meta$o#ic intermediates are resent on#y in the charged form and effective#y tra ed within the ce##. It is not Bust the sma## mo#ecu#es of intermediary meta$o#ism that are affected. The other critica##y im ortant as ect of the im ortance of H invo#ves roteins. The net rotein charge is de endent on the H and the function of roteins is de endent of this charge $ecause it determines the 3'. sha e of the mo#ecu#e and its $inding characteristics Geg ionic $ondingH. G(ee EIm ortance of Intrace##u#ar HEH E Acid-Base 1hysiology 12% - Alphastat Hypothesis 12%21 Beyond a/is : the Alphastat Hypothesis )eeves G1822H and )ahn e7tended the conc#usions reached $y .avis $y considering the dissociation constants G 5H for these meta$o#ic intermediates. They found that the 5 for a## the acid intermediates was #ess than 4.% and the 5 of a## the $asic intermediates was greater than 8.2 . The degree of dissociation of a## these com ounds at a H around neutra#ity was 1.: Gie fu##y ionisedH. The intermediates are a## charged and tra ed within the #i id ce## mem$rane. They suggested #oo9ing at acid'$ase hysio#ogy from the oint of view of the in'rac&llular environment instead of the usua# c#inica# e7trace##u#ar a roach. They first osed the fo##owing <uestionD 5hat is the ideal intracellular pH9 The wor9 of .avis and their findings concerning 5 va#ues suggested that the idea# state for intermediary meta$o#ism is the state of neutrality $ecause ma7ima# ionisation with conse<uent intrace##u#ar tra ing of meta$o#ic intermediates occurs at this H.

Dirst Hypothesis: pH?ICDA E pF If theoretica##y it is c#ear that the idea# I"6 H shou#d $e the H of neutra#ity G KH? then the ne7t ste is to as9 the <uestionD Is the actual intracellular pH as predicted9 According to )ahn? measurements confirmed that the mean intrace##u#ar H of man is %.3 at 32R" which is indeed the H of neutra#ity G KH at that tem eratureU Before going further we need to understandD 5hat is ,eant by GneutralityH9 Keutra#ity is defined? for a<ueous systems? as the state when +H,- L +OH'-. GThis definition derives from the Arrhenius acid'$ase theory and it is noted in assing that a criticism of the Bronsted'*owry theory is that it has no definition of neutra#ity.H By the *aw of Mass Action a #ied to the dissociation of water Gsee (ection 1:.4H? thenD K L :.! 7 5w> Gwhere 5w> is the ion roduct for water. H "onsideration of this e<uation is im ortant as it rovides us with a way to test the .avis? )eeves and )ahn hy othesis that intrace##u#ar H e<ua#s K Gwith conse<uent $io#ogica# advantage of intrace##u#ar tra ing of meta$o#ic intermediates. %h& clu& is 'ha' +Kw/is v&ry '&m+&ra'ur& d&+&nd&n'. (o K is tem erature de endent and if the hy othesis GI"6 H L KH is correct then intrace##u#ar H shou#d change with change in tem erature to maintain the redicted re#ationshi . An intrace##u#ar H at a$out K must sure#y a #y to other anima#s Gwith $ody tem eratures other than 32"H as there is no reason to $e#ieve that humans at 32R" a#one shou#d $e in a uni<ue osition. If this redicted change with tem erature does occur? it wou#d #end very strong su ort to the theory. (o? the ne7t <uestion isD oes intracellular pH change 4ith te,perature in order to re,ain eIual to pF at each te,perature9 ?And if so: Ho4 does this happen9A Measurements of intrace##u#ar H in s9e#eta# musc#es have $een carried out in severa# ectothermic anima#s which have $een acc#imatised at tem eratures ranging from !R" to 31R". These a## show the e7 ected H changeD intracellular pH is ,aintained at about pF 4ith change in te,peratureJJ It has $een ca#cu#ated that for the $ody to have this tem erature' H re#ationshi re<uires certain things. There must $e a $uffer system with a 5 which is a ro7imate#y one'ha#f that of water G$ecause a $uffer is most effective c#ose to its 5H and which changes its 5 so that it maintains this re#ationshi as tem erature changes. The $uffer must $e resent in sufficient concentration and have certain chemica# ro erties Geg de#ta HR L 2 9ca#s er mo#eH. 6or this system to wor9 o tima##y? it a#so re<uires a constant "O2 content. 17 erimenta# wor9 has shown that rotein $uffering? #arge#y due to the imida&o#e grou of histidine is res onsi$#e for maintaining this tem erature' H re#ationshi Gaided $y hos hate and $icar$onate $ufferingH. Of a## the rotein'dissocia$#e grou s that are avai#a$#e? it is only the i,idaKole of histidine that has the correct pK and 4hose pK changes 4ith te,perature in the appropriate 4ay2 The imida&o#e has a degree of dissociation Greferred to as a# haH of :.!! in the intrace##u#ar com artment and this remains constant des ite changes in tem erature Gie the 5 is changing with

change in tem eratureH. This theory a$out the constancy of the imida&o#e a# ha va#ue as ro osed $y )eeves and )ahn has $een termed the imida&o#e a# hastat hy othesis. A# hastat Hy othesis The degree of ionisation Ga# haH of the imida&o#e grou s of intrace##u#ar roteins remains constant des ite change in tem erature.

The other necessary condition for maintaining imida&o#e a# ha constant is that the "O2 content in $#ood must $e 9e t constant at different $ody tem eratures. This means that venti#ation must $e regu#ated to maintain the imida&o#e a# ha in the $#ood. It has $een found e7 erimenta##y that this regu#ation to maintain imida&o#e a# ha constant in $#ood wi## resu#t in imida&o#e a# ha $eing maintained in other com artments Geg intrace##u#ar f#uidH as we##. The res iratory contro# that adBusts venti#ation ro$a$#y invo#ves roteins whose activity is a#tered in an a ro riate direction $y an a# hastat mechanism. AdBustment of 1"6 "O2 is necessary as this maintains a constant re#ative a#9a#inity of the 1"6 re#ative to the I"6 so there is constancy of the gradient for H, across the ce## mem$rane. In rea#ity this does not mean that venti#ation has to increase mar9ed#y with decrease in tem erature $ecause the reduced meta$o#ic rate wi## automatica##y resu#t in decreased "O2 roduction. I,portant Fote: Many eo #e have an a#most unsha9ea$#e $e#ief that a H of 2.: is the Eneutra# HE and conse<uent#y have trou$#e understanding how the change in K with tem erature can $e ossi$#e. A so#ution to this is to understand that the definition of neutra#ity is the H when +H,- L +OH'-. At a tem erature of 2!"? this condition does indeed occur in ure water when H is 2.: and this is the $asis of the common high'schoo# teaching. But? as indicated in the ca#cu#ations in (ection 1:.4? this condition of +H,- L +OH'- occurs when H L :.! 7 5w>. This H Gthe KH is de endent only on the ion roduct of water G 5wEH' and this term is very tem erature de endent. (o the re<uired condition of +H,- L +OH'- occurs at different H va#ues at different tem eratures. 1ffective#y? this means that the dissociation of water is tem erature de endent. 12%22 Alpha-stat /ersus pH-stat The a#ternative theory is the pH-stat hypothesisD this argues that the H shou#d $e 9e t constant des ite changes in tem erature. This is the same as saying that 1"6 H shou#d $e 9e t at 2.4 whether the tem erature is 2:" or 2!" or whatever it is. B#ood gas resu#tsD To tem erature correct or notT The pH-stat approach is a#so im #icit#y the a roach used $y anyone who tem erature corrects $#ood gas resu#ts to the atient>s tem erature $ut inter rets the va#ues against the reference range re#evant to 32R". Ko reference range is avai#a$#e for tem eratures other than 32R" $ut the H'stat a roach is that the reference range for 32R" is va#id at a## tem eratures. The a# ha'stat a roach is to never tem erature correct $#ood gas resu#ts. .o not re ort the atientEs tem erature on the re<uest form? or if doing the gases yourse#f? on#y enter the tem erature as 32R" no matter what the atientEs actua#

tem erature. The resu#ts from the $#ood gas machine must then $e those as measured in the machine at 32R". The reference range for 32R" is o$vious#y the correct one to a #y when assessing these resu#ts. Fou shou#d $e carefu# $ecause if you or a co##eague indicate the atientEs actua# tem erature on the $#ood'gas re<uest form? the #a$ technician wi## enter this tem erature into the $#ood'gas machine and the rinted re ort wi## have the va#ues ca#cu#ated for this atient tem erature Gi.e. the EcorrectedE va#uesH. Kote that whatever the actua# atient tem erature? the machine is a#ways thermostatted to 32R" and a## measurements are conse<uent#y erformed at 32R". 6or other atient tem eratures? the com uter in the machine uses various correction formu#ae to ca#cu#ate what the va#ues for the arameters wou#d $e at the atientEs actua# tem erature. The H correction used in most machines is the )osentha# correction factor. The manua# for the $#ood gas machine has a com #ete #isting of the formu#ae it uses for a## ca#cu#ated va#ues.

This controversy over whether the a# ha'stat or the H'stat theory is corr&c' does have ractica# anaesthetic re#evance in atients who are rendered hy othermic Geg whi#e on cardio u#monary $y assH. Ohat is the H #eve# to aim for in these atientsT It seems that the a# ha'stat theory is now wide#y acce ted. This is ro$a$#y re#ated to the inte##ectua# attraction of the theoretica# arguments $ecause maBor differences in outcome $etween grou s of atients managed $y the H'stat or the a# ha'stat techni<ue have not $een c#ear. "e##s are ca a$#e of functioning des ite the resence of a certain #eve# of ertur$ation. "#inica# studies have concentrated on which a roach is $est for the heart Gmyocardia# outcomeH andIor which a roach is $est for the $rain Gneuro#ogica# outcomeH. The H'stat aim to maintain a H of 2.4 at the #ower tem eratures of hy othermic cardiac $y ass is achieved $y having a "O2 #eve# which is higher than that re<uired for a# ha'stat management. This means that from the a# hastat oint of view? H'stat management resu#ts in a res iratory acidosis at the #ower tem erature. One effect is that the cere$ra# $#ood f#ow is higher at a given tem erature with H'stat management than it is with a# hastat management. G(ee section 1.%.3H The a# hastat hy othesis is a$out maintaining a# ha which means that the net charge on a## roteins is 9e t constant des ite changes in tem erature. This ensures that a## roteins can function o tima##y des ite tem erature changes. The im ortance of H is not Bust a$out intrace##u#ar tra ing of meta$o#ic intermediates Gsma## mo#ecu#e effectH $ut a#so a$out rotein function G#arge mo#ecu#e effectH. This affects a## roteins? though en&ymes usua##y figure rominent#y as e7am #es. (o? to answer the <uestion a$out why H is so im ortant in meta$o#ism invo#ves these two reasons. (ummaryD The two reasons why H is so im ortant for meta$o#ism Cffect on s,all ,oleculesD Intrace##u#ar tra ing of intermediary meta$o#ites Gie the .avis hy othesisH Cffect on large ,olecules ?proteinsAD Maintaining o tima# rotein function $oth intrace##u#ar#y and e7trace##u#ar#y. "onse<uent#y? the $ody regu#ates H very tight#y

A fina# ointD According to chemists? the situation concerning H and tem erature is actua##y <uite com #e7D for e7am #e? the thermodynamic $asis of H measurement inc#udes a term for the =ground state otentia#> which must $e ar$itrari#y defined at every tem erature. This means that the a$so#ute va#ue of measured otentia# at any articu#ar tem erature cannot $e recise#y determined and thus that H va#ues o$tained at different tem eratures? strict#y s ea9ing? cannot $e com ared. This rea##y is not a concern to the c#inician.

12%23 C6a,ple: Alphastat $anage,ent during Induced Hypother,ia As a e7am #e? consider the management of a atient who is coo#ed during o en heart surgery. A atient is coo#ed to 2:R" for cardiac surgery whi#e on cardiac $y ass. Imagine an arteria# sam #e was drawn and ana#ysed at 2:R" and showed H 2.%! and "O2 13 mmHg. Kow if this same sam #e was ana#ysed at 32R" then at that tem erature? the va#ues wou#d $e H 2.4 and "O2 4: mmHg. 0o which valu& do you wan' r&+or'&d 'o you1 The va#ues for 32R" can $e inter reted against the 9nown reference va#ues for 32R" and they wou#d $e considered to $e norma#. This is the a# hastat a roach and is e<uiva#ent to assessing the resu#ts against the a ro riate reference range for 2:R" $ut without having to 9now what it is. The va#ues for 2:R" cou#d a#so $e inter reted against the reference va#ues for 32R". +Actua##y the $#ood gas machine measures at 32R" then a #ies the correction formu#ae and re orts what the va#ues wou#d $e if measured at 2:R"-. This is the H'stat a roach Gie the idea is that the H must $e 9e t at the semi'magica# 2.4 va#ue at every tem eratureH. By the H'stat a roach then? it wou#d $e decided that this atient had a significant res iratory a#9a#osis and measures wou#d $e ta9en to correct this. "#ear#y the two a roaches can resu#t in <uite different thera ies $eing a #ied.

0u,,ary of i,portant aspects of Chapter 3ne The a roach discussed in the maBority of this $oo9 is the =traditiona# a roach> to acid'$ase hysio#ogy as this is sti## a#most the on#y a roach discussed in hysio#ogy te7ts. An a#ternative a roach is the (tewart <uantitative a roach which is derived from $asic hysicochemica# rinci #es ' though now we## su orted $y evidence this a roach is more difficu#t to use in everyday c#inica# ractice ' this a roach is discussed in "ha ter 1:. The Bronsted'*owry acid'$ase theory is norma##y used in $io#ogy. .efinitionsD ' An acid is a roton donor C a $ase is a roton acce tor Hydrogen ions Gie rotonsH do not e7ist free in so#ution $ut are #in9ed to adBacent water mo#ecu#es $y hydrogen $onds. Because of this interaction it is the activity Gor =effective concentration>H of hydrogen ions rather than the actua# concentration that is im ortant for $io#ogica# effects H is the <uantity used to assess the acidity or a#9a#inity of a so#ution. It is defined as the negative #og of the hydrogen ion activity. It is measured using an ion'se#ective g#ass e#ectrode H is ty ica##y 2.4 in #asma G+H,- a$out 4: nmo#I#H $ut #ower va#ues of H are found intrace##u#ar#y. +H,- in the $ody is tight#y regu#ated. The hysio#ogica# advantages rinci a##y invo#ve

roviding conditions for o tima# intrace##u#ar function? articu#ar#yD ' intrace##u#ar tra ing of meta$o#ite intermediates is ma7imised at an intrace##u#ar H of neutra#ity ' activity of a## roteins Ginc# en&ymesH is o timised $ecause their net charge is 9e t constant In the $ody? there is strong evidence that intrace##u#ar H changes with tem erature such that the intrace##u#ar H remains at or c#ose to the H of neutra#ity. This is achieved $y a ro riate tem erature induced changes in the 5 of the imida&o#e grou of histidine. The idea that the degree of dissociation G9nown as a# haH of imida&o#e remains constant des ite changes in tem erature is 9nown as the =a# ha'stat hy othesis>. This has im #ications for c#inica# ractice Geg management of hy othermia during cardio u#monary $y ass.H E Acid-Base 1hysiology 221 - Acid-Base Balance 1ach day there is always a roduction of acid $y the $ody>s meta$o#ic rocesses and to maintain $a#ance? these acids need to $e e7creted or meta$o#ised. The various acids roduced $y the $ody are c#assified as res iratory Gor vo#ati#eH acids and as meta$o#ic Gor fi7edH acids. The $ody norma##y can res ond very effective#y to ertur$ations in acid or $ase roduction.

22121 "espiratory Acid The acid is more correct#y car$onic acid GH2"O3H $ut the term Eres iratory acidE is usua##y used to mean car$on dio7ide. But "O2 itse#f is not an acid in the Bronsted'*owry system as it does not contain a hydrogen so cannot $e a roton donor. However "O2 can instead $e thought of as re resenting a otentia# to create an e<uiva#ent amount of car$onic acid. "ar$on dio7ide is the end' roduct of com #ete o7idation of car$ohydrates and fatty acids. It is ca##ed a vo#ati#e acid meaning in this conte7t it can $e e7creted via the #ungs. Of necessity? considering the amounts invo#ved there must $e an efficient system to ra id#y e7crete "O2. The amount of "O2 roduced each day is huge com ared to the amount of roduction of fi7ed acids. Basa# "O2 roduction is ty ica##y <uoted at 12?::: to 13?::: mmo#sIday. Basa# "ar$on .io7ide 4roduction "onsider a resting adu#t with an o7ygen consum tion of 2!: m#sImin and a "O2 roduction of 2:: m#sImin G)es iratory <uotient :.3HD .ai#y "O2 roduction L :.2 7 %: 7 24 #itresIday divided $y 22.4 #itresImo#e L 12?3!2 mmo#esIday.

Increased #eve#s of activity wi## increase o7ygen consum tion and car$on dio7ide roduction so that actua# dai#y "O2 roduction is usua##y significant#y more than the oft'<uoted $asa# #eve#. +.ifferent te7ts <uote different figures usua##y in the range of 12?::: to 24?::: mmo#esIday $ut the actua# figure sim #y de ends on the #eve# of meta$o#ic activity and whether you <uote $asa# or ty ica# figures..ai#y "O2 roduction can a#so $e ca#cu#ated from the dai#y meta$o#ic water roduction. The com #ete o7idation of g#ucose roduces e<ua# amounts of "O2 and H2:. The com #ete o7idation of fat roduces a ro7imate#y e<ua# amounts of "O2 and H2O a#so. These two rocesses account for a## the $ody>s "O2 roduction. Ty ica##y? this meta$o#ic water is a$out 4:: m#s er day which is 22.2 mo#es Gie 4::I13H of water. The dai#y ty ica# "O2 roduction must a#so $e a$out 22?2:: mmo#es.

22122 $etabolic Acids This term covers a## the acids the $ody roduces which are non'vo#ati#e. Because they are not e7creted $y the #ungs they are said to $e =fi7ed> in the $ody and hence the a#ternative term fi6ed acids. A## acids other then H2"O3 are fi7ed acids. These acids are usua##y referred to $y their anion Geg #actate? hos hate? su# hate? acetoacetate or $' hydro7y$utyrateH. This seems strange at first $ecause the anion is? after a##? the *as& and not itse#f the acid. This useage is acce ta$#e in most circumstances $ecause the dissociation of the acid must have roduced one hydrogen ion for every anion so the amount of anions resent accurate#y ref#ects the num$er of H, that must have $een roduced in the origina# dissociation. Another otentia##y confusing as ect is that car$on dio7ide is roduced as an end' roduct of meta$o#ism $ut is not a =meta$o#ic acid> according to the usua# definition. This inconsistency causes some confusionD it is sim #est to $e aware of this and acce t the esta$#ished convention. Ket roduction of fi7ed acids is a$out 1 to 1.! mmo#es of H, er 9i#ogram er dayD a$out 2: to 1:: mmo#es of H, er day in an adu#t. This non'vo#ati#e acid #oad is e7creted $y the 9idney. 6i7ed acids are roduced due to incom #ete meta$o#ism of car$ohydrates Geg #actateH? fats Geg 9etonesH and rotein Geg su# hate? hos hateH. The a$ove tota# for net fi7ed acid roduction e7c#udes the #actate roduced $y the $ody each day as the maBority of the #actate roduced is meta$o#ised and is not e7creted so there is no net #actate re<uiring e7cretion from the $ody. Dor acid-base balanceL the a,ount of acid e6creted per day ,ust eIual the a,ount produced per day2 The routes of e7cretion are the #ungs Gfor "O2H and the 9idneys Gfor the fi7ed acidsH. 1ach mo#ecu#e of "O2 e7creted via the #ungs resu#ts from the reaction of one mo#ecu#e of $icar$onate with one mo#ecu#e of H,. The H, remains in the $ody as H2O.

22123 "esponse to an Acid-Base 1erturbation The $ody>s res onse1 to a change in acid'$ase status has three com onentsD 6irst defenceD Buffering (econd defenceD )es iratory D a#teration in arteria# "O2 Third defenceD )ena# D a#teration in H"O3' e7cretion The word EdefenceE is used $ecause these are the three ways that the $ody EdefendsE itse#f against acid' $ase distur$ances. This is not the com #ete icture as it neg#ects some meta$o#ic res onses Geg changes in meta$o#ic athwaysH that occur. This res onse can $e considered $y #oo9ing at how the com onents affect the G +H"O3- I "O2 H ratio in the Henderson'Hasse#$a#ch e<uation. The 3 com onents of the res onse are summarised $e#ow. *he I,,ediate "esponse : Buffering Buffering is a ra id hysico'chemica# henomenon. The $ody has a #arge $uffer ca acity. The $uffering of fi7ed acids $y $icar$onate changes the +H"O3- numerator in the ratio Gin the Henderson'Hasse#$a#ch e<uationH. *he "espiratory "esponse : Alteration in ;entilation AdBustment of the denominator "O2 Gin the Henderson'Hasse#$a#ch e<uationH $y a#terations in venti#ation is re#ative#y ra id Gminutes to hoursH. An increased "O2 e7cretion due to hy erventi#ation wi## resu#t in one of three acid'$ase outcomesD correction of a res iratory acidosis roduction of a res iratory a#9a#osis com ensation for a meta$o#ic acidosis. Ohich of these three circumstances is resent cannot $e deduced mere#y from the o$servation of the resence of hy erventi#ation in a atient. This res iratory res onse is articu#ar#y usefu# hysio#ogica##y $ecause of its effect on intrace##u#ar H as we## as e7trace##u#ar H. "ar$on dio7ide crosses ce## mem$ranes easi#y so changes in "O2 affect intrace##u#ar H ra id#y and in a redicta$#e direction. The system has to $e a$#e to res ond <uic9#y and to have a high ca acity $ecause of the huge amounts of res iratory acid to $e e7creted. *he "enal "esponse : Alteration in Bicarbonate C6cretion This much s#ower rocess Gsevera# days to reach ma7imum ca acityH invo#ves adBustment of $icar$onate e7cretion $y the 9idney. This system is res onsi$#e for the e7cretion of the fi7ed acids and for com ensatory changes in #asma +H"O3- in the resence of res iratory acid'$ase disorders. 2212! Balance: Internal /ersus C6ternal This refers to the difference $etween Hydrogen Ion Turnover in the $ody Gor Interna# Ba#anceH versus Ket H, 4roduction C 17cretion re<uiring e7cretion from the $ody Gie 17terna# Ba#anceH

Most discussions of hydrogen ion $a#ance refers to net roduction Gwhich re<uires e7cretion from the $ody to maintain a sta$#e $ody HH rather than to turnover of hydrogen ions Gwhere H, are roduced and consumed in chemica# reactions without any net roductionH. Ket roduction under $asa# conditions gives 12 mo#es of "O2 and :.1 mo#es of fi7ed acids. The maBority of the fi7ed acids are roduced from roteins Gsu# hate from the three su# hur containing amino acidsJ hos hate from hos ho roteinsH with a sma##er contri$ution from meta$o#ism of other hos hate com ounds Geg hos ho#i idsH. Key Dact: *urno/er of hydrogen ions in the body is H7BC 8 /ery ,uch larger then net acid e6cretion2 Turnover2 inc#udesD 1.! mo#esIday from #actic acid turnover 3: mo#esIday from adenine dinuc#eotide turnover 12: mo#esIday from AT4 turnover At #east another 3%: mo#esIday invo#ved in mitochondria# mem$rane H, movements GPohnston C A#$ertiH.

"om ared to the tota# of these huge turnover figures? the 12 mo#esIday of "O2 roduced #oo9s sma## and the :.1 mo#eIday of net fi7ed acid roduction #oo9s ositive#y uny. GA earances of course can $e dece tiveH. Because with turnover? these H, are roduced and consumed without any net roduction re<uiring e7cretion? they are #ess re#evant to this discussion where the em hasis is on e7terna# acid'$ase $a#ance. By definition? for acid'$ase e<ui#i$rium? the n&' acid roduction $y the $ody must $e e7creted. This discussion of e7terna# acid'$ase $a#ance a#so inc#udes any acids or $ases ingested or infused into the $ody. Acid'$ase $a#ance means that the net roduction of acid is e7creted from the $ody each day Gie Ee7terna# $a#anceEH. The interna# turnover of H, is #arge#y ignored Ge7ce t for #actic acidH in the rest of this $oo9. "eferences 1. Adrogue H1 and Adrogue HP. Acid"*as& +hysiolo)y. )es ir "are 2::1 A rJ 4%G4H 323'41. 4u$Med 2. Pohnston ./ and A#$erti 5/. Acid"*as& *alanc& in m&'a*olic acidos&s. "#in 1ndocrino# Meta$ 1833 Pu#J 12G2H 2%2'3!. 4u$Med

Acid-Base 1hysiology 222 Buffering

22221 efinition of a Buffer A $uffer is a so#ution containing su$stances which have the a$i#ity to minimise changes in H when an acid or $ase is added to it 1. A $uffer ty ica##y consists of a so#ution which contains a wea9 acid HA mi7ed with the sa#t of that acid C a strong $ase eg KaA. The rinci #e is that the sa#t rovides a reservoir of A' to re #enish +A'- when A' is removed $y reaction with H,. 22222 Buffers in the Body *he body has a /ery large buffer capacity2 This can $e i##ustrated $y considering an o#d e7 eriment Gsee $e#owH where di#ute hydroch#oric acid was infused into a dog. 04an 8 1itts C6peri,ent 2 In this e7 eriment? dogs received an infusion of 14 mmo#s H, er #itre of $ody water. This caused a dro in H from 2.44 G+H,- L 3% nmo#esI#H to a H of 2.14 G+H,- L 22 nmo#esI#H That is? a rise in +H,- of on#y 3% nmo#esI#. (OD If you Bust #oo9ed at the change in +H,- then you wou#d on#y notice an increase of 3% nmo#esI# and you wou#d have to wonder what had ha ened to the other 13?888?8%4 nmo#esI# that were infused. Where did the missing H+ go? They were hidden on $uffers and so these hydrogen ions were hidden from view.

Before we roceed? #ets Bust ma9e sure we a reciate what this e7 eriment revea#s 3. The dogs were infused with 14?:::?::: nmo#esI# of H, $ut the #asma +H,- on#y changed $y a $it over :.::2Q. By any ana#ysis? this is a system which po4erfully resists change in <H=>. GMy ersona# ana#ogy on a reciating the magnitude of this is to use the ana#ogy of de ositing V14?:::?::: in the $an9? $ut then finding that after E$an9 chargesE my account on#y went u $y V3%.H Ma9e no mista9eD the $ody hasD a H0/1 $uffering ca acity? and this system is essentia##y IMM1.IAT1 in effect. 6or these 2 reasons? hysicochemica# $uffering rovides a owerfu# first defence against acid'$ase ertur$ations. Buffering hides fro, /ie4 the real change in H= that occurs2 This huge $uffer ca acity has another not immediate#y o$vious im #ication for how we thin9 a$out the

severity of an acid'$ase disorder. Fou wou#d thin9 that the magnitude of an acid'$ase distur$ance cou#d $e <uantified mere#y $y #oo9ing at the change in +H,- ' B0T this is not so. Because of the #arge $uffering ca acity? the actua# change in +H,- is so sma## it can $e ignored in any <uantitative assessment? and instead? the magnitude of a disorder has to $e estimated indirect#y from the decrease in the tota# concentration of the anions invo#ved in the $uffering. The $uffer anions? re resented as A'? decrease $ecause they com$ine stoichiometrica##y with H, to roduce HA. A decrease in A' $y 1 mmo#I# re resents a 1?:::?::: nano'mo#I# amount of H, that is hidden from view and this is severa# orders of magnitude higher than the visi$#e few nanomo#esI# change in +H,- that is visi$#e.H ' As noted a$ove in the comments a$out the (wan C 4itts e7 eriment? 13?888?884 out of 14?:::?::: nano'mo#esI# of H, were hidden on $uffers and Bust to count the 3% that were on view wou#d give a fa#se im ression of the magnitude of the disorder. *he $a)or Body Buffer 0yste,s 0ite I0D Buffer 0yste, Bicar$onate 4hos hate 4rotein Blood Bicar$onate Haemog#o$in 4#asma rotein 4hos hate ICD 4roteins 4hos hates 7rine 4hos hate Ammonia Co,,ent 6or meta$o#ic acids Kot im ortant $ecause concentration too #ow Kot im ortant $ecause concentration too #ow Im ortant for meta$o#ic acids Im ortant for car$on dio7ide Minor $uffer "oncentration too #ow Im ortant $uffer Im ortant $uffer )es onsi$#e for most of ETitrata$#e AcidityE Im ortant ' formation of KH4,

Bone

"a car$onate

In ro#onged meta$o#ic acidosis

22223 *he Bicarbonate Buffer 0yste, The maBor $uffer system in the 1"6 is the "O2'$icar$onate $uffer system. This is res onsi$#e for a$out 3:Q of e7trace##u#ar $uffering. It is the most im ortant 1"6 $uffer for meta$o#ic acids $ut it cannot $uffer res iratory acid'$ase disorders. The com onents are easi#y measured and are re#ated to each other $y the Henderson'Hasse#$a#ch e<uation. Henderson-Hasselbalch CIuation H L 5>a , #og10 G +H"O3- I :.:3 7 "O2H The 5>a va#ue is de endent on the tem erature? +H,- and the ionic concentration of the so#ution. It has a va#ue of %.:88 at a tem erature of 32" and a #asma H of 2.4. At a tem erature of 3:" and H of 2.:? it has a va#ue of %.143. 6or ractica# ur oses? a va#ue of %.1 is genera##y assumed and corrections for tem erature? H of #asma and ionic strength are not used e7ce t in recise e7 erimenta# wor9. The 5Ea is derived from the 5a va#ue of the fo##owing reactionD "O2 , H2O WLX H2"O3 WLX H, , H"O3' Gwhere "O2 refers to disso#ved "O2H The concentration of car$onic acid is very #ow com ared to the other com onents so the a$ove e<uation is usua##y sim #ified toD "O2 , H2O WLX H, , H"O3' By the *aw of Mass ActionD 5a L +H,- . +H"O3'- I +"O2- . +H2:The concentration of H2O is so #arge G!!.!MH com ared to the other com onents? the sma## #oss of water due to this reaction changes its concentration $y on#y an e7treme#y sma## amount. This means that +H2O- is effective#y constant. This a##ows further sim #ification as the two constants G5a and +H2O- H can $e com$ined into a new constant 5>a. 5>a L 5a 7 +H2O- L +H,- . +H"O3'- I +"O2(u$stitutingD 5Ea L 3:: nmo#I# Gva#ue for #asma at 32"H +"O2- L :.:3 7 "O2 G$y Henry>s *awH +where :.:3 is the so#u$i#ity coefficientinto the e<uation yie#ds the Henderson 1<uationD +H,- L G3:: 7 :.:3H 7 "O2 I +H"O3'- L 24 7 "O2 I +H"O3'- nmo#I# Ta9ing the #ogs Gto $ase 1:H of $oth sides yie#ds the Henderson'Hasse#$a#ch e<uationD

H L #og1:G3::H ' #og G:.:3 "O2 I +H"O3'- H H L %.1 , #og G +H"O3- I :.:3 "O2 H On chemica# grounds? a su$stance with a 5a of %.1 shou#d not $e a good $uffer at a H of 2.4 if it were a sim #e $uffer. The system is more com #e7 as it is =o en at $oth ends> Gmeaning $oth +H"O3and "O2 can $e adBustedH and this great#y increases the $uffering effectiveness of this system. The e7cretion of "O2 via the #ungs is articu#ar#y im ortant $ecause of the ra idity of the res onse. The adBustment of "O2 $y change in a#veo#ar venti#ation has $een referred to as hysio#ogica# $uffering. *he bicarbonate buffer syste, is an effecti/e buffer syste, despite ha/ing a lo4 pKa because the body also controls pC32 2222! 3ther Buffers The other $uffer systems in the $#ood are the rotein and hos hate $uffer systems. These are the on#y $#ood $uffer systems ca a$#e of $uffering res iratory acid'$ase distur$ances as the $icar$onate system is ineffective in $uffering changes in H, roduced $y itse#f. *he phosphate buffer syste, is F3* an i,portant blood buffer as its concentration is too lo4 The concentration of hos hate in the $#ood is so #ow that it is <uantitative#y unim ortant. 4hos hates are im ortant $uffers intrace##u#ar#y and in urine where their concentration is higher. 4hos horic acid is tri rotic wea9 acid and has a 5a va#ue for each of the three dissociationsD 5a1 L 2 H34O4 WL L L X H, , H24O4' 5a2 L %.3 WL L LX H, , H4O4'2 5a3 L 12 WLLLX 4O4'3 , H,

The three 5a va#ues are sufficient#y different so that at any one H on#y the mem$ers of a sing#e conBugate air are resent in significant concentrations. At the revai#ing H va#ues in most $io#ogica# systems? monohydrogen hos hate GH4O4'2H and dihydrogen hos hate GH24O4'H are the two s ecies resent. The 5a2 is %.3 and this ma9es the c#osed hos hate $uffer system a good $uffer intrace##u#ar#y and in urine. The H of g#omeru#ar u#trafi#trate is 2.4 and this means that hos hate wi## initia##y $e redominant#y in the monohydrogen form and so can com$ine with more H, in the rena# tu$u#es. This ma9es the hos hate $uffer more effective in $uffering against a dro in H than a rise in H. KoteD The =true> 5a2 va#ue is actua##y 2.2 if measured at &ero ionic strength $ut at the ty ica# ionic strength found in the $ody its a arent va#ue is %.3. The other factor which ma9es hos hate a more effective $uffer intrace##u#ar#y and in urine is that its concentration is much higher here than in e7trace##u#ar f#uid. Hae,oglobin is an i,portant blood buffer particularly for buffering C32 4rotein $uffers in $#ood inc#ude haemog#o$in G1!:gI#H and #asma roteins G2:gI#H. Buffering is $y the

imida&o#e grou of the histidine residues which has a 5a of a$out %.3. This is suita$#e for effective $uffering at hysio#ogica# H. Haemog#o$in is <uantitative#y a$out % times more im ortant then the #asma roteins as it is resent in a$out twice the concentration and contains a$out three times the num$er of histidine residues er mo#ecu#e. 6or e7am #e if $#ood H changed from 2.! to %.!? haemog#o$in wou#d $uffer 22.! mmo#I# of H, and tota# #asma rotein $uffering wou#d account for on#y 4.2 mmo#I# of H,. .eo7yhaemog#o$in is a more effective $uffer than o7yhaemog#o$in and this change in $uffer ca acity contri$utes a$out 3:Q of the Ha#dane effect. The maBor factor accounting for the Ha#dane effect in "O2 trans ort is the much greater a$i#ity of deo7yhaemog#o$in to form car$amino com ounds. Isohydric 1rinciple A## $uffer systems which artici ate in defence of acid'$ase changes are in e<ui#i$rium with each other. There is after a## on#y one va#ue for +H,- at any moment. This is 9nown as the Isohydric 1rinciple. It means that an assessment of the concentrations of any one acid'$ase air can $e uti#ised to rovide a icture of overa## acid'$ase $a#ance in the $ody. This is fortunate as the measurement of the concentrations of a## the $uffer airs in the so#ution wou#d $e difficu#t. "onventiona##y? the com onents of the $icar$onate system Gie +H"O3- and "O2H a#one are measured. They are accessi$#e and easy to determine. B#ood gas machines measure H and "O2 direct#y and the +H"O3- is then ca#cu#ated using the Henderson'Hasse#$a#ch e<uation. Buffering in different sites )es iratory disorders are redominant#y $uffered in the intrace##u#ar com artment. Meta$o#ic disorders have a #arger $uffering contri$ution from the e7trace##u#ar f#uid Geg 1"6 $uffering of 4:Q for a meta$o#ic acidosis and 2:Q for a meta$o#ic a#9a#osisH. ;arious $uffer systems e7ist in $ody f#uids Gsee Ta$#eH to minimise the effects of the addition or remova# of acid from them. In 1"6? the $icar$onate system is <uantitative#y the most im ortant for $uffering meta$o#ic acids. Its effectiveness is great#y increased $y venti#atory changes which attem t to maintain a constant "O2 and $y rena# mechanisms which resu#t in changes in #asma $icar$onate. In $#ood? haemog#o$in is the most im ortant $uffer for "O2 $ecause of its high concentration and its #arge num$er of histidine residues. eo6yhae,oglobin is a better buffer than o6yhae,oglobin Another factor which ma9es haemog#o$in an im ortant $uffer is the henomemon of isohydric e6change. That is? the $uffer system GHH$O2'H$O2'H is converted to another more effective $uffer GHH$'H$'H e7act#y at the site where an increased $uffering ca acity is re<uired. More sim #y? this means that o7ygen un#oading increases the amount of deo7yhaemog#o$in and this $etter $uffer is roduced at e7act#y the #ace where additiona# H, are $eing roduced $ecause of $icar$onate roduction for "O2 trans ort in the red ce##s.

2222# :in& bet4een Intracellular 8 C6tracellular Co,part,ents Ho4 are changes in <H=> co,,unicated bet4een the ICD and CCD9 The two maBor rocesses invo#ved areD Transfer of "O2 across the ce## mem$rane Ionic shifts Gie roton'cation e7change mechanismsH Im ortant oints to note a$out "O2 areD It is very #i id so#u$#e and crosses ce## mem$ranes with ease causing acid'$ase changes due to formation of H, and H"O3'. Because of this ease of movement? "O2 is not im ortant in causing differences in H on the two sides of the ce## mem$rane. 17trace##u#ar $uffering of "O2 is #imited $y the ina$i#ity of the maBor e7trace##u#ar $uffer Gthe $icar$onate systemH to $uffer changes in +H,- roduced from the reaction $etween "O2 and water. The resu#t is that $uffering for res iratory acid'$ase disorders is redominant#y intrace##u#arD 88Q for res iratory acidosis and 82Q for res iratory a#9a#osis. The second maBor rocess which a##ows transfer of H, ions intrace##u#ar#y is entry of H, in e7change for either 5, or Ka,. 17change is necessary to maintain e#ectroneutra#ity. This cation e7change is the mechanism which de#ivers H, intrace##u#ar#y for $uffering of a meta$o#ic disorder. In the ce##? the rotein and hos hates Gorganic and inorganicH $uffer the H, de#ivered $y this ion e7change mechanism. 17 eriments in meta$o#ic acidosis have shown that !2Q of $uffering occurs intrace##u#ar#y and 43Q occurs e7trace##u#ar#y. The rocesses invo#ved in this $uffering areD 1rocesses in/ol/ed in Buffering 1"6 43Q G$y $icar$onate C rotein $uffersH I"6 !2Q G$y rotein hos hate and $icar$onate $uffersH due to entry of H, $yD Ka,'H, e7change 3%Q 5,'H, e7change 1!Q Other %Q Gsee (ection 1:.% for a chemica# e7 #anation of how an e7change of Ka, or 5, for H, across a mem$rane can a#ter the H $y changing the strong ion difference or =(I.>H Thirty'two ercent G32QH of the $uffering of a meta$o#ic a#9a#osis occurs intrace##u#ar#y and Ka,'H, e7change is res onsi$#e for most of the transfer of H,.

2222% "ole of Bone Buffering *he carbonate and phosphate salts in bone act as a long ter, supply of buffer especially during prolonged ,etabolic acidosis2 The im ortant ro#e of $one $uffers is often omitted from discussions of acid'$ase hysio#ogy4. Bone consists of matri7 within which s ecia#ised ce##s are dis ersed. The matri7 is com osed of organic +co##agen and other roteins in ground su$stance- and inorganic +hydro7ya atite crysta#sD genera# formu#a "a1:G4O4H%GOHH2- com onents. The hydro7ya atite crysta#s ma9e u two'thirds of the tota# $one vo#ume $ut they are e7treme#y sma## and conse<uent#y have a huge tota# surface area. The crysta#s contain a #arge amount of car$onate G"O3'2H as this anion can $e su$stituted for $oth hos hate and hydro7y# in the a atite crysta#s. Bone is the maBor "O2 reservoir in the $ody and contains car$onate and $icar$onate e<uiva#ent to ! mo#es of "O2 out of a tota# $ody "O2 store of % mo#es. G"om are this with the $asa# dai#y "O2 roduction of 12 mo#esIdayH "O2 in $one is in two formsD $icar$onate GH"O3'H and car$onate G"O3'2H. The $icar$onate ma9es u a readi#y e7changea$#e oo# $ecause it is resent in the $one water which ma9es u the =hydration she##> around each of the hydro7ya atite crysta#s. The car$onate is resent in the crysta#s and its re#ease re<uires disso#ution of the crysta#s. This is a much s#ower rocess $ut the amounts of $uffer invo#ved are much #arger. Ho4 does bone act as a buffer9 Two rocesses are invo#vedD Ionic e7change .isso#ution of $one crysta# Bone can ta9e u H, in e7change for "a,,? Ka, and 5, Gionic e7changeH or re#ease of H"O3'? "O3' or H4O4'2. In acute meta$o#ic acidosis u ta9e of H, $y $one in e7change for Ka, and 5, is invo#ved in $uffering as this can occur ra id#y without any $one $rea9down. A art of the so ca##ed =intrace##u#ar $uffering> of acute meta$o#ic disorders may re resent some of this acute $uffering $y $one. In chronic meta$o#ic acidosis? the maBor $uffering mechanism $y far is re#ease of ca#cium car$onate from $one. The mechanism $y which this disso#ution of $one crysta# occurs invo#ves two rocessesD direct hysicochemica# $rea9down of crysta#s in res onse to +H, osteoc#astic rea$sor tion of $one. The invo#vement of these rocesses in $uffering is inde endent of arathyroid hormone. Intrace##u#ar acidosis in osteoc#asts resu#ts in a decrease in intrace##u#ar "a,, and this stimu#ates these ce##s. Bone is ro$a$#y invo#ved in roviding some $uffering for a## acid'$ase distur$ances. *itt#e e7 erimenta# evidence is avai#a$#e for res iratory disorders. Most research has $een concerned with chronic meta$o#ic acidoses as these conditions are associated with significant #oss of $one minera# Gosteoma#acia? osteo orosisH. In terms of duration on#y two ty es of meta$o#ic acidosis are #ong'#asting enough to $e associated with #oss of $one minera#D rena# tu$u#ar acidosis G)TAH and uraemic acidosis. Bone is an im ortant $uffer in these two conditions. In uraemia? additiona# factors are more significant in causing the rena# osteodystro hy as the #oss of

$one minera# cannot $e e7 #ained $y the acidosis a#one. "hanges in vitamin . meta$o#ism? hos hate meta$o#ism and secondary hy er arathyroidism are more im ortant than the acidosis in causing #oss of $one minera# in uraemic atients. The #oss of $one minera# due to these other factors re#eases su$stantia# amounts of $uffer. 0u,,ary Bone is an im ortant source of $uffer in chronic meta$o#ic acidosis Gie rena# tu$u#ar acidosis C uraemic acidosisH Bone is ro$a$#y invo#ved in roviding some $uffering Gmost#y $y ionic e7changeH in most acute acid'$ase disorders $ut this has $een #itt#e studied. )e#ease of ca#cium car$onate from $one is the most im ortant $uffering mechanism invo#ved in chronic meta$o#ic acidosis. *oss of $one crysta# in uraemic acidosis is mu#tifactoria# and acidosis is on#y a minor factor BOTH the acidosis and the vitamin .3 changes are res onsi$#e for the osteoma#acia that occurs with rena# tu$u#ar acidosis.

"eferences 1. Oorth#ey *I. ,ydro)&n ion m&'a*olism. Anaesth Intensive "are 1822 KovJ !G4H 342'%:. midD23:14. 4u$Med 2. 4itts )6. M&chanisms for s'a*ili2in) 'h& al(alin& r&s&rv&s of 'h& *ody. Harvey *ect 18!2'18!3J 43 122'2:8. 4u$Med 3. Bernards O" 3n'&r+r&'a'ion of 4linical Acid"5as& 6a'a. )egiona# )efresher "ourses in Anesthesio#ogy. 1823J 1D 12'2% 4. Bushins9y .A. Acidosis and *on&. Miner 1#ectro#yte Meta$ 1884J 2:G1'2H 4:'!2. 4u$Med

Acid-Base 1hysiology 223 "espiratory "egulation of Acid-Base Balance

22321 Ho4 is the "espiratory 0yste, :in&ed to Acid-base Changes9 =)es iratory regu#ation> refers to changes in H due to "O2 changes from a#terations in venti#ation. This change in venti#ation can occur ra id#y with significant effects on H. "ar$on dio7ide is #i id so#u$#e and crosses ce## mem$ranes ra id#y? so changes in "O2 resu#t in ra id changes in +H,- in a## $ody f#uid com artments. A <uantitative a reciation of res iratory regu#ation re<uires 9now#edge of two re#ationshi s which

rovide the connection $etween a#veo#ar venti#ation and H via "O2. These 2 re#ationshi s areD 6irst e<uation ' re#ates a#veo#ar venti#ation G;AH and "O2 (econd e<uation ' re#ates "O2 and H. The two 9ey e<uations are out#ined in the $o7es $e#owD Dirst CIuation: Al/eolar /entilation - Arterial pC32 "elationship R&la'ionshi+D "hanges in a#veo#ar venti#ation are inverse#y re#ated to changes in arteria# "O2 GC direct#y ro ortiona# to tota# $ody "O2 roductionH. paC32 is ro ortiona# to <;C32 @ ;A> whereD a"O2 L Arteria# artia# ressure of "O2

;"O2 L "ar$on dio7ide roduction $y the $ody ;A L A#veo#ar venti#ation A#ternative#y? this formu#a can $e e7 ressed asD paC32 E -2(%3 6 < ;C32 @ ;A > Gif ;"O2 has units of m#sImin at (T4 and ;A has units of #Imin at 32" and at atmos heric ressure.H

0econd CIuation: Henderson-Hasselbalch CIuation R&la'ionshi+D These changes in arteria# "O2 cause changes in H Gas defined in the Henderson'Hasse#$a#ch e<uationHD pH E pKa = log M [HCO3] / ?0.03 x pCO2) }

or mor& sim+lyD *he Henderson eIuation: <H=> E 2! 6 ? pC32 @ <HC33> A The 9ey oint is that these 2 e<uations can $e used to ca#cu#ate the effect on H of a given change in venti#ation rovided of course the other varia$#es in the e<uations Geg $odyEs "O2 roductionH are

9nown. The ne7t <uestion to consider is how a## this is ut together and contro##ed? that is? how does it wor9T 22322 Control 0yste, for "espiratory "egulation The contro# system for res iratory regu#ation of acid'$ase $a#ance can $e considered using the mode# of a sim #e servo contro# system. The com onents of such a sim #e mode# are a contro##ed varia$#e which is monitored $y a sensor? a centra# integrator which inter rets the information from the sensor and an effector mechanism which can a#ter the contro##ed varia$#e. The servo contro# means that the system wor9s in such a way as to attem t to 9ee the contro##ed varia$#e constant or at a articu#ar set' oint. This means that a negative feed$ac9 system is in o eration and the e#ements of the system are connected in a #oo . "ontro# systems in the $ody are genera##y much more com #e7 than this sim #e mode# $ut it is sti## a very usefu# e7ercise to at first attem t such an ana#ysis.

Control 0yste, for "espiratory "egulation of Acid-base Balance Control Cle,ent "ontro##ed varia$#e 1hysiological or Anato,ical Correlate Arteria# "O2 Co,,ent

A change in arteria# "O2 a#ters arteria# H Gas ca#cu#ated $y use of the Henderson' Hasse#$a#ch 1<uationH. Both res ond to changes in arteria# "O2 Gas we## as some other factorsH

(ensors

"entra# and eri hera# chemorece tors The res iratory center in the medu##a

"entra# integrator 1ffectors

The res iratory musc#es An increase in minute venti#ation increases a#veo#ar venti#ation and thus decreases arteria# "O2 Gthe contro##ed varia$#eH as ca#cu#ated from E1<uation 1EGdiscussed revious#yH. The net resu#t is of negative feed$ac9 which tends to restore the "O2 to the Eset ointE.

Acid-Base 1hysiology 22! "enal "egulation of Acid-Base Balance 22!21 "ole of the Kidneys The organs invo#ved in regu#ation of e7terna# acid'$ase $a#ance are the lungs are the &idneys. The #ungs are im ortant for e7cretion of car$on dio7ide Gthe res iratory acidH and there is a huge amount of this to $e e7cretedD at #east 12?::: to 13?::: mmo#sIday. In contrast the 9idneys are res onsi$#e for e7cretion of the fi7ed acids and this is a#so a critica# ro#e even though the amounts invo#ved G2:'1:: mmo#sIdayH are much sma##er. The main reason for this rena# im ortance is $ecause there is no other way to e7crete these acids and it shou#d $e a reciated that the amounts invo#ved are sti## very #arge when com ared to the #asma +H,- of on#y 4: nanomo#esI#itre. There is a second e7treme#y im ortant ro#e that the 9idneys #ay in acid'$ase $a#ance? name#y the rea$sor tion of the fi#tered $icar$onate. Bicar$onate is the redominant e7trace##u#ar $uffer against the fi7ed acids and it im ortant that its #asma concentration shou#d $e defended against rena# #oss. In acid'$ase $a#ance? the 9idney is res onsi$#e for 2 maBor activitiesD )ea$sor tion of fi#tered $icar$onateD 4?::: to !?::: mmo#Iday 17cretion of the fi7ed acids Gacid anion and associated H,HD a$out 1 mmo#I9gIday. Both these rocesses invo#ve secretion of H, into the #umen $y the rena# tu$u#e ce##s $ut on#y the second #eads to e7cretion of H, from the $ody. The rena# mechanisms invo#ved in acid'$ase $a#ance can $e difficu#t to understand so as a sim+lifica'ion we wi## consider the rocesses occurring in the 9idney as invo#ving 2 as ectsD 4ro7ima# tu$u#ar mechanism .ista# tu$u#ar mechanism 22!22 1ro6i,al *ubular $echanis, The contri$utions of the ro7ima# tu$u#es to acid'$ase $a#ance areD first#y? rea$sor tion of $icar$onate which is fi#tered at the g#omeru#us second#y? the roduction of ammonium The ne7t 2 sections e7 #ain these ro#es in more detai#. 22!23 Bicarbonate "eabsorption .ai#y fi#tered $icar$onate e<ua#s the roduct of the dai#y g#omeru#ar fi#tration rate G13: #IdayH and the #asma $icar$onate concentration G24 mmo#I#H. This is 13: 7 24 L 432: mmo#sIday Gor usua##y <uoted as $etween 4::: to !::: mmo#sIdayH. A$out 3! to 8:Q of the fi#tered $icar$onate is rea$sor$ed in the ro7ima# tu$u#e and the rest is rea$sor$ed $y the in'&rcala'&d c&lls of the dista# tu$u#e and co##ecting ducts. The reactions that occur are out#ined in the diagram. 1ffective#y? H, and H"O3' are formed from "O2

and H2O in a reaction cata#ysed $y car$onic anhydrase. The actua# reaction invo#ved is ro$a$#y formation of H, and OH' from water? then reaction of OH' with "O2 Gcata#ysed $y car$onic anhydraseH to roduce H"O3'. 1ither way? the end resu#t is the same. The H, #eaves the ro7ima# tu$u#e ce## and enters the 4"T #umen $y 2 mechanismsD ;ia a Ka,'H, anti orter GmaBor routeH ;ia H,'AT4ase G roton um H 6i#tered H"O3' cannot cross the a ica# mem$rane of the 4"T ce##. Instead it com$ines with the secreted H, Gunder the inf#uence of $rush $order car$onic anhydraseH to roduce "O2 and H2O. The "O2 is #i id so#u$#e and easi#y crosses into the cyto #asm of the 4"T ce##. In the ce##? it com$ines with OH' to roduce $icar$onate. The H"O3' crosses the $aso#atera# mem$rane via a Ka,'H"O3' sym orter. This sym orter is e#ectrogenic as it transfers three H"O3' for every one Ka,. In com arison? the Ka,' H, anti orter in the a ica# mem$rane is not e#ectrogenic $ecause an e<ua# amount of charge is transferred in $oth directions. The $aso#atera# mem$rane a#so has an active Ka,'5, AT4ase Gsodium um H which trans orts 3 Ka, out er 2 5, in. This um is e#ectrogenic in a direction o osite to that of the Ka,'H"O3' sym orter. A#so the sodium um 9ee s intrace##u#ar Ka, #ow which sets u the Ka, concentration gradient re<uired for the H,'Ka, anti ort at the a ica# mem$rane. The H,'Ka, anti ort is an e7am #e of s&condary ac'iv& 'rans+or'. The net effect is the rea$sor tion of one mo#ecu#e of H"O3 and one mo#ecu#e of Ka, from the tu$u#ar #umen into the $#ood stream for each mo#ecu#e of H, secreted. This mechanism does not #ead to the net e7cretion of any H, from the $ody as the H, is consumed in the reaction with the fi#tered $icar$onate in the tu$u#ar #umen. +KoteD The differences in functiona# ro erties of the a ica# mem$rane from that of the $aso#atera# mem$ranes shou#d $e noted. This difference is maintained $y the tight Bunctions which #in9 adBacent ro7ima# tu$u#e ce##s. These tight Bunctions have two e7treme#y im ortant functionsD 7a'& func'ionD They #imit access of #umina# so#utes to the interce##u#ar s ace. This resistance can $e a#tered and this arace##u#ar athway can $e more o en under some circumstances Gie the =gate> can $e o ened a #itt#eH. 8&nc& func'ionD The Bunctions maintain different distri$utions of some of the integra# mem$rane roteins. 6or e7am #e they act as a =fence> to 9ee the Ka,'H, anti orter #imited to the a ica# mem$rane? and 9ee the Ka,'5, AT4ase #imited to the $aso#atera# mem$rane. The different distri$ution of such roteins is a$so#ute#y essentia# for ce## function.The 4 maBor factors which contro# $icar$onate rea$sor tion areD *umina# H"O3' concentration *umina# f#ow rate Arteria# "O2 Angiotensin II Gvia decrease in cyc#ic AM4H

An increase in any of these four factors causes an increase in $icar$onate rea$sor tion. 4arathyroid hormone a#so has an effectD an increase in hormone #eve# increases cAM4 and decreases $icar$onate rea$sor tion. 3utline of "eactions in 1ro6i,al *ubule :u,en 8 Cells .iagram to $e added

The mechanism for H, secretion in the ro7ima# tu$u#e is descri$ed as a high ca acity? #ow gradient systemD The high ca acity refers to the #arge amount G4::: to !::: mmo#sH of H, that is secreted er day. GThe actua# amount of H, secretion is 3!Q of the fi#tered #oad of H"O3'H. The #ow gradient refers to the #ow H gradient as tu$u#ar H can $e decreased from 2.4 down to %.2'2.: on#y. Though no net e7cretion of H, from the $ody occurs? this ro7ima# mechanism is e7treme#y im ortant in acid'$ase $a#ance. *oss of $icar$onate is e<uiva#ent to an acidifying effect and the otentia# amounts of $icar$onate #ost if this mechanism fai#s are very #arge. 22!2! A,,oniu, 1roduction Ammonium GKH4H is roduced redominant#y within the ro7ima# tu$u#ar ce##s. The maBor source is from g#utamine which enters the ce## from the eritu$u#ar ca i##aries G3:QH and the fi#trate G2:QH. Ammonium is roduced from g#utamine $y the action of the en&yme g#utaminase. 6urther ammonium is roduced when the g#utamate is meta$o#ised to roduce a# ha'9etog#utarate. This mo#ecu#e contains 2 negative#y'charged car$o7y#ate grou s so further meta$o#ism of it in the ce## resu#ts in the roduction of 2 H"O3' anions. This occurs if it is o7idised to "O2 or if it is meta$o#ised to g#ucose. The 5a for ammonium is so high Ga$out 8.2H that $oth at e7trace##u#ar and at intrace##u#ar H? it is resent entire#y in the acid form KH4,. The revious idea that #i id so#u$#e KH3 is roduced in the tu$u#ar ce##? diffuses into the tu$u#ar f#uid where it is converted to water so#u$#e KH4, which is now tra ed in the tu$u#e f#uid is incorrect. The su$se<uent situation with ammonium is com #e7. Most of the ammonium is invo#ved in cyc#ing within the medu##a. A$out 2!Q of the ro7ima##y roduced ammonium is removed from the tu$u#ar f#uid in the medu##a so that the amount of ammonium entering the dista# tu$u#e is sma##. The thic9 ascending #im$ of the #oo of Hen#e is the im ortant segment for removing ammonium. (ome of the interstitia# ammonium returns to the #ate ro7ima# tu$u#e and enters the medu##a again Gie recyc#ing occursH. An overview of the situation so far is thatD The ammonium #eve# in the ."T f#uid is #ow $ecause of remova# in the #oo of Hen#e Ammonium #eve#s in the medu##ary interstitium are high Gand are 9e t high $y the recyc#ing rocess via the thic9 ascending #im$ and the #ate 4"TH Tu$u#e f#uid entering the medu##ary co##ecting duct wi## have a #ow H if there is an acid #oad to

$e e7creted Gand the hos hate $uffer has $een titrated down. If H, secretion continues into the medu##ary co##ecting duct this wou#d reduce the H of the #umina# f#uid further. A #ow H great#y augments transfer of ammonium from the medu##ary interstitium into the #umina# f#uid as it asses through the medu##a. The #ower the urine H? the higher the ammonium e7cretion and this ammonium e7cretion is augmented further if an acidosis is resent. This augmentation with acidosis is Eregu#atoryE as the increased ammonium e7cretion $y the 9idney tends to increase e7trace##u#ar H towards norma#. If the ammonium returns to the $#ood stream it is meta$o#ised in the #iver to urea G5re$s'Hense#eit cyc#eH with net roduction of one hydrogen ion er ammonium mo#ecu#e. GKoteD (ection 2.4.2 discusses the ro#e of urinary ammonium e7cretion.H '"enal regulation of Acid-Base Balance' is continued on the ne6t page2

Acid-Base 1hysiology 22! "enal "egulation of Acid-Base Balance ?continuedA

22!2# istal *ubular $echanis, This is a #ow ca acity? high gradient system which accounts for the e7cretion of the dai#y fi7ed acid #oad of 2: mmo#sIday. The ma7ima# ca acity of this system is as much as 2:: mmo#sIday $ut this is sti## #ow com ared to the ca acity of the ro7ima# tu$u#ar mechanism to secrete H,. It can however decrease the H down to a #imiting H of a$out 4.! D this re resents a thousand'fo#d Gie 3 H unitsH gradient for H, across the dista# tu$u#ar ce##. The ma7ima# ca acity of 2:: mmo#sIday ta9es a$out ! days to reach. The rocesses invo#ved areD' 6ormation of titrata$#e acidity GTAH Addition of ammonium GKH4,H to #umina# f#uid )ea$sor tion of )emaining Bicar$onate 12 *itratable Acidity H, is roduced from "O2 and H2O Gas in the ro7ima# tu$u#ar ce##sH and active#y trans orted into the dista# tu$u#ar #umen via a H,'AT4ase um . Titrata$#e acidity re resents the H, which is $uffered most#y $y hos hate which is resent in significant concentration. "reatinine G 5a a ro7 !.:H may a#so contri$ute to TA. At the minimum urinary H? it wi## account for some of the titrata$#e acidity. If 9etoacids are resent? they a#so contri$ute to titrata$#e acidity. In severe dia$etic 9etoacidosis? $eta' hydro7y$utyrate G 5a 4.3H is the maBor com onent of TA. The TA can $e measured in the urine from the amount of sodium hydro7ide needed to titrate the urine H $ac9 to 2.4 hence the term =titrata$#e acidity>.

22 Addition of A,,oniu, As discussed revious#y? ammonium is redominant#y roduced $y ro7ima# tu$u#ar ce##s. This is advantageous as the ro7ima# ce##s have access to a high $#ood f#ow in the eritu$u#ar ca i##aries and to a## of the fi#trate and these are the two sources of the g#utamine from which the ammonium is roduced. The medu##ary cyc#ing maintains high medu##ary interstitia# concentrations of ammonium and #ow concentrations of ammonium in the dista# tu$u#e f#uid. The #ower the urine H? the more the amount of ammonium that is transferred from the medu##ary interstitium into the f#uid in the #umen of the medu##ary co##ecting duct as it asses through the medu##a to the rena# e#vis. +KoteD The medu##ary co##ecting duct is different from the dista# convo#uted tu$u#e.The net effect of this is that the maBority of the ammonium in the fina# urine was transferred from the medu##a across the dista# art of the tu$u#e even though it was roduced in the ro7ima# tu$u#e. +(im #istica##y $ut erroneous#y it is sometimes said that the ammonium in the urine is roduced in the dista# tu$u#e ce##s.Ammonium is not measured as art of the titrata$#e acidity $ecause the high 5 of ammonium means no H, is removed from KH4, during titration to a H of 2.4. Ammonium e7cretion in severe acidosis can reach 3:: mmo#Iday in humans. Ammonium e7cretion is e7treme#y im ortant in increasing acid e7cretion in systemic acidosis. The titrata$#e acidity is most#y due to hos hate $uffering and the amount of hos hate resent is #imited $y the amount fi#tered Gand thus the #asma concentration of hos hateH. This cannot increase significant#y in the resence of acidosis Gthough of course some additiona# hos hate cou#d $e re#eased from $oneH un#ess other anions with a suita$#e 5a are resent. 5etoanions can contri$ute to a significant increase in titrata$#e acidity $ut on#y in 9etoacidosis when #arge amounts are resent. In com arison? the amount of ammonium e7cretion can and does increase mar9ed#y in acidosis. The ammonium e7cretion increases as urine H fa##s and a#so this effect is mar9ed#y augmented in acidosis. 6ormation of ammonium revents further fa## in H as the 5a of the reaction is so high. In re/ie4 Titrata$#e acidity is an im ortant art of e7cretion of fi7ed acids under norma# circumstances $ut the amount of hos hate avai#a$#e cannot increase very much. A#so as urine H fa##s? the hos hate wi## $e a## in the dihyrogen form and $uffering $y hos hate wi## $e at its ma7imum. A further fa## in urine H cannot increase titrata$#e acidity Gun#ess there are other anions such as 9eto'anions resent in significant <uantitiesH The a$ove oints mean that titrata$#e acidity cannot increase very much Gso cannot $e im ortant in acid'$ase regu#ation when the a$i#ity to increase or decrease rena# H, e7cretion is re<uiredH In acidosis? ammonium e7cretion fi##s the regu#atory ro#e $ecause its e7cretion can increase very mar9ed#y as urine H fa##s.

A #ow urine H itse#f cannot direct#y account for e7cretion of a significant amount of acidD for e7am #e? at the #imiting urine H of a$out 4.4? +H,- is a neg#igi$#e :.:4 mmo#I#. This is severa# orders of magnitude #ower than H, accounted for $y titrata$#e acidity and ammonium e7cretion. Gie :.:4 mmo#I# is insignificant in a net rena# acid e7cretion of 2: mmo#s or more er dayH

32 "eabsorption of "e,aining Bicarbonate On a ty ica# Oestern diet a## of the fi#tered #oad of $icar$onare is rea$sor$ed. The sites and ercentages of fi#tered $icar$onate invo#ved areD 4ro7ima# tu$u#e 3!Q Thic9 ascending #im$ of *oo of Hen#e 1:'1!Q .ista# tu$u#e :'!Q The decrease in vo#ume of the fi#trate as further water is removed in the *oo of Hen#e causes an increase in +H"O3'- in the remaining f#uid. The rocess of H"O3' rea$sor tion in the thic9 ascending #im$ of the *oo of Hen#e is very simi#ar to that in the ro7ima# tu$u#e Gie a ica# Ka,'H, anti ort and $aso#atera# Ka,'H"O3' sym ort and Ka,'5, AT4aseH. Bicar$onate rea$sor tion here is stimu#ated $y the resence of #umina# frusemide. The ce##s in this art of the tu$u#e contain car$onic anhydrase. Any sma## amount of $icar$onate which enters the dista# tu$u#e can a#so $e rea$sor$ed. The dista# tu$u#e has on#y a #imited ca acity to rea$sor$ $icacar$onate so if the fi#tered #oad is high and a #arge amount is de#ivered dista##y then there wi## $e net $icar$onate e7cretion. The rocess of $icar$onate rea$sor tion in the dista# tu$u#e is somewhat different from in the ro7ima# tu$u#eD H, secretion $y the interca#ated ce##s in ."T invo#ves a H,'AT4ase Grather than a Ka,'H, anti ortH H"O3' transfer across the $aso#atera# mem$rane invo#ves a H"O3''"#' e7changer Grather than a Ka,'H"O3' sym ortH The net effect of the e7cretion of one H, is the return of one H"O3' and one Ka, to the $#ood stream. The H"O3' effective#y re #aces the acid anion which is e7creted in the urine. The net acid e7cretion in the urine is e<ua# to the sum of the TA and +KH4,- minus +H"O3- Gif resent in the urineH. The +H,- accounts for on#y a very sma## amount of the H, e7cretion and is not usua##y considered in the e<uation Gas mentioned ear#ierH. In meta$o#ic a#9a#osis? the increased $icar$onate #eve# wi## resu#t in increased fi#tration of $icar$onate rovided the /6) has not decreased. The 9idney is norma##y e7treme#y efficient at e7creting e7cess $icar$onate $ut this ca acity can $e im aired in certain circumstances. G(ee (ection 2.2 and 2.3H 3utline of "eactions in istal *ubule :u,en 8 Cells .iagram to $e added

22!2% "egulation of "enal H= C6cretion The discussion a$ove has descri$ed the mechanisms invo#ved in rena# acid e7cretion and mentioned some factors which regu#ate acid e7cretion. The maBor factors which regu#ate rena# $icar$onate rea$sor tion and acid e7cretion areD

12 C6tracellular /olu,e ;o#ume de #etion is associated with Ka, retention and this a#so enhances H"O3 rea$sor tion. "onverse#y? 1"6 vo#ume e7 ansion resu#ts in rena# Ka, e7cretion and secondary decrease in H"O3 rea$sor tion. 22 Arterial pC32 An increase in arteria# "O2 resu#ts in increased rena# H, secretion and increased $icar$onate rea$sor tion. The converse a#so a #ies. Hy erca nia resu#ts in an intrace##u#ar acidosis and this resu#ts in enhanced H, secretion. The ce##u#ar rocesses invo#ved have not $een c#ear#y de#ineated. This rena# $icar$onate retention is the rena# com ensation for a chronic res iratory acidosis. 32 1otassiu, 8 Chloride eficiency 4otassium has a ro#e in $icar$onate rea$sor tion. *ow intrace##u#ar 5, #eve#s resu#t in increased H"O3 rea$sor tion in the 9idney. "h#oride deficiency is e7treme#y im ortant in the maintenance of a meta$o#ic a#9a#osis $ecause it revents e7cretion of the e7cess H"O3 Gie now the $icar$onate instead of ch#oride is rea$sor$ed with Ka, to maintain e#ectroneutra#ityH. G(ee discussion in (ection 2.3H !2 Aldosterone 8 cortisol ?hydrocortisoneA A#dosterone at norma# #eve#s has no ro#e in rena# regu#ation of acid'$ase $a#ance. A#dosterone de# etion or e7cess does have indirect effects. High a#dosterone #eve#s resu#t in increased Ka, rea$sor tion and increased urinary e7cretion of H, and 5, resu#ting in a meta$o#ic a#9a#osis. "onverse#y? it might $e thought that hy oa#dosteronism wou#d $e associated with a meta$o#ic acidosis $ut this is very uncommon $ut may occur if there is coe7istent significant interstitia# rena# disease. #2 1hosphate C6cretion 4hos hate is the maBor com onent of titrata$#e acidity. The amount of hos hate resent in the dista# tu$u#e does not vary great#y. "onse<uent#y? changes in hos hate e7cretion do not have a significant regu#atory ro#e in res onse to an acid #oad. %2 "eduction in BD" It has recent#y $een esta$#ished that a reduction in /6) is a very im ortant mechanism res onsi$#e for the maintenance of a meta$o#ic a#9a#osis. The fi#tered #oad of $icar$onate is reduced ro ortionate#y with a reduction in /6). '2 A,,oniu, The 9idney res onds to an acid #oad $y increasing tu$u#ar roduction and urinary e7cretion of KH4,. The mechanism invo#ves an acidosis'stimu#ated enhancement of g#utamine uti#isation $y the 9idney resu#ting in increased roduction of KH4, and H"O3' $y the tu$u#e ce##s. This is very im ortant in increasing rena# acid e7cretion during a chronic meta$o#ic acidosis. There is a #ag eriodD the increase in ammonium e7cretion ta9es severa# days to reach its ma7imum fo##owing an acute acid #oad. Ammonium e7cretion can increase u to a$out 3:: mmo#Iday in a chronic meta$o#ic acidosis so this is im ortant in rena# acid'$ase regu#ation in this situation. Ammonium e7cretion increases with decreases

in urine H and this re#ationshi is mar9ed#y enhanced with acidosis. 22!2' 5hat is the "ole of 7rinary A,,oniu, C6cretion9 There are different views on the true ro#e of KH4, e7cretion in urine. How can the rena# e7cretion of ammonium which has a 5 of 8.2 re resent H, e7cretion from the $odyT One schoo# says the roduction of ammonium from g#utamine in the tu$u#e ce##s resu#ts in roduction of a# ha'9etog#utarate which is then meta$o#ised in the tu$u#e ce## to =new> $icar$onate which is returned to the $#ood. The net effect is the return of one $icar$onate for each ammonium e7creted in the urine. By this ana#ysis? the e7cretion of ammonium is e<uiva#ent to the e7cretion of acid from the $ody as one #asma H, wou#d $e neutra#ised $y one rena# $icar$onate ion for each ammonium e7creted. Thus an increase in ammonium e7cretion as occurs in meta$o#ic acidosis is an a ro riate res onse to e7crete more acid. The other schoo# says this is not correct. The argument is that meta$o#ism of a# ha'9etog#uarate in the ro7ima# tu$u#e ce##s to roduce this =new> H"O3' mere#y re resents regeneration of the H"O3 that was neutra#ised $y the H, roduced when a# ha'9etog#utarate was meta$o#ised to g#utamate in the #iver origina##y so there can $e no direct effect on net H, e7cretion. The 9ey to understanding is said to #ie in considering the ro#e of the #iver. "onsider the fo##owingD 1very day rotein turnover resu#ts in amino acid degradation which resu#ts in roduction of H"O3' and KH4,. 6or a ty ica# 1::gIday rotein diet? this is a net roduction of 1?:::mmo#Iday of H"O3' and 1?:::mmo#Iday of KH4,. GThese are roduced in e<ua# amounts $y neutra# amino acids as each contains one car$o7y#ic acid grou and one amino grou .H The high 5 of the ammonium means it cannot dissociate to roduce one H, to neutra#ise the H"O3' so conse<uent#y amino acid meta$o#ism is owerfu##y a#9a#inising to the $ody. The $ody now has two maBor ro$#emsD How to get rid of 1?:::mmo#Iday of a#9a#iT How to get rid of 1?:::mmo#Iday of the high#y to7ic ammoniumT The so#ution is to react the two together and get rid of $oth at once. This rocess is he atic urea synthesis G5re$s'Hense#eit cyc#eH. The cyc#e consumes significant energy $ut so#ves $oth ro$#ems. Indeed? the cyc#e in effect acts as a AT4'de endent um that transfers H, from the very wea9 acid KH4, to H"O3'. The overa## reaction in urea synthesis isD 2 FH!= = 2 HC33- EN urea = C32 = 3 H23 The $ody has two ways in which it can remove KH4,D 0rea synthesis in the #iver 17cretion of KH4, $y the 9idney The 9ey thing here is that the acid'$ase im #ications of these 2 mechanisms are diff&r&n'. 6or each ammonium converted to urea in the #iver one $icar$onate is consumed. 6or each ammonium e7creted in the urine? there is one $icar$onate that is not neutra#ised $y it Gduring urea synthesisH in the #iver. (o overa##? urinary e7cretion of ammonium is e<uiva#ent to net $icar$onate roduction '$ut $y the #iverU Indeed in a meta$o#ic acidosis? an increase in urinary ammonium e7cretion resu#ts in an e7act#y e<uiva#ent net amount of he atic $icar$onate G roduced from amino acid degradationH avai#a$#e to the $ody. (o the true ro#e of rena# ammonium e7cretion is to serve as an a#ternative route for nitrogen

e#inination that has a different acid'$ase effect from urea roduction. The ro#e of g#utamine is to act as the non'to7ic trans ort mo#ecu#e to carry KH4, to the 9idney. The $icar$onates consumed in the roduction of g#utamine and then re#eased again with rena# meta$o#ism of 9etog#utarate are not im ortant as there is no net gain of $icar$onate. Overa##D rena# KH4, e7cretion resu#ts indirect#y in an e<uiva#ent amount of net he atic H"O3 roduction. Other oints areD /#utamate meta$o#ism in the ro7ima# tu$u#e converts A.4 to AT4 and the #ow avai#a$i#ity of A.4 #imits the ma7ima# rate of KH4, roduction in the ro7ima# tu$u#e ce##s. 6urther as most AT4 is consumed in the rea$sor tion of Ka,? then it is u#timate#y the amount of Ka, rea$sor$ed in the ro7ima# tu$u#e that sets the u er #imit for KH4, roduction. The anion that is e7creted with the KH4, is a#so im ortant. 17cretion of $eta'hydro7y$utyrate Ginstead of ch#orideH with KH4, in 9etoacidosis #eads to a #oss of $icar$onate as this anion re resents a otentia# $icar$onate. 6ina##yD The ro#e of urine H in situations of increased acid secretion is worth noting. The urine H can fa## to a minimum va#ue of 4.4 to 4.% $ut as mentioned revious#y this itse#f re resents on#y a neg#igi$#e amount of free H,. As H fa##s? the 3 factors invo#ved in increased H, e7cretion areD 12 Increased a,,oniu, e6cretion Gincreases steadi#y with decrease in urine H and this effect is augmented in acidosisH +This is the ma9or and r&)ula'ory fac'or $ecause it can $e increased significant#y-. 22 Increased titratable acidity: Increased $uffering $y hos hate G$ut neg#igi$#e further effect on H, e7cretion if H W !.! as too far from 5a so minima# amounts of H4O4'2 remainingH Increased $uffering $y other organic acids Gif resentH may $e im ortant at #ower H va#ues as their 5a is #ower Geg creatinine? 9etoanionsH GAs discussed a#so in section 2.!.4? increases in TA are #imited and are not as im ortant as increases in ammonium e7cretionH 32 Bicarbonate reabsorption is co,plete at #ow urinary H so none is #ost in the urine G(uch #oss wou#d antagonise the effects of an increased TA or ammonium e7cretion on acid e7cretion.H

"omment The a$ove discussion focuses on the Etraditiona#E a roach to acid'$ase $a#ance and a short'coming of that a roach is that the e7 #anations are wrong. The (tewart a roach Gsee "ha ter 1:H rovides the e7 #anations and the insights into what is occurring. 6or e7am #e? the focus on e7cretion of H, and e7cretion of KH4, $y the 9idney is mis#eading. EAcid hand#ingE $y the 9idney is most#y mediated through changes in "#' $a#ance. KH4, is a wea9 anion that when e7creted with "#' a##ows the $ody to retain the strong ions Ka, and 5,. The urinary e7cretion of "#' without e7cretion of an e<uiva#ent amount of strong ion resu#ts in a change in the (I. Gor Estrong ion differenceEH and it is this change which causes the change in #asma H. The e7 #anatory focus shou#d $e on the e7cretion of "#' without strong ions and not on the e7cretion of KH4,. (ee "ha ter 1: for an introduction to the (tewart a roach.

Acid-Base 1hysiology 22# Acid Base "ole of the :i/er The #iver is im ortant in acid'$ase hysio#ogy and this is often over#oo9ed. It is im ortant $ecause it is a meta$o#ica##y active organ which may $e either a significant net roducer or consumer of hydrogen ions. The amounts of acid invo#ved may $e very #arge. The acid'$ase ro#es of the #iver may $e considered under the fo##owing headingsD "ar$on dio7ide roduction from com #ete o7idation of su$strates Meta$o#ism of organic acid anions Gsuch as #actate? 9etones and amino acidsH Meta$o#ism of ammonium 4roduction of #asma roteins Ges a#$uminH

22#21 0ubstrate 36idation "om #ete o7idation of car$ohydrates and fat which occurs in the #iver roduces car$on dio7ide $ut no fi7ed acids. As the #iver uses 2:Q of the $ody>s o7ygen consum tion? this he atic meta$o#ism re resents 2:Q of the $ody>s car$on dio7ide roduction a#so. The "O2 diffuses out of the #iver and reactions in red ce##s resu#t in roduction of H, and H"O3'. 22#22 Acid Anions The meta$o#ism of various organic anions in the #iver resu#ts in consum tion of H, and regeneration of the e7trace##u#ar $icar$onate $uffer. These anions may $eD 17ogenous Geg citrate in $#ood transfusion? acetate and g#uconate from 4#asma#yte 143 so#ution? #actate from Hartmann>s so#utionH? or 1ndogenous Geg #actate from active g#yco#ysis or anaero$ic meta$o#ism? 9eto'acids roduced in the #iverH

The term acid anion is used $ecause they are anions roduced $y dissociation of an acid. That isD HA 'X H, , A' Gwhere HA is the acid and A' is the acid anionH. The anions are the conBugate $ase of the acid GBronsted'*owry systemH and are not themse#ves acids. This is an im ortant distinction to ma9e $ecause they are often referred to as though they were acids and this #eads to confusion. If the endogenous roduction of these anions is fo##owed $y #ater consum tion in the #iver then there is no net roduction of acid or $ase $ecause the H, roduced Gfrom the dissociation of the acidH is consumed when the anion is su$se<uent#y meta$o#ised $y the #iver. Ohen these organic anions are e7ogenous#y administered Geg in intravenous f#uidsH? administration of the anion Gthe conBugate $aseH without any H, occurs $ecause the cation invo#ved is Ka,. Any su$se<uent meta$o#ism of these anions in the #iver wi## consume H, and resu#t in e7cess $icar$onate roduction. As an e7am #e? a meta$o#ic a#9a#osis can resu#t after a massive $#ood transfusion when the citrate anticoagu#ant is meta$o#ised to $icar$onate. GThe a#9a#osis is on#y transitory as the 9idney norma##y e7cretes it ra id#y' see (ection 2.3H. The im ortant oint to note is how some of these anions Geg #actate? acetateH are used in I; crysta##oid so#utions as a $icar$onate source Gthough this is indirect of course as the $icar$onate is on#y roduced when they are meta$o#ised in the $odyH. The situation with #actate sometimes causes confusion to students. The 9ey oint to remem$er is that #actic acid is an acid $ut #actate is a $ase. The administration of #actate in Hartmann>s so#ution can never resu#t in a #actic acidosis $ecause it is a $ase and not an acid. The so#ution contains sodium #actate and not #actic acid. The #actate anion is the conBugate $ase of #actic acid and re resents otentia# $icar$onate and not otentia# H,. 0o does this ,ean that Hart,annHs solution can be used for /olu,e resuscitation in patients 4ith lactic acidosis9 The answer to this <uestion is $ased on a consideration of the fo##owing ointsD Hartmann>s so#ution has a high +Ka,- Gwhich restricts the f#uid to the 1"6H so it is a usefu# 1"6 re #acement so#ution. Infusion of an a ro riate amount can correct an intravascu#ar vo#ume deficiency. *actate cannot $uffer H, Gto form #actic acidH at hysio#ogica# H as the 5a Ga$out 4H of the reaction is too #ow. Korma##y? #actate can $e meta$o#ised in the #iver and this resu#ts in the consum tion of H, Gor e<uiva#ent#yD roduction of H"O3'H 4atients with #actic acidosis have inade<uate he atic meta$o#ism of #actate so the roduction of H"O3' from the infused #actate is im aired. G(o unti# this ro$#em with he atic meta$o#ism can $e corrected then the infused #actate cannot act as a $icar$onate sourceH. The serum #actate #eve# is used as an inde7 of the severity of the #actic acidosis as each #actate genera##y means that one H, has $een roduced. If sodium #actate in Hartmann>s so#ution is now given then the #actate #eve# is not as usefu# a guide as now not a## the #actate im #ies the resence of an e<uiva#ent amount of H, that was roduced with it in the $ody. (oD Hartmann>s so#ution is an e7ce##ent 1"6 re #acement so#ution to correct hy ovo#aemia. If the circu#ation im roves and he atic meta$o#ism of #actate returns to norma# then $icar$onate wi## $e generated and the so#ution indirect#y assists in correcting the #actic acidosis as we##. GBut of course if

this ha ened then the $ody wou#d a#so meta$o#ise the endogenous#y roduced #actate and this wou#d $e the maBor factor in correction of the acidosis.H However? if this he atic meta$o#ism does not ha en? then the infused #actate Bust interferes with the usefu#ness of seria# #actate measurements as an seria# inde7 of severity of the acidosis. Overa## then? it is genera##y not the referred 1"6 re #acement so#ution. If it is the on#y so#ution readi#y avai#a$#e then it can $e used and the infused #actate Ga $aseH cannot worsen the acidaemia. The Eofficia#E recommendation is to not use Hartmann>s so#ution in atients with #actic acidosis. GAs a oint of interest? you might #i9e to consider whether norma# sa#ine which contains the non'meta$o#isa$#e ch#oride as the anion cou#d ossi$#y $e any $etterUH Cndogenous :actate (ome e7cess #actate is norma##y roduced in certain tissues and Es i##s overE into the circu#ation. This #actate can $e ta9en u and meta$o#ised in various tissues Geg myocardiumH to rovide energy. On#y in the #iver and the 9idney can the #actate can $e converted $ac9 to g#ucose Gg#uconeogenesisH as an a#ternative to meta$o#ism to car$on dio7ide. The g#ucose may re'enter the $#ood and $e ta9en u $y ce##s Ges musc#e ce##sH. This g#ucose'#actate'g#ucose cyc#ing $etween the tissues is 9nown as the "ori cyc#e. Ty ica##y there is no net #actate roduction which is e7creted from the $ody. The rena# thresho#d for #actate is re#ative#y high and norma##y a## the fi#tered #actate is rea$sor$ed in the tu$u#es. The tota# amount of #actate invo#ved is #arge G1?!:: mmo#sIdayH in com arison to the net fi7ed acid roduction G1 to 1.! mmo#sI9gIdayH. The meta$o#ism of #actate in the #iver indirect#y e#iminates the H, roduced su$se<uent to the tissue roduction of #actate. *actic acidosis wi## resu#t if this he atic meta$o#ism is not ade<uate. G(ee *actic Acidosis H. Meta$o#ism of #actate sourced from I; Hartmann>s so#ution a#so resu#ts in a net consum tion of H,? $ut as this #actate was associated with Ka,? the overa## resu#t is a net $icar$onate roduction. 1ffective#y? meta$o#ism of this #actate resu#ts in generation of an e<uiva#ent amount of $icar$onate. The situation is simi#ar with meta$o#ism of citrate and g#uconate in other I; f#uids. Ketones 5eto'acids such as acetoacetate are roduced in he atic mitochondria due to incom #ete o7idation of fatty acids. The 9etones are re#eased into the $#ood stream and meta$o#ised in the tissues Ges musc#eH. He atic roduction of 9etoacids roduces H, and the o7idation of the 9eto'anion in the tissues consumes H, and there$y regenerates the H"O3 which had $uffered it in the $#ood stream. In severe dia$etic 9etoacidosis? the 9eto'acid roduction may e7ceed 1?2:: mmo#sIday in an adu#tU In hea#thy individua#s? a modest amount of e7cess 9etones are roduced on#y with significant fasting. G(ee a#so (ection 3.2 5etoacidosisH A,ino Acids Amino acids are a## di o#ar ions G&witterionsH at hysio#ogica# H as they a## have $oth "OO' and KH3, grou s. These are the grou s that artici ate in formation of the e tide $ond. As these grou s are resent on a## amino acids? then the o7idation of these grou s in a## amino acids wi## resu#t in a roduction of e<ua# amounts of $icar$onate and ammoniumD ty ica##y 1?::: mmo#Iday of each. This as ect and the acid'$ase im #ications has $een covered in the revious section 2.4 and wi## not $e re eated here.

Amino acids a#so have side chains and incom #ete meta$o#ism of some of these has acid'$ase effects ' eg side chain meta$o#ism can resu#t in a net fi7ed acid roduction. (u# huric acid is roduced from meta$o#ism of methionine and cysteine. This is a maBor com onent of the net fi7ed acid #oad. Arginine? #ysine and histidine have nitrogen in their side chains so their meta$o#ism generates H, . /#utamate and as artate have car$o7y#ic acid grou s G"OO'H in their side chains so their meta$o#ism consumes H, Gand therefore roduces H"O3' H. The $a#ance of these reactions is a net dai#y roduction of H, and acid anions of !: mmo#Iday Gie roduction of 21: mmo#sIday and consum tion of 1%: mmo#IdayH. The #iver is the maBor net roducer of fi7ed acids. 22#23 $etabolis, of A,,oniu, (ee section 2.4 for detai#s. The conversion of KH4, to urea in the #iver resu#ts in an e<uiva#ent roduction of H,. Infusions of KH4"# have an acid #oading effect $ecause of this he atic meta$o#ism. H, cannot $e re#eased direct#y from KH4, in the $ody $ecause the high 5a of the reaction means that KH3 is resent in on#y minute <uantities at H 2.4. 22#2! 0ynthesis of 1las,a 1roteins The #iver is the maBor roducer of #asma roteins as near#y a## Ge7ce t the immunog#o$u#insH are roduced here. A#$umin synthesis accounts for !:Q of a## he atic rotein synthesis. The acid'$ase ro#es of a#$umin areD it is the maBor unmeasured anion in the #asma which contri$utes to the norma# va#ue of the anion ga e7trace##u#ar $uffer for "O2 and fi7ed acids a$norma# #eve#s can cause a meta$o#ic acid'$ase disorder Haemog#o$in is more im ortant than a#$umin for $uffering H, roduced from "O2. A#so? $icar$onate is more im ortant than a#$umin as a $uffer for fi7ed acids. The ro#e of #ow or high a#$umin #eve#s in causing acid'$ase disorders is difficu#t to e7 #ain within the traditiona# framewor9 of acid'$ase ana#ysis. The ro#e of a#$umin as the maBor non'vo#ati#e wea9 acid resent in #asma and its significance in acid'$ase $a#ance is discussed in (ection 1:. Hy oa#$uminaemia causes a meta$o#ic a#9a#osis. 22#2# 3/er/ie4 "onsideration of a## these factors shows that the #iver has an e7treme#y im ortant ro#e in norma# acid' $ase hysio#ogy. The traditiona# em hasis on the #ung and 9idney as the organs of acid'$ase regu#ation shou#d $e e7tended to a new conce t of the im ortance of the #ung'#iver'9idney com #e7. He atic disorders are often associated with acid'$ase disorders. The most common distur$ances in chronic #iver disease are res iratory a#9a#osis Gmost commonH and meta$o#ic a#9a#osis.

Acid-Base 1hysiology

22% "egulation of Intracellular Hydrogen Ion Concentration 22%21 I,portance of Intracellular <H=> *he ,ost i,portant <H=> for the body is the intracellular <H=> 5hy9 Because of its rofound effects on meta$o#ism and other ce## rocesses which occur due to the effects of +H,- on the degree of ionisation of intrace##u#ar com ounds. ( ecifica##yD 0,all ,olecule effectD Intrace##u#ar tra ing function 'due to the ionisation of meta$o#ic intermediates. :arge ,olecule effectD 1ffects on rotein functionD The function of many intrace##u#ar roteins Ges the activities of en&ymesH is a#tered $y effects on the ionisation of amino acid residues Ges histidine residuesH In assess,ent of acid-base disordersL the clinician is al4ays loo&ing fro, the outside in2 5hy9 6or 2 reasonsD 1ase of sam #ingD Arteria# $#ood is easy to sam #e. It is much more difficu#t to o$tain an intrace##u#ar sam #e Arteria# $#ood gives resu#ts which can $e considered a sort of Eaverage va#ueE. It wou#d $e more difficu#t to find an intrace##u#ar sam #e that cou#d $e considered to $e Ere resentativeE of a## I"6. *he basis of the clinical approach is to use the e6tracellular results to ,a&e inferences about intracellular conditions2 Both car$on dio7ide and the fi7ed acids are roduced intrace##u#ar#y and move down concentration gradients to the 1"6. "ar$on dio7ide crosses ce## mem$ranes very easi#y and it is im ortant to rea#ise that "O2 can move in or out de ending on the gradient across the ce## mem$rane. In dia$etic 9etoacidosis G.5AH? the 9etoacids are roduced in the #iver and not in every ce## in the $ody. The intrace##u#ar a#9a#inising effect of the com ensatory hy oca nia that occurs wi## however affect every ce## and not Bust the he atocytes. .oes this mean that .5A roduces an e7trace##u#ar rise in +H,- $ut the o osite change in most tissues Ge7c#uding the #iverH where the net effect is a fa## in intrace##u#ar +H,- due to the com ensatory hy oca niaT 5etoacids can enter most ce##s and $e used as an energy su$strate and this wou#d initia##y cause a fa## in intrace##u#ar +H,-. Intrace##u#ar H may not $e a#tered much once ma7ima# res iratory com ensation has $een achieved $ecause of these o osing effects. It is ossi$#e that though the ma7ima# res iratory com ensation does not fu##y correct the e7trace##u#ar acidaemia? it may $e sufficient to revent much change in intrace##u#ar H. This discussion is s ecu#ative and has not $een fu##y investigated. The ur ose here is mere#y to show that #oo9ing at acid'$ase disorders from the intrace##u#ar view oint can #ead to ideas which are different from those of the conventiona# e7trace##u#ar view oint. The hy othesis of )ahn and cowor9ers Gsee section 1.%H is that the intrace##u#ar H is maintained at a$out the H of neutra#ity G KH $ecause this is the H at which meta$o#ite intermediates are a## charged and tra ed inside the ce##. 17trace##u#ar H is higher $y :.! to :.% H units and this re resents a$out a fourfo#d gradient favouring the e7it of hydrogen ion from the ce##. Measurements of intrace##u#ar H in a variety of mamma#ian s9e#eta# musc#e re arations have found H va#ues most#y in the %.3 to 2.1 range. ;a#ues found in other tissues have sometimes $een higher de ending on the e7 erimenta#

arrangements. This va#ue is a #itt#e higher then the K G%.3 at 32"H $ut is sti## a$#e to effective#y tra intermediates within the ce##. A further com #ication is that intrace##u#ar H is not uniform and measurements have $een a$#e to give on#y mean H va#ues for the who#e intrace##u#ar com artment. These mean va#ues may $e mis#eading as there may $e acidic and $asic areas within different ce## areas or organe##es and it is this #oca# H which is im ortant. Because of the po4erful effects of intracellular <H=> on ,etabolis, it is useful to consider the processes 4hich atte,pt to ,aintain it at a stable /alue2 *his assists us in ,a&ing inferences about intracellular e/ents fro, an e6tracellular acid-base sa,ple2 The rocesses res onsi$#e for maintaining a sta$#e intrace##u#ar H areD =Intrace##u#ar $uffering> AdBustment of arteria# "O2 *oss of fi7ed acids from the ce## into the e7trace##u#ar f#uid 22%22 GIntracellular BufferingH This term refers to those ra id reversi$#e rocesses occurring within the intrace##u#ar f#uid which minimise changes in H in res onse to an acid or a#9a#i stress. The term =$uffering> is used here in a much $roader sense then that discussed in section 2.2 where it was used to refer to the rocess of hysicochemica# $uffering a#one. Intrace##u#ar#y? there are other ra id and reversi$#e rocesses which act to minimise acute changes in intrace##u#ar +H,- and which can usefu##y $e considered a form of =$uffering>. =Intrace##u#ar $uffering> inc#udes the fo##owing rocessesD 4hysicochemica# $uffering Meta$o#ic $uffering Organe##ar $uffering 17 eriments have shown that these three rocesses can neutra#ise over 88.88Q of any acid or a#9a#i added acute#y to the intrace##u#ar f#uidU These rocesses rovide ra id $ut tem orary re#ief from acute intrace##u#ar acid'$ase changes. 1hysicoche,ical buffering In <uantitative terms this is the most im ortant rocess which resists change in intrace##u#ar +H,-. G4hysicochemica# $uffering is discussed in section 2.2.H In the intrace##u#ar environment? proteins G articu#ar#y imida&o#e of histidineH and phosphates Gorganic and inorganicH are the most im ortant $uffers $ecause they have a 5 c#ose to the norma# intrace##u#ar H and are resent in the highest concentrations. The I"6 is res onsi$#e for 82 to 88Q of the $ody>s tota# $uffering of res iratory acid'$ase disorders. The intrace##u#ar contri$ution to $uffering is #ess with meta$o#ic disorders G%:Q for meta$o#ic acidosisJ 3:Q for meta$o#ic a#9a#osisH $ut is sti## su$stantia#. The $icar$onate system is resent intrace##u#ar#y and is invo#ved in $uffering for meta$o#ic acidosis. Intrace##u#ar amino acids rovide a sma## amount of the $uffering. 6ree histidine has a 5a of a$out %.: which is #ower than the average %.3 va#ue when it is incor orated into roteins. A sma## amount of H, is used u into roducing a#anine and g#utamine. $etabolic buffering Meta$o#ic Gor $iochemica#H $uffering refers to changes in the meta$o#ism of acids within the ce## which

tend to o

ose changes in +H,-.

"hanges in intrace##u#ar H affect the activity of en&ymes. The net effect of differentia# changes in en&yme activity in various athways Ginc#uding the main g#yco#ytic athwayH is an a#teration in the #eve#s of acidic meta$o#ites in such a way that changes in +H,- are minimised. 6or e7am #e? the meta$o#ism of #actate to g#ucose or to water and "O2 Gwhich can readi#y #eave the ce##H wi## effective#y remove H, from intrace##u#ar f#uid. This is c#ear#y not sim #y hysicochemica# $uffering. "onsider another e7am #eD If intrace##u#ar "O2 decreases due to acute hy erventi#ation? this roduces a re#ative intrace##u#ar a#9a#osis. "hanges in en&yme activities resu#t in increased #eve#s of #actate? yruvate and other acidic intermediates. This occurs <uic9#y? is reversi$#e and tends to minimise the change in intrace##u#ar H. Meta$o#ic $uffering can account for a hydrogen ion consum tion u to ha#f of that due to the rocess of hysicochemica# $uffering within the ce##. 3rganellar buffering This refers to the acute se<uestration in or re#ease of H, from intrace##u#ar organe##es in a direction which o oses the change of intrace##u#ar H. The overa## contri$ution of this rocess to intrace##u#ar $uffering is not c#ear. The energy re#eased during the e#ectron transfers in the res iratory chain in mitochondria is used to e7trude hydrogen ions. The energy is stored as a roton gradient across the inner mitochondria# mem$rane. Ohen the hydrogen ions re'enter via mem$rane'$ound AT4ase? the energy is re#eased and used to roduce AT4 from A.4. Mitochondria e7trude a tota# of si7 rotons for every o7ygen atom that is reduced to water. A rise in cyto #asmic +H,- rovides additiona# H, which can enter the mitochondria. This wi## contri$ute to AT4 formation via the inner mem$rane roton gradient and wi## $uffer changes in cyto #asmic H. *ysosomes contain en&ymes which have ma7ima# activity at acidic H. In some e7 eriments? the interna# H of #ysosomes increases when e7trace##u#ar H increases. This can $e inter reted as a mechanism which assists in $uffering changes in cyto #asmic H. The overa## significance of this rocess is not esta$#ished. 22%23 Ad)ust,ent of Arterial pC32 "ar$on dio7ide is roduced in huge <uantities $y ce##sD ty ica##y 12?::: G$asa##yH to as much as 1!?::: to 2:?::: mmo#sIday with ty ica# #eve#s of activity. An efficient system e7ists for its remova#. The arteria# "O2 is of critica# im ortance for intrace##u#ar acid'$ase $a#ance $ecause of $oth its otentia# to change ra id#y and $ecause of its effectiveness in a#tering intrace##u#ar +H,-. "ar$on dio7ide crosses ce## mem$ranes easi#y. A change in venti#ation affects the arteria# "O2 #eve# and the intrace##u#ar "O2 throughout the $ody. The com ensatory res onse to a meta$o#ic acid'$ase disorder is to increase a#veo#ar venti#ation and thus decrease arteria# "O2 #eve#s. This changed "O2 wi## affect intrace##u#ar H and this effect is ra id. 6or e7am #e an acute meta$o#ic acidosis wi## $e com ensated $y a fa## in "O2 which wi## minimise the intrace##u#ar effects of the acidosis. 22%2! Di6ed Acid C6trusion fro, Cells Meta$o#ism Gan intrace##u#ar eventH roduces e7cess acid. In the #ong term? hydrogen ion $a#ance

within the ce## is de endent on #oss of these acids from the ce##. The various $uffering rocesses discussed revious#y are on#y short'term measures as the acid is not removed from the ce##. 17 eriments show that ce##s res ond to an acute acid #oad Geg hy erca niaH $y an initia# fa## in H Gminimised $y intrace##u#ar $uffering discussed a$oveH $ut that the H su$se<uent#y returns s#ow#y towards norma# des ite the continued resence of the acid stress. This is due to net acid e7trusion from the ce## across the ce## mem$rane. This rocess invo#ves a cou #ed e7change of ions GH,? H"O3'? Ka, and "#'H across the mem$rane. The rocess does not affect the mem$rane otentia# so it must $e e#ectroneutra#. ;arious mode#s have $een ro osed $ut the re#ative im ortance of these in verte$rates has not $een fu##y esta$#ished. The res onse of ce##s to an a#9a#ine #oad is much #ess deve#o ed and much #ess studied than the res onse to an acid #oad. The movement of H, or H"O3' across the mem$rane is not im ortant in changing +H,- Gsee discussion in section 1:.%H $ut the movement of strong e#ectro#ytes Gsuch as Ka,? "#'? #actateH wi## a#ter intrace##u#ar +H,-. The im ortant oint is that it is the movement of the acid anion out of the ce## Grather than hydrogen ion er seH that resu#ts in a net #oss of fi7ed acid from the ce##. A simi#ar situation a #ies in the 9idneyD the em hasis shou#d $e on the urinary #oss of the acid anions Gwith the H, $uffered on hos hate of ammoniumH rather than hydrogen ion itse#f. The traditiona# use of hydrogen ion in e7 #anations must $e <uantitative#y e<uiva#ent $ut does serve to disguise the true nature of the rocess. In su,,ary: In e7 eriments where ce##s are su$Bected to an acid #oad? they res ond $y an increase in the rate of acid e7trusion from the ce##. This returns intrace##u#ar +H,- towards norma#. The res onse is not as ra id as the mechanisms invo#ved in intrace##u#ar $uffering. WU'' ''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''' ''X Acid-Base 1hysiology 321 - *er,inology of Acid-Base isorders

32121 efinitions The definitions of the terms used here to descri$e acid'$ase disorders are those suggested $y the Ad' Hoc "ommittee of the Kew For9 Academy of (ciences in 18%!. Though this is over 3! years ago? the definitions and discussion remain va#id today. Basic efinitions Acidosis ' an a$norma# rocess or condition which wou#d #ower arteria# H if there were no secondary changes in res onse to the rimary aetio#ogica# factor. Al&alosis ' an a$norma# rocess or condition which wou#d raise arteria# H if there were no secondary changes in res onse to the rimary aetio#ogica# factor. 0i,ple ?Acid-BaseA isorders 1 are those in which there is a sing#e rimary aetio#ogica# acid' $ase disorder. $i6ed ?acid-BaseA isorders 2,3 are those in which two or more rimary aetio#ogica# disorders are resent simu#taneous#y. Acidae,ia ' Arteria# H W 2.3% Gie +H,- X 44 nM H

Al&alae,ia ' Arteria# H X 2.44 Gie +H,- W 3% nM H The meaning of the terms acid? $ase? +H,- and H has $een discussed revious#y in (ections 1.2 and 1.3. An acidaemia of course must $e due to an acidosis so is an indicator of the resence of this disorder. In mi7ed acid'$ase disorders? there may $e co'e7isting disorders each having o osite effects on the 1"6 H so a <uic9 chec9 of the arteria# H is insufficient to fu##y indicate a## rimary acid'$ase disorders. In mi7ed disorders? it does indicate in genera# terms the most severe disorder. That is? if the arteria# H is 2.2 Gan acidaemiaH? there must $e an acidosis resent? and any a#9a#osis resent must $e of #esser magnitude. GThis idea is the $asis of an initia# ste in the systematic a roach to ana#ysis of arteria# $#ood gas resu#tsH. *he isorders The 4 sim #e acid $ase disorders areD )es iratory acidosis )es iratory a#9a#osis Meta$o#ic acidosis Meta$o#ic a#9a#osis.

)es iratory disorders are caused $y a$norma# rocesses which tend to a#ter H $ecause of a rimary change in "O2 #eve#s. Meta$o#ic disorders are caused $y a$norma# rocesses which tend to a#ter H $ecause of a rimary change in +H"O3'-. 32122 Correct *er,inology for Co,pensatory "esponses 0econdary or co,pensatory responses should F3* be designated as acidosis or al&alosis2 The committee recommended the use of the adBectives =secondary> or =com ensatory> to descri$e the change in the com osition of the $#ood or the rocess Geg venti#ationH $ut not to modify the nouns =acidosis> or =a#9a#osis>. This is the ractice ado ted here. Many u$#ished artic#es refer to com ensatory rocesses as though they were rimary rocesses. This #a&y and incorrect use of these terms is e7treme#y confusing so caution must $e e7ercised and u#timate#y one shou#d not $e too edantic in insisting on correct termino#ogy in others as the ractice is wides read in the c#inica# #iterature. 6or e7am #eD A atient with dia$etic 9etoacidosis and com ensatory 5ussmau# res irations shou#d $e descri$ed as having a Emeta$o#ic acidosis with com ensatory hy erventi#ationE. The use of the term =secondary res iratory a#9a#osis> in this case wou#d $e wrong as the change is a com ensatory one and not a rimary rocess and so $y definition then it cannot $e an a#9a#osis. It is ossi$#e that a atient such as this cou#d have a mi7ed disorder with a res iratory acid'$ase disorder as we## as the meta$o#ic acidosis. The inter retation of these more com #icated cases is discussed in (ection 3.4. The terms acidaemia and a#9a#aemia may $e used to descri$e the net H deviation in the $#ood $ut the Ad",oc 4ommi''&& recommended the re orting of the actua# H va#ue or the use of the terms =#ow>?

=high> and =norma#> as refera$#e. 32123 isorders are defined by their CCD Cffects The c#inica# acid'$ase disorders are defined $y their effects in the e7trace##u#ar f#uid Gor more s ecifica##y? in the arteria# $#oodH. The disorder may arise $ecause of changes intrace##u#ar#y Geg e7cess #actate roductionH $ut the effect e7trace##u#ar#y is what is a$#e to $e easi#y measured. .es ite the definitions of acidosis and a#9a#osis a$ove? it is common to s ea9 of an Eintrace##u#ar acidosisE or an Eintrace##u#ar a#9a#osisE. This use is not consistent with the definitions a$ove $ut as there are no other satisfactory terms avai#a$#e so this common ractice is fo##owed here. "eferences 1. Karins )/ and 1mmett M. 0im+l& and mi:&d acid"*as& disord&rs: a +rac'ical a++roach. Medicine GBa#timoreH 183: MayJ !8G3H 1%1'32. 4u$Med 2. Oa#ms#ey )K and Ohite /H. Mi:&d acid"*as& disord&rs. "#in "hem 183! 6e$J 31G2H 321'!. 4u$Med 3. AdroguY HP. Mi:&d acid"*as& dis'ur*anc&s. P Ke hro# 2::% Mar'A rJ 18 (u # 8 (82'1:3. 4u$Med A## Med#ine a$stractsD 4u$Med Hu$Med 4revious S Inde7 S To of age S Ke7t EAcid'$ase Hysio#ogyE $y 5erry Brandis 'from htt DIIwww.anaesthesiaM"A.com Acid-Base 1hysiology 322 *he Anion Bap 32221 efinition 8 Clinical 7se The term anion ga GA/H re resents the concentration of a## the unmeasured anions in the #asma. The negative#y charged roteins account for a$out 1:Q of #asma anions and ma9e u the maBority of the unmeasured anion re resented $y the anion ga under norma# circumstances. The acid anions Geg #actate? acetoacetate? su# hateH roduced during a meta$o#ic acidosis are not measured as art of the usua# #a$oratory $iochemica# rofi#e. The H, roduced reacts with $icar$onate anions G$ufferingH and the "O2 roduced is e7creted via the #ungs Gres iratory com ensationH. The net effect is a decrease in the concentration of measured anions Gie H"O3H and an increase in the concentration of unmeasured anions Gthe acid anionsH so the anion ga increases. A/ is ca#cu#ated from the fo##owing formu#aD Anion ga L +Ka,- ' +"#'- ' +H"O3')eference range is 3 to 1% mmo#I#. An a#ternative formu#a which inc#udes 5, is sometimes used articu#ar#y $y Ke hro#ogists. In )ena# 0nits? 5, can vary over a wider range and have more effect on the measured Anion /a . This a#ternative formu#a isD

A/ L +Ka,- , +5,- ' +"#'- ' +H"O3'The reference range is s#ight#y higher with this a#ternative formu#a. The +5,- is #ow re#ative to the other three ions and it ty ica##y does not change much so omitting it from the e<uation doesn>t have much c#inica# significance. $a)or Clinical 7ses of the Anion Bap To signa# the resence of a meta$o#ic acidosis and confirm other findings He# differentiate $etween causes of a meta$o#ic acidosisD high anion ga versus norma# anion ga meta$o#ic acidosis. In an inorganic meta$o#ic acidosis Geg due H"# infusionH? the infused "#' re #aces H"O3 and the anion ga remains norma#. In an organic acidosis? the #ost $icar$onate is re #aced $y the acid anion which is not norma##y measured. This means that the A/ is increased. To assist in assessing the $iochemica# severity of the acidosis and fo##ow the res onse to treatment 32222 *he Anion Bap can be $isleading It is determined from a ca#cu#ation invo#ving 3 other measured ions? so the error with an A/ is much higher than that of a sing#e e#ectro#yte determination. The commonest cause of a #ow anion ga is #a$oratory error in the e#ectro#yte determinations. The 8!Q error range for the A/ is a$out ,I' ! mmo#I# Gie a 1:mmo#sI# rangeUH If the A/ is greater than 3: mmo#I#? than it invaria$#y means that a meta$o#ic acidosis is resent. If the A/ is in the range 2: to 28 mmo#I#? than a$out one third of these atients wi## not have a meta$o#ic acidosis. Other c#inica# guides shou#d a#so $e used in deciding on the resence and severity of a meta$o#ic acidosis. (ignificant #actic acidosis may $e associated with an anion ga which remains in the reference range. *actate #eve#s of ! to 1: mmo#sI#itre are associated with a high morta#ity if associated with se sis? $ut the A/ may $e re orted as within the reference range in as many as !:Q of these casesU G.orwart C "ha#mers 182!H G(ee a#so discussion in (ection 3.4 regarding #actate'ch#oride anti ort.H The anion ga is usefu# es ecia##y if very e#evated or used to confirm other findings. "auses of a high anion ga acidosis can $e sorted out more s ecifica##y $y using other investigations in addition to the history and e7amination of the atient. Investigations which may $e very usefu# areD *actate "reatinine 4#asma g#ucose 0rine 9etone test

Key Dact: Hypoalbu,inae,ia causes a lo4 anion gap A#$umin is the maBor unmeasured anion and contri$utes a#most the who#e of the va#ue of the anion ga . 1very one gram decrease in a#$umin wi## decrease anion ga $y 2.! to 3 mmo#es. A norma##y high anion ga acidosis in a atient with hy oa#$uminaemia may a ear as a norma# anion ga acidosis. This is articu#ar#y re#evant in Intensive "are atients where #ower a#$umin #eve#s are common. A #actic acidosis in a hy oa#$uminaemic I"0 atient wi## common#y $e associated with a norma# anion ga .

"eferences 1. 1mmett M and Karins )/. 4linical us& of 'h& anion )a+. Medicine GBa#timoreH 1822 PanJ !%G1H 33'!4. 4u$Med Hu$Med 2. /ood9in .A? 5rishna //? and Karins )/. %h& rol& of 'h& anion )a+ in d&'&c'in) and mana)in) mi:&d m&'a*olic acid"*as& disord&rs. "#in 1ndocrino# Meta$ 1834 Pu#J 13G2H 333'48. 4u$Med Hu$Med +good18343. Moe OO and 6uster .. 4linical acid"*as& +a'ho+hysiolo)y: disord&rs of +lasma anion )a+. Best 4ract )es "#in 1ndocrino# Meta$ 2::3 .ecJ 12G4H !!8'24. 4u$Med Hu$Med 4. Badric9 T and Hic9man 41. %h& anion )a+. A r&a++raisal. Am P "#in 4atho# 1882 AugJ 83G2H 248'!2. 4u$Med Hu$Med !. *o#e9ha 4H? ;anavanan (? Teera9arnBana K? and "haichanaBarern9u# 0. R&f&r&nc& ran)&s of &l&c'roly'& and anion )a+ on 'h& 5&c(man E;A, 5&c(man 0ynchron 4<!, =ova 4R%, and =ova 0'a' Profil& >l'ra. "#in "him Acta 2::1 MayJ 3:2G1'2H 32'83. 4u$Med Hu$Med %. .orwart O; and "ha#mers *. 4om+arison of m&'hods for calcula'in) s&rum osmolali'y form ch&mical conc&n'ra'ions, and 'h& +ro)nos'ic valu& of such calcula'ions. "#in "hem 182! 6e$J 21G2H 18:'4. 4u$Med Hu$Med 2. 6igge P? Pa$or A? 5a&da A? and 6enc# ;. Anion )a+ and hy+oal*umin&mia. "rit "are Med 1883 KovJ 2%G11H 13:2'1:. 4u$Med Hu$Med 3. "arvounis "4 and 6einfe#d .A. A sim+l& &s'ima'& of 'h& &ff&c' of 'h& s&rum al*umin l&v&l on 'h& anion 7a+. Am P Ke hro# 2::: (e 'OctJ 2:G!H 3%8'22. 4u$Med Hu$Med 8. 4owner .P? 5e##um PA C .ar$y PM. 4onc&+'s of 'h& 0'ron) 3on 6iff&r&nc& a++li&d 'o ?ar)& @olum& R&susci'a'ion P Intensive "are Med 2::1J 1%D 1%8'12% 1:.5raut PA C Madias K1. 0&rum Anion 7a+: 3's >s&s and ?imi'a'ions in 4linical M&dicin& "#in P Am (oc Ke hro# 2::2J 2D 1%2'124 4u$Med

Acid-Base 1hysiology 323 - *he elta "atio 32321 efinition This .e#ta )atio is sometimes usefu# in the assessment of meta$o#ic acidosis 1,2,3,4. As this conce t is re#ated to the anion ga GA/H and $uffering? it wi## $e discussed here $efore a discussion of meta$o#ic acidosis. The .e#ta )atio is defined asD elta ratio E ?Increase in Anion Bap @ ecrease in bicarbonateA Others ! have used the d&l'a )a+ Gdefined as rise in A/ minus the fa## in $icar$onateH? $ut this uses the same information as the de#ta ratio and has does not offer any advantage over it. 32322 Ho4 is this useful9 In order to understand this? consider the fo##owingD If one mo#ecu#e of meta$o#ic acid GHAH is added to the 1"6 and dissociates? the one H, re#eased wi## react with one mo#ecu#e of H"O3' to roduce "O2 and H2O. This is the rocess of $uffering. The net

effect wi## $e an increase in unmeasured anions $y the one acid anion A' Gie anion ga increases $y oneH and a decrease in the $icar$onate $y one. Kow? if a## the acid dissociated in the 1"6 and a## the $uffering was $y $icar$onate? then the increase in the A/ shou#d $e e<ua# to the decrease in $icar$onate so the ratio $etween these two changes Gwhich we ca## the de#ta ratioH shou#d $e e<ua# to one. The de#ta ratio <uantifies the re#ationshi $etween the changes in these two <uantities. C6a,ple If the A/ was say 2% mmo#sI# Gan increase of 14 from the average va#ue of 12H? it might $e e7 ected that the H"O3' wou#d fa## $y the same amount from its usua# va#ue Gie 24 minus 14 L 1:mmo#sI#H. If the actua# H"O3' va#ue was different from this it wou#d $e indirect evidence of the resence of certain other acid'$ase disorders Gsee /uide#ines $e#owH. 1roble, A ro$#em thoughD the a$ove assum tions a$out a## $uffering occurring in the 1"6 and $eing tota##y $y $icar$onate are not correct. 6ifty to si7ty ercent of the $uffering for a meta$o#ic acidosis occurs intrace##u#ar#y. This amount of H, from the meta$o#ic acid GHAH does not react with e7trace##u#ar H"O3' so the e7trace##u#ar +H"O3'- wi## not fa## as far as origina##y redicted. The acid anion Gie A'H however is charged and tends to stay e7trace##u#ar#y so the increase in the anion ga in the #asma wi## tend to $e as much as redicted. Overa##? this significant intrace##u#ar $uffering with e7trace##u#ar retention of the unmeasured acid anion wi## cause the va#ue of the de#ta ratio to $e greater than one in a high A/ meta$o#ic acidosis. Caution Inaccuracies can occur for severa# reasons? for e7am #eD "a#cu#ation re<uires measurement of 4 e#ectro#ytes? each with a measurement error "hanges are assessed against EstandardE norma# va#ues for $oth anion ga and $icar$onate concentration. (ometimes these errors com$ine to roduce <uite an incorrect va#ue for the ratio. As an e7am #e? atients with hy oa#$uminaemia have a #ower Enorma#E va#ue for anion ga so using the standard va#ue of 12 to com are against must #ead to an error. .o not overinter ret your resu#t and #oo9 for su ortive evidence es ecia##y if the diagnosis is une7 ected. 32323 Buidelines for 7se of the elta "atio (ome genera# guide#ines for use of the de#ta ratio when assessing meta$o#ic acid'$ase disorders in rovided in the ta$#e $e#ow. Overa## AdviceD Be /ery 4ary of o/er-interpretation ' A#ways chec9 for other evidence to su ort the diagnosis as an une7 ected va#ue without any other evidence shou#d a#ways $e treated with great caution.

elta "atio W :.4 :.4 ' :.3

Assess,ent Buideline Hy erch#oraemic norma# anion ga acidosis "onsider com$ined high A/ C norma# A/ acidosis B0T note that the ratio is often W1 in acidosis associated with rena# fai#ure 0sua# for uncom #icated high'A/ acidosis *actic acidosisD average va#ue 1.% .5A more #i9e#y to have a ratio c#oser to 1 due to urine 9etone #oss Ges if atient not dehydratedH (uggests a re'e7isting e#evated H"O3 #eve# so considerD a concurrent meta$o#ic a#9a#osis? or a re'e7isting com ensated res iratory acidosis

1 to 2

X2

5arning Be very wary of over'inter retation ' A#ways chec9 for other evidence to su ort the diagnosis as an une7 ected va#ue without any other evidence shou#d a#ways $e treated with great caution. A high ratio A high de#ta ratio can occur in the situation where the atient had <uite an e#evated $icar$onate va#ue at the onset of the meta$o#ic acidosis. (uch an e#evated #eve# cou#d $e due to a re'e7isting meta$o#ic a#9a#osis? or to com ensation for a re'e7isting res iratory acidosis Gie com ensated chronic res iratory acidosisH. Oith onset of a meta$o#ic acidosis? using the EstandardE va#ue of 24 mmo#I# as the reference va#ue for com arison when determining the Edecrease in $icar$onateE wi## resu#t in an odd resu#t. A lo4 ratio A #ow ratio occurs with hy erch#oraemic Gor norma# anion ga H acidosis. The reason here is that the acid invo#ved is effective#y hydroch#oric acid GH"#H and the rise in #asma +ch#oride- is accounted for in the ca#cu#ation of anion ga Gie ch#oride is a Emeasured anionEH. The resu#t is that the Erise in anion ga E Gthe numerator in the de#ta ration ca#cu#ationH does not occur $ut the Edecrease in $icar$onateE Gthe denominatorH does rise in numerica# va#ue. The net of of $oth these changes then is to cause a mar9ed dro in de#ta ratio? common#y to W :.4 :actic acidosis In #actic acidosis? the average va#ue of the de#ta ratio in atients has $een found to $e is 1.% due to intrace##u#ar $uffering with e7trace##u#ar retention of the anion. As a genera# ru#e? in uncom #icated #actic acidosis? the rise in the A/ shou#d a#ways e7ceed the fa## in $icar$onate #eve#.

iabetic &etoacidosis The situation with a ure dia$etic 9etoacidosis is a s ecia# case as the urinary #oss of 9etones decreases the anion ga and this returns the de#ta ratio downwards towards one. A further com #ication is that these atients are often f#uid resuscitated with Enorma# sa#ineE so#ution which resu#ts in a increase in #asma ch#oride and a decrease in anion ga and deve#o ment of a Ehy erch#oraemic norma# anion ga acidosisE su erim osed on the 9etoacidosis. The resu#t is a further dro in the de#ta ratio. "eferences 1. Oster P)? 4ere& /O? and Materson BP. >s& of 'h& anion )a+ in clinical m&dicin&. (outh Med P 1833 6e$J 31G2H 228'32. 4u$Med 2. 4au#son O. and /ada##ah M6. 6ia)nosis of mi:&d acid"*as& disord&rs in dia*&'ic (&'oacidosis. Am P Med (ci 1883 KovJ 3:%G!H 28!'3::. 4u$Med 3. Oi##iamson P". Acid"*as& disord&rs: classifica'ion and mana)&m&n' s'ra'&)i&s. Am 6am 4hysician 188! AugJ !2G2H !34'8:. 4u$Med 4. 5im HF? Han P(? Peon 0(? Poo 5O? 1arm PH? Ahn "? 5im (? *ee P(? and 5im /H. 4linical si)nificanc& of 'h& frac'ional &:cr&'ion of anions in m&'a*olic acidosis. "#in Ke hro# 2::1 PunJ !!G%H 443'!2. 4u$Med !. Orenn 5. %h& d&l'a )a+: an a++roach 'o mi:&d acid"*as& disord&rs. Ann 1merg Med 188: KovJ 18G11H 131:'3. 4u$Med

Acid-Base 1hysiology 32! - *he 7rinary Anion Bap

32!21 efinition The cations norma##y resent in urine are Ka,? 5,? KH4,? "a,, and Mg,,. The anions norma##y resent are "#'? H"O3'? su# hate? hos hate and some organic anions. On#y Ka,? 5, and "#' are common#y measured in urine so the other charged s ecies are the unmeasured anions G0AH and cations G0"H. Because of the re<uirement for macrosco ic e#ectroneutra#ity? tota# anion charge a#ways e<ua#s tota# cation charge? soD "#' , 0A L Ka, , 5, , 0" )earrangingD

7rinary Anion Bap E ? 7A - 7C A E <Fa=>= <K=> - <Cl-> 32!22 Clinical 7se Key Dact: *he urinary anion gap can help to differentiate bet4een BI* and renal causes of a hyperchlorae,ic ,etabolic acidosis2 It has $een found e7 erimenta##y that the 0rinary Anion /a G0A/H rovides a rough inde7 of urinary ammonium e7cretion. Ammonium is ositive#y charged so a rise in its urinary concentration Gie increased unmeasured cationsH wi## cause a fa## in 0A/ as can $e a reciated $y ins ection of the formu#a a$ove. How is this usefu#T "onsider the fo##owingD 0tep 3FC: $etabolic acidosis can be di/ided into t4o groups based on the anion gap ?ABA: High anion ga acidosis Korma# anion ga Gor hy erch#oraemicH acidosis. It is easy to ca#cu#ate the anion ga so this differentiation is easy and indeed c#inica##y usefu#. 0tep *4o: Consider the hyperchlorae,ic group for further analysis2 Hyperchlorae,ic acidosis can be caused by: *oss of $ase via the 9idney Geg rena# tu$u#ar acidosisH *oss of $ase via the $owe# Geg diarrhoeaH. /ain of minera# acid Geg H"# infusionH. 0tep *hree: Bo4el or &idney as the cause9 .iagnosis $etween the a$ove 3 grou s of causes is usua##y c#inica##y o$vious? $ut occasiona##y it may $e usefu# to have an e7tra aid to he# in deciding $etween a #oss of $ase via the 9idneys or the $owe#. If the acidosis is due to #oss of $ase via the $owe# then the 9idneys can res onse a ro riate#y $y increasing ammonium e7cretion to cause a net #oss of H, from the $ody. The 0A/ wou#d tend to $e decreased? That isD increased KH4, Gwith resuma$#y increased "#'H LX increased 0" LXdecreased 0A/. If the acidosis is due to #oss of $ase via the 9idney? then as the ro$#em is with the 9idney it is not a$#e to increase ammonium e7cretion and the 0A/ wi## not $e increased. oes this 4or&9 17 erimenta##y? it has $een found that atients with diarrhoea severe enough to cause hy erch#oraemic acidosis have a negative 0A/ Gaverage va#ue '22 ,I' 1: mmo#I#H and atients with acidosis due to a#tered urinary acidification had a ositive 0A/. In many cases? the cause Ggut or 9idneyH wi## $e o$vious? $ut occasiona##y ca#cu#ation of the urinary anion ga can $e usefu#. 32!23 Conclusion In a atient with a hy erch#oraemic meta$o#ic acidosisD A negative 0A/ suggests /IT #oss of $icar$onate Geg diarrhoeaH

A ositive 0A/ suggests im aired rena# dista# acidification Gie rena# tu$u#ar acidosisH. As a memory aid? remem$er =ne/0Tive> ' negative 0A/ in $owe# causes. 6or more detai#s of the use of the 0A/ in differentiating causes of dista# urinary acidification? see Bat##e et a# G1838H. )emem$er that is most cases the diagnosis may $e c#inica##y o$vious Geg severe diarrhoea is hard to missH and consideration of the urinary anion ga is not necessary.

Acid-Base 1hysiology 32# - 3s,olar Bap KBD EOsmo#ar ga E has severa# a#ternative namesD Eosmo# ga E? Eosmo#e ga E? Eosmo#arity ga E C Eosmo#a# ga EJ these a## refer to the same thing. 6or consistency? the term @osmo#ar ga @ is used e7c#usive#y through this $oo9. 32#21 5hat is the 'os,olar gap'9 .efinitions An os,ole is the amount of a su$stance that yie#ds? in idea# so#ution? that num$er of artic#es GAvogadro>s num$erH that wou#d de ress the free&ing oint of the so#vent $y 1.3%5 3s,olality of a so#ution is the num$er of osmo#es of so#ute er 9i#ogram of so#vent. 3s,olarity of a so#ution is the num$er of osmo#es of so#ute er #itre of so#ution. (o osmo#a#ity is a measure of the num$er of artic#es resent in a unit weight of so#vent. It is inde endent of the si&e? sha e or weight of the artic#es. It can on#y $e measured $y use of a ro erty of the so#ution that is de endent on the artic#e concentration. These ro erties are co##ective#y referred to as "o##igative 4ro erties. Osmo#a#ity is ,easured in the #a$oratory $y machines ca##ed osmometers. The units of osmo#a#ity are mOsmI9g of so#ute Osmo#arity is calculated from a formu#a which re resents the so#utes which under ordinary circumstances contri$ute near#y a## of the osmo#a#ity of the sam #e. There are many such formu#ae which have $een used. One wide#y used formu#a for #asma which is used at my hos ita# isD Calculated os,olarity E ?12(% 6 <Fa=>A = <glucose> = <urea> = + Kote regarding unitsD 6or the a$ove e<uation? a## concentrations are in mmo#I#? and not mgI1::m#s. The resu#t wi## then $e in mOsmI# of so#ution. This e<uation is often e7 ressed different#y in Korth America where g#ucose C $#ood urea nitrogen GB0KH are re orted in mgId#. This version is essentia##y identica# as it Bust inc#udes conversion factors to convert mgId# to mmo#I#D "a#cu#ated osmo#arity L G1.3% 7 +Ka,-H , g#ucoseI13 , B0KI2.3 , 8 This formu#a $ecome o u#ar after a study G$y .orwart C "ham$ersH com aring 13 different formu#ae found this one to yie#d the most accurate resu#ts.

Ohat #eve# of osmo#ar ga is @a$norma#@T An osmo#ar ga X 1: mOsmI# is often stated to $e a$norma#. The su ort for this contention is oor. One study GHoffman )( et a#? 1883H suggested the use of this formu#aD Calculated os,olarity E ? 2 6 <Fa=> A = glucose@1( = B7F@22( = ethanol@!2% They found a mean osmo#ar ga of 2.2 with (. !.! mOsmI#. The 8!Q range Gmean ,I' 2(.H was '14 to ,1:. This study is ro$a$#y the $asis for the X1: va#ue as $eing a$norma#. The range for norma# va#ues is very de endent on the articu#ar formu#a that is used. Osmo#arity is easy to ca#cu#ate $ecause it on#y re<uires the measurement of 3 su$stances and these are routine#y measured in every hos ita# $iochemistry #a$oratory. Its ca#cu#ation is usua##y rogrammed into the $iochemistry autoana#yser and is routine#y rinted on the standard resu#t sheet and is avai#a$#e to you even without having to as9. The osmo#ar ga is the difference $etween the 2 va#uesD the osmolali'y Gwhich is measuredH and the osmolari'y Gwhich is ca#cu#ated from measured so#ute concentrationsH. 3s,olar gap E 3s,olality - 3s,olarity In hea#thy ersons? the osmo#ar ga is sma## as the osmo#arity Gca#cu#ated using the formu#a a$oveH is a fair#y good estimate of the osmo#a#ity. But in some conditions? there are significant amounts of a$norma# su$stances resent which contri$ute to the tota# osmo#a#ity and then the osmo#arity wi## underestimate the osmo#a#ity. "onse<uent#y the osmo#ar ga wi## necessari#y $e increased. A given concentration of a$norma# other so#utes Gin mgId#H wi## contri$ute more artic#es GmOsmI9gH if they have a #ow mo#ecu#ar weight. It fo##ows then that if the osmo#ar ga is significant#y e#evated? this rovides indirect evidence that there must $e a significant concentration of one or more #ow mo#ecu#ar su$stances resent. It does not identify these a$norma# so#utes $ut a#erts you to their resence. A minor oint for com #etenessD The units of osmo#a#ity GmOsmI9gH and osmo#arity GmOsmI#itreH are different so strict#y they cannot $e su$tracted from one another. That said though? the va#ue of the difference is c#inica##y usefu# so this ro$#em wi## $e ignored. 32#22 *ype of 3s,o,eter Fou M0(T chec9 the ty e of osmometer used $y your hos ita# The osmo#a#ity is measured in the atho#ogy #a$oratory using an instrument ca##ed an osmometer which uses one of the co##igative ro erties as the $asis for its measurement. "urrent#y avai#a$#e osmometers fa## into 2 grou sD Those using the co##igative ro erty of free&ing oint de ression Those using the co##igative ro erty of va our ressure de ression. 3nly os,o,eters using freeKing point depression ,ethod should be used OhyT Because they are the on#y ty e of osmometer that can detect a## the vo#ati#e a#coho#s which can

a$norma##y increase the osmo#ar ga . The other ty e of osmometer cannot do this. An e7 #anation for this difference isD @;a or ressure osmometry? in contrast to osmometry using the free&ing oint de ression method? re<uires an e<ui#i$rium $etween va or and #i<uid hases and is unre#ia$#e when vo#ati#e chemica#s such as ethano# and methano# are resent $ecause these chemica#s tend to remain in the va or hase@ Gfrom /#aser? 188%H Fou must chec9 what ty e your atho#ogy #a$oratory is using otherwise you wi## $e mis#ed $y s urious#y norma# osmo#ar ga resu#ts.

32#23 5hat is the ,eaning 8 usefulness of a high os,olar gap9 An e#evated osmo#ar ga rovides indirect evidence for the resence of an a$norma# so#ute which is resent in significant amounts. To have much effect on the osmo#ar ga ? the su$stance needs to have a #ow mo#ecu#ar weight and $e uncharged so it can $e resent in a form and in a concentration Gmeasured in mmo#I#H sufficient to e#evate the osmo#ar ga . 1thano#? methano# C ethy#ene g#yco# are three such so#utes that? when resent in a recia$#e amounts? wi## cause an e#evated osmo#ar ga . If you sus ect that your atient may have ingested one of these su$stances than you shou#d determine the osmo#ar ga . $ain 7se of 3s,olar gap: 0creening test for detecting abnor,al lo4 $5 solutes ?esp ethanolL ,ethanol 8 ethylene glycol 1thy#ene g#yco# is used as an anti'free&e in car radiators and ingestions may $e more common in co#d c#imates. I havenEt yet found a case in my own re#ative#y #arge hos ita# and undou$ta$#y this is $ecause the warm c#imate means that ethy#ene g#yco# is not common#y used in cars here. Osmo#ar /a D 0se with "aution Im ortant reservations need to $e made a$out the c#inica# uti#ity of the osmo#ar ga ? in articu#arD Its ca#cu#ation de ends on measurement of three su$stances and an osmo#a#ity measurement? so the error is the sum of the errors of a## these measurements Many formu#ae are avai#a$#e to ca#cu#ate osmo#arity and the ca#cu#ated va#ue varies significant#y de ending on which one is used The osmo#ar ga has a wide norma# range in the o u#ation The wide#y <uoted a$norma# va#ue of X1: has a #ow sensitivity The osmo#ar ga may $e norma# with ethy#ene g#yco# ingestion $ecause of its higher MO Gin com arison to methano#H. The sensitivity of the test in detecting to7ic ingestion of ethy#ene g#yco# is not high As ethy#ene g#yco# C methano# are meta$o#ised? the osmo#ar ga decreases GC the anion ga increasesH so a Enorma#E va#ue is more #i9e#y if the atient resents #ate

Cthanol Cloa&ing: A 1ractical 1roble, An e#evated osmo#ar ga indicates an un9nown so#ute $ut does not identify it. It is im ortant to fo##ow' u and determine what su$stance Gor su$stancesH is res onsi$#e. As an e7am #e? consider the fo##owing situationD "onsider a atient who has ingested ethano# as we## as ethy#ene g#yco# or methano#. The ethano# wi## increase the osmo#ar ga and you can miss the resence of the more to7ic su$stances if you ma9e the assum tion that the ga is due to the ethano# a#one. This mista9e cou#d have serious adverse conse<uences for the atient. 0olution 1: 6or this reason? it is advisa$#e to re<uest an ethano# #eve# whenever you re<uest a measured osmo#a#ity. Fou can then correct the osmo#ar ga for any ethano# resent and determine a Ecorrected osmo#ar ga E. This a roach is genera##y readi#y avai#a$#e in hos ita#s and has the advantage of indirect#y detecting the resence of AKF other such #ow mo#ecu#ar weight to7in and not Bust ethano#. Fou wonEt 9now what this other so#ute is yet $ut your sus icions are raised and you can roceed to more s ecifc ana#yses. +KBD To convert ethano# #eve#s in mgId# to mmo#I# divide $y 4.%. 6or e7am #e? an ethano# #eve# of :.:!Q is !:mgId#. .ivide $y 4.% gives 1:.8mmo#sI#0olution 2: Another way to sort this out is if there is c#inica# sus icion AK. your #a$oratory has the faci#ities? is to re<uest s ecific assays for methano# or ethy#ene g#yco#. However? de ending on the techni<ue your #a$oratory uses? you may or may not detect other rare ingestions. Fou can miss the s ecific to7ins that you are trying to measure if time has assed and they have a#ready $een e7tensive#y meta$o#ised to their to7ic roducts. In this #atter case? you wou#d $e mis#ed as to the to7ic otentia# #ur9ing in your atient. The ro$#em with this so#ution is that many #a$oratories do not measure these #eve#s so your s ecimen may need to $e sent to a distant #arge #a$oratory. The method used in our referring #a$ is a gas chromatogra hic se aration fo##owed $y a mass s ectrosco ic detection. This is #a$our intensive and time consuming so the #a$oratory adds an additiona# #ayer of the need to discuss the case with a chemica# atho#ogist $efore the ana#ysis is agreed to. On#y a$out 1!Q of re<uests get through this ste in our #oca# e7 erience. "eferences .orwart O C "ham$ers *. "om arison of Methods for "a#cu#ating (erum Osmo#a#ity from "hemica# "oncentrations? and the 4rognostic ;a#ue of (uch "a#cu#ations. "#in "hem 182!J 21D 18:'184 /#aser .(. 0ti#ity of the (erum Osmo# /a in the .iagnosis of Methano# or 1thy#ene /#yco# Ingestion. Ann 1merg MedJ 188%D 343'34%H Hoffman )( et a#. Osmo# ga s revisitedD Korma# ;a#ues and *imitations. "#in To7ico# 1883J 31D 31'83.

Acid-Base 1hysiology !21 "espiratory Acidosis - efinition

A respiratory acidosis is a pri,ary acid-base disorder in 4hich arterial pC32 rises to a le/el higher than e6pected2 At onset? the acidosis is designated as an Eacute respiratory acidosisE. The $odyEs initia# com ensatory res onse is #imited during this hase. As the $odyEs rena# com ensatory res onse increases over the ne7t few days? the H returns towards the norma# va#ue and the condition is now a Echronic respiratory acidosisE. The differentiation $etween acute and chronic is determined $y time $ut occurs $ecause of the rena# com ensatory res onse Gwhich is s#owH.

Acid-Base 1hysiology !22 "espiratory Acidosis - Causes The arteria# "O2 is norma##y maintained at a #eve# of a$out 4: mmHg $y a $a#ance $etween roduction of "O2 $y the $ody and its remova# $y a#veo#ar venti#ation. If the ins ired gas contains no "O2 then this re#ationshi can $e e7 ressed $yD paC32 is proportional to ;C32 @ ;A whereD ;"O2 is "O2 roduction $y the $ody ;A is A#veo#ar venti#ation An increase in arteria# "O2 can occur $y one of three ossi$#e mechanismsD 4resence of e7cess "O2 in the ins ired gas .ecreased a#veo#ar venti#ation Increased roduction of "O2 $y the $ody "O2 gas can $e added to the ins ired gas or it may $e resent $ecause of re$reathing D Anaesthetists are fami#iar with $oth these mechanisms. In these situations? hy erca nia can $e induced even in the resence of norma# a#veo#ar venti#ation and norma# car$on dio7ide roduction $y the $ody. An adu#t at rest roduces a$out 2::m#s of "O2 er minuteD this is e7creted via the #ungs and the arteria# "O2 remains constant. An increased roduction of "O2 wou#d #ead to a res iratory acidosis if venti#ation remained constant. The system contro##ing arteria# "O2 is very efficient Gie ra id and effectiveH and any increase in "O2 very rom t#y resu#ts in a #arge increase in venti#ation. The resu#t is that increased "O2 roduction a#most never resu#ts in res iratory acidosis. It is on#y in situations where venti#ation is fi7ed that increased roduction wi## cause res iratory acidosis. 17am #es of this

wou#d $e a venti#ated atient who deve#o s acute ma#ignant hy erthermiaD the arteria# "O2 wi## rise un#ess the a#veo#ar venti#ation is su$stantia##y increased. $ost cases of respiratory acidosis are due to decreased al/eolar /entilation2 The defect #eading to this can occur at any #eve# in the res iratory contro# mechanism. This rovides a convenient way to c#assify causes that is used in the fo##owing ta$#e. Al/eolar hypo/entilation ,ay i,pair o6ygen upta&e2 The degree of arteria# hy o7aemia wi## $e re#ated to the amount of hy oventi#ation. Increasing the ercent of o7ygen in the ins ired gas can com #ete#y correct the hy o7aemia if hy oventi#ation is the on#y factor invo#ved. If u#monary disease #eading to shunt or venti#ation' erfusion mismatch is resent? then the hy o7aemia wi## not $e so easi#y corrected. The fo##owing #ist c#assifies causes $y the mechanism or site causing the res iratory acidosis. Causes of "espiratory Acidosis ?classified by $echanis,A A: InadeIuate Al/eolar ;entilation Central Respiratory Depression & Other CNS Problems .rug de ression of res . center Geg $y o iates? sedatives? anaestheticsH "K( trauma? infarct? haemorrhage or tumour Hy oventi#ation of o$esity Geg 4ic9wic9ian syndromeH "ervica# cord trauma or #esions Gat or a$ove "4 #eve#H High centra# neura# $#oc9ade 4o#iomye#itis Tetanus "ardiac arrest with cere$ra# hy o7ia

Nerve or Mus le Disorders /ui##ain'Barre syndrome Myasthenia gravis Musc#e re#a7ant drugs To7ins eg organo hos hates? sna9e venom ;arious myo athies

!ung or Chest Wall De"e ts Acute on "OA.

"hest trauma 'f#ai# chest? contusion? haemothora7 4neumothora7 .ia hragmatic ara#ysis or s #inting 4u#monary oedema Adu#t res iratory distress syndrome )estrictive #ung disease As iration

#ir$ay Disorders 0 er Airway o$struction *aryngos asm Bronchos asmIAsthma %&ternal 'a tors Inade<uate mechanica# venti#ation B: 3/er-production of Carbon io6ide Hyper ataboli Disorders Ma#ignant Hy erthermia C: Increased Inta&e of Carbon io6ide Rebreathing o" CO() ontaining e&pired gas #ddition o" CO( to inspired gas *nsu""lation o" CO( into body avity +eg "or laparos opi surgery,

The genera#isation made in this section is that though there are three ossi$#e distinct mechanisms that can resu#t in a res iratory acidosis? in clinical practice, nearly all cases are due to

inadequate alveolar ventilation. This is a very im ortant oint. Keverthe#ess the rare causes shou#d $e considered es ecia##y in Anaesthetic and Intensive "are ractice where atients are often intu$ated and connected to circuits. 4articu#ar issues here inc#udeD Ma#ignant hy erthermia GMHH is an e7treme#y rare $ut otentia##y fata# condition which occurs a#most e7c#usive#y in Anaesthetised atients e7 osed to certain drugs ;arious circuit misconnections C ma#functions? or soda #ime e7haustion? can resu#t in significant re$reathing of e7 ired car$on dio7ide 4atients who are ara#ysed and on contro##ed venti#ation cannot increase their a#veo#ar venti#ation to e7crete any increased amounts of "O2 roduced $y the $ody Geg in hy ercata$o#ic states such as se sis or MHH 17ogenous car$on dio7ide is introduced into the $ody in certain rocedures Geg #a arosco yH and this increases the amount of car$on dio7ide to $e e7creted $y the #ungs Adding "O2 to the ins ired gas as a res iratory stimu#ant has resu#ted? a#$eit rare#y? in adverse outcomes in the ast. GThis ractice is now a$andoned in modern Anaesthetic racticeH "ontinuous ca nogra hy monitoring is now mandatory in Anaesthetic ractice.

Acid-Base 1hysiology !23 "espiratory Acidosis - $aintenance

Key Dact: A rise in arterial pC32 is a potent sti,ulus to /entilation so a respiratory acidosis 4ill rapidly correct unless so,e abnor,al factor is ,aintaining the hypo/entilation2 This feed$ac9 mechanism is res onsi$#e for the norma# tight contro# of arteria# "O2. The factor causing the disorder is a#so the factor maintaining it. The revai#ing arteria# "O2 re resents the $a#ance $etween the effects of the rimary cause and the res iratory stimu#ation due to the increased "O2. Other then $y venti#atory assistance? the "O2 wi## return to norma# on#y $y correction of the cause of the decreased a#veo#ar venti#ation. An e7treme#y high arteria# "O2 has direct anaesthetic effects and this wi## #ead to a worsening of the situation either $y centra# de ression of venti#ation or as a resu#t of #oss of airway atency or rotection.

Acid-Base 1hysiology !2! "espiratory Acidosis - $etabolic Cffects

!2!21 epression of Intracellular $etabolis, As C32 rapidly and easily crosses lipid barriersL a respiratory acidosis has rapid 8 generally depressing effects on intracellular ,etabolis,2 Hy erca nia wi## ra id#y cause an intrace##u#ar acidosis in a## ce##s in the $ody. The c#inica# icture wi## $e affected $y the arteria# hy o7aemia that is usua##y resent. The effects descri$ed $e#ow are the meta$o#ic effects of hy erca nia rather than res iratory acidosis. 4atients with res iratory acidosis can $e hy oca nic if a severe meta$o#ic acidosis is a#so resent. Im ortant effects of Hy erca nia (timu#ation of venti#ation via $oth centra# and eri hera# chemorece tors "ere$ra# vasodi#ation increasing cere$ra# $#ood f#ow and intracrania# ressure (timu#ation of the sym athetic nervous system resu#ting in tachycardia? eri hera# vasoconstriction and sweating 4eri hera# vasodi#ation $y direct effect on vesse#s "entra# de ression at very high #eve#s of "O2

!2!22 I,portance of Cerebral Cffects *he cerebral effects of hypercapnia are usually the ,ost i,portant2 These effects areD increased cere$ra# $#ood f#ow? increased intracrania# ressure? C otent stimu#ation of venti#ation. This can resu#t in dys noea? disorientation? acute confusion? headache? menta# o$tundation or even foca# neuro#ogic signs. 4atients with mar9ed e#evations of arteria# "O2 may $e comatose $ut severa# factors contri$ute to thisD Anaesthetic effects of very high arteria# "O2 Geg X 1::mmHgH Arteria# hy o7aemia Increased intracrania# ressure As a ractica# c#inica# e7am #e? the rise in intracrania# ressure due to hy erca nia may $e articu#ar#y mar9ed in atients with intracrania# atho#ogy Geg tumours? head inBuryH as the usua# com ensatory mechanism of "(6 trans#ocation may $e readi#y e7hausted. Any associated hy o7aemia wi## contri$ute to an adverse outcome. !2!23 Cffects on Cardio/ascular 0yste, *he effects on the cardio/ascular syste, are a balance bet4een the direct and indirect effects2 Ty ica##y? the atient is warm? f#ushed? sweaty? tachycardic and has a $ouncing u#se.

The c#inica# icture may $e modified $y effects of hy o7aemia? other i##nesses and the atient>s medication. Arrhythmias may $e resent articu#ar#y if significant hy o7aemia is resent or sym athomimetics have $een used. Acute#y the acidosis wi## cause a right shift of the o7ygen dissociation curve. If the acidosis ersists? a decrease in red ce## 2?3 .4/ occurs which shifts the curve $ac9 to the #eft. An arterial pC32 in e6cess of about +- ,,Hg is not co,patible 4ith life in patients breathing roo, air2 5hy9 This is $ecause of the o$#igatori#y associated severe hy o7aemia. The a#veo#ar gas e<uation redicts an a#veo#ar O2 of 32mmHg Gand the arteria# Osu$X2 wou#d $e #ower than thisH when the "O2 is 8:mmHgD
AO2

L +:.21 7 G2%:'42H- ' 8: I :.3 L 32 mmHg.

Higher va#ues of a"O2 have $een recorded in atients $reathing an increased ins ired o7ygen concentration which revents the hy o7aemia. ;a#ues u to a$out 2%:mmHg have $een recorded with inadvertent administration of high ins ired "O2 $ut this is /uinness Boo9 of )ecords stuffU High "O2 #eve#s a#so have an anaesthetic effect. Hy erca nia 'vs' )es iratory acidosisT Kote that Ehy erca niaE and Eres iratory acidosisE are not synonymous as? for e7am #e? a atient with a severe meta$o#ic acidosis and a concomitant res iratory acidosis cou#d have an arteria# "O2 #ess than 4:mmHg. However? most of the discussion of Emeta$o#ic effectsE on this age is more correct#y the Emeta$o#ic effects of hy erca niaE rather than res iratory acidosis er se. .es ite this? even in the mi7ed disorder Bust mentioned? the effects of an e#evated arteria# "O2 are #inear? so com ared to the situation of a severe meta$o#ic acidosis a#one? the meta$o#ic effects of the higher "O2 of the mi7ed acid'$ase disorder Gie with the concomitant res iratory acidosisH are most#y sti## re#ative#y correct.

Acid-Base 1hysiology !2# "espiratory Acidosis - Co,pensation

!2#21 *he co,pensatory response is a rise in the bicarbonate le/el This rise has an immediate com onent Gdue to a resetting of the hysicochemica# e<ui#i$rium ointH which raises the $icar$onate s#ight#y. Ke7t is a s#ower com onent where a further rise in #asma $icar$onate due to enhanced rena# retention of $icar$onate. The additiona# effect on #asma $icar$onate of the rena# retention is what converts an @acute@ res iratory acidsosis into a @chronic@ res iratory acidosis. As can $e seen $y ins ection of the Henderson'Hasse#$a#ch e<uation G$e#owH? an increased +H"O3'wi## counteract the effect Gon the HH of an increased "O2 $ecause it returns the va#ue of the +H"O3-I:.:3 "O2 ratio towards norma#. pH = pKa + log([HCO3]/0.03 pCO2) !2#22 Buffering in Acute "espiratory Acidosis *he co,pensatory response to an acute respiratory acidosis is li,ited to buffering2 By the #aw of mass action? the increased arteria# "O2 causes a shift to the right in the fo##owing reactionD CO2 + H2O <-> H2CO3 <-> H+ + HCO3In the $#ood? this reaction occurs ra id#y inside red $#ood ce##s $ecause of the resence of car$onic anhydrase. The hydrogen ion roduced is $uffered $y intrace##u#ar roteins and $y hos hates. "onse<uent#y? in the red ce##? the $uffering is most#y $y haemog#o$in. This $uffering $y remova# of hydrogen ion? u##s the reaction to the right resu#ting in an increased $icar$onate roduction. The $icar$onate e7changes for ch#oride ion across the erythrocyte mem$rane and the #asma $icar$onate #eve# rises. In an acute acidosis? there is insufficient time for the 9idneys to res ond to the increased arteria# "O2 so this is the on#y cause of the increased #asma $icar$onate in this ear#y hase. The increase in $icar$onate on#y artia##y returns the e7trace##u#ar H towards norma#. 1m irica##y? the +H"O3'- rises $y 1 mmo#I# for every 1:mmHg increase in "O2 a$ove its reference va#ue of 4:mmHg. 6or e7am #e? if arteria# "O2 has risen acute#y from 4:mmHg to %:mmHg Gdue to decreased a#veo#ar venti#atonH then this acute rise of 2 tens Gi.e. %:'4:L2:mmHg riseH resu#ts in a rise of #asma $icar$onate $y 2 from its reference va#ue of 24mmo#I# u to 2% mmo#I#. "onse<uent#y? we wou#d redict that if this acute res iratory acidosis was the on#y $ase disorder resent? then #asma $icar$onate wou#d $e 2%mmo#I#. Though very im ortant for carria)& of car$on dio7ide in the $#ood? the $icar$onate system is not itse#f res onsi$#e for any $uffering of a res iratory acid'$ase disorder. This is $ecause a system cannot $uffer itse#f. If H"O3 were to react with H, roduced from the dissociation of H2"O3 this wou#d Bust roduce H2"O3 again ' reversing the reaction is not E$ufferingE. Kinety'nine ercent of the $uffering of an acute res iratory acidosis occurs intrace##u#ar#y. 4roteins Ges ecia##y haemog#o$in in red ce##sH and hos hates are the most im ortant $uffers invo#ved. These ta9e u the H, roduced from the dissociation of H2"O3. This intrace##u#ar $uffering resu#ts in a further increase in intrace##u#ar +H"O3- $ecause it u##s the "O2 hydration reaction to the right. The

H"O3 that #eaves the ce## causes the rise in e7trace##u#ar H"O3. The amount of $uffering is #imited $y the concentration of rotein as that is #ow re#ative to the amount of car$on dio7ide re<uiring $uffering. In summaryD "om ensation for an acute res iratory acidosis is $y intrace##u#ar $uffering and #asma $icar$onate rises s#ight#y as a resu#t of this $uffering. The $uffering is redominant#y due to intrace##u#ar roteinsJ the $icar$onate system does not contri$ute to this $uffering. !2#23 Chronic "espiratory Acidosis: "enal Bicarbonate "etention 5ith continuation of the acidosisL the &idneys respond by retaining bicarbonate2 If the res iratory acidosis ersists then the #asma $icar$onate rises to an even higher #eve# $ecause of rena# retention of $icar$onate. Thus in a chronic res iratory acidosis there are TOO factors resent which e#evate the #asma $icar$onateD' 6irst#yD The acute hysicochemica# change and conse<uent $uffering es $y intrace##u#ar rotein. GImmediate onset ' as occurs with an acute res iratory acidosis.H (econd#yD The rena# retention of $icar$onate as rena# function is a#tered $y the e#evated arteria# "O2 and additiona# $icar$onate is added to the $#ood assing through the 9idney. G(#ow onsetH (tudies have shown that an average 4 mmo#I# increase in +H"O3'- occurs for every 1:mmHg increase in "O2 from the reference va#ue of 4:mmHg. 6or e7am #e? if arteria# "O2 has risen from 4:mmHg to %:mmHg Gdue to decreased a#veo#ar venti#atonH and remained e#evated for severa# days? then this chronic rise of @2 tens@ Gi.e. %:'4:L2:mmHg rise L 2 rises of 1:mmHgH resu#ts in a rise of #asma $icar$onate $y 3 from its reference va#ue of 24mmo#I# u to 32 mmo#I#. "onse<uent#y? we wou#d redict that if this chronic res iratory acidosis was the on#y $ase disorder resent? then #asma $icar$onate wou#d $e 32mmo#I#. The rena# res onse in underway $y % to 12 hours with a ma7ima# effect reached $y 3 to 4 days. This ma7ima# effect is not sufficient to return #asma H to norma#? $ut $ecause of the additiona# rena# contri$ution? the H is returned towards norma# much more than occurs in an acute res iratory acidosis. The res onse occurs $ecause increased arteria# "O2 increases intrace##u#ar "O2 in ro7ima# tu$u#ar ce##s and this causes increased H, secretion from the 4"T ce##s into the tu$u#ar #umen. This resu#ts inD increased H"O3 roduction which crosses the $aso#atera# mem$rane and enters the circu#ation Gso #asma +H"O3- increases.H increased Ka, rea$sor tion in e7change for H, and #ess in e7change for "#' Gso #asma +"#'fa##sH increased EKH3E roduction to E$ufferE the H, in the tu$u#ar #umen Gso urinary e7cretion of KH4"# increasesH !2#2! '$a6i,al co,pensation' /ersus 'full co,pensation'92 The increase in #asma +H"O3- resu#ts in an increase in amount of $icar$onate fi#tered in the 9idney and this amount increases as #asma $icar$onate continues to increase. 1ventua##y a new steady state is

reached which is referred to as =,a6i,al co,pensation>. This #eve# of com ensation has #ong $een $e#ieved to $e #ess than that re<uired to return the #asma H to norma#. That is the actua# com ensation GEma7ima# com ensationEH is #ess than Efu## com ensationE. If the H was found to actua##y $e within the norma# range? the inter retation of this was that there was a co'e7isting meta$o#ic a#9a#osis Ge.g. due to use of diuretics or corticosteroidsH or there had $een transient hy erventi#ation from the stress of arteria# uncture. A recent study1 e7amined the actua# ma7ima# res onse in a grou of atients with sta$#e chronic hy erca nic res iratory fai#ure without a c#inica# condition or medications those cou#d cause a meta$o#ic a#9a#osis. The maBority of these atients had H va#ues in the norma# range as the com ensation was greater than that redicted $y the c#assic 4 for 1: ru#e. They found that $icar$onate increased $y !.1 mmo#sI# for every 1:mmHg "O2 rise. "onse<uent#y? a diagnosis of mi#d meta$o#ic a#9a#osis shou#d not $e made in atients with sta$#e chronic res iratory acidosis with H va#ues in the norma# range un#ess there is other evidence Ge.g. use of thia&ide or #oo diuretics? or corticosteroidsH consistent with the diagnosis. In summary? the com ensation for hy erca nia isD AcuteD Buffering on#y and redominant#y intrace##u#ar G88QH "hronicD )ena# retention of $icar$onate Gin addition to $ufferingH 0u,,ary notes about the co,pensation ter,s $a6i,al co,pensation refers to the actua# ma7ima# amount of com ensation that is ty ica##y seen in a atient with a sim #e acid'$ase disorder. Dull co,pensation refers to the amount of com ensation that wou#d correct the H a## the way $ac9 to within the norma# range. The genera# ru#e for a## acid'$ase disorders is that the $odyEs com ensatory res onse is a#most never sufficient to return the #asma H to norma#. If the H is norma# then it suggests that a second? com ensating acid'$ase disorder is resent. "ontrary to this Ec#assicE teaching? a recent a er1 suggests that in many atients with chronic sta$#e hy erca nia? com ensation may $e sufficient to return H to within the norma# range. !2#2# iffering ti,e courses of co,pensation and correction The situation may $e com #icated $ecause of the differing time courses of com ensation C correction. "onsider a cou #e of ty ica# situations which sometimes cause confusion in inter retationD 0cenario 1 "orrection of a chronic res iratory acidosis can occur more ra id#y than correction of the rena# com ensation so it is ossi$#e that the $#ood gases in an individua# atient may a ear to show Efu## com ensationE if the a#veo#ar venti#ation has increased and $efore the 9idneys have had time to adBust. The stimu#ation of $eing in the 1mergency )oom may resu#t in such a situation and the sna shot rovided $y a sing#e set of gases may revea# such a situation. G)emem$er this when the Bunior doctor a#ights u on such a set of resu#ts and says? @But I thought you said that com ensation never Efu##yE returns the H to norma# $ut this is what has ha ened hereT@H

0cenario 2 If a atient with chronic res iratory acidosis is intu$ated and venti#ated? the arteria# "O2 can $e ra id#y corrected G$y adBusting the venti#ator arametersH. This can occur <uite ra id#y? $ut the e#evated $icar$onate ta9es #onger #onger than this to fa##. The situation can $e more com #icated $ecause some such atients have additiona# factors which inhi$it the ready e7cretion of the e#evated $icar$onate? as occurs in E ost'hy erca nic meta$o#ic a#9a#osisE.H "eferences 1. Martinu T? Men&ies .? and .ia# (. R&"&valua'ion of acid"*as& +r&dic'ion rul&s in +a'i&n's wi'h chronic r&s+ira'ory acidosis. "an )es ir P 2::3 (e J 1:G%H 311'!. 4u$Med +0&& also 'h& accom+anyin) &di'orial-

Acid-Base 1hysiology !2% "espiratory Acidosis - Correction

!2%21 "estoration of AdeIuate Al/eolar ;entilation *he pC32 rapidly returns to nor,al 4ith restoration of adeIuate al/eolar /entilation Treatment usua##y needs to $e directed to correction of the rimary cause if this is ossi$#e. In severe cases? intu$ation and mechanica# venti#ation wi## $e necessary to restore a#veo#ar venti#ation. The atient can deteriorate fo##owing intu$ation and venti#ation which resu#ts in a ra id fa## in "O2 es ecia##y if the res iratory acidosis has $een resent for some time. This first $ecame a arent when mechanica# venti#ation was instituted in the chronica##y hy erca nic atients during the o#io e idemic in "o enhagen in a$out 18!:. )a id return of "O2 towards norma# was often accom anied $y severe hy otension. 4resuma$#y the sym athetic stimu#ation due to hy erca nia resu#ted in atients who were re#ative#y vasoconstricted and vo#ume de #eted. The acute dro in "O2 decreased the sym athetic stimu#ation and hy otension resu#ted. These atients re<uired significant f#uid #oading. GIncidenta##y? this e idemic and the e7 erience in venti#ating #arge num$ers of atients resu#ted in the $irth of =)es iratory 0nits> which gradua##y evo#ved into the Intensive "are 0nit of today. (ee 4onto idan H et a#. )es iratory Intensive "are. Anesthesio#ogy. 1822J 42D 8%'11% for more detai#sH In some other situations? it is refera$#e not to return arteria# "O2 to 4: mmHg with mechanica# venti#ation eg in atients with chronic "O2 retention from severe chronic o$structive airways disease. In some asthmatics resenting with severe $ronchos asm G$ut not res iratory arrestH? the ro$#ems associated with venti#ation in this situation may suggest that administration of high o7ygen concentrations to revent hy o7aemia and to#erance of significant hy erca nia G= ermissive hy erca nia>H is a $eneficia# strategy. The idea is to adBust venti#ation to a##ow ade<uate o7ygenation using #ower ressures which decrease the ris9 of $arotrauma.

!2%22 5hat is Gpost hypercapnic al&alosisH9 The correction of the e#evated $icar$onate Grena# com ensationH associated with chronic res iratory acidosis may not $e ra id. )eturn of #asma $icar$onate to norma# re<uires rena# e7cretion of the e7cess $icar$onate. The 9idney has a #arge ca acity to e7crete $icar$onate $ut in certain a$norma# conditions this ca acity is im aired and the $icar$onate #eve# remains e#evated. This ersistence of e#evated $icar$onate des ite reso#ution of the chronic res iratory acidosis is referred to $y some as = ost'hy erca nic a#9a#osis>. G(ee "ase History 13 in (ection 8.%H The factors causing maintenance of high $icar$onate #eve#s are the same as those invo#ved in maintenance of a meta$o#ic a#9a#osis. These factors are ch#oride de #etion? otassium de #etion? 1"6 vo#ume de #etion and reduction of /6). G(ee (ection 2.3 for discussionH. This situation occurs a#most e7c#usive#y in I"0 atients with chronic hy erca nia who are acute#y venti#ated $ac9 to a norma# arteria# "O2. "h#oride de #etion occurring during the hy erca nia is ro$a$#y the most im ortant factor invo#ved in the maintenance of the high $icar$onate #eve#s. The coe7istence of disorders which can cause a meta$o#ic a#9a#osis is a#so im ortant in many of these com #icated I"0 atients. The use of diuretics and #oss of acidic gastric secretions G$y nasogastric drainageH are usua##y the most im ortant factors. It shou#d $e noted that high nasogastric drainage des ite the use of H2'$#oc9ers such as ranitidine can sti## resu#t in significant ch#oride #osses which may not fu##y re #aced $y the I; f#uids given to the atients. These atients are often avid#y retaining sodium in the 9idneys and this is associated with high #eve#s of $icar$onate rea$sor tion. In genera#? $icar$onate #eve#s in this situation are in the 3: to 4! mmo#I# range.

Acid-Base 1hysiology !2' "espiratory Acidosis - Assess,ent The arteria# "O2 va#ue is used to <uantify the magnitude of the a#teration in a#veo#ar venti#ation Gassuming "O2 roduction is constant and ins ired "O2 is neg#igi$#eH. The arteria# "O2 a#one is not satisfactory for assessing the magnitude of a res iratory acidosis in some cases. In articu#ar? coe7isting meta$o#ic acid'$ase disorders cause com ensatory changes in "O2 and these must $e accounted for. *he best a/ailable Iuantitati/e inde6 of the ,agnitude of a respiratory acidosis is the difference bet4een the 'actual' pC32 and the 'e6pected' pC32 .efinition of Terms Actua# "O2 ' the measured va#ue o$tained from arteria# $#ood gas ana#ysis. 17 ected "O2 ' the va#ue of "O2 that we ca#cu#ate wou#d $e resent ta9ing into account the resence of any meta$o#ic acid'$ase disorder. If there is no meta$o#ic acid'$ase disorder then a "O2 of 4: mmHg is ta9en as the reference oint ' ie we wou#d use 4:mmHg as the e7 ected "O2

The reason we have to a##ow for a meta$o#ic acid'$ase disorder is that the "O2 va#ue changes from 4:mmHg due so#e#y to the $odyEs com ensatory venti#atory res onse to a meta$o#ic acidosis or a#9a#osis so Bust using a va#ue of 4:mmHg as norma# wou#d $e wrong and #ead us to incorrect conc#usions. Oith an acute meta$o#ic acidosis? the $ody res onds $y increasing a#veo#ar venti#ation. This res onse is com ensatory $ecause hy erventi#ation resu#ts in a decrease in arteria# "O2 which tends to return the arteria# H towards 2.4 +ar'ially correcting the acute deviation of #asma H from norma#. The va#ue of "O2 at ma7ima# com ensation can $e redicted using a sim #e $edside Eru#e of thum$E and this ca#cu#ated va#ue is the Ee7 ectedE "O2 which we use to com are with the Eactua#EGmeasuredH "O2 va#ue. If a meta$o#ic disorder is resent? we can ca#cu#ate Gusing a sim #e formu#aH a new reference va#ue of "O2 G the =e7 ected "O2>H that we wou#d e7 ect that wou#d $e resent with ty ica# #eve#s of res iratory com ensation. Oe use this ca#cu#ated Ee7 ected va#ueE to com are with the actua# measured va#ue. Fou wi## now note as a conse<uence of this a roach something that you might thin9 to $e rather oddD that is? it is ossi$#e for a atient to have a significant res iratory acidosis and yet $e hy oca nicU This seems counter'intuitive if you wrong#y considered that the terms Eres iratory acidosisE and Ehy erca niaE to $e synonomous. An 17am #e "onsider a atient with dia$etic 9etoacidosis who has a $icar$onate #eve# of 3 mmo#I# ' c#ear#y a severe meta$o#ic acidosis ' and a measured arteria# "O2 of 4:mmHg. 0sing the formu#a in (ection !.!? we ca#cu#ate Gand so redictH that if the meta$o#ic acidosis was the on#y acid'$ase disorder resent? thenD 4atientEs E17 ectedE "O2 L +G1.! 7 3H , 3 - L 2: mmHg. But the Eactua#E arteria# "O2 is 4:mmHg then? as this is much higher than the e7 ected va#ue? we wou#d decide that our origina# assum tion that this was the on#y acid'$ase disorder resent was wrong. In this e7am #e? a co'e7isting res iratory acidosis was resent. The H in this atient with a mi7ed acidosis wou#d $e much #ower than it wou#d $e if on#y the meta$o#ic acidosis was resent. As an e7ercise? use the Henderson'Hasse#$a#ch e<uation to ca#cu#ate the H for $oth va#ues of "O2H. If we Bust acce ted a "O2 of 4:mmHg as Enorma#E then we wou#d have missed this significant second acid'$ase disorder. Of course? the term Eres iratory acidosisE is not Bust words to e7 #ain a num$er ' there must $e some ro$#em resent which wou#d e7 #ain the re#ative hy oventi#ation in this atient. 6or res iratory disorders one tends to thin9 of the #ung first? $ut such disorders are fre<uent#y caused $y an a$norma#ity at another arts of the res iratory contro# athway Geg musc#e wea9ness? coma? airway o$structionH A fina# ointD There is a wides read use of the term Eres iratory a#9a#osisE to refer to the com ensatory

hy erventi#ation that occurs with a meta$o#ic acidosis $ut this term is <uite wrong in this situation. The terms EacidosisE C Ea#9a#osisE refer to rimary a$norma# rocesses G$y definitionH and shou#d never $e used to refer to com ensatory rocesses. G)efer to (ection 3.1 for definitions C discussionH.

Acid-Base 1hysiology !2( "espiratory Acidosis - 1re/ention (ome causes are not amena$#e to reventive measures. Monitoring of at'ris9 atients with ca nogra hy is a ro riate in some situations Geg in an Intensive "are 0nit? intrao erative#y and in the )ecovery )oomH and wi## a##ow ear#ier detection of a ro$#em. The end'tida# "O2 is ty ica##y #ower than the arteria# "O2 and the difference $etween these va#ues is an inde7 of the magnitude of the a#veo#ar dead s ace. (o if the end'tida# "O2 is e#evated then the arteria# "O2 is usua##y even more e#evated. Dirst Key Dact: 5atch for inadeIuate al/eolar /entilation Inade<uate a#veo#ar venti#ation is the under#ying ro$#em in near#y a## atients so any atient who cou#d have im aired venti#ation is at ris9 of deve#o ing res iratory acidosis. (o recognise these at'ris9 situations. 0econd Key Dact: Bi/e o6ygen to a/oid hypo6ae,ia Inade<uate venti#ation wi## a#so necessari#y affect arteria# o7ygenation so ste s to avoid? recognise andIor treat arteria# hy o7aemia are very im ortant. The sim #e measure of roviding su #ementa# o7ygen $y face mas9 to atients can often correct or revent hy o7aemia. (ome articu#ar medica# situations where revention can $e uti#ised areD Better airway care and attention to safe ositioning of cere$ra##y o$tunded atients Gie revent airway o$structionH. Increased care in the use of drugs Gsuch as "K( sedatives or o iate drugsH which can de ress venti#ation Increased attention to the care of atients at ris9 of as iration Geg unconscious atientsH 1nsuring ade<uate reversa# of neuromuscu#ar re#a7ants

Acid-Base 1hysiology #21 - $etabolic Acidosis : efinition

A ,etabolic acidosis is an abnor,al pri,ary process or condition leading to an increase in fi6ed acids in the blood2 This causes the arteria# #asma $icar$onate to fa## to a #eve# #ower than e7 ected. The fa## in #asma $icar$onate is due to titration of H"O3' $y H,. 0econdary or co,pensatory processes which cause a fa## in #asma $icar$onate shou#d not $e confused with rimary rocesses. A fa## in $icar$onate occurring in res onse to a chronic res iratory a#9a#osis shou#d $e referred to as a com ensatory res onse and never as a =secondary meta$o#ic acidosis>. This distinction $etween a rimary rocess and a secondary one has $een discussed revious#y in section 3.1.2 when discussing termino#ogy of acid'$ase disorders. It is of course ossi$#e for a atient to have a mi7ed acid'$ase disorder with $oth a meta$o#ic acidosis and a res iratory a#9a#osis. An e7am #e wou#d $e an adu#t resenting fo##owing a sa#icy#ate overdose. In this situation? direct stimu#ation of the res iratory centre occurs resu#ting in a res iratory a#9a#osis as we## as the sa#icy#ate're#ated meta$o#ic acidosis.

Acid-Base 1hysiology #22 $etabolic Acidosis - Causes

#2221 Classification by 1atho-physiological $echanis, A decrease in #asma $icar$onate can $e caused $y two mechanismsD A gain of strong acid A #oss of $ase A## causes of a meta$o#ic acidosis must wor9 $y these mechanisms. The gain of strong acid may $e endogenous Geg 9etoacids from #i id meta$o#ismH or e7ogenous GKH4"# infusionH. Bicar$onate #oss may occur via the $owe# Gdiarrhoea? sma## $owe# fistu#asH or via the 9idneys Gcar$onic anhydrase inhi$itors? rena# tu$u#ar acidosisH. #2222 Classification by Anion Bap An a#ternative to the a$ove? is to c#assify the causes of meta$o#ic acidosis into two grou s de ending on whether the anion ga is e#evated or norma#. These 2 grou s are referred to asD Ehigh anion ga meta$o#ic acidosisE Enorma# anion ga meta$o#ic acidosisE The term /hy+&rchlora&mic m&'a*olic acidosis/ is a#so often used for the /normal anion )a+/ )rou+ *u' 'h& '&rms ar& no' r&ally synonomous Gas discussed in section 3.4H. This is the mos' clinically us&ful way to c#assify meta$o#ic acidosis and it is used e7tensive#y when assessing meta$o#ic acidosis. The further su$'divisions within this c#assification are out#ined in the ta$#e $e#ow.

Causes of $etabolic Acidosis ?classified by Anion BapA A: High Anion-Bap Acidosis 12 Ketoacidosis .ia$etic 9etoacidosis A#coho#ic 9etoacidosis (tarvation 9etoacidosis 22 :actic Acidosis Ty e A *actic acidosis GIm aired erfusionH Ty e B *actic acidosis GIm aired car$ohydrate meta$o#ismH 32 "enal Dailure 0raemic acidosis Acidosis with acute rena# fai#ure !2 *o6ins 1thy#ene g#yco# Methano# (a#icy#ates

B : For,al Anion-Bap Acidosis ?or Hyperchlorae,ic acidosisA 12 "enal Causes )ena# tu$u#ar acidosis "ar$onic anhydrase inhi$itors 22 BI* Causes (evere diarrhoea 0retero'enterostomy or O$structed i#ea# conduit .rainage of ancreatic or $i#iary secretions (ma## $owe# fistu#a

32 3ther Causes

)ecovery from 9etoacidosis Addition of H"#? KH4"#

Acid-Base 1hysiology #23 $etabolic Acidosis : $aintenance The disorder is maintained as #ong as the rimary cause ersists. Additiona##y? in many cases the acid'$ase distur$ance tends to increase in severity whi#e the ro$#em causing it ersists though this is not a$so#ute. 6or e7am #e with dia$etic 9etoacidosis? the H wi## remain #ow as #ong as the ro$#em Gre#ative or a$so#ute insu#in deficiencyH ersists and the #eve#s of #asma 9eto'anions continue to rise. However? these increased #asma #eve#s of 9eto'anions e7ceed the rena# thresho#d and are e7creted in the urine. This wi## #imit the rate of rise as #ong as this additiona# mechanism of e7creting the acid anions ersists. This rena# e7cretion a#so means that once treatment commences? there is now a deficiency of 9eto' anions to $e meta$o#ised to regenerate $icar$onate and conse<uent#y there is can $e a significant de#ay in the return of the #asma H to norma#.

Acid-Base 1hysiology #2! $etabolic Acidosis - $etabolic Cffects

#2!21 Cardiorespiratory Cffects A meta$o#ic acidosis can cause significant hysio#ogica# effects? articu#ar#y affecting the res iratory and cardiovascu#ar systems. $a)or Cffects of a $etabolic Acidosis "espiratory Cffects Hy erventi#ation G 5ussmau# res irationsH ' this is the com ensatory res onse (hift of o7yhaemog#o$in dissociation curve GO."H to the right .ecreased 2?3 .4/ #eve#s in red ce##s Gshifting the O." $ac9 to the #eftH Cardio/ascular Cffects .e ression of myocardia# contracti#ity (ym athetic overactivity Ginc# tachycardia? vasoconstriction?decreased arrhythmia

thresho#dH )esistance to the effects of catecho#amines 4eri hera# arterio#ar vasodi#atation ;enoconstriction of eri hera# veins ;asoconstriction of u#monary arteries 1ffects of hy er9a#aemia on heart 3ther Cffects

Increased $one resor tion Gchronic acidosis on#yH (hift of 5, out of ce##s causing hy er9a#aemia

#2!22 0o,e Cffects ha/e 3pposing Actions2 The cardiac stimu#atory effects of sym athetic activity and re#ease of catecho#amines usua##y counteract the direct myocardia# de ression whi#e #asma H remains a$ove 2.2. At systemic H va#ues #ess than this? the direct de ression of contracti#ity usua##y redominates. The direct vasodi#atation is offset $y the indirect sym athetica##y mediated vasoconstriction and cardiac stimu#ation during a mi#d acidosis. The venoconstriction shifts $#ood centra##y and this causes u#monary congestion. 4u#monary artery ressure usua##y rises during acidosis. The shift of the o7ygen dissociation curve to the right due to the acidosis occurs ra id#y. After % hours of acidosis? the red ce## #eve#s of 2?3 .4/ have dec#ined enough to shift the o7ygen dissociation curve GO."H $ac9 to norma#. Acidosis is common#y said to cause hy er9a#aemia $y a shift of otassium out of ce##s. The effect on otassium #eve#s is e7treme#y varia$#e and indirect effects due to the ty e of acidosis resent are much more im ortant. 6or e7am #e hy er9a#aemia is due to rena# fai#ure in uraemic acidosis rather than the acidosis. (ignificant otassium #oss due to osmotic diuresis occurs during dia$etic 9etoacidosis and the otassium #eve# at resentation is varia$#e Gthough tota# $ody otassium stores are invaria$#y de #etedH. Treatment with f#uid and insu#in can cause a rom t and mar9ed fa## in #asma otassium. Hy o9a#aemia may then $e a ro$#em.

Acid-Base 1hysiology #2# $etabolic Acidosis - Co,pensation

#2#21 Hyper/entilation Co,pensation for a ,etabolic acidosis is hyper/entilation to decrease the arterial pC322 This hy erventi#ation was first descri$ed $y 5ussmau# in atients with dia$etic 9etoacidosis in 1324. The meta$o#ic acidosis is detected $y $oth the eri hera# and centra# chemorece tors and the

res iratory center is stimu#ated. The initia# stimu#ation of the centra# chemorece tors is due to sma## increases in $rain I(6 +H,-. The su$se<uent increase in venti#ation causes a fa## in arteria# "O2 which inhi$its the venti#atory res onse. $a6i,al co,pensation ta&es 12 to 2! hours The chemorece tor inhi$ition acts to #imit and de#ay the fu## venti#atory res onse unti# $icar$onate shifts have sta$i#ised across the $#ood $rain $arrier. The increase in venti#ation usua##y starts within minutes and is usua##y we## advanced at 2 hours of onset $ut ma7ima# com ensation may ta9e 12 to 24 hours to deve#o . This is =ma7ima#> com ensation rather than =fu##> com ensation as it does not return the e7trace##u#ar H to norma#. In situations where a meta$o#ic acidosis deve#o s ra id#y and is short'#ived there is usua##y #itt#e time for much com ensatory venti#atory res onse to occur. An e7am #e is the acute and sometimes severe #actic acidosis due to a ro#onged genera#ised convu#sionD this corrects due to ra id he atic u ta9e and meta$o#ism of the #actate fo##owing cessation of convu#sive muscu#ar activity? and hy erventi#ation due to the acidosis does not occur. *he e6pected pC32 at ,a6i,al co,pensation can be calculated fro, a si,ple for,ula The arteria# "O2 at ma7ima# com ensation has $een measured in many atients with a meta$o#ic acidosis. A consistent re#ationshi $etween $icar$onate #eve# and "O2 has $een found. It can $e estimated from the fo##owing e<uationD C6pected pC32 E 12# ?Actual <HC33> A = ( ,,Hg G0nitsD mmo#sI# for +H"O3-? and mmHg for "O2H. The #imiting va#ue of com ensation is the #owest #eve# to which the "O2 can fa## ' this is ty ica##y 3 to 1:mmHg? though #ower va#ues are occasiona##y seen. #2#22 An C6a,ple If the measured H"O3 is 12 mmo#sI#? then the e7 ected "O2 Gat ma7ima# com ensationH wou#d $eD G1.! 7 12H , 3 L 13 , 3 L 2% mmHg. If the actua# "O2 was within ,I' 2 mmHg of this Gand 12 to 24 hours have assed from onsetH then the res iratory com ensation has reached it ma7ima# va#ue Gand there wou#d $e no evidence of a rimary res iratory acid'$ase disorderH. If the actua# "O2 was say 4: mmHg in this situation? this is mar9ed#y different from the e7 ected va#ue of 2% mmHg and indicates the resence of <uite a mar9ed second rimary acid'$ase disorderD a res iratory acidosis. A ty ica# c#inica# situation may $e a dia$etic atient with 9etoacidosis and severe neumonia where the res iratory disease has resu#ted in the res iratory acid'$ase disorder. Kote that in this situation? a severe res iratory acidosis has $een diagnosed des ite the resence of a "O2 at the va#ue G4: mmHgH ty ica##y considered =norma#>U #2#23 $aintain hyper/entilation in /entilated patients If a atient with a severe meta$o#ic acidosis re<uires intu$ation and contro##ed venti#ation in hos ita#?

the acidosis can mar9ed#y worsen un#ess the hy erventi#ation is maintained. The venti#ation shou#d $e set to mimic the com ensatory hy erventi#ation to 9ee the "O2 #ow. If venti#ation is set to some standard va#ue and the "O2 a##owed to rise towards 4:mmHg? then this re resents the im osition of an acute res iratory acidosis and H can fa## ra id#yU "ar$on dio7ide crosses ce## mem$ranes readi#y so intrace##u#ar H fa##s ra id#y a#so? resu#ting in de ression of myocardia# contracti#ity? arrhythmias and a rise in intracrania# ressure. The atient may deteriorate soon after intu$ation and venti#ation and the medica# staff usua##y don>t a reciate how they have contri$uted to this outcome. Beware when initiating venti#ation in a atient with a significant acidosisD the situation descri$ed a$ove is not wide#y a reciated and the outcome cou#d $e fata#. (et the venti#ator settings so that the arteria# "O2 remains #ow. 0se the @e7 ected "O2@ formu#a as a guide to a suita$#e target #eve#.

Acid-Base 1hysiology #2% $etabolic Acidosis - Correction

#2%21 *reat,ent 1rinciples The most im ortant a roach to managing a meta$o#ic acidosis is to treat the under#ying disorder. Then with su ortive management? the $ody wi## correct the acid'$ase disorder. Accurate ana#ysis C diagnosis is essentia# to ensure the correct treatment is used. 6ortunate#y? in most cases this is not articu#ar#y difficu#t in rinci #e. )emem$er though that a atient with a severe meta$o#ic acidosis may $e very serious#y i## and even with o tima# management the atient may not survive. The 1"*( A roach to Management of Meta$o#ic Acidosis

1. C,ergencyD 1mergency management of immediate#y #ife'threatening conditions a#ways has the highest riority. 6or e7am #e? intu$ation and venti#ation for airway or venti#atory contro#J cardio u#monary resuscitationJ severe hy er9a#aemia 2. CauseD Treat the under#ying disorder as the rimary thera eutic goa#. "onse<uent#y? accurate diagnosis of the cause of the meta$o#ic acidosis is very im ortant. In some cases Ge.g. methano# to7icityH there may $e a su$stantia# de#ay $ecome the diagnosis can $e confirmed so management must $e $ased on suggestive evidence otherwise it wi## $e too #ate. 3. :osses )e #ace #osses Ge.g. of f#uids and e#ectro#ytesH where a ro riate. Other su ortive care Go7ygen administrationH is usefu#. In most cases? I; sodium $icar$onate is KOT necessary? KOT he# fu#? and may even $e harmfu# so is not genera##y recommended. 4. 0pecifics There are often s ecific ro$#ems or com #ications associated with s ecific causes or s ecific cases which re<uire s ecific management. 6or e7am #eD 1thano# $#oc9ing treatment with methano# ingestionJ rha$domyo#ysis re<uires management for reventing

acute rena# fai#ureJ haemodia#ysis can remove some to7ins.

(ome e7am #es of s ecific treatments for under#ying disordersD 6#uid? insu#in and e#ectro#yte re #acement is necessary for dia$etic 9etoacidosis Administration of $icar$onate andIor dia#ysis may $e re<uired for acidosis associated with rena# fai#ure )estoration of an ade<uate intravascu#ar vo#ume and eri hera# erfusion is necessary in #actic acidosis. The detai#ed treatment of the various s ecific disorders is not considered here? $ut the im ortant message is that the treatment of each under#ying disorder differs so an accurate diagnosis is essentia# for se#ection of correct treatment. Treatment of the under#ying disorder wi## resu#t in correction of the meta$o#ic acidosis Gie the $icar$onate #eve# wi## return to norma#H. #2%22 "epair of the Bicarbonate eficit Correction in/ol/es repair of the bicarbonate deficit in the body2 (o where does this $icar$onate come fromT There are three usua# sourcesD 12 Kidney: "enal generation of ne4 bicarbonate This usua##y occurs as a conse<uence of an increase in ammonium e7cretion. 22 :i/er: Hepatic ,etabolis, of acid anions to produce bicarbonate The norma# #iver has a #arge ca acity to meta$o#ise many organic acid anions Geg #actate? 9etoanionsH with the resu#t that $icar$onate is regenerated in the #iver. In severe 9etoacidosis there is often a #arge #oss of 9etoanions due to the hy erg#ycaemia induced osmotic diuresis. This #eaves a shortfa## of 9etoanions to $e used to regenerate $icar$onate as a conse<uence of their meta$o#ism in the 9idney. 32 C6ogenous Ad,inistration of sodiu, bicarbonate This is the time honoured method to Es eed u E the return of $icar$onate #eve#s to norma#. Indeed? this may $e usefu# in minera# acidosis Ghy erch#oraemic meta$o#ic acidosisH where there are no endogenous acid anions which can $e meta$o#ised $y the #iver. However? in most other cases of meta$o#ic acidosis this administration is either not he# fu# or may $e disadvantageous. 0odiu, bicarbonate solutions should F3* be gi/en on a routine basis no ,atter 4hat the arterial pH is2 6o##owing the a$ove stricture in c#inica# ractice may $e very difficu#t. A severe #actic acidosis may $e associated with a very high ris9 of death no matter how carefu# the management. If the atient dies there are often those who wi## criticise. .eve#o ment of Ginstitutiona#H evidence'$ased rotoco#s or guide#ines can $e usefu# to aid in se#ection of agreed treatments. Administration of sodium $icar$onate may $e usefu# in treatment of s&v&r& hy er9a#aemia. (uch hy er9a#aemia may $e immediate#y #ife'threatening. "a#cium g#uconate wi## $e more ra id#y rotective against serious arrhythmias. It shou#d $e noted that correction of a meta$o#ic acidosis does not necessari#y invo#ve r&nal e7cretion of acid or r&nal regeneration of $icar$onate $ecause of the ro#e of he atic meta$o#ism of some anions. 6or e7am #e? in #actic acidosis and 9etoacidosis? treatment resu#ts in significant correction $ecause of

redominant#y he atic meta$o#ism of the acid anions to regenerate $icar$onate. If acid anions have $een #ost in the urine? then rena# regeneration of $icar$onate is very im ortant for correction of the acid'$ase disorder. In a severe 9etoacidosis? there is a #arge #oss of 9etoanions in the urine. Ohen the disorder is treated Gf#uids C insu#inH there is a re#ative deficiency of acid anions which can $e meta$o#ised in the #iver with regeneration of $icar$onate. "onse<uent#y? it is common to find that treatment resu#ts in a ra id correction Gfew hoursH of the hy erg#ycaemia and the hy ovo#aemia $ut the acidosis may ta9e over 24 hours to return to norma#. This is $ecause EnewE $icar$onate has to $e regenerated $y the 9idneys and this ta9es #onger to correct the $icar$onate deficit. There has $een a ast tendency to s eed u the rocess $y administration of intravenousKaH"O3 so#ution $ut this is not necessary and has not $een shown to have any advantage. The #iver has severa# im ortant ro#es in acid'$ase meta$o#ism and its im ortance is genera##y understated in te7ts. Meta$o#ism of other $icar$onate recursors Geg citrate from $#ood transfusion? acetate from E4#asma#yte 143E so#utionH a#so occurs in the #iver. The #iver is the maBor site for the synthesis of #asma roteins and this is very significant for acid'$ase hysio#ogy Gsee a#so (ection 1:.%H. '''' '''' KoteD E4#asma#yte 143E is an I; f#uid that is avai#a$#e in some countries. It is used as an 1"6 re #acement f#uid. It is simi#ar to HartmannEs so#ution in that it contains a $icar$onate recursor Gacetate in 4#asma#yteJ #actate in HartmannsH. .ifferences from Hartmanns are that 4#asma#yte has a +Ka,- of 14:mmo#I# and contains Mg,, instead of "a,,.

Acid-Base 1hysiology #2' $etabolic Acidosis - Assess,ent

Main As ects of Assessment The three as ects of assessment of this acid'$ase disorder areD 6irstD )ecognise its resence (econdD .iagnose the cause 6ina##yD Measure the severity #2'21 In/estigations A meta$o#ic acidosis is often strong#y sus ected $ecause of the c#inica# resentation of the atient Geg dia$etes? rena# fai#ure? severe diarrhoeaH. Three c#ues from a ty ica# hos ita# automated $iochemica# rofi#e areD *ow =$icar$onate> Gor #ow =tota# "O2>H High ch#oride High anion ga

5hat is Gtotal C32H9 This is often re orted as art of the #a$oratory>s automated $iochemica# rofi#e on a venous $#ood sam #e. It re resents the tota# concentration of a## the s ecies in the sam #e which can $e converted to car$on dio7ide gas. This isD *otal C32 E <HC33> = <H2C33> = <carba,ino C32> = <dissol/ed C32> A art from $icar$onate? a## the other s ecies are resent in on#y sma## concentrations. The usefu#ness of the Etota# "O2E is as an estimate of the arteria# $icar$onate C which can $e o$tained without co##ecting an arteria# sam #e. The va#ue wi## usua##y $e severa# mmo#sI#iter higher than the actua# arteria# va#ue due to the inc#usion of car$amino C disso#ved "O2 and $ecause of the higher "O2 content of venous $#ood. Arteria# $#ood gases are im ortant for diagnosis $ut shou#d a#ways $e inter reted in conBunction with the c#inica# detai#s. In addition to arteria# $#ood gases? some other investigations usefu# for indicating a meta$o#ic acidosis and for differentiating $etween the various maBor causes areD 0rine tests for g#ucose and 9etones 1#ectro#ytes Ginc# ch#oride? anion ga ? =$icar$onate>H 4#asma g#ucose 0rea and creatinine *actate

#2'22 7se of Ancillary Indices There are severa# indices Gwhich can $e ca#cu#ated from atho#ogy resu#tsH which may $e usefu# in assessing a meta$o#ic acidosisD Anion ga .e#ta ratio 0rinary anion ga Osmo#ar ga

The anion ga is usefu# in a cou #e of waysD Alerting "ole: An e#evated anion ga Ges if A/ X 2: mmo#I#H wi## a#ert the c#inician to the resence of a high anion ga meta$o#ic acidosis. This can $e e7treme#y usefu# in sorting out com #icated mi7ed disorders. Classification "ole: It is used to divide meta$o#ic acidosis into two maBor su$grou s. The ne7t ste then is to consider either the 4 maBor categories of high anion ga acidosis G9etoacidosis? #actic acidosis? uraemic acidosis? acidosis due to7insH or the 2 maBor categories of norma# anion ga acidosis Grena# grou ? /IT grou H. History and a few ertinent investigations wi## usua##y distinguish the cause. The de#ta ratio can $e usefu# articu#ar#y in the difficu#t situation of a meta$o#ic acidosis due to two rocesses where one e#evates the anion ga and the other does not. An e7am #e is the hy erch#oraemic norma# anion ga acidosis which may deve#o in atients who have dia$etic 9etoacidosis Ghigh anion ga H. The ratio gives an indication of the re#ative contri$ution of the two rocesses. 0nfortunate#y? its inter retation is #imited somewhat $y the wide error margin in this derived varia$#e.

The urinary anion ga and the osmo#ar ga may $e usefu# in certain atients with acidosis.

Acid-Base 1hysiology #2( $etabolic Acidosis - 1re/ention 4revention of the rimary disease or $etter management may $e an o tion in some cases. A articu#ar e7am #e wou#d $e the revention of e isodes of dia$etic 9etoacidosis in insu#in'de endent dia$etic atients. Most adu#t I"0s are fami#iar with some usua##y teenage or young adu#t atients who are admitted mu#ti #e times with acute .5A due to oor com #iance with insu#in administration. (ome of these ro$#ems may res ond to $etter dia$etic education and counse##ing. Better security of drugs may revent accidenta# ingestion Geg of sa#icy#atesH $y young chi#dren.

0u,,ary of i,portant aspects of Chapter # : $etabolic Acidosis Meta$o#ic acidosis is an a$norma# rimary rocess causing an increase in fi7ed acids in the $#ood. Buffering causes the #asma $icar$onate to fa## to a #eve# #ower than e7 ected and tends to cause an acidaemia. The decrease in $icar$onate #eve# occurs either $ecause of a gain of fi7ed acid or a #oss of $ase. A more c#inica##y usefu# c#assification is to divide meta$o#ic acidosis into 2 grou sD High anion ga acidosis and Korma# anion ga acidosis. Im ortant meta$o#ic effects inc#ude hy erventi#ation? sym athetic stimu#ation? decreased arrhythmia thresho#d? direct myocardia# de ression? eri hera# arterio#ar vasodi#atation? eri hera# venoconstriction and u#monary vasoconstriction. The eri hera# chemorece tors sense the acidaemia and stimu#ate the res iratory centre. The resu#ting hy erventi#ation causes a com ensatory decrease in arteria# "O2 which art#y returns the arteria# H towards norma#. (uch com ensation rare#y if ever returns the H to norma#. The most im ortant as ect of management invo#ves correction of the rimary disorder if ossi$#e. .ifferent causes of acidosis have some different s ecific management rinci #es. The anion ga C the de#ta ratio may $e usefu# aids in assessment of meta$o#ic acidosis.

Acid-Base 1hysiology %21 - "espiratory Al&alosis : efinition

%2121 efinition A respiratory al&alosis is a pri,ary acid-base disorder in 4hich arterial pC32 falls to a le/el lo4er than e6pected2 If there was no com ensation and no other acid'$ase disorder resent? then this must necessari#y #ead to an increase in arteria# H. If there is no meta$o#ic acid'$ase disorder resent? then the actua# measured arteria# "O2 is com ared against the standard reference va#ue of 4:mmHg. If there is a co'e7isting meta$o#ic acidosis? then the e7 ected "O2 used for com arison is not 4:mmHg $ut a ca#cu#ated va#ue which adBusts for the amount of change in arteria# "O2 which occurs due to res iratory com ensation. GThe formu#a used is discussed in (ection 8.3H. This decrease in "O2 that occurs as com ensation for a meta$o#ic acidosis is not a res iratory a#9a#osis as it is not a rimary rocess. 6or this reason? hy oca nia is not synonymous with res iratory a#9a#osis. %2122 1rocesses 8 Interpretation Key fact: A respiratory al&alosis is A:5AO0 due to increased alveolar /entilation Kow? consider the fo##owing? which are a#so correctD A rimary increase in tota# Gor minuteH venti#ation does KOT a#ways resu#t in a res iratory a#9a#osis? andD Increased a#veo#ar venti#ation wi## KOT a#ways resu#t in a res iratory a#9a#osis This may seem a $it confused $ut consider the fo##owingD DirstlyL note the difference bet4een an increased ,inute /entilation and an increased al/eolar /entilation2 Minute Gor tota#H venti#ation is the roduct of res iratory rate and tida# vo#ume. A#veo#ar venti#ation can $e defined as the roduct of res iratory rate and Gtida# vo#ume minus hysio#ogica# dead s ace vo#umeH. If? for e7am #e? a erson has a #arge increase in dead s ace then minute venti#ation can $e much increased $ut a#veo#ar venti#ation cou#d remain unchanged. It is on#y the a#veo#ar venti#ation that resu#ts in e7cretion of car$on dio7ide. Any increased venti#ation of dead s ace is Ewasted venti#ationE. The c#inica# re#evance is that some atients may $e c#inica##y hy erventi#ating or have o$vious res iratory distress $ut yet their arteria# "O2 wi## not $e decreased. 0econdlyL hypocapnia does not necessarily ,ean a respiratory al&alosis2 The two ossi$#e situations areD hy res hy res oca nia Gor increased a#veo#ar venti#ationH occurring as a rimary rocess 'this is a iratory a#9a#osis? orD oca nia occurring as a com ensatory res onse to a meta$o#ic acidosis 'this com ensatory onse is secondary so is not a res iratory a#9a#osis.

The ractica# ointD If you #oo9 at a set of $#ood gas resu#ts and find a #ow arteria# "O2 Ghy oca niaHD this indicates increased a#veo#ar venti#ation $ut this may $e a com ensatory res onse to a meta$o#ic acidosis and hy oca nia from this cause is not a rimary rocess? and so $y definition is not a res iratory a#9a#osis. This may sound a $it of a technica# <ui$$#e $ut there are adverse effects of the a#ternative ractice. 6or e7am #e? if a## com ensatory res onses were considered an acidosis or an a#9a#osis then a## acid'$ase disorders wou#d tend to occur in airs Gsuch as a Emeta$o#ic acidosisE and a Eres iratory a#9a#osisEH. It wou#d a#so mean that c#inica##y significant diagnoses may $e missed in atients with some mi7ed acid' $ase disorders. 6or e7am #e? a atient with $oth a meta$o#ic acidosis and a res iratory acidosis cou#d $e inter reted as a having a meta$o#ic acidosis a#one C the res iratory ro$#em wou#d $e missed and #ead to <uite ina ro riate treatment Geg #arge doses of sodium $icar$onateH.

Acid-Base 1hysiology %22 "espiratory Al&alosis - Causes

Hyper/entilation is the ,echanis, in A:: cases Hy erventi#ation Gie increased a#veo#ar venti#ationH is the mechanism res onsi$#e for the #owered arteria# "O2 in A** cases of res iratory a#9a#osis. This #ow arteria# "O2 wi## $e sensed $y the centra# and eri hera# chemorece tors and the hy erventi#ation wi## $e inhi$ited un#ess the atient>s venti#ation is contro##ed. Causes of "espiratory Al&alosis 12 Central Causes ?direct action /ia respiratory centreA Head InBury (tro9e An7iety'hy erventi#ation syndrome G sychogenicH Other Esu ra'tentoria#E causes G ain? fear? stress? vo#untaryH ;arious drugs Geg ana#e tics? ro anidid? sa#icy#ate into7icationH ;arious endogenous com ounds Geg rogesterone during regnancy? cyto9ines during se sis? to7ins in atients with chronic #iver diseaseH

22 Hypo6ae,ia ?act /ia peripheral che,oreceptorsA )es iratory stimu#ation via eri hera# chemorece tors 32 1ul,onary Causes ?act /ia intrapul,onary receptorsA

4u#monary 1m$o#ism 4neumonia Asthma 4u#monary oedema Ga## ty esH

!2 Iatrogenic ?act directly on /entilationA 17cessive contro##ed venti#ation

Can a decreased C32 production cause respiratory al&alosis9 Hy erventi#ation is the mechanism in a## of the situations in the a$ove #ist C indeed in a## cases. Theoretica##y? a decreased car$on dio7ide roduction cou#d resu#t in res iratory a#9a#osis if a#veo#ar venti#ation remained fi7ed. But this wou#d not occur in a norma# erson $ecause any dro in arteria# "O2 wou#d ref#e7#y cause a decreased venti#ation Gvia chemorece tor inhi$itory in ut into the res iratory centreH. A$out the on#y situation where may$e a decrease in "O2 roduction cou#d $e the mechanism of res iratory a#9a#osis wou#d $e in an intu$ated atient on fi7ed venti#ation during Anaesthesia or in Intensive "are 0nit and where the "O2 roduction was #ow due to hy othermia and decreased meta$o#ic rate. However? even in such a circumstance? this mechanism is usua##y referred to as Ee7cessive contro##ed venti#ationE Gwhich it is re#ative to the amount of "O2 roductionH. (o the answer to the <uestion osed must $e no. Misce##aneous Kotes on "auses Hy erventi#ation due to res iratory centre stimu#ation is a feature of sa#icy#ate to7icity? es ecia##y in adu#ts? and resu#ts in a mi7ed disorder Gmeta$o#ic acidosis and res iratory a#9a#osisH. 4ro anidid was once used as an anaesthetic induction agent ' it caused rominent hy erventi#ation. A res iratory a#9a#osis is the commonest acid'$ase disorder found in atients with chronic #iver disease. Hy erventi#ation syndrome re#ated to an7iety can cause a#9a#osis severe enough to cause car o eda# s asm. A mi#d fair#y we## com ensated res iratory a#9a#osis is the usua# finding in regnancy. Any condition which decreases u#monary com #iance causes a sensation of dys noea. )es iratory a#9a#osis is common#y found in atients with asthma? neumonia C u#monary em$o#ism.

Acid-Base 1hysiology %23 "espiratory Al&alosis - $aintenance

*he al&alosis persists as long as the initiating disorder is acting The a#9a#osis ersists as #ong as the initiating disorder ersists un#ess some other disorder or com #ication causing im airment of the hy erventi#ation intervenes. 6or e7am #e? a hy erventi#ating head inBury atient may deve#o acute neurogenic u#monary oedema and this com #ication wou#d tend to cause the arteria# "O2 to rise. This is different to the situation with a meta$o#ic a#9a#osis where maintenance of the disorder re<uires an a$norma#ity to maintain it as we## as the ro$#em which initiated it. 3nly one respiratory acid-base disorder can be present at one ti,e2 A atient cannot have $oth a res iratory a#9a#osis and a res iratory acidosis. There may of course $e mu#ti #e factors acting to a#ter an individua#Es a#veo#ar venti#ation $ut each of these various factors are not considered se arate res iratory acid'$ase disorders. 1ssentia##y this is $ecause a erson cannot $e $oth hy erventi#ating and hy oventi#ating at the same time. 0sing the a$ove hy erventi#ating head inBured atient e7am #eD This atient has a neurogenic cause for hy erventi#ation and if the arteria# "O2 is #owered? then she is said to have a res iratory a#9a#osis. If neurogenic u#monary oedema deve#o s su$se<uent#y and decreases a#veo#ar venti#ation to norma# and returns arteria# "O2 to 4:mmHg Gassuming no meta$o#ic acid'$ase disorders are resentH? then she now has no res iratory acid'$ase disorder. $ore than one ,etabolic acid-base disorder can be present at the one ti,e The a$ove res iratory situation is different to that occurring with a meta$o#ic disorder. A atient can have a #actic acidosis and then deve#o a meta$o#ic a#9a#osis Geg due to vomitingH and end u with a H"O3 #eve# C H which are norma#. This is ossi$#e if the acidosis and the a#9a#osis e7act#y $a#ance each other. This atient is then said to have $oth a meta$o#ic acidosis AK. a meta$o#ic a#9a#osis. It is thera eutica##y usefu# to 9now this rather then to say there is no acid'$ase disorder resent.

Acid-Base 1hysiology %2! "espiratory Al&alosis - $etabolic Cffects +I,portant Fote: The distinction $etween hy oca nia C res iratory a#9a#osis has $een made in (ection %.1. The meta$o#ic effects mentioned here are those of hy oca nia rather than res iratory a#9a#osis er se.Cffects of Hypocapnia

12 Feurological effects Increased neuromuscu#ar irrita$i#ity Geg araesthesias such as circumora# ting#ing C num$nessJ car o eda# s asmH .ecreased intracrania# ressure Gsecondary to cere$ra# vasoconstrictionH Increased cere$ra# e7cita$i#ity associated with the com$ination of hy oca nia C use of enf#urane Inhi$ition of res iratory drive via the centra# C eri hera# chemorece tors 22 Cardio/ascular effects "ere$ra# vasoconstriction Gcausing decreased cere$ra# $#ood f#owH +short' term on#y as ada tation occurs within 4 to % hours "ardiac arrhythmias .ecreased myocardia# contracti#ity 32 3ther effects (hift of the haemog#o$in o7ygen dissociation curve to the #eft Gim airing eri hera# o7ygen un#oadingH (#ight fa## in #asma +5,F3*C0 Most of these effects decrease with time. A chronic hy oca nia is associated with few sym toms $ecause of the com ensation that occurs. The under#ying cause wi## a#so have effects other than hy erventi#ation C these may dominate the c#inica# icture ' for e7am #e? the adverse effects of hy o7aemia

*he reduction in cerebral blood flo4 is ,ar&ed2 "ere$ra# $#ood f#ow G"B6H decreases <uite mar9ed#y with hy oca niaD a decrease of 4Q er mmHg reduction in "O2. 6or e7am #e? an acute dro in "O2 from 4: down to 2!mmHg wi## decrease "B6 $y a$out %:Q. In awa9e su$Bects this can cause #ight'headedness and even confusion. 4atients with sic9#e ce## anaemia may $e very adverse#y affected $y the decrease in cere$ra# $#ood f#ow Geg deve#o ment of cere$ra# throm$osisH.

Hypocapnia causes neuro,uscular irritability2 The atient may com #ain of araesthesias Ginc# circumora# num$ness C ting#ingH. Tetany may a#so occur and may manifest as car o eda# s asm. This is a we## 9nown ro$#em in atients with an7iety' hy erventi#ation syndrome and the sym toms can $e re#ieved $y re$reathing into a a er $ag Gwith recautions to avoid hy o7aemia of courseH. 4articu#ar 1ffects of Hy oca nia in Anaesthetised 4atients .ecreased cere$ra# $#ood f#ow G"B6H +This effect may $e $eneficia#.e ression of myocardia# contracti#ity "ardiac arrhythmias "ere$ra# e7cita$i#ity may occur in association with high #eve#s of enf#urane (hift of the o7ygen dissociation curve to the #eft Gim airing o7ygen un#oading eri hera##yH 6a## in #asma otassium Gusua##y s#ight on#yH O$#igatory hy oventi#ation at end of the o eration GThis is e7acer$ated $y residua# drug effects as we##H

It has $een argued that these adverse effects of hy oca nia are significant enough that the Anaesthetist shou#d aim to maintain normoca nia throughout the duration of anaesthesia in most cases. There are some situations where intrao erative hy erventi#ation and hy oca nia is s ecifica##y usefu# eg to acute#y reduce increased intracrania# ressure GI"4H in neuroanaesthesia. In this situation? a thera eutic res iratory a#9a#osis is usefu#. These effects are short'#ived Ghours rather then daysH as $icar$onate e<ui#i$ration occurs across the $#ood'$rain $arrier and "B6 and I"4 returns to norma#. This is now a dangerous situation as any increase in "O2 towards norma# wi## cause a rise in "B6. Hy erventi#ation to reduce I"4 is usefu# $ecause of its ra id onset $ut as the effect on#y #asts for 4 to % hours. The main ro#e of acute thera eutic hy oca nia is to rovide acute reduction in I"4 so that surgica# treatment of intracere$ra# mass #esions can $e faci#itated. One argument for routine intrao erative use of hy oca nia is to use the induced cere$ra# vasoconstriction to counteract the cere$ra# vasodi#ator effects of vo#ati#e anaesthetic agents. A articu#ar disadvantage of this is the hy oventi#ation at the end of the o eration which de#ays recovery from genera# anaesthesia. *he clinical picture is often do,inated by the signs and sy,pto,s of the underlying disorder2

Acid-Base 1hysiology %2# "espiratory Al&alosis - Co,pensation

*he co,pensatory response is a fall in bicarbonate le/el2 As can $e seen $y ins ection of the Henderson'Hasse#$a#ch e<uation G$e#owH? a decreased +H"O3'wi## counteract the effect of a decreased "O2 on the H. Mathematica##y? it returns the va#ue of the +H"O3-I :.:3 "O2 ratio towards norma#. pH E pKa = log M?<HC33>@ -2-3 pC32 P Key points regarding co,pensation in respiratory al&alosis: 4hysicochemica# effectD Initia##y there is an immediate hysicochemica# change which #owers the $icar$onate s#ight#y. )o#e of 5idneyD The effector organ for com ensation is the 9idney. (#ow )es onseD The rena# res onse has a s#ow onset and the ma7ima# res onse ta9es 2 to 3 days to $e achieved. OutcomeD The dro in $icar$onate resu#ts in the e7trace##u#ar H returning on#y +ar'iallytowards its norma# va#ue. "om ensation in an A"0T1 )es iratory A#9a#osis $echanis,:"hanges in the hysicochemica# e<ui#i$rium occur due to the #owered "O2 and this resu#ts in a s#ight decrease in H"O3'. There is insufficient time for the 9idneys to res ond so this is the on#y change in an acute res iratory a#9a#osis. The $uffering is redominant#y $y rotein and occurs intrace##u#ar#yJ this a#ters the e<ui#i$rium osition of the $icar$onate system. $agnitude: There is a dro in H"O3' $y 2 mmo#I# for every 1:mmHg decrease in "O2 from the reference va#ue of 4:mmHg. :i,it: The #ower #imit of Ecom ensationE for this rocess is 13mmo#I# ' so $icar$onate #eve#s $e#ow that in an acute res iratory a#9a#osis indicate a co'e7isting meta$o#ic acidosis. GA#ternative#y? their may $e some rena# com ensation if the a#9a#osis has $een resent #onger than rea#ised.H "om ensation in a "H)OKI" )es iratory A#9a#osis $echanis,: )ena# #oss of $icar$onate causes a further fa## in #asma $icar$onate Gin addition to the acute dro due to the hysicochemica# effect and rotein $ufferingH. $agnitude: (tudies have shown an average ! mmo#I# decrease in +H"O3'- er 1:mmHg decrease in "O2 from the reference va#ue of 4:mmHg. This ma7ima# res onse ta9es 2 to 3 days to reach. :i,it: The #imit of com ensation is a +H"O3'- of 12 to 1! mmo#I#.

Acid-Base 1hysiology %2% "espiratory Al&alosis - Correction Hy o7aemia is an im ortant cause of res iratory stimu#ation and conse<uent res iratory a#9a#osis. The decrease in arteria# "O2 inhi$its the rise in venti#ation. The hy oca nic inhi$ition of venti#ation Gacting via the centra# chemorece torsH may #eave the atient with an im aired state of tissue o7ygen de#ivery. Ada tation occurs over a few days and the centra# chemorece tor inhi$ition is #essened and venti#ation increases. *he nu,ber one priority is correction of any co-e6isting hypo6ae,ia "orrection of hy o7aemia is the most urgent concern and is many times more im ortant than correction of the res iratory a#9a#osis. Administration of o7ygen in sufficient concentrations and sufficient amounts is essentia#. Attention to other as ects necessary to im rove o7ygen de#ivery and minimise tissue o7ygen consum tion is im ortant. As regards the al&alosis: In ,ost cases correction of the underlying disorder 4ill resol/e the proble,2 In some cases this is easy Geg adBustment of venti#ator settings? re$reathing via a a er $ag with sychogenic hy erventi#ationH $ut in some cases it is a s#ow rocess.

Acid-Base 1hysiology %2' "espiratory Al&alosis - Assess,ent

*he se/erity of a respiratory al&alosis is deter,ined by the difference bet4een the actual pC3 2 and the e6pected pC322 The actua# "O2 is the measured va#ue from the $#ood gas resu#ts. If no meta$o#ic acid'$ase disorder is resent? a "O2 of 4: mmHg is ta9en as the reference oint Gie the e7 ected "O2 H. If a meta$o#ic disorder is resent? res iratory com ensation wi## roduce a new reference va#ue of "O2 for com arison. The e7 ected "O2 can $e estimated using the formu#a in (ection !.! Gfor meta$o#ic acidosisH or (ection 2.! Gfor meta$o#ic a#9a#osisH.

Acid-Base 1hysiology %2( "espiratory Al&alosis - 1re/ention Hy erventi#ation of the anaesthetised atient is common and reventa$#e. Monitoring $y ca nogra hy a##ows ear#y recognition and correction. In maBor o erations? seria# arteria# gases for assessment of o7ygenation and venti#ation is a ro riate es ecia##y as the si&e of the endtida#'arteria# "O2 gradient can $e determined and this is usefu# for determining venti#ation settings $etween $#ood'gas ana#yses.

0u,,ary of i,portant aspects of Chapter 0i6: "espiratory Al&alosis )es iratory a#9a#osis is a rimary acid'$ase disorder in which the "O2 fa##s to a #eve# #ower than e7 ected. A## cases are due to increased a#veo#ar venti#ation The com ensatory res onse is rena# #oss of $icar$onate which causes a fa## in #asma $icar$onate The fa## in $icar$onate can $e redicted from a sim #e formu#a Meta$o#ic effects inc#ude decreased cere$ra# $#ood f#ow? decrease in myocardia# contracti#ity and a shift of the o7ygen dissociation curve to the #eft Hy erventi#ation is used to acute#y decrease intracrania# ressure as the onset is ra id. The effect on "B6 is time'#imited as e<ui#i$ration of $icar$onate across the $#ood'$rain $arrier occurs over 4 to % hours and "B6 and I"4 return towards norma#.

Acid-Base 1hysiology '21 $etabolic Al&alosis: efinition

A 1ri,ary 1rocess A meta$o#ic a#9a#osis is a rimary acid'$ase disorder which causes the #asma $icar$onate to rise to a #eve# higher than e7 ected. The severity of a meta$o#ic a#9a#osis is determined $y the difference $etween the actua# +H"O3- and the e7 ected +H"O3-. Fot a Co,pensatory 1rocess (econdary or com ensatory rocesses which cause an e#evation in #asma $icar$onate shou#d not $e confused with the rimary rocesses. An e#evation in $icar$onate occurring in res onse to a chronic res iratory acidosis shou#d $e referred to as a Ecom ensatory res onseE and never as a =secondary meta$o#ic a#9a#osis>. Fou shou#d $e aware that many artic#es Ges in the surgica# #iteratureH wi## refer to a Ecom ensated meta$o#ic a#9a#osisE as a Emeta$o#ic a#9a#osis with a GsecondaryH res iratory acidosisE. This is wrong as the hy oventi#ation is a com ensatory rocess and does not indicate any rimary res iratory ro$#em.

Another im #ication of the incorrect termino#ogy is that acid'$ase disorders a#ways occur in airs and this is ridicu#ous and of no he# in atient management. The termino#ogy of acid'$ase disorders is covered in (ection 3.1. om Acid-Base 1hysiology '22 $etabolic Al&alosis - Causes

'2221 *he &idney rapidly e6cretes bicarbonate if the plas,a le/el is ele/ated Ohenever the #asma $icar$onate rises a$ove 24mmo#sI#? $icar$onate is e7creted $y the 9idney. This res onse is reasona$#y rom t and effective so a meta$o#ic a#9a#osis wi## $e ra id#y corrected. If you infuse say 1::m#s of 3.4Q sodium $icar$onate into a hea#thy erson with norma# rena# function? the rise in #asma $icar$onate is $rief $ecause of rom t $icar$onaturia. This is one way to a#9a#inise the urine. An infusion of a#9a#i causes on#y a $rief meta$o#ic a#9a#osis due to this ra id rena# e7cretion. This a$i#ity of the 9idney to ra id#y e7crete $icar$onate if its #eve# is high is in com #ete contrast to its owerfu# a$i#ity to rea$sor$ a## of the fi#tered #oad if #asma +H"O3- is #ow or norma#. A usefu# ana#ogy here is to fi##ing a $uc9et. Ko water is #ost unti# the $uc9et is fu##? $ut after that? a## e7tra water is #ost. This is sometimes ca##ed a waterfa## effect. '2222 Ho4 can a ,etabolic al&alosis e/er persist9 The ersistence of a meta$o#ic a#9a#osis re<uires an additional process which acts to im air rena# $icar$onate e7cretion. In our ana#ogy? this wou#d $e something that increased the height of wa##s of the $uc9et. This means that two issues must to $e considered when ana#ysing a meta$o#ic a#9a#osisD InitiationD Ohat rocess is initiating the disorderT $aintenanceD Ohat rocess is maintaining the disorderT Ohen discussing the EcauseE of a meta$o#ic a#9a#osis? note this term is used in severa# ways. 6or e7am #e it may $e used to descri$e the initiating rocess? or the rocess maintaining the disorder or it can $e used to refer to the com$ination of $oth rocesses? so $e mindfu# of this when reading the rest of this section as otherwise you may $ecome a #itt#e confused. '2223 *he Initiating 1rocess Korma##y? #asma $icar$onate is 9e t at a steady #eve# of a$out 24 mmo#sI# $y two rena# rocessesD Tu$u#ar rea$sor tion of near#y a## of the #arge dai#y fi#tered #oad of $icar$onate 17cretion of the net dai#y roduction of the fi7ed acid Gwhich resu#ts in regeneration of the titrated #asma $icar$onateH "auses of a meta$o#ic a#9a#osis can $e c#assified into severa# grou s as out#ined in the ta$#e.

'Causes' : Classification of Initiating 1rocesses for $etabolic Al&alosis

Bain of al&ali in the CCD from an e7ogenous source Geg I; KaH"O3 infusion? citrate in transfused $#oodH from an endogenous source Geg meta$o#ism of 9etoanions to roduce $icar$onateH :oss of H= fro, CCD via 9idneys Geg use of diureticsH via gut Geg vomiting? K/ suctionH

17cessive intravenous administration of a#9a#i a#one wi## cause a meta$o#ic a#9a#osis which is on#y short'#ived $ecause of ra id rena# e7cretion of $icar$onate Gas mentioned revious#yH. He atic meta$o#ism of citrate? #actate? acetate or certain other organic acid anions to $icar$onate can cause a $rief meta$o#ic a#9a#osis. This may occur after a massive $#ood transfusion $ecause of the meta$o#ism of the administered citrate. The 9idneys e7crete the $icar$onate and the urine wi## $e re#ative#y a#9a#ine. '222! 1rocesses responsible for $aintenance of the Al&alosis This is discussed in section 2.3. E"ausesE of c#inica##y significant chronic meta$o#ic a#9a#osis are usefu##y divided into 2 maBor grou ings $ased on the maBor factor invo#ved in the maintenance of the disorderD The ch#oride de #etion grou The otassium de #etion grou Maintenance of the a#9a#osis re<uires a rocess which great#y im airs the 9idneyEs a$i#ity to e7crete $icar$onate and revent the return of the e#evated #asma #eve# to norma#. "h#oride deficiency #eads to a situation where the 9idney rea$sor$s more $icar$onate anion than usua# $ecause there is not sufficient ch#oride anion resent. )ea$sor tion of an anion is necessary to maintain e#ectroneutra#ity as Ka, C 5, are rea$sor$ed so the deficiency of ch#oride #eads to a re'setting u wards of the maintained #asma $icar$onate #eve#. "h#oride and $icar$onate are the on#y anions resent in a recia$#e <uantities in e7trace##u#ar f#uid so a deficiency of one must #ead to an increase in the other $ecause of the strict re<uirement for macrosco ic e#ectroneutra#ity. '222# Chloride epletion *he co,,onest causes in clinical practice are those causing chloride depletion Administration of ch#oride is necessary to correct these disorders. The four maBor su$'grou s of meta$o#ic a#9a#osis are #isted in the ta$#e $e#ow. The two commonest causes of chronic meta$o#ic

a#9a#osis are #oss of gastric Buice and diuretic thera y. The gastric secretion of H, resu#ts in generation of new $icar$onate which is returned to the $#ood. :oss of gastric acid ?/o,itingL FB drainageA and diuretic use account for +-Q of clinical cases of ,etabolic al&alosis Bastric al&alosis is most mar9ed with vomiting due to y#oric stenosis or o$struction $ecause the vomitus is acidic gastric Buice on#y. ;omiting in other conditions may invo#ve a mi7ture of acid gastric #oss and a#9a#ine duodena# contents and the acid'$ase situation that resu#ts is more varia$#e. Histamine H2'$#oc9ers a#so decrease gastric H, #osses des ite continued vomiting or nasogastric drainage and a#9a#osis wi## not occur if the f#uid #ost is not articu#ar#y acidic ' indeed #oss of a#9a#ine sma## intestina# contents can even resu#t in an acidosis if gastric acid secretion is su ressed. iuretics such as frusemide and thia&ides interfere with rea$sor tion of ch#oride and sodium in the rena# tu$u#es. 0rinary #osses of ch#oride e7ceed those of $icar$onate. The atients on diuretics who deve#o an a#9a#osis are those who are a#so vo#ume de #eted Gincreasing a#dosterone #eve#sH and have a #ow dietary ch#oride inta9e GEsa#t restrictedE dietH. Hy o9a#aemia is common in these atients. If dietary ch#oride inta9e is ade<uate then an a#9aosis is un#i9e#y to deve#o . This is the main reason why every atient ta9ing diuretics such as thia&ides or #asi7 does not deve#o a meta$o#ic a#9a#osis. The effect of diuretic use on urinary ch#oride #eve#s de ends on the re#ationshi of the time of urine co##ection to diuretic effectD it is high whi#e the diuretic is acting? $ut dro s to #ow #eve#s afterwards. ;i##ous adenomas ty ica##y e7crete $icar$onate and can cause a hy erch#oraemic meta$o#ic acidosis. (ometimes they e7crete ch#oride redominant#y and the resu#t is then a meta$o#ic a#9a#osis. "h#oride diarrhoea is a rare congenita# condition due to an intestina# trans ort defect? where the chronic faeca# ch#oride #oss can Gif associated with vo#ume de #etion and 5, #oss as maintenance factorsH resu#t in a meta$o#ic a#9a#osis. '222% 1otassiu, epletion 4otassium de #etion occurs with situations of minera#ocorticoid e7cess. Bicar$onate rea$sor tion in $oth the ro7ima# and dista# tu$u#es is increased in the resence of otassium de #etion. 4otassium de #etion decreases a#dosterone re#ease $y the adrena# corte7. A Co,,on Hybrid Classification of 'Causes' of $etabolic Al&alosis A: Addition of Base to CCD Mi#9'a#9a#i syndrome 17cessive KaH"O3 inta9e )ecovery hase from organic acidosis Ge7cess regeneration of H"O3H Massive $#ood transfusion Gdue meta$o#ism of citrateH

B: Chloride epletion *oss of acidic gastric Buice .iuretics

4ost'hy erca nia 17cess faeca# #oss Geg vi##ous adenomaH C: 1otassiu, epletion 4rimary hy era#dosteronism "ushing>s syndrome (econdary hy era#dosteronism (ome drugs Geg car$eno7o#oneH 5a#iuretic diuretics 17cessive #icorice inta9e Gg#ycyrrhi&ic acidH BartterEs syndrome 1 (evere otassium de #etion

: 3ther isorders *a7ative a$use 2,3,4 (evere hy oa#$uminaemia 5

1ri,ary Hyperaldosteronis, This condition is one cause of Esa#ine'resistantE meta$o#ic a#9a#osis. The increased a#dosterone #eve#s #ead to increased dista# tu$u#ar Ka, rea$sor tion and increased 5, C H, #osses. The increased H, #oss is matched $y increased amounts of rena# H"O3' #eaving in the rena# vein. The net resu#t is meta$o#ic a#9a#osis with hy och#oraemia and hy o9a#aemia? often with an e7 anded 1"6 vo#ume. Cushing's 0yndro,e The e7cess corticosteroids have some minera#ocorticoid effects and $ecause of this can roduce a meta$o#ic a#9a#osis. The a#9a#osis is most severe with the syndrome of ecto ic A"TH roduction. 0e/ere K= depletion "ases have $een re orted of atients with meta$o#ic a#9a#osis and severe hy o9a#aemia G+5,- W 2 mmo#I#H due to severe tota# $ody otassium de #etion. Investigation has not shown increased minera#ocorticoid activity. The aetio#ogy in these atients is not understood $ut correction of the a#9a#osis re<uires correction of the otassium deficit. These atients do not res ond to sa#ine #oading un#ess 5, re #acement is sufficient to correct the deficit. 0rinary ch#oride #osses are high GX2:mmo#I#H. Bartter's syndro,e This is a syndrome of increased renin and a#dosterone #eve#s due to hy er #asia of the Bu7tag#omeru#ar a aratus 1,6. It is inherited as an autosoma# recessive disorder. The increased a#dosterone #eve#s usua##y resu#t in a meta$o#ic a#9a#osis. The condition is usua##y found in chi#dren. 4atients who resent

with hy o9a#aemic a#9a#osis of uncertain cause are often sus ected of having this condition $ut other causes which may $e denied $y the atient shou#d $e considered eg surre titious vomiting andIor use of diuretics for weight #oss or sycho#ogica# ro$#ems. These situations have $een termed E seudo' BartterEs syndromeE. )are genetic disorders such as /ite#mannEs syndrome shou#d a#so $e considered. C6cessi/e inta&e of glycyrrhiKin /#ycyrrhi&in is recent in #icorice root. It has a sweet taste with a #icorine tang and is used in some countries Geg articu#ar#y Pa anH as a food additive or in traditiona# medicines. It inhi$its the conversion of cortiso# to cortisone $y inhi$iting the en&yme 11'$etahydro7ysteroid dehydrogenase. The resu#ting high cortiso# #eve#s have a minera#ocorticoid effect G seudohy era#dosteronismH causing Ka, retention and e7cessive urinary 5, #oss. 17cessive inta9e may resu#t in hy ertension? oedema? hy o9a#aemia and meta$o#ic a#9a#osis. 7 '222' 7sefulness of 7rinary Chloride $easure,ents $etabolic al&alosis ,ay be di/ided into t4o general groups based on the ,easured urinary chloride le/el2 In most cases the cause is o$vious Geg vomiting? diuretic useH $ut if not then measurement of a s ot urinary ch#oride can $e usefu#. Two things to $e aware of when inter reting the resu#tD )ecent diuretic use can acute#y e#evate the urinary ch#oride #eve# $ut as the diuretic effect asses the urinary ch#oride #eve# wi## fa## to #ow #eve#s. (o see9 information on the timing of diuretic use when assessing the resu#t. GThis varia$i#ity in urine ch#oride #eve#s has $een used as an indicator of surre tious diuretic useH. A Es otE urine ch#oride may $e mis#eading if $#adder urine contains a mi7ture of urine from during and after diuretic effect. A high urinary chloride in association 4ith hypo&alae,ia suggests ,ineralocorticoid e6cess G rovided that recent thia&ide use has $een e7c#udedH. If the c#inica# information is not sufficient to ma9e a diagnosis the term Eidio athic meta$o#ic a#9a#osisE is sometimes used. The urinary ch#orideIcreatinine ratio may occasiona##y $e usefu# as it is e#evated if there is an e7tra'rena# cause of a#9a#osis.

$etabolic Al&alosis Based on 7rinary Chloride 7rine Cl- R 1- ,,ol@l Often associated with vo#ume de #etion Gincreased ro7ima# tu$u#ar rea$sor tion of H"O3H )es ond to sa#ine infusion Gre #aces ch#oride and vo#umeH

"ommon causesD revious thia&ide diuretic thera y? vomiting G8:Q of casesH 7rine Cl- N 2- ,,ol@l Often associated with vo#ume e7 ansion and hy o9a#aemia )esistant to thera y with sa#ine infusion "auseD 17cess a#dosterone? severe 5, deficiency Other causesD diuretic thera y GcurrentH? Bartter>s syndrome

"eferences 1. Brimacom$e P) and Breen .4. An&s'h&sia and 5ar''&r/s syndrom&: a cas& r&+or' and r&vi&w. AAKA P 1883 A rJ %1G2H 183'2. 4u$Med 2. Adam O and /oe$e# 6.. A0&condary )ou' and +s&udo"5ar''&r syndrom& in f&mal&s wi'h la:a'iv& a*us&B. 5#in Oochenschr 1832 (e 1J %!G12H 333'8. 4u$Med 3. Mitche## P1? 4y#e )*? 1c9ert 1.? Hatsu9ami .? and *ent& ). El&c'roly'& and o'h&r +hysiolo)ical a*normali'i&s in +a'i&n's wi'h *ulimia. 4sycho# Med 1833 MayJ 13G2H 223'3. 4u$Med 4. Oster P)? Materson BP? and )ogers AI. ?a:a'iv& a*us& syndrom&. Am P /astroentero# 183: KovJ 24G!H 4!1'3. 4u$Med !. McAu#iffe PP? *ind *P? *eith .1? and 6enc# ;. ,y+o+ro'&in&mic al(alosis. Am P Med 183% Pu#J 31G1H 3%'8:. 4u$Med %. ;antyghem M"? .oui##ard "? Binaut )? and 4rovot 6. A5ar''&r/s syndrom&sB. Ann 1ndocrino# G4arisH 1888 .ecJ %:G%H 4%!'22. 4u$Med 2. Iida )? Otsu9a F? Matsumoto 5? 5uriyama (? and Hosoya T. Ps&udoaldos'&ronism du& 'o 'h& concurr&n' us& of 'wo h&r*al m&dicin&s con'ainin) )lycyrrhi2in: in'&rac'ion of )lycyrrhi2in wi'h an)io'&nsin"conv&r'in) &n2ym& inhi*i'or. "#in 17 Ke hro# 2::% PunJ 1:G2H 131'!. 4u$Med A## Med#ine a$stractsD 4u$Med Hu$Med

Acid-Base 1hysiology '23 - $etabolic Al&alosis - $aintenance

'2321 $aintenance factors Oithout a second mechanism acting to maintain it? the a#9a#osis wou#d $e on#y transitory. 5hy99 This is $ecause the 9idney norma##y has a #arge ca acity to e7crete $icar$onate and return the

#asma #eve# to norma#. This rise in urinary $icar$onate #oss occurs re#ative#y rom t#y Gie onset within an hourH $ut e7cretion ta9es 24 hours to ea9 un#ess some a$norma# condition is causing rena# retention of $icar$onate. The factors invo#ved in maintenance of the disorder are very im ortant not on#y $ecause they are necessary to deve#o a ersisting Gie chronicH a#9a#osis $ut a#so $ecause they can maintain the a#9a#osis even after the rimary rocess generating it has reso#vedU *he al&alosis can persist after the initiating process has resol/ed 3F:O ID there are additional factors ,aintaining it '2322 5hat are these abnor,al ',aintenance factors'9 The four factors that cause maintenance of the a#9a#osis G$y increasing $icar$onate rea$sor tion in the tu$u#es or decreasing $icar$onate fi#tration at the g#omeru#usH areD "h#oride de #etion )educed g#omeru#ar fi#tration rate G/6)H 4otassium de #etion 1"6 vo#ume de #etion

Chloride depletion is the ,ost co,,on factor ;o#ume de #etion and otassium de #etion may coe7ist in some disorders Geg vomitingH. (evere otassium de #etion a#one can cause a meta$o#ic a#9a#osis $ut this is ty ica##y on#y of mi#d to moderate degree. The mechanism seems to $e re#ated to an intrace##u#ar shift of H, GEintrace##u#ar acidosisEH in e7change for 5,. The a#9a#osis is generated redominant#y due to non'rena# mechanisms. )ena# mechanisms are fre<uent#y invo#ved in causing the otassium de #etion Geg in syndromes of minera#ocorticoid e7cessH. ;o#ume de #etion has #ong $een im #icated in maintenance of an a#9a#osis. The idea is that hy ovo#aemia is associated with increased f#uid and sodium rea$sor tion in the ro7ima# tu$u#e and $icar$onate is rea$sor$ed in reference to ch#orideJ the a#9a#osis thus $eing maintained. The ro#e of vo#ume de #etion has ro$a$#y $een over'em hasisedD the co'e7isting ch#oride de #etion is the most im ortant factor res onsi$#e for ersistence of the a#9a#osis. "orrection of the vo#ume deficit without correction of the ch#oride deficit wi## not resu#t in correction of the a#9a#osis. These deficits are often corrected together with a sa#ine infusion. .iuretics can cause e7cess rena# #oss of fi7ed acid anions and resu#t in a#9a#osis. Their use can a#so cause de #etion of ch#oride? water Ghy ovo#aemiaH and otassium. These factors together maintain the a#9a#osis. 6or an a#9a#osis to deve#o in atients on diuretic thera y? there genera##y has to some decrease in ch#oride inta9e as we## Geg if the atient is on a Esa#t restrictedE dietH. A continued norma# ora# ch#oride inta9e Gusua##y as Ka"#H revents atients on diuretics from getting an a#9a#osis.

Acid-Base 1hysiology '2! - $etabolic Al&alosis - $etabolic Cffects

'2!21 Ad/erse effects of al&alosis The effects of the al(alosis are often difficu#t to distinguish from the effects of associa'&d +ro*l&ms such as hy ovo#aemia? otassium and ch#oride de #etion.This ma9es it more difficu#t to characterise the effects of the a#9a#osis itse#f. Adverse 1ffects of A#9a#osis decreased myocardia# contracti#ity arrhythmias decreased cere$ra# $#ood f#ow confusion menta# o$tundation neuromuscu#ar e7cita$i#ity im aired eri hera# o7ygen un#oading Gdue shift of o7ygen dissociation curve to #eftH.

The disorder is associated with significant#y increased mor$idity and morta#ity es ecia##y in critica##y i## atients. The com ensatory rise in arteria# "O2 wi## tend to counteract some of these effects Geg the effect on cere$ra# $#ood f#owH '2!22 "is& of Hypo6ae,ia Hy o7aemia may occur and o7ygen de#ivery to the tissues may $e reduced. 6actors invo#ved in im aired arteria# o7ygen content areD Hy oventi#ation Gdue res iratory res onse to meta$o#ic a#9a#osisH 4u#monary microate#ectasis Gconse<uent to hy oventi#ationH Increased venti#ation' erfusion mismatch Gas a#9a#osis inhi$its hy o7ic u#monary vasoconstrictionH 4eri hera# o7ygen un#oading may $e im aired $ecause of the a#9a#otic shift of the haemog#o$in o7ygen dissociation curve to the #eft. The $ody>s maBor com ensatory res onse to im aired tissue o7ygen de#ivery is to increase cardiac out ut $ut this a$i#ity is im aired if hy ovo#aemia and decreased myocardia# contracti#ity are resent. Bi/e o6ygenJ The need for administration of su art of thera y. #ementa# o7ygen to atients with meta$o#ic a#9a#osis is a neg#ected

Acid-Base 1hysiology '2# $etabolic Al&alosis - Co,pensation

*he co,pensatory response is hypo/entilation It was $e#ieved that the eri hera# chemorece tors a#one acted as the initia# sensor res onding to the

rise in $#ood H $ut further anima# studies have indicated that meta$o#ic acid'$ase disorders do cause a s#ow change in $rain I(6 +H,- and this change a##eged#y cou#d $e sufficient for account for the change in venti#ation that occurs. This view is not acce ted $y a## ' see discussion in (ection 2.3H The hy oventi#ation causes a com ensatory rise in arteria# "O2 $ut the magnitude of the res onse has genera##y $een found to $e <uite varia*l&. More recent studies have a#most invaria$#y shown that hy oventi#ation does re#ia$#y occur in meta$o#ic a#9a#osis. 5hy is hypo/entilation not al4ays found9 This has $een attri$uted to various ro$#ems with some of the o#der studies which did not account for the resence of conf#icting factors? articu#ar#y those causing hy erventi#ationD Hyper/entilation due to pain ' in res onse to the stress of a ainfu# arteria# uncture. This cou#d #ower the measured "O2 during the rocedure. Hyper/entilation due to pul,onary congestion2 (ome atients with meta$o#ic a#9a#osis due to diuretic use have su$c#inica# u#monary congestion sufficient to stimu#ate intra u#monary rece tors and cause tachy noea and give a sensation of dys noea. This s#ight hy erventi#ation is sufficient to negate the rise in arteria# "O2. Hyper/entilation due to hypo6ae,ia2 An associated hy o7aemia wi## stimu#ate the eri hera# chemorece tors and cause hy erventi#ation if the arteria# O2 is $e#ow !: to !!mmHg. This may not have $een considered in ear#y studies. This common association of meta$o#ic a#9a#osis with factors causing hy erventi#ation ro$a$#y accounts for most of the ast findings of varia$i#ity of the change in arteria# "O2. In effect? this is saying that many of these atients had a co'e7istent res iratory a#9a#osis. *he arterial pC32 can be Iuite high in se/ere cases It was a#so wide#y $e#ieved that the ma7imum va#ue of arteria# "O2 due to com ensatory hy oventi#ation was !! to %:mmHg. There is no dou$t that this is wrong. Arteria# "O2 can rise higher than this and va#ues u to 3%mmHg have $een re orted in severe cases of meta$o#ic a#9a#osisU If hy oventi#ation is sufficient to cause hy o7aemia? this a#so may stimu#ate res iration via the eri hera# chemorece tors. As mentioned a$ove? associated hy o7aemia is ro$a$#y res onsi$#e for varia$i#ity in the measured arteria# "O2 in atients who a#so have a sufficient#y #ow arteria# O2. 4atients who resent with hy o7aemia and hy erca nia may $e diagnosed with res iratory fai#ure if the association with meta$o#ic a#9a#osis is not a reciated. It is usua##y $est in these atients to administer o7ygen and to avoid intu$ation and venti#ation. A cou #e of cautions for severe casesD 6or atients that you do not intu$ate and venti#ateD If significant hy o7aemia was resent? its re#ief can remove the hy o7ic res iratory drive with resu#tant hy oventi#ation and a rise in arteria# "O2. This revea#s the =a ro riate> Gin acid'$ase termsH hysio#ogica# res onse $ut can cause concern. 6or atients that you you intu$ate and venti#ateD It is easy to render venti#ated atients hy oca nic and this res iratory a#9a#osis can great#y worse the a#9a#emia. "onvu#sions have

occurred in such atients. The e7 ected "O2 due to a ro riate hy oventi#ation in sim #e meta$o#ic a#9a#osis can $e estimated from the fo##owing formu#aD C6pected pC32 E -2' <HC33> = 2- ,,Hg ?range: =@- #A Kote the wide variation a##owed Gie a 1: mmHg rangeH $ecause of the conf#icting factors that affect venti#ation Gdiscussed a$oveH. This formu#a is used to determine if a coe7istent res iratory acid'$ase disorder is resent. 6or e7am #e? if "O2 is much #ower than e7 ected? a res iratory a#9a#osis is a#so resent.

Acid-Base 1hysiology '2% $etabolic Al&alosis - Correction

'2%21 1rinciples The main rinci #es areD "orrect the rimary cause of the disorder "orrect those factors which maintain the disorder Ges "#- deficient casesH hloride administration in the common

)e #etion of ch#oride? otassium and 1"6 vo#ume wi## romote rena# $icar$onate e7cretion and return #asma $icar$onate to norma#. $ust Bi/e Chloride "h#oride administration1 is essentia# for correction of ch#oride'de #etion meta$o#ic a#9a#osis and the a#9a#osis can $e corrected with ch#oride even if vo#ume de #etion ersists. Because of e#ectroneutra#ity re<uirements it is not ossi$#e to give ch#oride a#one? so Egiving ch#orideE is e<uiva#ent to Egiving sa#ineE in most cases. GOne e7ce tion to this is giving a di#ute H"# infusion 'see $e#owH ;o#ume administration wi## not correct the a#9a#osis un#ess the administered f#uid contains ch#oride. This is not difficu#t though as a## avai#a$#e 1"6 re #acement f#uids contain ch#oride so administering these I; f#uids to correct the vo#ume deficiency must necessari#y re #enish ch#oride. Maintenance I; f#uids Geg !Q de7troseH are oor at re #enishing I; vo#ume and contain #itt#e or no ch#orideJ they are not usefu# for this correction and shou#d not $e used. Minera#ocorticoid e7cess causes rena# otassium wasting. This can maintain a meta$o#ic a#9a#osis even in the a$sence of ch#oride de #etion. )are#y? it may $e advantageous to institute treatments Geg H"# infusionJ aceta&o#amideH that can return the $icar$onate #eve# to norma# more <uic9#y. Rar&ly? it may $e advantageous to institute treatments Ghydroch#oric acid infusion? or aceta&o#amideH that can return the $icar$onate #eve# to norma# more <uic9#y. These are not routine com onents of

management? and shou#d not def#ect attention from correcting the rimary cause and from correcting a ch#oride deficiency? $ut may $e usefu# for occasiona# atients with EresistantE meta$o#ic a#9a#osis managed in an Intensive "are 0nit. 4roton um inhi$itors Geg ome re&o#eH have $een successfu##y used to decrease gastric acid #oss and revent or ame#iorate meta$o#ic a#9a#osis 2,3,4 '2%22 Hydrochloric Acid Infusion An infusion of hydroch#oric acid 5 can $e given via a centra# #ine 6,7,8. The correct #acement of the #ine very im ortant. It is confirmed $y the a$i#ity to easi#y withdraw $#ood AK. $y 7'ray confirmation of the ti osition. "ontinued vigi#ance of the ti osition is re<uiredJ e7travasation of acid from a centra# #ine has caused death9. The infusion wi## se#ective#y correct the ch#oride deficiency and the infusion can $e titrated to an end' oint of a s ecific $icar$onate #eve# of H #eve#. The H, wi## consume H"O3' rovided the e7cess "O2 can $e venti#ated off. (tudies have shown that im rovement in gas e7change occurs with a fa## in arteria# "O2 and an increase in arteria# O2. These changes were origina##y considered to $e due to the increase in venti#ation that occurs Gand the su$se<uent decrease in u#monary microate#ectasisH $ut the aO2 wi## increase even in atients maintained on constant venti#ation7,10. The ro$a$#e cause is an im rovement in venti#ation' erfusion matching. A#9a#osis im airs the efficiency of hy o7ic u#monary vasoconstriction so its correction cou#d acute#y resu#t in im rovements in the #ung>s ;IA matching and an increase in arteria# O2. The correction of a#9a#osis wi## a#so resu#t in a right shift in the o7ygen dissociation curve which wi## im rove eri hera# o7ygen un#oading. A H"# infusion is a dramatic way of administering ch#oride $ut u$#ished re orts 7,11,12 attest to its safety and successfu# use. An increase in arteria# O2 and a decrease in "O2 genera##y occurs and may assist with weaning from mechaica# venti#ation. The administration of ch#oride in a sma## vo#ume 12 may $e usefu# in atients who are at ris9 of vo#ume over#oad. G6urther detai#s a$out hydroch#oric acid infusionsH '2%23 7se of AcetaKola,ide Aceta&o#amide is a car$onic anhydrase inhi$itor which has a#so $een used to s eed the ra idity of correction of a#9a#osis 13. It is usua##y more readi#y avai#a$#e than steri#e hydroch#oric acid so#utions and is a more acce ta$#e thera eutic o tion. It causes rena# $icar$onate #oss to increase and #asma $icar$onate #eve#s fa##. On#y one or two doses ro$a$#y shou#d $e used. (ome ro$#ems with aceta&o#amide areD )ena# #osses of water? Ka, and 5, increase Gso a ro riate adBustments in I; f#uids and 5, su #ementation are necessaryH It interferes with "O2 trans ort It is s#ower acting and more difficu#t to titrate to a given $icar$onate #eve# Other sources of H"# have $een used Geg #ysine H"#? ammonium ch#orideH. He atic meta$o#ism of the ammonium generates hydrogen ions.

These anci##ary measures may rove usefu# in a sma## num$er of atients $ut are not genera##y recommended. *reat,ent 3utline -$etabolic Al&alosis 1. "orrect cause if ossi$#e Geg correct y#oric o$struction? cease diureticsH 2. "orrect the deficiency which is im airing rena# $icar$onate e7cretion Gie give ch#oride? water and 5,H 3. 17 and 1"6 ;o#ume with KIsa#ine Gand 5"# if 5, deficiencyH 4. )are#y anci##ary measures such asD H"# infusion Aceta&o#amide Gone or two doses on#yH Ora# #ysine hydroch#oride !. (u ortive measures Geg give O2 in view of hy oventi#ationJ a ro riate monitoring and o$servationH %. Avoid hy erventi#ation as this worsens the a#9a#aemia

"eferences 1. )osen )A? Pu#ian BA? .u$ovs9y 1;? /a##a PH? and *u9e )/. Cn 'h& m&chanism *y which chlorid& corr&c's m&'a*olic al(alosis in man. Am P Med 1833 MarJ 34G3 4t 1H 448'!3 4u$Med 2. 5inahan TP? 5houry A1? Mc*orie /A? and "hurchi## BM. Cm&+ra2ol& in +os'" )as'rocys'o+las'y m&'a*olic al(alosis and aciduria. P 0ro# 1882 6e$J 142G2H 43!'2. 4u$Med 3. Hi7son ) and "hristmas .. >s& of om&+ra2ol& in lif&"'hr&a'&nin) m&'a*olic al(alosis. Intensive "are Med 1888 OctJ 2!G1:H 12:1. 4u$Med 4. Hsu ("? Oang M"? *iu H*? Tsai M"? and Huang PP. E:'r&m& m&'a*olic al(alosis 'r&a'&d wi'h normal *icar*ona'& h&modialysis. Am P 5idney .is 2::1 A rJ 32G4H 131. 4u$Med !. 1ditoria#D Hydroch#oric acid for meta$o#ic a#9a#osis. *ancet 1824 A r 2:J 1G23%:H 22:. midD4132434. 4u$Med %. 5wun 5B? Boucherit T? Oong P? )ichards F? and Bryan'Brown "O. %r&a'm&n' of m&'a*olic al(alosis wi'h in'rav&nous infusion of conc&n'ra'&d hydrochloric acid. Am P (urg 1833 (e J 14%G3H 323'3:. 4u$Med 2. Brimiou##e (? ;incent P*? .ufaye 4? Berre P? .egaute P4? and 5ahn )P. ,ydrochloric acid infusion for 'r&a'm&n' of m&'a*olic al(alosis: &ff&c's on acid"*as& *alanc& and o:y)&na'ion. "rit "are Med 183! (e J 13G8H 233'42. 4u$Med 3. Brimiou##e (? Berre P? .ufaye 4? ;incent P*? .egaute P4? and 5ahn )P. ,ydrochloric acid infusion for 'r&a'm&n' of m&'a*olic al(alosis associa'&d wi'h r&s+ira'ory acidosis. "rit "are Med 1838 MarJ 12G3H 232'%. 4u$Med Hu$Med 8. Buchanan IB? "am $e## BT? 4ec9 M.? and "airns BA. 4h&s' wall n&crosis and d&a'h s&condary 'o hydrochloric acid infusion for m&'a*olic al(alosis. (outh Med P 2::! AugJ 83G3H 322'4. 4u$Med 1:.Brimiou##e ( and 5ahn )P. Eff&c's of m&'a*olic al(alosis on +ulmonary )as &:chan)&. Am )ev )es ir .is 188: MayJ 141G! 4t 1H 113!'8. 4u$Med 11.Oorth#ey *I. 3n'rav&nous hydrochloric acid in +a'i&n's wi'h m&'a*olic al(alosis and hy+&rca+nia. Arch (urg 183% OctJ 121G1:H 118!'3. 4u$Med 12.5or9ma& A? Fi#dirim 1? Aras K? and 1rcan 6. ,ydrochloric acid for 'r&a'in) m&'a*olic

al(alosis. P n P (urg 1838 (e J 18G!H !18'23. 4u$Med 13.Mari9 41? 5ussman B.? *i man P? and 5raus 4. Ac&'a2olamid& in 'h& 'r&a'm&n' of m&'a*olic al(alosis in cri'ically ill +a'i&n's. Heart *ung 1881 (e J 2:G! 4t 1H 4!!'8. 4u$Med A## Med#ine a$stractsD 4u$Med Hu$Med

Acid-Base 1hysiology '2' $etabolic Al&alosis - Assess,ent The attern of high va#ues of +H"O3- and "O2 occurring together suggests either a meta$o#ic a#9a#osis or a res iratory acidosis Gor $othH. If "O2 is over %:mmHg? the meta$o#ic a#9a#osis is either very severe or there is a mi7ed disorder with a res iratory acidosis. Meta$o#ic a#9a#osis is sus ected if one of the 9nown causes of the disorder is resent es ecia##y vomiting? nasogastric suction? y#oric o$struction? e7cess minera#ocorticoid syndromes or diuretic use. The de#ta ratio can $e a usefu# adBunct in detecting the resence of a second acid'$ase disorder in atients with a meta$o#ic acidosis. In atients who have a meta$o#ic acidosis and a chronic meta$o#ic a#9a#osis the de#ta ratio has a va#ue greater then 2. (uch a high va#ue can a#so occur in atients with a re'e7isting chronic res iratory acidosis $ecause the $icar$onate is a#so e#evated in that disorder as we##. Because of otentia# errors? the de#ta ratio shou#d $e assessed cautious#y. 4ractica# Hints for Bedside .iagnosis of Meta$o#ic A#9a#osis Most cases are easy to diagnose on history and then can $e confirmed on arteria# $#ood gases. In atients with mi7ed acid'$ase disorders? the structured a roach to assessment Gdiscussed in "ha ter 8H? wi## usua##y resu#t in a correct diagnosis. The most common causes G8:Q of casesH areD ;omiting Gor K/ tu$e drainageH .iuretic use Other causes shou#d $e most#y o$vious Geg ost'hy erca noeic a#9a#osis in I"0? ost' massive transfusionH. If you>re sti## stuc9 for a diagnosisD ( ot urine ch#oride is usefu# hereD #ow #eve#s suggest "#' de #etion and need for re #acementJ high #eve#s suggest adrenocortica# e7cess and need for 5, re #acement "onsider surre tious diuretic use in fema#es as there is a certain grou who a$use diuretics for Eweight #ossE. G0rine "#' may $e high or #ow de ending on timing of #ast

diuretic doseH If nothing more o$vious is a arent? don>t forget a$out adrenocortica# e7cess syndromes which are rare $ut do occur. .on>t #et diagnostic <ui$$#es de#ay re #acement of 5, if needed as #ow +5,- can $e #ife'threatening G C may $e worsened $y treatmentUH

Acid-Base 1hysiology '2( $etabolic Al&alosis - 1re/ention There are 2 as ects of revention for a meta$o#ic a#9a#osisD 4revention of the rimary or initiating rocess? and-or 4revention of the factors that are invo#ved in maintaining the a#9a#osis. 4atients with nasogastric drainage and y#oric o$struction shou#d receive ade<uate f#uid re #acement using a ch#oride containing f#uid. 4atients receiving thia&ide diuretics #i9ewise need to have ade<uate ch#oride inta9e. 4roton um inhi$itors can $e used to great#y decrease gastric acid #oss 1,2,3 des ite continuing nasogastric drainage. "eferences 1. 5inahan TP? 5houry A1? Mc*orie /A? and "hurchi## BM. Cm&+ra2ol& in +os'" )as'rocys'o+las'y m&'a*olic al(alosis and aciduria. P 0ro# 1882 6e$J 142G2H 43!'2. 4u$Med 2. Hi7son ) and "hristmas .. >s& of om&+ra2ol& in lif&"'hr&a'&nin) m&'a*olic al(alosis. Intensive "are Med 1888 OctJ 2!G1:H 12:1. 4u$Med 3. Hsu ("? Oang M"? *iu H*? Tsai M"? and Huang PP. E:'r&m& m&'a*olic al(alosis 'r&a'&d wi'h normal *icar*ona'& h&modialysis. Am P 5idney .is 2::1 A rJ 32G4H 131. 4u$Med A## Med#ine a$stractsD 4u$Med Hu$Med

I,portant 1oints - Chapter ' : $etabolic Al&alosis Meta$o#ic a#9a#osis is an a$norma# rimary rocess causing a decrease in fi7ed acids in the $#ood. Buffering resu#ts in an increase in #asma $icar$onate #eve#. An acute meta$o#ic a#9a#osis wi## KOT ersist #ong as the norma# 9idney ra id#y increases $icar$onate e7cretion from the $ody A meta$o#ic a#9a#osis re<uires BOTH an initiating process and a ,aintaining process. Oithout an a$norma# rocess maintaining it? the a#9a#osis wi## ra id#y

correct as the 9idney ours out H"O3 in the urine. The maintaining rocess causing ersistence of the e#evated #asma $icar$onate #eve# wor9s $y im airing rena# $icar$onate e7cretion. The four factors which are invo#ved in maintaining the disorder areD ch#oride de #etion reduced /6) otassium de #etion 1"6 vo#ume de #etion The initiating cause in most cases is #oss of gastric acid Geg /o,itingH or diuretic use. "h#oride de #etion is the a$norma#ity that im airs rena# $icar$onate e7cretion. A## these atients GX8:Q of c#inica# casesH re<uire ch#oride re #acement Gusua##y as sa#ine so#utionH $efore they can $e corrected )are causes inc#ude various adrenocortica# e7cess syndromes. Hy o9a#aemia is the most common associated e#ectro#yte a$norma#ity and can $e #ife'threatening itse#f Meta$o#ic a#9a#osis is classified into 2 maBor grou sD those causes associated with ch#oride de #etion Gurinary ch#oride X 1: mmo#I#H? and those causes not associated with ch#oride de #etion Gurinary ch#oride X 2:mmo#I#H 0rinary ch#oride #eve#s are articu#ar#y usefu# in differentiating the cause in those cases where vomiting or thia&ide diuretic use are uncertain. The com ensatory res onse is hy oventi#ation $ut there is variation in the degree of this. O7ygen thera y shou#d $e used in most hos ita# atients. )emem$erD "orrection usua##y re<uires repla ement o" hloride usua##y in association with f#uid and otassium. In rare severe cases? hydroch#oric acid infusion or use of aceta&o#amide may $e used $ut there are ris9s

Acid-Base 1hysiology (21 :actic Acidosis *actic acidosis is a common cause of meta$o#ic acidosis. 1,2,3 (2121 aily 1roduction of :actate 1ach day the $ody has an e7cess roduction of a$out 1!:: mmo#s of #actate Ga$out 2: mmo#sI9gIdayH which enters the $#ood stream and is su$se<uent#y meta$o#ised most#y in the #iver. This interna# cyc#ing with roduction $y the tissues and trans ort to and meta$o#ism $y the #iver and 9idney is 9nown as the "ori cyc#e. This norma# rocess does not re resent any net fi7ed acid roduction which re<uires e7cretion from the $ody.

A## tissues can roduce #actate under anaero$ic conditions $ut tissues with active g#yco#ysis roduce e7cess #actate from g#ucose under norma# conditions and this #actate tends to s i## over into the $#ood. *actate is roduced from yruvate in a reaction cata#ysed $y #actate dehydrogenaseD 1yru/ate = FA H = H= REN :actate = FA
=

This reaction is so ra id that yruvate and #actate can $e considered to $e a#ways in an e<ui#i$rium situation. Korma##y the ratio of #actate to yruvate in the ce## is 1: to 1. The ratio +KA.H-I+KA. ,- $y the *aw of Mass Action determines the $a#ance $etween #actate and yruvate. This ratio is a#so used to denote the redo7 state within the cyto #asm. *actic acid has a 5 va#ue of a$out 4 so it is fu##y dissociated into #actate and H, at $ody H. In the e7trace##u#ar f#uid? the H, titrates $icar$onate on a one for one $asis. (2122 *issue 1roduction 8 $etabolis, *actate is re#eased from ce##s into the I(6 and $#ood. *issues 1roducing C6cess :actate At rest? the tissues which norma##y roduce e7cess #actate areD s9in ' 2!Q of roduction red ce##s ' 2:Q $rain ' 2:Q musc#e ' 2!Q gut ' 1:Q

.uring heavy e7ercise? the s9e#eta# musc#es contri$ute most of the much increased circu#ating #actate. (4,5) .uring regnancy? the #acenta is an im ortant roducer of #actate which asses into $oth the materna# and the foeta# circu#ations. *actate is meta$o#ised redominant#y in the #iver G%:QH and 9idney G3:QH6. Ha#f is converted to g#ucose Gg#uconeogenesisH and ha#f is further meta$o#ised to "O2 and water in the citric acid cyc#e. The resu#t is no net roduction of H, Gor of the #actate anionH for e7cretion from the $ody. Other tissues can use #actate as a su$strate and o7idise it to "O2 and water $ut it is on#y the #iver and 9idney that have the en&ymes that can convert #actate to g#ucose. KoteD The $a#ance $etween re#ease into the $#oodstream and he atorena# u ta9e maintains #asma #actate at a$out one mmo#I#. The rena# thresho#d for #actate is a$out ! to % mmo#sI# so at norma# #asma #eve#s? no #actate is e7creted into the urine. The sma## amount of #actate that is fi#tered G13:mmo#IdayH is fu##y rea$sor$ed.

(2123 $echanis,s in/ol/ed in :actic Acidosis *actic acidosis can occur due toD e7cessive tissue #actate roduction im aired he atic meta$o#ism of #actate In most c#inica# cases it is ro$a$#e that $oth rocesses are contri$uting to the deve#o ment of the acidosis. The #iver has a #arge ca acity to meta$o#ise #actate so increased eri hera# roduction a#one is un#i9e#y to #ead to other than transient acidosis. The situation is ana#ogous to a res iratory acidosis where increased "O2 roduction a#one is rare#y res onsi$#e $ecause of the efficient venti#atory regu#ation of "O2. Im aired venti#ation Gim aired e7cretion of "O2H is a#most invaria$#y resent and res onsi$#e for a res iratory acidosis. In situations where #actic acidosis is c#ear#y due to e7cessive roduction a#one Gsuch as severe e7ercise or convu#sionsH? the acidosis usua##y reso#ves Gdue to he atic meta$o#ismH within a$out an hour once the reci itating disorder is no #onger resent. In severe e7ercise? #actate #eve#s can rise to very high #eve#s eg u to 3: mmo#I#. )es iratory com ensation for the acidosis may not $e significant $ecause of the short time invo#ved. However? there are other causes of hy erventi#ation resent and arteria# "O2 is ty ica##y reduced roviding artia# com ensation. 6or e7am #e? e7ercise resu#ts in mar9ed#y increased venti#ation and the cause of this is #arge#y un9nown. The arteria# "O2 usua##y fa##s with e7ercise and this is not considered to $e due to the #actic acidosis as it occurs even in #ess severe e7ercise where there is #itt#e e7cess #actate roduced. A continuing #actic acidosis means that there is continuing roduction of #actate that e7ceeds the #iverEs ca acity to meta$o#ise it. This may $e due to c#ear#y very e7cessive roduction Geg convu#sionsH with a norma# #iver at one e7treme? or to increased roduction in associated with great#y im aired he atic ca acity to meta$o#ise it Geg due to cirrhosis? se sis? hy o erfusion due hy ovo#aemia or hy otension? hy othermia? or some com$inations of adverse factorsH at the other e7treme. (212! efinitions .efinitions differ concerning the $#ood #eve# at which a #actic acidosis is regarded as EsignificantE. 6or our ur osesD Hyperlactae,ia: a le/el fro, 2 ,,ols@l to # ,,ol@l2

0e/ere :actic Acidosis: 4hen le/els are greater than # ,,ols@l As #eve#s rise a$ove !mmo#sI#? the associated morta#ity rate can $ecome very high. A serious #actic acidosis can $e resent without much noticea$#e e#evation of the anion ga . This is $ecause the #actate #eve#s associated with high morta#ity Gsay % to 1: mmo#sI#H may not cause much change in a derived varia$#e Gthe anion ga H which has a 8!Q reference range of ,I'!mmo#sI#. The $rief and often very high #actate #eve#s that occur with severe e7ercise or genera#ised convu#sions Geg u to 3: mmo#I#H are associated with an e7treme#y #ow morta#ity rate. Indeed the morta#ity rate in these causes is usua##y e7treme#y #ow. A #actate #eve# of 1! mmo#sI# in an e#der#y i## se tic atient in an Intensive "are 0nit wou#d $e associated with a very high ris9 of death.

*he absolute lactate le/el ?aloneA is not a good predictor of outco,e unless the cause of the high le/el is also considered2 *actate can $e converted to g#ucose in the #iver and 9idney. This art of the "ori cyc#e is an e7am #e of g#uconeogenesis. Anaero$ic g#yco#ysis roduces #actate and e<uiva#ent amounts of H, from AT4 hydro#ysis. If $oth these reactions are com$ined? then there is effective#y a net roduction of e<ua# amounts of #actate and H, $ut the #ow 5a of #actic acid dissociation means that #actic acid Gthe undissociated formH is resent on#y in miniscu#e amounts. (212# Causes of :actic Acidosis *actic acidosis is common#y c#assified into either Ty e A or Ty e B G"ohen C Ooods? 182%H with the main differentiating oint $eing the ade<uacy of tissue o7ygen de#ivery. In $oth ty es? the fundamenta# ro$#em is the ina$i#ity of the mitochondria to dea# with the amount of yruvate with which they are resented. *ype A lactic acidosis refers to circumstances where the c#inica# assessment is that tissue o7ygen de#ivery is inade<uate. This is the most common c#inica# situation. The inade<uate o7ygen su #y s#ows mitochondria# meta$o#ism and yruvate is converted to #actate Gand KA.H to KA.,H The conversion of KA.H to KA., is im ortant as it regenerates KA., needed for g#yco#ysis to continue. This situation is 9nown as anaero$ic meta$o#ism and resu#ts in a sma## net AT4 roductionD two mo#es of AT4 er mo#e of g#ucose. The mitochondria# reactions are resumed to $e intact $ut una$#e to function $ecause of inade<uate o7ygen If hy o7aemia is the on#y factor resent? it needs to $e severe Geg aO2 W 3!mmHgH to reci itate #actic acidosis $ecause of the rotection afforded $y the $ody>s com ensatory mechanisms which increase tissue $#ood f#ow. (imi#ar#y anaemia needs to $e severe Geg +H$- W!/QH if resent a#one $ecause tissue $#ood f#ow is increased in com ensation. "educed perfusion is the ,ost i,portant factor in causing i,paired o6ygen deli/ery in type A lactic acidosis2

Anae,ia or hypo6ae,ia alone is not sufficient unless se/ere or associated 4ith reduced perfusion2 *ype B lactic acidosis refers to situations in which there is no c#inica# evidence of reduction in tissue o7ygen de#ivery. "ar$ohydrate meta$o#ism is disordered for some reason and e7cess #actic acid is formed. )esearch using more so histicated methods to assess tissue erfusion have now shown that occu#t tissue hy o erfusion is resent in many cases of Ty e B acidosis. An ischae,ic bo4el can roduce #arge amounts of #actate. Mesenteric ischaemia can cause a severe #actic acidosis even if erfusion in the rest of the $ody is ade<uate. This situation can easi#y $e over#oo9ed es ecia##y in those cases where a$domina# c#inica# signs are minima#. 1henfor,in is a $iguanide ora# hy og#ycaemic agent which was associated with a severe form of Ty e B #actic acidosis. The incidence was highest among dia$etics with rena# insufficiency where $#ood #eve#s are highest. The mechanism of action is not fu##y esta$#ished $ut the drug ro$a$#y interferes with mitochondria# function. High #eve#s of henformin significant#y de ress myocardia# contracti#ity. The decrease in cardiac out ut undou$ta$#y contri$utes a maBor com onent of tissue hy o erfusion to

many cases. 3ther factors redis osing to deve#o ment of #actic acidosis are se sis? #iver fai#ure and some ma#ignancies. 4atients with cirrhosis often have a much reduced a$i#ity to ta9e u and meta$o#ise #actate. .es ite this? atients with chronic he atic disease a#one do not common#y deve#o #actic acidosis un#ess other factors such as se sis? shoc9? $#eeding or ethano# a$use are a#so resent. (o? the deve#o ment of #actic acidosis in atients with cirrhosis suggests severe #iver damage and the resence of other factors. In this setting? death rates are high. Any factor which stimu#ates g#yco#ysis Geg catecho#amine administration? cocaineH wi## #ead to an increased #actate roduction. *actic acidosis occurs in u to 1:Q of atients resenting with dia$etic 9etoacidosis. This may $e due to oor eri hera# erfusion or henformin administration $ut may occur without the resence of these factors.

Classification of 0o,e Causes of :actic Acidosis G"ohen C Ooods? 182%H *ype A :actic Acidosis : Clinical C/idence of InadeIuate *issue 36ygen eli/ery Anaero$ic muscu#ar activity Geg s rinting7? genera#ised convu#sionsH Tissue hy o erfusion Geg shoc9 'se tic? cardiogenic or hy ovo#aemicJ hy otensionJ cardiac arrestJ acute heart fai#ureJ regiona# hy o erfusion es mesenteric ischaemiaJ ma#aria8,9H )educed tissue o7ygen de#ivery or uti#isation Geg hy o7aemia? car$on mono7ide oisoning? severe anaemiaH *ype B :actic Acidosis: Fo Clinical C/idence of InadeIuate *issue 36ygen eli/ery type B1 D Associated with under#ying diseases Geg 9etoacidosis? #eu9aemia? #ym homa? AI.(H type B2D Assoc with drugs C to7ins Geg henformin? cyanide? $eta'agonists? methano#? nitro russide infusion? ethano# into7ication in chronic a#coho#ics? anti'retrovira# drugsH type B3D Assoc with in$orn errors of meta$o#ism Geg congenita# forms of #actic acidosis with various en&yme defects eg yruvate dehydrogenase deficiencyH =o'&: %his lis' do&s no' includ& all caus&s of lac'ic acidosis

(212% iagnosis The condition is often sus ected on the history and e7amination Geg shoc9? heart fai#ureH and is easi#y confirmed and <uantified $y measuring the $#ood #actate #eve#. A articu#ar ro$#em is the diagnosis of the condition when resent as art of a mi7ed acid'$ase disorder. It may $e associated with other causes of a high anion ga acidosis Geg 9etoacidosis? uraemic acidosisH and not $e sus ected. "oe7istent #actic acidosis and meta$o#ic a#9a#osis may resu#t in minima##y a#tered #asma $icar$onate #eve#. A high anion ga may $e a c#ue in this #ater situation $ut the anion ga is not invaria$#y e#evated out of the reference range. 5hy do clinicians ha/e difficulty diagnosing lactic acidosis9 The main reason is that traditiona##y a #actate #eve# was an uncommon investigation and the diagnosis of #actic acidosis was $y e7c#usion in atients with a high anion ga meta$o#ic acidosis and some evidence of im aired erfusion. Other factors were a #ow inde7 of c#inica# sus icion and a tendency to not a reciate the significance of an e#evated #actate resu#t. The $asic investigations needed to su #ement the history? e7amination and e#ectro#yte resu#ts in differentiating the causes of a high anion ga acidosis areD $#ood g#ucose #eve# urinary 9etones urea C creatinine urine out ut $#ood #actate #eve# ca#cu#ation of osmo#ar ga

(212' $anage,ent The rinci #es of management of atients with #actic acidosis areD .iagnose and correct the under#ying condition Gif ossi$#eH )estore ade<uate tissue o7ygen de#ivery Ges restore ade<uate erfusionH Avoid sodium $icar$onate Ge7ce t ossi$#y for treatment of associated severe hy er9a#aemiaH Ohen the circu#ation is restored? the #iver can meta$o#ise the circu#ating #actate. If #actic acidosis is severe and the cause cannot $e corrected? the morta#ity can $e <uite high. 5hat is the role of I; bicarbonate9 Auite #arge doses of $icar$onate Geg 1?::: to 3?::: mmo#sIdayUH have traditiona##y $een administered to severe cases $ut the success rate is #ow. Interesting#y? meta$o#ic a#9a#osis induced $y administration of sodium $icar$onate can #ead to a su$stantia# increase in the roduction of #actate. This may $e $ecause the intrace##u#ar acidosis strong#y inhi$its hos hofructo9inase which is the rate'#imiting en&yme in g#yco#ysis. This suggests that $icar$onate thera y cou#d resu#t in induction of a#9a#osis intrace##u#ar#y which cou#d re#ease this inhi$ition and increase yruvate and #actate roduction GC thus a vicious cyc#eH. Ko wonder massive doses of $icar$onate seem necessary and why the outcome is so oor. +(ee a#soD 0se of Bicar$onate in Meta$o#ic Acidosis-

"eferences 1. 5ruse PA and "ar#son )O. ?ac'a'& m&'a*olism. "rit "are "#in 1832 OctJ 3G4H 22!'4%. 4u$Med 2. *uft 6". ?ac'ic acidosis u+da'& for cri'ical car& clinicians. P Am (oc Ke hro# 2::1 6e$J 12 (u # 12 (1!'8. 4u$Med 3. (tac oo#e 4O. ?ac'ic acidosis. 1ndocrino# Meta$ "#in Korth Am 1883 PunJ 22G2H 221'4!. midD332!234. 4u$Med 4. Pue# ". Muscl& +, r&)ula'ion: rol& of 'rainin). Acta 4hysio# (cand 1883 MarJ 1%2G3H 3!8'%%. 4u$Med !. Pue# ". ?ac'a'&"+ro'on co'rans+or' in s(&l&'al muscl&. 4hysio# )ev 1882 A rJ 22G2H 321'!3. 4u$Med %. Be##omo ). 5&nch"'o"*&dsid& r&vi&w: lac'a'& and 'h& (idn&y. "rit "are 2::2 AugJ %G4H 322'%. 4u$Med 2. )o$ergs )A? /hiasvand 6? and 4ar9er .. 5ioch&mis'ry of &:&rcis&"induc&d m&'a*olic acidosis. Am P 4hysio# )egu# Integr "om 4hysio# 2::4 (e J 232G3H )!:2'1%. 4u$Med 3. 4asvo# /. %h& 'r&a'm&n' of com+lica'&d and s&v&r& malaria. Br Med Bu## 2::!J 2!'2% 28'42. 4u$Med 8. Mait#and 5 and Kewton "). Acidosis of s&v&r& falci+arum malaria: h&adin) for a shoc(1. Trends 4arasito# 2::! PanJ 21G1H 11'%. 4u$Med A## Med#ine a$stractsD 4u$Med

Acid-Base 1hysiology (22 Ketoacidosis

(22212 5hat is &etoacidosis9 5etoacidosis is a high anion ga meta$o#ic acidosis due to an e7cessive $#ood concentration of 9etone $odies G9eto'anionsH. 5etone $odies Gacetoacetate? $eta'hydro7y$utyrate? acetoneH are re#eased into the $#ood from the #iver when he atic #i id meta$o#ism has changed to a state of increased 9etogenesis. A re#ative or a$so#ute insu#in deficiency is resent in a## cases. The maBor reactions starting from the roduction of acetoacetate from he atic acety# "oA are out#ined in the $o7. )eactions in 5etoacidosis GTO B1 "OM4*1T1.H KA., KA.H acety# "oA W X acetoacetic acid W X $eta'hydro7y$utyric acid 5a 3.!3 5a 4.2: acetoacetate $eta'hydro7y$utyrate , H, , H, H"O3' H2"O3 H2O , "O2

KoteD There is one H, roduced for each acid anion roduced Buffering resu#ts in the #oss of one H"O3 for each H, $uffered Therefore one redicts thatD Increase in Anion /a L .ecrease in +H"O3'The maBor 9etone $odies are acetoacetate and $eta'hydro7y$utyrate and the ratio $etween these two acid anions de ends on the revai#ing redo7 state Geg as assessed $y the KA.HIKA., ratioH. A mi7ed acid'$ase disorder may $e resent Geg #actic acidosis from eri hera# circu#atory fai#ure? or meta$o#ic a#9a#osis from vomitingH. An associated #actic acidosis may mas9 the resence of the 9etoacidosis. This occurs $ecause the #actic acidosis decreases the acetoacetate D $eta'hydro7y$utyrate ratio Gie more $eta'hydro7y$utyrate roduced H $ecause KA., is roduced in the roduction of #actate. The common test used to detect 9etones Geg =Acetest>H de ends on the reaction of acetoacetate Gand to a #esser e7tent acetoneH with the nitro russide reagent. A decreased acetoacetate #eve# may #ead to a wea9 or a$sent test reaction des ite high tota# #eve#s of tota# 9etoanions Gacetoacetate and $eta' hydro7y$utyrate com$inedH $ecause the $eta'hydro7y$utyrate is not detected. Out#ine of Interaction $etween *actic Acidosis C 5etoacidosis Acetoacetate WLX $eta'hydro7y$utyrate GBOHBH KA., KA.H *actate WLX 4yruvate KoteD Increased #actate cause increased BOHB C decreased AcAc $y *aw of Mass Action The three maBor ty es of 9etosis areD (tarvation 9etosis A#coho#ic 9etoacidosis .ia$etic 9etoacidosis (2222 0tar/ation Ketosis Ohen he atic g#ycogen stores are e7hausted Geg after 12'24 hours of tota# fastingH? the #iver roduces 9etones to rovide an energy su$strate for eri hera# tissues. 5etoacidosis can a ear after an overnight fast $ut it ty ica##y re<uires 3 to 14 days of starvation to reach ma7ima# severity. Ty ica# 9etoanion #eve#s are on#y 1 to 2 mmo#I# and this wi## not much a#ter the anion ga . The acidosis even with <uite ro#onged fasting is on#y ever of mi#d to moderate severity with 9etoanion #eve#s u to a ma7imum of 3 to ! mmo#I# and #asma H down to 2.3. This is ro$a$#y due to the insu#in #eve#? which though #ower? is sti## enough to 9ee the 66A #eve#s #ess than 1mM. This #imits su$strate de#ivery to the #iver restraining he atic 9etogenesis. 5etone $odies a#so stimu#ate some insu#in re#ease from the is#ets. The anion ga wi## usua##y not $e much e#evated.

(2223 Alcoholic Ketoacidosis *ypical 1resentation This ty ica# situation #eading to a#coho#ic 9etoacidosis is a chronic a#coho#ic who has a $inge? then sto s drin9ing and has #itt#e or no ora# food inta9e. 6ood inta9e may $e #imited $ecause of vomiting. The two 9ey factors are the com$ination of ethano# and fasting. 4resentation is ty ica##y a cou #e of days after the drin9ing $inge has ceased. 1athophysiology The oor ora# inta9e resu#ts in decreased g#ycogen stores? a decrease in insu#in #eve#s and an increase in g#ucagon #eve#s. He atic meta$o#ism of ethano# to aceta#dehyde and then to acetate $oth invo#ve KA., as a cofactor. The KA.HIKA., ratio rises and thisD inhi$its g#uconeogenesis favours the roduction of $eta'hydro7y$utyrate over acetoacetate The insu#in deficiency resu#ts in increased mo$i#isation of free fatty acids from adi ose tissue. The decreased insu#inIg#ucagon ration resu#ts in a switch in he atic meta$o#ism favouring increased $eta' o7idation of fatty acids. This resu#ts in an increased roduction of acety#"oA which forms acetoacetate Ga 9eto'acidH. GThe atho hysio#ogy of the insu#in deficiency and the switch in he atic meta$o#ism is discussed in more detai# in .5A section $e#ow.H Other oints to noteD ;o#ume de #etion is common and this can resu#t in increased #eve#s of counter'regu#atory hormones Geg g#ucagonH *eve#s of 66A can $e high Geg u to 3.!mMH roviding #enty of su$strate for the a#tered he atic #i id meta$o#ism to roduce #enty of 9etoanions /IT sym toms are common Geg nausea? vomiting? a$domina# ain? haematemesis? me#aenaH Acidaemia may $e severe Geg H down to 2.:H 4#asma g#ucose may $e de ressed or norma# or even e#evated Magnesium deficiency is not uncommon 4atients are usua##y not dia$etic $anage,ent This syndrome is ra id#y reversed $y administration of g#ucose and insu#in. This diagnosis is often over#oo9ed. A strong sus icion shou#d $e raised in any i## chronic a#coho#ic with a sweet 9etone $reath who resents to a hos ita# 1mergency .e artment. (uch atients are often disheve##ed? and can $e noisy and genera##y uncoo erative. A mi7ed acid'$ase disorder may $e resentD high anion ga due to 9etoacidosis? meta$o#ic a#9a#osis due to vomiting and a res iratory a#9a#osis. (222! iabetic Ketoacidosis ? KAA 1athophysiology An a$so#ute or re#ative #ac9 of insu#in #eads to dia$etic meta$o#ic decom ensation with hy erg#ycaemia

and 9etoacidosis. A reci itating factor Geg infection? stressH which causes an e7cess of stress hormones Gwhich antagonise the actions of insu#inH may $e resent. (ituations #eading to .5A The most common situations in atients resenting with .5A areD Infection as reci itant G3:Q of casesH Treatment non'com #iance G2:QH Kew diagnosis of dia$etes G2!QH Ko 9nown reci itating event G2!QH ed dramatica##y

(ince the discovery and thera eutic use of insu#in? the morta#ity from .5A has dro from 1::Q to erha s 2 to !Q in Oestern countries today. G*e$ovit&? 188!H

An out#ine of the atho hysio#ogy is resented $e#ow. The athogenesis re<uires two eventsD Increased mo$i#isation of free fatty acids G66AH from adi ose tissue to the #iver A switch of he atic #i id meta$o#ism to 9etogenesis 66A mo$i#isation is initiated $y the effect of a$so#ute or re#ative insu#in deficiency on fat ce##s. 66A #eve#s can $e <uite high Geg 2.! to 3.! mMH. This rovides the #iver with #enty of su$strate. These 66A #eve#s are much #ess then 9etone #eve#s and contri$ute on#y a sma## amount to the meta$o#ic acidosis. The maBor switch in he atic #i id meta$o#ism occurs in res onse not Bust to insu#in deficiency $ut additiona##y to the concomitant rise in #eve#s of the stress hormones Gg#ucagon? corticosteroids? catecho#amines? growth hormoneH. The ro#e of g#ucagon is the most c#ear#y esta$#ished. The he atic effects of a fa## in the insu#inDg#ucagon ratio areD Increased g#ycogeno#ysis Increased g#uconeogenesis Increased 9etogenesis The net effect is an increase in the he atic out ut of $oth 9etone $odies and g#ucose. Initia# 1vents in 4atho hysio#ogy of .ia$etic 5etoacidosis GIK"OM4*1T1H Insu#in .eficiency (tress Hormone 17cess

.ecreased g#ucose u ta9e eri hera##y

Mo$i#isation of 66A from fat ce##s $y musc#e and fat , (witch in He atic *i id Meta$o#ism

Hy erg#ycaemia

5etoacidosis

(ym toms C signs of .5A

5hy does the ,a)or s4itch in hepatic ,etabolis, occur9 The inhi$ition of the en&yme acety# "oA car$o7y#ase is ro$a$#y the 9ey ste . This en&yme is inhi$ited $y increased 66A #eve#s? decreased insu#in #eve#s and articu#ar#y $y the rise in g#ucagon. A## three of these factors are resent in .5A. The effect is to decrease the roduction and #eve# of ,alonyl CoA. This com ound has a centra# ro#e in the regu#ation of he atic fatty acid meta$o#ism as is mediates the reci roca# re#ationshi $etween fatty acid synthesis and o7idation. It is the first committed intermediate in fatty acid meta$o#ism. Ma#ony# "oA inhi$its fatty acid o7idation $y inhi$iting carnitine acy#transferase I. A fa## in ma#ony# "oA #eve#s removes this inhi$ition resu#ting in e7cessive fatty acid o7idation with e7cessive roduction of acety# "oA and e7cess acetoacetate. Hyperglycae,ia 8 Ketoacidosis cause ,ost sy,pto,s Two $asic mechanisms under#ie the atho hysio#ogy of .5AD hy erg#ycaemia and 9etoacidosis. The a$ove discussion shows how $oth these ro$#ems fo##ow from re#ative insu#in deficiency cou #ed with stress hormone e7cess. The ro$#em however is not Bust of he atic over' roduction of g#ucose and 9etones $ut a#so of eri hera# underuti#isation of $oth g#ucose and 9etones. Acetoacetic acid G 5a 3.!3H and $eta'hydro7y$utyric acid G 5a 4.2:H dissociate roducing H, which is $uffered $y H"O3' in the $#ood. 6or each anion roduced there is a #oss of one $icar$onate. The increase in the anion ga Gre resenting the increase in the unmeasured acid anionsH shou#d a ro7imate#y e<ua# the decrease in the +H"O3'-. A = ure> high anion ga meta$o#ic acidosis resu#ts. e/elop,ent of hyperchlorae,ic acidosis In some cases? a hy erch#oraemic meta$o#ic acidosis deve#o sD this is most common during the treatment hase. Ohy does this occurT Acetoacetate and $eta'hydro7y$utyrate are moderate#y strong acids and even at the #owest urinary H are significant#y ionised. They are e7creted with a cation Gusua##y Ka, or 5,H to maintain e#ectroneutra#ity. The net effect is the #oss of = otentia# $icar$onate> e<ua# to the #eve# of urinary 9etone $ody #oss. The H"O3' is re #aced in the $#ood $y "#' derived from rena# rea$sor tion? gut a$sor tion or G articu#ar#yH I; sa#ine administered during treatment. The effect is to cause a rise in #asma +"#'- and the anion ga returns towards norma# des ite the ersistence of the meta$o#ic acidosis. At resentation? $oth ty es of acidosis may $e resent and the e#evation in the anion ga wi## $e #ess than e7 ected for the degree of de ression in the $icar$onate #eve# Gresu#ting in .e#ta ratio W :.3H. A redominant hy erch#oraemic acidosis Gdefined as a .5A atient with a de#ta ratio W :.4H is resent

in a$out 1:Q of atients on arriva# at hos ita# and in a$out 2:Q after 3 hours of treatment. 4atients who are more severe#y dehydrated retain more 9eto'anions and have a #ower incidence of hy erch#oraemic acidosis. Administration of #arge vo#umes of norma# sa#ine in resuscitation of atients with acute .5A romotes continued diuresis Gand continued #oss of 9etone $odies with Ka, as the cationH and rovides #enty of ch#oride to re #ace the #ost 9etoanions. This hy erch#oraemic acidosis is s#ower to reso#ve $ecause the 9eto'anions needed for regeneration of $icar$onate have $een #ost. 4atients who have $een a$#e to maintain f#uid inta9e during deve#o ment of their i##ness are more #i9e#y to have a hy erch#oraemic acidosis com onent resent on admission. 3ther acid base disorders ,ay be present It shou#d not Bust $e assumed that the atient on#y has a dia$etic 9etoacidosis. 4ossi$#e com #icating acid'$ase disorders areD *actic acidosis due to hy o erfusion and anaero$ic musc#e meta$o#ism Meta$o#ic a#9a#osis secondary to e7cessive vomiting )es iratory acidosis due to neumonia or menta# o$tundation )es iratory a#9a#osis with se sis )ena# tu$u#ar acidosis Gty e 4H

)ena# tu$u#ar acidosis Gty e 4H is resent in some dia$etic atients and the associated urinary acidification defect can cause a hy erch#oraemic norma# anion ga acidosis. This syndrome G9nown as hy+or&nin&mic hy+oaldos'&ronismH occurs in some e#der#y dia$etics who have re'e7isting moderate rena# insufficiency $ut is not a common ro$#em in acute .5A. (ummary of 1vents in 4atho hysio#ogy of .5A 6irstD A reci itating event occurs which resu#ts in insu#in deficiency Ga$so#ute or re#ativeH and usua##y an e7cess of stress hormones G articu#ar#y g#ucagonH Hy erg#ycaemia occurs due to decreased g#ucose u ta9e in fat and musc#e ce##s Gdue to insu#in deficiencyH *i o#ysis in fat ce##s now occurs romoted $y the insu#in deficiency re#easing 66A into the $#ood 1#evated 66A #eve#s rovide su$strate to the #iver A switch in he atic #i id meta$o#ism occurs due to the insu#in deficiency and the g#ucagon e7cess? so the e7cess 66A is meta$o#ised resu#ting in e7cess roduction of acety# "oA. The e7cess he atic acety# "oA is converted to acetoacetate Ga 9eto'acidH which is re#eased into the $#ood 5etoacidosis and hy erg#ycaemia $oth occur due to the #ac9 of insu#in and the increase in g#ucagon and most of the c#inica# effects fo##ow from these two factors Other acid'$ase and e#ectro#yte disorders may deve#o as a conse<uence and com #icate the c#inica# condition

Acid-Base 1hysiology (22 Ketoacidosis ?continuedA 4revious S Inde7 S Ke7t (222# $anage,ent of KA An out#ine of management is resentedD this shou#d $e tai#ored to individua# circumstances. Management of .5A has assed through 3 stages in the #ast 1:: yearsD (tage 1D 4reinsu#in era G6eatureD morta#ity of 1::QH (tage 2D High dose insu#in regime G6eatureD morta#ity down to 1:Q $ut meta$o#ic com #ications due to the treatmentH (tage 3 Gthe resentHD *ow dose insu#in regime G6eatureD #ow morta#ityH Morta#ity with the #ow dose insu#in regime is down to a$out 2 to !Q overa##. In o#der atients with .5A reci itated $y a maBor medica# i##ness Geg acute ancreatitis? myocardia# infarction? se ticaemiaH? the morta#ity rate is sti## high due to the severity of the reci itating ro$#em. Overa## aims of treatment )e #ace f#uid and e#ectro#yte #osses )estore norma# car$ohydrate and #i id meta$o#ism Treat the under#ying cause Manage s ecific com #ications

Management can $e considered in terms of emergency and routine com onents. C,ergency $anage,ent A: Air4ay 4rotect $y intu$ation with a cuffed tu$e if atient is significant#y o$tunded. "onsider #acing a nasogastric tu$e in a## atients. B: Breathing O7ygen $y mas9 initia##y in a## atients Intu$ation may $e necessary for airway rotection or venti#ation Geg if as iration? coma? neumonia? u#monary oedema? acute ancreatitis and A).(H $ut this is not common. ( ecia# .anger in ;enti#ated 4atients $aintain co,pensatory hyper/entilation in intubated patients 4atients with meta$o#ic acidosis Geg severe .5AH have mar9ed hy erventi#ation Gie res iratory com ensation? =5ussmau# res irations>H and ty ica##y #ow arteria# "O2 #eve#s. If intu$ated and venti#ated? venti#atory arameters Gtida# vo#ume and rateH need to $e set to continue a high minute venti#ation. If this is not done and "O2 is ina ro riate#y high? a

severe acidaemia and conse<uent severe cardiovascu#ar co##a se may occur This is a articu#ar ro$#em in a## situations where a atient with a com ensated meta$o#ic acidosis is intu$ated and venti#ated. The ru#e of thum$ is to aim for a "O2 #eve# of 1.! times the $icar$onate #eve# #us eight as this mimics the norma# res onse $y the $ody. As $icar$onate #eve#s recover? adBust venti#ation downwards. C: Circulation If shoc9 is resent? this re<uires urgent co##oid infusion to restore intravascu#ar vo#ume and tissue erfusion Arrhythmias re<uire urgent c#inica# management de endent on the ty e and the c#inica# situation Geg hy er9a#aemia? myocardia# infarctionH The ty ica# atient who resents with oor eri hera# erfusion $ut normotension can $e ade<uate#y managed initia##y with 1"6 re #acement f#uids Geg Hartmann>s so#ution or Korma# sa#ineH 3ther 0pecific C,ergency *reat,ent Cerebral oede,a is a dangerous com #ication that occurs in a$out 1Q of chi#dren and ado#escents with .5A. Onset of headache and deteriorating #eve# of consciousness ty ica##y occurs $etween 2 and 24 hours after onset of treatment. Onset of sym toms is often sudden. Morta#ity is a$out 2:Q in this grou . )ecommended treatment is immediate I; mannito# in a dose of :.! to 2.: gI9g $ody weight. .e7amethasone or hy erventi#ation have no roven $enefit. G*e$ovit&? 188!H KA : "outine $anage,ent 12 Beneral O7ygen $y mas9 0rinary catheter "onsider #ow dose ca#cium he arin to decrease ris9 of arteria# throm$osis Investigate for under#ying i##ness Ghistory? e7amination? cu#tures of $#ood? urine or s utum? chest 7ray? 1"/ etcH

22 Dluids Immediate aim is to restore intravascu#ar vo#ume to im rove tissue erfusion. )e #acement so#utions Geg Korma# sa#ine or Hartmann>s so#utionH are a ro riate for initia# management. (u$se<uent#y f#uids need to $e adBusted to rovide =free water> to re #enish intrace##u#ar f#uid and to rovide g#ucose. Maintenance f#uids such as de7trose'sa#ine or ora# f#uid inta9e are a ro riate at this #ater stage de ending on the individua# circumstances $ut such so#utions shou#d not $e used initia##y. "o##oids are necessary on#y in shoc9ed atients. "o##oids are e7 ensive and have a #ow $ut significant ris9 of reactions. A#$umin so#utions are not re<uired.

32 1otassiu, (erum #eve# is common#y norma# or high Gdue to the acidosisH at resentation des ite the resence of a #arge tota# $ody otassium deficit Gdue to rena# #ossesH. The $est a roach is to commence thera y with f#uid and insu#in and monitor the serum +5,-. 4otassium re #acement can $e commenced when the +5,- fa##s $e#ow ! mmo#sI#. Infuse at 1: to 3: mmo#Ihr de endent on +5,-. )ates greater than 2: mmo#sIhr are reserved for severe hy o9a#aemia and re<uire at #east hour#y +5,- monitoring. Kever commence a otassium infusion without chec9ing the #eve#. !2 Insulin 6#uid resuscitation is necessary to de#iver insu#in to its sites of action in #iver? musc#e and adi ose tissue. )ehydration itse#f wi## cause a fa## in $#ood g#ucose #eve#. A ty ica# regime wou#d $e to give a stat dose initia##y Gsay 1:'2:0 I;H and commence the atient on a continuous insu#in infusion at ! to 1: 0Ihr decreasing to 1'3 0Ihr to maintain $#ood g#ucose at ! to 1: mmo#sI#. A aediatric regime wou#d $eD insu#in at :.10I9g I; #oading dose then infusion at :.10I9gIhr. The $#ood g#ucose a#ways fa##s on this regime and contro# of $#ood g#ucose is a#most never a ro$#em. Insu#in reverses the eri hera# mo$i#isation of 66A and a#ters he atic meta$o#ism to switch off 9etone $ody roduction. These effects are ma7ima# at insu#in #eve#s of 1:: micromo#esI# and this #eve# is achieved with the #ow dose regime. The average rate of fa## of #asma g#ucose at this insu#in #eve# is a$out 4.! mmo#I#Ihr. There is no advantage in giving more insu#in once the cei#ing #eve# is reached. This a$sence of additiona# effectiveness with very high insu#in #eve#s has $een referred to in the ast as insulin r&sis'anc& #2 1hosphate Though a tota# $ody deficiency is a#ways resent? it has not $een ossi$#e to show that acute hos hate administration ma9es any difference to outcome. However the occasiona# atient deve#o s e7treme#y #ow hos hate #eve#s and hos hate administration is undou$ta$#y necessary in these atients and must $e given. 4hos hate #eve# on resentation is ty ica##y high so hos hate administration shou#d $e de#ayed. By twe#ve hours after commencement of treatment? the maBority G8:QH of atients are hy o hos hataemic. Am ou#es of hos hate avai#a$#e in my hos ita# contain a$out 1! mmo#es of hos hate and 2: mmo#es of otassium and one am ou#e can $e di#uted in the I; f#uids and infused over an hour. %2 Bicarbonate (odium $icar$onate in .5A has argua$#y a minor ro#e is in urgent management of serious arrhythmias due to hy er9a#aemia in .5A. However? g#ucose'insu#in is the referred treatment in this atient grou . Kone of the studies done in .5A have shown any $enefit of $icar$onate treatment. 4otentia# ro$#ems are sodium over#oad? "(6 acidosis? intrace##u#ar acidosis? e7acer$ation of hy o9a#aemia? re$ound a#9a#osis and im aired tissue o7ygen de#ivery Gshift of o7yhaemog#o$in dissociation curveH. After treatment of .5A starts? the s#owest $iochemica# arameter to recover is usua##y the serum $icar$onate ' this is es ecia##y so when su$stantia# amounts of 9etones have $een #ost in the urine. Kew $icar$onate

is generated when the condition is reversed and the 9etones are meta$o#ised. Bicar$onate administration is not necessary. '2 $onitoring Management in an Intensive "are 0nit is recommended. Monitoring shou#d inc#ude o$servations of airway? $reathing? circu#ation and #eve# of consciousness? seria# $#ood gases and e#ectro#ytes? urinary 9etones and urine out ut. (erum #actate is occasiona##y usefu#. A 5ioch&mis'ry 8lowchar' of resu#ts is strong#y recommended. "ere$ra# oedema resents 2 to 12 hours after start of treatment "ere$ra# oedema is the commonest sing#e cause of morta#ity? articu#ar#y in chi#dren. It ty ica##y deve#o s after treatment has commenced. A headache or decreasing #eve# of consciousness are the usua# initia# sign. Onset may $e sudden. Treat urgent#y with I; mannito#. Intu$ation for airway rotection may $e re<uired. Maintain hy erventi#ation in venti#ated atients. (2 *reat the 7nderlying Cause The commonest reci itants in young dia$etics are inade<uate insu#in Geg first resentation of dia$etes? omission of dosesH and infection. Often no s ecific cause can $e found. In o#der dia$etics? .5A may $e reci itated $y a maBor medica# i##ness Ges infectionH. Anti$iotics or surgica# management are necessary in some cases. 4atient education to revent further e isodes is very im ortant. WU'' ''''''''''''''''''''''''''''''''''''''''''''''''''''''' ''X

Acid-Base 1hysiology (23 Acidosis and "enal Dailure

(2321 $echanis,s Meta$o#ic acidosis occurs with $oth acute and chronic rena# fai#ure and with other ty es of rena# damage. The anion ga may $e norma# or may $e e#evated. A genera#isation that can $e made isD If the rena# damage affects $oth g#omeru#i and tu$u#es? the acidosis is a high'anion ga acidosis. It is due to fai#ure of ade<uate e7cretion of various acid anions due to the great#y reduced num$er of functioning ne hrons. If the rena# damage redominant#y affects the tu$u#es with minima# g#omeru#ar damage? a different ty e of acidosis may occur. This is ca##ed )ena# Tu$u#ar Acidosis G)TAH and this is a norma# anion ga or hy erch#oraemic ty e of acidosis. The /6) may $e norma# or on#y minima##y affected.

(2322 7rae,ic Acidosis The acidosis occurring in uraemic atients 1 is due to fai#ure of e7cretion of acid anions G articu#ar#y hos hate and su# hateH $ecause of the decreased num$er of ne hrons. There is a maBor decrease in the num$er of tu$u#e ce##s which can roduce ammonia and this contri$utes to uraemic acidosis. (erious acidosis does not occur unti# the /6) has decreased to a$out 2: m#sImin. This corres onds to a creatinine #eve# of a$out :.3:':.3! mmo#sI#. The #asma $icar$onate in rena# fai#ure with acidosis is ty ica##y $etween 12 C 2: mmo#sI#. Intrace##u#ar $uffering and $one $uffering are im ortant in #imiting the fa## in $icar$onate. This $one $uffering wi## cause #oss of $one minera# Gosteoma#aciaH. Most other forms of meta$o#ic acidosis are of re#ative#y short duration as the atient is either treated with reso#ution of the disorder or the atient dies. 0raemic acidosis is a maBor e7ce tion as these atients survive with significant acidosis for many years. This #ong duration is the reason why #oss of $one minera# Gand $one $ufferingH is significant in uraemic acidosis $ut is not a feature of other causes of meta$o#ic acidosis. (2323 Acidosis due to Acute "enal Dailure )etention of meta$o#ic acids occurs with acute rena# fai#ure. The c#inica# detai#s in these atients are often com #e7 and the actua# severity of acidosis is varia$#e. (ome other com #icating factors are cata$o#ism Gincreased meta$o#ic acid roductionH? vomiting? diarrhoea? #actic acidosis due to oor erfusion? $icar$onate thera y and dia#ysis. Hy er9a#aemia is often resent and is often the factor determining the need for acute dia#ysis. "eferences 1. 5raut PA and 5urt& I. M&'a*olic acidosis of 4K6: dia)nosis, clinical charac'&ris'ics, and 'r&a'm&n'. Am P 5idney .is 2::! PunJ 4!G%H 823'83. 4u$Med

Acid-Base 1hysiology (2! Hyperchlorae,ic $etabolic Acidosis

(2!21 Is this the sa,e as nor,al anion gap acidosis9 In hy erch#oraemic acidosis? the anion'ga is norma# Gin most casesH. The anion that re #aces the titrated $icar$onate is ch#oride and $ecause this is accounted for in the anion ga formu#a? the anion ga is norma#. There are *53 proble,s in the definition of this ty e of meta$o#ic acidosis which can cause confusion. "onsider the fo##owingD

5hat is the difference bet4een a Shyperchlorae,ic acidosisS and a Snor,al anion gap acidosisS9 These terms are used here as though they were synonymous. This is most#y true? *u' if hy onatraemia is resent the #asma +"#'- may $e norma# des ite the resence of a norma# anion ga acidosis. This cou#d $e considered a Er&la'iv& hy+&rchlora&miaE. However? you shou#d $e aware that in some cases of norma# anion'ga acidosis? there wi## not $e a hy erch#oraemia if there is a significant hy onatraemia. In a disorder that typically causes a high anion gap disorder there ,ay so,eti,es be a nor,al anion gapJ The anion ga may sti## $e within the reference range in #actic acidosis. Kow this can $e mis#eading to you when you are trying to diagnose the disorder. Once you note the resence of an anion ga within the reference range in a atient with a meta$o#ic acidosis you natura##y tend to concentrate on #oo9ing for a rena# or /IT cause. Fo4 ho4 could this happen9 12 3ne possibility is the increase in anions ,ay be too lo4 to push the anion gap out of the reference range2 In #actic acidosis? the c#inica# disorder can $e severe $ut the #actate may not $e gross#y high Geg #actate of %mmo#I#H and the change in the anion ga may sti## #eave it in the reference range. (o the causes of high anion ga acidosis shou#d $e considered in atients with hy erch#oraemic acidosis if the cause of the acidosis is otherwise not a arent. Administration of I; sa#ine so#ution may re #ace #ost acid anion with ch#oride so that treatment may resu#t in the acidosis converting to a hy erch#oraemic ty e. 22 Another possibility is intracellular ,o/e,ent of acid anions in e6change for chloride In #actic acidosis? the movement of #actate intrace##u#ar#y in e7change for ch#oride occurs via an anti ort. It has $een found that when #actic acidosis occurs in association with grand ma# sei&ures then as many as 3:Q of this grou of atients may resent with a hy erch#oraemic com onent to their acidosis. This is an interesting situation $ecause the #actic acidosis is due so#e#y to muscu#ar over' roduction? occurs ra id#y C can $e severe B0T it a#so reso#ves ra id#y. This shou#d therefore $e a = ure> #actic acidosis initia##y without any res iratory com ensation or evidence of other acid'$ase ro$#em. (o if we find a hy erch#oraemic com onent this c#ear#y suggests that the #actate is $eing ta9en u $y some ce##s in e7change for ch#oride. This movement of the acid anion intrace##u#ar#y is one mechanism res onsi$#e for a hy erch#oraemic com onent in some ty es of high anion ga acidosis. 32 *he situation ,ay also be due to the 4ide nor,al range of the anion gap2 This cou#d resu#t in a situation where the anion ga is on#y e#evated s#ight#y or sti## within the norma# range due to the com$ination of sma## errors in the measurement of the com onent e#ectro#ytes. (2!22 Causes of Hyperchlorae,ic Acidosis (ome of the causes are #isted in the Ta$#e in (ection !.2 and some of these are discussed $e#ow. )ena# tu$u#ar acidosis is discussed in the ne7t section. A review of these causes shows that the redominant mechanism is loss of base G$icar$onate or $icar$onate recursorsH and this may occur $y either /IT or rena# mechanisms. A gain of acid can occur with certain infusions $ut this situation can $e diagnosed easi#y on history. In genera# then the diagnosis of a norma# anion ga acidosis is Bust to #oo9 for evidence of one of on#y

two mechanismsD /IT #oss of $ase )ena# #oss of $ase A 9ey <uestion is to distinguish /IT causes from rena# causes. In most cases? this wi## $e o$vious from the history. In some cases though some factors may $e invo#ved or there may $e some dou$t as to which cause is the most significant. (2!23 BI* Bicarbonate :oss (ecretions into the #arge and sma## $owe# are most#y a#9a#ine with a $icar$onate #eve# higher than that in #asma. 17cessive #oss of these f#uids can resu#t in a norma# anion ga meta$o#ic acidosis. (ome ty ica# at ris9 c#inica# situations areD severe diarrhoea vi##ous adenoma e7terna# drainage of ancreatic or $i#iary secretions Geg fistu#asH chronic #a7ative a$use administration of acidifying sa#ts

0e/ere diarrhoea This can cause either a meta$o#ic acidosis or a meta$o#ic a#9a#osis. .eve#o ment of a significant acid' $ase distur$ance re<uires a significant increase in stoo# water #oss a$ove its norma# va#ue of 1:: to 2:: m#sIday. The more f#uid and anions #ost? the more mar9ed the ro$#em. Hy erch#oraemic meta$o#ic acidosis tends to $e associated with acute infective diarrhoea. This is the c#assica# finding in atients with cho#era. The ro$#em is an e7cessive #oss of $icar$onate in the diarrhoea# f#uid. .iarrhoeas which are caused $y redominant#y colonic atho#ogy may cause a meta$o#ic a#9a#osisD this inc#udes chronic diarrhoeas due to u#cerative co#itis? co#onic "rohn>s disease and chronic #a7ative a$use. The acid'$ase situation with severe diarrhoea can $e com #icated $y other factors Gsee Ta$#e $e#owH and it may not $e ossi$#e to com #ete#y sort out a## the factors in the acid'$ase distur$ance in an individua# case. $ultiple Dactors 4hich affect Acid-Base balance in patients 4ith 0e/ere iarrhoea 0ituation Acute infective diarrhoea Gsma## $owe# originH "hronic co#onic diarrhoea Hy ovo#aemia causing rerena# rena# fai#ure Hy ovo#aemia causing eri hera# Co,,ent Korma# anion ga Ghy erch#oraemicH meta$o#ic acidosis due #oss of $icar$onate May $e meta$o#ic a#9a#osis due redominant #oss of "#' High anion ga acidosis due to rena# retention of hos hate Csu# hate. Ty e A #actic acidosis

circu#atory fai#ure Hy ovo#aemia causing an increase in #asma rotein concentration Gincreased unmeasured anionH ;omiting A$domina# ain Increased anion ga

Meta$o#ic a#9a#osis due #oss of gastric H"# Hy erventi#ation Gres iratory a#9a#osisH

;illous adeno,a This can cause hy o9a#aemia. Acid'$ase disorders may a#so occurD this isD a hy erch#oraemic acidosis if $icar$onate is the rinci a# anion #ost? or: a meta$o#ic a#9a#osis if ch#oride is the redominant anion #ost. If hy ovo#aemia occurs? this may cause a meta$o#ic acidosis. 4#asma $icar$onate #eve#s of #ess than 1: mmo#I# have $een recorded. rainage of pancreatic or biliary secretions *oss of these secretions can cause a hy erch#oraemic acidosis due to the high $icar$onate #eve#s in these secretions. The fre<uency and severity de end on the dai#y vo#ume of secretions #ost. *ow out ut fistu#ae don>t cause a ro$#em. 4harmaco#ogica# treatments Geg somatostatinH which decrease the vo#ume #ost $y high out ut fistu#ae are effective at reventing the acidosis. :osses /ia a nasogastric tube In atients with a sma## $owe# o$struction? these #osses can $e redominant#y of $i#e and ancreatic secretions and cause an acidosis Grather than an a#9a#osis as is usua# with severe vomitingH. 4atients on roton um inhi$itors or H2'$#oc9ers may a#so $e more #i9e#y to #ose redominant#y a#9a#ine secretions. (2!2! 7rinary i/ersions Im #antation of the ureters into the sigmoid co#on or a vesicoco#ic fistu#a can resu#t in a hy erch#oraemic acidosis due to a$sor tion of "#' in e7change for H"O3' across the $owe# mucosa. A$sor tion of urinary KH 4, in the sigmoid co#on may a#so contri$ute to the deve#o ment of acidosis as meta$o#ism of the ammonium in the #iver resu#ts in roduction of H,. (ome of these atients deve#o rena# fai#ure re#ated to infection? stones or urinary o$struction. This can resu#t in uraemic acidosis or rena# tu$u#ar acidosis as we##. Acidosis is much #ess of a ro$#em with an i#ea# conduit Gacidosis incidence 2 to 2:QH than it was with the o#der rocedure of ureterosigmoidostomy Gincidence 3:'3:QH. GIncidence data from "ru&? 1882H This is $ecause the continuous e7terna# drainage from the i#ea# conduit usua##y resu#ts in a short dwe## time in the conduit with minima# time for "#''H"O3' e7change. The resence of urinary diversion o erations wi## usua##y $e o$vious from the history.

(2!2# 3ther Causes "eco/ery 1hase of iabetic Ketoacidosis Hy erch#oraemic meta$o#ic acidosis common#y deve#o s during thera y of dia$etic 9etoacidosis. The mechanisms invo#ved have $een discussed in (ection 3.2. The mechanism is effective#y rena# #oss of $ase even though it is not $icar$onate which is #ost in the urine. The actua# #oss is of 9etoacids G9eto' anionsH and water. Ohen thera y commences? the 9etoacids are meta$o#ised in the #iver resu#ting in the roduction of e<ua# amounts of $icar$onate. If e7cessive 9etoacids have $een #ost in the urine and f#uid thera y is initia##y with norma# sa#ine? there is a deficiency of $icar$onate recursors and a surfeit of ch#oride to re #ace $icar$onate. "orrection of the acidosis wi## now invo#ve rena# e7cretion of ch#oride and its re #acement with $icar$onate. This is a s#ower rocess than meta$o#ism of 9etoacids to regenerate $icar$onate. The net resu#t then is that fu## correction of the acidosis is much s#ower when a hy erch#oraemic acidosis deve#o s. Chronic Ad,inistration of Carbonic Anhydrase Inhibitors Korma##y 3!Q of fi#tered $icar$onate is rea$sor$ed in the ro7ima# tu$u#e and the remaining 1!Q is rea$sor$ed in the rest of the tu$u#e. In atients receiving aceta&o#amide Gor other car$onic anhydrase inhi$itorsH? ro7ima# rea$sor tion of $icar$onate is decreased and dista# de#ivery is increased. The dista# tu$u#e has on#y a #imited ca acity to rea$sor$ $icar$onate and when e7ceeded $icar$onate a ears in the urine. This resu#ts in a hy erch#oraemic meta$o#ic acidosis. This can $e considered as essentia##y a form of ro7ima# rena# tu$u#ar acidosis Gsee section 3.!H $ut is usua##y not c#assified as such. 3ral Ingestion of Acidifying 0alts Ora# administration of "a"#2 or KH4"# is e<uiva#ent to giving an acid #oad. Both of these sa#ts are used in acid #oading tests for the diagnosis of rena# tu$u#ar acidosis. "a"#2 reacts with $icar$onate in the sma## $owe# resu#ting in the roduction of inso#u$#e "a"O3 and H,.The he atic meta$o#ism of KH4, to urea resu#ts in an e<uiva#ent roduction of H ,.

Acid-Base 1hysiology (2# "enal *ubular Acidosis

(2#21 efinition )ena# Tu$u#ar Acidosis G)TAH is a syndrome due to either a defect in ro7ima# tu$u#e $icar$onate rea$sor tion? or a defect in dista# tu$u#e hydrogen ion secretion? or $oth. This resu#ts in a hy erch#oraemic meta$o#ic acidosis with norma# to moderate#y decreased /6). Anion ga is norma#. A ty ica# situation where )TA wou#d $e sus ected is if urine H is greater than 2.: des ite the resence of a meta$o#ic acidosis. In contrast? the acidosis that occurs with acute? chronic? or acute on chronic rena# fai#ure is a high anion ga meta$o#ic acidosis.

As a genera# overview to he# understand why rena# disease can give different ty es of acidosis consider the fo##owingD Acidosis due to rena# disease is considered in 2 categories de ending on whether the redominant site of rena# damage is in the )lom&ruli or in the 'u*ul&s. )ena# tu$u#ar acidosis is a form of hy erch#oraemic meta$o#ic acidosis which occurs when the rena# damage rimari#y affects tu$u#ar function without much effect on g#omeru#ar function. The resu#t is a decrease in H, e7cretion which is greater than can $e e7 #ained $y any change in /6). In contrast? if g#omeru#ar function Gie /6)H is significant#y de ressed Ghence Erena# fai#ureEH? the retention of fi7ed acids resu#ts in a high anion ga acidosis. Acidosis and :ocation of "enal a,age 4redominant#y tu$u#ar damage ---N Korma# anion ga acidosis G)ena# tu$u#ar acidosis ' )TAH .ista# Gor ty e 1H )TA 4ro7ima# Gor ty e 2H )TA Ty e 4 )TA 4redominant#y g#omeru#ar damage ---N High anion ga acidosis Acidosis of acute rena# fai#ure 0raemic acidosis Three main c#inica# categories or Ety esE of rena# tu$u#ar acidosis G)TAH are now recognised $ut the num$er of ossi$#e causes is #arge. The mechanism causing the defect in a$i#ity to acidify the urine and e7crete acid is different in the three ty es. 1,2 (2#22 istal ?*ype 1A "enal *ubular Acidosis This is a#so referred to as c#assic )TA or dista# )TA. The ro$#em here is an ina$i#ity to ma7ima##y acidify the urine. Ty ica##y urine H remains X !.! des ite severe acidaemia G+H"O3- W 1! mmo#I#H. (ome atients with #ess severe acidosis re<uire acid #oading tests Geg with KH4"#H to assist in the diagnosis. If the acid #oad dro s the #asma +H"O3- $ut the urine H remains X !.!? this esta$#ishes the diagnosis. There are many different causes $ut the maBority of cases can $e #aced into one of severa# grou sD Beneral Classification of Causes Hereditary GgeneticH 3,4 Autoimminue diseases Geg (Bogren>s syndrome? (*1? thyroiditisH .isorders which cause ne hroca#cinosis Geg rimary hy er arathyroidism? vitamin . into7icationH .rugs or to7ins Geg am hotericin B? to#uene inha#ationH Misce##aneous ' other rena# disorders Geg o$structive uro athyH The $asic ro$#em is reduced H, secretion in the dista# ne hron $ut there are severa# ossi$#e mechanisms Gsee ta$#e $e#owH. 1athophysiological $echanis,s in "educed H= 0ecretion in istal *ubule S5ea& pu,pS ' Ina$i#ity for H, um to um against a high H, gradient

S:ea&y ,e,braneS ' Bac9'diffusion of H, +eg This occurs in )TA due am hotericin B S:o4 pu,p capacityS ' Insufficient dista# H, um ing ca acity due to tu$u#ar damage. Ty ica# findings are an ina ro riate#y high urine H Gusua##y X !.!H? #ow acid secretion and urinary $icar$onate e7cretion des ite severe acidosis. )ena# sodium wasting is common and resu#ts in de #etion of 1"6 vo#ume and secondary hy era#dosteronism with increased #oss of 5, in the urine. The diagnosis of ty e 1 )TA is suggested $y finding a hy erch#oraemic acidosis in association with an a#9a#ine urine articu#ar#y if there is evidence of rena# stone formation. Treatment with KaH"O3 corrects the Ka, deficit? restores the e7trace##u#ar f#uid vo#ume and resu#ts in correction of the hy o9a#aemia. Ty ica# a#9a#i re<uirements are in the range of 1 to 4 mmo#I9gIday. 5, su #ements are on#y rare#y re<uired. (odium and otassium citrate so#utions can $e usefu# articu#ar#y if hy o9a#aemia is resent. "itrate wi## $ind "a,, in the urine and this assists in reventing rena# stones. iagnosis of istal "enal *ubular Acidosis Hyperchlorae,ic ,etabolic acidosis associated 4ith a urine pH N #2# despite plas,a <HC33> R 1# ,,ol@l 0uppporti/e findingsD hy o9a#aemia? ne roca#cinosis? resence of a disorder 9nown to $e associated with )TA Gsee #ist in te7tH KoteD If +H"O3 X 1! mmo#I#? then acid #oading tests are re<uired to esta$#ish the diagnosis. (2#23 1ro6i,al ?*ype 2A "enal *ubular Acidosis 1athophysiology Ty e 2 )TA is a#so ca##ed ro7ima# )TA $ecause the main ro$#em is great#y im aired rea$sor tion of $icar$onate in the ro7ima# tu$u#e. At norma# #asma +H"O3-? more than 1!Q of the fi#tered H"O3 #oad is e7creted in the urine. Ohen acidosis is severe and H"O3 #eve#s are #ow Geg W12 mmo#sI#H? the urine may $ecome $icar$onate free. (ym toms are reci itated $y an increase in #asma +H"O3-. The defective ro7ima# tu$u#e cannot rea$sor$ the increased fi#tered #oad and the dista# de#ivery of $icar$onate is great#y increased. The H, secretion in the dista# tu$u#e is now overwhe#med $y attem ting to rea$sor$ $icar$onate and the net acid e7cretion decreases. This resu#ts in urinary #oss of H"O3 resu#ting in systemic acidosis with ina ro riate#y high urine H. The $icar$onate is re #aced in the circu#ation $y "#'. The increased dista# Ka+ de#ivery resu#ts in hy era#dosteronism with conse<uent rena# 5, wasting. The hy o9a#aemia may $e severe in some cases $ut as hy o9a#aemia inhi$its adrena# a#dosterone secretion? this often #imits the severity of the hy o9a#aemia. Hy erca#ciuria does not occur and this ty e of )TA is not associated with rena# stones. .uring the KH4"# #oading test? urine H wi## dro $e#ow !.!.

Kote that the acidosis in ro7ima# )TA is usua##y not as severe as in dista# )TA and the #asma +H"O3is ty ica##y greater than 1! mmo#I#. Causes There are many causes $ut most are associated with mu#ti #e ro7ima# tu$u#ar defects eg affecting rea$sor tion of g#ucose? hos hate and amino acids. (ome cases are hereditary.5 Other causes inc#ude vitamin . deficiency? cystinosis? #ead ne hro athy? amy#oidosis and medu##ary cystic disease. *reat,ent Treatment is directed towards the under#ying disorder if ossi$#e. A#9a#i thera y GKaH"O3H and su #ementa# 5, is not a#ways necessary. If a#9a#i thera y is re<uired? the dose is usua##y #arge Gu to 1: mmo#sI9gIdayH $ecause of the increased urine $icar$onate wasting associated with norma# #asma #eve#s. 5, #oss is much increased in treated atients and su #ementation is re<uired. (ome atients res ond to thia&ide diuretics which cause s#ight vo#ume contraction and this resu#ts in increased ro7ima# $icar$onate rea$sor tion so #ess $icar$onate is needed. (2#2! *ype 3 "enal *ubular Acidosis .his term is no longer used. Ty e 3 )TA is now considered a su$ty e of Ty e 1 where there is a ro7ima# $icar$onate #ea9 in addition to a dista# acidification defect. (2#2# *ype ! "enal *ubular Acidosis A num$er of different conditions have $een associated with this ty e $ut most atients have rena# fai#ure associated with disorders affecting the rena# interstitium and tu$u#es. In contrast to uraemic acidosis? the /6) is greater than 2: m#sImin. 7seful differentiating point: Hyper&alae,ia occurs in type ! "*A ?but F3* in the other typesA The under#ying defect is im airment of cation'e7change in the dista# tu$u#e with reduced secretion of $oth H, and 5,. This is a simi#ar finding to what occurs with a#dosterone deficiency and ty e 4 )TA can occur with Addison>s disease or fo##owing $i#atera# adrena#ectomy. Acidosis is not common with a#dosterone deficiency alon& $ut re<uires some degree of associated rena# damage Gne hron #ossH es affecting the dista# tu$u#e. The H, um in the tu$u#es is not a$norma# so atients with this disorder are a$#e to decrease urine H to W !.! in res onse to the acidosis.

The ta$#e $e#ow rovides a usefu# summary of some of the 9ey oints in differentiating the ty es of rena# tu$u#ar acidosis. Comparison of Major Types of RTA Type 1 Type 2 Type 4

Hyperchloraemi Yes c acidosis i!im"m pH #ri!e $5%5

Yes

Yes

&5%5 ('"( "s"ally &5%5 $5%5 'e)ore (he acidosis 'ecomes es(a'lished) +o,-!ormal High

*lasma po(assi"m -e!al s(o!es /e)ec(

+o,-!ormal

Yes -ed"ced H+ e0cre(io! i! dis(al ("'"le

.o 1mpaired H233 rea'sorp(io! i! pro0imal ("'"le

.o 1mpaired ca(io! e0cha!4e i! dis(al ("'"le

Incom #ete forms of )TA a#so occur. The arteria# H is norma# in these atients and acidosis deve#o s on#y when an acid #oad is resent. "eferences 1. *aing "M? Toye AM? "a asso /? and 0nwin )P. R&nal 'u*ular acidosis: d&v&lo+m&n's in our und&rs'andin) of 'h& mol&cular *asis. Int P Biochem "e## Bio# 2::! PunJ 32G%H 11!1'%1. 4u$Med 2. *aing "M and 0nwin )P. R&nal 'u*ular acidosis. P Ke hro# 2::% Mar'A rJ 18 (u # 8 (4%'!2. 4u$Med 3. Kico#etta PA and (chwart& /P. 6is'al r&nal 'u*ular acidosis. "urr O in 4ediatr 2::4 A rJ 1%G2H 184'3. 4u$Med 4. (haya9u# " and A# er (*. 3nh&ri'&d r&nal 'u*ular acidosis. "urr O in Ke hro# Hy ertens 2::: (e J 8G!H !41'%. 4u$Med !. Igarashi T? (e9ine T? and Oatana$e H. Mol&cular *asis of +ro:imal r&nal 'u*ular acidosis. P Ke hro# 2::2 Mar'A rJ 1! (u # ! (13!'41. 4u$Med A## Med#ine a$stractsD 4u$Med Hu$Med

Acid-Base 1hysiology (2% $etabolic Acidosis due to rugs and *o6ins 3.%.1 Methano# oisoning

3.%.2 1thy#ene g#yco# oisoning 3.%.3 (a#icy#ate to7icity 3.%.4 To#uene to7icity 3.%.! Overview of To7ic Ingestions

(evera# drugs and to7ins have $een im #icated as direct or indirect causes of a high'anion ga meta$o#ic acidosis GHA/MAH. A consideration of these drugs needs to $e inc#uded in an differentia# diagnosis of a HA/MA. The three most common ones to consider are methano#? ethy#ene g#yco# and sa#icy#ates. Other to7ins which can cause acidosis are iso ro y# a#coho# and $uto7yethano#. To#uene a#so causes an acidosis and the anion ga may $e norma# or e#evated. The acidosis caused $y these to7ins may sometimes resent as a norma# anion'ga hy erch#oraemic acidosis so donEt e7c#ude the diagnosis in such a circumstance. "o'ingestion of ethano# de#ays the meta$o#ism of the more to7ic methano# and ethy#ene g#yco# $ut can a#so de#ays the diagnosis. In this situation the osmo#ar ga wi## $e even more e#evated than can $e e7 #ained $y the measured ethano# #eve# a#one. +(ee a#so (ection 11.3D Acid'Base .isorders due to .rugs C To7ins.(2%21 $ethanol 1oisoning 1resentation 8 iagnosis Ingestion of methano# can occur accidenta##y? or de#i$erate#y if used as an ethano# su$stitute. Methano# itse#f is non'to7ic. Onset of sym toms is de#ayed unti# the to7ic meta$o#ites are roduced $y #iver. Because the he atic meta$o#ism is s#ow? there is usua##y a considera$#e latent period G12'43 hoursH $efore any to7ic effects deve#o . 4atients resenting ear#y with a history of ingestion wi## $e asym tomatic. 4atients resenting #ate are often dee #y comatose and $radycardic with de ressed res irations. (urvivors have a high incidence of irreversi$#e $#indness. A$domina# ain is a common sym tom and may $e due to acute ancreatitis. iagnosis ,ay be delayed if the history is not avai#a$#e Geg o$tunded atientH or $ecause of the significant de#ay $etween ingestion and sym toms. 1ar#y diagnosis is im ortant $ecause rom t and effective treatment can decrease morta#ity and decrease the incidence of $#indness. A usefu# screening test is determination of the osmo#ar ga . If the osmo#ar ga is greater than 1:? it indicates the resence of a recia$#e <uantities of #ow mo#ecu#ar weight su$stances such as methano#. This can a#ert you to the diagnosis $efore the acidosis Gdue to meta$o#itesH deve#o s. As the methano# is meta$o#ised? the osmo#ar ga returns toward norma# and the anion ga increases. A atient resenting #ate after a significant ingestion may have a norma# osmo#ar ga and a high anion ga acidosis. The osmo#ar ga is more #i9e#y to $e e#evated in methano# ingestion than with ethy#ene g#yco# ingestions $ecause of the #ower mo#ecu#ar weight of methano#. Osmo#ar ga s of X1:: have $een re orted. The idea# way to assess and monitor res onse to treatment is to measure methano# $#ood #eve#s. This test is KOT readi#y avai#a$#e in #a$oratories $ecause of infre<uent need and $ecause the test is #a$our intensive. Treatment shou#d KOT $e de#ayed $y de#ays in o$taining a $#ood methano# #eve#. Methano# #eve#s X2:mgId# are associated with severe to7icity.

The most serious to7ic manifestations areD meta$o#ic acidosis visua# im airment u to ermanent $#indness "K( de ression GEinto7icationEH u to coma death

In atients with severe acidosis Gindicating high formic acid #eve#sH? the morta#ity rate may $e !:Q or more. 1athophysiology Methano# is s#ow#y converted to forma#dehyde G$y a#coho# dehydrogenaseH and then to formic acid in the #iver. Methano# is not to7ic $ut $oth the maBor meta$o#ites interfere with o7idative hos hory#ation and it is these meta$o#ites that cause the to7ic effects. The acidosis is due to formic acid. As methano# is converted to its meta$o#ites the osmo#ar ga fa##s and the anion ga rises.

Dig2 $etabolis, of $ethanol (ome atients ingest ethano# as we## as methano# and this Gfortuitous#yH is rotective as it further de#ays the meta$o#ism and #imits the ea9 #eve#s of the to7ic meta$o#ites. (uch co'ingestion of ethano# can cause diagnostic ro$#ems. "#inicians are ty ica##y a#erted to the ossi$i#ity of ingestion of methano# Gor ethy#ene g#yco#H $y the com$ination of an acidosis and "K( sym toms Geg into7icationH. 1thano# can mis#ead the c#inician $ecause its further de#ays the onset of the acidosis? Ee7 #ainsE the resence of into7ication and a#so e7 #ains the resence of an osmo#ar ga . G(ee here for more detai#sH. EMethy#ated s iritsE is free#y avai#a$#e in Austra#ia from hardware stores. It is used $y some down'and' out a#coho#ics. This roduct contains 8!Q ethano# and u to !Q methano#J yridine is added to give a $itter taste to discourage drin9ing. Ingestion of this roduct may cause methano# to7icity $ut the ethano# content is rotective. Acid'Base .isorders in Methano# To7icity Initia##y no acid'$ase disorder due to #ong #atent eriod whi#e methano# is meta$o#ised *ater? ty ica##y deve#o a high anion ga meta$o#ic acidosis 'due to formic acid

May a#so deve#o a res iratory acidosis secondary to "K( de ression Gwith de ression of res iratory centre andIor airway o$structionH May occasiona##y resent with norma# anion ga acidosis if sma##er ingestion If atient is an a#coho#ic? there may other ty es of acidosis resent as we## Geg a#coho#ic 9etoacidosis? starvation 9etoacidosis? #actic acidosis? res iratory acidosis due as iration? res iratory a#9a#osis due chronic #iver disease.H *reat,ent /enera# rinci #es of treatment are out#ined $e#ow. Treatment must $e individua#ised to individua# atient circumstances. The $est outcome is o$tained with atients who resent ear#y? articu#ar#y during the #atent eriod. 4rinci #es of Treatment of Methano# 4oisoning 12 C,ergency $anage,ent )esuscitationD Airway? Breathing? "ircu#ation. O$tunded atients re<uire intu$ation for airway rotection and venti#ation. 2 2 $ethanol "e,o/al fro, body Hae,odialysis is the most effective techni<ueJ it a#so removes ethano# so ethano# infusion rate must $e increased during eriods of dia#ysis 3 2 Bloc&ing of $etabolis, This invo#ves com etitive inhi$ition of a#coho# dehydrogenase GA.HH. The aim is to de#ay the roduction of the to7ic meta$o#ites and #imit the ea9 concentrations achieved. Two agents are current#y in useD CthanolD @1thano# $#oc9ing@ treatment is the traditiona# treatment $ut has the disadvantage of causing into7ication G"K( de ressionH. It is a#so irritant and shou#d $e given via a centra# #ine. Do,epiKole Ga9a 4'methy# yra&o#eHD This is current#y a roved for this use in some countries G eg 0(A and "anada as EAnti&o#EH. Its advantages are effectiveness? ease of administration and a$sence of into7ication. Its use may o$viate the need for haemodia#ysis in atients without visua# im airment or severe acidosis. !2 Intensi/e supporti/e care 8 ,onitoring Management in an Intensive "are 0nit is recommendedJ Intu$ation C mechanica# venti#ation may $e indicated if there is inade<uate airway rotection Geg "K( de ressionH or inade<uate venti#ationJ Monitor res onse to treatment with methano# #eve#s Gif avai#a$#eH.

If intu$ated? hy erventi#ation must $e maintained to mimic the $odyEs com ensatory res onse

Do,epiKole 7se 6ome i&o#e is referred to ethano# if it is avai#a$#e. The drug is considered an Eor han drugE and can $e s ecia##y o$tained in Austra#ia from Or han Austra#ia 4ty *td. The cost of a ac9 of four 1.!g am ou#es is VA0.%?::: Gin 2::!H. The com any does not 9ee any stoc9 within Austra#ia so you have to order we## ahead. A ty ica# course of fome i&o#e wou#d $eD Initia# 1!mgI9g I; $o#us Gover 3: minutesH 1:mgI9g I; $o#us at 12 hour#y interva#s for 4 doses Increase to 1!mgI9g I; after 43 hours "ontinue unti# methano# #eve#s are #ow Geg W2:mgId#H

6ome i&o#e has an affinity for a#coho# dehydrogenase which is 3?::: times higher than that of methano#. Its use can resu#t in methano# #eve#s remaining a#most constant. This effective#y $#oc9s roduction of the to7ic meta$o#ites $ut the methano# remains in the $ody. Because of this? haemodia#ysis is now re<uired to remove the drug from the $ody. 6ome i&o#e is an e7treme#y effective antidote to methano# oisoning if started soon after the ingestion. 6ome i&o#e induces its own meta$o#ism so its dose needs to $e increased after 43 hrs. 1thano# thera y re<uires a $#ood #eve# of 1::'1!: mgId# to $e effective and to maintain this #eve# regu#ar monitoring of $#ood ethano# #eve# and adBustment of infusion rate is re<uired. The atient is significant#y into7icated $y this thera eutic ethano# #eve#. 6ome i&o#e does not cause any into7ication. +17am #e "ase ' "hi#d with ingestion of Oindscreen washer f#uid-

Acid-Base 1hysiology (2% $etabolic Acidosis due to rugs and *o6ins 3.%.1 Methano# oisoning 3.%.2 1thy#ene g#yco# oisoning 3.%.3 (a#icy#ate to7icity 3.%.4 To#uene to7icity 3.%.! Overview of To7ic Ingestions

(2%22 Cthylene Blycol 1oisoning 1thy#ene g#yco# is a co#or#ess sweet tasting so#vent which is used in antifree&e so#utions. It is nonto7ic itse#f $ut is converted to to7ic meta$o#ites in the #iverD

Blycolic acid G'Xg#yco#ate anionH is the maBor contri$utor to the often severe high anion ga acidosis that deve#o s 36alic acid G'Xo7a#ate anionH is one of the fina# meta$o#ic roducts which is e7creted in the urine. 4reci itation of ca#cium o7a#ate crysta#s in the 9idney causes rena# fai#ure if a sufficient dose has $een ingested.

Dig: $etabolis, of Cthylene Blycol If untreated? ingestion of on#y 3: to %: m#s may $e sufficient to cause ermanent organ damage or death. The osmo#ar ga may $e raised Gto X 1:H ear#y in the course $ut this is varia$#e. The detection of ca#cium o7a#ate crysta#s in the urine is often stated to $e a usefu# guide $ut this is wrong. "ertain#y. these crysta#s have a characteristic a earance G#see figure $e#owH and a urinana#ysis wi## easi#y detect them. The ro$#em is that o7a#ate crysta#s in urine are genera##y very common G3:Q of s ecimensH and their resence a#one means nothing for a diagnosis of ethy#ene g#yco# ingestion. Odd#y? cases of ethy#ene g#yco# ingestion have a#so $een re orted without o7a#ate crysta#s in the urine. There is a#so no oint in differentiating $etween the monohydrate and the dihydrate crysta#s.

Dig: Calciu, dihydrate crystals in urine - the ones 4ith the 'folded en/elope' appearance To7icity is usua##y considered as occurring in 3 stagesD into7ication? cardiores iratory changes and rena# to7icity Gsee $e#owH 0tages of Cthylene Blycol *o6icity 0tage 1: Into6ication 7p to 12 hours post-ingestion An ethano#'#i9e into7icated state Gwithout an a ro riate odour on the $reathH rogressing to "K( de ression 6its and coma may occur A high anion ga meta$o#ic acidosis deve#o s Kausea? vomiting? arrhythmias and tetany Gdue to hy oca#caemiaH may occur 0tage 2: Cardiorespiratory Changes Dro, 12 to 2! hours post-ingestion2 Tachycardia? tachy noea. (hoc9 may occur in maBor ingestions 0tage 3: "enal *o6icity At 2!-'2 hrs post-ingestion

Acute anuric rena# fai#ure may occur due to reci itation of ca#cium o7a#ate crysta#s in the rena# tu$u#es.

1rinciples of *reat,ent of Cthylene Blycol 1oisoning 12 C,ergency $anage,ent ) esuscitationD Airway? Breathing? "ircu#ation. O$tunded atients re<uire intu$ation for airway rotection and venti#ation. 22 Cthylene Blycol "e,o/al fro, body Haemodia#ysis is the most effective techni<ueJ it a#so removes ethano# so ethano# infusion rate must $e increased during eriods of dia#ysis Avoid #avage ' *avage is effective on#y if used within the first hour after ingestion and atients do not resent within this interva#. Avoid activated charcoa# ' This is KOT effective 32 Bloc&ing of $etabolis, CthanolD @1thano# $#oc9ing@ treatment is the traditiona# treatment $ut has the disadvantage of causing into7ication G"K( de ressionH. It is a#so irritant and shou#d $e given via a centra# #ine. Do,epiKole GEAnti&o#EHD This is current#y a roved for this use in some countries Geg 0(A and "anadaH. Its advantages are effectiveness? ease of administration and a$sence of into7ication. Its use may o$viate the need for haemodia#ysis in atients without severe acidosis. !2 Intensi/e supporti/e care 8 ,onitoring Management in Intensive "are 0nit is recommendedJ Intu$ation C mechanica# venti#ation may $e indicated if there is inade<uate airway rotection Geg "K( de ressionH or inade<uate venti#ation. If intu$ated? hy erventi#ation must $e maintained to mimic the $odyEs com ensatory res onse

Acid-Base 1hysiology (2% $etabolic Acidosis due to rugs and *o6ins 3.%.1 Methano# oisoning

3.%.2 1thy#ene g#yco# oisoning 3.%.3 (a#icy#ate to7icity 3.%.4 To#uene to7icity 3.%.! Overview of To7ic Ingestions

(2%23 0alicylate *o6icity (a#icy#ate overdose causes a high anion ga meta$o#ic acidosis in $oth chi#dren and adu#ts. Adu#ts common#y deve#o a mi7ed acid'$ase disorder as a res iratory a#9a#osis due to direct res iratory centre stimu#ation occurs as we##. This second disorder is uncommon in chi#dren. Acid'Base .isorders in (a#icy#ate To7icity AdultsD Meta$o#ic acidosis AK. )es iratory a#9a#osis ChildrenD Meta$o#ic acidosis If fastingLXstarvation 9etosis may deve#o )egarding harmaco9inetics of sa#icy#ateD A$sor tionD (a#icy#ates are readi#y a$sor$ed in the unionised form from the sma## intestine Meta$o#ismD The maBor route of $iotransformation is conBugation with g#ycine in the #iver 17cretionD The amount of drug e7creted unchanged in the urine is sma## $ut can $e mar9ed#y increased if urine is a#9a#ine *arge overdoses of as irin can cause a #arge ta$#et mass or $e&oar in the stomach. This de#ays a$sor tion and #asma sa#icy#ate #eve#s continue to rise over 2: hours or more. 6or this reason? seria# sa#icy#ate #eve#s shou#d $e measured unti# the ea9 has $een reached. )e eated ora# doses of activated charcoa# are indicated in this situation. High #eve#s of sa#icy#ate are to7ic $ecause the drug uncou #es o7idative hos hory#ation as we## as inhi$iting some en&ymes in the ce##. (a#icy#ates direct#y stimu#ate the res iratory center to cause hy erventi#ation Gres iratory a#9a#osisH which is dose'de endent. This stimu#ation is much more ronounced in adu#ts than in chi#dren. Meta$o#ic acidosis is the most serious acid'$ase disorder and is due to increased roduction of endogenous acids rather than the sa#icy#ate itse#f. 4#asma sa#icy#ate #eve#s rare#y e7ceed a ma7imum of a$out ! mmo#I# and the decrement in the +H"O3- is significant#y higher than this in these severe cases. Acidosis is much more ronounced in infants as com ared to adu#ts? which is the reverse of the situation with the hy erventi#ation. In adu#ts? res iratory a#9a#osis usua##y redominates. The articu#ar organic acid anions invo#ved in the acidosis of sa#icy#ate into7ication have not $een identified. 5etoacidosis may a#so occur in chi#dren who are i## and fasted Gie starvation 9etosisH. The com$ination of meta$o#ic acidosis and res iratory a#9a#osis can $e a difficu#t situation to diagnose from the $#ood gases. The ro$#em re#ates to whether the hy erventi#ation is rimary Gie res iratory a#9a#osisH or is com ensatory for the meta$o#ic acidosis.

(im #e urinary a#9a#inisation with administration of sodium $icar$onate is used to increase urine H to $etween 2.! and 3.!. Hy o9a#aemia is a ris9 and otassium shou#d $e given at the same time. Hy o9a#aemia a#so interferes with the 9idneyEs a$i#ity to a#9a#inise the urine. One recommended regime for an adu#t is to administer one #itre of 1.2%Q sodium $icar$onate so#ution Gcontaining 2:' 4:mmo#s of 5,H I; over a 3 hour eriod Clinical 1resentation The resentation in severe overdose is a comatose atient with mar9ed hy erventi#ation and ossi$#y convu#sions. (ma## chi#dren usua##y have a fever. In adu#ts? the diagnosis of overdose or over'ingestion is usua##y easi#y made from the history. "#inicians shou#d have a high inde7 of sus icion in chi#dren with a meta$o#ic acidosis articu#ar#y if 9etoacidosis? #actic acidosis and rena# fai#ure have $een e7c#uded. Another c#ue is that sa#icy#ates great#y increase urinary uric acid e7cretion and #asma urate #eve# is usua##y very #ow. If sus icious of overdose it is $etter to measure sa#icy#ate #eve# urgent#y. 0rine can $e screened with a ferric ch#oride test for sa#icy#ates. 4rinci #es of Treatment of (a#icy#ate To7icity 12 C,ergency $anage,ent )esuscitationD Airway? Breathing? "ircu#ation. O$tunded atients re<uire intu$ation for airway rotection and venti#ation. 22 0alicylate "e,o/al fro, body Al&aline diuresisD 0rinary e7cretion is very significant#y increased $y a#9a#isation of the urine. This may $e easi#y achieved $y giving I; sodium $icar$onate to raise urine H to $etween 2.! and 3.!J It is advisa$#e to give 5, to avoid hy o9a#aemia. 4#asma +5,- shou#d $e regu#ar#y monitored. GE6orced a#9a#ine diuresisE shou#d $e avoided as it confers no advantage and can cause f#uid over#oad.H However? I; fluid loading is genera##y im ortant to assist in maintaining an ade<uate urine out ut. Hae,odialysis is more effective and is the treatment of choice in severe oisonings. "riteria for dia#ysis are severe c#inica# features? resistant meta$o#ic acidosis? rena# fai#ure or sa#icy#ate #eve# X2::mgI#. /astic #avage is not usefu# un#ess time from ingestion is short. Activated charcoa# ' re eated doses can de#ay a$sor tionJ articu#ar#y indicated if ta$#et concretion has formed in the stomach 32 Intensi/e supporti/e care 8 ,onitoring Management in Intensive "are 0nit is recommendedJ Intu$ation C mechanica# venti#ation is indicated in comatose or significant#y o$tunded atients. If intu$ated? hy erventi#ation must $e maintained to mimic the $odyEs com ensatory

res onse WU'' ''''''''''''''''''''''''''''''''''''''''''''''''''''''' ''X (2%2! *oluene to6icity Inha#ation of to#uene Geg $y Eg#ue'sniffingEH may cause either a high anion'ga or a norma# anion ga acidosis. The high anion ga is ro$a$#y a conse<uence of its meta$o#ism to hi uric acid. To#uene may a#so cause significant rena# damage es ecia##y with chronic use. A conse<uence of this is a to#uene'induced rena# tu$u#ar acidosis in some atients. 4atients with to#uene to7icity may initia##y $e sus ected of having ethy#ene g#yco# to7icity es ecia##y as the resentation may $e simi#ar Geg a atient with menta# o$tundation? a earance of into7ication and a meta$o#ic acidosisH. These disorders have different treatments and differentiation is im ortant. To#uene to7icity can cause very rofound hypo&alae,ia and often resent with musc#e wea9ness and may deve#o serious arrhythmias Geg ventricu#ar tachycardiaH.

(2%2 # 3/er/ie4 of *o6ic Ingestions 3/er/ie4 of iagnosis of *o6ic Ingestions2 As a genera# ru#e? the diagnosis of a to7ic ingestion shou#d $e active#y investigated in a atient with a high anion ga acidosis where a diagnosis of 9etoacidosis? #actic acidosis or rena# fai#ure is not a arent. Treatment can $e #ife'saving if diagnosis is made ear#y. /ey Points0 High inde7 of sus icion Ges if atient a ears into7icatedH A#ways chec9 the osmo#ar ga if you have the s#ightest concern GIf X1: then sus ect ethy#ene g#yco#? methano# or ethano#H on't be put off if there is a nor,al anion gap or a nor,al os,olar gap as both these situations can occur e/en 4ith life-threatening ingestions2

Buidelines A#ways ursue a cause for a high anion ga acidosis and consider factors suggestive of to7ic ingestions To7ic ingestions usua##y have redominant neurological signs and sy,pto,s )outine measurement of a #actate #eve# is usefu# in e7c#uding this as the cause of the acidosis I,portant 1oints in iagnosing High Anion Bap Acidosis 5etoacidosis "an $e e7c#uded if normog#ycaemia C urine negative for 9etones

*actic acidosis

17c#uded if #actate #eve# is norma#. (uggested if shoc9 or eri hera# hy o erfusion.

)ena# fai#ure 17c#uded as cause of acidosis if urea and creatinine norma# or on#y s#ight#y e#evated. GIn chronic rena# fai#ure acidosis is uncommon if creatinine is W :.3: mmo#I# H Methano# (uggested if visua# im airment and "K( de ression or into7ication. A$domina# ain is common. "hec9 the osmo#ar ga . .o KOT de#ay thera y unti# $#ood #eve# o$tained. (uggested if a ear into7icated and no visua# distur$ance. "hec9 the osmo#ar ga $ut it is often norma#. (uggested if mar9ed hy erventi#ation Ges in adu#tsH and menta# o$tundation.

1thy#ene g#yco# (a#icy#ate

Acid-Base 1hysiology (2' 7se of Bicarbonate in $etabolic Acidosis Meta$o#ic acidosis causes adverse meta$o#ic effects Gsee (ection !.4H. In articu#ar the adverse effects on the cardiovascu#ar system may cause serious c#inica# ro$#ems. Bicar$onate is an anion and cannot $e given a#one. Its thera eutic use is as a so#ution of sodium $icar$onate. An 3.4Q so#ution is a mo#ar so#ution Gie it contains 1mmo# of H"O3' er m#H and is the concentration c#inica##y avai#a$#e in Austra#ia. This so#ution is very hy ertonic Gosmo#a#ity is 2?::: mOsmI9gH. (2'21 5hy 7se Al&ali9 The main goa# of a#9a#i thera y is to counteract the e7trace##u#ar acidaemia with the aim of reversing or avoiding the adverse c#inica# effects of the acidosis Ges the adverse cardiovascu#ar effectsH. Other reasons for use of $icar$onate in some cases of acidosis areD emergency management of hy er9a#aemia to romote a#9a#ine diuresis Geg to hasten sa#icy#ate e7cretionH (2'22 7ndesirable effects of bicarbonate ad,inistration In genera#? the severity of these effects are re#ated to the amount of $icar$onate used. These undesira$#e effects inc#udeD hy ernatraemia

hy erosmo#a#ity vo#ume over#oad re$ound or =overshoot> a#9a#osis hy o9a#aemia im aired o7ygen un#oading due to #eft shift of the o7yhaemog#o$in dissociation curve acce#eration of #actate roduction $y remova# of acidotic inhi$ition of g#yco#ysis "(6 acidosis hy erca nia

(2'23 I,portant points about bicarbonate 12 ;entilation ,ust be adeIuate to eli,inate the C32 produced fro, bicarbonate Bicar$onate decreases H, $y reacting with it to to roduce "O2 and water. 6or this reaction to continue the roduct G"O2H must $e removed. (o $icar$onate thera y can increase e7trace##u#ar H on#y if venti#ation is ade<uate to remove the "O2. Indeed if hy erca nia occurs then as "O2 crosses ce## mem$ranes easi#y? intrace##u#ar H may decrease even further with further deterioration of ce##u#ar function. 22 Bicarbonate ,ay cause clinical deterioration if tissue hypo6ia is present If tissue hy o7ia is resent? then the use of $icar$onate may $e articu#ar#y disadvantageous due to increased #actate roduction Gremova# of acidotic inhi$ition of g#yco#ysisH and the im airment of tissue o7ygen un#oading G#eft shift of O." due increased HH. This means that with #actic acidosis or cardiac arrest then $icar$onate thera y may $e dangerous. 32 Bicarbonate is probably not useful in ,ost cases of high anion gap acidosis *actic acidosis can get worse if $icar$onate is given. "#inica# studies have shown no $enefit from $icar$onate in dia$etic 9etoacidosis. In these cases? the on#y indication for $icar$onate use is for the emergency management of severe hy er9a#aemia. !2 *he preferred ,anage,ent of ,etabolic acidosis is to correct the pri,ary cause and to use specific treat,ent for any potentially dangerous co,plications The organic acid anions serve as $icar$onate recursors to regenerate new $icar$onate once the rimary cause is treated. In some forms of acidosis s ecific treatment to revent ro$#ems is ossi$#e Geg ethano# $#oc9ing thera y in ethy#ene g#yco# oisoning.H If hy er9a#aemia is resent then +5,- can $e decreased $y $icar$onate thera y. A#so? $icar$onate thera y can cause an a#9a#ine diuresis which hastens rena# sa#icy#ate e7cretion. #2 Bicarbonate therapy ,ay be useful for correction of acidae,ia due to non-organic ?or ,ineralA acidosis ?ie nor,al anion gap acidosisA In non'organic acidosis? there is no organic anion which can $e meta$o#ised to regenerate $icar$onate. Once the rimary cause is corrected? reso#ution of the acidaemia occurs more ra id#y if $icar$onate thera y is used. Amounts sufficient for on#y artia# correction of the disorder shou#d $e given. The aim is to increase arteria# H to a$ove 2.2 to minimise adverse effects of the acidaemia and to avoid the

adverse effects of $icar$onate thera y. If the atient is im roving without serious c#inica# ro$#ems then waiting Gfor rena# $icar$onate regenerationH and watching Gfor c#inica# im rovementH is a $etter strategy than giving $icar$onate.

Acid-Base 1hysiology +21 0tructured Approach to Assess,ent The ur ose of this cha ter is to teach a structured method for the assessment of acid'$ase disorders. The three stages invo#ved are out#ined in the ta$#e $e#ow. Structured Approach to Diagnosis o !atients "ith Acid#$ase Disorders %irst& 'nitia( C(inica( Assess)ent A clinical assessment based on clinical details is an essential first step 6rom the history? e7amination and initia# investigations? ma9e a c#inica# decision as to what is the most #i9e#y acid'$ase disorderGsH. This is very im ortant $ut $e aware that in some situations? the history may $e inade<uate? mis#eading or the range of ossi$#e diagnoses #arge. Mi7ed disorders are often difficu#tD the history and e7amination a#one are usua##y insufficient in sorting these out. Second& Acid#$ase Diagnosis Perform a systematic evaluation of the blood gas and other results and make an acid-base diagnosis The ste s are out#ined in (ection 8.2 %ina((*& C(inica( Diagnosis Synthesise the information to make an overall clinical diagnosis

Attem t to roduce an overa## diagnosis of the atient>s condition to guide thera y. .o not view the acid'$ase disorder in iso#ation. The history? e7amination and resu#ts often a##ow very ear#y diagnosis $ut it is very usefu# to systematica##y chec9 the who#e icture.

The essentia# first ste is to assess the avai#a$#e c#inica# information Ghistory? e7amination? investigationsH and use this to ma9e a c#inica# decision as to the ossi$#e and most #i9e#y acid'$ase diagnosis. A 9now#edge of the atho hysio#ogy of conditions which cause acid'$ase disorders is e7treme#y usefu# in ma9ing these initia# assessments. (ometimes these initia# assessments are easy $ut sometimes they are mis#eading $ut in a## cases they rovide an initia# c#inica# hy othesis used to guide the ne7t ste . "onsider the fo##owing c#inica# scenario as a ractica# e7am #e. Initia# "#inica# Assessment D An 17am #e HistoryD A 23 year o#d woman with a history of insu#in'de endent dia$etes me##itus is on ho#idays and is not using her insu#in regu#ar#y. (he resents with vomiting? o#yuria and fee#s unwe##. "#inica##y she is tachy noeic and #oo9s i##. 6indings on urina#ysis are 4, g#ucose and 2, 9etones. Asess,ent: The diagnosis is o$vious on this informationD the atient has a significant dia$etic 9etoacidosis. 6urther investigations such as arteria# $#ood gases and #asma $iochemistry wi## rovideD confirmation of the diagnosis assessment of severity of the acid'$ase disorder evidence of the resence of other acid'$ase disorders Gie a mi7ed disorderH The c#inica# assessment rovides your initia# orientation as to what is most #i9e#y. 1ffective#y? you are ma7imising your use of the avai#a$#e c#inica# information and setting u a hy othesis a$out the diagnosis which you then test. Fou a#so use your 9now#edge of the atho hysio#ogy to consider what other disorders or com #ications may coe7ist or may deve#o . 5hat other acid-base disorders could be present9 If she has neumonia? res iratory com ensation cou#d $e inade<uate indicating the resence of a res iratory acidosis. These atients are significant#y vo#ume de #eted and im aired erfusion can #ead to a #actic acidosis and rerena# a&otaemia. 17cessive infusion of norma# sa#ine can #ead to a hy erch#oraemic meta$o#ic acidosis and this has im #ications for thera y and e7 ectations for the rate of correction of the acidosis. ;omiting can #ead to a meta$o#ic a#9a#osis. 0sefu# investigations to sort out these are arteria# $#ood gases? e#ectro#ytes? anion ga ? urea and creatinine? g#ucose and #actate. (o the o$vious sim #e diagnosis can turn out to $e much more com #e7.

Acid-Base 1hysiology +22 0yste,atic C/aluation of Acid-Base 0tatus The ne7t stage of assessment is to systematica##y eva#uate the arteria# $#ood gas resu#ts and other resu#ts to ma9e a com #ete diagnosis of the acid'$ase distur$ance. An overview of the si7 se<uentia# ste s invo#ved are out#ined $e#ow and then again in detai# on the o osite age. CA7*I3FD An occasiona# ro$#em occurs due to incorrect transcri tion of $#ood'gas resu#ts. If you are wor9ing from a hand'written co y of resu#ts then you shou#d a#ways consider whether there has $een an error in writing the resu#ts down Geg mis'heard over the hone for e7am #eH. A chec9 of H? "O2 C H"O3 against the Henderson'Hasse#$a#ch e<uation is usua##y difficu#t without a ca#cu#ator. However? a <uic9 chec9 of the #ogica# consistency of the resu#ts is often ossi$#e. 6or e7am #e? H must $e #ess then 2.4 if 4"O2 is high C H"O3 is #ow. It is refera$#e to review the resu#t rint'out

from the machine. The Six Steps of Systematic Acid- ase !"a#$ation 12 pHD Assess the net deviation of H from norma# 22 1atternD "hec9 the attern of $icar$onate C "O2 resu#ts 32 CluesD "hec9 for additiona# c#ues in other investigations !2 Co,pensationD Assess the a ro riateness of the com ensatory res onse #2 Dor,ulationD Bring the information together and ma9e the acid $ase diagnosis %2 Confi,ationD "onsider if any additiona# tests to chec9 or su necessary or avai#a$#e C revise the diagnosis if necessary ort the diagnosis are

The first step is to #oo9 at the arteria# H. A net acidaemia means that an acidosis must $e resent. A net a#9a#aemia means that an a#9a#osis must $e resent. A norma# H gives 2 ossi$i#itiesD no acid'$ase disorder or a mi7ed disorder with an a#9a#osis com ensating for an acidosis The ne6t step is to determine whether any disorder is of the res iratory or meta$o#ic ty e $y reviewing the attern and magnitude of the $icar$onate and "O2 resu#ts. If the disorder is a sim #e one Gie on#y one rimary disorder resentH then the acid'$ase disorder is diagnosed at this ste . But the rea# ro$#em is that this is not 9nown so the evidence must a#ways $e chec9ed for evidence of a mi7ed disorder. This is an im ortant art of ste s 2? 3 and 4 S*ste)atic Approach to $(ood +as Ana(*sis ,. pH& Chec- arteria( pH !rincip(e& The net deviation in pH will indicate whether an acidosis or an alkalosis is present (but will not indicate mixed disorders) Buidelines: I6 an acidaemia is resent TH1K an acidosis must $e resent I6 an a#9a#aemia is resent TH1K an a#9a#osis must $e resent I6 H is norma# H TH1K 1ither Gno acid'$ase disorder is resentH or G"om ensating disorders are resent ie a mi7ed disorder with an acidosis and an a#9a#osisH 22 1A**C"F: :oo& for suggesti/e pattern in pC32 8 <HC33>

1rinciple: 1ach of the sim #e disorders roduces redicta$#e changes in +H"O3- C "O2. Buidelines: I6 Both +H"O3- C "O2 are #ow TH1K (uggests resence of either a Meta$o#ic Acidosis or a )es iratory A#9a#osis G$ut a mi7ed disorder cannot $e e7c#udedH I6 Both +H"O3- C "O2 are high TH1K (uggests resence of either a Meta$o#ic A#9a#osis or a )es iratory Acidosis G$ut a mi7ed disorder cannot $e e7c#udedH I6 +H"O3- C "O2 move in o osite directions TH1K a mi7ed disorder M0(T $e resent Ohich disorder is resent is de endent on which change is rimary and which is com ensatory? and this re<uires an assessment $ased on the history? e7amination C other resu#ts. 32 C:7C0: Chec& for clues in the other bioche,istry results 1rinciple: "ertain disorders are associated with redicta$#e changes in other $iochemistry resu#ts C6a,ples: (ee se arate #ist of EAids to Inter retationE $e#ow !2 C3$1CF0A*I3F: Assess the Co,pensatory "esponse 1rinciple: The % Bedside )u#es are used to assess the a ro riateness of the com ensatory res onse. Buidelines: If the e7 ected C actua# va#ues match LX no evidence of mi7ed disorder If the e7 ected C actua# va#ues differ LX a mi7ed disorder is resent #2 D3"$7:A*I3F: Dor,ulate the Acid-Base iagnosis "onsider a## the evidence from the history? e7amination C investigations and try to formu#ate a com #ete acid'$ase diagnosis %2 C3FDI"$A*I3F: Chec& for specific bioche,ical e/idence of particular disorders for confir,ation 1rinciple: In some cases? further $iochemica# evidence can confirm the resence of articu#ar disorders. "hanges in these resu#ts may $e usefu# in assessing the magnitude of the disorder or the res onse to thera y. C6a,ples: *actate? urinary 9etones? sa#icy#ate #eve#? a#dosterone #eve#? various tests for rena#

tu$u#ar acidosis 0tep 3 invo#ves reviewing other resu#ts #oo9ing for s ecific evidence of articu#ar disorders. (ome of these Ec#uesE are out#ined in the ta$#e $e#ow. In most circumstances? these c#ues are confirmatory of the e7 ected diagnosis $ut on occasion can a#ert to the resence of an unantici ated second disorder. An e#evated anion ga can $e articu#ar#y usefu#. Most of these Ec#uesE are o$tained from the $iochemistry rofi#e. An a#ert c#inician can often correct#y ic9 the diagnosis $efore the gas resu#ts are $ac9. 0o,e Aids to Interpretation of Acid-Base isorders D4lu&D High anion ga Hy erg#ycaemia Hy o9a#aemia andIor hy och#oraemia Hy erch#oraemia 1#evated creatinine and urea 1#evated creatinine 0i)nificanc& Always strong#y suggests a meta$o#ic acidosis. If 9etones a#so resent in urine 'X dia$etic 9etoacidosis (uggests meta$o#ic a#9a#osis

"ommon with norma# anion ga acidosis (uggests uraemic acidosis or hy ovo#aemia G rerena# rena# fai#ureH "onsider 9etoacidosisD 9etones interfere in the #a$oratory method GPaffe reactionH used for creatinine measurement C give a fa#se#y e#evated resu#tJ ty ica##y urea wi## $e norma#. "onsider 9etoacidosis or hy erosmo#ar non'9etotic syndrome /#ucose detected if hy erg#ycaemiaJ 9etones detected if 9etoacidosis

1#evated g#ucose

0rine di stic9 tests for g#ucose and 9etones

*he !th step is to assess acid'$ase com ensation. The a roach discussed here invo#ves the use of a set of si7 ru#es. These are discussed in (ection 8.3. Much of the em hasis here is to ic9 the resence of a second acid'$ase disorder. 0tep #D The stage shou#d now $e reached in that a definitive overa## acid'$ase assessment can $e made. 0tep %D (ometimes the diagnosis suggests additiona# tests that can $e used to confirm the diagnosis or at #east a##ow more recise diagnosis. An e7am #e wou#d $e a measurement of $#ood sa#icy#ate #eve# in a chi#d which if high can confirm a c#inica# sus icion of a sa#icy#ate overingestion. If a diagnosis of

rena# tu$u#ar acidosis is sus ected then further s ecific tests can $e done to further s ecify the diagnosis.

Acid-Base 1hysiology +23 Bedside "ules for Assess,ent of Co,pensation

+2321 *he 0i6 Bedside "ules The method of assessing acid'$ase disorders discussed here uses a set of si7 ru#es which are used rimari#y to assess the magnitude of the atient>s com ensatory res onse. These ru#es are now wide#y 9nown and are sound#y $ased e7 erimenta##y. These ru#es are used at (te 4 of the method of (ystematic Acid'Base .iagnosis out#ined in (ection 8.2.' GFou shou#d read section 8.1 C 8.2 $efore this section.H These ru#es are ca##ed E$edside ru#esE $ecause that can $e used at the atientEs $edside to assist in the assessment of the acid'$ase resu#ts. The ru#es shou#d refera$#y $e committed to memory ' with ractice this is not difficu#t. A fu## assessment of $#ood'gas resu#ts must $e $ased on a c#inica# 9now#edge of the individua# atient from whom they were o$tained and an understanding of the atho hysio#ogy of the c#inica# conditions under#ying the acid'$ase disorder. .o not inter ret the $#ood'gas resu#ts as an inte##ectua# e7ercise in itse#f. It is one art of the overa## rocess of assessing and managing the atient. Kno4 the clinical details of the patient A set of $#ood'gas and e#ectro#yte resu#ts shou#d KOT $e inter reted without these initia# c#inica# detai#s. They cannot $e understood fu##y without 9now#edge of the condition $eing diagnosed. Dind the cause of the acid-base disorder .iagnosing a =meta$o#ic acidosis>? for e7am #e? is $y itse#f? often of #itt#e c#inica# use. Ohat is rea##y re<uired is a more s ecific diagnosis of the cause of the meta$o#ic acidosis Geg dia$etic 9etoacidosis? acute rena# fai#ure? #actic acidosisH and to initiate a ro riate management. The acid'$ase ana#ysis must $e inter reted and managed in the conte7t of the overa## c#inica# icture. *he snapshot proble,: Are the results 'current'9 )emem$er a#so that a set of $#ood gas resu#ts rovides a sna shot at a articu#ar oint in time and the situation may have changed since the $#ood gases were co##ected so seria# assessment of resu#ts can $e im ortant in assessment Geg of res onse to thera yH. eter,ine the ,a)or pri,ary process then select the correct rule The maBor rimary rocess is usua##y suggested $y the initia# c#inica# assessment and an initia# erusa# of the arteria# H? "O2 and +H"O3'- resu#ts. Once this maBor rimary rocess is 9nown? then the a ro riate ru#e is chosen to assess the a ro riateness of the atient>s com ensatory res onse. The ru#es assess com ensation and are a guide to detecting the resence of a second rimary acid'$ase disorderD 6or e7am #e in a atient with a meta$o#ic acidosis if the measured "O2 #eve# was higher

than is e7 ected for the severity and duration of the meta$o#ic disorder? than this oints to the coe7istence of a res iratory acidosis. Oith a #itt#e ractice the ru#es are sim #e to remem$er and are <uic9 and easy to a #y at the $edside. )u#es 1 to 4 are $est remem$ered $y the descri tion rather then memori&ing the formu#a. These ru#es are out#ined $e#ow +2322 "ules for "espiratory Acid-Base isorders )u#e 1 D The 1 for 1: )u#e for Acute )es iratory Acidosis *he <HC33> 4ill increase by 1 ,,ol@l for e/ery 1- ,,Hg ele/ation in pC32 abo/e !,,Hg2 C6pected <HC33> E 2! = M ?Actual pC32 - !-A @ 1- P Co,,ent:The increase in "O2 shifts the e<ui#i$rium $etween "O2 and H"O3 to resu#t in an acute increase in H"O3. This is a sim #e hysicochemica# event and occurs a#most immediate#y. C6a,pleD A atient with an acute res iratory acidosis G "O2 %:mmHgH has an actua# +H"O3- of 31mmo#I#. The &:+&c'&d A,4CEB for this acute e#evation of "O2 is 24 , 2 L 2%mmo#I#. The actua# measured va#ue is higher than this indicating that a meta$o#ic a#9a#osis must a#so $e resent.

)u#e 2 D The 4 for 1: )u#e for "hronic )es iratory Acidosis *he <HC33> 4ill increase by ! ,,ol@l for e/ery 1- ,,Hg ele/ation in pC32 abo/e !-,,Hg2 C6pected <HC33> E 2! = ! M ?Actual pC32 - !-A @ 1-P Co,,ent: Oith chronic acidosis? the 9idneys res ond $y retaining H"O3? that is? rena# com ensation occurs. This ta9es a few days to reach its ma7ima# va#ue. C6a,pleD A atient with a chronic res iratory acidosis G "O2 %:mmHgH has an actua# +H"O3- of 31mmo#I#. The e7 ected +H"O3- for this chronic e#evation of "O2 is 24 , 3 L 32mmo#I#. The actua# measured va#ue is e7treme#y c#ose to this so rena# com ensation is ma7ima# and there is no evidence indicating a second acid'$ase disorder.

)u#e 3 D The 2 for 1: )u#e for Acute )es iratory A#9a#osis *he <HC33> 4ill decrease by 2 ,,ol@l for e/ery 1- ,,Hg decrease in pC32 belo4 !-

,,Hg2 C6pected <HC33> E 2! - 2 M ? !- - Actual pC32A @ 1- P Co,,entD In ractice? this acute hysicochemica# change rare#y resu#ts in a +H"O3- of #ess than a$out 13 mmo#Is. GAfter a## there is a #imit to how #ow "O2 can fa## as negative va#ues are not ossi$#eUH (o a +H"O3- of #ess than 13 mmo#I# indicates a coe7isting meta$o#ic acidosis.

)u#e 4 D The ! for 1: )u#e for a "hronic )es iratory A#9a#osis *he <HC33> 4ill decrease by # ,,ol@l for e/ery 1- ,,Hg decrease in pC32 belo4 !,,Hg2 C6pected <HC33> E 2! - # M ? !- - Actual pC32 A @ 1- P ? range: =@- 2A Co,,ents: It ta9es 2 to 3 days to reach ma7ima# rena# com ensation The li,it of co,pensation is a +H"O3- of a$out 12 to 1! mmo#I#

+2323 "ules for $etabolic Acid-Base isorders )u#e ! D The One C a Ha#f #us 3 )u#e ' for a Meta$o#ic Acidosis *he e6pected pC32 ?in ,,HgA is calculated fro, the follo4ing for,ula: C6pected pC32 E 12# 6 <HC33> = ( ?range: =@- 2A Co,,ents: Ma7ima# com ensation may ta9e 12'24 hours to reach The li,it of co,pensation is a "O2 of a$out 1: mmHg Hy o7ia can increase the amount of eri hera# chemorece tor stimu#ation C6a,ple: A atient with a meta$o#ic acidosis G+H"O3- 14mmo#I#H has an actua# "O2 of 3:mmHg. The e7 ected "O2 is G1.! 7 14 , 3H which is 28mmHg. This $asica##y matches the actua# va#ue of 3: so com ensation is ma7ima# and there is no evidence of a res iratory acid'$ase disorder G rovided that sufficient time has assed for the com ensation to have reached this ma7ima# va#ueH. If the actua# "O2 was 4!mmHg and the e7 ected was 28mmHg? then this difference G4!'28H wou#d indicate the resence of a res iratory acidosis

and indicate its magnitude. (ee (ection !.! for more detai#s.

)u#e % D The 4oint (even #us Twenty )u#e ' for a Meta$o#ic A#9a#osis *he e6pected pC32?in ,,HgA is calculated fro, the follo4ing for,ula: C6pected pC32 E -2' <HC33> = 2- ?range: =@- #A Co,,ent: The variation in "O2 redicted $y this e<uation is re#ative#y #arge. GThe reasons for this are discussed in section 2.!H

The com$ination of a #ow +H"O3- and a #ow "O2 occurs in meta$o#ic acidosis and in res iratory a#9a#osis. If on#y one disorder is resent it is usua##y a sim #e matter to sort out which is resent. The factors to consider areD The history usua##y strong#y suggests the disorder which is resent The net H change indicates the disorder if on#y a sing#e rimary disorder is resent Geg acidaemia LX acidosisH An e#evated anion ga or e#evated ch#oride define the 2 maBor grou s of causes of meta$o#ic acidosis )emem$er that on#y rimary rocesses are ca##ed acidosis or a#9a#osis. The com ensatory rocesses are Bust that ' com ensation. 4hrases such as =secondary res iratory a#9a#osis> shou#d not $e used. Gsee (ection 3.1H

Chec& Anion Bap and elta "atio An ele/ated Anion Bap al4ays strongly suggests a $etabolic Acidosis2 If A/ is 2:'3: then high chance G%2QH of meta$o#ic acidosis If A/ is X 3: then a meta$o#ic acidosis is definite#y resent

If a ,etabolic acidosis is diagnosedL then the elta "atio should be chec&ed

elta "atio Assess,ent Buidelines in patients 4ith a ,etabolic acidosis W :.4 ' Hy erch#oraemic norma# anion ga acidosis :.4 to :.3 ' "om$ined high A/ and norma# A/ acidosis 1 ' "ommon in .5A due to urinary 9etone #oss

1 to 2 ' Ty ica# attern in high anion ga meta$o#ic acidosis X 2 "hec9 for either a co'e7isting Meta$o#ic A#9a#osis Gwhich wou#d e#evate +H"O3-H or a co'e7isting "hronic )es iratory Acidosis Gwhich resu#ts in com ensatory e#evation of +H"O3-H

Acid-Base 1hysiology +2! Assess,ent: *he "ationale

*he rules assess co,pensation 8 are therefore a guide to detecting the presence of a second pri,ary acid-base disorder )u#es 1 to 4 dea# with res iratory acid'$ase disorders and rovide a sim #e way to ca#cu#ate the +H"O3'- that wou#d $e e7 ected in a erson who has a sim #e res iratory acid'$ase disorder. That is they redict the ma7ima# amount of com ensation that wou#d occur. .uestion: Ho4 4ere these rules deter,ined9 Ans4er: By direct anima# and human e7 erimentation. 6or e7am #e? the "O2 of the su$Bects was a#tered and the $#ood gases were measured. The data from these who#e'$ody titrations a##owed the norma# hysio#ogica# res onse and its time course to $e <uantified. .uestion: 5hat is the principle behind the use of these rules9 Ans4er: The ru#es a##ow ca#cu#ation of the com ensatory res onse that wou#d $e Ee7 ectedE if the rimary res iratory or meta$o#ic acid'$ase disorder were the on#y disorder resent. That is? we redict the e7 ected com ensatory res onse so that we can se arate what is e7 ected Gie com ensationH from the une7 ected Gie a co'e7istent second disorderH. 6or e7am #e? consider a atient with a rimary meta$o#ic acidosis. 0sing ru#e !? we ca#cu#ate what we e7 ect the arteria# "O2 wi## $e in that erson if this meta$o#ic acidosis was the OK*F acid'$ase disorder resent. Oe then com are this Ee7 ectedE "O2 with the actua# "O2 Gie the measured va#ue in the atientH. If there is a significant difference $etween these two va#ues? then this Erevea#sE the resence of a second rimary acid'$ase disorder GIn this case? a discre ancy wou#d revea# a co'e7istent res iratory acid'$ase disorder.H .uestion: Are there li,itations in this ,ethod9 Ans4er: Fes. "ertain com$inations of rimary acid'$ase disorders cannot $e revea#ed in this way. In articu#ar? if the atient has two ty es of rimary meta$o#ic acidosis? then this cannot $e detected $y this method GHowever? there are other ways to detect this as discussed e#sewhereH. In genera#? the ru#es are usefu# for detecting a co'e7istent res iratory disorder in a atient with a meta$o#ic disorder Gor? converse#y detecting a co'e7istent meta$o#ic disorder in a atient with a

res iratory disorder.H $i6ed acid-base disorders A mi7ed acid'$ase disorder is resent when two or more rimary disorders are resent simu#taneous#y. Assessment of mi7ed disorders re<uires 9now#edge of the e7 ected degree of com ensation that is resent with a## of the sim #e acid'$ase disorders. This is the 9now#edge that is summmarised in the Inter retation )u#es descri$ed in section 8.1. The history and e7amination are necessary to diagnose a## acid'$ase disorders $ut are articu#ar#y usefu# in sorting out a mi7ed disorder. A double disorder is resent when any two rimary acid'$ase disorders occur together? $ut not a## com$inations of disorders are ossi$#e. *he particular e6clusion here is that a mi&ed respiratory disorder an never o ur as carbon dio6ide can ne/er be both o/er- and under-e6creted by the lungs at the sa,e ti,eJ Fou can however have a mi7ed acid $ase disorder with simu#taneous meta$o#ic acidosis and a#9a#osis. 6or e7am #e you cou#d have a atient with gastric out#et o$struction who has $een vomiting for severa# days to the e7tent they have $ecome severe#y vo#ume de #eted with oor eri hera# erfusion and re' rena# fai#ure. (uch a atient cou#d have a severe meta$o#ic a#9a#osis Gfrom the #oss of gastric acid from vomitingH and a#so a meta$o#ic acidosis Geg #actic acidosis from oor erfusion C may$e an acidosis from the acute rena# fai#ureH. A triple disorder is resent when a res iratory acid'$ase disorder occurs in association with a dou$#e meta$o#ic disorder.

Acid-Base 1hysiology +2# *he Breat *rans-Atlantic Acid-Base ebate The a roach to eva#uation of acid'$ase disorders used in this on'#ine te7t is 9nown as the Boston a roach. The researchers romoting this a roach are from Boston. An a#ternative method of eva#uation romoted $y Astru and (iggaard'Anderson from "o enhagen uses the =Base 17cess> a roach. At times the differences $etween the two grou s has stirred controversy Gca##ed the EBreat *rans-Atlantic Acid-Base ebateE $y Bun9er in 18%!H. Many of the differences $etween the two grou s ersist and it is im ortant to have some understanding of the issues invo#ved. The controversy has recent#y $een stirred again $y (everinghaus G1883H who favours the "o enhagen a roach. The $asic idea is that we need a way to <uantify the various acid'$ase disorders. This te##s us the severity of the acid'$ase distur$ance and this is im ortant c#inica# information. Oe a#so need to determine whether the $odyEs com ensation for the acid'$ase disorder is a ro riate. If not? this indicates the resence of a second acid'$ase disorder. +2#21 Bac&ground to Copenhagen Approach Acid'$ase disorders are c#assified as $eing of res iratory origin G rimary change in "O2H or of meta$o#ic origin G rimary change in fi7ed acidsH. (ome $asic <uestions to $e answered $y any a roach areD

How can the magnitude of a res iratory disorder $e determinedT How can the magnitude of a meta$o#ic disorder $e determinedT )es iratory disorders are <uantified $y the amount of change in "O2 in the arteria# $#ood. If the "O2 is further away from its norma# va#ue? then a #arger disorder is resent. This seems sim #e enough as "O2 is the =res iratory acid> and can $e easi#y measured. Meta$o#ic disorders are <uantified $y the amount of e7cess fi7ed acids Gthe =meta$o#ic acids>H resent in the $#ood. If more fi7ed acids are resent? then a disorder of #arger magnitude is resent. This is c#ear enough *u' in a articu#ar meta$o#ic disorder? we may not 9now what are the articu#ar fi7ed acids that are causing the acidosis. Indeed there may $e more than one ty e invo#ved. Is it feasible to ,easure e/ery possible fi6ed acid9 Ko. B0T we can estimate the tota# amount of e7cess fi7ed acid resent indirect#y. The argument goes #i9e thisD 1. Buffering of fi7ed acids in the e7trace##u#ar f#uid is redominant#y $y $icar$onate. 2. One $icar$onate mo#ecu#e wi## react with one H, mo#ecu#e roduced $y one mo#ecu#e of fi7ed acid. 3. (o +H"O3- wi## decrease $y one mo#ecu#e for every mo#ecu#e of fi7ed acid resent. 4. The tota# amount of e7cess fi7ed acids shou#d therefore $e e<ua# to the amount $y which the $icar$onate concentration dro s from its usua# va#ue. "onc#usionD The magnitude of the meta$o#ic disorder Gin the 1"6H can $e <uantified indirect#y $y the amount of change in the +H"O3-. This seems an im rovement $ecause now there is on#y one <uantity to measure and a#so it is easy to EmeasureE GBicar$onate is not actua##y measured in a $#ood'gas machine $ut instead is ca#cu#ated? using the Henderson'Hasse#$a#ch e<uation? $y su$stituting into this e<uation the measured va#ues of H C "O2H. But there are other proble,s: The im #icit assum tion so far that "O2 and H"O3 are inde endent of one another is not correct GWhat this means is that changes in "O2 a#so wi## change the $icar$onate #eve# $ecause these 2 com ounds are in chemica# e<ui#i$rium. This interferes with the usefu#ness of changes in $icar$onate as a way to <uantify the meta$o#ic com onent of an acid'$ase disorder $ecause res iratory disorders a#so a#ter the $ase#ine H"O3H The $uffering $y the H"O3 in the $#ood sam #e is not re resentative of the $uffering $y the 1"6 as a who#e GWhat this means is that $ecause $#ood is a $etter $uffer than 1"6 as a who#e then doing your measurements in a $#ood'gas machine on $#ood wi## not give you resu#ts re resentative of the whol& E48. B#ood is a $etter $uffer then the who#e 1"6 $ecause of its content of the $uffer haemog#o$in.H The assum tion that a## $uffering of meta$o#ic acids is $y H"O3 and not other unmeasured 1"6 $uffers is not tota##y correct. Buffering $y intrace##u#ar $uffers is ignored The system assesses com ensation as another rimary disorder *he Copenhagen approach has de/eloped se/eral '4or&-arounds' to cope 4ith so,e of these proble,s2 As stated a$ove? the "O2 and the +H"O3- are not inde endent of one another as the argument so far has tacit#y assumed. An increase in "O2 wi## cause an increase in +H"O3-. This occurs $ecause of the

*aw of Mass Action in the fo##owing e<uationD C32 = H23 REN H2C33 REN H= = HC32This is a ro$#em $ecause a change in res iratory acid is changing the $ase#ine used for assessment of the meta$o#ic disorder. Ohat we need is some way of assessing the meta$o#ic disorder that corrects or a##ows for this interaction $etween "O2 and H"O3. (evera# pC32-independent indices have $een ro osed as $eing suita$#e for this ur oseD (tandard $icar$onate Buffer Base Base 17cess 0tandard bicarbonate is the $icar$onate concentration of a sam #e when the "O2 has $een adBusted Gor =standardised>H to 4: mmHg at a tem erature of 32". This wou#d remove the inf#uence of changes in "O2 $y seeing what the +H"O3- wou#d $e if the res iratory com onent was made the same for a## measurements. The term was introduced $y Porgensen C Astru in 18!2 $ut is conce tua##y the same as the idea of a Estandard HE Gat "O2 of 4:mmHg C tem erature of 32"H introduced $y Henderson much ear#ier. Buffer base is a measure of the concentration of all the $uffers resent in either #asma or $#ood. Base C6cess GB1H is a measure of how far Buffer Base has changed from its norma# va#ue C was introduced $y Astru and (iggaard'Andersen in 18!3. B1 in who#e $#ood is inde endent of "O2 in the sam #e when measured in the $#ood gas machine. B1 is ro osed as a measure of the magnitude of the meta$o#ic disorder $ecause it assesses a## the e7trace##u#ar $uffers Gin the $#ood sam #eH and is inde endent of "O 2 Gin vitroH. 0nfortunate#y? there are severa# ro$#ems with the use of B1 in this way. 6or e7am #eD It is not inde endent of "O2 in vivo GThis is $ecause $#ood 'which contains haemog#o$in ' is a $etter $uffer than the tota# 1"6 It does not distinguish com ensation for a res iratory disorder from the resence of a rimary meta$o#ic disorder If B1 is ca#cu#ated for a haemog#o$in concentration of 3: or !: gI# instead of the actua# haemog#o$in? the differences $etween in vitro and in vivo $ehaviour can $e most#y e#iminated G(ee (everinghaus? 182%H. This #ower +H$- is considered to $e the =effective +H$-> of the who#e 1"6 Gie what the +H$wou#d $e if the haemog#o$in was distri$uted throughout the who#e 1"6 rather than Bust the intravascu#ar com artmentH. This attem ts to e#iminate the error introduced $y the incorrect assum tion that the $uffering of $#ood is the same as the $uffering $y the who#e 1"6. The Radiom&'&r range of $#ood gas machines are made in "o enhagen and are very successfu##y used wor#dwide. These machines rovides a rintout with the fu## fami#y of EderivedE Gor EcontrivedE? de ending on your ers ectiveH "o enhagen'ty e $#ood gas varia$#es for those who are interested. Other $rands of machine have usua##y fo##owed this ractice so they can survive in the com etitive mar9et #ace. This assists in the surviva# of the "o enhagen a roach. +2#22 Bac&ground to Boston Approach The a#ternative method of <uantifying acid'$ase disorders has $een deve#o ed $y investigators from Boston Geg (chwart& C )e#manH. This =Boston a roach> is the method used so far in this $oo9 and the si7 $edside ru#es have $een out#ined in section 8.3

This a roach is $ased on actua# e7 erimenta# wor9 in humans Geg who#e $ody titrationsH rather than on $#ood sam #es in a machine. *he ai, has been to deter,ine the ,agnitude of the co,pensation that occurs to graded degrees of acid-base disturbance2 These resu#ts are $ased on $uffering and com ensatory rocesses that affect the who#e $ody rather than Bust the $#ood. Additiona##y? a ro riate com ensation for $oth acute and chronic disorders can $e determined and corrected for when inter reting the $#ood gas resu#ts. The resu#ts are resented in a cou #e of different waysD as gra hs with 8:Q confidence interva#s? or as a set of ca#cu#ation ru#es. This $oo9 uses the ru#es method $ecause these can $e easi#y committed to memory and can $e easi#y used at the $edside when assessing atients with acid'$ase disorders. This does not re<uire the introduction of new terms #i9e Base 17cess and Buffer Base. The assessment of the magnitude of meta$o#ic distur$ances is $ased on a com arison of the =actua#> Gie measuredH and the =e7 ected> va#ues of +H"O3-. The determination of the =e7 ected = va#ue Gusing c#inica# 9now#edge and the ru#es of section 8.3H incor orates the corrections necessary to adBust for the interaction $etween "O2 and H"O3. +2#23 5hat Approach is '*he Best'9 Conclusion: Boston approach is better the Copenhagen approach Oithin the traditiona# a roach to acid'$ase ana#ysis? the Boston E$icar$onate methodE is refera$#e to the "o enhagen E$ase e7cess methodE $ecauseD it is sim #er to understand and to teach it is $ased on who#e $ody e7 eriments rather than on test tu$e resu#ts on a $#ood sam #e it em hasises the need for c#inica# assessment and inter retation rather than $eing driven $y #a$oratory $ased derived <uantities Auote from the origina# criti<ue of (chwart& and )e#man in 18%3 @The traditiona# measurements of H? "O2 and #asma $icar$onate concentration continue to $e the most re#ia$#e $iochemica# guides in the ana#ysis of acid'$ase distur$ances. These measurements? when considered in the #ight of the a ro riate c#inica# information and a 9now#edge of the e7 ected res onse of the intact atient to rimary res iratory or meta$o#ic distur$ance? a##ow rationa# eva#uation of even the most com #icated acid'$ase disorders.@ B7* is the 0te4art Approach the best of all9 .es ite the a$ove? it shou#d $e noted that the <uantitative a roach ioneered $y (tewart may $e a $etter a roach. It has great strength in aiding understanding a$out what is going on $ut unfortunate#y it is difficu#t to use c#inica##y. It is very #imited in usefu#ness for routine c#inica# a #ication and inter retation of $#ood'gas resu#ts. An introduction to this a#ternative a roach is resented in "ha ter 1:.

Acid-Base 1hysiology

+2% Clinical C6a,ples

+2%21 *he Feed for C6perience: 1racticing on C6a,ple Cases The ru#es of the Boston a roach are usefu# on#y if we 9now how to a #y them c#inica##y to atient care. This section rovides a series of e7am #es of their use in rea# atients so you can gain e7 erience in inter retation. Many of these cases are from our own unit $ut some are $ased on u$#ished cases. These e7am #es rovide good ractice in the a #ication of the ru#es. The centra# im ortance of the history and your c#inica# 9now#edge of the atient in assessment is em hasised. In some cases? an en#arged history and seria# resu#ts are rovided. This shou#d rovide some e7 erience inD discriminating the im ortant data from the c#inica# icture seeing the acid'$ase assessment as Bust one com onent of the tota# atient assessment getting a =fee#> for how the resu#ts change with thera y (ome of the assessments are #ong and erha s re etitive $ut revious e7 erience has indicated that this =thin9ing out #oud> a roach increases the usefu#ness of the e7am #es as teaching materia#. Brief e7 #anations don>t seem to teach much. The inde7 to the "ase Histories is at the $ottom of this age. +2%22 *he 1ri,e irecti/e: I,portance of the Clinical etails But first? to i##ustrate how the history and e7amination are of rime im ortance in correct inter retation of $#ood gas resu#ts? consider the fo##owing set of arteria# $#ood gasesD

Arteria# H 2.21

#ood %ases

"O2 2: mmHg O2 2! mmHg H"O3 22 mmo#I# These identica# gases were o$tained from the fo##owing two atients G$ased on BernardsH. Case 1: A hea#thy 32 year o#d man is having an e#ective o en cho#ecystectomy under a K2OI1nf#uraneI4ancuronium anaesthetic. He has no significant ast medica# history and is on no routine medication. 4reo erative urea and e#ectro#ytes were a## within the reference range. Case 2: A 2! year o#d man with a #ong history of severe acute chronic o$structive airways disease G"OA.H is admitted to hos ita# with fever? confusion and significant res iratory distress. He #ives a#one $ut his neigh$our says he has $een unwe## for a wee9 and has

deteriorated over the revious 4 days. There is a #ong history of heavy smo9ing. Biochemistry C haemato#ogy resu#ts are not yet avai#a$#e. Is the assess,ent of the results the sa,e e/en though the clinical situation is /ery different9 FoJ The attern G "O2 C H"O3 $oth e#evatedH suggests either a res iratory acidosis or a meta$o#ic a#9a#osis $ut the severe acidaemia means that it is a res iratory acidosis that is resent. This much is common ground to these two cases. The c#inica# detai#s are necessary to decide if a sim #e or a mi7ed acid'$ase disorder is resent. Assess,ent of Case 1: This atient is receiving a re#a7ant anaesthetic for an u er a$domina# rocedure. His venti#ation is fu##y contro##ed. A erusa# of the resu#ts in the #ight of the c#inica# detai#s Gres iratory acidosis in a we## atient on contro##ed venti#ationH suggests strong#y that the most #i9e#y rimary ro$#em is hy oventi#ation in a atient with revious#y norma# acid'$ase resu#ts. A mar9ed acute res iratory acidosis is resent. +In any anaesthetised atient with an acute acidosis? ma#ignant hy erthermia? though rare? shou#d a#ways $e considered.Is a meta$o#ic disorder a#so resent in this atientT Geg due to #actic acidosisH The +H"O3- wou#d $e e7 ected to increase $y 1 mmo#I# for each 1: mmHg rise in "O2 a$ove the nomina# usua# va#ue of 4: mmHg. G)u#e 1 in (ection 8.3H. A rise of 3:mmHg redicts a +H"O3- of 22 Gie 24 , 3H. The actua# va#ue matches the redicted va#ue. There is no meta$o#ic com onent resent. If the history suggested that the situation may $e more com #e7 then a chec9 shou#d $e made for any suggestive evidence of a mi7ed meta$o#ic com onent Gcoe7istent meta$o#ic acidosis and meta$o#ic a#9a#osisH as we## as the acute res iratory acidosis. This chec9 wou#d inc#ude initia##y anion ga ? +5,-? +"#'- and g#ucose. In this case there is no c#inica# indication. Acute res iratory acidosis due to a#veo#ar hy oventi#ation is the acid'$ase assessment in this case. The cause for this shou#d $e found and corrected. The a$sence of a meta$o#ic com onent and the other c#inica# evidence ma9es a diagnosis of e7cessive "O2 roduction Geg ma#ignant hy erthermiaH very un#i9e#y. Assess,ent of Case 2: This man has severe chronic o$structive airways disease and has an e#evation in his "O2 which has ro$a$#y $een resent for at #east 3 or 4 days. He is ro$a$#y a chronic "O2 retainer with some chronic e#evation in his "O2. )eview of revious $#ood gas resu#ts or =$icar$onate> Gie =tota# "O2>H #eve#s on a $iochemistry rofi#e may confirm this. In any case? the history suggests chronic res iratory acidosis. Based on ru#e 2? the redicted +H"O3- is 3% mmo#I# +ieD 24 , M G 2:'4: I 1: H 7 4 N -. The actua# +H"O3- is 8 mmo#I# #ower then this indicating a coe7istent severe meta$o#ic acidosis. Kote that the O2 is not severe#y de ressed. 4atients admitted with res iratory distress are a#most invaria$#y commenced on o7ygen $y am$u#ance and hos ita# staff. This may $e #ife'saving as the O2 in increased. A #actic acidosis re#ated to hy o7aemia and may$e eri hera# circu#atory fai#ure is the ro$a$#e cause of the meta$o#ic acidosis. Other causes of meta$o#ic acidosis shou#d $e considered. Infection is a otent reci itant of dia$etic 9etoacidosis. A finger' ric9 test for g#ucose and urine tests for g#ucose and 9etones shou#d $e erformed on arriva# in the "asua#ty de artment. The anion ga wi## define the ty e of meta$o#ic acidosis resent and guide further investigation. This atient has a severe mi7ed acidosis. An acute severe meta$o#ic acidosis is su erim osed on a com ensated chronic res iratory acidosis. The meta$o#ic com ensation for the res iratory disorder has disguised the magnitude of the meta$o#ic acidosis.

It is noted that the gas resu#ts in these two cases are identica#? $ut that the inter retation and therefore management are different. Co,,enting on an isolated set of blood gas results 4ithout benefit of any pertinent history can lead to serious error2 )emem$er that the c#inician is focusing on the assessment of the atient and here our attention is redominant#y on the acid'$ase assessment. +2%232 Clinical Cases Inde6 to Clinical C6a,ples 6urther e7am #es with more e7tensive discussions can $e found in the Bas Archi/es 1. 4osto erative "ardiac Arrest 3. A wea9 o#d #ady !. A motor vehic#e crash 2. A (ic9 .ia$etic 4atient 4. A case of neumonia %. A "OA. atient with acute a$domina# ain 3. A dia$etic atient with vomiting and o#yuria 1:. A semi'comatose dia$etic ta9ing diuretics 12.A wea9 atient fo##owing a wee9 of diarrhoea 14. A man with an out'of'hos ita# cardiac arrest 1%. A woman with musc#e wea9ness and vomiting 13. A smo9er with fever and rigors 2:. An a#coho#ic with /IT $#eeding and shoc9 22. An o#d man with hiccoughs and confusion 24. A man with a #ea9ing aneurysm

2. A dehydrated man with diarrhoea 8. A man with a osto cardiac arrest 11. A man with ""6 C vomiting

13. A case with a osto mor hine infusion

1!. An o#d man with a$domina# ain C shoc9 12. An into7icated $a$y 18. A young man who ingested $arium car$onate 21. A vague historian with wea9ness and diarrhoea 23. A dia$etic using henformin

2!. An o#d #ady with a$domina# ain C vomiting 22. To $e added

2%. A man with a gunshot wound C a cardiac arrest 23. A #ady with a rigid a$domen

28. A teenage $oy with an o$structed co#onic 3:. A chi#d with ingestion of windscreen $#adder washer f#uid

Acid-Base 1hysiology 1-21 : .uantitati/e Acid-Base Analysis - *he 0yste,

1-2121 *he 'Fe4 1aradig,'9 )ecent#y? attention has shifted to a <uantitative hysicochemica# a roach to acid'$ase hysio#ogy. Many of the genera##y acce ted conce ts of hydrogen ion $ehaviour Gas discussed a$oveH are viewed different#y and indeed are often shown to $e wrongU This ana#ysis introduced $y 4eter (tewart 1,2 in 1823 3 rovides a chemica# insight into the com #e7 chemica# e<ui#i$rium system 9nown as acid'$ase $a#ance. The im act of the (tewart ana#ysis has $een s#ow in coming $ut there has $een a recent resurgence in interest? articu#ar#y as this a roach rovides e7 #anations for severa# areas which are otherwise difficu#t to understand Geg di#utiona# acidosis? acid'$ase disorders re#ated to changes in #asma a#$umin concentrationH. +As discussed in section 1.1? the maBority of this $oo9 covers the traditiona# acid'$ase a roach.(tewartEs $oo9 now on#ine 4eter (tewartEs inf#uentia# 1831 $oo9 G@How to 0nderstand Acid'Base@H 1 has #ong $een out' or' rint and it has $een difficu#t for many eo #e to o$tain access to a co y. )ecent#y? (tewartEs widow has given the co yright on the $oo9 to 4au# 1#$ers from Amsterdam and 4au# has #aced the who#e $oo9 on'#ine at his new we$site htt DIIwww.AcidBase.org The interested reader is referred to Be##omoG1888H4 and the associated review artic#es in that edition of ="urrent O inion in "ritica# "are> where the Enew aradigmE of (tewartEs acid'$ase a roach is considered with the enthusiasm of the true $e#iever. 0ndou$ted#y the hysiochemica# a roach wi## $ecome more im ortant in the future and this cha ter rovides an introduction. A $it of $ac9ground is necessary first. 1-2122 *er,s 8 Concepts This a roach re<uires a consideration of so#utions as systems. In articu#arD

S2 2 2 it is a general property of syste,s that the Iuantitati/e results of se/eral interacting but independent ,echanis,s can not be e6plained or understood solely in ter,s of the action of any single one of these ,echanis,s2S G(tewart 1833? 1444'!H2 A sim #e introduction to the conce ts and the terms which are used $y (tewart is necessary to understand the framewor9 in which he discusses acid'$ase chemistry in the $ody. A $io#ogica# f#uid is a very com #e7 dynamic system $ut usefu# ana#ysis is ossi$#e $y considering the chemica# s ecies invo#ved and how they interact chemica##y with each other. "onsider the argument deve#o ing in this wayD There are often mu#ti #e mechanisms invo#ved in inf#uencing the articu#ar concentration of any sing#e chemica# s ecies. Hydrogen ion is an e7am #e of one of these s ecies whose concentration is de endent on severa# interacting chemica# mechanisms Ge<ui#i$riumsH. 6ina##y Gand ra id#yH these mu#ti #e mechanisms must come into e<ui#i$rium and the +H,- in the so#ution at that oint in time is determined. An attem t to ca#cu#ate the e<ui#i$rium concentration of any s ecies must ta9e into account a## the mechanisms invo#ved. This is not <uite as difficu#t as may $e su osed $ecause certain sim #ifications are ossi$#e. GThese wi## $e considered #aterH. 6ina##y? a formu#a for the ca#cu#ation of the e<ui#i$rium va#ue of a chemica# s ecies Geg +H,-H can $e o$tained. The e<uation for +H,- is com #e7 $ut so#ution of it is easy and <uic9 on a com uter. Ohat we are #anning to do is to decide what it is that determines +H,- Gand the other chemica# concentrationsH in a $io#ogica# so#ution $y considering the severa# interacting mechanisms invo#ved. One aim is to deve#o a formu#a for ca#cu#ating +H,-? $ut more im ortant#y a new understanding of how acid'$ase hysio#ogy rea##y wor9s at the chemica# #eve# shou#d $e gained. The concentrations of the various chemica# s ecies resent are the varia$#es whose va#ues are used in the e<uations. 6rom the ers ective of considering a $io#ogica# so#ution as a system of interacting chemica# s ecies? we can consider these varia$#es as $eing of two ty es. A## the varia$#es can $e c#assified as either de endent varia$#es or as inde endent varia$#es. This is e7treme#y im ortant in discussing cause and effect so first consider the meaning of these termsD .e endent and Inde endent ;aria$#es ependent /ariables have va#ues which are determined interna##y $y the system. They are determined $y the e<uations Gchemica# e<ui#i$riaH which determine the system and can $e a#tered on#y $y changes in the va#ues of the inde endent varia$#es. Independent /ariables have va#ues which are determined $y rocesses or conditions which are e7terna# to the systemJ they are im osed on the system rather than $eing determined $y it.

Consider a si,ple analogyD A go#dfish in a $ow# which is fu## to the $rim. The $ow#'water'go#dfish com$ination is the system in this e7am #e. The amount of o7ygen in the so#ution is a de endent varia$#eD its va#ue at any time is determined $y the rate of o7ygen consum tion of the go#dfish and this

is a rocess which is com #ete#y interna# to the system. Kow consider the vo#ume of water in the $ow#D this is an inde endent varia$#e as its va#ue is determined $y factors e7terna# to the system within the $ow#. If there were any reactions within the $ow# that roduced more water Geg meta$o#ic water roduction $y the go#dfishH then it wou#d sim #y overf#ow the edges of the fu## $ow#. The vo#ume wou#d $e he#d constant des ite interna# changes within the $ow#. "onsider further the de endent varia$#e =o7ygen content in the $ow#>. This is not Bust determined $y the interna# rocess GO2 consum tion $y the go#dfishH $ut is affected $y the va#ue of various inde endent varia$#es such as the vo#ume of the $ow# and the tem erature of the water. More o7ygen wi## disso#ve in water at a #ower tem erature. The tem erature of the water is determined $y the environmenta# tem erature which is inde endent of the go#dfish in $ow# system. The water tem erature is another inde endent varia$#e. Ohy is the conce t of de endent and inde endent varia$#es so im ortantT The reason is that the va#ues of a## the de endent varia$#es are determined $y and can $e ca#cu#ated from the va#ues of the inde endent varia$#es. And a very im ortant articu#ar ointD In the acid'$ase system in $ody f#uids? <H=> is a dependent /ariableJ The traditiona# ana#ysis of acid'$ase ma9es the im #icit assum tion that +H,- is an inde endent varia$#e and this is wrong. Hydrogen ion concentration can therefore $e ca#cu#ated if the va#ues of the inde endent varia$#es are 9nown. 1reli,inary "e,ar&s about the 0ignificance of this Kow the significance of this and why it is so different from the traditiona# understanding may not $e immediate#y a arent to you. (o #ets consider the fo##owingD "onsider a ce## where H, ions are $eing um ed out of a ce## into the I(6. 0sing the traditiona# a roach we wou#d redict that this wou#d decrease the intrace##u#ar +H,- Gand increase the HH $ecause there is now #ess H, in the I"6 in that ce##. But the (tewart a roach wou#d say this understanding was wrong. Because +H,- is a de endent varia$#e? its concentration cannot $e changed in this wayJ its concentration can on#y $e changed if the va#ue of one of the inde endent varia$#es changes and a## that is ha ening is a um ing of H, ions. The (tewart a roach wou#d redict that the chemica# e<ui#i$ria within the ce## wou#d readBust to re #ace any H, #ost G$y $eing um ed out of the ce##H with the resu#t that the intrace##u#ar +H,- wou#d remain unchanged. (o? what rea##y ha ensT Oe## if the um ing of H, out of the ce## was the on#y change occurring than the I"6 +H,- wou#d not change and the (tewart a roach wou#d correct#y redict this. The source of the re #acement H, wou#d $e an e7treme#y sma## increase in the dissociation of H2O within the ce##. But? wait a minute? sure#y this cannot $e so. As another e7am #e? consider what ha ens in the arieta# ce##s in the stomach. After a mea#? the arieta# ce##s active#y um #arge amounts of H, into the gastric #umen. The +H,- in the arieta# ce##s decreases and this is ref#ected in the gastric venous $#ood as an increase in H Gthe E ost' randia# a#9a#ine tideEH. .oesnEt this mean then that the rediction of the (tewart a roach is wrong aftera##T Kot at a##. In fact? a ro er ana#ysis of this e7am #e shows that the outcome is consistent with that redicted $y the

(tewart a roach. One im ortant fact that has $een over#oo9ed in our ana#ysis so far is the re<uirement for e#ectroneutra#ity. It is Bust not ossi$#e to um much H, $ecause this sets u a otentia# difference across the ce## mem$rane. Kow the ce## can on#y to#erate an e7treme#y tiny charge se aration Gand such a minute charge se aration is sufficient to set u a transmem$rane otentia# difference or )M4 of say 1::m;H. The actua# concentration difference that this )M4 re resents is too sma## to measure other than as a otentia# difference Gie mem$rane otentia#H. Ohat is ha ening in the arieta# ce## is that $oth H, and "#' are $eing transferred out of the ce## and into the gastric #umen. 1#ectroneutra#ity is maintained. The vita# oint to notice here is the movement of "#' and the effect of this. As there is no otentia# difference set u $y um ing H, and "#' together there is no e#ectrochemica# force inhi$iting the movement. "onse<uent#y #arge amounts of "#' are $eing moved out of the ce##. This causes a change in the strong ion difference G(I.H. .onEt worry a$out what this means at resent Git wi## $e e7 #ained in section 1:.3H? Bust note that it is one of the inde endent varia$#es in this system and thus determines the va#ues of the de endent varia$#es? of which +H,- is one. The correct e7 #anation Gas rovided $y the (tewart a roachH is that yes? the +H,- in the gastric arieta# ce## does decrease $ut it is not the um ing of the H, which causes this? $ut rather the #oss of "#' from the ce##. The #oss of "#' changes the va#ue of one of the inde endent varia$#es. The e7 #anations of the two a roaches as to why the +H,- changes is <uite different. The (tewart a roach is the one that is correct in the sense of e7 #aining the cause. "eferences 1. (tewart 4A ,ow 'o >nd&rs'and Acid"5as&. =&w For(D 1#sevier? 1831 2. (tewart 4A. Mod&rn Guan'i'a'iv& acid"*as& ch&mis'ry. "an P 4hysio# 4harmaco# 1833 .ecJ %1G12H 1444'%1. 4u$Med 3. (tewart 4A. 3nd&+&nd&n' and d&+&nd&n' varia*l&s of acid"*as& con'rol. )es ir 4hysio# 1823 A rJ 33G1H 8'2%. 4u$Med 4. Be##omo ) C )onco " =&w +aradi)ms in acid"*as& +hysiolo)y "urrent O inion in "ritica# "are 1888J !D422 A## Med#ine a$stractsD 4u$Med Hu$Med

Acid-Base 1hysiology 1-22 .uantitati/e Acid-Base Analysis - *he Bac&ground (ome chemica# $ac9ground a$out the c#assifications of su$stances in so#ution is necessary $efore we roceed further. In articu#ar? the su$stances which affect acid'$ase $a#ance in $ody f#uids can a## $e c#assified into 3 grou s $ased on their degree of dissociation. This a##ows certain genera#isations C sim #ifications which are usefu# in understanding com #e7 so#utions. Body f#uids can $e considered as a<ueous so#utions that containD strong ions wea9 ions

non'e#ectro#ytes

0trong ions in solution are al4ays fully dissociated They e7ist on#y in the charged form. 6or e7am #eD disso#ving sodium ch#oride in water roduces a so#ution containing Ka, and "#'. There is no Ka"# resent so it is strict#y incorrect to s ea9 of =sodium ch#oride so#utions> as this s ecies does not e7ist in the so#utionU An im ortant ractica# conse<uence of this when ana#ysing so#utions is that the amount of the strong ion resent is not affected $y conversion $ac9 to the arent com ound Gas occurs with wea9 ions 'see $e#owH AK. the dissociation e<ui#i$rium of this reaction does not need to $e inc#uded in the ana#ysis. The concentration of any individua# strong ion in the so#ution is fi7ed un#ess it is trans orted out of the so#ution Geg $y a ce## mem$rane um or trans orter.H (trong ions are most#y inorganic Geg Ka,? "#'? 5,H $ut some are organic Geg #actateH. In genera#? any su$stance which has a dissociation constant greater then 1:'4 1<I# is considered as a strong e#ectro#yte.

5ea& ions are those ions produced fro, substances that only partially dissociate in solution Ions that are c#assified as Ewea9 ionsE are roduced from su$stances which on#y art#y dissociate when disso#ved in water. 6or the ur oses of acid'$ase ana#ysis? the wea9 ions in $ody f#uids as c#assified into 2 grou sD "ar$on dio7ide and associated ions Gvo#ati#eH Oea9 acids Gnonvo#ati#eH D HA WLX H, , A' Incom #ete dissociation of the wea9 acids means that the so#ution contains the wea9 acid #us the roducts of its dissociation. A dissociation e<ui#i$rium e<uation can $e writtenD <H=> 6 <A-> E KA 6 <HA> ' where 5A is the dissociation constant for the wea9 acid.

Fon-electrolytes are those substances in solution 4hich ne/er dissociate into ions2 Kon'e#ectro#ytes are not charged. As a conse<uence? non'e#ectro#ytes contri$ute to the osmo#a#ity of a so#ution $ut do not contri$ute to the charge $a#ance in the so#ution. Ho4 clearcut is the distinction bet4een strong ionsL 4ea& ions 8 non-electrolytes9 The distinction is not com #ete#y c#earcut of course B7* for ractica# ur oses it is a sufficient#y accurate C usefu# a ro7imation. (tewart uses the va#ue of the dissociation constant G5AH to rovide a c#ear G$ut sti## a $it ar$itraryH distinction $etween the three grou sD

Kon'e#ectro#yte D 5A W 1:'12 1<I# Oea9 e#ectro#yte D 5A $etween 1:'4 and 1:'12 1<I# (trong e#ectro#yte D 5A X 1:'4 1<I# ''''''''''''''''''''''''''''' C6tra Fotes: =(trong> in this section means s'ron)ly dissocia'&d and does not mean a Estrong so#utionE Gie meaning a concentrated oneH. Those strong ions eg "a,, which are art#y $ound to #asma roteins donEt <uite fit into the system $ut this is not a maBor ro$#em art#y $ecause their concentrations are #ow.

Acid-Base 1hysiology 1-23 .uantitati/e Acid-Base Analysis: *he ;ariables The e<uation for ca#cu#ating +H,- deve#o ed $y (tewart contains 3 inde endent varia$#es and % de endent ones. The nature of the inde endent varia$#es wi## seem strange at first $ut the ur ose of this section is to introduce them and $rief#y discuss what they are and why they are inde endent. The Three Inde endent ;aria$#es These areD pC32 'the artia# ressure of "O2 in the so#ution under e7amination 0I 'this stands for the Estrong ion differenceE in the so#ution <A*ot> 'the tota# concentration of wea9 acid in the so#ution. GThese 3 varia$#es are e7 #ained further in the su$sections $e#owH 1-2321 *he first independent /ariable : pC32 The "O2 is the easiest to understand. (ome factsD "ar$on dio7ide is roduced $y a## ce##s in the $ody It crosses a## ce## mem$ranes easi#y? traverses the I(6 and enters the $#ood It is e7creted from the $ody $y the #ungs The arteria# "O2 is under sensitive and owerfu# feed$ac9 contro# via the eri hera# and centra# chemorece tors

These rece tors res ond to an increase in arteria# "O2 $y increasing venti#ation and this returns arteria# "O2 to norma#. Arteria# "O2 is fre<uent#y said to $e determined $y the ratio of "O2 roduction to a#veo#ar venti#ation G(ee (ection 2.3H. This is <uite correct $ut does not indicate the effect of the contro# system which is very effective at maintaining norma# arteria# "O2. A consideration of the e<uation wou#d suggest that a dou$#ing of "O2 roduction wou#d resu#t in a dou$#ing of arteria# "O2 $ut this does not occur in the intact erson Gun#ess venti#ation is fi7ed eg as in an anaesthetised venti#ated atientH. Any rise in arteria# "O2 is detected $y the sensors Gie the chemorece torsH and activates the contro# system resu#ting in increased a#veo#ar venti#ation. This returns the arteria# "O2 towards norma#. In a$norma# situations? the contro# system is distur$ed or otherwise ineffective at 9ee ing arteria# "O2 constant. The gist is that the va#ue of "O2 in arteria# $#ood and a## $ody f#uids is effective#y set $y mechanisms other than the chemica# e<ui#i$ria occurring in the f#uids. The va#ue is determined and contro##ed $y factors e7terna# to the chemica# system in the $ody f#uids. It is therefore an inde endent varia$#e. 1-2322 *he second independent /ariable: 0I This a$$reviation stands for (trong Ion .ifference. It is defined asD (I. L Gthe sum of a## the strong cation concentrations in the so#utionH minus Gthe sum of a## the strong anion concentrations in the so#utionH. 6or e7am #eD if a so#ution contained Ka,? 5, and "#' as the on#y strong ions resent? thenD (I. L +Ka,- , +5,- ' +"#'If these strong ions were the on#y charged s ecies resent? then the owerfu# re<uirement for e#ectrica# neutra#ity wou#d mean that (I. wou#d $e &ero. Most $io#ogica# f#uids contain wea9 e#ectro#ytes Gmost#y wea9 acidsH. If the (I. is not &ero? then it means that the so#ution must contain other charged s ecies ie wea9 e#ectro#ytes. The (I. re resents the net charge which must $e $a#anced $y charges on the wea9 acids in the so#ution for e#ectrica# neutra#ity to $e maintained. In #asma? the formu#a for (I. is a ro7imate#yD 0I E M <Fa=> = <K=> = <Ca==> = <$g==> P - M <Cl-> = <3ther strong anions-> P

5hy is 0I considered an 'independent /ariable'9 The com onents Gie the strong ionsH which are used to ca#cu#ate the (I. are not a#tered $y any of the reactions in the system. Kone of these ions are roduced or consumed. The concentrations are im osed on the so#ution from outside and are contro##ed $y outside mechanisms. The 9idney is the most im ortant regu#ator of most of these ion concentrations. Inorganic strong ions Geg Ka,? "#'H are most#y a$sor$ed from the gut and contro# is most#y $y variations in rena# e7cretion due to various contro# systems in the $ody. Organic strong ions Geg #actate? 9eto'anionsH are roduced $y meta$o#ism and may $e meta$o#ised in

the tissues or e7creted in the urine. However? their concentrations in most $ody f#uids are not de endent on the reactions within the so#ution $ut are regu#ated $y mechanisms e7terna# to the system. The derived va#ue 0I is used $ecause it is a term which arises in the e<uation for e#ectrica# neutra#ity and a##ows us to lum+ 'o)&'h&r a## the inde endent concentrations in the form in which the strong ions are invo#ved in affecting acid'$ase $a#ance Gie $y their overa## net chargeH. The (I. is that art of the charge on the strong ions which has to $e $a#anced G$ecause of the e#ectroneutra#ity re<uirementH $y the net o osite charges of the tota# wea9 ions resent. 0n#i9e the strong ions? the amount of these wea9 ions varies $ecause of varying amounts of dissociation. The amount of dissociation of these wea9 ions varies such that the net amount of charge of them a## considered together? is e<ua# and o osite to the charge due to the strong ions. This is Bust a chemica# fact due to the re<uirement for e#ectroneutra#ity that is im osed on the system $y hysica# #aws. If on#y the strong ions which are ty ica##y resent in hea#th are considered? the =apparent 0I H ?0I aA can $e ca#cu#ated asD 0I a E M <Fa=> = <K=> = <Ca==> = <$g==> P - M <Cl-> = <lactate-> P (I.a has a norma# va#ue of 4: to 42 m1gI#. This is a usefu# sim #ification $ut it is ossi$#e to go further. On#y +Ka,- and +"#'- are resent in high concentrations so the (I. can $e rough#y a ro7imated as G +Ka,- ' +"#'- H. Kow if we remem$er that +Ka,- is tight#y contro##ed $y the $ody $ecause it contro#s tonicity? then the maBor way that the 1"6 H can $e a#tered is $y changes in +"#'- re#ative to a constant +Ka,-. 1-2323 *he third independent /ariable: <A*ot> The a$$reviation re resents the tota# amount of non'vo#ati#e wea9 acid resent in the system. A## the wea9 acids in the system are re resented co##ective#y as HA. The anion for each acid wi## $e different $ut $ecause they a## $ehave simi#ar#y a## the wea9 acids are re resented as though they were a sing#e acid Gfor which the sym$o# HA is usedH which has a sing#e a arent dissociation constant. This is a usefu# sim #ifying assum tion which is $asica##y an averaging rocess. The dissociation reaction isD HA WLX H, , A'' The #aw of conservation of mass means that 'h& 'o'al amoun' of A Gsym$o#D +ATot-H in the system must $e constant. Kone of the reactions in the system roduce or consume A. "onservation of A can $e re resented asD <A*ot> E <HA> = <A> In #asma? the maBor non'vo#ati#e wea9 acids resent areD 4roteins G +4rTot- L +4r'- , +H4r-H 4hos hates G +4iTot- L +4O4'3- , +H4O4'2- , +H24O4'- , +H34O4-H Albu,in is the most im ortant rotein resent that acts as a wea9 acid so the tota# amount of rotein is a ro7imated $y the a#$umin concentration G+A#$-H. /#o$u#ins do not contri$ute significant#y to the tota# negative charge due to #asma rotins. The #eve# of a#$umin in $ody f#uids is im osed u on the acid'$ase system and is not regu#ated $y it. The co##oid osmotic ressure C osmo#a#ity of the

e7travascu#ar #iver s ace is the rimary factor which contro#s the rate of roduction of a#$umin. G4ietrange#o et a#? 1882H. 1hosphates are resent in severa# forms $ut the tota# amount is norma##y fair#y constant. Its #eve# in #asma is contro##ed as art of the system for regu#ating ca#cium #eve#s. 4hos hates norma##y contri$ute on#y a$out 1mM of ATot. 4hos hates re resent on#y !Q of ATot at norma# hos hate #eve#s. If hos hate #eve#s are e#evated then its contri$ution $ecomes more im ortant. *he point of all this is that the <Albu,in> alone can be used as an esti,ate of A*ot in plas,a2 As an overview of these inde endent factors? consider the fo##owing genera#isations that have $een madeD The first inde endent varia$#e is "O2 which is contro##ed $y a res iratory contro# system. The 2nd inde endent varia$#e is (I. and this can $e rough#y estimated as G+Ka,- ' +"#'-H and this is contro##ed $y the 9idney. The 3rd inde endent varia$#e is ATot and this is estimated as +A#$- which is contro##ed $y the #iver.

Acid-Base 1hysiology 1-2! .uantitati/e Acid-Base Analysis - *he CIuations The who#e ur ose of (tewart>s mode# is to discover what determines the +H,- Gand thus HH in a<ueous so#utions such as $ody f#uids. *ets #oo9 at two sim #e systems to gain some e7 erience in deciding what determines the +H,- in these systems. 1-2!21 C6a,ple 0olution 3ne: 1ure 5ater "onsider first a so#ution of ure water and as9 the <uestion hereD Ohat determines the +H,-T Oe can determine a formu#a for this as fo##owsD Oater dissociates into H, and OH' to a very sma## degreeD H2: WLX H, , OH' The dissociation e<ui#i$rium e<uation for this reaction isD +H,- 7 +OH'- L 5w 7 +H2O- Gwhere 5w is the dissociation constant for 4aterH. The va#ue for 5w is tem erature de endent. The term +H2O- is very #arge G!!.!M at 32"H and the va#ues of +H,- and +OH'- are $oth very sma##D that is water dissociates to such a very sma## e7tent that the va#ue of +H2O- is essentia##y constant. The terms 5w and +H2O- can $e com$ined into a new constant 5Ew. 5>w which is ca##ed the ion product for 4ater. ThusD

5>w L +H,- 7 +OH'1#ectrica# neutra#ity must a#so $e resent in the so#ution. As H, and OH' are the on#y ions resentD +H,- L +OH'These 2 simu#taneous e<uations have two un9nowns so a so#ution for +H,- is ossi$#eD <H=> E ?KH4A1@2 This is the sim #est system ossi$#e $ut i##ustrates the oint that ana#ysis of a system resu#ts in severa# e<uations that can $e so#ved for +H,-. Overview of Basic 4rinci #es The $asic rinci #es used in ana#ysing a## systems and determining the e<uation for +H,- are sim #eD 1#ectroneutra#ity must $e conserved Mass must $e conserved A## dissociation e<ui#i$riums must $e met The resu#t is a set of simu#taneous e<uations which may $e so#ved. Ko matter how com #e7 the so#ution? a## these 3 conditions must $e met. 1-2!22 C6a,ple *4o: A 0olution of 0odiu, chloride Kow consider a s#ight#y more com #icated systemD an a<ueous so#ution containing on#y Ka, and "#'. This e7am #e shows how the (I. term arises. Ohat determines the +H,- in this so#utionT Oe can write the fo##owing e<uations for this systemD Oater .issociation 1<ui#i$riumD 5>w L +H,- 7 +OH'1#ectrica# Keutra#ityD +Ka,- , +H,- L +"#'- , +OH'(o#ving for +H,-D +Ka,- ' +"#'- L +OH'- ' +H,+OH'- L 5>w I +H,"om$ining theseD +H,-2 , +H,- G+Ka,- ' +"#'-H ' 5>w L : Kow G+Ka,- ' +"#'-H L (I. for the so#ution in this e7am #e? soD +H,-2 , G (I. . +H,- H ' 5>w L : (o#ving this <uadratic e<uation? the 2 so#utions areD <H=> E -0I @2 = sIuare root of ? KH4 = 0I and
2@!A

<H=> E -0I @2 - sIuare root of ? KH4 = 0I

2@!A

6or so#utions containing Ka, and "#' in water? the +H,- is determined $y the (I. alone Gas this is the on#y varia$#e on the right hand side of the e<uationHU This sim #e e7am #e i##ustrates how the (I. term is usefu# as a inde endent varia$#e which arises out of the e<uations used to ana#yse the chemica# systems in $ody f#uids. 1-2!23 *he CIuation 0et for Body Dluids The receding two e7am #es out#ine the a roach that can $e ta9en with any a<ueous so#ution. 1ven though $ody f#uids are much more com #e7? (tewart was a$#e to find the e<uations which descri$e the system and so#ve them for +H,-. Body f#uids are a<ueous so#utions which contain strong ions Ginorganic and organicH and wea9 ions Gthe vo#ati#e "O2IH"O3 system and various non'vo#ati#e wea9 acids HAH. The inde endent varia$#es which determine the +H,- in a## $ody f#uids are the "O2? (I. and +ATot-. A## the other varia$#es G eg +H,-? +OH'-? +H"O3-? +A'- H are de endent on the va#ues of the 3 inde endent varia$#es. There are si7 simu#taneous e<uations necessary to descri$e this system Gsee ta$#e $e#owH A full discussion and d&riva'ion of 'h&s& &Gua'ions is no' +r&s&n'&d h&r&: 'h& in'&r&s'&d r&ad&r is r&f&rr&d 'o P&'&r 0'&war'-s *oo( D,ow 'o >nd&rs'and Acid"5as&D HI# IJ *he 0i6 0i,ultaneous CIuations used by 0te4art 12 5ater issociation CIuilibriu, +H,- 7 +OH'- L 5>w 22 Clectrical Feutrality CIuation +(I.- , +H,- L +H"O3'- , +A'- , +"O3'2- , +OH'32 5ea& Acid issociation CIuilibriu, +H,- 7 +A'- L 5A 7 +HA!2 Conser/ation of $ass for SAS +ATot- L +HA- , +A'#2 Bicarbonate Ion Dor,ation CIuilibriu, +H,- 7 +H"O3- L 5" 7 "O2 %2 Carbonate Ion Dor,ation CIuilibriu, +H,- 7 +"O3'2- L 53 7 +H"O3'-

1<uation ! is the $asis of the fami#iar Henderson'Hasse#$a#ch e<uation. It is interesting to note that the traditiona# a roach to acid'$ase hysio#ogy uses the Henderson'Hasse#$a#ch e<uation a#one and ignores a## the other e<uationsU The three $asic constraints that #ead to these si7 e<uations are chemica# or hysica# #aws that must $e o$eyed $y the systemD 1#ectrica# neutra#ity must $e resent in the so#ution "onservation of mass must occur A## dissociation e<ui#i$ria must $e satisfied simu#taneous#y

Acid-Base 1hysiology 1-2# .uantitati/e Acid-Base Analysis: *he 0olutions The set of si7 simu#taneous e<uations derived $y (tewart Gsee revious sectionH inc#udeD the 3 inde endent varia$#es G "O2? (I. and +ATot-H the % de endent varia$#es G +HA-? +A'-? +H"O3'-? +"O2'3-? +OH'-? +H,- H These e<uations can $e so#ved mathematica##y to e7 ress the va#ue of any one of the de endent varia$#es in terms of the 3 inde endent varia$#es Gand the various e<ui#i$rium constantsH. The va#ues of the e<ui#i$rium constants have $een e7 erimenta##y determined under a range of conditions and can $e o$tained from various reference sources. To focus on#y on the so#ution of the si7 e<uations for +H,-? one derives a formu#a of the fo##owing formD a6! = b63 = c62 = d6 = e E Mathematicians ca## this ty e of e<uation a @1th order polynomial@. The un9nown va#ue is 7 and a?$?c?d and e are constants. GThe actua# va#ue of these @constants@ can change ' eg with change in tem erature ' $ut are a fi7ed va#ue under a given set of conditions. If? for e7am #e? the tem erature changes? then different va#ues of the constants have to $e used.H The actua# e<uation for +H,- that (tewart derived is #isted $e#ow.

1<uation used to (o#ve for +H,a2<H=>! = b2<H=>3 = c2<H=>2 = d2<H=> = e E whereD aL1 $ L +(I.- , 5A c L M5A 7 G+(I.- ' +ATot-H ' 5>w ' 5" 7 "O2N d L ' M5A 7 G5>w , 5" 7 "O2H ' 53 7 5" 7 "O2N e L ' G5A 7 53 7 5" 7 "O2H

Gsee (tewartEs $oo9 for va#ues of the constants in this e<uationH A daunting e<uation $ut so#ution is fast and easy on an a ro riate#y rogrammed com uter. A simi#ar ty e of e<uation can $e roduced for any of the % de endent varia$#es. The oint here is not to $ecome invo#ved in com #icated mathematics $ut to show that it is ossi$#e to so#ve the e<uation and determine the hydrogen ion concentration Gie +H,- H in the so#ution using on#y the va#ues of the three inde endent varia$#es and various e<ui#i$rium constants. + 6or the curious? such 4th order o#ynomia# e<uations can $e so#ved on'#ine. To use this on'#ine resource to so#ve for H you wi## of course first need to 9now the va#ues for the constants.-

Acid-Base 1hysiology 1-2% .uantitati/e Acid-Base Balance : *he I,plications

0te4art has essentially produced a ,athe,atical ,odel of the acid-base balance of body fluids2 His ana#ysis gives new insights into what is rea##y ha ening at the chemica# #eve# and this is different from the conventiona# a roach. The conventiona# understanding of acid'$ase $a#ance isD =clu''&r&d wi'h 9ar)on, ch&mically m&anin)l&ss d&riv&d Guan'i'i&s, a misund&rs'andin) of wha' is ha++&nin) and an ar'ificial us& of 'h& ,&nd&rson",ass&l*alch &Gua'ion as 'h& sin)l& &Gua'ion d&'&rminin) acid"*as& *alanc& in any *ody fluid- G(tewartH. The Henderson'Hasse#$a#ch e<uation is Bust one of the % e<uations which must a#ways $e simu#taneous#y satisfied.

All disturbances of acid-base balance $70* result fro, a changes in the independent /ariables ?8 only the independent /ariables2 "espiratory acid-base disorders are caused by changes in the independent /ariable pC32 $etabolic acid-base disorders are caused by changes in 0I and@or <A*ot> "hanges in "O2 can occur <uic9#y as venti#ation can $e ra id#y a#tered. "hanges in (I. are due to changes in the concentrations of strong ions. The $asic system for strong ions is a$sor tion from the gut and e7cretion via the 9idneys. These are $oth much s#ower rocesses than "O2 changes. The main contri$utor to +ATot- in $ody f#uids are the roteins. 6or the 1"6? this is essentia##y +a#$umin- as discussed revious#y. Most #asma roteins are roduced $y the #iver. "hanges in rotein concentration occur even more s#ow#y than strong ion changes so changes in (I. account for most meta$o#ic acid' $ase distur$ances. If #asma rotein #eve#s are norma# G+ATot- constantH? then acid'$ase distur$ances can $e ana#ysed in terms of changes in "O2 and (I.. 1-2%21 Interactions across $e,branes The (tewart a roach see9s to determine the factors that determine the acid'$ase state in a given $ody f#uid com artment. The f#uid com artments in the $ody are se arated $y ce## mem$ranes or $y e ithe#ia# #ayers. In each com artment? the +H,- is determined $y the va#ues of the inde endent varia$#es. An acid'$ase distur$ance in a com artment is due to a change in one or more of the inde endent varia$#es occurring in that com artment. Ho4 do acid-base interactions occur across the ,e,branes that separate the different co,part,ents9 "onsider the fo##owingD The 3 maBor f#uid com artments in the $ody are the I"6? I(6 and #asma. These com artments interact with each other across mem$ranes Geg ce## mem$rane? ca i##ary mem$raneH. Acid'$ase interactions occur across these mem$ranes a#so. These interactions can roduce changes in acid'$ase status on#y if the resu#t of the interaction is to change the va#ue of one or more of the inde endent varia$#es. "ar$on dio7ide diffuses across mem$ranes ra id#y and easi#y. "hanges in "O2 can occur ra id#y via venti#atory changes. This has 2 im ortant conse<uencesD +H,- in a## f#uid com artments can $e a#tered ra id#y? $ut e<ua##y. "hanges in "O2 cannot $e used to roduce differences in +H,- in f#uids on o mem$rane. osite sides of a

4roteins are resent in significant concentrations in I"6 and in #asma $ut the I(6 #eve# is #ow. 4roteins such as a#$umin are #arge mo#ecu#es which cannot cross mem$ranes e7ce t in unusua# circumstances. The effect of this is that +H,- changes across a mem$rane cannot $e due to movement of rotein $etween the f#uids. The hos hate #eve# in #asma is #ow and regu#ated $y the ca#cium contro# system. Transfer of hos hates across mem$ranes cou#d roduce acid'$ase changes $ut these movements do not contri$ute significant#y to acid $ase interactions.

This #eaves on#y (I. to consider. (trong e#ectro#ytes can cross mem$ranes $ut usua##y via s ecific mechanisms such as ion channe#s and trans ort um s. (trong ions can move down or against a concentration gradient. The movement of strong ions can $e varied Geg um s can $e activated? ion channe#s can $e o en or c#osed H (o of the 3 inde endent varia$#esD "O2 D "O2 crosses mem$ranes very easi#y and cannot contri$ute to causing acid'$ase differences across a mem$rane +ATot- D 4roteins cannot cross mem$ranes at a## and so cannot contri$ute to causing acid'$ase differences (I. D (trong ions Gthe determinants of (I.H can cross mem$rane and this trans ort can $e varied. Conclusion: A change in <0I > alone is the ,a)or ,echanis, by 4hich acid-base di""eren es occur across a ,e,brane as the other t4o independent /ariables cannot be responsible2 Im ortant rocesses invo#ved inc#ude Ka,'H, e7change and 5,'H, e7change across the ce## mem$rane. The 9idney is usua##y said to e7crete acid from the $ody Gie if urine has a #ower H than #asma? some net amount of H, is $eing e7cretedH. This is not correct. The 9idney certain#y has a ro#e in decreasing the +H,- of #asma $ut the rea# mechanism is different from the conventiona# e7 #anation. As roteins cannot cross mem$ranes? this decrease in #asma +H,- must $e due to the 9idney causing changes in (I. across the rena# tu$u#es. The change in +H,- is due to differentia# movement of strong e#ectro#ytes Geg Ka,? "#'? 5,H across the tu$u#es causing a change in the (I. on each side of the mem$raneD it cannot $e due direct#y to the secretion or a$sor tion of H, or H"O3' Gor adBustment in any of the other de endent varia$#esH. 6or e7am #e in the dista# tu$u#e. it is not the secretion of H, that causes the H of the dista# tu$u#ar f#uid to fa## $ut the movement of the strong ion Geg Ka,H associated with the rocess. A further e7am #e of acid'$ase interactions across a mem$rane is that occurring in the stomach. /astric Buice is acidic not $ecause of the trans ort of H, into the stomach $ut $ecause of the movement of "#' that occurs. A#ternative#y? if the H, was e7changed for a ositive ion #i9e Ka, or 5, then the (I. wou#d $e a#tered $y the same amount and again gastric secretions wou#d $e acidic. The factor which determines the +H,- is the change in (I. due to movement of "#' into the gastric Buice. The intrace##u#ar H is a#tered most#y $y contro# of intrace##u#ar (I.. The ion um s regu#ate concentrations of the various ions and there$y indirect#y contro# the intrace##u#ar (I. and H. The contro# of +H,- in a## $ody f#uids is due to changes in the 3 inde endent varia$#es. 4roteins don>t norma##y contri$ute much to acid'$ase interactions $ecause they cannot cross mem$ranes. Most #asma roteins are synthetised in the #iver. If rotein #eve#s fa## Geg due to he atic dysfunction or e7cretion as in the ne hrotic syndromeH this wi## have redicta$#e effects on acid'$ase $a#ance. (trong ions are norma##y a$sor$ed in the gut and e7creted $y the 9idney. Ohat is im ortant is not the a$so#ute concentrations of the individua# strong ions? $ut the tota# amount of charge which is resent on them which is not $a#anced $y other strong ions Gie (I.H. The "O2 is under res iratory contro#. "hanges in "O2 can cause ra id changes in the +H,- of a## $ody f#uids. "hanges in (I. are very im ortant in contro##ing transmem$rane e7changes which affect the acid'$ase

situation in adBacent f#uid com artments. 1-2%22 Acid-Base isorders )es iratory acidosis and a#9a#osis are due to hy erca nia and hy oca nia res ective#y Gie the "O2 is the im ortant inde endent varia$#e in these disordersH. Meta$o#ic acidosis is most#y due to a decreased (I. and meta$o#ic a#9a#osis is most#y due to an increase in (I.. However changes in +ATot- can a#so cause meta$o#ic acid'$ase disorders. Hy oa#$uminaemia causes a meta$o#ic a#9a#osis and hy era#$uminaemia causes a meta$o#ic acidosis. An e7am #e is the contri$ution of #ow a#$umin #eve#s to the a#9a#osis associated with cirrhosis or the ne hrotic syndrome. An increase in hos hate in #asma occurs in rena# fai#ure and contri$utes to the meta$o#ic acidosis of uraemia. The hos hate #eve# is #ow in #asma so a dro in hos hate #eve# in #asma cannot contri$ute to causing a detecta$#e meta$o#ic a#9a#osis. 1-2%23 Conclusion The (tewart a roach Dshows 'h& way 'o a com+l&'& Guan'i'a'iv& 'r&a'm&n' of *ody fluids as +hysico" ch&mical sys'&ms, 'hrou)h num&rical solu'ion of 'h& s&'s of simul'an&ous &Gua'ions 'ha' d&scri*& 'h&ir acid"*as& *&haviour.D G6enc# C *eith? 1883H. This a roach is s#ow#y gaining acce tance in research a ers and in mode##ing of the acid'$ase homeostasis of $ody f#uids. It a#so rovides an insight into the chemica# rocesses that determine the H of $ody f#uids. The conc#usions are often <uite different to those of the traditiona# a roach. 6or e7am #e? the traditiona# a roach to meta$o#ic acid'$ase disorders is concerned with $icar$onate $ut the (tewart a roach em hasises that ch#oride is the most im ortant anion when causative factors are considered. 0oL should 4e be using this approach9 6rom anaesthetist.com .uoteD @There is #itt#e dou$t in my mind that the (tewart a roach ma9es sense? and rovides a s#ight#y $etter mode# of how acid'$ase wor9s than does the conventiona# a roach. I $e#ieve that (tewart rovides a refinement of the conventiona# a roach. 0nder many? erha s most circumstances? the Eo#d'fashionedE a roach wor9s fine? $ut we shou#d $e aware of the e7ce tions Ggross vo#ume di#ution with f#uids which have a #ow (I.J hy oa#$uminaemia in association with meta$o#ic acidosisH and invo9e the hysicochemica# a roach in these circumstances. This new a roach a#so he# s us e7 #ain how our thera eutic interventions wor9. Much sti## needs to $e done. Oe need a via$#e mode# $ased on hysicochemica# rinci #es that can $e consistent#y shown to $e as good as or $etter than the o#der mode#s. Idea##y this mode# shou#d a#so e7tend to assessment of who#e $#ood acid'$ase status? and even a##ow us to redict who#e'$ody H changes in res onse to thera eutic interventions.@ 6rom acid'$ase.com

.uoteD @6or most acid'$ase distur$ances? and for the foreseea$#e future? the traditiona# a roach to acid'$ase $a#ance seems certain to revai#. 6or the c#inician? the three varia$#es of greatest us are the H? 4"O2? and standard $ase e7cess G(B1H. Ohat might change thisT The answer wou#d have to $e u$#ished cases where c#inica# management has $een critica##y im roved $y using (tewartEs a roach. (uch cases wou#d have to $e accumu#ated? eva#uated? and a roved $efore any maBor switch to his a roach seems warranted.@ An editoria# view .uoteD @ . . . . it wou#d $e remature at resent to ro ound the (I. a roach. A#though it certain#y wi## remain a owerfu# too# in acid'$ase research? for c#inica# management it is more cum$ersome? ossi$#y more e7 ensive? and not sufficient#y $etter than a critica# assessment of the $ase e7cess? anion ga ? or HI4"O2 ma s to warrant its wides read ado tion.18 Inter retation of acid'$ase disorders wi## a#ways remain art#y an art? one that com$ines an inte##igent synthesis of the c#inica# history? hysica# e7amination? and other anci##ary #a$oratory data ta9en together in the conte7t of the individua# atient and the nature and tem ora# course of his or her disease.@

Acid-base 1hysiology 1121 Acid-Base Aspects of 1regnancy

112121 Hyper/entilation The hy erventi#ation that occurs during regnancy is ro$a$#y due in art to rogesterone stimu#ating the res iratory center. *ung vo#ume changes and a#tered com #iance may a#so contri$ute. The effect is a chronic res iratory a#9a#osis which is com ensated $y rena# e7cretion of $icar$onate. Ty ica# $#ood gases resu#ts in the third trimester areD *ypical ABBs in the *hird *ri,ester H 2.43 "O2 33mmHg +H"O3- 21mmHg O2 1:4 mmHg. The reduction in $icar$onate resu#ts in a s#ight#y reduced a$i#ity to $uffer a meta$o#ic acid #oad. The #ower "O2 wou#d shift the o7ygen dissociation curve to the #eft? $ut the minima# change in H and the increased 2?3 .4/ #eve#s during regnancy mean the O." is #itt#e a#tered in osition.

112122 Hypere,esis Kausea and vomiting occur common#y in the first trimester. )are#y? this may $e severe Ghy eremesis gravidarumH and intracta$#e vomiting can cause f#uid #oss and e#ectro#yte distur$ances. The acid'$ase resu#t is ty ica##y a meta$o#ic a#9a#osis $ut 9etosis may a#so occur if ora# inta9e is oor. The actua# acid'$ase effect of vomiting de ends on the actua# mi7 of acidic gastric f#uid and a#9a#ine intestina# secretions in the vomitus. A#9a#osis does not a#ways occur with ro#onged vomiting. 112123 $aternal Ketosis The regnant woman is rone to deve#o e#evated 9etone #eve#s $ecauseD fasting during regnancy more ra id#y resu#ts in hy og#ycaemia and #ow insu#in #eve#s insu#in resistance deve#o s as regnancy rogresses G ro$a$#y due to #acenta# hormonesH 6asting 9etosis deve#o s in #ess than 1% hours in #ate regnancy as com ared to usua##y greater than 24 hours in the non' regnant fema#e. 5etones can cross the #acenta and the foetus can ada t to use them as an energy source. 5etones may $e im ortant in mye#ination in the deve#o ing centra# nervous system. This mi#d 9etosis that occurs with fasting does not seem to have any adverse effect on the mother or foetus. There is no information on which to $ase treatment of 9etosis in #a$ouring women.1 5etoacidosis due to materna# dia$etes is more serious and can have very serious adverse effects on the foetus. 11212! 3ther .iuretic use may cause a meta$o#ic a#9a#osis. This resu#ts in a mi7ed a#9a#osis $ecause the hy erventi#ation has a#ready reduced the "O2. "eferences 1. Toohi## P? (oong B? and 6#enady ;. 3n'&rv&n'ions for (&'osis durin) la*our. "ochrane .ata$ase (yst )ev 2::3 Pu# 1% ".::423:. 4u$Med

Acid- ase &hysio#ogy 11'2 Acid- ase &hysio#ogy in Chi#dren

os( aspec(s o) acid-'ase physiolo4y i! childre! are (he same as )or ad"l(s a!d ,ill !o( 'e repea(ed here% 5ome di))ere!ces i! !eo!a(es a!d i!)a!(s are 'rie)ly i!dica(ed 'elo,% 6he mos( commo! acid-'ase pro'lems i! !eo!a(es are respira(ory disorders d"e (o respira(ory i!s"))icie!cy% a!y i!heri(ed disorders a))ec(i!4 i!(ermediary me(a'olism ca! res"l( i! a! acc"m"la(io! o) or4a!ic acids a!d (hese !early all prese!( d"ri!4 childhood%

6hese are 'rie)ly co!sidered 'elo,%

11%2%1 7e!eral 8ac(ors a))ec(i!4 9cid-:ase :ala!ce i! 1!)a!(s (o) icar*onate depends on %estationa# Age 9s compared (o !ormal ad"l(s, (he plasma ;H233< i! !eo!a(es is lo,er d"e (o (he lo,er re!al (hreshold a!d lo,er capaci(y (o rea'sor' 'icar'o!a(e% 6he more imma("re (he !eo!a(e, (he lo,er (he le=el% >ery lo, 'ir(h ,ei4h( 'a'ies ha=e 'icar'o!a(e le=els o) 12-16 mmoles?l '"( (erm 'a'ies ha=e le=els o) 20-22 mmol?l% (o) Reser"e to excrete an Acid (oad At birth in term infants, acid excretion is working near maximum capacity and there is little reserve to deal with acidosis. The lower bicarbonate levels in preterm babies means they have even less capacity than a term neonate to buffer an acid load. The ability to excrete an acid load improves over the first couple of months of life. +ther ,actors 7ro,(h res"l(s i! deposi(io! o) 'ase i! !e, 'o!e as (he calci"m sal(s i! 'o!e are al@ali!e sal(s% 3! a ,ei4h( 'asis, )i0ed acid prod"c(io! is hi4her (ha! i! ad"l(s (e4 !eo!a(es a!d childre! & 12 mo!(hs A )i0ed acid prod"c(io! is 2 (o 3 mmol?@4?day)%

11'2'2

-nfanti#e

Meta*o#ic

Acidosis

9s me!(io!ed pre=io"sly, a lar4e !"m'er o) di))ere!( i!'or! errors o) me(a'olism ca"se a me(a'olic acidosis% 6his may 'eA or4a!ic acidosis (e!Byme de)ec( res"l(i!4 i! acc"m"la(io! o) acidic me(a'olic i!(ermedia(es) lac(ic acidosis hyperchloraemic acidosis 8eedi!4 di))ic"l(ies o)(e! i! associa(io! ,i(h (achyp!oea are commo! i! !eo!a(al

me(a'olic acidosis% 5ome e0amples o) or4a!ic acidoses i! childre! areA maple syr"p "ri!e disease me(hylmalo!ic acidaemia propio!ic acidaemia iso=aleric acidaemia 4l"(aric acid"ria% 5ome o) (hese disorders also ca"se a @e(oacidosis%

6ypical *rese!(a(io! 9 (ypical prese!(a(io! o) ma!y or4a!ic acidaemias is as rec"rre!( episodes o) me(a'olic acidosis ,i(h coma o)(e! preceded 'y =omi(i!4, me!(al o'("!da(io!, hypo(o!ia or seiB"res% Cpisodes may 'e precipi(a(ed 'y 'rea@do,! associa(ed ,i(h s"r4ery% i!creased pro(ei!

6hese i!heri(ed co!di(io!s, (ho"4h i!di=id"ally "!commo!, sho"ld 'e co!sidered i! a!y child ,i(h a! acidosis especially i) associa(ed ,i(h coma% .e"rolo4ical ma!i)es(a(io!s are commo!% C0per( ad=ice a!d i!=es(i4a(io! is reD"ired (o sor( o"( (hese disorders% ;6he i!(eres(ed are re)erred (o 3Ba!d E 7asco! (1991) )or a re=ie, o) or4a!ic acidaemias%< +ac(ic acidosis ca! also res"l( )rom e!Byme de)ec(s a!d prese!( d"ri!4 childhood% 8or e0ample, pyr"=a(e car'o0ylase de)icie!cy, )r"c(ose-1,6diphospha(ase de)icie!cy a!d pyr"=a(e dehydro4e!ase de)icie!cy% 6he lac(ic acidosis is !o( a! isola(ed )i!di!4 as (hese childre! ha=e serio"s dys)"!c(io!s o) or4a! sys(ems esp a))ec(i!4 'rai!, li=er a!d m"scle% -e!al ("'"lar acidosis may 'e heredi(ary a!d ca"se a hyperchloraemic acidosis i! i!)a!(s% Fi(ho"( (rea(me!(, 4ro,(h re(arda(io! occ"rs i! (hese childre!%

11'2'. +ther Acid- ase /isorders in Chi#dren 8i!al poi!(sA 1!s"li! depe!de!( dia'e(es melli("s "s"ally prese!(s d"ri!4 childhood or adolese!ce% *oiso!i!4 i! childre! may ca"se a! acid-'ase disorder a!d (he disorder may 'e di))ere!( )rom (ha( (ypically see! i! a! ad"l( (e4 salicyla(e poiso!i!4)%

(ast $pdated A## materia# 0 Copyright - 1erry

randis2 2332

Acid#$ase !h*sio(og* ,,.3 Acid#$ase Disorders due to Drugs . /oxins [ D0A%/ O123 ]

C(assi ication 4* 5echanis) Drug-induced acid-base disorders: ,. 5eta4o(ic acidosis induced 4* (arge acid (oads - from exogenous sources (e.g. H!"l# or toxin ingestion) - from endogenous acid production (e.g. generation of ketoacids or lactic acids b$ alcohol or phenformin) - from base loss (eg laxative abuse). 2. 0ena( tu4u(ar acidosis 2. 5eta4o(ic a(-a(osis resulting from exogenous bicarbonate loads or effective extracellular fluid contraction# potassium depletion plus h$peraldosteronism 6. 0espirator* acidosis from drug-induced respirator$ depression or neuromuscular impairment 7. 0espirator* a(-a(osis from drug-induced h$perventilation

So)e Drugs . /oxins "hich ha8e 4een in8o(8ed in 8arious Acid#$ase Disorders Respiratory Acidosis " % depressants arcotics

&uscle 'elaxants High Anion Gap Metabolic Acidosis &ethanol (th$lene gl$col (due gl$colic acid) %alic$lates )araldeh$de )henformin * metformin (lactic acidosis) %odium nitroprusside (lactic acidosis due c$anide) Renal Tubular Acidosis +mphotericin , +ceta-olamide Toluene .ithium "$clamate +nalgesics "arbonic +nh$drase /nhibitors (eg aceta-olamide) .ead %+/Ds

0utdated tetrac$cline )entamidine in +/D% patients ther causes of Hyperchloraemic Metabolic Acidosis )otassium-sparing diuretics +cidif$ing infusions (eg H"l# H!"l# l$sine-H"l * arginine-H"l infusions) "a"l1 ingestion (loss of H"02 due to precipitation of carbonate) Respiratory Alkalosis %alic$lates )ropanidid Metabolic Alkalosis (metics Diuretics

.ast updated

Acid#$ase !h*sio(og* ,,.6 O8er8ie" o /reat)ent o Acid#$ase Disorders 9D0A%/ O123)

:A023 D0A%/ ,,.6., /he /hree Aspects o /reat)ent The treatment options in management of an$ acid-base disorder can be divided into 2 aspects: Treating the "+3%( Treating the +"/D-,+%( +, 0'&+./T4 (the pH)

Treating the "0&)./"+T/0 % %ome examples are outlined in the table.

C(assi ication o /reat)ents in Acid#$ase Disorders Treating the "ause /nsulin infusion in diabetic ketoacidosis +dministration of ox$gen * restoration of cardiac output in t$pe + lactic acidosis %pecific treatments for respirator$ failure (eg antibiotics# bronchodilators# streptokinase) )s$chological management for anxiet$h$perventilation s$ndrome Dantrolene for malignant h$perthermia )e air the deficit res onsi$#e for maintenance of a meta$o#ic a#9a#osis Geg sa#ine #oading? administration of 5,H Indirect#y $y treating the cause +dministration of sodium bicarbonate (to restore pH in metabolic acidosis) /ntubation * ventilation for respirator$ failure (to correct arterial p"01 * pH) Indirect#y $y treating the cause Indirect#y $y treating the acid'$ase a$norma#ity Administration of 5, for hy o9a#aemia 0se of insu#in'g#ucose treatment for hy er9a#aemia

Treating the +cid-,ase +bnormalit$

Treating the "omplications

,,.6.2 /reating the Cause Often $est a roach as u#timate#y reso#ves the ro$#em Treatment de ends on the cause so there is a great re<uirement for an accurate diagnosis Often s#ow return to norma# C may $e too s#ow or ina ro riate way to treat some com #ications Inc#udes as ects of revention Geg atient education? insu#in for dia$eticsH ,,.6.3 /reating the Acid#$ase A4nor)a(it* M&'a*olic disord&rsD Traditiona# a roach has $een to give KaH"O3 in meta$o#ic acidosis with #itt#e or no evidence of efficacy

Other $urffers used eg THAM R&s+ira'ory disord&rs: 0sefu#ness of venti#ation to correct H Gvia "O2H Adverse ro$#ems due to "O2 can $e corrected ,,.6.6 /reating the Co)p(ications &a$ be life-threatening re5uiring emergenc$ management (eg 6 7# ",8 * /")) /ncludes treating the complications of treatment99 (such as bicarbonate problems# problems with lines) ,,.6.7 /reat)ent Contro8ersies . Con (icts To be added ,,.6.; /rips . /raps To $e added

.ast updated - +ll material : "op$right - 6err$ ,randis# 1;;1

Acid-Base 1hysiology Contents Home S "onditions of 0se S "ase Inde7 S 6#uid 4hysio#ogy te7t S (tart 5elco,e2 This te7t is $eing s#ow#y edited and e7 anded and references and other #in9s are $eing added. If you notice any errors? or have a <uery? or wou#d #i9e to rovide feed$ac9? #ease c#ic9 here This Acid'$ase tutoria# has recent#y G2::%H $een inde endent#y reviewed $y the Am&rican %horacic 0oci&'y for their @Best of the Oe$@ series. (ee their com rehensive reviews of the to "#inica# Acid'Base sites. This on'#ine tutoria# was rated 4 and a ha#f stars Gout of !H and shared eIual top ran&ing )ecent changes ' Kovem$er 2::3D I have started adding in references for some of the sections. 1ach reference wi## $e #in9ed to 4u$Med. Chapter 1 : Introduction 1.1 Overview 1.2 Acids and Bases 1.3 The Hydrogen Ion 1.4 Measurement of H 1.! Im ortance of H in "e##u#ar Meta$o#ism 1.% Imida&o#e A# ha'(tat Hy othesis

Chapter 2 : Control of Acid-Base Balance 2.1 Acid'Base Ba#ance 2.2 Buffering 2.3 )es iratory )egu#ation Chapter 3 : Acid-Base isorders 3.1 Termino#ogy of Acid'Base .isorders 3.2 Anion /a 3.3 The .e#ta )atio Chapter ! : "espiratory Acidosis 4.1 .efinition 4.2 "auses 4.3 Maintenance 4.4 Meta$o#ic 1ffects Chapter # : $etabolic Acidosis !.1 .efinition !.2 "auses !.3 Maintenance !.4 Meta$o#ic 1ffects Chapter % : "espiratory Al&alosis %.1 .efinition %.2 "auses %.3 Maintenance %.4 Meta$o#ic 1ffects Chapter ' : $etabolic Al&alosis 2.1 .efinition 2.2 "auses 2.3 Maintenance 2.4 Meta$o#ic 1ffects 2.! "om ensation 2.% "orrection 2.2 Assessment 2.3 4revention %.! "om ensation %.% "orrection %.2 Assessment %.3 4revention 3.4 0rinary Anion /a 3.! Osmo#ar /a 2.4 )ena# )egu#ation 2.! The Acid'Base )o#e of the *iver 2.% )egu#ation of Intrace##u#ar +H,-

4.! "om ensation 4.% "orrection 4.2 Assessment 4.3 4revention

!.! "om ensation !.% "orrection !.2 Assessment !.3 4revention

Chapter ( : $a)or *ypes of $etabolic Acidosis 3.1 *actic Acidosis 3.2 5etoacidosis 3.3 Acidosis and )ena# 6ai#ure 3.4 Hy erch#oraemic Acidosis 3.! )ena# Tu$u#ar Acidosis 3.% Acidosis due to .rugs and To7ins 3.2 0se of Bicar$onate in Meta$o#ic Acidosis

Chapter + : Assess,ent of Acid-Base isorders

8.1 (tructured A roach to Assessment 8.2 (ystematic 1va#uation 8.3 Bedside )u#es to Assess "om ensation

8.4 The )ationa#e 8.! The /reat Trans'At#antic Acid'Base .e$ate 8.% "#inica# 17am #es "ase History Inde7 for wor9ed e7am #es

Chapter 1- : .uantitati/e Acid-Base Analysis 1:.1 The (ystem 1:.2 The Bac9ground 1:.3 The ;aria$#es 1:.4 The 1<uations 1:.! The (o#utions 1:.% The Im #ications

Chapter 11 : 0pecial Aspects of Acid-Base 1hysiology 11.1 4regnancy 11.2 "hi#dren 11.3 Acid'Base .isorders due to .rugs and To7ins

'Acid-base pHysiology' by Kerry Brandis -fro, http:@@4442anaesthesia$C.2co, *his 4or& is licensed under a Creati/e Co,,ons :icense2 FB: Fon-co,,ercial use only2