(1997) Handbook ICU - Australian Shot Course

The Australian
Short Course on
Intensive Care Medicine
1997 Handbook
The Australian
Short Course on
Intensive Care Medicine
1997 Handbook
Editor
L.I.G. Worthley
Published in 1997 by
The Australasian Academy of Critical Care Medicine
Department of Critical Care Medicine
Flinders Medical Centre, Bedford Park
South Australia 5042
ISSN 1327-4759
1997 The Australasian Academy of Critical Care Medicine
Requests to reproduce original material should be addressed to
the publisher.
Printed by Gillingham Printers Pty Ltd
153 Holbrooks Road
Underdale
South Australia 5032
CONTENTS
page
1
Inotropic drugs in the intensive care unit

A. Bersten
Lactic acidosis: a generation or a clearance problem
J. Cooper
11
Nutrition in the critically ill

D. Bihari
17
Acute trauma management

B. Griggs
27
Acute renal failure

A. Holt
39
Intensive care obstetrics

E. Everest
53
Sedation, analgesia and relaxants in the intensive care patient

L. Worthley
61
Paediatric fluid, renal and nutritional support

N. Matthews
75
Principles of mechanical ventilation

A. Bersten
81
Scoring systems and the prediction of outcome in the intensive care unit
D. Bihari
91
Pulmonary embolism
L. Worthley
97
Management of acute asthma

J. Cooper
107
Postoperative management of cardiac surgery patients

L. Worthley
115
Trainee Presentations
121
Index
155
iii
iv
1997 SHORT COURSE PROGRAMME

April
1st
FMC
Travel to
2nd
RAH
3rd
QEH
Travel to
4th
FMC
Travel to
Lecture
Head injury
management
QEH
Interactive
Biochemistry in
the ICU
FMC
Lecture
Acute renal failure
0815
FMC
Lecture
Introduction:
- ICU clinical methods
- The ICU exam
L.W
Lecture
Principles of
mechanical ventilation
J.M
Clinical cases
P.P
Clinical cases
A.H.
Interactive
J.M M.B P.T D.C
M.OF A.H C.K T.C
Path forms
A.B
Clinical cases
Lecture
A.V L.W A.B A.H
Trauma
1245
Lunch
B.G
Lunch
Lecture
Myocardial
infarction
update
J.H
Travel to WCH
1400
Interactive
0900
1015
1130
ECGs
1515
1630
1745
L.W
Lecture
Understanding fluid
and electrolyte
disorders
L.W
Interactive
Lecture
Severity scoring
systems: principles and
practice
D.B
Clinical cases
Path forms
L.W
Travel To RAH
D.B
Travel to RAH
FMC = Flinders Medical Centre

WCH = Womens and Children's Hospital
X-Rays
L.W
Lunch
Lecture
Common paediatric
ICU problems
Lecture
Management of acute
asthma
S.K
Short questions
J.C
Interactive
D.C J.M M.B P.T
Lecture
Nutrition in the
critically ill
A.V
Interactive
S.K.
A.S
Travel to RAH
Presentations
L.W.
Interactive
Clinical
vignettes
L.W.
QEH = Queen Elizabeth Hospital

RAH = Royal Adelaide Hospital
Code
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
REGISTRANTS
Institution
Intensive Care Unit, John Hunter Hospital, New South Wales
Intensive Care Unit, Royal Brisbane Hospital, Queensland
Intensive Care Unit, Queen Elizabeth Hospital, Hong Kong
Intensive Care Unit, Royal Childrens Hospital. Victoria
Intensive Care Unit, Royal Prince Alfred Hospital, New South Wales
Intensive Care Unit, Liverpool Hospital, New South Wales
Intensive Care Unit, Royal Perth Hospital, Western Australia
Intensive Care Unit, Alfred Hospital, Victoria
Intensive Care Unit, St George Hospital, New South Wales
Intensive Care Unit, Queen Elizabeth Hospital, South Australia
Intensive Care Unit, Prince of Wales Hospital, Hong Kong
Intensive Care Unit, Illawarra Regional Hospital, New South Wales
Intensive Care Unit, Princess Alexandra Hospital, Queensland
Intensive Care Unit, Monash Medical Centre, Victoria
Intensive Care Unit, Princess Alexandra Hospital, Queensland
Intensive Care Unit, St Vincents Hospital, Victoria
Intensive Care Unit, The St. George Hospital, New South Wales
Intensive Care Unit, Westmead Hospital, New South Wales
Intensive Care Unit, Prince of Wales Hospital, Hong Kong
Intensive Care Unit, Griffith Base Hospital, New South Wales
Intensive Care Unit, Starship Childrens Hospital, New Zealand
Intensive Care Unit, Royal Perth Hospital, Western Australia
Intensive Care Unit, John Hunter Hospital, New South Wales
Intensive Care Unit, Austin and Repatriation Hospital, Victoria
Intensive Care Unit, Monash Medical Centre, Victoria
Intensive Care Unit, Tuen Mun Hospital, Hong Kong
Intensive Care Unit, Royal Childrens Hospital, Victoria
Intensive Care Unit, Waikato Hospital, New Zealand
Intensive Care Unit, Auckland Hospital, New Zealand
Intensive Care Unit, Royal Childrens Hospital, Victoria
Intensive Care Unit, The Geelong Hospital, Victoria
Intensive Care Unit, Royal Adelaide Hospital, South Australia
Intensive Care Unit, Royal Brisbane Hospital, Queensland
Intensive Care Unit, St Vincents Hospital, New South Wales
FACULTY
QEH
RAH
WCH
Dr. M.OFathartaigh (M.OF) Dr. J. Myburgh (J.M) Dr. N. Matthews (NM)
Dr. J. Moran
(J.M)
Dr. P. Thomas (P.T) Dr. S. Keeley (S.K)
Dr. S. Peake
(S.P)
Dr. B. Griggs
(B.G) Dr. A. Slater
(A.S)
Dr. J. Horowitz
(J.H)
Dr. R. Young
(R.Y)
Dr. P. Pannall
(P.P)
Dr. D. Clayton (D.C)
Name
Dr. C. Bhringer
Dr. B. Venkatesh
Dr. P. W. Cheung
Dr. D. Stephens
Dr. D. Green
Dr. C. Woolfe
Dr. C. Edibam
Dr. M. Pinder
Dr. C. Nolan
Dr. M. Parmar
Dr. C. Motherway
Dr. C. A. Cheng
Dr. P Nair
Dr. J. Evans
Dr. V. Pellegrino
Dr. D. Chu
Dr. B. Dixon
Dr. H. L. Chee
Dr. J. Awad
Dr. R. Calcroft
Dr. D. Corbett
Dr. J. Liang
Dr. F. Colreavy
Dr. N. Kavanagh
Dr. P. Frost
Dr. H Opdam
Dr. E. Wheatley
Dr. P. Lam
Dr. C. Hill
Dr. K. OConnor
Dr. T. Williams
Dr. T. Duke
Dr. P. Seal
Dr. N. Widdicombe
Dr. D. Mullany
Dr. M Gopalakrishnan
Dr. A. Purdon
FMC
Dr. L. Worthley
Dr. A. Vedig
Dr. A. Bersten
Dr. A. Holt
Dr. E. Everest
GUESTS
Dr. D. Bihari
(L.W)
(A.V)
(A.B)
(A.H)
(E.E)
(D.B) Dr. J. Cooper
(J.C)
vi
PREFACE
The Australian Short Course on Intensive Care Medicine is a teaching programme with lectures
and interactive sessions. This handbook includes many of the course lectures and the one page
summaries of the 5 minute talks given by the registrants and is designed to be a working text.
During the sessions, you may find it useful to mark and note the text to facilitate your recall and
review of the course at a later date. I hope that you find this book useful.
Dr. L.I.G. Worthley
Adelaide, April 1997
vii
viii
INOTROPIC DRUGS IN THE INTENSIVE CARE UNIT

A. Bersten, MB BS, MD, FANZCA, FFICANZCA
Critical Care Consultant,
Department of Critical Care Medicine,
Flinders Medical Centre, Bedford Park,
SOUTH AUSTRALIA 5042
1. Sympathomimetic amines
Exogenous catecholamines, synthetic amines and related agents are amongst the most
commonly used drugs in intensive care practice. In general their use can be classified as:
perfusion pressure;
cardiac output, and hence systemic oxygen delivery (DO2); or
manipulation of regional vascular resistance.
Certainly, an inadequate perfusion pressure can contribute to cerebral, left ventricular (LV),
right ventricular (RV), renal or diaphragmatic ischaemia and dysfunction in various disease
states. Recent studies question the endpoint of targeting supranormal DO2; however, at the
lower end of the spectrum an inadequate cardiac output may also result in hypotension or a
lactic acidosis. Finally, while the aim of specifically manipulating regional vascular resistance
(for example renal vasodilation with low-dose dopamine) remains attractive, few data suggest
this is ever achieved in clinical usage.
Drugs and receptors
While changes in - and -adrenoceptor number and function have been described in sepsis
and heart failure, the general approach of examining receptor based effects remains a useful
introduction to these drugs.
1: intracellular Ca2+ via G-protein mediated activation of phospholipase C and then the
phosphoinositol pathway and diacylglycerol. Direct vascular smooth muscle vasoconstriction,
myocardial contractility without an in heart rate.
2: adenyl cyclase activity via an inhibitory G-protein. Prejunctional action inhibits
neurotransmitter release, but also found at postjunctional sites where they mediate contraction.
1 : force and rate of cardiac contraction, renin secretion, relax coronary arteries and
gastrointestinal smooth muscle. 1+2-adrenoceptors linked to adenyl cyclase (c-AMP) via a
stimulatory G-protein. Presynaptic 1-adrenoceptors facilitate neurotransmitter release.
2 : smooth relaxation at bronchi, most blood vessels, uterus; force and rate of cardiac
contraction (comprise 15% of myocardial -receptors); prejunctional 2 -receptors act to
facilitate release of neruotransmitters.
3 : lipolysis in white adipose tissue, thermogenesis in brown adipose tissue, insulin
secretion, glycogen synthesis in skeletal muscle, inhibition of gastrointestinal and smooth
muscle contraction, myocardial contractility,1 bronchial smooth muscle relaxation and
vasodilatation of skin and fat. Not downregulated in chronic heart failure, and some suggestion
that it is coupled to an inhibitory G-protein that is upregulated in heart failure.
DA-1: vasodilatation of regional vascular beds including renal, splanchnic, and cerebral, found
both on the brush border and the basolateral membranes in renal proximal tubule with agonistinduced natriuresis (Fig 1).
1
Inotropic Drugs in the ICU

DA-2: nausea, vomiting, prolactin release. Presynaptic DA-2 similar action to 2adrenoceptor effects.
Figure 1: Schematic diagram demonstrating dopamine receptor mediated natriuresis at proximal
tubular cells.
Ultrafiltrate
Basolateral membrane
L-dopa
L-AADC
DA
DA
Dopamine (DA)
PIP2
Na+
DA-1
c-AMP
DA-1
PLC
IP3
DAG
Na+
PKC
Na+
K+
H+
Na+ reabsorption
Natriuresis
Legend: Dopamine is an important component of sodium (Na+) homeostasis. Circulating l-dopa

is converted to dopamine within proximal renal tubular cells by the enzyme l-aminoacid
decarboxylase (L-AADC) which is upregulated during sodium loading. DA may stimulate
DA-1 receptors on the luminal membrane leading to an increase in the production of adenyl
cyclase and c-AMP with inhibition of the Na+/H+ antiport, or may stimulate basolateral
membrane receptors with inhibition of Na+/K+-ATPase via stimulation of phospholipase C
(PLC) and conversion of PIP2 (phosphoinositol biphosphate) to IP3 (inositol triphosphate),
DAG (diacyl glycerol) and PKC (protein kinase C). Both of these actions result in a reduction
in Na+ reabsorption and natriuresis.
Downregulation of receptors in disease states
1. Heart failure:2 1- but not 2-receptor density is downregulated with an increase in 2receptor density from 15 to 40%; an in the inhibitory G-protein complex leading to a
functional in adenyl cyclase activity; and depletion of tissue noradrenaline. In general
these effects are proportional to the degree of heart failure and the chronic elevation seen in
plasma noradrenaline levels in these patients. Both -blocking drugs and angiotensin
enzyme inhibitors reduce sympathetic drive with amelioration of these changes. As the
2

positive inotropic effects of dopamine and dopexamine are, at least in part, indirect with
displacement of neuronal noradrenaline, both drugs are considerably less active in heart
failure than under normal circumstances.3 In addition to using a directly acting agent it may
be wise to use one with 2-receptor agonism, and to consider the sole or additional use of a
phosphodiesterase inhibitor, such as milrinone, which bypasses these problems and restores
1-receptor sensitivity with additive inotropic effects.4
2. Sepsis: Impaired vascular responsiveness (vasoconstriction and vasorelaxation) and
myocardial depression are typically found during septic states. These vascular abnormalities
have a complex pathogenesis with current focus on the effects of cytokines and local
smooth muscle production of nitric oxide. However, some studies show evidence of receptor downregulation, while the phospholipid second messenger system is clearly
impaired. The pathogenesis of myocardial depression is also complex: again cytokines and
nitric oxide have been shown to reduce contractility,5 with some evidence of -receptor
downregulation. Consequently, the haemodynamic responses to a given drug infusion will
likely differ from that described under healthy conditions. Indeed, the pressor response to a
given dose of noradrenaline is typically reduced under septic conditions.
Non-cardiovascular Effects
Numerous metabolic and immune effects are attributable to -receptor stimulation.
1. Immunomodulatory effects: In-vitro adrenaline and noradrenaline decrease the
lipopolysaccharide-induced release of tumour necrosis factor (TNF) from monocytes, with
similar modulation of plasma TNF, and elevation of interleukin-10 following human
lipopolysaccharide challenge.6 While this raises the potential for use of catecholamine
infusions as modulators of the inflammatory response, these effects have, so far, only been
shown with noradrenaline and adrenaline.
2. Metabolic effects: listed below are generally attributed to 2-receptor stimulation, and have
variously been shown to be greater with some agents.
K+, Mg2+, PO43-, Ca2+ (transcellular shift)
glucose, free fatty acids (insulin resistance, glucagon, cortisol)
lactate7 ( glycogenolysis)
O2 consumption (20-30%) .
Receptor pharmacology of selected agents
noradrenaline
adrenaline
isoprenaline
dopamine
dopexamine
dobutamine (-)
dobutamine (+)
dobutamine ()
1
++
++
2
++
++
++
+
-
1
++
++
++
++
++
++
+
++
+
+
+
+
++
++
3
+
+
++
?
?
?
?
?
DA-1
DA-2
++
++
++
Legend: DA, dopamine; +, agonist activity; -, antagonist activity; (-) and (+), isomers; (),
racemic mixture; ?, uncertain.
Given their receptor affinity it is possible to broadly predict the circulatory effects of
individual drugs. However, numerous factors contribute to their final effect. In addition to the
3

changes in receptor density, transduction and contractility discussed previously, regional
factors and altered pharmacokinetics will also influence the final effect. Since catecholamine
metabolism occurs in the liver, lung and kidney the normal strong relation between drug
infusion rate and plasma level will be perturbed in some disease states. For instance the
relationship between dopamine infusion rate and plasma level is best described as a scattergram
with patients with liver or renal failure having relatively higher levels than those without,
independent of infusion rate.
Regional blood flow
& ) is determined by perfusion pressure (PP), mean blood pressure

Regional blood flow ( Q
(BP) - outflow pressure (intracranial pressure for the brain), and regional vascular resistance
& = PP/RVR. The brain and kidney have robust pressure-flow autoregulation with the
(RVR): Q
lower limit of the autoregulatory threshold 80 mmHg mean BP. Certainly this is only an
average value and some individuals will autoregulate down to 40-50mmHg just as others have
high autoregulatory thresholds. Pre-existent hypertension and excessive -adrenoceptor
stimulation (>0.5g/kg/min adrenaline in the healthy sheep) right shift the autoregulatory
curve, while some disease states result in a loss of autoregulation and linear pressure-flow
relations.
Figure 2: Schematic diagram of autoregulated pressure-flow relations
reactive hyperaemia
Flow
subautoregulatry
slope
autoregulated zone
autoregulatory threshold
Blood pressure
As BP falls progressive vasodilatation maintains a relatively constant flow down to the
autoregulatory threshold. At this point the vasodilator reserve has been exhausted and flow
becomes linearly dependent upon PP (the subautoregulatory slope). Consequently, the
4

maximum flow response to a period of ischaemia (maximum vasodilatation) lies on the
subautoregulatory slope at the instantaneous PP achieved upon release of ischaemia (reactive
hyperaemia).
Kidney8
Loss of pressure-flow autoregulation has been repeatedly shown following ischaemic acute
renal failure with absence of vasoconstriction despite high doses of intra-arterial noradrenaline,
and this persists until renal function starts to recover. While elevating BP with a potential renal
vasoconstrictor may seem counterintuitive, and no clinical study has randomized patients to
differing BP strategies, numerous case series describe improvement in renal function with
noradrenaline-induced elevation in BP.
Selective DA-1 stimulation should reduce renal vascular resistance and increase renal blood
flow and hence ameliorate an ischaemic renal injury; however, this has not been convincingly
demonstrated. Since dopamine at least in part acts by increasing prostacyclin production within
the kidney, it is possible that the kidney is already prostaglandin driven as a homeostatic
response to ischaemia thereby minimizing any direct renovascular effect. An ongoing
multicentre trial is examining whether low-dose dopamine ameliorates renal dysfunction in
patients with septic inflammatory response syndrome (SIRS). It is important to note that
dopamine worsens contrast nephropathy in diabetic patients (impaired vascular
responsiveness), perhaps by its proximal natriuretic action resulting in medullary ischaemia.9
Given that dopamine antagonists such as metoclopramide and haloperidol prevent
dopaminergic vasodilatation, care should be taken to avoid these drugs if a specific
renovascular effect is desired.
Brain
No particular cerebrovascular effects make one drug preferable over another. While the
intact blood-brain barrier prevents access of catecholamines (hence direct cerebrovascular
effects), little data allows conclusions as to direct cerebrovascular effects when the blood-brain
barrier is markedly impaired. Vasopressor catecholamines such as dopamine, adrenaline and
noradrenaline may be needed to maintain an adequate cerebral perfusion pressure.
Liver, Intestine
While maintenance of an adequate PP may be important in these organs, they are more
dependent upon an adequate cardiac output than the kidney or brain, with liver blood flow
typically proportional to cardiac output. Comparing dobutamine with dopamine in septic
patients laser Doppler flowmetry demonstrated a 28% reduction in gastric mucosal blood flow
with dopamine at an infusion rate of 5g/kg/min, while a similar infusion of dobutamine
increased flow by 32%.10 While cardiac output and DO2 were increased by both drugs, BP was
unchanged. Other data support the increase in gastric mucosal blood flow with dobutamine, and
the lack of benefit or deleterious effects with dopamine, even in low doses. There are no
comparable studies with adrenaline or noradrenaline; however, dopexamine appears to have
some independent hepatic protective effect in the septic pig.11
Left Ventricle
Myocardial ischaemia is a persistent concern when using inotropic drugs since an increase
in heart work will demand an increase in oxygen supply. An intraortic balloon often allows
adequate myocardial perfusion without additional support, but inotropic drugs may also be
needed. As the myocardium has minimal ability to increase oxygen extraction (normally 7075%) vasodilator reserve must subserve the necessary increase in coronary blood flow. While
5

coronary vasodilator reserve is normally huge (>10 fold) coronary artery disease, an increase in
heart rate (diastolic time) or an inadequate perfusion pressure may prevent an adequate
increase in coronary blood flow and precipitate ischaemia. The difficult balance is that an
increase in heart work may provide a more than compensatory increase in left ventricular
coronary perfusion pressure (usually taken as diastolic BP-wedge pressure) with ischaemia
ameliorated. Finally, coronary blood flow alone is an excellent inotropic agent.
Intracoronary noradrenaline is a potent coronary vasoconstrictor; however, when its
systemic administration elevates LV coronary perfusion pressure ischaemia is ameliorated.12 In
the same study protocol (patients with cardiogenic shock) isoprenaline and dopamine13 failed to
elevate diastolic BP with an exacerbation of myocardial ischaemia. Similar studies in
cardiogenic shock using dobutamine or adrenaline have not been done. In stable patients with
coronary artery disease adrenaline increases contractility, stroke volume and cardiac output
with a commensurate increase coronary blood flow,14 while numerous studies have generally
shown dobutamine to be a safe inodilator (inotrope and vasodilator). However, if either drug
erodes diastolic pressure sufficiently ischaemia may occur. As a vasopressor catecholamine
noradrenaline, if anything, evokes a reflex bradycardia; however all of the other drugs increase
heart rate. Isoprenaline and dopexamine cause the greatest increases in heart rate with some
studies showing that dobutamine is worse than adrenaline or dopamine. While safe limits for
heart rate will vary depending upon age, coronary anatomy and myocardial perfusion,
particular attention must be made to drug-induced tachycardia. Certainly a number of studies
demonstrate ischaemia and wall motion abnormalities when excessive dobutamine infusion
rates precipitate tachycardia.
Right Ventricle
While many of the issues discussed for the left ventricle also apply to the RV it is worth
noting that RV coronary perfusion pressure is usually calculated as (mean BP-mean RV
pressure) since coronary flow occurs equally during systole and diastole. Mean RV pressure
can be directly measured using the right ventricular port of a paceport pulmonary artery
catheter or calculated as central venous pressure plus 1/3 of the difference between pulmonary
artery systolic and central venous pressure. Severe pulmonary hypertension can erode RV
coronary perfusion pressure <30-35 mmHg resulting in ischaemia and RV failure.
Experimentally, augmentation of BP with noradrenaline reverses this process. As before, this
may seem counterintuitive as vasopressor drugs could constrict the pulmonary bed and
exacerbate the pulmonary hypertension. However, this does not appear to be the case with
neither dopamine or noradrenaline changing pulmonary pressure-flow relations. On the other
hand isoprenaline and dobutamine do appear to improve pulmonary impedance. Isoprenaline is
only beneficial in models of pulmonary embolism when RV perfusion pressure is adequate,
again, reinforcing the importance of perfusion pressure.
2. Other Drugs
1. Milrinone: of the FIII selective phosphodiesterase inhibitors milrinone is the most
commonly used in critically ill patients. Since phosphodiesterase inhibits the conversion of
c-AMP to AMP these drugs increase c-AMP levels independent of the -receptor complex.
There are broadly five classes of phosphodiesterase; theophylline a non-selective
phosphodiesterase inhibitor acts at the heart, peripheral circulation, bronchial smooth
muscle, kidney (differential effects on the intrarenal distribution of blood flow) and brain.
The FIII selective phosphodiesterase inhibitors predominantly act on the heart and
peripheral circulation with lesser effects elsewhere. Although the long term use of this class
of agents appears to increase mortality in congestive heart failure,15 the combination of
6

inotropy, diastolic relaxation and vasodilatation of peripheral and pulmonary beds with
minimal increase in heart rate makes milrinone a useful acute agent. Using intracoronary
infusion (to minimize systemic vasodilatation) milrinone has an equivalent inotropic effect
to dobutamine, and when infused in combination significantly increases the inotropic effect
of dobutamine.4 Finally, milrinone has been increasingly used to prevent or treat internal
mammary artery spasm following cardiac surgery, with a comparative study showing it to
be more effective than sodium nitroprusside.16 However, the slow predominantly renal
clearance and potent vasodilating properties of milrinone need to be considered in clinical
usage.
2. Digoxin: although digoxin has been relegated behind vasodilators (angiotensin converting
enzyme inhibitors) and diuretics in the treatment of patients in sinus rhythm with congestive
heart failure, it may be a useful inotropic agent in the intensive care unit. In acute cardiac
failure digoxin significantly increases LV stoke work, stroke volume and cardiac index;17
however, its tendency to reduce diastolic LV compliance may mitigate against its use in
patients with predominant diastolic failure. Similar effects have been reported in septic
patients which were equivalent to 5-12 g/kg/min of dopamine.18 It is not known whether
these effects last greater than the 6 hours studied.
3. Calcium: given that many of these inotropic drugs act to elevate intracellular calcium it is
intuitive that calcium will be a potent inotrope. Indeed varying plasma ionized calcium with
dialysis in chronic renal failure patients demonstrates a direct relationship with myocardial
contractility.19 However, following cardiopulmonary bypass calcium chloride elevates BP
without increasing cardiac output, and attenuates the increase in BP and cardiac output
produced by an adrenaline infusion.20
Choice of Individual Agent
At a practical level the choice of agent(s) must be targeted to some measurable endpoint;
usually BP or DO2. An advantage of the catecholamines and synthetic amines is their short
half-life allowing rapid titration of infusion rates. However dopamine and adrenaline vary their
agonist profile with -effects dominating at low doses and -effects dominating at higher
doses. As suggested disease specific factors and patient variation will alter their dose response
curves so that clinical judgement and measurement of systemic haemodynamic effects will be
needed to allow effective titration. For instance if BP is being maintained at the expense of flow
an appropriate response may be to reduce the vasopressor drug while adding an inodilator or
vasodilator agent.
While the purported infusion-rate receptor specificity for dopamine is well known (<2
g/kg/min DA-receptor, 5 g/kg/min DA+-receptors, > 10 g/kg/min predominantly receptors), a similar profile is seen with adrenaline. In healthy adults infusion rates of 0.01
g/kg/min (7-8 g/min) result in predominantly -receptor effects with large increases in
contractility and stroke volume with a significant fall in systemic vascular resistance and mean
BP. Animal data demonstrate balanced receptor stimulation at 3 times this rate followed by
predominantly -receptor stimulation. Again, there will be significant patient variability in
these effects, and if an issue, this systemic hemodynamics need to be measured. In vasodilated
patients it is rare to see further vasodilatation with low doses of adrenaline. Given these
provisos both drugs are useful first line agents.
In patients with a profoundly dilated circulation or where a high BP is targeted, for instance
intracranial hypertension, noradrenaline is particularly useful. Particular care must be made that
noradrenaline is not used in hypovolaemia as this is the setting for particularly deleterious
effects on flow. In patients with an adequate cardiac output but an adequate perfusion pressure
dobutamine or milrinone or their combination can augment flow followed by titration to
7

chronic vasodilator therapy. At times an inodilator will need addition of a vasopressor to allow
adequate perfusion pressure and augmentation of flow.
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heart. J Clin Invest 1996;98:556-562.
2. Feldman, AM; and Bristow MR. The ?-adrenergic pathway in the failing human heart:
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3. Port DJ, Gilbert EM, Larrabee P, et al. Neurotransmitter depletion compromises the ability
of indirect-acting amines to provide inotropic support for the failing human heart.
Circulation 1990;81:929-938.
4. Colucci WS, Denniss AR, Leatherman GF, et al. Intracoronary infusion of dobutamine to
patients with and without severe heart failure. Dose-response relationships, correlation
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1988;81:1103-1110.
5. Kumar A, Thota V, Olson J, et al. Tumor necosis factor alpha and interleukin 1 beta are
responsible for in vitro myocardial cell depression induced by human septic shock serum.
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6. van der Poll T, Coyle SM, Barbosa K, et al. Epinephrine inhibits tumor necrosis factor-?
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7. Day NPJ, Phu NH, Bethell DP, et al. The effects of dopamine and adrenaline infusions on
acid-base balance and systemic haemodynamics in severe infection. Lancet 1996;348:219223.
8. Bersten AD, Holt AW. Vasoactive drugs and the importance of renal perfusion pressure.
New Horizons 1995;3:650-661.
9. Weisberg LS, Kurnik PB, Kurnik BRC. Risk of radiocontrast nephropathy in patients with
and without diabetes mellitis. Kidney Int 1994;45:259-265.
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dopamine on gastric mucosal perfusion in septic patients. Am J Respir Crit Care Med
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11. Tighe D, Moss R, Heywood G, et al. Goal-directed therapy with dopexamine,
dobutamine, and volume expansion: effects of systemic oxygen transport on hepatic
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12. Mueller H, Ayres SM, Giannelli S, et al. Effect of isoproterenol, l-norepinephrine, and
intraaortic counterpulsation on hemodynamics amd myocardial metabolism in shock
following myocardial infarction Circulation 1972:45:335-351.
13. Mueller HS, Evans R, and Ayres SM. Effect of dopamine on hemodynamics and
myocardial metabolism in shock following myocardial infarction in man. Circulation
1978;57:361-365.
14. Sullivan JM, Gorlin R. Effect of l-epinephrine on the coronary circulation in human
subjects with and without coronary artery disease. Circ Res 1967;21:919-923.
15. Packer M, Carver JR, Rodeheffer RJ, et al. Effect of oral milrinone in severe chronic heart
failure. The PROMISE study research group. N Engl J Med 1991;325:1468-1475.
16. Thorin-Trescases N, Dimitri WR, Dominiczak AF, et al. Vasorelaxant properties of
isolated human internal mammary arteries and saphenous veins: comparative effects of
milrinone and sodium nitroprusside. J Cardiovasc Pharmacol 1993;22:673-680.

17. Rackow EC, Packman MI, and Weil MH. Hemodynamic effects of digoxin during acute
cardiac failure: A comparison in patients with and without acute myocardial infarction.
Crit Care Med 1987;15:1001-1005.
18. Nasraway SA, Rackow EC, Astiz ME, et al. Inotropic response to digoxin and dopamine
in patients with severe sepsis, cardiac failure and systemic hypoperfusion Chest
1989;95:612-615.
19. Lang RM, Fellner SK, Neumann A, et al. Left ventricular contractility varies directly with
blood ionized calcium. Ann Intern Med 1988;108:524-529.
20. Zaloga GP, Strickland RA, Butterworth JF, et al. Calcium attenuates epinephrines ?adrenergic effects in post-operative heart surgery patients. Circulation 1990;81:196-200.
10
LACTIC ACIDOSIS: A GENERATION OR A CLEARANCE

PROBLEM.
D. James Cooper, MD, FRACP, FANZCA, FFICANZCA
Intensive Care Department,
Alfred Hospital,
Commercial Rd, Prahran,
VICTORIA 3144
Definition
Lactic acidosis has been variously defined as a blood lactate concentration of greater than 2
mmol/L or more commonly of greater than 5 mmol/L, in combination with acidemia - also
being variously defined as an arterial pH of either < 7.35 or of < 7.25.1 One problem with all
definitions is that although acidemia may be present it may be partially or completely
compensated by preexisting metabolic or respiratory alkalemia.
Formation of lactic acid
Formation and metabolism of lactate in cells is catalysed by lactate dehydrogenase
Pyruvate + NADH + H+
LDH
<-->
Lactate + NAD+
Whole body lactate production during health is about 0.8 mmol/kg/hr which results in blood
lactate concentrations of < 1 mmol/L and basal lactate concentrations about 10 x basal pyruvate
concentrations. Lactate formation is in part dependent upon pyruvate concentrations with
pyruvate being sourced from lactate (via LDH), from proteolysis (about 15 %) and from
glycolysis (about 85%). Glucose is obtained from absorption, from glycogen, and from
gluconeogenesis, and its glycolysis is controlled by 3 unidirectional enzymes. The activity of
one of these enzymes is increased by increasing intracellular pH. Alkalosis therefore increases,
and acidosis decreases both pyruvate and lactate formation from glycolysis. During oxygen
excess, pyruvate is oxidised (in cells with mitochondria) and lactate does not accumulate. The
onset of anaerobic metabolism is associated with lactate accumulation and an increase in the
lactate/pyruvate ratio. Measurement of the lactate/pyruvate ratio (reflecting the cellular
cytoplasmic redox state) however, is considered to be a poor indicator of the mitochondrial
redox potential, and therefore of little clinical use.
Classification (Types A and B)
Although most causes of lactic acidosis are acquired, some are congenital and are associated
with defects in gluconeogenesis, in pyruvate dehydrogenase, in the TCA cycle or in the
respiratory chain. Cohen and Woods 1976 classification of lactic acidosis has been widely
recognised.2 In this classification, Type A lactic acidosis includes patients with clinical
evidence of tissue hypoxia and is by far the most common in critically ill patients. In these
patients, lactic acidosis is primarily due to increased generation of lactate due to tissue hypoxia.
Causes include: shock, regional hypoperfusion, severe hypoxaemia, severe anaemia, carbon
monoxide poisoning and severe asthma.
Type B lactic acidosis is much less common, and includes patients with no clinical evidence
of tissue hypoxia. The type B subgroups are: B1 (presence of an underlying disease state)
including diabetes, liver disease, malignancy, sepsis, pheochromocytoma, thiamine deficiency;
B2 (drug or toxin induced) including biguanides, ethanol, methanol, ethylene glycol, fructose,
11
Lactic Acidosis
sorbitol, xylitol, salicylates, paracetamol, adrenaline, salbutamol, cyanide, nitroprusside,
isoniazid, propylene glycol; and B3 (inborn errors of metabolism including glucose-6
phosphatase deficiency, fructose 1,6 di-phosphatase deficiency, pyruvate carboxylase
deficiency and oxidative phosphorylation defects. Some patients with type B lactic acidosis
have increased lactate generation (for example some malignancies and toxins which impair
cellular oxygen utilisation), and others have decreased lactate clearance (liver disease being
probably the most common).
Combined (Types A and B) abnormalities
Many patients have combined abnormalities and both increased lactate generation from
tissue hypoxia and decreased lactate clearance may be present simultaneously. For example, in
patients with cancer, there may be a high anaerobic glycolysis rate and hepatic lactate
metabolism may also be impaired by tumour replacement. In non insulin dependent diabetes
there may be a mild defect in pyruvate oxidation and in diabetic ketoacidosis there may be an
inhibitory effect of ketones on hepatic lactate uptake. Thiamine and biotin are essential
cofactors for pyruvate dehydrogenase activity and for conversion of pyruvate to oxaloacetate so
chronic malnutrition may be associated with cofactor deficiency causing lactic acidosis, by
increasing pyruvate availability and thereby increasing lactate generation. Ethanol oxidation
encourages the conversion of pyruvate to lactate and inhibits other pathways of pyruvate
metabolism. Phenformin increases glycolysis to lactate in peripheral tissues, inhibits pyruvate
oxidation, increases splanchnic lactate production, and decreases hepatic lactate clearance.
Interestingly, although phenformin was considered a classic inducer of type B lactic acidosis
and was used in frequently cited animal models used to study lactic acidosis, it was later
realised to be a potent cardiac depressant which induced type A lactic acidosis concurrently.
Catecholamines induce hepatic vasoconstriction and impair hepatic lactate clearance, and
adrenaline also increases hepatic glycogenolysis (to lactate).3
Lactic acidosis in critically ill patients
Critically ill patients do not usually have solely type A or B lactic acidosis. For example in
patients with sepsis there may be decreased myocardial preload and myocardial depression,
both of which reduce cardiac function and may therefore reduce oxygen delivery to tissues.
Also in sepsis, hypotension may reduce critical perfusion pressures to vital organs. However, at
the same time there are excess catecholamines which may impair hepatic lactate extraction (by
reducing regional hepatic blood flow), increasing lactate production via increased
glycogenolysis. At the same time and in addition, pyruvate dehydrogenase activity is reduced in
both skeletal muscle and liver. There may also be defects in mitochondrial pyruvate oxidation
during sepsis which might increase pyruvate availability further. A second example of critically
ill patients with mixed type A and B lactic acidosis may be observed in patients with shock
superimposed on a background of alcoholic cirrhosis. These patients have increased lactate
production from tissue hypoxia together with decreased lactate clearance due to liver disease
and commonly have much greater blood lactate concentrations than patients with healthy livers
who have undergone a similar shock insult. Determining the severity of a shock insult from a
single blood lactate concentration may therefore be quite misleading.
In critically ill patients with shock, type A lactic acidosis occurs when tissue perfusion is
inadequate to sustain aerobic metabolism. Thus, an increasing blood lactate concentration in
patients with shock is a good indicator of ongoing impaired tissue perfusion and is correlated
with increased risk of a fatal outcome.4 More recent data reported from the placebo patients in a
multicentre clinical trial confirms the relationship between increased blood lactate
concentrations (mean 10.4 mmol/L) and a fatal outcome (83% mortality).5 In these patients a
12
Lactic Acidosis
blood lactate concentration of 5 mmol/L indicated a mortality approaching 80%. Survival was
better in those whose hyperlactemia resolved, and in those without shock. The clinical
relevance of these observations is that it is extremely important to monitor acid-base status and
blood lactate concentrations repeatedly in patients presenting acutely with shock and lactic
acidosis. Failure of improvement in acidemia or in blood lactate concentrations during the first
few hours of resuscitation suggests that either the initial therapies have been inadequate, or that
there is an additional lactic acid clearance problem. Similarly, if resuscitation measures
(excluding buffer agents like bicarbonate) and appropriate surgery are associated with
decreasing acidosis and decreased blood lactate concentrations, then survival is more likely.
Hyperlactemia may also occur without tissue hypoperfusion - due to impaired lactate
clearance, in hypermetabolic states where accelerated aerobic glycolysis may contribute (sepsis,
trauma, burns), in conditions with increased muscle activity (extreme exercise and seizures) or
during exogenous lactate administration (intravenous haemofiltration fluid). In some of these
patients (for example patients with seizures) very high blood lactate concentrations have
minimal prognostic value because the lactic acidosis is usually cleared very rapidly and few
significant physiologic effects have been described. Furthermore, there is recent evidence using
NMR spectroscopy, that the hyperlactemia of sepsis may occur without tissue hypoxia.6 Clearly
the genesis of hyperlactemia in sepsis is complex and requires further investigation.
Cardiac dysfunction in patients with lactic acidosis
Lactic acidosis may cause cardiac dysfunction, or instead lactic acidosis may be an
epiphenomenon - an end result of tissue hypoperfusion due to cardiac dysfunction from other
factors. Although this subject continues to be controversial, an extensive literature review7
concluded that in most critically ill patients with lactic acidosis cardiac dysfunction is present
but is due to a combination of other factors of which cytokines appear to be increasingly
important. Lactic acidosis in most patients is a consequence rather than a cause of cardiac
dysfunction and therapies intended to correct acidosis or clear lactate may miss the point and
leave a patient clinically deteriorating despite improving blood gases. A false sense of security
may be induced in clinicians during the often short therapeutic window which exists for
resuscitation to be successful. Bicarbonate and other buffers may suffer from this problem in
addition to adverse side effects of the agents themselves.
For many years it was believed that acidemia was a major cause of cardiac dysfunction in
patients, and for this reason, aggressive attempts to normalise arterial pH as rapidly as possible
with buffer therapies - usually bicarbonate, were often part of widespread clinical practice.8
This belief was based upon an extensive body of research in isolated muscle preparations,
isolated heart preparations, in animal models and upon a handful of clinical case reports.
Together these studies suggested that acidosis (respiratory, hydrochloric, ammonium chloride,
and others) decreased cardiac function, decreased the haemodynamic response to
catecholamines, increased arrhythmias, and shortened survival.
This literature is in large part however not generally applicable to critically ill patients who
have lactic acidosis. Respiratory and metabolic acidosis are now recognised to have different
cardiovascular effects.9 None of the animal models truly imitate human lactic acidosis; drugs
and anaesthetics themselves known to decrease myocardial contractility were often used, many
studies were uncontrolled, and interspecies differences are significant and difficult to interpret
making application from animal models to clinical practice hazardous. Furthermore, studies that
demonstrated significantly deceased cardiac function during metabolic acidosis often did so at
an arterial pH much below that which is seen clinically in critically ill patients - ie outside the
physiologically observed range in humans. (Arterial pH's of 6.6 - 6.9). By contrast, in a group
of critically ill patients with severe shock and a high mortality, taking part in a prospective
13
Lactic Acidosis
study of bicarbonate therapy in lactic acidosis a mean arterial pH of 7.22 was reported.10
Clearly many factors including respiratory compensation which may be therapeutically applied
by mechanical ventilation, combine to ensure that the arterial pH experienced by critically ill
patients with lactic acidosis is usually within a range of about 7.1 - 7.30. Finally, many studies
in large animals made inferences about changes in myocardial contractility without measuring
myocardial contractility directly. Reliable load independent measurements of left ventricular
contractility which are applicable to large animal models and to human studies have only been
developed in recent years.
A generation or a clearance problem
In health, lactate is continually produced as a metabolic product, predominantly in skeletal
muscle, and at the same time is metabolised, primarily in the liver and kidneys. In health, owing
to constant turnover, blood lactate concentrations remain low. However, during shock when
compensatory mechanisms are insufficient to maintain tissue oxygen delivery and aerobic
metabolism, anaerobic metabolic processes commence and lactate production increases. Blood
lactate concentrations then increase depending upon the capacity of the metabolising organs to
accommodate the increased load. Shocked patients who have liver disease often develop greater
blood lactate concentrations than previously healthy subjects who have the same degree of
tissue hypoxia. Production of acid is closely related to tissue hypoxia because hydrogen ions
cannot easily be oxidised under anaerobic conditions. Production of lactate may also be directly
related to tissue hypoxia but may also relate instead more closely to acceleration of glycolysis
in situations unrelated to tissue hypoxia.
Conclusion
In critically ill patients therefore, lactic acidosis is both a problem of increased lactate
generation and decreased lactate clearance. In most patients it is primarily a generation
problem. However there are many clinical scenarios where increased lactic acid generation is
complicated by decreased clearance, and there are some patients in whom decreased clearance
is the primary problem. In all cases, therapies which decrease lactate generation or increase
clearance are likely to be more successful than those which solely increase pH. However all
therapies have been unsuccessful when the underlying process causing lactic acidosis is
irreversible.
REFERENCES
1. Hindman B. Sodium bicarbonate in the treatment of subtypes of acute lactic acidosis:
physiologic considerations. Anesthesiology 1990;72:1064-1076.
2. Cohen R and Woods H. Clinical and biochemical aspects of lactic acidosis. Boston:
Blackwell Scientific Publications, 1976.
3. Stacpoole P. Lactic acidosis. Endo Metab Clin North Am 1993;22:221-245.
4. Broder G, WeiL M. Excess lactate: an index of reversibilitv of shock in human patients.
Science 1964;143:1457-1459.
5. Stacpoole P, Wright E, Baumgauter T, et al. Natural history and course of acquired lactic
acidosis in adults. Am J Med 1994;97:47-54.
6. Hotchkiss R, Karl I. Revaluation of the role of cellular hypoxia and bioenergetic failure in
sepsis. JAMA 1992;267:1503-1510.
7. Cooper DJ.
Cardiac dysfunction and lactic acidosis during hyperdynamic and
hypovolemic shock. MD Thesis. University of Adelaide. 1996.
8. Narins R, Cohen J. Bicarbonate therapy for organic acidosis: the case for its continued
use. Ann Intern Med 1987;106:615-618.
14
Lactic Acidosis
9.
10.
11.
12.
13.
14.
15.
Walley K, Lewis T, Wood L. Acute respiratory acidosis decreases left ventricular

contractility but increases cardiac output in dogs. Circ Res 1990;67:628-635.
Cooper D, Walley K, Wiggs B, Russell J. Bicarbonate does not improve hemodynamics in
critically ill patients who have lactic acidosis: a prospective controlled clinical study. Ann
Intern Med 1990;112:492 - 498.
Stacpoole P. Lactic acidosis: the case against bicarbonate therapy. Ann Intern Med
1986;105:276-279.
Walley K, Cooper D, Baile E, Russell J. Bicarbonate does not improve left ventricular
contractility during resuscitation from hypovolemic shock in pigs. J Crit Care 1992;7:1421.
Cooper D, Herbertson M, Werner H, Walley K. Bicarbonate does not increase left
ventricular contractility during L-Lactic acidemia in pigs. Am Rev Resp Dis
1993;148:317-322.
Stacpoole P, Harman E, Curry S, Baumgartner T, Mishin R. Treatment of lactic acidosis
with dichloroacetate. N Engl J Med 1983;309:390-396.
Mizock B. Controversies in lactic acidosis. Implications in critically ill patients. JAMA
1987;258:497-501.
15
16
NUTRITION IN THE CRITICALLY ILL

D. Bihari, FRACP
Department of Intensive Care,
St. George Hospital, Kogarah,
NEW SOUTH WALES 2217
Introduction
Malnutrition is common in patients in hospital and for some time, the association between
malnutrition and increased morbidity and mortality during hospitalisation has been recognised.
Whilst it seems intuitively likely that well nourished patients respond better to treatment, such
intuitive thinking has been difficult to prove using the technique of randomised controlled
clinical trials.1 In the intensive care unit, where patients are often severely catabolic and
extraordinarily heterogeneous in the severity of their illness and their underlying comorbidities, it has been even more difficult to define precisely the role of nutritional support in
reducing morbidity and mortality from critical illness.2 That all patients can be given nutritional
support has been made possible by the development of two techniques: firstly, the intraluminal
administration of specific enteral diets using a feeding tube placed somewhere in the upper
gastrointestinal tract; and secondly, by the intravenous infusion of hypertonic nutrient solutions
which usually requires the presence of central venous catheter. A considerable problem has
surrounded the assessment of outcome in patients supported in these ways as most
investigations have centred upon biochemical and physical indices of host wasting rather than
examining hard endpoints of clinical outcome, for example 28 day / ICU / hospital mortality
rates or even length of ICU stay or duration of ventilatory support. Clearly starvation is not an
option for the critically ill patient since experience from the concentration camps of Nazi
Germany, the British prisons in Northern Island and famines in Africa all confirm that death is
inevitable in initially well nourished individuals after some 60 to 80 days of starvation (water
and electrolytes being provided in some form). The debate concerns the exact timing of
nutritional support in the critically ill, its route of administration and finally, the formulation of
the diet which now may be used to modulate the host response to critical illness.3
1.
Identification of Malnourished Patients.

Protein calorie malnutrition (starvation) results in a reduction in body cell mass (the
actively functioning protein rich tissue and its intracellular fluid) and adipose tissue. This is
best assessed by measuring the weight of the patient in relation to their height (kgs / m = body
mass index). Whilst protein calorie malnutrition may also be assessed by examining the serum
concentration of proteins synthesised in the liver (for example, serum albumin, prealbumin,
caeruloplasmin), various anthropometric measurements (for example, mid arm circumference)
and grip strength, all of which probably have little value in the every day assessment of the
nutritional status of a patient in the ICU. Similarly, the available tests of cell mediated
immunity - anergy to common allergens, and the more sophisticated tests of immunological
function whilst having an important role in nutrition research, have little to offer in the
assessment of the individual patients.
Nutritional assessment is best performed by identifying the relevant features of a patients
history and physical examination in order to elicit a subjective global assessment of their
nutritional status.4,5 The critical issues are unintentional weight loss (more than 10% weight
loss in the last 3 months or a reduction in body mass index to less than 20 kgs/m), a change in
17
Nutrition in the Critically Ill

dietary intake in relation to the patients usual pattern of eating, the presence or absence,
severity and duration of gastrointestinal symptoms (nausea, vomiting, diarrhoea, anorexia) and
the patients functional capacity. Three features of the physical examination are also of
importance: firstly, loss of subcutaneous fat, particularly over the triceps region of the arms, the
mid axillary line up to the costal margin, the interosseous and palmar areas of the hand and the
deltoid regions of the shoulder; secondly, muscle wasting particularly of the quadriceps and
deltoids; and finally loss of fluid from the intravascular to extravascular space, namely, ankle or
sacral oedema and ascites.
Using such as system, the subjective global assessment of a patients nutritional status
may be rated as being either 1) well nourished; 2) moderately (or suspected of being)
malnourished; and finally 3) severely malnourished. This system has been assessed
prospectively and has been demonstrated to be both sensitive and specific in the identification
of malnourished hospitalised patients with the greatest chance of suffering major complications
following elective surgery.6 Its use in the ICU has not been formally tested in this way but
would seem a logical aid in the initial assessment of critically ill patients.
2.
The Stress Response to Surgery, Trauma and Infection - Catabolism and Septic
Autocannabolism
Not surprisingly, the metabolic stress applied to an individual patient effects the extent of
the risk that malnutrition creates in the setting of elective surgery in critical illness. Depending
upon the severity of the injury and the duration of the disease, weight loss associated with the
loss of body fat and skeletal muscle mass may vary from being relatively insignificant to being
life-threatening, primarily through the development of immunosuppression and a decrease or
delay in wound healing and tissue repair. Muscle weakness may be reflected in a patients
inability to weaned from a mechanical ventilator. Catabolic disease causes an increase in the
extracellular fluid compartment accompanied by sodium retention and initial weight gain.7
Adipose tissue and the body cell mass actually shrink resulting in loss of weight, body fat and
protein. The underlying rationale for providing nutritional support to such patients is that the
accelerated net break down of body protein (measured as the nitrogen excretion) can be slowed
by the administration of adequate quantities of energy, protein (amino acids) and other essential
nutrients. In fact, it is extraordinary difficulty to prevent weight loss and negative nitrogen
balance in severely catabolic patients and it is now generally accepted that aggressive
nutritional support does not prevent substantial body protein loss during severe catabolic
illness. It is the treatment of the underlying problem that eventually reverses the catabolic
phase of the illness and it is at that time that anabolism can be promoted by the provision of
nutrients.8
Infection and injury are followed by a series of well described neurohormonal events
together with the release of mediators of the acute inflammatory response. A complex network
of events characterises the host response to injury and infection and when for some reason this
host response is inappropriate - either exaggerated and prolonged or inappropriately subdued,
the consequence is widespread and severe tissue injury arising either as a result of the infection
itself or the host response itself.9 It is this acute inflammatory response which increases the
metabolic rate as a consequence of fever, the activation of the sympathetic nervous system and
the release of catecholamines, the direct effect of cytokines, the increased synthetic activity of
the liver in the production of acute phase proteins, the presence of a large wound and very often
increases in the work of breathing. In general, the increase in metabolic rate is less than 10% in
the majority of patients undergoing uncomplicated elective surgery. On the other hand, in
severely injured patients, the increase in metabolic rate may be as great as 20 to 50%
particularly in those patients who suffer a severe burn. In any event, the patients previous
18

nutritional status, the disease process itself, and the magnitude and anticipated duration of the
associated catabolic stresses will determine the requirement and timing of nutritional support.
Given these variations in responses, it is not surprising that there has been great difficulty in
performing appropriate randomised controlled clinical trials to demonstrate the effectiveness of
nutritional support in such cases.
3.
Energy and Nitrogen Requirements in the Critically Ill.

In general, studies of resting energy expenditure in the critically ill using the techniques of
indirect calorimetry, have indicated that most patients require between 20 to 30 non-protein
kilocalories per kilogram per day.8,10 This energy requirement is recommended as nonprotein kilocalories so that any protein administered can be utilised in anabolic processes, i.e.
rebuilding the body mass of the patient rather than used as an energy source. Nitrogen
requirements appear to be between 0.2 to 0.4 grams of nitrogen per kilo per day, i.e. 1.2 to 2.4
grams of protein per kilogram per day.10 Greater intakes of nitrogen have not been shown to
improve nitrogen balance but rather the extra protein is broken down and excreted as urea in
the urine. In the past, emphasis has been placed upon the kilocalorie : nitrogen ratio, the
assumption being that any nitrogen administered could not be used in anabolic processes unless
a critical number of non-protein kilocalories were administered at the same time for the
purposes of energy. Much less emphasis is placed today on these rather arbitrary ratios with the
realisation that positive nitrogen balance is virtually impossible to achieve, until the underlying
illness of the patient has been treated. Nevertheless, it is possible to minimise the degree of
negativity of the nitrogen balance by providing some protein preferably by the enteral route.
Patients with large burns and severe sepsis have an increased stress response and may require
30 to 35 non protein kilocalories per kilogram per day, but the danger of overfeeding is now
much more appreciated and the development of hyperglycaemia should be an early warning
sign that that too many kilocalories may be being supplied.
Electrolyte requirements should not be forgotten and careful monitoring of the nutritional
support is also required particularly in those malnourished patients who are undergoing
refeeding, the complications of hypokalaemia, hypophosphatemia and hypomagnesaemia being
more likely in such cases. Nitrogen balance in the critically ill is not difficult to perform
providing the patient is passing urine and not in renal failure. Nevertheless, its relevance to
clinical outcome has yet to be demonstrated and nowadays is very often ignored.
4.
Indications for Nutritional Support.

As the rationale for nutritional support depends upon two main assumptions - the
prevention of the effects of starvation and the favourable alteration of the natural history or
treatment of a specific disease - there are established indications for the use of nutritional
support and some unproven indications in which nutritional support is often used on the basis
of best guess (rather than best practice).1
There are groups of critically ill patients in whom adequate food intake is not possible for
a prolonged period of time and nutritional support is required in their case to prevent death
from starvation. These disorders include patients with severe neurological diseases (e.g.
Guillain-Barre Syndrome or severe head injury), patients with oropharyngeal disease who are
unable to eat (e.g. facial fractures, cancer of the head and neck), patients with specific intestinal
disorders (short gut syndrome following mesenteric infarction) and premature infants. The
Veterans Affairs TPN Co-operative Study Group of Perioperative Parenteral Nutrition has also
demonstrated that severely malnourished patients (weight loss greater than 10% in the last 3
months, albumin less than 28 g/L on admission to hospital) undergoing elective surgical
procedures also benefit from 10 days of perioperative intravenous nutrition.11 In contrast well
19

nourished minimally stressed patients who are unable to eat for 7 to 10 days do not require
nutritional support but is seems that in those who are unable to eat for more than 14 days, their
outcome is improved if they receive some support.12 In the setting of the ICU, it is difficult to
identify these patients early on but such data argue against the requirement for early nutrition of
any form in any elective surgical patient who starts off well nourished. In contrast, early enteral
nutrition has been shown to improve survival in patients with major trauma, burns and in
patients with head injuries (table 1). Finally, there are two randomised controlled clinical trials
indicating the benefit of either TPN or a combination of TPN and enteral nutrition in patients
undergoing bone marrow transplantation.1 Benefits of nutritional support are unproven in other
settings and this is particularly the case in patients with liver and renal failure, patients with
pancreatitis and gastrointestinal fistulae, who very often receive support in the setting of critical
illness.
TABLE 1 RESULTS OF CLINICAL STUDIES COMPARING TEN with TPN
Studies
Results
Adams et al 198619 46 trauma patients

randomised to receive either TPN or TEN
(via a jejunostomy). No significant
difference in age (TPN 2910yr TEN
309 yr)
Early post-operative jejunostomy feeding is

as safe and efficacious as TPN, with
comparable complication rates.
Moore, Jones et al 198920 63 patients with

major abdominal trauma randomised to a
control or enterally fed group, via a needle
catheter jejunostomy. (control: 29.3 2.1
yr TEN : 30.5 2.2yr).
Reduced septic complications in TEN group.

Early enteral nutrition well tolerated in
severely injured.
Moore et al21 Meta analysis of 8 trials 1992

Comparing TEN with TPN in high risk
surgical patients with trauma and non
traumatic conditions (TEN 41.0 1.5 yr
TPN 41.8 1.5yr ).
High risk post operative surgical patients will

tolerate early TEN. These patients have
reduced morbidity rates compared with those
patients administered TPN.
Kudsk et al 199222 96 trauma patients

randomised to TPN or enteral nutrition.
(TPN 30.6 1.4 yr TEN 30.4 1.7 yr)
Significantly lower incidence of septic

morbidity in patients fed enterally after blunt
and penetrating abdominal trauma.
Wicks et al 199428 24 patients undergoing

primary orthotopic liver transplantation
randomised to either enteral feed or TPN.
(mean age 46, range 16 - 62 yr)
Enteral feeding after liver transplantation is

practical, efficacious and less expensive than
TPN.
5.
Route of Nutritional Support

With regard to the question of the preferred route of nutritional support, the position is
more clear; whenever possible, feeding using the enteral route is preferred.13,14 Normal gut
structure and function depends upon an adequate delivery of oxygen and other nutrients to the
20

mucosa. During starvation, critical illness or the administration of TPN, these basic
requirements may not be met. Many different animal studies have demonstrated that in these
circumstances gut atrophy and changes in mucosal permeability can ensue. It has been
suggested that these changes might allow the passage of bacteria (translocation) or
macromolecules such as endotoxin into the systemic circulation resulting in inflammatory
mediator activation, a systemic acute (SIRS) and ultimately single or multiple organ failure
(MOF). However, the evidence for this hypothesis is largely derived from small animal [rodent]
models of burns, trauma and sepsis and not surprisingly, the rat and human small intestines
behave differently when subjected to similar stresses. For example, starvation in the rat can
result in small bowel atrophy within four days whereas the human bowel may remain normal
for up to two weeks of starvation. If total parenteral nutrition (TPN) is administered to a rat, gut
atrophy may occur within three days, whereas there is very little evidence to demonstrate
whether TPN induced intestinal atrophy actually occurs in humans. Further confusion exists
over the exact relationship between changes in gut permeability (the clinical relevance of which
is unclear), the presence or absence of mucosal atrophy and the occurrence of bacterial
translocation.15 At this time there is little direct evidence in humans to implicate gut bacterial,
or bacterial product translocation as a cause of MOF. As simple splanchnic (including hepatic)
ischaemia and reperfusion is enough to initiate a profound inflammatory response, it may not
be necessary to invoke translocation as an absolute requirement for the development of organ
dysfunction.
Given the importance of splanchnic ischaemia and reperfusion in shock states (its early
development in any form of shock and its relatively late reversal during the phase of
resuscitation), enteral nutrition may have a cyto-protective effect by enhancing or maintaining
splanchnic blood flow. Whilst it is difficult to imagine that early enteral nutrition could
improve splanchnic blood flow in the setting of uncorrected hypovolaemia or an inadequate
cardiac output, the presence of nutrients within the lumen of the gastrointestinal tract might act
to preserve blood flow and this could have important implications for the prevention of
mucosal breakdown and stress ulceration.16
Aside from the possible association of TPN with impaired gastrointestinal barrier
function, there are other important consequences associated with the unphysiological practice
of bypassing the gut and delivering nutrients directly into the blood. In addition to the well
described mechanical complications of central venous cannulation, venous thrombosis, catheter
related sepsis and severe metabolic disturbances such as hyperglycaemia and hepatic
dysfunction, there is justifiable concern regarding the hazards of intravenous lipids. Intravenous
fat has many well-documented immunosuppressive effects:
intravenous long chain
triglycerides reduce the functions of the reticulo-endothelial system, neutrophils and the ratio of
T helper to T suppressor cells. An important observation has been that the risk of coagulase
negative staphylococcal bacteraemia in neonates is considerably increased (by six times) by the
administration of lipid emulsions.17
The gut also regulates the absorption of trace elements and when the gut is bypassed with
trace elements being given parenterally, there may be no effective way to increase their
excretion. Excessive tissue deposition of iron has been demonstrated in children on long-term
TPN. Other complications of TPN which continue to warrant attention include TPN induced
steatosis and cholecystitis.18
In addition to the array of detrimental effects associated with TPN, there has been a steady
accumulation of clinical trials comparing total enteral nutrition (TEN) with TPN (table
1).19,20,21,22,23 In general, these demonstrate better outcomes in enterally fed patients although
the case mix of patients studied has been rather limited. Even if, as has been suggested,
apparent improvements in outcome are due to the avoidance of the harmful effects of TPN
21

rather than any benefits associated with TEN these trials still suggest that TPN is best avoided
whenever it is possible to feed an individual via the enteral route. The methodology of some of
these studies has also been criticised because they were not blinded but it is difficult to imagine
a practical protocol that would avoid this weakness. In an analysis of the effects of TPN alone,
the multicentre, Veterans Affairs TPN Co-operative Study Group were able to demonstrate that
preoperative TPN (in elective surgical patients) in well nourished patients was associated with
an increase in post-operative infectious complications.11 As previously stated the beneficial
effects were only seen in patients who were severely malnourished but as none of the groups
studied were critically ill, it is difficult to transpose these results directly to patients requiring
intensive care. Nevertheless, these clinical trials taken in conjunction with the possible benefits
of early enteral nutrition on gastric mucosal function and the known hazards of TPN make the
enteral route the route of choice. Despite this considerable body of evidence, a recent survey
found that only 74% of patients eligible to receive enteral nutrition in the ICU were started on
enteral feeds.24 There were a variety of reasons for this disappointing observation not least the
widespread misconception that bowel sounds must be present before enteral feeding can be
initiated, their absence indicating an adynamic bowel. In fact, it is known that the critically ill,
and patients who have undergone laparotomy often have normal small intestinal motility in
association with gastric and colonic paresis. In these patients it is hardly surprising that bowel
sounds are absent since any noise requires the presence of gas in the gut; if the stomach is being
drained by a nasogastric tube or is not contracting and transferring gas into the duodenum, then
the small intestine contracts silently. In fact 80% to 90% of critically ill patients who require
nutritional support tolerate some enteral feed in the first few days of admission regardless of
whether bowel sounds are present or not. It is also erroneously thought that certain types of
abdominal surgery, e.g. bowel resections, are relative contraindications to enteral feeding but
there is no evidence to suggest that this is the case. Similarly, acute pancreatitis is not a
contraindication to enteral nutrition. Gastric paresis which may present an obstacle to
successful enteral feeding can often be overcome by perseverance and the judicious use of
prokinetic agents (cisapride or erythromycin). In the small number of patients unable to tolerate
a fine nasogastric tube, a variety of other routes are available by which enteral nutrition can be
provided (table 2). Nevertheless for various biological reasons the intragastric route for enteral
feeding is favoured eg. gastric acid secretion (the principal bactericidal mechanism of the
stomach) is diminished during jejunal feeding. The combination of TPN and enteral nutrition to
provide nutritional support, TPN being withdrawn once successful enteral nutrition is
established, has inherent dangers; firstly it exposes the critically ill patient unnecessarily to the
adverse effects of TPN. Secondly it introduces the potential for less rigorous pursuit of
successful enteral feeding, attending staff being lulled into a false sense of security.
5.
Formulation of the nutritional support

Controversy surrounds the benefits associated with the various formulations available and the
effect of any specific supplementation of the enteral feed. One area of interest has been the use of
high fat mixtures for patients with CO2 retention who are difficult to wean from mechanical
ventilatory support. Undoubtedly, one physiological effect of reducing the proportion of energy
given as carbohydrate, replacing those CHO kilocalories with fat kilocalories, is to reduce the CO2
production and the requirement for a given minute ventilation. Pulmocare (Abbott Laboratories)
is one such enteral formulation but it is difficult to know whether this physiological effect translates
into a meaningful clinical outcome.25
22
TABLE 2 ROUTES OF ACCESS FOR DELIVERY OF ENTERAL NUTRITION

Route
Methods of placement
Nasoenteric
Nasogastric
via nasopharynx or at laparotomy
Nasoduodenal / jejunal
Enterocutaneous
Percutaneous endoscopic
gastroscopy (PEG)
endoscopy, image intensification

blind techniques
at the time of laparotomy.
endoscopic placement through
anterior abdominal wall
Percutaneous endoscopic
jejunoscopy(PEJ)
placement of feeding
tube as above beyond the pylorus.
Feeding gastroscopy
jejunostomy
open surgical procedure or via the

laparoscope
More evidence surrounds the importance of supplementing TPN regimens with glutamine.26
Previously considered a non-essential amino acid, glutamine deficiency may occur in the setting
of acute catabolic illness with a rapid decline occurring in the concentration of free glutamine in the
intracellular amino acid pool of skeletal muscle. Glutamine is exported from skeletal muscle and
used by the visceral organs - as an ammonia donor in the kidney in its role in acid-base homeostasis
and as a primary oxidisable fuel source for enterocytes and colonocytes in the gastrointestinal tract.
It is also required (in combination with glycine and cyteine) for the formation of the tri-peptide,
glutathione, an important component of the cellular protection mechanisms against oxygen radical
injury. Glutamine supplementation (0.2 - 0.5 g per kilogram) may certainly improve nitrogen
balance and increase skeletal muscle concentrations of the amino acid. There are now 2 studies
demonstrating that the addition of glutamine can reduce the number of nosocomial infections and
length of hospital stay in patients undergoing bone marrow transplantation1 and a single study in
general ICU patients demonstrating much the same thing. The effect is more marked in patients
receiving TPN, not surprisingly since the standard amino acid solutions contain none whereas all
enteral feeds contain some glutamine albeit in low concentrations.
Finally, a recent study in a relatively homogeneous group of patients requiring intensive care
suggested that supplementation of enteral feeds with three specific immunonutrients may have
beneficial effects.27 These ingredients - arginine, purine nucleotides (in the form of yeast RNA) and
omega-3 polyunsaturated fatty acids - were chosen because of their well established effects on in
vitro and in vivo markers of immune function - promotion of T cell blastogenesis, enhancement of
cellular immunity and increased levels of the trienoic eicosanoids respectively. These three have
been combined into a single, commercially available enteral feed ("IMPACT", Sandoz Nutrition Ltd.,
Switzerland) with the aim of appropriate immune modulation in those patients in whom sepsis is
considered likely. Whilst there are at least 8 studies demonstrating its benefits in elective surgery
patients further work is required to examine the potential benefits of such an immunonutrient feed
in the general population (ie. non-trauma) of critically ill patients.
23
6.
Economical considerations in the provision of nutritional support

Cost benefit analysis, particularly the allocation of costs in dollars to intangible effects
associated with nutritional support - for example the suffering associated with a day of nausea
or abdominal bloating in the ICU, applied at the bedside of an individual patient remains an
anathema to most physicians and rightly so! However, in these days of scarce resources, a
knowledge of the cost effectiveness of various interventions is a reasonable expectation of
practising ICU clinicians so as to allow appropriate forward planning in the implementation of
the necessary budgetary restrictions. When considering nutritional support, it has become clear
that feeding by the enteral route is more cost effective than TPN . A recent study comparing
enteral feeding and TPN after liver transplantation noted that the cost of providing post
transplant parenteral nutrition was 75 to 85 per patient day, whilst commercially prepared
enteral feed cost only 7 per day (a potential saving of around 70 per patient day).28 TPN
remains a common therapeutic intervention at least in European ICUs, the European Prevalence
of Infection in Intensive Care (EPIC) study documenting that on the day of survey (29/4/92),
45% of 10,038 patients surveyed were receiving some form of parenteral nutrition.29 The third
national survey of artificial nutritional support in the UK noted that in 1993 some 62,997 days
of TPN were administered in hospital,30 (this figure probably being considerably higher since it
was derived from incomplete data). It is not difficult to see how TPN can have an enormous
impact on health care budgets. Using data from the Department of Veterans Affairs Cooperative Trial of perioperative TPN, Eisenberg et al addressed the question of whether TPN
used in this way saved money in any subgroup of patients, particularly those who were
malnourished.31 They concluded that perioperative TPN did not result in decreased costs for
any sub-group of patients re-emphasising the present view that the indications for TPN are
specific and limited to a small group of malnourished patients who are unable to absorb
nutrients from their gastrointestinal tracts. Given the cost implications of TPN, it is
disappointing that it continues to be prescribed so frequently when enteral nutrition would be
more appropriate. In a retrospective study of 31 patients receiving artificial nutritional support,
a nutritional support team (NST) identified 12 patients for whom TPN had been prescribed in
whom enteral feeding would have been more appropriate.32 Apart from ensuring the
appropriate use of TPN or indeed any sort of nutritional support, which may often be used
inappropriately in the hospital setting, eg. in the treatment of any patient with severe
irreversible disease, it has been suggested that nutritional support teams provide cost
containment in a variety of other ways.33 Overfeeding can have significant cost implications
and it has been suggested that the cost of TPN could be cut by 22% by utilising metabolic cart
studies routinely.
Finally, although it is clear that enteral feeding involves lower staff and material costs
than TPN, it is true to say that on occasion the need to consult gastroenterologists and
radiologists to obtain access to the gastrointestinal tract beyond the pylorus can increase patient
management costs. However, it has been suggested that the cost savings achieved by
abandoning TPN may allow intensive care staff to purchase endoscopes and develop the
necessary skills to access the gastrointestinal tract themselves. In any event, there are many
good physiological and economic reasons why the enteral route is the preferred method of
delivering nutritional support.
24

REFERENCES
1. Souba WW. Nutritional support. N Engl J Med 1997;336:41-48.
2. Kortez RL. Nutritional supplementation in the ICU. How critical is nutrition for the
critically ill? Am J Respir Crit Care Med 1995;151:570-573.
3. Soeters PB, Steven WM and Damink O. Nutritional considerations in the critically ill.
Current opinion in Critical Care 1996;2:153 -160.
4. Detsky AS, Smalley PS and Chang J. Is this patient malnourished ? JAMA 1994;271:5458.
5. Nightingale JMD, Walsh N, Bullock ME and Wicks AC. Three simple methods of
detecting malnutrition on medical wards. J Roy Soc Med 1996;89:144-148.
6. Baker JP, Detsky AS, Wesson DE, Wolman SL et al. Nutritional assessment - a
comparison of clinical judgement and objective measurements. N Engl J Med
1982;306:969-972.
7. Wilmore DW. Catabolic illness - strategies for enhancing recovery. N Engl J Med
1991;325:695-702.
8. Meeting report. Round table conference on metabolic support of critically ill patients.
Intensive Care Med 1994;20:298-299.
9. Bone RC. Immunologic dissonance: a continuing evolution in our understanding of the
systemic inflammatory response syndrome (SIRS) and the multiple organ dysfunction
syndrome (MODS). Ann Intern Med 1996;125:680-687.
10. Wilmore DW, Carpentier YA (eds). Metabolic support of the critically ill patient. Update
in intensive care and emergency medicine volume 17. Springer, Berlin Heidelberg 1993.
11. The Veterans Affairs Total Parenteral Nutrition Cooperative Study Group. Perioperative
Total Parenteral Nutrition in Surgical Patients. N Engl J Med 1991;325:525-32.
12. Sandstrom R, Drott C, Hyltander A et al. The effect of postoperative intravenous feeding
(TPN) on outcome following major surgery evaluated in a randomized study. Ann Surg
1993;217:185-195.
13. Atkinson S and Bihari D. Enteral nutrition in intensive care: no more 'gastrointestinal
neglect.' Current Medical Literature - Anaesthesiology 1994;8;3-8.
14. Frost P and Bihari D. Route of nutritional support in the critically ill - physiological and
economical considerations. Nutrition 1997 (in press).
15. Riddington DW, Boivin CM, Bonser RS et al. Intestinal permeability and systemic
endotoxaemia in patients undergoing cardiopulmonary bypass. JAMA 1996;275:10771012
16. Heyland DK, Cook DJ, Guyatt GY. Enteral Nutrition in the critically ill patient. A
critical review of the evidence. Intensive Care Med 1993;19:435-442.
17. Freeman J, Goldmann DA, Smith NE, Sidebottom DG, Epstein M Fand Platt R.
Association of intravenous lipid emulsion and coagulase-negative staphylococcal
bacteremia in neonatal Intensive Care Units. N Engl J Med 1990;23:301-8.
18. Braxton C, Lowry SF. Parenteral nutrition and liver dysfunction, new insight? JPEN
1995;19:3 - 4.
19. Adams S, Dellinger EP, Wertz J, Oreskovich MR, Simonowitz D, Johansen K. Enteral
versus parenteral nutritional support following laparotomy for trauma - a prospective
randomised study. J Trauma 1986;26:882-891.
20. Moore EE and Jones TN . Benefits of immediate jejunostomy feeding after major
abdominal trauma - a prospective randomised study. J Trauma 1989;26:874-881.
25

21. Moore FA, Feliciano DV Andrassy RJ et al . Early enteral feeding, compared with
parenteral reduces postoperative septic complications. The results of a meta-analysis. Ann
Surg 1992;216:177-183.
22. Kudsk, KAS, Croce MA, Fabian TA et al. Enteral versus parenteral feeding effects on
septic morbidity after blunt and penetrating abdominal trauma. Ann Surg 1992;215:503511
23. Grahm TW, Zadrozny DB and Harrington T. The benefits of early jejunal
hyperalimentation in the head injured patient. Neurosurgery 1989;25:729-735
24. Heyland D, Cook DJ, Winder B, Brylowski L, Van de Monk H, Guyatt G. Enteral
nutrition in the critically ill patient: A prospective survey. Critical Care Medicine
1993;23:1055-1060
25. Al-Saady NM. Does dietry manipulation influence weaning from artificial ventilation ?
Intensive Care Med 1994;20:463-465
26. Minard G and Janu P. Status and clinical utility of pharmaconutrients. Current Opinion in
Critical Care 1996;2:253-254.
27. Bower RH, Cerra FB, Bershadsky B et al. Early enteral administration of a formula
(Impact) supplemented with arginine, nucleotides, and fish oil in intensive care unit
patients: results of a multicenter prospective randomized clinical trial. Crit Care Med
1995;23:436-449.
28. Wicks C, Somasundaram S, Bjavnason I et al . Comparison of enteral feeding and total
parenteral nutrition after liver transplantation. Lancet 1994;344:837-840.
29. Vincent JL, Bihari DJ, Suter PM, et al. The prevalence of nosocomial infection in
intensive care units in Europe. Results of the European Prevalence of Infection in
Intensive Care .(EPIC) study. JAMA.1995;274:639 - 44.
30. Payne-James JJ, DeGavaCJ, Grimble GK, Silk DBA. Artificial nutrition support in
hospitals in the United Kingdom 1994,
Third National Survey. Clinical
Nutrition1995;14:329-335.
31. Eisenberg JM, Slick HA, Buzby GP, Bruce K, Williford WD. Does perioperative total
parenteral nutrition reduce medical care costs? JPEN 1993;17:201-209.
32. O'Brien DD, Hodges, RE, Day AT, Waxman KS, Rebello T. Recommendations of
nutrition support team promote cost containment. JPEN 1985;10:300-302.
33. Roberts M F Levine GM. Nutrition support team recommendations can reduce hospital
costs. Nutrition in Clinical Practice 1992;7:227-230
26
ACUTE TRAUMA MANAGEMENT

W. Griggs, FANZCA, FFICANZCA
Director, Department of Trauma,
Royal Adelaide Hospital,
INTRODUCTION
There is good evidence that management of patients with severe trauma is improved if an
organized and systematic approach is used. The following guidelines and notes are consistent
with the approach to severe trauma recommended by the Royal Australasian College of
Surgeons through its Committee on Early Management of Severe Trauma (EMST).1 This
approach has now been adopted by the Royal Australasian College of Surgeons as Official
College Policy. It is a mandatory requirement for training in a number of specialities. All
medical personnel who may be involved in looking after acute trauma should ensure that they
are familiar with the EMST approach. In many larger hospitals a Trauma Team2 is used to
facilitate the rapid assessment and management of major trauma victims. These Teams are
called out for injured patients fulfilling standard callout criteria.
This chapter will contain a brief outline of the basic principles of the EMST system,
followed by a more detailed discussion of some airway, breathing and circulation issues.
Finally a brief mention is made of some of the various scoring systems used in trauma patients.
OUTLINE OF EMST
The EMST system is divided into four main phases. These are a) Primary Survey,
b) Resuscitation, c) Secondary Survey and d) Definitive Care. These are expected to proceed
sequentially, with the exception that the Primary Survey and Resuscitation usually proceed in
parallel with life threatening problems being managed as soon as they are found.
a) Primary Survey: This includes five points
Airway:
Airway maintenance with cervical spine control.
Breathing:
Oxygenation and ventilation.
Circulation:
Circulation with haemorrhage control.
Disability:
Rapid neurological status. Includes AVPU (Alert, responds to Voice,
responds to Pain, Unresponsive) scale and pupils.
Exposure:
Completely undress the patient.
b) Resuscitation: Matching this to the Primary Survey.
Airway:
Manoeuvres include removal of foreign debris, chin lift, jaw thrust,
oropharyngeal airway, nasopharyngeal airway, oro- or nasotracheal
intubation and cricothyrotomy.
Maintain the cervical spine in a neutral position with manual
immobilization by a second person if necessary.
Breathing:
Always administer high concentrations of oxygen (minimum is 12
litres/minute via face mask.)
Alleviate tension pneumothorax.
Seal open pneumothorax.
Ventilate if ventilatory failure.
27
Acute Trauma Management

Circulation:
Control exsanguinating haemorrhage. Start TWO large (at least 16

gauge) intravenous lines. Obtain bloods for cross matching,
haematology, biochemistry and (if required) blood alcohol.
Disability:
May require intubation and or ventilation due to altered conscious
state alone.
Exposure:
May require active temperature control. Leads on to secondary
survey.
At this stage the patient should have an ECG monitor connected and urinary and oro or nasogastric catheters inserted provided that there are no contraindications.
c) Secondary Survey:
Significant injuries can be missed if this is not performed with rigorous attention to detail.
The Secondary Survey has been described as a top to toe examination with fingers and/or tubes
in every orifice. The body areas to be covered include
Head/Face:
Neck:
Includes inspection, palpation, cranial nerves and pupils.

Includes inspection, palpation, lateral cervical spine xray (MUST be
down to C7/T1 interspace).
Chest:
Includes inspection, palpation, percussion, and auscultation.
May need pleural decompression, pericardiocentesis, chest xray.
Abdomen:
Includes inspection, palpation, percussion, auscultation.
May need peritoneal lavage, CT scan, MAST suit, laparotomy.
Perineum:
Abnormalities include blood at meatus, scrotal haematoma, and high
riding prostate which are all suggestive of ruptured urethra.
PR to assess anal sphincter tone, rectal blood, rectal wall integrity,
prostate position.
Urethrogram required before catheter if evidence of rupture.
Back:
Includes bony deformity, penetrating or blunt trauma - must log roll
patient to inspect back.
Extremities:
Include inspection and palpation.
May need appropriate splinting, mast suit, analgesia (NOT i.m.), and
tetanus prophylaxis.
Neurologic:
Includes sensorimotor evaluation.
May need adequate immobilization of whole patient.
Xrays (apart from lateral cervical spine, chest and pelvis) should usually only be performed
after the assessment side of the Secondary Survey is finished.
d) Definitive Care:
This is embarked upon only when the previous three sections have been completed. By this
time all injuries both major and minor should have been identified.
Tertiary Survey:
There is evidence to suggest that a repeat of the secondary survey performed at 24 hours or
so after the patient has been initially seen will pick up important injuries. Signs and symptoms
of these injuries may have initially been masked by the presence of drugs, alcohol, other
distracting injuries and altered conscious state. Accordingly a tertiary survey is recommended
before discharge to ensure that injuries are not missed.
28

ACUTE AIRWAY MANAGEMENT
Introduction:
Airway assessment and management takes absolute precedence in the acute management of
the trauma patient. It is important that anyone who may have to manage an acutely injured
patient has a good understanding of the principles and practice of airway care.
At all times during assessment and management of the airway, consideration must be given
to the possibility of cervical spinal injury. This is particularly true in the presence of neck pain,
neurological signs or symptoms, or any injury above the level of the clavicles. Many airway
manoeuvres can be managed with the cervical spine immobilised as much as possible.
Airway Assessment:
Initial assessment of airway patency can be as simple as getting the patient to answer a
question. A lucid response to the question "How are you?" indicates not only airway patency,
but also provides information about ventilation and circulation to the extent that the brain is
getting enough oxygenated blood to enable thought processes to occur. However, if there is not
a lucid response, further investigation of the airway is essential. Early application of high flow
oxygen (at least 12L/Min) should be used wherever available.
A hand placed in front of the mouth and nose may detect warmth or moisture from exhaled
gases. It is important to determine whether or not there is evidence of respiratory movement as
absent respirations remove many of the signs of airway obstruction. The mouth should be
opened and a visual inspection made to seen if any foreign bodies are present such as vomitus,
false and/or broken teeth, chewing gum etc are present. Any obvious foreign bodies should be
removed with the exception that correctly sited false teeth should be left in-situ.
If breathing is present, the presence of noisy respirations indicates a degree of respiratory
obstruction. Total obstruction, of course, results in no flow and therefore no noise. In the
prehospital setting it may not always be easy to hear respiratory noises over other noises. In
these circumstances, a hand placed over the larynx may detect vibrations due to partial
obstruction. This is also a useful technique if travelling by helicopter or road ambulance.
Airway Management:
Removal of foreign bodies is important and often overlooked. Opening the mouth and
clearing large pieces with a gloved finger is the first option. A wide bore sucker can be used for
material out of reach of the finger.
Simple manoeuvres should always be tried first. Correct positioning of the jaw should be
achieved to eliminate possible obstruction from the tongue lying against the back of the
pharynx. This can be either by chin-lift or jaw-thrust. These both rely on the translational
movement of the temporo-mandibular joint. It is easiest to translate the jaw forward with it
slightly open. This should be done without extending the neck.
Either oropharyngeal or nasopharyngeal airways can be tried. Insertion of an oropharyngeal
airway may not be tolerated by a patient with an intact gag reflex. Nasopharyngeal airways can
be difficult to insert although they tend to stimulate the gag reflex less. The nasal turbinates can
physically obstruct passage through the nose, and these may fracture during insertion. It is also
possible to push them submucosally into the retropharynx if excessive force is used for
insertion. This usually causes significant bleeding and further airway problems and is ideally
avoided.
Endotracheal intubation should be considered if the above are all unsuccessful or if IPPV is
required for other reasons. Either nasal or oral routes can be used. The nasal route is preferred
for blind intubation as the tube is firmly supported. However all the problems of the naso29

pharyngeal airway can occur with a nasotracheal tube. There have been reported cases of
intracranial insertion of nasal tubes in the presence of a fractured skull (in particular the
cribriform plate). Whilst these reports have mainly been due to attempted nasogastric insertion,
the problem has also occurred with nasotracheal tubes. Care should be exercised in the presence
of head injuries. Oral endotracheal intubation can not usually be performed blind and requires a
laryngoscope and direct laryngoscopy. Correct positioning of the endotracheal tube MUST
always be confirmed by auscultation of both sides of the chest AND the epigastrium. Air
rushing up and down the oesophagus can simulate normal breath sounds and therefore it is
important to listen over the epigastrium in all cases. If the ambient noise is too high, visual
chest wall movement is helpful. Sometimes air entry can be felt and palpation over both sides of
the chest wall and the epigastrium may be helpful.
The gold standard for confirming intubation is use of end-tidal CO2 analysis. An
endotracheal tube should be inserted to about the 22 cm mark in the average size adult. This
will position the cuff below the vocal cords and still leave the tip of the tube above the carina.
During laryngoscopy the tube should be inserted until the cuff is just below the cords. A tube
inserted too far will usually go down the right main bronchus resulting in unequal ventilation.
The endotracheal tube may become obstructed by secretions, blood or by the cuff herniating
over the end. Consideration should be given to removing/replacing the endotracheal tube in
cases of inability to ventilate or adequately oxygenate a patient. Relaryngoscopy may be useful
to confirm that the tube has not become dislodged and is still passing through the vocal cords.
Severe bronchospasm can simulate airway obstruction in the intubated patient.
If intubation is impossible and airway access is urgently required consideration must be
given to the creation of a surgical airway.
Cricothyroid insufflation has been advocated as a temporising measure to provide
oxygenation although it is not adequate for carbon dioxide clearance. A large bore (16 gauge at
least) cannula is passed through the cricothyroid membrane and the cannula connected to a high
flow oxygen source. The source must be intermittent to allow exhalation. This can be achieved
by using a special injector, or by using a constant flow with a Y-piece which is occluded for
inspiration to occur. Other than for prepubescent children, the value of this technique for
anything other than extremely short term is questionable.
Cricothyrotomy is the making of a formal incision through the cricothyroid membrane. This
membrane lies very superficial and can usually be easily felt between the thyroid cartilage and
the cricoid ring. A scalpel is used to make an incision through the skin and the membrane. A
tube is then passed into the trachea. An endotracheal tube may be used, but care must be taken
not to pass it into the right main bronchus (check for equal chest movement and breath sounds).
The procedure should take only a few seconds. It is not recommended for prepubescent
children.
BREATHING AND IMMEDIATELY LIFE-THREATENING CHEST TRAUMA
Breathing Assessment:
The same initial question used for airway assessment ("How are you?") may help with
assessment of breathing. A person who responds in a lucid manner, is able to get enough
oxygenation and ventilation for brain function and speech. No lucid response requires further
assessment. Again, high flow oxygen (12 L/Min) should be applied early. Once the airway has
been addressed, it is essential to check for presence and adequacy of respiration. Chest
movement, and warmth or moisture from exhaled gases are useful signs.
Once breathing is identified as being present, it is necessary to determine its adequacy.
Respiratory rate and depth are important. Tachypnoea may be associated with any form of
30

shock or with anxiety, but it should always be assumed to be due to respiratory difficulties until
proven otherwise.
Examination of the chest using inspection, palpation and auscultation may reveal a number
of abnormalities. It is essential to expose the chest to adequately assess any disordered
breathing.
Inspection should reveal a chest which moves symmetrically with no paradoxical
movements and no indrawing. Asymmetrical chest movement may suggest a number of
underlying pathologies including voluntary splinting due to fractures, simple fractures alone,
flail segment, partial lung collapse on one side, or haemo-/pneumo-thorax. A particular
diagnosis to exclude is tension pneumothorax. On inspection, seat belt and other bruising may
suggest underlying pathology. Penetrating wounds are usually obvious, but may be missed if
the back of the chest and axillae are not examined. A flail segment should be visible by virtue
of the paradoxical movement associated with it. However side impacts may result in flail
segments in the axillae which can be hidden by a dependant arm.
Palpation may detect crepitus from either surgical emphysema, fractured ribs or both.
Vibrations felt under the hand may indicate fluid in the bronchial tree. This could be blood or
aspirated vomitus. It is unlikely to be acute pulmonary oedema following injury with the
exception of neurogenic pulmonary oedema which may occur after severe head injury. The
clavicles, scapula, sternum and individual ribs should all be felt. Pain or tenderness may be
quite localised.
Auscultation should reveal equal vesicular breath sounds on either side. Decrease of sounds
on one side or the other should be viewed in association with other signs. For example,
decreased or absent breath sounds on the right with distended neck veins, midline shift away
from that side, shock, decreased movement of the right chest and apparent hyperexpansion all
lead to the suggestion of tension pneumothorax. The same signs but without midline shift or
distended neck veins may suggest a massive haemothorax. Percussion may also help but is
usually of limited value in trauma.
Management:
EMST lists six immediately life threatening chest injuries which should be considered
during the primary survey. These are:
Airway obstruction
Open pneumothorax
Tension pneumothorax
Massive Haemothorax
Flail Chest
Cardiac Tamponade
Management of airway obstruction was dealt with earlier. Cardiac tamponade is a circulatory
problem and will be addressed in the next section. The others will be addressed sequentially. All
patients should have high flow oxygen and ventilatory support if respiratory failure occurs.
Open Pneumothorax:
Most penetrating injuries to the chest will seal themselves. However some wounds
particularly larger ones may remain open causing a "sucking chest wound". The presence of
bubbling at the wound in any wound indicates an open pneumothorax. Usually there will also
be underlying lung damage. The immediate management is to seal the wound with a hand,
followed by the use of a sterile occlusive dressing. This should be taped securely on three sides.
The fourth side is left untaped so that if a tension pneumothorax occurs the air will leak out
31

during expiration at the open fourth side. During inspiration the dressing is sucked into the
wound, effectively sealing the hole. This method is not fail-safe, however, and if signs of a
tension pneumothorax appear, the dressing should be temporarily removed to allow venting to
occur. As soon as possible after sealing an open chest wound a formal underwater seal drain
(UWSD) should be inserted in an area remote from the wound (ideally 6th ICS anterior axillary
line). An alternative is to seal all four sides but being ready to release the dressing if a tension
pneumothorax develops before an UWSD has been inserted.
Tension pneumothorax:
A tension pneumothorax develops when a one-way valve effect allows air into the pleural
cavity during part of the respiratory cycle, but not out again during the rest of the cycle. Air
accumulates in the pleural space, causing lung collapse and eventually midline mediastinal shift
towards the other side. The increase in intrathoracic pressure will tend to collapse intrathoracic
vessels (especially low pressure veins) and interfere with cardiac filling. This can significantly
reduce venous return and therefore cardiac output.
It is important to remember that tension pneumothorax should be a clinical rather than a
radiological diagnosis. It requires immediate decompression. A mechanism for use with a sealed
open pneumothorax is mentioned above. For other cases, (and if removing the dressing above
does not help) immediate decompression should be accomplished by inserting a large bore (at
least 16g) needle in the second intercostal space mid clavicular line. Penetration of the pleura
results in a characteristic hissing sound as air rushes out, and an immediate improvement in the
patients condition. This manoeuvre has converted the tension pneumothorax into an ordinary
pneumothorax. Leave the cannula in place. It is then necessary to insert a formal UWSD. This is
true even if air failed to rush out as there is a possibility that the needle itself could damage the
lung and lead to further air leak. Tension pneumothorax should always be looked for after
beginning positive pressure ventilation (IPPV) in the trauma patient, as IPPV is associated with
a higher incidence of this problem.
Massive Haemothorax:
This entity is rare but life threatening. The presentation is similar to tension pneumothorax
but the ipsilateral chest is dull to percussion. Usually more than 1500ml of blood has been lost
into the chest cavity which may lead to lung compression. Thus blood loss is compounded by
hypoxia. UWSD insertion may result in release of a tamponade effect on the bleeding points
and as such it is essential to restore adequate intravascular volume as soon as possible.
Thoracotomy will need to be considered if the initial drainage of blood is 1500ml+ or if the
ongoing loss is 200ml+/hr.
Flail Chest:
Flail chest occurs when a segment of the thoracic wall does not have bony continuity with
the rest of the thoracic cage. Most commonly this is caused by multiple rib fractures, but
damaged cartilages and sternal fractures may also contribute. The flail segment moves
paradoxically, (i.e. moves in when the rest of the chest is expanding and out when the rest of
the chest is moving in). This paradox will, of course, only be present in the spontaneously
breathing patient as IPPV will cause all segments to move the same way at the same time. Flail
chest is invariably associated with underlying lung contusion. There is no value to respiratory
function in splinting or binding the chest.
Occasionally flail chest may be initially missed. This may be because of splinting of the
chest wall due to muscular spasm, or to the flail segment being placed in the axilla and splinted
by the adjacent arm. Always examine the side and the back of the chest.
32

Many of these patients can be managed with oxygen, analgesia and careful fluid
administration. However in the acute situation, if ventilation appears inadequate, consideration
should be given to early IPPV. The requirement for IPPV is not related to the size of the flail
alone, but rather to the underlying lung contusion. Respiratory function will usually deteriorate
over the first 24-48 hours after a lung contusion. An alternative requirement for IPPV will
obviously be when other injuries mandate it.
CIRCULATION AND HAEMORRHAGE CONTROL
Circulation Assessment: Hypovolaemia due to blood loss is probably the major cause of
preventable death due to trauma. It must be aggressively treated. Frequent reassessment during
resuscitation is the cornerstone of good management.
One of the major errors in acute trauma management is to assume that a normal blood
pressure indicates that the circulation is intact. Blood pressure alone can be extremely
misleading and should be considered in conjunction with other parameters of circulatory
assessment. These include pulse rate, capillary refill, respiratory rate, conscious state, urine
output and the expected effects from identified injuries. Haemorrhage can be arbitrarily
grouped into four classes which will be discussed out of numerical sequence for reasons that
should become clear.
Class 1 is equivalent to a trip to the blood bank to donate blood. This results in virtually no
detectable physiological change and the blood bank manages this by giving oral fluids. In
trauma, although apparently cardiovascularly normal, the patient with a class 1 haemorrhage
has less reserve if he/she is still bleeding.
Class 4 haemorrhage has been described as blood loss that non medical people can identify.
The patient has lost more than 40% of their blood volume and is in extremis. He/she will be
lethargic or unconscious, pale, sweaty, virtually anuric (do not be tricked by residual urine
present in the bladder on catheterisation), hypotensive, tachypnoeic and tachycardic. This
person will die soon unless major resuscitation efforts are urgently instituted. Young fit patients
may retain consciousness right up to the time of bradycardic arrest from blood loss.
Class 3 haemorrhage has been described as blood loss that a medical student can identify.
The patient has lost 30-40% of his/her blood volume and is obviously unwell. He/she will be
confused, hypotensive, oliguric, tachypnoeic, tachycardic and hypotensive. This person also
requires urgent resuscitation. It is safer to initially assume that confusion or agitation is due to
blood loss rather than head injury, because an incorrect assumption in the other direction could
lead to underestimation of blood loss. Beware the confused or agitated patient who becomes
quiet and stops fighting. It may mean that they have gone from class 3 to class 4 haemorrhage
and are about to die.
Class 2 haemorrhage is more difficult to diagnose. The patient has lost 15-30% of his/her
blood volume and yet has a mixture of mainly normal and few abnormal signs. This is the
patient that at a cursory glance may appear to be "alright". The only positive findings may be
mild tachycardia, mild tachypnoea, anxiety and delayed capillary refill. BLOOD PRESSURE
WILL USUALLY STILL BE NORMAL. These soft signs, however, can be mimicked by other
things such as pain, anxiety about the event, cold etc, therefore it is vitally important to look at
as wide a variety of parameters as possible as the more parameters that suggest blood loss, the
more likely it exists. At this stage it becomes important to be able to identify individual injuries
and the blood loss that might be associated with them.
The table below indicates how some of these parameters change with varying degrees of
hypovolaemia due to haemorrhage.
33

EST. INITIAL FLUID REQUIREMENTS/70 kg man*
Haemorrhage Class
1
2
3
Blood loss (ml)
Blood loss (% BV)
Pulse rate
Blood pressure
Capill. Refill Test
Respiratory rate
Urine (ml/hr)
Mental State
Fluids
<750
<15
<100
Normal
<2 sec
14-20
>30
Normal
Crystalloid
750-1500
15-30
>100
Normal
>2 sec
20-30
20-30
Anxious
Colloid
1500-2000
30-40
>120
Decrease
>2 sec
30-40
5-15
Confused
Blood
4
>2000
>40
>140
Decrease
>2 sec
>35
0-5
Lethargic
Blood
Crystalloid:
Colloid:
Blood:
Hartmann's solution in volumes 3 times that of blood lost

Albuminex or Haemaccel
Whole blood or packed cells + Albuminex or Haemaccel or saline
FFP and platelets for massive transfusion
Note that Blood Pressure may not drop until 30% + of blood volume has been lost.
* (reproduced from EMST course manual Page 59 with permission)
Limb fractures are inevitably associated with blood loss. The following table makes suggestions
as to the expected blood loss from different fractures and other injuries.
Bleeding Site
Estimated Blood Loss
Comments
Shaft of femur
1000-1500 mls
Double if compound
Tibia and fibula
500-750 mls
Double if compound
Shaft of humerus
500-750 mls
Double if compound
Radius and ulna
250-500 mls
Double if compound
Pelvis
1500 mls+
May loose many litres
Intraabdominal
Any amount
Includes retroperitoneum
Intrathoracic
Any amount
If the class of haemorrhage is worse than the obvious injuries would predict then it is likely
that there is concealed blood loss. This can be either in the pelvis, abdomen (including
retroperitoneum) or chest. In an adult it is virtually never in the head. Hypotension in the
presence of a head injury should not be assumed to be due to the head injury. Thus a person
with an isolated shaft of femur fracture who has a class 4 haemorrhage is bleeding from
somewhere else. Inadequate response to resuscitation fluids also suggests ongoing and perhaps
concealed bleeding.
34

The history of the event is also important, in that it may give a guide to expected injuries
e.g. a high speed frontal deceleration impact may result in a torn aortic arch or duodenum, and
a posterior hip dislocation.
Two other specific injuries can simulate the clinical picture of blood loss. These are tension
pneumothorax and cardiac tamponade. In both, the neck veins may be distended with a
hypotensive patient. Tension pneumothorax will be associated with unilateral decreased breath
sounds and hyperresonance and a midline shift away from that side. Cardiac tamponade is
usually associated with soft heart sounds.
Although neurogenic, cardiogenic and even septic shock can occur acutely in a trauma
patient, inadequate circulation should always be assumed to be due to hypovolaemia until
proven otherwise.
Circulation Management: Likening the damaged human circulation to a bucket of water
with a hole in it, the principles of management become logical and straightforward - plug the
hole(s) and refill the bucket.
Probably the most important part of correct management is to get the assessment right.
If circulation is inadequate, the steps to be considered are (1) Stop external haemorrhage - this can nearly always be managed by direct pressure. If you
can see the bleeding point, you can control it with pressure. Use large dressings and firm
bandages. M.A.S.T. may be considered in some cases. Tourniquets should NOT be used except
for extremely short term control. If the bleeding point is not externally visible then a surgeon
may have to look for it inside.
(2) Establish 2 large bore IV lines (14 or 16 g.) and administer intravenous
fluid/Haemaccel/blood - this should be done early and fluids begun as the response to a fluid
load is a good additional factor in assessment. The choice of fluid will depend on the degree of
identified blood loss. As a guide, Hartmann's solution or Haemaccel can be used to start with,
progressing to blood if more than three or four litres of fluid are required. A rule of thumb for
crystalloids is that 3 times the blood volume lost will be required, but a much better rule is to
adequately reassess the patient regularly and give as much as is required. Large transfusions
(greater than one blood volume) will lead to consideration being given to administration of
platelets and other coagulation factors.
(3) Drain cardiac tamponade - this is identified by the presence of Beck's Triad of muffled heart
sounds, decreased blood pressure and distended neck veins. Drainage is done with a cardiac
needle using a subxyphoid approach aiming for the angle of the scapula whilst aspirating on a
syringe. An ECG lead connected to the needle can be useful in identifying where the tip of the
needle is. If echocardiography is rapidly available then this is an additional way of diagnosing
this condition. It is also useful in placing a catheter. Most traumatic cardiac tamponades will
require a surgical approach for definitive management.
(4) Relieve tension pneumothorax - this should have been identified and performed during the
"breathing" assessment.
(5) Take blood for cross match, blood picture, electrolytes, etc.
35

Frequent reassessment during ongoing fluid replacement is essential. The answer to the
question of "How much fluid does this patient need?" is "Enough!". It may be 1 litre; it may be
50 litres. Only frequent reassessment will enable the correct decisions to be made to arrive
successfully at "Enough!".
Penetrating Torso Injuries and Fluid Resuscitation: A prospective study in 1994
suggested that survival in penetrating trauma is increased if minimal fluid resuscitation occurs
prior to surgery.3 These data make sense when considered in the light of the management of the
ruptured abdominal aortic aneurysm which for years has involved resuscitation to subnormal
haemodynamic parameters. It is important to emphasize that there is no corresponding data for
blunt trauma and also that it is still not clear whether no fluid is optimal for penetrating trauma,
or whether perhaps a more cautious approach such as used for aortic aneuryms might give an
even better outcome. While it may seem intuitively likely that the last approach may prove to be
correct, adequate data are not currently available. Therefore extreme care should be exercised in
fluid resuscitation of patients with penetrating torso injury, with the emphasis on the need for
early surgical intervention.
Summary: Good trauma resuscitation relies on an understanding of methods and patterns
of injury, thorough assessment, a good understanding of physiology and pathophysiology, and
the ability to perform the procedures necessary to resuscitate the injured patient. Utilisation of a
systematic approach such as EMST enables issues to be addressed in the correct order.
SCORING SYSTEMS and OUTCOME
Various scoring systems have been devised as a way to determine severity of injury and/or
likelihood of survival. Of these the Glasgow Coma Scale (GCS), the Trauma Score (TS), the
Revised Trauma Score (RTS), the Abbreviated Injury Score (AIS), the Injury Severity Score
(ISS) and TRISS are commonly used. There is not adequate space to discuss these in detail
which can be obtained from the original papers if required.
Glasgow Coma Score (GCS):
This is an assessment of the level of conscious state and is not limited to trauma. Possible
scores range from 3 to 15. Three scores, one each for eye opening, verbal and motor responses
are added together to give the total score. The score should be displayed as with both the total
and the component parts e.g. GCS 7 (E1 V2 M4). GCS of 8 or less defines unconsciousness.
Obvious limitations include focal signs and use in the intubated patient or child.
Trauma Score (TS):
First described in 1981,4 this is an assessment of degree of physiological disturbance as a
result of injury. It contains a weighting for the GCS. Points are also given for blood pressure,
capillary refill, respiratory rate and respiratory effort.
Revised Trauma Score:
The original TS was revised in the late 80s5 and demonstrated substantially improved
reliability in outcome predictions. Points are given for systolic blood pressure, GCS, and
respiratory rate only. There are two versions, the Triage version where the scores are added to
assist in triage decisions and the true version where each number is weighted before being
summed.
36

Abbreviated Injury Score (AIS):
This is an assessment of severity of injury based on anatomical regions.6 It is used to derive
the ISS. It is a scale of from 1 (for the least severe injury) to 5 (for the most severe injury).
A score of 6 may also be used for non-survivable injuries.
Injury Severity Score (ISS):
First described in 19747 this is an assessment of severity of injury based on seven
anatomical regions. It is the sum of the squares of the three highest AIS. Thus the range is from
1 to 75 for injured patients. Note that one AIS of 6 means that the ISS is considered to be 75.
TRISS:
The TRISS system8 is a widely used method of predicting mortality from outcome. It is
derived from the ISS, RTS and the patients age.
Other Trauma Scoring Systems:
A Severity Classification of Trauma (ASCOT) was described in 19909 and the Z score first
described for burns patients in 1978 has been extrapolated to other trauma. The W statistic is
used for institutional comparison of Z scores and more recently the M statistic has been used to
compare similarities in trauma severities between different data sets.10
The Major Trauma Outcome Study:
This 5 year study of 80,544 trauma patients has become a key reference on severity and
outcome in trauma and has been used a baseline for comparison of Trauma Systems.11 Similar
studies have been performed in the UK and in parts of Australia.
REFERENCES
1. Trauma Committee - Royal Australasian Colleg of Surgeons: Early Management of
Severe Trauma. 1992.
2. Sugrue M, Seger M, Kerridge R et al: A prospective study of the perofrmance of the
trauma team leader. J Trauma 1995 38: 79-82.
3. Bickell WH, Wall MJ, Pepe PE et al: Immediate versus delayed fluid resuscitation for
hypotensive patients with penetrating torso injuries. NEJM 1994: 331;1105-1109.
4. Champion HR, Sacco WJ, Carazzo AJ et al: Trauma Score. Crit Care Med 1981: 9;672676.
5. Champion HR, Sacco WJ, Copes WS et al: A Revision of the Trauma Score. J Trauma
1989: 29; 623-629.
6. Committee on Trauma of the American College of Surgeons: Rating the severity of tissue
damage: I The Abbreviated Injury Scale. J.A.M.A. 1971: 215;277-280.
7. Baker SP, ONeill B, Haddon W Jr. et al: The Injury Severity Score: A method for
describing patients with multiple injuries and evaluating emergency care. J Trauma 1974:
14;187-196.
8. Boyd CR, Tolson MA, Copes WS: Evaluating trauma care: The TRISS method. J Trauma
1987: 27; 370-378.
9. Champion HR, Copes WS, Sacco WJ et al: A new characterisation of injury severity. J
Trauma 1990 30; 539-546.
10. Hollis S, Yates DW, Woodford M et al: Standardized comparison of performance
indicators in Trauma: A new approach to case-mix variation. J Trauma 1995: 38;763-766.
11. Champion HR, Copes WS, Sacco WJ et al: The Major Trauma Outcome Study:
Establishing National Norms for Trauma Care. J Trauma 1990: 30;1356-1365.
37
38
ACUTE RENAL FAILURE

A. Holt, FFARACS
Flinders Medical Centre,
INTRODUCTION
Acute renal failure (ARF) with its adverse effects on body water balance, electrolyte
composition, drug elimination and immune, central nervous and gastro-intestinal function is
associated with a mortality in excess of 50%. However, the true impact of ARF is best seen in
the multi-system injury of the critically ill where the occurrence of ARF markedly worsens the
outcome of other system failure. For example, the mortality from adult respiratory distress
syndrome is more than trebled by ARF.1 While the mortality from ARF has not changed over
the last 20 years despite improvement in our understanding of the pathophysiology of ARF and
advances in medical and dialytic therapies, the outcome is primarily determined by the nature
and magnitude of the precipitating insult, which has changed over this period of time. For
example, the incidence of critically ill patients with ARF has increased and they are older with
greater comorbidity and multi-system injury which has resulted in the improvement in outcome
being difficult to measure.
The spectrum of ARF has changed with the emergence of increasing numbers of patients
with non-oliguric renal failure (over 50% of reported cases in some series). This trend probably
reflects an improvement in care, particularly in circulatory resuscitation leading to a reduction
in renal injury and renal dysfunction. This assertion is supported by laboratory studies showing
fluid replacement, shorter periods of ischaemia and smaller doses of nephrotoxins result in nonoliguric ARF in otherwise oliguric models.2 The benefits of non-oliguric ARF include fewer
complications, requirement of less frequent dialysis and lower mortality rate.
PATHOPHYSIOLOGY
Ischaemic Renal Injury
The apparent sensitivity of the kidney to ischaemia is not explained by total organ blood
flow. This seemingly luxurious blood flow does not subserve renal metabolic demands but is
driven by glomerular filtration and the excretion of flow dependent waste.
Distribution of renal blood flow and oxygen consumption within the kidney
The kidney has a unique arrangement of blood vessels. The glomerular afferent arterioles
give rise to the glomerular capillaries, which then coalesce to form the efferent arterioles,
which in turn give rise to the peritubular capillary network. In the juxtamedullary region only,
these branches contribute to the vasa recta. The majority of renal blood flow is therefore
supplied to the renal cortex with little flow to the renal medulla. The vasa recta, along with
tubules of the medulla, form a hairpin loop descending down into the medulla enabling a
countercurrent exchange of solutes and the development of a mechanism that allows the
efficient concentration of urine. The countercurrent exchange of solutes is also associated with
oxygen diffusion from descending to the ascending branches of the vasa recta leading to a
reduced delivery of oxygen to the medulla. Limited medullary blood flow is also important in
39
Acute Renal Failure

preventing the washout of the hyperosmolar interstitium. At the same time metabolic demand
of chloride reabsorption by the thick ascending limb of Henles loop produces a high local
oxygen consumption. Therefore the anatomical arrangement of medullary blood vessels and the
magnitude of blood flow to the medulla, so crucial to the concentration of urine, together with
high regional metabolic activity sees the outer medulla enduring a physiologic form of hypoxia.
Laboratory studies involving intra-parenchymal measurements of oxygen tensions have
confirmed this normal regional hypoxia ( PO2 < 20 mmHg )3 and a substantial proportion of
the medullary mitochondrial cytochrome enzyme system is in a reduced state.4 Therefore the
medulla has a marginal oxygen reserve with an oxygen extraction fraction as high as 90%
under normal circumstances.5
Normal physiologic control of outer medullary blood flow
Medullary blood flow, unlike cortical blood flow which is greatly reduced by the
neurohumoral response to any reductions in effective intravascular blood volume, is largely
preserved or even increased in this setting. This cortico-medullary redistribution of renal blood
flow not only prevents further hypoxia of the medulla but also shifts the filtration process from
superficial cortical to deep juxtamedullary glomeruli which have greater urinary concentrating
capacity. The mechanism of this redistribution is the regional opposition of global
neurohumoral vasoconstriction mediated by sympathetic stimuli or release of vasopressin and
angiotensin II by the local release of vasodilatory prostaglandins, adenosine, nitric oxide and
other mediators. The synthesis of PGE2 and PGI2 is most abundant in the renal medulla. The
importance of these mediators is best illustrated by the effects of cyclooxygenase inhibition by
indomethacin which does not significantly reduce total or cortical renal blood flow but greatly
reduces outer medullary blood flow and medullary PO2.6 Nitric oxide production is also
important for maintenance of medullary blood flow. Inducible nitric oxide synthetase is
primarily located in the outer medulla and its inhibition decreases medullary blood flow which
aggravates medullary hypoxia.7 There is also evidence that susceptibility of aged, diabetic or
hypertensive patients to acute renal failure relates to defective nitrovasodilation. Finally,
adenosine released by the breakdown of adenosine triphosphate when medullary oxygen
demand is not matched by supply, increases medullary blood flow. This effect is mediated by
vasodilatory purine A2 receptors.8
Tubuloglomerular feedback
Tubuloglomerular feedback is a complex protective intrarenal mechanism that couples
glomerular filtration rate with tubular reabsorptive capacity. This coupling also serves as a
physiologic controller of outer medullary oxygen consumption. While the mediators of this
coupling are likely to be many, adenosine appears to have a central role within the
juxtaglomerular apparatus.9 An increase in distal tubular solute load, presented to the macula
densa, results in an increased metabolic burden of solute reabsorption causing adenosine
release. This produces adenosine mediated afferent purine A1 receptor vasoconstriction and
mesangial cell contraction and efferent purine A2 receptor vasodilation. Distal solute delivery
is decreased by the resulting fall in glomerular filtration rate from this A1 and A2 mediated fall
in glomerular capillary hydrostatic pressure and glomerular capillary ultrafiltration coefficient.
In summary, the normally physiologically hypoxic medulla has no oxygen extraction
reserve. Medullary injury from neurohumoral reductions in renal blood flow from
everyday variations in extracellular fluid volume or non-critical reductions in blood
volume is prevented by down regulation of metabolic demand by tubuloglomerular
feedback and regional vasodilation maximising oxygen supply. However this flow reserve
and down regulation protection is rapidly exhausted by relatively minor hypoperfusion
40
Acute Renal Failure

insults, and the resulting at risk or prostaglandin driven kidney is readily injured by
any further insult.
Nephrotoxic Renal Injury
Both ischaemic and nephrotoxic injuries produce similar morphological changes and
clinical syndromes. Animal nephrotoxic models consistently show the predominance of injury
located to the outer medulla which is greatly exaggerated by concomitant kidney
hypoperfusion. Indeed some weaker nephrotoxins such as haem proteins appear to require
coexisting ischaemia as a necessary priming factor to cause injury. Nephrotoxic episodes of
ARF are more likely to be a non-oliguric syndrome and a more favourable outcome. This
reflects that in isolation, a nephrotoxic insult produces less injury. However many episodes of
ARF in critically ill patients are multifactorial, with both ischaemic and nephrotoxic
components to the insult. Nephrotoxins may produce their injury by reducing medullary blood
flow, as with nonsteroidal anti-inflammatory drugs and haem proteins, or by both reducing
blood flow and increasing medullary metabolic demand, like hypercalcaemia and
amphotericin B. Other agents reduce total kidney blood flow by the release of endothelin, as in
the case of cyclosporine and radiocontrast dyes. Given the common end point injury of
ischaemia, once steps to eliminate the toxin are undertaken, the therapeutic approach to
nephrotoxic insults is similar to that of ischaemia.
Mechanisms of Reduced Glomerular Filtration Following Renal Injury
Early animal models of ARF demonstrated histological changes of widespread tubular
necrosis and epithelial sloughing.10 From this it was concluded that tubular backleak and
obstruction from sloughed epithelial cells were responsible for a significant component of the
resulting fall in glomerular filtration rate. However, renal biopsies from patients with ARF
show far less impressive changes. Tubular epithelial cell necrosis is often absent and if present
is in the form of single cell necrosis only. Changes are often subtle, with diffuse change and at
times, only loss of the epithelial brush border. There is also prominence of the juxtaglomerular
apparatus and tubularisation of Bowmans capsule. Therefore, there is little morphological
basis supporting a significant effect from backleak. Occlusion of tubules, when present, is not
associated with morphological evidence of proximal luminal dilation or obstruction.11
The reduction in glomerular filtration rate would appear to be largely functional, involving
a decrease in renal blood flow, glomerular capillary hydrostatic pressure and ultrafiltration
coefficient. The mediators of these changes are likely multifactorial and those implicated
include adenosine and endothelin.
Adenosine:
Renal ischaemia produces a rapid rise in tissue adenosine,12 which will produce an
exaggerated or pathological tubuloglomerular feedback. The A1 vasoconstriction of arcuate
and afferent arterioles, the reduction in glomerular surface area by A1 mediated mesangial cell
contraction and A2 efferent vasodilation, may explain many of the functional disturbances
observed in ARF. Adenosine antagonists also restores renal function in a number of models of
ARF.
Endothelin:
Endothelin-1 is a potent peptide vasoconstrictor, particularly within the kidney, which
produces both afferent and efferent arteriolar vasoconstriction and a reduction in glomerular
capillary ultrafiltration coefficient. Despite the rapid clearance of endothelin-1, renal
dysfunction similar to ARF may persist for 24 hours following an exogenous intravenous
41
Acute Renal Failure

bolus.13 Several insults known to produce ARF, including hypoxia,14 endotoxaemia15 and some
nephrotoxins result in an increase in endothelin-1. Furthermore, patients with ARF have an
elevated level of plasma endothelin-1 which falls with recovery.16 The possible role of
endothelin-1 in the initiation of ARF is strengthened by recent laboratory studies that
demonstrate both functional and morphological protection from ischaemic insults with
endothelin antagonists.
Intra-abdominal pressure:
Increased intra-abdominal pressure is associated with reduced renal perfusion pressure and
impaired renal function. In an animal model the elevation of intra-abdominal pressure above 20
mmHg resulted in a linear reduction of blood flow to the kidney, splanchnic region and
hindlimb in association with reduced venous return and cardiac output.17 It is proposed that the
intra-abdominal organs act as Starling resistors, as their surrounding pressure rises. The level of
critical pressure may be lower than generally appreciated, as elevations in intra-abdominal
pressure above 12 mmHg during laparoscopic procedures resulted in a marked reduction in
effective renal plasma flow, glomerular filtration rate and urine output.18
STRATEGIES TO PREVENT ACUTE RENAL FAILURE19
While prevention of ARF is the ideal goal, reduction of renal injury and therefore
dysfunction, routinely measured by peak levels of plasma nitrogenous wastes will likely have
multi-system benefits. With more severe insults, attenuation that results in the avoidance of
renal replacement therapy appears to improve outcome significantly.20
Renal injury may result from a predictable, discrete insult such as aortic surgery which
allows for planned pre-insult prophylactic intervention. However, more often, renal insult and
resulting injury occurs over hours to days as in septic shock. In this setting therapeutic
intervention can attempt to minimise the insult or reduce the extent of injury and resulting renal
dysfunction for a given insult. Finally, patients may present following a renal insult with an
established injury where the remaining therapeutic option is to attenuate the resulting
dysfunction. It must be remembered that interventions that generate urine flow only, without
modification of renal injury or dysfunction in terms of glomerular filtration rate have not been
shown to confer clinical benefit. Whatever strategy is adopted in the hope of preventing ARF
or minimising its severity, needs to take into account these differing therapeutic windows.
General Measures
Rapid patient assessment, diagnosis and definitive management is central to preventing endorgan damage and a favourable outcome. Specific measures to minimise renal injury need to fit
within a global approach to the entire patient. It may be that renal goals of therapy may not be
achievable in the context of other problems. For example, myocardial ischaemia or arrhythmia
preventing achievement of renal haemodynamic goals, or the presence of severe acute lung
injury dictating modest levels of volume resuscitation.
Haemodynamic Resuscitation:
As restoration or maintenance of medullary blood flow is crucial to the prevention or
minimisation of renal injury, haemodynamic resuscitation must result in adequate renal blood
flow. Renal blood flow is determined by renal perfusion pressure, which equates with mean
arterial pressure unless there is raised renal venous or intra-abdominal pressure, and renal
vascular resistance. An adequate mean arterial pressure most often results in an adequate renal
blood flow unless there is a marked reduction in cardiac output resulting in severe reflex
42
Acute Renal Failure

neurohumoral renal vasoconstriction. Not surprisingly, goals of haemodynamic resuscitation
from a renal perspective has blood pressure and cardiac output components.
Blood pressure:
Renal autoregulation maintains renal blood flow and glomerular filtration rate over a range
of renal perfusion pressures by compensatory changes in renal vascular resistance. The
autoregulatory threshold is the lowest pressure at which autoregulation is maintained and is
defined as the intercept of the horizontal autoregulatory zone and the downward sloping
subautoregulatory zone (Fig 1). The autoregulatory threshold of renal blood flow determined
from careful laboratory studies is approximately 80 mmHg.21 The similar threshold for
glomerular filtration rate was noted to be 15 mmHg higher.22 In healthy volunteers,
haemorrhage which decreased mean arterial pressure from 80 to 67 mmHg resulted in a fall in
renal blood flow by 20% and a fall in glomerular filtration rate by 30%.23 This suggests that the
autoregulatory threshold for renal blood flow in healthy humans is also approximately 80
mmHg. It must also be remembered that chronic hypertension will result in a right curve shift
in the renal pressure-flow relationship. The loss of normal renal autoregulation has been
demonstrated in animal models of ARF.24 Instead of compensatory renal vasodilation as
perfusion pressure decreased there was a marked paradoxical increase in renal vascular
resistance and a fall in flow. Figure 1 demonstrates the change in pressure-flow relationships
between the normal and acutely injured kidney. It has been shown that this loss of
autoregulation results in renal hypoperfusion, injury and dysfunction with modest
haemorrhagic reductions in blood pressure that would normally fail to alter renal blood flow.25
In support of this is the finding of fresh necrotic lesions in renal biopsies of ARF patients some
time after the initial injury.26 These findings may represent sensitivity to episodes of
hypotension such as haemodialysis.
Volume resuscitation alone is often insufficient to generate mean arterial pressures of 80 85 mmHg in critically ill patients and vasopressor catecholamines are required. The choice of
agent is not as important as the execution of setting, re-evaluating and achieving blood pressure
goals. As argued below dopamine does not confer any specific beneficial renal effects.
Dopamines variable pharmacokinetics and the limitation of its indirect action at beta receptors
result in adrenaline being our agent of choice in critically ill patients. However, noradrenaline
may be needed in some patients to achieve target pressures. The concern about these agents and
alpha receptor mediated renal vasoconstriction is not founded. Their net effect on renal blood
flow will depend on the interplay between their direct vascular effects and the resulting
increase in renal perfusion pressure. In an ischaemic model of ARF, renal blood flow was
unaffected by the intra-arterial administration of noradrenaline until renal function started to
recover.27 A number of clinical studies report the improvement in urine output and glomerular
filtration rate with the use of noradrenaline to elevate mean arterial pressure).28,29 Together this
data would support the use of noradrenaline to achieve target blood pressures.
In summary, the autoregulatory threshold of blood pressure is higher than that seen in
most critically ill patients and renal blood flow and function will be pressure dependent.
The renal vasocontrictive effect and loss of autoregulation associated with acute renal
injury argue for resuscitation mean arterial pressure targets in excess of 80-85 mmHg.
43
Renal blood flow
Acute Renal Failure
A
B
B l ood pressure
Figure 1. A represents the normal kidney with intact autoregulation demonstrating a constant
glomerular filtration rate as blood pressure is lowered. Below the autoregulatory threshold
glomerular filtration rate becomes linearly dependent on pressure. B represents the acutely
injured kidney with its linear pressure-function relationship over the entire pressure range. No
autoregulatory threshold is identified and the line is depressed representing the vasoconstricted
state of the acutely injured kidney
Cardiac output:
While the pressure dependency of the kidney in the critically ill appears more important,
cardiac output cannot be ignored. This is particularly so in patients with low output states and
vasoconstriction and intact blood pressure. In patients with congestive cardiac failure there is a
linear reduction in renal blood flow with decreased cardiac output, with no relationship
between renal blood flow and blood pressure.30 In these patients the restoration of cardiac
output to more normal levels and correction of mixed venous desaturation with inotropes and
vasodilators improves renal function.
Haematocrit:
The optimal haematocrit for the kidney oxygen delivery is 40.31 This is much greater than
that usually aimed for in critically ill patients, and from a purely kidney perspective transfusion
thresholds should be higher.
Intra-abdominal pressure:
When clinically relevant intra-abdominal pressure should be measured by instilling 50-100
ml of sterile fluid into the empty bladder and measuring the pressure through a manometer side
port to the urinary catheter. Threshold pressure for decompression is 30 cm water. The timing
of decompression may be dictated by other factors, for example correction of coagulopathy in
post operative haemoperitoneum. However, sustained pressures of this magnitude will result in
progressive oliguria and declining renal function.
44
Acute Renal Failure

Specific Measures
These measures conceptually belong to one of 4 strategies:
1) Augmentation of renal blood flow
2) Reduction of renal oxygen consumption during the insult
3) Administration of cytoprotective agent during the insult
4) Antagonism of the mediators of reduced GFR following the insult
Augmentation of blood pressure:
During an insult or following injury, the loss of a pressure-function autoregulation and the
vasocontricted state of the kidney (Fig 1), would suggest that augmentation of blood pressure to
supra-normal levels would result in greater renal blood flow and improved function following
injury. Although the use of catecholamines to augment renal perfusion pressure to supranormal levels appears logical and is supported by some studies, there is no controlled data
showing a renal protective effect. However, there does appear to be clinical benefit from a
functional point of view in the injured kidney. Therefore, depending on the patients premorbid
blood pressure and the individualised risks-benefits of vasopressors, mean arterial pressures of
90-100 mmHg may be targeted.
Solute Loading:
Solute loading prior to a renal insult has been one of the most consistent protective
measures described in animal models. Indeed salt depletion is essential to many laboratory
models of ARF. In clinical studies it is often hard to separate solute loading from correction of
hypovolaemia. However solute loading in euvolaemic patients is protective in the setting of
renal transplant and cisplatin and radiocontrast dye nephrotoxicity.
Frusemide:
Frusemide is the classic example of a strategy where the therapeutic window is crucial to
benefit. Frusemide will reduce medullary work by inhibition of chloride reabsorption by the
thick ascending limb of Henles loop and improve the medullary oxygen supply-demand
balance. However, the dose and method of administration is important, as large bolus doses of
frusemide results in systemic and medullary vasoconstriction.32 Furthermore, the resulting
diuresis if not replaced may result in a renal insult itself.
In laboratory studies frusemide is protective in isolated perfused models of injury and in
noradrenaline, clamping-induced and nephrotoxic models of ARF when administered prior to
the insult. The protective effects are seen from both a morphological and function
perspective.33,34 However, the administration of, at times, large doses of frusemide to patients
following an insult and with established injury may reverse oliguria but has not been associated
with reduced need for dialysis, duration of ARF or mortality rate. The use of high dose
frusemide post insult exposes the patient to the adverse effects of frusemide in a therapeutic
window in which there is no experimental basis for expecting benefit other than improving
water balance.
The experimental basis for using frusemide, loading dose 1-1.5 mg/Kg slowly followed by a
low dose infusion 5 mg/hr, prior to or during an insult to improve medullary oxygenation and
reduce injury, is sound, and controlled clinical studies are warranted.
Adenosine antagonists:
The proposed role adenosine in the functional disturbance of ARF has led to laboratory
studies of various adenosine antagonists throughout the evolutionary stages of ARF.
Theophylline is a competitive adenosine (A1 and A2) receptor antagonist at plasma levels
45
Acute Renal Failure

substantially lower than that required for phosphodiesterase inhibition. Doses of theophylline
used to antagonise the renal effects of adenosine in the setting of ARF have varied among
different laboratory models, with loading doses of 0.02-1 mg/kg and maintenance doses of 15200 g/kg/min, and while not all studies have measured plasma levels they are generally low
and range from 0.3-0.6 mg/L. Administration of theophylline prior to an ischaemic, hypoxic or
nephrotoxic insult attenuates,35 or prevents36,37 the fall in renal blood flow and glomerular
filtration rate. Furthermore, in models of established renal dysfunction following an insult,
theophylline increases renal blood flow and glomerular filtration rate; however the greatest
benefit is seen when theophylline is administered prior to an insult and continued into the
maintenance phase. In addition to theophylline, other adenosine antagonists have also conferred
benefit in the setting of ARF.
As well as its role in tubuloglomerular feedback, adenosine contributes to the corticomedullary redistribution of blood flow and increase in medullary oxygen tensions. This effect
has raised concerns about potentially deleterious effects of adenosine antagonism, particularly
prior to re-establishing adequate renal blood flow. However, a randomised, double-blind,
placebo controlled trial has demonstrated that pre-treatment with 5 mg/kg of theophylline prior
to radiocontrast dye prevented a decrease in glomerular filtration rate.38
The use of low dose theophylline, 1 mg/Kg followed by 6 mg/hour, during renal insult and
following injury to reduce injury and resulting dysfunction requires further investigation.
Calcium channel blockers:
The administration of agents such as verapamil and diltiazem before the initiation of an
insult results in morphological and functional protection.39 Proposed mechanisms include a
number of direct vascular effects with preservation of renal autoregulation, a smaller fall in
renal blood flow and enhanced recovery of renal blood flow for a given insult and the
attenuation of cytotoxic calcium accumulation in tubular epithelial cells. Controlled studies in
the setting of renal transplantation examining graft function have demonstrated the benefit of
calcium channel blockers,40,41 however the doses used are unlikely to be tolerated in critically ill
patients.
Prostaglandins:
The appropriate balance between the vasodilatory prostaglandins and vasoconstrictive
thromboxanes are integral to the control of renal blood flow, particularly the protective corticomedullary re-distribution, and renal function. Non-steroidal anti-inflammatory drugs are
commonly associated with acute deteriorations in renal function and have been shown to
abolish autoregulation. Pre-treatment with thromboxane synthetase inhibitors produces a higher
prostaglandin to thromboxane ratio post ischaemic insult and prevents fall in renal blood flow
and glomerular filtration rate.42 The exogenous administration of PGE1 and PGE2 attenuate
dysfunction in ischaemic and nephrotoxic models.43,44 Prostaglandin analogues have also been
shown to prevent cyclosporine nephrotoxicity. The beneficial effects of prostaglandins appear
to be mediated by increasing renal blood flow and a cytoprotective effect.
The benefits of continuous infusions of prostaglandins during renal insults will need to be
weighed against any erosion of renal perfusion pressure produced by their potent systemic
vasodilation. The administration of PGE1 (0.25 - 0.10 g/kg/hour) following graft re-perfusion
in liver transplantation in the hope of reducing early graft dysfunction, demonstrated the side
benefit of improvement in renal function as measured by peak post operative creatinine levels.45
46
Acute Renal Failure

Endothelin antagonists:
The proposed role that endothelin-1 has in the initiation of ARF has led to the evaluation of
endothelin antagonists in the prevention of renal injury. Laboratory studies have used rabbit
polyclonal antibodies, mouse monoclonal endothelin antibodies and a selective endothelin
receptor antagonist. Administration of these agents before and following ischaemic insults has
resulted in prevention of functional and morphological changes.46 Furthermore, the
administration of endothelin antibodies 48 hours after ischaemic injury improved function
suggesting that endothelin may not only be involved in initiating renal injury but also in the
post-injury dysfunction.47 Clinical studies are awaited and again the balance of adverse
haemodynamic effects and renal protection is likely to be important.
Atrial natriuretic peptide:
The renal effects of atrial natriuretic peptide (i.e. an increase in glomerular capillary
hydrostatic pressure due to afferent arteriolar vasodilation and efferent vasoconstriction and
mesangial cell relaxation increasing glomerular capillary ultrafiltration coefficient), would
suggest that it may reduce the functional disturbance following injury. Indeed, atrial natriuretic
peptide has conferred morphological and functional protection from ischaemic and toxic
injuries.48 Once again the application to clinical practise may be plagued by the systemic effects
of plasma volume contraction and hypotension. Early clinical trials have been disappointing,
with the use of atrial natriuretic peptide following kidney transplant having no demonstrable
benefit.49
Mannitol:
Mannitol has been used widely as a renal protective agent. This was based on a number of
laboratory studies showing benefit with pre-treatment. The proposed benefits included; an
osmotic diuresis reducing tubular backleak and obstruction, free radicle scavenging and renal
vasodilation. The criticism of this early work is twofold. Firstly, like all early models of ARF,
the degree of cortical necrosis was marked and not clinically relevant. As previously discussed
tubular backleak and obstruction appear to play minimal, if any, role in clinical ARF. Secondly,
as with much of the work with mannitol, it has been impossible to dissect out the effects of
volume from solute loading.
In clinical studies, when volume and solute loading are controlled, prospective randomised
studies have not shown a clear beneficial effect. Mannitol is also commonly used in the
management of crush injuries and myoglobinuria. There have been no prospective randomised
studies to support this practise and the published series with impressive results are remarkable
for their aggressive fluid replacement regimes. Mannitol has been shown to cause electrolyte
disturbances, predispose to medullary hypoxia by increasing oxygen demand with enhanced
solute delivery and large doses even cause ARF. There is now little relevant evidence to
support the use of mannitol as a renal protective agent.
Dopamine:
The role of dopamine in protecting the kidney and enhancing function has been widely
debated in recent times,50 and the ubiquitous use of renal dose dopamine is changing as
critical care specialists look past the urine drainage bag. Dopamine via dopamine-1 receptors
produces inhibition of proximal tubular Na-K-ATPase resulting in decreased sodium
reabsorption and diuresis. It is true to say that this diuretic effect of dopamine was not widely
appreciated at the stage that renal dose dopamine became common practise. Furthermore,
regardless of specific renal effects, dopamine, like any catecholamine will augment renal blood
flow in critically ill patients. This systemic effect is certainly demonstrable at the supposedly
47
Acute Renal Failure

low dose, particularly since variable impairment of dopamine clearance in critically ill
patients can result in not so low plasma levels.
At a medullary level, dopamine increases blood flow by vasodilation but regional hypoxia is
not improved. The explanation of this paradox probably relates to the increased medullary
oxygen demand consequent on the proximal diuretic effect.51 In the clinical setting where renal
function is threatened, the kidney has already exhausted medullary vasodilatory reserve and the
local effects of introduction of dopamine would be an increase in medullary oxygen demand
without any increase in supply. The ability for dopamine to potentiate renal injury has now
been well shown in patients receiving radiocontrast dye.52,53 The fact that dopamine has not
been more consistently shown to be a potentiator of renal injury in at risk patients must relate to
its co-existing systemic augmentation of renal blood flow.
As clinically studies have changed from healthy volunteers (with medullary vasodilator
reserve) to critical care disease states (with no medullary vasodilator reserve), with methods to
control for systemic augmentation of renal blood flow and assessment of renal function beyond
urine output, no specific renal benefits have been found. There is now little evidence to support
the use of dopamine for specific renal protective effects.
CONCLUSION
Significant advances in our understanding of the pathophysiology of ARF has enabled the
critical care specialist to take another step beyond the level of resuscitate and dialyse. Greater
appreciation of renal targets of resuscitation and the increasing availability of strategies to
prevent injury and dysfunction will hopefully continue the trend of confining ARF to the more
and more severe insults.
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respiratory distress syndrome. Ann Intern Med 1983; 99:293-299
2. Honda N, Hashida A. Pathophysiology of experimental non-oliguric acute renal failure.
Kidney Int 1993; 43:513-521.
3. Brezis M, Rosen SN, Epstein FH. The pathophysiological implications of medullary
hypoxia. Am J Kidney Dis 1989; 13:253-258.
4. Epstein FH, Balaban RS, Ross BD. Redox state of cytochrome a,a3 in isolated perfused
rat kidney. Am J Physiol 1982; 243:F356-F363.
5. Brezis M, Rosen S, Silva P, et al. Renal ischaemia: A new perspective. Kidney Int 1984;
26:375-383.
6. Agmon Y, Brezis M. Effects of nonsteroidal anti-inflammatory drugs upon intrarenal
blood flow: Selective medullary hypoperfusion. Exp Nephrol 1993; 1:357-363.
7. Brezis M, Heyman SN, Dinur D, et al. Role of nitric oxide in renal medullary oxygen
balance. Studies in isolated and intact rat kidneys. J Clin Invest 1991; 88:390-395.
8. Agmon Y, Dinour D, Brezis M. Disparate effects of adenosine A1 and A2 receptor
agonists on intrarenal blood flow. Am J Physiol 1993; 265:802-806.
9. Osswald H, Muhlbauer B, Schenk F. Adenosine mediates tubuloglomerular feedback
response: an element of metabolic control of kidney function. Kidney Int 1991; 39:S128S131.
10. Burke TJ, Cronin RE, Duchin KL, Peterson LN, Schrier RW. Ischaemia and tubular
obstruction during acute renal failure in dogs: mannitol protection. AM J Physiol 1980;
238:F305-F314.
11. Bohle A, Christensen J, Kokot F, et al. Acute renal failure in man: new aspects concerning
pathogenesis. Am J Nephrol 1990; 10:374-388.
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12. Miller WL, Thomas RA, Berne RM, Rubio R. Adenosine production in the ischaemic
kidney. Circ Res 1978; 43:390-397.
13. Shbouta Y, Suzuki N, Shino A et al. Pathophysiological role of endothelin in acute renal
failure. Life Sci 1990; 46:1611-1618.
14. Rubanyi GM, Vanhoutte PM. Hypoxia releases a vasoconstrictor substance from the
canine vascular endothelium. J Physiol 1985; 364:45-56.
15. Sugiura M, Inagami T, Kon V. Endotoxin stimulates endothelin release in vivo and in
vitro as determined by radioimmunoassay. Boich Biophys Res Commun 1989; 161-12201227.
16. Tomita K, Ujiie K, Nakanishi T et al. Plasma endothelin levels in patients in acute renal
failure. New Engl J Med 1989; 321:1127.
17. Barnes GE, Laine GA, Giam PY et al. Cardiovascular responses to elevation of intraabdominal pressure. Am J Physiol 1985; 248:R208-R213.
18. Iwase K, Takenaka H, Ishizaka I et al. Serial changes in renal function during
laparoscopic cholecystectomy. Eur Surg Res 1993; 25:203-212.
19. Bersten AD, Holt AW. Prevention of acute renal failure in the critically ill patient. Acute
Renal Failure in the Critically Ill, Editors R. Bellomo, C. Ronco. Update in Intensive Care
and Emergency Medicine, No. 20. Springer-Verlag 1995.
20. Chew SL, Lins RL, Daelemans R, et al: Outcome in acute renal failure. Nephrol Dial
Transplant 1993; 8:101-107.
21. Shipley RE, Study RS. Changes in renal blood flow, extraction of inulin, glomerular
filtration rate, tissue pressure and urine flow with acute alterations in renal artery pressure.
Am J Physiol 1951; 167:676-688.
22. Kircheim HR, Ehmke H, Hackenthal E, et al. Autoregulation of renal blood flow,
glomerular filtration rate and renin release in conscious dogs. Pflugers Arch 1987;
410:441-449.
23. Stone AM, Stahl WM. Renal effects of hemorrhage in normal man. Ann Surg 1970;
172:825-836.
24. Adams PL, Adams FF, Bell PD, et al. Impaired renal blood flow autoregulation in
ischaemic acute renal failure. Kidney Int 1980; 18:68-78.
25. Kelleher SP, Robinette JB, Miller F, et al. Effect of hemorrhagic reduction in blood
pressure on recovery from acute renal failure. Kidney Int 1987; 31:725-730.
26. Solez K, Morel-Maroger L, Sraer J-D. The morphology of acute tubular necrosis in
man: Analysis of 57 renal biopsies and a comparison with the glycerol model. Medicine
1979; 58:362-376.
27. Kelleher SP, Robinette JB, Conger JD. Sympathetic nervous system in the loss of
autoregulation in acute renal failure. Am J Physiol 1984; 246:F379-F386.
28. Hesselvik JF, Brodin B. Low dose norepinephrine in patients with septic shock and
oliguria: effects on afterload, urine flow and oxygen transport. Crit Care Med 1989;
17:179-180.
29. Redl-Wenzl EM, Armbruster C, Edelmann G et al. The effects of norepinephrine on
haemodynamics and renal function in severe septic shock. Intensive Care Med 193;
19:151-154.
30. Leithe ME, Margorien RD, Hermiller JB et al. Relationship between central
haemodynamics and regional blood flow in normal subjects and in patients with
congestive heart failure. Circulation 1984; 69:57-64.
31. Fan F-C, Chen RY, Schuessler GB et al. Effects of hematocrit variations on regional
hemodynamics and oxygen transport in the dog. Am J Physiol 1980; H545-H552.
49
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32. Francis GS, Siegel RM, Goldsmith SR et al. Acute vasoconstrictor response to
intravenous furusemide in patients with chronic congestive heart failure. Activation of
neurohumoral axis. Ann Intern Med 1985; 103:1-6.
33. Heyman SN, Brezis M, Epstein FH et al Early medullary hypoxic injury from
radiocontrast and rindomethacin. Kidney Int 1991; 40:632-642.
34. Brezis M, Rosen S, Silva P, Epstein FH. Transport activity modifies thick ascending limb
damage in isolated perfused kidey. Kidney Int 1984; 25:65-72.
35. Gouyon G-B, Guignard J-P. Theophylline prevents the hypoxemic-induced renal
hemodynamic changes in rabbits. Kidney Int 1988; 33:1078-1083.
36. Lin J-P, Churchill PC, Bidani AK. Effects of theophylline on the initiation phase of
postischemic acute renal failure in rats. J Lab Invest 1986; 108:150-154.
37. Lin J-P, Churchill PC, Bidani AK. Theophylline in rats during maintenance phase of
postischemic acute renal failure. Kidney Int 1988; 33:24-28.
38. Erley CM, Duda SH, Schlepckow S et al. Adenosine antagonist theophylline prevents the
reduction of glomerular filtration rate after contrast media application. Kidney Int 1994;
45:1425-1431.
39. Schrier RW, Arnold PE, Van Putten VJ et al. Cellular calcium in ischemic acute renal
failure: role of calcium entry blockers. Kidney Int 1987; 32:313-321.
40. Duggan KA, MacDonald GJ, Charlesworth JA et al. Verapamil prevents post-transplant
oliguric renal failure. Clin Nephrol 1985; 24:289-291.
41. Wagner K, Albrecht S, Neumayer H_H. Prevention of post-transplant acute tubular
necrosis by the calcium antagonist diltiazem: a prospective randomised study. Am J
Nephrol 1987; 7:287-291.
42. Cumming AD, McDonald JW, Lindsay RM et al. The protective effect of thromboxane
synthetase inhibition on renal function in systemic sepsis. Am J Kidney Dis 1989; 13:114119.
43. Neumayer H-H, Wagner K, Groll J et al. Beneficial effects of long-term prostaglandin E2
infusion on the course of post-ischemic acute renal failure: long-term studies in
chronically instrumented conscious dogs. Renal Physiol 1985; 8:159-168.
44. Paller MS, Manivel JC. Prostaglandins protect kidneys against ischemic and toxic injury
by a cellular effect. Kidney Int 1992; 42:1345-1354.
45. Klein AS, Cofer JB, Pruett TL, et al. Prostaglandin E1 administration following orthotopic
liver transplantation: a randomized prospective multicentre trial. Gastroenterol
1996;111:710-715.
46. Mino N, Kobayashi M, Nakajima A et al. Protective effect of a selective endothelin
receptor antagonist, BQ-123, in ischemic acute renal failure in rats. Eur J Pharmacol 1992;
221:77-83.
47. Kon V, Toshimasa Y, Fogo A, Ichikawa I. Glomerular actions of endothelin in vivo. J
Clin Invest 1989; 83:1762-1767.
48. Shaw SG, Weidman P, HodlerJ et al. Atrial natriuretic peptide protects against acute
ischemic renal failure in the rat. J Clin Invest 1987; 80:1232-1237.
49. Sands JM, Neylan JF, Olson RA et al. Atrial natriuretic factor does not improve the
outcome of cadaveric renal transplant. J Am Soc Nephrol 1991; 1:108-1086.
50. Duke GJ, Bersten AD. Dopamine and renal salvage in the critically ill patient. Anaesth
Intensine Care 1992; 20:277-302.
51. Heyman SN, Kaminski N, Brezis M. Dopamine increases medullary blood flow without
improving regional hypoxia. Exp Nephrol In Press.
52. Weisberg LS, Kurnik PB, Kurnik BR. Risk of radiocontrast nephropathy in patients with
and without diabetes mellitus. Kidney Int 1994; 45:259-265.
50
Acute Renal Failure

53. Weisberg LS, Kurnik PB, Kurnik BR. Dopamine and renal blood flow in radiocontrast
nephropathy in humans. Ren Fail 1993; 15:61-68.
51
52
INTENSIVE CARE OBSTETRICS

E. Everest, FRACP
Introduction
The number of pregnant patients admitted to Critical Care units remains small. Some are
due to complications of an existing condition exacerbated by the pregnancy (eg. congenital
heart disease), while others are specifically related to the pregnancy. This review will
concentrate on conditions caused by pregnancy, or attempts to achieve pregnancy. A state of
the art review addressing all aspects of Critical Care in the pregnant patient appeared in the
American Journal of Respiratory and Critical Care Medicine in 1995.1
Pre-eclampsia
Severe pre-eclampsia or eclampsia is the most common pregnancy related complication
leading to admission to Critical Care units. The cause of this unique abnormality in the
maternal vascular endothelium, unlike that seen in any other type of hypertension is not clear.
Numerous terms have been used to describe the disorder. The Australian Society for the
study of Hypertension of Pregnancy recent released a consensus statement on the classification
and management of hypertension in pregnancy.2 They have elected to use the term Preeclampsia so that clinicians do not limit their thoughts to an abnormality of blood pressure in
pregnancy, but rather to a complex multi-system disorder that leads to or from an impaired
placental function and can affect the maternal brain, kidneys, liver, coagulation and cardiac
systems.
Hypertension in pregnancy
The types of hypertension encountered in pregnancy can be
Pre-eclampsia: mild or severe
Chronic hypertension: essential or secondary
Pre-eclampsia superimposed on chronic hypertension
Patients are considered to have hypertension if they have either of the following
1. Systolic blood pressure140 mmHg and /or diastolic blood pressure 90mmHg
(phase IV - muffling - Korotkoff sound)
or
2. Rise in the systolic pressure 25 mmHg and/or rise in the diastolic pressure
15 mmHg from preconception or first trimester readings (confirmed by two
readings six hours apart)
The rise in diastolic pressure is of greater significance, correlating with a sharp rise in perinatal
mortality.3
53
Intensive Care Obstetrics

If hypertension is present, pre-eclampsia exists if the patient has:
1. Hypertension developing after 20 weeks of pregnancy (a rare exception before this
time would be a hydatidiform mole).
2. Normal BP before pregnancy or in the first trimester.
3. Absence of a history of hypertension or renal disease.
4. Return of blood pressure to normal within months post partum.
Is the pre-eclampsia mild or severe?
Severe pre-eclampsia
1. BP >170 mmHg and /or diastolic >110 mmHg
2. Renal
Proteinuria >300g/day or > 2+ on dipstick if 24 hour urinary protein
collection not possible.
Decreased glomerular filtration rate. Serum creatinine > 0.09 mmol/l by
autoanalyser or > 0.07 mmol/l if endogenous creatinine.
3. Hepatic
Epigastric pain.
Elevated bilirubin and/or transaminases.
4. Neurological
Persistent headaches.
Visual disturbances.
Abnormal neurological signs including hyperreflexia and clonus.
5. Haematological
Thrombocytopenia.
Disseminated intravascular coagulation.
Haemolysis
6. Cardiac
Pulmonary oedema.
Mild pre-eclampsia
Pregnant women with hypertension in pregnancy with none of the severe features have mild
pre-eclampsia.
The HELLP (Haemolysis Elevated Liver function and Low Platelets) syndrome and Acute
fatty liver of pregnancy are no longer regarded as distinct syndromes but rather another
presentation within the wide spectrum of pre-eclampsia. Despite this it is still worth
considering Acute fatty liver of pregnancy as a separate abnormality due to its unusual
presentation and prognosis if not recognised.
Elevated serum urate is not a marker of severe pre-eclampsia but is useful in supporting the
diagnosis and the increased foetal risk. Proteinuria is a an indicator of severe pre-eclampsia but
should no longer be considered a prerequisite for the diagnosis.
Pathophysiology
The exact mechanisms that cause pre-eclampsia remain to be elucidated. Known risk factors
include primigravida, a new partner, diabetes, a history of renal disease, hypertension, previous
pre-eclampsia and SLE. The production blocking antibodies or the development of immune
tolerance to the womens partner are thought to play a part as a short sexual cohabitation also
appears to increase the risk.4
54

One of the earliest abnormalities is the failure of the trophoblast to invade completely into
the uterine spiral arteries. This failure of placentation inhibits the cardiovascular adaptations of
increased blood volume and reduced peripheral vascular resistance that occurs in normal
pregnancy. Peripheral vascular resistance is markedly increased and endothelial function is
disturbed in many ways. Prostaglandin homeostasis is shifted with a predominance of
vasoconstrictor prostaglandins such as thromboxane A2 activity over vasodilatory
prostaglandins such PG I2 (Prostacyclin) and PGE2.
The role of tumour necrosis factor (TNF) and endotoxin is not clear. In one study where
increased levels of Interleukin 6 (IL-6) and TNF were found in patients with severe preeclampsia, the authors concluded that the endothelial dysfunction seen could, in part be
contributed to by the excessive release of TNF into the circulation.5 Other authors suggest the
TNF does not contribute to the disease but the raised levels are a consequence of the
pathological process occurring in pre-eclampsia.6
Metabolites of nitric oxide(NO) are low in patients with severe pre-eclampsia suggesting
that decreased production of NO contributes to the changes seen in reactivity of the peripheral
vasculature.7
The nervous system may also play a role the development of the peripheral vasoconstriction
seen in pre-eclampsia. Scobel et al,8 measured the postganglionic sympathetic-nerve activity in
the blood vessels of skeletal muscle by intraneural microelectrodes in nine pre-eclamptic
women, eight normotensive pregnant women, six non pregnant normotensive women and seven
non pregnant women with hypertension. The pre-eclamptic women had significantly higher
sympathetic discharges per minute than the other groups. When repeated 1 - 3 months
following delivery, the discharge rate had fallen to the same levels as found in the controls. The
exact mechanism of the increased sympathetic activity is not clear but it does reinforce the use
of alpha methyldopa, which reduces central sympathetic outflow, for the treatment of
hypertension in pre-eclampsia.
While it had been hoped that the manipulation of endothelial prostaglandin production with
low dose aspirin would be useful in preventing pre-eclampsia, the CLASP study did not
support the use of low dose aspirin in prevention of pre-eclampsia.9
Management
The aim is to prolong the pregnancy to a stage of foetal viability without endangering
maternal health. A number of trials have demonstrated increased neonatal survival and
decreased short and long term morbidity with aggressive conservative treatment.10,11 Blood
pressure should be controlled with the use of methyldopa, beta blockers or nifedipine. ACE
inhibitors should be avoided. The use of diuretics to treat peripheral oedema may cause further
hypovolaemia in patients with an already constricted blood volume.
Acute rises in BP were, until recently, easily controlled by oral or sublingual nifedipine, but
the short acting capsule form has been removed from the market. The options for the
management of acute rises in blood pressure now include hydralazine (but this may mimic
signs of worsening pre-eclampsia); magnesium, diazoxide and sodium nitroprusside.
Magnesium
Magnesium has been extensively used in the USA and some parts of Australia for the
treatment of eclamptic fits. Its ability to prevent fitting in patients with pre-eclampsia, and
recurrent fitting in patients with eclampsia has been recently compared against phenytoin.12,13
In both studies magnesium was shown to be significantly better than phenytoin. However, both
studies did not control for blood pressure and the successful outcome for magnesium group
55

could have been due to its hypotensive effects, with similar results being obtained with
aggressive management of blood pressure by other agents.
Magnesium has little or no anticonvulsant activity, but it is a potent cerebral vasodilator.
The exact causative mechanism of fitting during eclampsia not been established, but ischaemia
secondary to low cerebral blood flow from the intense vasospasm has been suggested. In
patients that remain twitchy, hyperreflexic and have visual symptoms, hypertension should be
controlled aggressively. The use of magnesium for the treatment of hypertension and eclamptic
prophylaxis is widespread in obstetric units in Australia.
Delivery
Pre-eclampsia will only resolve after the baby has been delivered. In severe cases of preeclampsia the choice between operative and vaginal delivery has to be considered. If an
operative delivery is required the use of lumbar epidural anaesthesia with appropriate fluid
loading assists in the control of any hypertension. Low dose aspirin, provided the platelet count
and coagulation are normal, is not a contraindication to epidural anaesthesia. Acute rises in BP
during this phase can be managed by 25mg boluses of diazoxide (not 300mg over 1 minute as
recommended on the pack), or an infusion of nitroprusside. The aim of therapy is to prevent
cerebral complications such as haemorrhage or encephalopathy. The blood pressure should be
reduced to a mean arterial pressure of less than 126 mmHg but greater than 105 mmHg. Foetal
monitoring must occur as any hypotensive treatment may further decrease placental blood flow
resulting in further foetal distress.14 Following delivery of the baby, a more aggressive control
of the blood pressure can be undertaken.
Invasive monitoring of arterial pressures, central or pulmonary capillary wedge pressures
are indicated for patients with on going difficult to control blood pressure, marked renal
impairment associated with oliguria and pulmonary oedema. The use of methyldopa or
clonidine should also be considered, especially in patients with renal failure where the on going
use of magnesium and thiocynate toxicity from nitroprusside may limit there use. While in
theory ACE inhibitors should be useful, clinical experience has shown that in the early post
partum stages they do not contribute significantly to blood pressure control.
Acute Fatty Liver of Pregnancy (ALP)
ALP is characterised by the accumulation of microvesicular fat in the hepatocytes. The
traditional incidence is quoted as 1:13,000, but with the introduction of automated biochemistry
analysers the incidence is probable lower with more mild cases now being detected. The
symptoms begin in the mid to late part of the third trimester and include;
Nausea and vomiting.
Right upper quadrant or epigastric pain.
Intense thirst and associated polyuria.
Jaundice.
The intense thirst and polyuria is due to a transient diabetes insipidus, the cause of which is
unknown. Possible mechanisms include; activation of a normally inactive enzyme or increased
production of vasopressinase from the placenta with decreased metabolism of the enzyme
secondary to the liver failure. These mechanisms result in decreased circulating ADH levels
and diabetes insipidus. The vasopressinase theory is strengthened by the success of DDAVP,
which is resistant to the action of vasopressinase, when used in treating these patients.15
In the later stages there can be renal failure, DIC and development of fulminant hepatic
failure. Glucose metabolism can be markedly impaired with profound and prolonged
hypoglycaemia. The hypoglycaemia maybe one of the strongest contributors to foetal death and
56

often persist for many days after all other liver function tests have returned to normal. Liver
transplantation is required at times.
Management
Correct any hypoglycaemia
Deliver the baby.
Treat any coagulopathy, hepatic encephalopathy in the usual manner. Consider
transfer to a liver transplant unit.
Ovarian Hyperstimulation Syndrome (OHSS)
Ovarian hyperstimulation syndrome has emerged with the development of reproductive
technology and pharmacological ovarian stimulation. While mild cases require little more than
observation severe cases often require intensive care for hypovolaemic shock, renal failure or
hypoxia secondary to pleural effusions. OHSS is classified into five grades
Grade one. Mild hyperstimulation with ovarian diameter of 5-12 cm,

abdominal distension and discomfort.
Grade two. Grade one symptoms plus nausea or vomiting.
Grade three. Features of Grades 1 and 2 plus ultrasonic evidence of ascites.
Grade four. Grade three features plus clinically apparent ascites with or without
pleural effusions or dyspnoea.
Grade fiveis characterised by additional changes in blood volume,

haemoconcentration, coagulation abnormalities and reduced renal
perfusion and function.
Grades four and five are severe OHSS. The renal failure seen in grade five is probably due
to a combination of hypovolaemia plus decreased renal perfusion from to raised intra
abdominal pressure. Severe cases are also at risk of deep venous thrombosis as a consequence
of the haemoconcentration.
The mode of ovarian stimulation influences the incidence of OHSS. The use of
gonadotrophin-releasing-hormone-agonist leads to substantially higher preovulatory oestradiol
concentrations and more frequent and severe hyperstimulation. The disease can be prevented by
identification of at risk patients, such as women with polycystic ovarian syndrome, high serum
oestradiol levels above 4,000pg/ml before HCG administration, multiple follicle development
(>35) and in young patients with lean body habitus.16
The pathophysiology of OHSS is not well understood.. Capillary permeability of the
mesothelium is markedly increased, and although the frequency of OHSS is correlated with
levels of oestradiol, administration of large doses of oestrogen fail to produce the syndrome. A
Melbourne group has proposed high levels of the cytokine ,vascular endothelial growth factor
(VEGF) maybe implicated17 while others suggest that angiotension II and prorenin may play a
role.
Management
Prevention: If high levels of oestradiol and multiple follicles are present, ovulation is either
abandoned or a reduced dose of hCG used. A decreased incidence has been reported with the
use of an albumin infusion immediately after oocyte retrieval.18
Treatment: Mild cases can usually managed with bed rest, and diuretics. Severe cases of
hypotension require volume resuscitation and DVT prophylaxis. For the less severe cases there
is some debate between a conservative approach using plasma expanders, diuretics and
dopamine infusions, and a more aggressive approach including drainage of pleural effusions
57

and ascites. However, at times drainage of ascites and pleural effusions for symptomatic relief
of dyspnoea or pain maybe required during a conservative approach.19 As the ovarian size may
increase dramatically, ascitic pockets should be identified with ultrasound before undertaking
paracentesis. Most cases settle within 4-6 days.
REFERENCES
1. Lapinsky S, Krucynski K, Slutsky, A. Critical Care in the pregnant patient. Am J Respir
Crit Care Med 1995;152:427-455
2. Working Party on behalf of the council of the Australasian Society for the Study of
Hypertension in Pregnancy (ASSHP). Management of hypertension in pregnancy.
Consensus statement. 1994
3. MacGillivary I. Pre-eclampsia. The hypertensive disease of pregnancy. W. B. Saunders.
London 1983:174-190.
4. Robillard P, Hulsey T, Perianin J, Janky E, Miri E and Papiernik E. Association of
pregnancy induced hypertension with duration of sexual cohabitation before conception.
Lancet 1994; 344: 973-75.
5. Vince G, Starkey P, Austgulen R, Kwiatkowski D, Redman C. Interleukin-6, tumour
necrosis factor and soluble tumour necrosis factor receptors in women with pre-eclampsia.
Brit J Obstet Gynaecol 1995;102: 20-25
6. Meekins J McLaughlin P, West D, McFadyen I, Johnson P. Endothelial cell activation by
tumour necrosis factor alpha(TNF-alpha) and the development of pre-eclampsia. Clin Exp
Immunol 1994, 98: 110-4.
7. Seligman S, Buyon J, Clancy R, Young B, Abramson S. The role of nitric oxide in the
pathogenesis of pre-eclampsia. Am J Obstet Gynecol 1994; 171: 944-98.
8. Schobel H, Fischer T, Heuszer K, Geiger H, Schimieder R. Pre-eclampsia- a state of
sympathetic overactivity. N Engl J Med 1996; 335: 1480-85.
9. Collaborative low dose aspirin study in pregnancy (CLASP). CLASP A randomised trial
of low dose aspirin for the prevention and treatment of pre-eclampsia among 9364
pregnant women. Lancet 1994; 343:619-29.
10. Sibai BM, Mercer BM, Schiff E, Friedman S. Aggressive or expectant management of
severe pre-eclampsia at 28 to 32 weeks gestation: a randomised trial. Am J Obstet
Gynecol 1994; 171:818-22
11. Odendaal H, Pattinson R Bam R, Grove D, Kotze T. Aggressive or expectant management
for patients with severe pre-eclampsia between 28-34 weeks gestation: a randomised
controlled trial. Obstet Gynecol 1990, 76: 555-58.
12. The eclampsia trial collaborative group. Which anticonvulsant for women with eclampsia?
Evidence from the collaborative eclampsia trial. Lancet 1995; 345: 1445-63.
13. Lucas M, Leveno K, Cunningham F. A comparison of magnesium sulfate with phenytoin
for the prevention of eclampsia. N Engl J Med 1995; 333:201-5.
14. Siai B. Treatment of hypertension in pregnant women. N Engl J Med 1996; 335: 257-65.
15. Kennedy S, Hall P, Seymour A, Hague W. Transient diabetes insipdus and acute fatty
liver of pregnancy. Brit J Obstet Gynecol 1994, 101:387-391.
16. Mukherjee D, Lange P, Sferry C, Joseph J, Mehta A. Dyspnea, cough and chest pain in a
pregnant women. Chest 1995, 107: 1460-62.
17. Robertson D, Selleck K, Suikkari A, Hurley V, Moohan J, Healy D. Urinary vascular
endothelial growth factor concentrations in women undergoing gonadotrophin treatment.
Hum Reprod 1995; 10:2478-82.
58

18. Shalev E, Giladi Y, Matilsky M, Ben-Ami M. Decreased incidence of severe ovarian
hyperstimulation syndrome in high risk in-vitro fertilization patients receiving intravenous
albumin: a prospective study. Hum Reprod 1995;10:1373-76.
19. Moriss R, Miller C, Jocobs L, Miller K, Conservative management of ovarian
hyperstimulation syndrome. J Reprod Med 1995; 40: 711-77.
59
60
SEDATION, ANALGESIA AND RELAXANTS IN THE INTENSIVE

CARE PATIENT
L.I.G. Worthley, FRACP, FANZCA, FFICANZCA
Consultant Intensivist,
Analgesics are agents that reduce the sensation of pain without producing a loss of
consciousness. Hypnotics are agents that produce a condition of insensibility from which
arousal by physical stimulation may be achieved easily. Sedatives are agents that may relieve
the patients anxiety without making the patient excessively drowsy. Tranquillisers are agents
used to calm agitated and delirious patients without causing excessive drowsiness1.
These agents are used singly or in combination in intensive care patients to treat, pain,
delirium, acute confusional states, and to facilitate mechanical ventilation (i.e. to allow the
patient to tolerate an endotracheal tube and to facilitate patient synchronization with the
ventilator).
ANALGESICS
Opioids
There are specific sites on cell surfaces of the gastrointestinal tract, central nervous system,
peripheral sensory nerves and in the substantia gelatinosa of the spinal cord which interact in a
highly selective fashion with opioid drugs. These receptors mediate the major known
pharmacological actions of opioids and the functions of endogenous opioid-like substances,
and are known as opioid receptors. The mammalian brain contains peptides known as the
enkephalins and endorphins, which interact with opioid receptors and have pharmacological
properties similar to those of morphine2. In the substantia gelatinosa, enkephalin secreting
neurones terminate presynaptically on pain mediating primary afferent fibres, inhibiting the
release of the neurotransmitter, substance P, to the dorsal horn spinothalamic neurone. There
are also important links between the opioid pathways and noradrenaline and serotonergic
pathways, with selective alpha 2 agonists (e.g. clonidine), noradrenaline uptake inhibitors (e.g.
desimipramine) and serotonin uptake inhibitors and release facilitators (e.g. tramadol),
enhancing the effect of opioid analgesia3.
The major opioid receptor subtypes (mu, delta and kappa) are coupled to intracellular
processes via G proteins. Mu and delta receptors operate through the potassium channel,
whereas the kappa receptor operates through the calcium channel4. The previously described
sigma receptors are most likely due to N-methyl-D-aspartate receptor activity. The clinical
effects of opioid receptor stimulation, the opioid subtypes, and the receptor subtype agonists
and antagonists are listed in Table 15.
Opioid peptides
The opioid peptides (i.e. enkephalins, endorphins and dynorphins) originate from the three
prohormones of pro-enkephalin (producing methionine enkephalin, and leucine enkephalin),
pro-opiomelanocortin (producing beta-endorphin) and pro-dynorphin (producing dynorphin A
and dynorphin B). The enkephalins are found in the gastrointestinal tract (particularly the
61
Sedation, Analgesia and Relaxants in the ICU

myenteric plexus), substantia gelatinosa of the spinal cord and adrenal medulla. Beta-endorphin
(and melanocyte-stimulating hormone and ACTH) are isolated from the hypothalamusneurohypophysis and are produced from the prohormone, pro-opiomelanocortin. The
dynorphins are found in both spinal and central nervous tissue and in the gastrointestinal tract.
The enkephalins and most of the endorphins are, on a molar basis, about as active as morphine
whereas beta-endorphin is five to 10 times more potent than morphine.
Table 1 Clinical and pharmacological characteristics of the opioid receptors
Receptor
Mu
Kappa
Delta
Clinical effects
Analgesia (supraspinal)
Respiratory depression
Depression temp regulation
Miosis
Euphoria
Physical dependence
Analgesia (spinal)
Sedation
Miosis
Little or no resp depression
Agonist
Antagonist
Met-enkephalin
Beta-endorphin
Morphine
Naloxone
Pentazocine
Nalorphine
Dynorphins
Naloxone
Butorphanol
Morphine
Nalorphine (partial)
Pentazocine
leu-enkephalin
Naloxone
Beta-endorphin
? Respiratory depression
Opioid analgesics
Action: Opioid analgesics (or narcotics) reproduce some of the effects of the endogenous
opioid peptides. Their clinical effects include the following.
1. CNS effects.
Analgesia: the sites of action for analgesic effects are located principally in the
brainstem and the spinal cord. The degree of pain relief is related to the dose of opioids,
intensity and type of pain, and patient's perception of pain. Opioids tend to preserve the
perception of pain, whilst the threshold of pain tolerance is increased (particularly for
visceral rather than musculoskeletal pain).
Dysphoria, drowsiness, sedation and coma: these effects are often dose dependent.
Nausea and vomiting: these effects are due to chemoreceptor trigger zone stimulation.
Miosis: this is due to direct stimulation of the Edinger-Westphal nucleus (as a rare
phenomenon, dilated pupils with morphine toxicity has been described6).
Excitatory effects: agitation and delirium may occur due to excessive N-methyl-Daspartate receptor stimulation (although rare, it is more commonly observed with
pethidine, pentazocine and fentanyl)
Physical and psychological dependence: these effects are common with recreational use
of opioids.
2. CVS effects. venous capacitance is often increased both directly and indirectly (e.g. due
to histamine release). Both morphine and pethidine release histamine causing pruritus, urticaria,
hypotension and a decrease in the systemic vascular resistance. The histamine-release effect is
not blocked by naloxone. Fentanyl does not release histamine or decrease blood pressure even
in large doses. While it is commonly believed that opioids have a direct vagal effect, this has
62

recently been disputed7. Opioids have no direct chronotropic or inotropic effects in clinical
doses8.
3. Respiratory effects. Opioids decrease the respiratory rate, respiratory tract mucus
secretion, and the cough reflex.
4. Gastrointestinal effects. Opioids commonly cause gastrointestinal stasis (and therefore
when prescribed to relieve musculoskeletal pain they are often used with 10 - 20 ml lactulose or
sorbitol 70% 12-hourly). They can also increase sphincter muscle tone of the pylorus and
sphincter of Oddi, causing right hypochondrial and epigastric pain, respectively, both of which
may be relieved by nitrates or opioid antagonists. Nausea and vomiting are CNS effects.
5. Musculoskeletal effects. All opioids may produce muscle rigidity. However, it is most
commonly observed with fentanyl, and may even occur 2 - 24 h postoperatively after apparent
recovery from anaesthesia9. It is often truncal and, if severe, can produce opisthotonos and
even respiratory failure due to a severe reduction in chest-wall compliance.
6. Cutaneous effects. Peripheral vasodilation, urticaria, and pruritus are histamine release
effects. Piloerection is a nonspecific opioid effect.
Indications: The opioid analgesics have been used for euphoric, antidepressant and
hypnotic purposes for many years, although their addictive properties have limited their
therapeutic indications to analgesic, antidiarrhoeal and antitussive roles.
Dosage: The dosage and pharmacokinetics of the commonly used opioid analgesics are
shown in Table 2. Hepatic biotransformation is the primary route of elimination of opioids.
Morphine, pethidine, and codeine are metabolized to active compounds that are excreted by the
kidney, thus modification of doses of these agents are required in patients with renal failure.
Approximately 65% of morphine is metabolized to morphine-3-glucuronide, which has no
activity, 10% is metabolized to morphine-3-etherial sulphate, 5% to normorphine, 5% to
morphine-6-glucuronide, and small amounts are metabolized to morphine oxide and codeine.
Morphine-6-glucuronide is an active metabolite which has a potency of up to 40 times that of
morphine10. The elimination half-life of morphine-6-glucuronide is normally 2-4 h; however, in
patients with renal failure, it is increased to 100 h, and may be associated with prolonged
narcosis in critically ill patients11.
Norpethidine is the only active metabolite of pethidine. It has an elimination half-life that is
extended from 2 - 4 h to 34 h with renal failure, which may account for the mixed picture of
stupor, twitching, tremor and convulsions reported in patients with renal failure and prolonged
pethidine administration12. Pethidine and norpethidine are the active metabolites of
phenoperidine.
While 100 g of intravenous fentanyl has an analgesic equivalence of 10 mg of morphine,
this effect will last for 30 min only, due to redistribution. The volume of distribution of fentanyl
is 4 l/kg; thus 300 g saturates the volume of distribution in a 70 kg man, producing an
effective therapeutic level of 1 g/l. However, the therapeutic half-life increases to 2 - 4 h with
doses greater than 300 g due to the saturation of the volume of distribution and an elimination
half-life of 2-4 h13.
Side-effects: All opioids share the side-effects of respiratory depression, cough suppression,
reduced intestinal mobility, nausea, vomiting, and urinary retention. Tolerance to their effects
and both physical and psychological dependence may also develop.
63

Table 2
Pharmacokinetics of the common opioid analgesics

Therapeutic elimination
equivalence
half
life (h)
Natural
Morphine
Codeine
Semisynthetic
Pethidine
Synthetic
Phenoperidine
Fentanyl
Alfentanyl
Pentazocine
duration plasma
Dose/70 kg
of action protein
IM
IV infusion
(h)
binding (%) (mg/4h) (mg/h)
10
120
3-4
3-4
2-4
2-4
35
7
10
1-5
100
3-4
2-4
65
100
25 - 50
1
0.1
0.4
15
3-4
3-4
1-2
3-4
1-2
0.5 - 1
0.25 - 0.5
2-4
65
83
91
60
0.5 - 1
0.05 - 0.3
0.1 - 4
10
Opioid antagonists
Opioid antagonists bind to opioid receptors without activating the receptor. Partial opioid
agonists (i.e. opioid agonist/antagonists) have an intermediate effect.
Naloxone is a pure antagonist with no agonist activity, it reverses the analgesia, respiratory
depression, sedative and miosis associated with opioids. Its effect, if administered
intravenously (e.g. 0.1 - 0.4 mg), begins in minutes and lasts for 15 - 90 min. It has also been
reported to reverse the respiratory depression associated with diazepam14 and ethanol
toxicity15. Naloxone, in doses of 10 - 20 mg, has also been used with some success in septic
shock16. However, it may cause hypertension, pulmonary oedema, and ventricular fibrillation
when administered to antagonize the effect of prolonged opioid administration17
Opioid withdrawal
During opiate withdrawal, the first 8 - 16 h of abstinence is usually uneventful. Over the
next few hours there is excessive yawning, lacrimation, diaphoresis, rhinorrhoea, insomnia,
agitation, tremor, waves of 'goose flesh', hot and cold flushes, tachycardia, hypertension, joint
and muscle aches, abdominal pain, nausea, vomiting, diarrhoea and pyrexia. The symptoms
peak at 48 - 72 h then slowly subside over 5 - 10 days.
Paracetamol and non-steroidal anti-inflammatory drugs
Non-steroidal anti-inflammatory drugs (NSAIDs) are a large group of structurally diverse
organic acids which reversibly (the acetylation of cyclooxygenase by aspirin is an exception as
it is irreversible) inhibit prostaglandin synthesis and cause analgesic, antipyretic, antiplatelet
and anti-inflammatory therapeutic effects and gastric mucosal damage and renal dysfunction
side effects18. While paracetamol also inhibits cyclooxygenase and has analgesic and
antipyretic actions it has no antiplatelet and anti-inflammatory actions and does not cause
gastric mucosal damage.
Indications: Analgesia (particularly for dental pain, headache and musculoskeletal pain),
antipyretic effects, anti-inflammatory effects (for rheumatic and connective tissue diseases),
antiplatelet effects (for TIAs, post coronary artery bypass surgery, ischaemic heart disease),
prophylactic effects (pre eclampsia, colon carcinoma) and other rare disorders (e.g. closure of
patent ductus, Bartter's syndrome). Paracetamol (1 g, 4-hourly) is the antipyretic and
musculoskeletal analgesic agent of choice in the acutely ill patient. While aspirin and
64

indomethacin have potent analgesic and antipyretic actions, the side effects of gastric mucosal
damage (in patients who are at risk of acute gastric erosions) and renal dysfunction (in patients
who are at risk of acute renal failure) make these agents hazardous in the acutely ill patient.
Dosage: The dosage and pharmacokinetic data for paracetamol and the commonly used
NSAIDs are given in Table 3. The agents are often taken with food and in divided dosage (i.e.
4 to 12-hourly).
Table 3
Pharmacokinetics of paracetamol and common NSAIDs

elimination
half
life (h)
duration plasma
Formulation
of action protein
(mg/tab)
(h)
binding (%)
Paracetamol
Aspirin
Diclofenac
Diflunisal
Ibuprofen
Indomethacin
2
0.25*
1.1
13
2.1
4.6
4-8
4 - 8**
4-8
12 - 24
4-8
6 - 12
20
70
99
99
99
90
Ketoprofen
Naproxen
Piroxicam
Sulindac
1.8
14
57
14
4-8
12 - 24
24
12 - 24
95
99
99
96
Dose/70 kg
Oral
(mg/24h)
500
2000 - 4000
100 -325
600 - 2600
25 - 50
75 - 150
250
500 - 1000
200 - 400
1200 - 1600
25
50 - 200
100 (suppository)
50 - 100
100 - 200
250 - 500
375 - 1000
10
10 - 20
100 - 200
200 - 400
* Half life of active metabolite (i.e. salicylic acid) is 2 - 30 h

** antiplatelet action 8 days
Side-effects: Gastrointestinal damage occurs with all NSAIDs (ibuprofen has the lowest
incidence) due to a reduction in mucosal prostaglandin production (particularly PGE2 which
inhibits acid secretion and can accelerate ulcer healing). Dyspepsia and heartburn are common
symptoms although the mucosal damage may be so severe that peptic ulceration, haemorrhage
and perforation occurs. NSAIDs also impair renal function in patients who are at risk (e.g.
patients with shock, septicaemia or dehydration) and should be used cautiously in these
circumstances.
Other side effects include, hypertension, hyperkalaemia, interstitial nephritis, erythema
multiforme, urticaria, hepatitis, nausea, headache, dizziness, agitation, hallucinations, asthma,
pulmonary oedema, anaphylactoid reactions, aplastic anaemia, haemolytic anaemia,
neutropenia and thrombocytopenia19. In general paracetamol rather than NSAIDs is most often
used for adults with peptic ulcer disease as well as in children (due to the very small risk of
Reye's syndrome associated with NSAIDs in children).
65

SEDATIVES
Benzodiazepines
Action: Benzodiazepines act by combining with the benzodiazepine (BZ) receptor, which in
turn enhances the effect of GABA on the chloride channel, so that chloride ions enter the cell to
increase the resting membrane potential and inhibit excitation. Both GABA and
benzodiazepines attach to the GABA and BZ receptor, respectively, at the cell surface. By
themselves, benzodiazepines do not open the Cl- channel or cause neuronal inhibition. The BZ
receptor has five groups of ligands; agonists, partial agonists (e.g. conventional
benzodiazepines), inverse agonists (i.e. agents that bind with high affinity to the BZ receptor
but which cause effects which are opposite to agonists, e.g. anxiety and seizures), partial
inverse agonists (i.e. agents that do not cause convulsions by themselves but which potentiate
the convulsive properties of other agents) and antagonists (i.e. agents that bind competitively
with the receptor and inhibit the effects of both agonists and inverse agonists, e.g.
flumazenil)20.
Agonists and inverse agonists are believed to induce different conformational changes in
the receptor, leading to increased and decreased GABA-mediated neurotransmission,
respectively, whereas antagonists are thought to stabilize the receptor in a predominantly
neutral state and so prevent functionally important conformational changes21. Barbiturates
potentiate GABA mediated inhibition by a more direct action with the Cl- ionophore,
increasing the time the channel is open, contrasting with benzodiazepines which appear to
increase the frequency of channel openings.
Indications: Benzodiazepines are often used for antianxiety, anticonvulsant, sedative,
centrally-mediated muscle relaxant and amnesic purposes. Clinical indications for these agents
include treatment of anxiety, panic attacks, insomnia, seizures, muscle spasm, spasticity,
alcohol withdrawal and as an anaesthetic agent (i.e. premedication, induction agent, anaesthetic
agent for endoscopy, or sedative agent for mechanically ventilated patients).
Dosage: The dosage and pharmacokinetic data for the commonly used benzodiazepines are
given in Table 4. Diazepam has a prolonged sedative effect because it is metabolized to the
active compounds of desmethyldiazepam (which has a half-life of up to 3 days), 3hydroxydiazepam and oxazepam. These metabolites are finally conjugated to inactive watersoluble glucuronides and excreted. Lorazepam undergoes direct conjugation to inactive
glucuronides. The water soluble agent, midazolam, is hydroxylated by a hepatic cytochrome
P450 to -hydroxymidazolam which is conjugated to -hydroxymidazolam glucuronide and
eliminated by the kidney; -hydroxymidazolam glucuronide is generally thought to be
pharmacologicaly inactive. In one study where midazolam was used to produce basal sedation,
using 0.3 mg/kg over 30 min (20 mg/70 kg) followed by an infusion at 0.06 mg.kg-1.h-1
(4 mg/70 kg), accumulation of the drug effect was not noted and normalization of mental state
occurred 1.5 h after discontinuing the infusion22. However, in five patients with renal failure,
prolonged sedation after the administration of midazolam (which was reversed by flumazenil)
was associated with high concentrations of -hydroxymidazolam glucuronide and
subtherapeutic concentrations of the uncongugated metabolite and the parent drug, indicating
that the conjugated metabolites of midazolam probably have substantial pharmacological
activity23.
In intensive care patients or patients with hepatic disease the half-lives of the parent drug of
all benzodiazepines generally increase by up to two to three times (i.e. the half-life of diazepam
66

may increase up to 10 days and the half-life of midazolam may increase up to 10 h in the
critically ill patient).
Side effects: Because of dependence and the undesirable effects of tachycardia, agitation,
sweating, nausea, tremor, depression, hallucinations, and seizures, with withdrawal of longterm benzodiazepine therapy, benzodiazepines are only given on an occasional basis.
Table 4
Pharmacokinetic data for the commonly used benzodiazepines
Drug
therapeutic
equivalence
Diazepam
Flurazepam
Clonazepam
Nitrazepam
Lorazepam
Alprazolam
Temazepam
Oxazepam
Midazolam
Flumazenil
10
elimination
half-life (h)
plasma protein
binding (%)
20
5
20 - 40
20 - 40
20
20
15
15
10
6
2-5
96
1-5
40
0.1
2.5
98
Dosage
IV (mg/70 kg/h)
2 - 10
0.25 - 0.5
90
0.5-2
98
Benzodiazepine antagonists
Flumazenil has an elimination half-life of 1 h, and in large doses may have an intrinsic (i.e.
agonist or reverse agonist) activity. With intravenous administration of 0.5 - 1 mg, complete
reversal of the benzodiazepine effect is apparent after 5 min, and the duration of action varies
from 15 - 140 min depending on the dose. In the presence of long-acting benzodiazepines, a
continuous infusion of 0.1 - 0.4 mg/70 kg/h of flumazenil may be used to maintain a state of
alertness. It has been used to reverse benzodiazepine sedation associated with, weaning patients
from mechanical ventilation, reversing anaesthesia (e.g. endoscopy anaesthesia), and treating
overdosage. It has also been used to reverse hepatic encephalopathy and alcohol intoxication24.
The side-effects associated with flumazenil are usually mild and include agitation, nausea
and vomiting. However, malignant side effects have also been reported and include deaths
which were probably due to partial or ineffective reversal of respiratory depression25,
convulsions in patients in whom epilepsy had been controlled by benzodiazepines26 or when
used to treat a combined tricyclic and benzodiazepine overdosage27, and seizures with
ventricular tachycardia when used to treat combined tricyclic28 or chloral hydrate29, and
benzodiazepine overdosage.
Barbiturates
Thiopentone and phenobarbitone have been used as a sedative agent in the critically ill
patient, particularly when a reduction in the cerebral oxygen consumption and ICP may be
desirable (e.g. neurosurgical patients). A dosage of 15 - 20 mg/kg (i.e., 1000 - 1500 mg/70 kg)
will saturate the distribution space for thiopentone. Thus a continuous infusion of thiopentone
at 2 - 4 mg.kg-1.h-1 (i.e. 150-300 mg/70 kg/h) should keep a plasma level at 10-15 mg/l. As the
half-life of thiopentone is 5 - 12 h, to reduce the plasma level by 95% will take 1 - 2 days, and
with hepatic or cardiac failure this may increase up to 7 days.
67
Propofol
Propofol is a non water soluble agent formulated as an aqueous emulsion in a 1% Intralipid
solution. It may be used as an induction agent (e.g. 2 - 2.5 mg/kg or 150 - 175 mg/70 kg,
usually titrated at 40 mg every 10 s until the patient shows signs of anaesthesia), anaesthetic
agent (e.g. 6 - 12 mg.kg-1.h-1 or 400 - 800 mg/70 kg/h) or as a sedative agent (e.g., 1.5 - 6
mg.kg-1.h-1 or 100 - 400 mg/70 kg/h) in the intensive care patient. It has no anticonvulsant or
analgesic effects and may even provoke epilepsy in an epileptic patient30. Propofol is excreted
in the urine as 1-glucuronide, 4-glucuronide and 4-sulphate conjugates of 2,6-di-isopropyl-1,4quinol which may produce green urine with prolonged infusions31.
The major advantage of propofol is the rapid speed of recovery in comparison to other
agents. In a two-compartment model, the elimination half-life is 100 - 300 min; it is 98% bound
to plasma proteins.
Propofol produces a dose-dependent reduction in blood pressure, predominantly due to a
fall in systemic vascular resistance, which may present as a profound reduction in blood
pressure in the critically ill and elderly patient. While it appears to have no significant
adrenocortical function inhibition, and has the advantage of rapid reversal when discontinued,
propofol as a single sedative agent used for 3 or more days has been associated with metabolic
acidosis, bradycardia, progressive and unresponsive myocardial failure, lipaemic serum and
death, in five paediatric intensive care patients32.
The lipid base of propofol supports bacterial growth when contaminated, and infectious
complications have occurred due to bacterial contamination of propofol infusions, particularly
when 50-100 ml ampoules have been used as multidose vials33. It is recommended that the
unused portion of a propofol infusion should be discarded after 6 h after initial use (or within
12 h if administered directly from the vial for sedation in an intensive care unit)34.
Ketamine
Ketamine is a phencyclidine derivative with NMDA receptor antagonist and opioid receptor
agonist effects (as well as calcium channel, muscarinic receptor, and serotonin receptor
activities), providing analgesic as well as sedative effects35. An intravenous infusion of 3 -15
g/kg/min has been used in intensive care patients (particularly when severe bronchospasm or
shock exists)36.
TRANQUILIZERS
Phenothiazines
These are DA1 and DA2 dopamine receptor blockers, which may block muscarinic, alpha1-adrenergic and H1 histamine receptors as well. Their antipsychotic activity is due largely to
their DA2 dopamine receptor blocking effect in the limbic system.
Chlorpromazine is the standard phenothiazine tranquilliser. An initial oral or intramuscular
dose of 50 - 100 mg is commonly administered to manage an agitated patient and its effect is
usually assessed 1 h later. If required, further doses of 50 - 100 mg may be administered hourly.
While up to 1000 mg has been used in some severely disoriented patients, if 400 - 600 mg does
not produce the desired effect, then supplemental doses of a benzodiazepine (e.g. diazepam 2 10 mg) will act synergistically and produce profound sedation which often lasts for 24 - 48 h.
While an intravenous bolus dose of 2.5 - 10 mg of chlorpromazine often causes severe
hypotension, an intravenous infusion at 10-20 mg/h usually does not, and can be used safely.
The elimination half-life of chlorpromazine is 24 - 48 h.
68

The side-effects of phenothiazines include dry mouth, constipation, urinary retention and
blurred vision (due to a muscarinic receptor blocking effect) and hypotension and hypothermia
(due to an alpha-1-adrenoreceptor blocking effect). Parkinsonian side-effects occur due to
nigrostrial dopamine-receptor blockade which may cause acute extrapyramidal effects (e.g.
oculogyric crisis or akathisia, which may be treated with intravenous benztropine 1 - 2 mg) or a
late-onset, tardive dyskinesia37. The other side effects include QTc interval prolongation with
torsades de pointes, malignant neuroleptic syndrome, leucopenia, eosinophilia, cholestatic
jaundice and photosensitivity.
Butyrophenones
Haloperidol is most commonly used butyrophenone in the intensive care unit, although 5 10 mg i.v. may not provide the same sedative effect as chlorpromazine and thus may not be as
effective as chlorpromazine for the severely agitated patient. In one study haloperidol infusions
ranging from 3 to 25 mg/h were used successfully to control agitation in critically ill patients38,
although complete heart block, ventricular tachycardia and QTc prolongation (with the risk of
torsades de pointes) which were also described indicates that this form of therapy may not be
without risk39.
DRUG WITHDRAWAL
Ethyl alcohol
In the acutely ill alcohol-dependent patient, intravenous ethanol (5% ethanol in 5%
dextrose, i.e. 50 ml of 100% alcohol per litre of 5% dextrose at 50 - 100 ml/h) has been used
successfully, for both delirium tremens prophylaxis and for pre-delirium tremens agitation. The
serum ethanol levels are reportedly low or unmeasurable and patients are usually able to be
weaned from the mixture after 3 - 7 days40. Oral and intravenous methadone, nicotine patches,
and caffeine infusions have also been used for agitation prophylaxis in the acutely ill drug and
substance dependent patient.
Propranolol
The sympathetic effects of acute agitation following withdrawal of sedative drugs
(e.g. tachycardia, hypertension, diaphoresis) have been treated successfully with beta-blockers
(e.g. propranolol 40 - 80 mg orally 4 hourly, or 5 mg intravenously 2- to 4-hourly).
SEDATION (AND RELAXATION) IN THE INTENSIVE CARE UNIT
Intermittent doses or continuous infusions of opioids (e.g. morphine, pethidine or
phenoperidine), benzodiazepines (e.g. diazepam, midazolam or lorazepam), propofol,
phenothiazines (e.g. chlorpromazine), butyrophenones (e.g. haloperidol), barbiturates (e.g.
thiopentone, phenobarbitone), NMDA receptor antagonists (e.g. ketamine) or neuromuscular
blockers (e.g. pancuronium, atracurium, or vecuronium) are used in varying combinations and
in varying amounts by different intensive care units41. Generally these agents are used to
control patients who are being mechanically ventilated to provide a state of consciousness
where the patient is asleep but easily arousable and comfortable, without necessarily being
completely pain free (i.e. a sedation-agitation scale of 0. Table 5) although, an assessment of
the reasons for the agitation (e.g. discomfort or pain from surgery, trauma, an acute abdomen,
the endotracheal tube, hypoxia, hypercapnoea, etc) should always be performed first to
consider appropriate therapy. The use of neuromuscular blocking agents to manage the
ventilator dependent patient is undesirable because they do not sedate, relieve anxiety or reduce
69

pain and they put patients at risk should they become disconnected from the respirator.
Furthermore, when using these agents there is an increased incidence of deep vein thrombosis,
peripheral nerve injury and pressure sores from careless positioning. The patient is also unable
to cough with endotracheal suction (i.e. pulmonary sputum clearance is reduced), and
prolonged weakness caused by an acute diffuse myopathy (particularly when administered with
corticosteroids) may occur42.
Table 5
Sedation-agitation scale*
Score
Description
Example
+3
Immediate threat to safety Pulling at endotracheal tube
or catheters, trying to climb over
bedrail, striking at staff.
+2
Dangerously agitated
+1
Agitated or restless
Physically agitated or restless, continually

moves around the bed, attempts to sit up
alms down with verbal instruction.
Calm and cooperative
Calm, arousable, follows commands
-1
Oversedated
Difficult to arouse or unable to attend to

conversation or commands.
-2
Very oversedated
Awakens to noxious stimuli only.
-3
Unarousable
Does not awaken to any stimuli.
Requiring physical restraints

and frequent verbal reminding of limits,
biting endotracheal tube, thrashing from
side to side, sits up.
* modified from Riker RR, et al. Crit Care Med 1994;22:433-440.

Nevertheless, in some patients who are adequately sedated, neuromuscular blockade may
still be required (e.g. tetanus patients). Pancuronium has the disadvantage of producing
tachycardia and, in the critically ill patient, may have a prolonged effect43. Vecuronium has
little effect on the cardiovascular system, although it may also accumulate in the critically ill
patient causing prolonged paralysis44. Atracurium is often preferred in the critically ill patient
because it has little effect on the cardiovascular system and largely undergoes nonenzymatic
degradation to inactive metabolites, without requiring renal or hepatic excretion45. However,
prolonged weakness (when atracurium has been used with corticosteroids) has been reported46
and the possibility of central nervous system toxic effects of the atracurium metabolite
laudanosine (particularly in patients with renal failure), which has been suggested47 (but not yet
reported48), indicates that atracurium is not without hazard.
Agents such as althesin and etomodate are no longer used for sedation in intensive care
because of a high incidence of anaphylactoid reactions with complement activation (due to the
solvent) with the former, and increase in mortality in critically ill patients (with a reduction in
adrenocortical function) in the latter49.
70

To control a mechanically ventilated patient, intravenous midazolam (e.g. 2 - 5 mg/70 kg)
and morphine (e.g. 4 - 10 mg/70 kg), followed by an infusion of a 1:1 mixture of morphine and
midazolam at a rate of 2 - 4 mg/70 kg/hr of morphine and 2 - 4 mg/70 kg/h of midazolam, is
often used. Where rapid reversal of sedation is required, propofol at 50 - 150 mg/70 kg/h with
or without morphine at 2 - 4 mg/70 kg/h50, or alfentanyl (e.g. 0.4 - 1 mg/h) with or without
midazolam51 may be used. Both of these regimens have been used for analgesia and sedation in
intensive care patients with good cardiovascular stability and absence of adrenocortical
depression. If muscle relaxation is also required then atracurium (20 - 30 mg/h), cisatracurium
(7 - 10 mg/h), vecuronium (2-4 mg/h) or pancuronium (2 - 4 mg/h) may be administered as an
intermittent bolus or continuous intravenously infusion, although their use should be assessed
regularly as they should be discontinued at the earliest opportunity.
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Co, 1980
2. Snyder SH. Opiate receptors in the brain. N Engl J Med 1977;296:266-271.
3. Koski G. Off the beaten path: emerging issues in the pharmacology and physiology of
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4. McQuay HJ. Opioids in chronic pain. Br J Anaesth 1989;63:213-226.
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6. Shelly MP, Park GR. Morphine toxicity with dilated pupils. Br Med J 1984;289:10711072.
7. Semenkovich CF, Jaffe AS. Adverse effects due to morphine sulphate: challange to
previous clinical doctrine. Am J Med 1985;79:325-431.
8. Maltby JR, Williams RT Jr. Morphine-induced cardiac pain. Anesthesiology 1986;64:527528.
9. Mirenda J, Tabatabai M, Wong K. Delayed and prolonged rigidity greater than 24 h
following high-dose fentanyl anesthesia. Anesthesiology 1988;69:624-625.
10. Osborne R, Joel S, Trew D, Slevin M. Analgesic activity of morphine-6-glucuronide.
Lancet 1988;i:828.
11. Osborne RJ, Joel SP, Slevin ML. Morphine intoxication in renal failure: the role of
morphine-6-glucuronide. Br Med J 1986;292:1548-1549.
12. Chan GLC, Matzke GR. Effects of renal insufficiency on the pharmacokinetics and
pharmacodynamics of opioid analgesics. Drug Intell Clin Pharm 1987;21:773-783.
13. Aitkenhead AR. Analgesia and sedation in intensive care. Br J Anaesth 1989;63:196-206.
14. Bell EF. The use of naloxone in the treatment of diazepam poisoning. J Pediat
1975;87:803-804
15. Sorensen SC, Mattisson K. Naloxone as an antagonist in severe alcohol intoxication.
Lancet 1978;ii:688-689.
16. Groeger JS, Carlon GC, Howland WS. Naloxone in septic shock. Crit Care Med
1983;11:650-654.
17. Prough DS, Roy R, Bumgarner J, Shannon G. Acute pulmonary oedema in healthy
teenagers following conservative doses of intravenous naloxone. Anesthesiology
1984;60:485-489.
18. Champion GD. Therapeutic usage of the non-steroidal anti-inflammatory drugs. Med J
Aust 1988;149:203:206-213.
19. Brooks PM. Side-effects of non-steroidal anti-inflammatory drugs. Med J Aust
1988;148:248-251.
20. Whitwam JG. Benzodiazepines. Anaesthesiology 1987;42:1255-1257.
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21 Editorial. Flumazenil. Lancet 1988;ii:828-230.

22. Michalk S, Moncorge C, Fichelle A, Huot O, Servin F, Farinotti R, Desmonts JM.
Midazolam infusion for basal sedation in intensive care: absence of accumulation. Intens
Care Med 1988;15:37-41.
23 . Bauer TM, Ritz R, Haberthr, Ha HR, Hunkeler W, Sleight AJ, Scollo-Lavizzari G,
Haefeli WE. Prolonged sedation due to accumulation of conjugated metabolites of
midazolam. Lancet 1995;346:145-147.
24. Brogden RN, Goa KL. Flumazenil. A preliminary review of its benzodiazepine antagonist
properties, intrinsic activity and therapeutic use. Drugs 1988;35:448-467.
25. Lim AG. Death after flumazenil. Brit Med J 1989;299:858-859.
26. Lopez A, Rebollo J. Benzodiazepine withdrawal syndrome after a benzodiazepine
antagonist. Crit Care Med 1990;18:1480-1481.
27. Mordel A, Winkler E, Almog S, Tirosh M, Ezra D. Seizures after flumazenil
administration in a case of combined benzodiazepine and tricyclic antidepressant
overdose. Crit Care Med 1992;20:1733-1734.
28. Marchant B, Wray R, Leach A, Nama M. Flumazenil causing convulsions and ventricular
tachycardia. Brit Med J 1989;299:860.
29. Short TG, Maling T, Galletly DC. Ventricular arrhythmia precipitated by flumazenil. Brit
Med J 1988;296:1070-1071.
30. Sutherland MJ, Burt P. Propofol and seizures. Anaesth Intens Care 1994;22:733-737.
31. Bodenham A, Culank LS, Park GR. Propofol infusion and green urine. Lancet
1987;ii:740.
32. Parke TJ, Stevens JE, Rice ASC, Greenaway CL, Bray RJ, Smith PJ, Waldmann CS,
Verghese C. Metabolic acidosis and fatal myocardial failure after propofol infusion in
children: five case reports. Br Med J 1992;305:613-616.
33 . Bennett SN, McNeil MM, Bland LA, Arduino MJ, Villarino ME, Perrotta DM, Burwen
DR, Welbel SF, Pegues DA, Stroud L, Zeitz PS, Jarvis WR. Postoperative infections
traced to contamination of an intravenous anaesthetic, propofol. N Engl J Med
1995;333:147-154.
34 . Nichols RL, Smith JW. Bacterial contamination of an anesthetic agent. N Engl J Med
1995;333:184-185.
35. Hirota K, Lambert DG. Ketamine: its mechanism(s) of action and unusual clinical uses. Br
J Anaesth 1996;77:441-444.
36. Strube PJ, Hallam PL. Ketamine by continuous infusion in status asthmaticus.
Anaesthesia 1986;41:1017-1019.
37. Editorial. Clozapine. Lancet 1989;ii:1430-1432.
38. Riker RR, Fraser GL, Cox PM. Continuous infusion of haloperidol controls agitation in
critically ill patients. Crit Care Med 1994;22:433-440.
39. Stern TA. Continuous infusion of haloperidol in agitated, critically ill patients Crit Care
Med 1994;22:378-379.
40. Hansbrough JF, Zapata-Sirvent RL, Carroll WJ, et al. The use of intravenous alcohol for
prevention of withdrawal in alcoholic burned patients. Am J Surg 1984;148:266-271.
41. Hansen-Flaschen JH, Brazinsky S, Basile C, Lanken PN. Use of sedating drugs and
neuromuscular blocking agents in patients in patients requiring mechanical ventilation for
respiratory failure. A national survey. JAMA 1991;266:2870-2875.
42. Vender JS. Sedation, analgesia, and neuromuscular blockade in critical care: an overview.
New Horizons 1994;2:2-7.
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43. Hansen-Flaschen J, Cowen J, Raps EC. Neuromuscular blockade in the intensive care
unit. More than we bargained for. Am Rev Resp Dis 1993;147:234-236.
44. Segredo V, Caldwell JE, Matthay MA, Sharma ML, Gruenke DL, Miller RD. Persistent
paralysis in critically ill patients after long-term administration of vecuronium. N Engl J
Med 1992;327:524-528.
45. Bion JF, Bowden MI, Chow B, Honisberger L, Weatherley BC. Atracurium infusions in
patients with fulminant hepatic failure awaiting liver transplantation. Intens Care Med
1993;19:S94-S98.
46 . Meyer KC, Prielipp RC, Grossman JE, Coursin DB. Prolonged weakness after infusion of
atracurium in two intensive care unit patients. Anesth Analg 1994;78:772-774.
47. Parker CJ, Jones JE, Hunter JM. Disposition of infusions of atracurium and its metabolite,
laudenosine, in patients with renal and respiratory failure in an ITU. Br J Anaesth
1988;61:531-540.
48. Hunter JM. Atracurium and laudanosine pharmacokinetics in acute renal failure. Intens
Care Med 1993;19:S91-S93.
49. Watt I, Ledingham IM. Mortality amongst multiple trauma patients admitted to an
intensive therapy unit. Anaesthesia 1984;39:973-981.
50. Aitkenhead AR, Pepperman ML, Willatts SM, Coates PD, Park GR, Bodenham AR,
Collins CH, Smith MB, Ledingham IMcA, Wallace PGM. Comparison of propofol and
midazolam for sedation in critically ill patients. Lancet 1989;ii:704-709.
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73
74
PAEDIATRIC FLUID, RENAL AND NUTRITIONAL SUPPORT

N. T. Matthews, FANZCA, FFICANZCA
Director, Intensive Care Unit,
Womens and Childrens Hospital, North Adelaide,
Introduction
Intravenous therapy is indicated for replacement of fluid and electrolytes when enteric
feeding is contraindicated, when correction of acute fluid losses is required, and for
administration of intravenous drugs. An approach to decision-making in the paediatric patient
is:
- what volume should be given?;
- how quickly should it be given?; and
- what type of fluid is necessary?
There are several methods for calculating requirements for water, calories, and electrolytes
in paediatrics, and these are usually based on weight, body surface area, and caloric
requirements1. Therapy should be customised for individual variations in age, for growth rate,
metabolism and responses to trauma and illness. Repeated evaluation of clinical status and
therapeutic response is important in management. There are unique features in paediatric
patients which alter insensible water loss2. For example:
Increased insensible water loss may be due to:
- air currents;
- radiant heaters;
- low birth weight;
- motor activity;
- phototherapy;
- fever;
- increased minute ventilation;
- dry or cool inspired gases; and
- low ambient humidity.
Reduced insensible water loss may be due to:
- high ambient humidity;
- humidification of inspired gases;
- inactivity;
- hypothermia;
- inappropriate ADH secretion; and
- renal failure.
Technical Aspects
Venous cannulation in the paediatric patient is difficult when veins are small and difficult to
visualise. Optimal sites for percutaneous cannulation are the dorsum of the hand, the
antecubital fossa, the dorsum of the foot, the scalp and the long saphenous and external jugular
veins. Percutaneous central venous cannulation is routine with small bore, non-thrombogenic
catheters, but should not be persisted at the expense of resuscitation. Accidental infusion of
75
Paediatric Fluid, Renal and Nutritional Support

large volumes of fluid is prevented by using infusion pumps, syringe pumps, microdrip
chambers (60 drops per minute) and volume limiting chambers.
Complications of intravenous lines are fluid overload, electrolyte imbalance, tissue
infiltration, phlebitis, haematoma, infection, arterial infusion, and air embolus which is
important in the presence of congenital heart disease. Excessive pressure from limb restraint
causes pressure necrosis, compromised circulation, and peripheral nerve palsy.
Volume Requirements
The formula introduced by Bush3 is commonly used for calculation of maintenance
requirements outside the neonatal age group:
For the first 1st 10kg weight
For the next 10kg weight
For additional weight over 20kg
For neonates the following is used:
Day 1: 60mls/kg/day
Day 2: 80mls/kg/day
Day 3: 100mls/kg/day
Day 4 and over: 120mls/kg/day
give 4mls/kg/hr
add 2mls/kg/hr
add 1ml/kg/hr
Adjustments for neonates allow a 10% to 15% weight loss in the first few days which
minimises morbidity4. Any calculated volume must incorporate fluid volumes flushed through
monitoring catheters, fluid given with drugs (eg antibiotics), and blood products. Low birth
weight neonates have relatively larger insensible water losses.
Continuous Haemofiltration
Haemofiltration is either arterio-venous (CAVH) with flow resulting from the arteriovenous pressure difference, or veno-venous (CVVH) requiring flow from an extrinsic pump.
Haemodiafiltration is where dialysate is perfused across the filter.
Indications for haemofiltration include renal failure, fluid overload, metabolic derangements
(electrolyte, acid base), and fluid volume limitations that restrict nutrition. Haemofiltration is
most useful for fluid removal in cardiovascularly unstable patients, but is less rapid and
effective than haemodialysis5. It removes middle weight vasoactive peptides that may lead to
capillary leakage. Problems of continuous haemofiltration in children are:
- additional arterial and/or venous lines are required;
- blood flow and ultrafiltrate flow are dependent on arterial blood pressure (which is
lower in children), pressure on the venous side of the filter, haematocrit, and position,
size and length of catheters;
- regional heparinisation may cause bleeding;
- platelets are trapped by the filter especially at low blood flows in paediatric patients;
- small blood aggregates are flushed into the venous circulation.
CAVH is simpler because the A-V pressure gradient drives blood through the filter. This
provides safety and haemodynamic stability. However because blood flow rates are low with
small paediatric cannulas and lower blood pressure, urea clearance is reduced. Blood flow can
be improved by increasing blood pressure, correcting hypovolaemia, and reducing blood flow
resistance by reducing cannula length, increasing cannula size, changing cannula position.
Continuous arterio-venous diafiltration improves urea clearance.
76

CVVH via a central venous dialysis catheter must be pump driven, but provides higher
blood flow and ultrafiltration rates, with better urea clearance. CVVH is technically more
difficult than CAVH in infants6.
Dialysis
Peritoneal dialysis is inexpensive and provides smooth changes in fluid volume. A soft,
purpose-designed catheter is inserted into the peritoneal cavity using a Seldinger technique.
However, respiratory function may be effected in infants because raised intra-peritoneal
pressure impairs diaphragm function which is important under two years of age. Complications
include infection, catheter blockage, leakage of dialysate fluid and bowel perforation. It is
contraindicated where abdominal pathology is present or recent surgery has been performed.
Haemodialysis allows controlled ultrafiltration and dialysis. It requires relatively large
central vascular access, specialised personnel and regional heparinisation. It may cause rapid
osmotic shifts and haemodynamic instability.
Nutrition
The critically ill child has problems of decreased intake and increased metabolic demands,
and this leads to poor wound healing, reduced immune response, lack of growth, and reduced
energy and protein stores. The metabolic requirements of children are relatively high7, and the
metabolic response to injury and illness results in a drain of energy and protein stores, with
utilisation of glucose, glycogen and fat, except in sepsis where this utilisation is impaired. The
aim of nutrition is to provide ordinary caloric requirements, as well as those needed for growth
and development, without fluid retention.
Assessment of appropriate caloric assimilation is difficult. It is helpful to measure body size
(weight, height, and head circumference), tissue composition (skinfold thickness), and
biochemical and immunological parameters (creatinine/height index; albumin; transferrin; and
cellular response by skin testing and lymphocyte count). However, a simple nutritional
assessment system is required because those suggested for adults have not proved useful in
paediatrics. Daily caloric requirements vary with age :
Age
Newborn
1 year
7 years
12 years
18 years
Calories/kg/day
120
90
75
60
30
Caloric intake should be increased for some disease processes where energy consumption is
high. Disease processes requiring increased caloric expenditure are:
- fever;
- surgery;
- sepsis;
- cardiac failure;
- respiratory failure;
- burns; and
- malnutrition.
Protein requirements are 2-3 gm/kg/day, while glucose requirements are 10-15 gm/kg/day,
although neonates may require up to 20 gm/kg/day. Fat administration prevents essential fatty
acid deficiency and when metabolised produces less CO2, which may be important in patients
77

with respiratory distress. Fat requirements are 1-3 gm/kg/day. There are recommended daily
allowances for vitamins and minerals in children. Calorie content differs with each substrate,
namely glucose 10 calories/gram, protein 4 calories/ gram, and fat emulsion 4 calories/gram.
Daily monitoring of caloric intake is important. The choice of caloric administration (enteral or
parenteral) depends on disease processes and adequacy of gut function8.
Enteral Nutrition
Enteral feeding is more physiological and maintains better gut function. It also results in
less complications. Diets include:
- homogenised food which causes less diarrhoea and abdominal distension;
- formula, with added calories (as carbohydrate) if volume is limited; and
- elemental diets (simple sugars and proteins) where digestive ability is limited.
Elemental diets consist of amino acids and short chain peptides with simple sugars,
electrolytes, trace elements and vitamins. They provide complete absorption in the upper small
intestine, but their high tonicity may cause abdominal distension and osmotic diarrhoea unless
introduced gradually. Enteral feeds can be given via nasogastric or gastrostomy silastic feeding
tubes into the stomach or jejunum. Jejunal feeds bypass the dilutional effect of gastric
secretions, gastric digestion, and the stomach's anti-infective mechanismsi. Where reflux and
aspiration is present, consideration should be given to continuous feeds or administration via
jejunal feeding tubes. Nasal tubes are difficult to maintain long term, and obstruct the nares
resulting in an increase in work of breathing which is important in the presence of respiratory
failure. When enteral feeding is to be introduced, high volumes and tonicity should be avoided
initially, and the patient observed for nausea, vomiting, gastric distension and reflux.
Parenteral Nutrition
Parenteral nutrition is required where enteral feeds are precluded because of disease or
surgery. Most commonly, indications are for therapy of primary gastrointestinal diseases, such
as short bowel syndrome and inflammatory bowel disease, and supportive therapy for
prematurity, necrotising enterocolitis, neoplasia, burns, and pre- and post-operative surgery (eg
small bowel atresia, tracheo-oesophageal fistula, gastroschisis, omphalocoele).
Long term central venous administration is via percutaneous or surgically inserted small
bore silicone catheters. Peripheral administration has fewer side-effects and is technically
easier, but has limitations in the amount of calories that can be delivered, and problems with
long-term IV maintenance in children because repeated percutaneous intravenous cannulation
is limited. When given intravenously, glucose, protein and fat should be introduced slowly over
3-4 days. Monitoring is aimed at assessing the effects of therapy and avoiding complications. It
includes:
- daily: weight; observation for glycosuria, fever, fluid overload, and catheter related
problems;
- thrice weekly: electrolytes and glucose;
- twice weekly: urea, creatinine, calcium, magnesium, and phosphate;
- weekly: liver function tests, haemoglobin and triglyceride levels (when fat emulsion is
used); and
- weekly: head circumference and length.
78

Technical, infectious, metabolic and psychiatric complications are similar to those in adult
patients9. Fat is contra-indicated in liver disease, bleeding disorders, pulmonary hypertension,
premature neonates and sepsis, because reduced fat clearance reduces capillary blood flow and
affects white cell and platelet function. Serum lipaemia and triglyceride levels should be
frequently monitored when fat is commenced or clinical conditions change. Where tube enteral
feeding or parenteral nutrition is continued for long periods of time in infants, it is important to
maintain an oral stimulation programme so that sucking, chewing and swallowing skills are
maintained.
REFERENCES
1. Ichikawa I. Pediatric textbook of fluid and electrolytes. Williams and Wilkins, Maryland
1990 : 18.
2. Gregory AG (ed). Pediatric anesthesia 2nd Edition. Churchill Livigstone, New York
1989; Vol 1:597
3. Bush GH. Intravenous therapy in paediatrics. Ann R Coll Surg Engl 1971; 49:92-101.
4. Lorenz JM, Kleinman LI, Kotagal UR, Reller MD. Water balance in very low-birthweight infants. Relationship to water and sodium intake and effect on outcome. J Pediatr
1982; 101:423-432.
5. Fanconi S, Leumann EP. Acute renal failure in paediatric patients: the role of continuous
haemofiltration. Intensive Care Med 1991; 17:311-312.
6. Zobel G, Ring E, Kuttnig M, Grubbauer HM. Five years experience with continuous
extracorporeal renal support in paediatric intensive care. Intensive Care Med 1991;
17:315-319.
7. Ichikawa I. Pediatric textbook of fluid and electrolytes. Williams and Wilkins, Maryland
1990: p 471.
8. Reimer SL, Michener WM, Steiger E. Nutritional support of the critically ill. Pediatr Clin
North Am 1980; 27:647-660.
9. Zlotkin SH, Stallings VA, Pencharz PB. Total parenteral nutrition in children. Pediatr Clin
North Am 1985; 32:381-400.
79
80
PRINCIPLES OF MECHANICAL VENTILATION

A. Bersten, MB BS, MD, FANZCA, FFICANZCA
Introduction
Through a review of the forces that are overcome during spontaneous breathing it is easier
to understand the forces and pressures generated during mechanical ventilation (MV).
Contraction of the respiratory muscles expands the thorax and lowers intrapleural pressure. The
resultant pressure gradient from airway to alveolus leads to inspiratory gas flow. With loss of
muscle contraction the alveolar to airway pressure gradient falls and gas flow ceases.
Expiration is normally passive with recruitment of expiratory muscles only occurring during
high minute ventilation and elevated respiratory work.
The pressures generated may be modelled using the equation of motion (essentially assumes
the respiratory system consists of a balloon and a tube):
P = Pel + Pres + Pinert
ie the total pressure is the sum of elastic pressure (Pel), resistive pressure (Pres) and inertive
pressure (Pinert). Inertive pressure (inertance x acceleration) is such a small component of the
total pressure during gas flow that it can be ignored. This allows simplification of the equation
to:
P = Pel + Pres
& where E is elastance (the inverse of compliance), V is

and since Pel = EV and Pres = R V
& is gas flow:

volume, R is resistance and V
& .
P = EV + R V
When this is applied during MV:
&
Pao = ErsV + Rrs V
where Pao is the airway pressure, Ers is the dynamic respiratory system elastance and Rrs is the
dynamic respiratory system resistance. Of course the end-expiratory pressure may not be 0 so
the equation becomes:
& + Po
Pao = ErsV + Rrs V
where Po is an estimate of the alveolar pressure at end-expiration. This is equivalent to the total
PEEP and the intrinsic PEEP may be calculated as Po - Pmin, where Pmin is the minimum
recorded airway pressure referenced to atmosphere.
While more complex equations allow better modelling of the respiratory system,
particularly during disease states, most of the principals can be illustrated with this simple
model. It is important to note that respiratory work (W) can be calculated as:
W = PV
allowing easy development of the notion of elastic work and resistive work. Elastic work will
comprise lung and chest wall components, and viscolelastic properties of the lung and chest
wall; and flow resistive work will include airway and apparatus (depending upon the site of
measurement of Pao).
81
Principles of Mechanical Ventilation

Whereas the ventilator will generate all of Pao and the consequent respiratory work during
passive inspiration, the respiratory muscles will provide this inspiratory pressure during
spontaneous breathing, and both will contribute during assisted or supported ventilation.
Objectives of Mechanical Ventilation1
1. alveolar ventilation ( PaCO2): ICP, pulmonary vascular resistance, reverse an acute
respiratory acidosis.
2. oxygenation: ventilation to perfusion (V/Q) matching is often better during spontaneous
breathing, high inspired oxygen fractions and positive end-expiratory pressure (PEEP) can
be applied without intubation; however other factors often mean that intubated ventilation is
required during hypoxaemic acute respiratory failure. It is also vital that the objective be
tissue oxygenation and not just PaO2.
3. end-inspiratory lung volume: prevent or treat atelectasis.
4. functional residual capacity: through the use of PEEP which may oxygenation or
reduce lung injury though adequate recruitment with prevention of repeated opening and
closure of alveoli.
5. unload the respiratory muscles: when an imbalance between load and the ability to cope
results in respiratory muscle insufficiency and ventilatory failure, or to systemic or
& O2. High levels of respiratory work commonly occur in acute respiratory
myocardial V
failure and demand massive increases in respiratory muscle blood flow to provide adequate
substrate. Laboratory studies demonstrate that despite a redistribution of regional blood
flow away from vital organs, respiratory muscle blood flow may become inadequate with
subsequent respiratory muscle fatigue and apnoea. In addition calculated oxygen
consumption by the respiratory muscles may become a large proportion of systemic oxygen
& O2). Consequently in shock states or acute hypoxaemic respiratory failure
consumption ( V
& O2 is limited, it may be appropriate to abolish this demand.

where systemic V
6. sedation paralysis
7. left ventricular (LV) preload, LV afterload: while raised intrathoracic pressure may
have beneficial effects in patients with heart failure, deleterious cardiovascular effects may
be seen in patients with normal LV function particularly if they are hypovolaemic. The
issues involved are complex and debated; however the major beneficial effect in LV failure
is a reduction in LV afterload due to a reduction in LV transmural pressure. Techniques
such as continuous positive airway pressure (CPAP) combine this benefit with spontaneous
ventilation thereby reducing the impact on venous return and LV preload.
8. stabilize the chest wall: it is unusual for loss of chest wall integrity to compromise function
(flail chest, chest wall resection); however, the sum of other issues (analgesia, other injuries,
premorbid respiratory disease) may contribute to the requirement for MV.
Complications of Mechanical Ventilation
1. Airway Intubation: include epistaxis + sinusitis (nasal tube), risk of nosocomial
pneumonia, malplacement + inability to intubate + dislodgment, glottic injury, tracheal
stenosis, obstruction and complications specific to tracheostomy such as bleeding,
pneumothorax and local infection.
2. Barotrauma: broadly includes pneumothorax, pneumomediastinum, pneumopericardium,
pulmonary interstitial air, air cysts and acute lung injury. While barotrauma has often been
considered to reflect the effect of high airway pressure it is more correct to attribute these
changes to excessive lung stretch. This can occur during either spontaneous breathing at
zero end-expiratory pressure (ZEEP) or during supported, assisted or controlled MV, with
82

some of the earliest reports of barotrauma occurring after respiratory stimulants had induced
high tidal volumes (VT) spontaneous ventilation. However, we most commonly recognize
barotrauma during MV when high airway pressures are generated.
Strategies to minimize barotrauma in this setting have focused on limiting transalveolar
pressure by limiting peak or plateau airway pressure (Ppk or Pplat). Pplat approximates the
airway pressure minus flow resistive forces, ie Pel + total PEEP (PEEPtot = intrinsic PEEP +
extrinsic PEEP = PEEPi + PEEPe), reflecting alveolar pressure better than Ppk. Since in the
normal lung total lung capacity is achieved at transalveolar pressures of 30-35 cmH2O this
pressure is often the recommended limit for Pplat. However, using either static volumepressure curves or a volume-dependent equation of motion it is clear that regional
overinflation may be achieved in ARDS patients at lower airway pressures ( 50% in some
studies). On the other hand if chest wall compliance is greatly elevated (massive abdominal
distension, chest trauma) then the alveolus may not see the distending effects of this
pressure. It is clearly preferable to actually measure overinflation and titrate MV
accordingly.
If inadequate PEEP is applied to the injured lung recruitment and derecruitment will
occur during tidal breathing. This opening and closing of alveoli appears to impose
repetitive shear forces on the lung also resulting in acute lung injury.
3. Oxygen Toxicity: while an FiO2 60% causes experimental lung damage only one study2
has demonstrated oxygen toxicity in the setting of acute lung injury (80% O2 plus
pneumonia yielded similar lung injury to 100% O2 alone and greater injury than pneumonia
alone in the baboon). No convincing clinical data examining the effects of FiO2, its
duration, and underlying lung injury on outcome are available. Consequently the vigour
undertaken to utilize non-toxic FiO2s varies.
4. Cardiovascular Complications: cardiac output with regional blood flow, LV
preload, LV afterload, pulmonary vascular resistance, RV afterload, no net effect on
lung water, peripheral oedema (due to an capillary microvascular pressure, Pcap, due to
right atrial pressure, Pra).
These well described effects appear to be best correlated with mean lung volume and
hence mean alveolar pressure during MV, and when inspiratory resistance expiratory
resistance, mean airway pressure (Pmean) can be substituted. Again, the equation of motion
delineates the relevant pressures determining Pmean , and emphasizes the importance of
accounting for PEEPtot and not just PEEPe. Finally, the proportion of this pressure
transmitted to the pleural space, and hence the vascular structures, is proportional to
CL/CL+CCW , where CL is lung compliance and CW is chest wall compliance, so the effects
are relatively minimized by stiff lungs or normal chest wall compliance.
5. Work of Breathing: while a major objective of MV may be to respiratory work, an
additional load will be imposed by the endotracheal tube, connector and ventilator. Narrow
endotracheal tubes and poor demand valve design can impose significant apparatus work
during assisted, supported or spontaneous breaths. The site of sensing is relatively
unimportant as the transducer is always located within the ventilator minimizing any
advantage of proximal sensing. However, flow by, sensing a loss of bias flow, allows a
reduction in sensing threshold while avoiding autocycling that often occurs with minimally
adjusted pressure sensing. In patients with PEEPi sensing may be a major problem as the
respiratory muscles must first reduce alveolar pressure below airway pressure for flow to
occur. This threshold work may be reduced by applying a low level of PEEPe, below the
level of PEEPi to avoid further overinflation, to reduce the gradient between airway
pressure and end-expiratory alveolar pressure3,4, 5.
83

Schematic diagram illustrating the threshold load imposed by PEEPi and the potential
beneficial effect of CPAP in severe airflow obstruction.
0
12
12
-5
normal
12 cmH2O PEEPi
-1
-1
-7
-15
-6
15
pre-inspn
PEEPi + 8 cmH2O CPAP
inspiration
Legend: bar represents the upper airway; the circle is the representative alveolus; the
triangle is the pleural space; and DP is the change in pleural with initiation of inspiration. In
this example a large threshold load is imposed by PEEPi, and this is markedly reduced with
the application of CPAP.
6. Sedation and Paralysis: may result in hypotension and muscle weakness.
7. Other: agitation, sleep disturbance, renal dysfunction (predominantly due to cardiac
output), ICP due to impaired venous drainage with high levels of PEEP.
MODES OF VENTILATION
1. Controlled Mechanical Ventilation (CMV): the most basic form of MV supplying all
ventilation in the apnoeic patient; spontaneous breaths are not available. During pressure
controlled ventilation (PCV) each breath is delivered as a time preset pressure controlled
breath and VT varies; however, during CMV ventilators usually deliver time preset flow
controlled breaths, and the pressure profile will depend upon the inspiratory flow pattern,
Pel, Pres and PEEPtot.
The schematic diagram below represents these components during CMV with a constant
inspiratory flow pattern. In a relaxed patient if an inspiratory pause long enough to allow
equilibration were present, the airway pressure would decay bi-exponentially, due to
dissipation of flow-resistive and viscoelastic forces (usually a small component), to Pel.
While somewhat oversimplified this approach allows a reasonable understanding of the
forces the ventilator is overcoming during MV, rather than just noting that the patient is
84

hard to ventilate. For instance in acute severe asthma the patient may be hard to ventilate
because of increased airways resistance; however while invariably increased the effects of
dynamic hyperinflation reflected in PEEPi and lung compliance are common causes of
high airway pressures. Appropriate treatment must include prolonging expiration to
minimize this effect.
Estimates of respiratory system compliance (Crs) and resistance (Rrs) can be made from
this data provided there is no patient effort, PEEPi is accounted for, and a measured inspired
VT and adequate pause are used:
Crs = VT /(Pplat-PEEPtot)
& .
Rrs = (Ppk-Pplat)/ V
Ppk
Pres
Pel
Pressure
Pmean
}PEEP
tot
Time
2. Assist/control Ventilation (ACV): in addition to a preset background rate of CMV breaths,
patient inspiratory effort initiates a standard CMV breath. The ability to control respiratory
rate means that less sedation is required; however the respiratory muscles continue to
contract during these assisted breaths6 with only a small reduction in work compared to
unassisted spontaneous breaths7.
3. Intermittent Mandatory Ventilation (IMV): in concept IMV was introduced to allow
unimpeded spontaneous breaths while still ventilated with intermittent CMV breaths, to
minimize sedative use and reduce respiratory muscle discoordination allowing more rapid
weaning. In addition the reduction in intrathoracic pressure may ameliorate many of the
cardiovascular and respiratory complications of CMV.
Synchronized IMV (SIMV) is designed to avoid breath stacking by partitioning the
inspiratory time into patient initiated, or spontaneous, breaths. Neither IMV or SIMV has
been clearly shown to allow easier weaning than T-piece trials8, perhaps due to the
inspiratory workload imposed by the endotracheal tube, connector and ventilator demand
valve9,10. Since respiratory effort is strongly influenced by respiratory drive patient initiated
breaths do not effectively unload the respiratory muscles, with the workload decreased by
only 40% when over half the minute volume is supplied by SIMV breaths11.
4. Pressure Support Ventilation (PSV): during PSV spontaneous patient breaths are
supported to a preset pressure using additional gas flow. Inspiration is usually terminated
when the inspiratory gas flow falls to 25% of the initial flow rate or less than 5 L/min.
While PSV may assist in unloading the respiratory muscles12 and offset the apparatus work
85

imposed by the endotracheal tube, connector and ventilator demand valve13,14, this again
depends upon respiratory drive. The precise level of PSV required to overcome apparatus
work will depend upon the disease state, size of the endotracheal tube, the ventilator used
and the inspiratory flow rate, but is usually between 5-10 cmH2O14,15. Consequently PSV is
often used during periods of stable ventilatory assistance and has been shown to provide
significant benefit during weaning as compared to either SIMV or T-piece techniques8;
however, T-piece weaning was found to be quicker than either SIMV or PSV techniques in
a Spanish study16. Disadvantages of PSV are that the (i) VT is not fixed so that minute
volume will depend upon respiratory drive, pressure support level and respiratory system
mechanics, (ii) that excessively large tidal volumes resulting in lung stretch may be
delivered and (iii) that the high initial flow and termination algorithm may be unsuitable for
patients with severe airflow obstruction, although the ability to adjust the initial flow rate or
pressure slope is present on some new ventilators.
Volume assured pressure support (VAPS) is a mode of adaptive PSV where breath to
breath logic is used to assure a preset VT17. Similar concepts are encompassed with volume
support (VS), a mode of assisted, spontaneous ventilation where the VT is preset, and
pressure regulated volume control (PRVC) where VT and respiratory rate are preset and a
decelerating flow pattern aims to achieve these parameters at a minimum constant pressure.
No real benefit over PSV has been shown.
5. Positive End-Expiratory Pressure (PEEP, Constant Positive Airway Pressure (CPAP):
while PEEP elevates the baseline pressure during MV, CPAP is reserved for spontaneous
breathing with PEEP. Both aim to increase lung volume and oxygenation, although no
consistent effect on lung water has been found. Ventilators and CPAP circuits are designed
to minimize fluctuations in airway pressure as this increases apparatus work.
Severe expiratory airflow obstruction and relatively short expiratory times result in
dynamic hyperinflation reflected as PEEPi. End-expiratory occlusion is the most common
method of measurement in the ventilated patient, and this may be performed manually18,
through diversion of inspiratory flow19, or through an end-expiratory hold built in to the
ventilator. There must be no respiratory effort and end-expiration must be clearly identified.
This may be difficult to achieve manually; consequently techniques incorporated into the
ventilator are desirable. In spontaneously breathing subjects the fall in oesophageal pressure
required to retard expiratory flow is probably the best method for determining PEEPi.
6. Airway Pressure Release Ventilation (APRV): APRV is similar to a bi-level CPAP with
intermittent decreases in airway pressure augmenting alveolar ventilation in addition to
spontaneous breaths at the higher CPAP level. APRV without spontaneous breathing has a
similar profile to pressure controlled inverse ratio ventilation (PCIRV), and similarly is
intended to limit peak airway pressure and barotrauma. However, comparative studies with
conventional ventilation do not demonstrate that APRV has any real advantages20,21.
7. Non-invasive Ventilation (NIV): Most of the ventilatory modes can be applied noninvasively, with CPAP, PSV and CMV being the most commonly used. The role of NIV in
critically ill patients is still being defined; however, it appears particularly useful in either
preventing intubation or in the weaning from ventilatory support in patients with acute
pulmonary oedema or acute airflow limitation. Apart from patients with Pneumocystis
pneumonia NIV is usually only a temporizing measure in hypoxaemic respiratory failure.
Bi-level CPAP (BiPAP), PSV and CMV are also useful in patients with respiratory muscle
weakness, both in chronic management and during acute exacerbations.
86
Other Ventilatory Features

1. Inspiratory: Expiratory (I:E) Ratio: depending upon the ventilator the inspiratory time is
& and VT, and is often 0.8-1.2 s. Longer inspiratory times elevate Pmean
determined by V
without increasing Ppk, and shorter times prolong expiration which may be desirable in
severe airflow obstruction as this will reduce gas trapping22. During inverse ratio ventilation
the inspiratory time is so prolonged that the I:E ratio is less than 1:1. The resultant
shortening of expiration often leads to gas trapping and PEEPi. This can be applied with
pressure controlled (PCIRV) or volume controlled (VCIRV) modes. While commonly used
in patients with ARDS there are no convincing studies that show benefit over conventional
ventilation when PEEPtot is matched23,24,25.
2. Inspiratory Flow Pattern: when the I:E ratio and VT are taken into account there is no
demonstrated difference between the available wave forms.
3. Inspiratory Pause: An end-inspiratory pause may improve oxygenation through
prolonging the inspiratory time; however, for a given mean airway pressure and inspiratory
time there is no advantage.
4. Sigh: the role of various recruitment manoeuvres (large VT, sigh or PEEP) remains
uncertain; however in their absence monotonous small -moderate VT ventilation results in
progressive atelectasis. A major factor contributing to this is lack of lung stretch leading to
release of surfactant26. This is particularly concerning as modern strategies of small VT
ventilation may promote stiff lungs; however regular suctioning preceded by hand
ventilation may well provide an appropriate stimulus.
PARTICULAR CLINICAL SETTINGS
1. ARDS
Increased permeability, increase in lung water, inflammatory infiltrate, proliferation of type
II cells, abnormal surfactant and fibrosing alveolitis results in dependent collapse, PO2,
physiologic dead space and respiratory work (Rrs due to lung volume and Crs due to
lung and chest wall effects). Ventilation with PEEP is a standard approach while the underlying
condition is diagnosed and treated. CT-based dependent collapse with ventilation of relatively
normal non-dependent lung has increased concerns that lung overdistension may occur unless
VT is reduced. However, inadequate PEEP will increase local shear forces (140 cmH2O
applied to atelectatic lung by surrounding normal lung at a transpulmonary pressure of 30
cmH2O27) due to repeated opening and closing of unstable alveoli. In states of abnormal
surfactant function this results in an acute lung injury. Ideally then tidal ventilation would occur
between the lower and upper inflection points of the lung volume-pressure relation,
representing the limits of recruitment of unstable alveoli with PEEP and pulmonary
overinflation. Amato and colleagues have titrated ventilation from static relations and
suggested this results in better outcome28, but some continuous measure such as volumedependent elastance servo controlled to ventilation is even more appealing.
87
Upper Inflection Point

Volume
Lower Inflection Point
Pressure
2. ASTHMA
Avoidance of MV remains an important goal in patients with acute severe asthma. While
the role of NIV, particularly CPAP, remains uncertain there are a number of potential
advantages. Many patients develop high levels of PEEPi with elevated threshold work making
a significant contribution to their work of breathing and ventilatory failure. Application of
CPAP below this level appears to help overcome this threshold and assists inspiration without
obviously worsening hyperinflation. This can be quite spectacular and allow effective
bronchodilator therapy time to act. However, skilled personal are essential in case intubation
becomes necessary.
In the intubated patients sedationparalysis is needed to allow an adequately long expiratory
time to be delivered so as to minimize dynamic hyperinflation and PEEPi in order to minimize
the risk of barotrauma or shock due to acute right heart failure and reduced venous return. This
will usually mean accepting low respiratory rates and markedly elevated PaCO2s until
improvement in the degree of airflow obstruction. PEEP should be reserved for improving
ventilator sensing during spontaneous or assisted breaths, and may exacerbate hyperinflation
during CMV.
3. WEANING
While it is often said that weaning, sometimes referred to as liberation, from the ventilator
should start once the patient is intubated, premature attempts can result in respiratory muscle
fatigue and atelectasis. Clearly the initial process should be resolving and it helps if the patient
is cooperative and demonstrates sufficient strength and good enough oxygenation to no longer
need ventilatory assistance. However this is not always possible and many of the predictive
indices such as oxygenation, the respiratory rate to tidal volume ratio (f/VT ratio), the
inspiratory occlusion pressure at 0.1 seconds (P0.1) and an index derived from compliance,
respiratory rate, oxygenation and pressure (CROP index) have wide confidence limits29, and do
88

not assess upper airway reflexes. Probably the most common bedside assessment remains
respiratory pattern during spontaneous ventilation, an attempted vital capacity manoeuvre
(preferably >8 ml/kg) and conscious state.
While apparatus work may be at least partly overcome by low levels of PSV data evaluating
PSV or SIMV in the weaning process are contradictory. However, in some patients extubation
can be performed without any need for weaning, in others a T-piece trial or gradual weaning
using PSV allows assessment of progress.
REFERENCES
1. Slutsky AS. Mechanical Ventilation. Chest 1993;104:1833-1859.
2. Coalson JJ, King RJ, Winter VT, et al. O2- and pneumonia-induced lung injury 1.
Pathological and morphological studies. J Appl Physiol 1989;67:346-356.
3. Smith TC, Marini JJ. Impact of PEEP on lung mechanics and work of breathing in severe
airflow obstruction in severe airflow obstruction. J Appl Physiol 1988;65:1488-1499.
4. Petrof BJ, Legare M, Goldberg P, et al. Continuous positive airway pressure reduces work
of breathing and dyspnea during weaning from mechanical ventilation in severe chronic
obstructive pulmonary disease. Am Rev Respir Dis 1990;141:281-289.
5. Shade E, Kawagoe Y, Brower R, et al. Effects of hyperinflation and CPAP on work of
breathing and respiratory failure in dogs. J Appl Physiol 1994;77:819-827.
6. Flick GR, Bellamy PE, Simmons DH. Diaphragmatic contraction during assisted
mechanical ventilation. Chest 1989;96:130-135.
7. Marini JJ, Rodriguez M, Lamb V. The inspiratory workload of patient-initiated
mechanical ventilation. Am Rev Respir Dis 1986;134:902-909.
8. Brochard L, Rauss A, Benito S, et al. Comparison of three methods of gradual withdrawl
from ventilatory support during weaning from mechanical ventilation. Am J Respir Crit
Care Med 1994;150:896-903.
9. Gibney RTN, Wilson RS, Pontoppidan H. Comparison of work of breathing on high gas
flow and demand valve continuous positive airway pressure systems. Chest 1982;82:692695.
10. Bersten AD, Rutten AJ, Vedig A, et al. Additional work of breathing imposed by
endotracheal tubes, breathing circuits, and intensive care ventilators. Crit Care Med
1989;17:671-677.
11. Imsand C, Feihl F, Perret C, et al. Regulation of inspiratory neuromuscular output during
synchronized intermittent mechanical ventilation. Anesthesiology 1994;80:13-22.
12. Brochard L, Harf A, Lorino H, et al. Inspiratory pressure support prevents diaphragmatic
fatigue during weaning from mechanical ventilation. Am Rev Respir Dis 1989;139:513521.
13. Fiastro JF, Habib MP, Quan SF. Pressure support compensation for inspiratory work due
to endotracheal tubes and demand continuous positive airway pressure. Chest
1988;93:499-505.
14. Brochard L, Rua F, Lorino H, et al. Inspiratory pressure support compensates for the
additional work of breathing caused by the endotracheal tube. Anesthesiology
1991;75:739-745.
15. Bersten AD, Rutten AJ, Vedig AE. Efficacy of pressure support in compensating for
apparatus work. Anaesth Int Care 1993;21:67-71.
16. Esteban A, Frutos F, Tobin MJ, et al. A comparison of four methods of weaning patients
from mechanical ventilation. Spanish lung failure collaborative group. N Engl J Med
1995;332:345-50.
89
17. MacIntyre NR, Gropper C, Westfall T. Combining pressure-limiting and volume-cycling

features in a patient-interactive mechanical breath. Crit Care Med 1994;22:353-357.
18. Pepe PE, Marini JJ. Occult positive end-expiratory pressure in mechanically ventilated
patients with airflow obstruction: The auto-PEEP effect. Am Rev Respir Dis
1982;126:166-170.
19. Iotti G, Braschi A. Respiratory mechanics in chronic obstructive pulmonary disease. In
Vincent JL, ed. Update in intensive care and emergency medicine, Volume 10. Berlin:
Springer-Verlag, 1990:223-230.
20. Rasanen J, Cane RD, Downs JB, et al. Airway pressure release ventilation during acute
lung injury: A prospective multicentre trial. Crit Care Med 1991;19:1234-1241.
21. Calzia E, Lindner KH, Witt S, et al. Pressure-time product and work of breathing during
biphasic continuous positive airway pressure and assisted spontaneous breathing. Am J
Respir Crit Care Med 1994;150:904-910.
22. Tuxen DV, Lane S. The effects of ventilatory pattern on hyperinflation, airway pressures,
and circulation in mechanical ventilation of patients with severe airflow obstruction. Am
Rev Respir Dis 1987;136:872-879.
23. Shanholtz C, Brower R. Should inverse ratio ventilation be used in adult respiratory
distress syndrome. Am J Respir Crit Care Med 1994;149:1354-1358.
24. Lessard MR, Guerot E, Lorino H, et al. Effects of pressure-controlled with different I:E
ratios versus volume-controlled ventilation on respiratory mechanics, gas exchange, and
hemodynamics in patients with adult respiratory distress syndrome. Anesthesiology
1994;80:983-991.
25. Morris AH, Wallace CJ, Menlove RL, et al. Randomized clinical trial of pressurecontrolled inverse ratio ventilation and extracorporeal CO2 removal for adult respiratory
distress syndrome. Am J Respir Crit Care Med 1994;149:295-305.
26. Nicholas TE, Power JHT, Barr HA. The pulmonary consequences of a deep breath. Respir
Physiol 1982;49:315-324.
27. Mead J, Takishima T, and Leith D. Stress distribution in lungs: a model of pulmonary
elasticty. J Appl Physiol 1970;28:596-608.
28. Amato MBP, Barbas CSV, Medeiros DM, et al. Beneficial effects of the open lung
approach with low distending pressures in acute respiratory distress syndrome. Am J
Respir Crit Care Med 1995;152:1835-46.
29. Yang KL, and Tobin MJ. A prospective study of indexes predicting the outcome of trials
of weaning from mechanical ventilation. N Engl J Med 1991;324:1445-50.
90
SCORING SYSTEMS AND THE PREDICTION OF OUTCOME IN THE

INTENSIVE CARE UNIT
D. Bihari, FRACP
Department of Intensive Care,
St. George Hospital, Kogarah,
NEW SOUTH WALES 2217
Introduction
Intensive care is costly in both human and financial terms since technological advances
have made it possible to maintain the lives of patients in whom the prognosis is extremely
grave, if not hopeless. Together with the emphasis on evidence based medicine and given the
limited resources experienced by all health care systems in the developed world, unavoidable
questions arise regarding the appropriate application and benefit of intensive care. In this
regard, scoring systems have been developed and used for over the last decade for the
measurement of severity of illness and therapeutic intervention in an attempt to describe more
objectively the case mix of and outcome from intensive care. Currently, three severity of illness
scoring systems - APACHE II1 and III2, SAPS 23 and MPM I and II4,5 are in widespread use so
as to provide an estimated probability of hospital mortality for groups of patients. Their
refinement continues but there is a certain amount of confusion regarding their role in clinical
research, quality assurance and clinical decision making. These issues were addressed at the 2nd
European Consensus Conference in Intensive Care Medicine (Paris 1993)6 where five specific
questions relating to their use in predicting outcome in ICU patients were identified (table 1)
and some consensus obtained. Since that time little has changed although more emphasis has
been placed upon over time scoring systems as being more useful in the assessment of
individual patients5,7,8,9.
Table 1 - the five questions considered by the
Conference
1)
2)
3)
4)
5)
jury of the European Consensus
how should outcome of intensive care be defined and assessed ?

how accurately can we measure severity of illness in ICU patients?
can the various means of measuring illness severity be used in the ICU to predict outcome
in groups of patients and in individual cases ?
what are the human and economic costs of treating patients in the ICU who have a very
high risk of death or severe disability ?
in clinical practice, can the measurement of illness severity be used to provide appropriate,
and avoid useless intensive therapy ?
Definition and assessment of outcome from intensive care

Outcome from intensive care may be defined as mortality-related or morbidity-related10.
Recording mortality provides a measure of survival at various arbitrary end-points such as ICU
mortality, hospital mortality, or later (eg. at 6,12 months or 3 years). By convention 28 day
mortality has been the endpoint for many trials and, although aomewhat questionable in
relevance, has facilitated comparisons between studies. Particularly important in the clinical
trial setting is disease-specific or cause-specific mortality which, in order to avoid bias, requires
independent assessment of the cause of death. Mortality prediction models which produce a
ratio of observed to expected mortality (standardised mortality rate, SMR) for specific groups
91
Scoring Systems in the ICU

of patients are also thought to be valuable provding the model used for obtaining the expected
mortality calibrates and discriminates well in the population of patients studied. This
information is seldom provided. It is a particular concern in the setting of clinical trials in
which patients are entered and scored after the first 24 hours of intensive care. Other than the
APACHE III system11, no scoring system have been carefully validated after the first 48 hours
of intensive care admission and presently, the idea that it is possible to use a SAPS II score, an
APACHE II score or an organ failure score on the day of intervention (new drug,
haemofiltration etc.) is a considerable act of faith.
As a measure of ICU outcome mortality alone is not sufficient. Recognition of morbidity,
disability and quality of life following ICU stay is essential. Length of ICU and/or hospital stay
has previously been used as a surrogate for patient morbidity but is inevitably influenced by
discharge policy, which creates difficulty in making comparisons between institutions.
Measures of therapeutic intervention, for example daily scoring with the therapeutic
intervention scoring system (TISS)12, is another way of attempting to document the intensity of
treatment and hence morbidity but the use of the various interventions included does vary from
unit to unit. There are many established instruments for recording patient perceived quality of
life and disability. These vary in appropriateness and ease of application, the choice of method
therefore depending on the type of study. In neonates and infants long-term follow-up (until
school age) is usually necessary to evaluate fully influences on development. Instruments used
to measure quality of life should have a number of properties (table 2). Nevertheless, future
quality of life research in the ICU setting needs to include comparisons between the values of
patients, proxies and health care professionals.
Table 2. Properties of a useful system for the assessment of patient perceived quality of
life
1)
2)
3)
4)
5)
6)
reliability -. the same score is obtained if measured in a stable patient at two different
times
criterion validity - the system should be measuring what it purports to be measuring
according to an independent standard
content validity - the system should be comprehensive, according to the intended purpose.
responsiveness - the system should detect change in patients who are changing over time.
discrimination - the system should discriminate between individuals with the same
condition, but with different degrees of severity
relative simplicity and ease of administration.
The accuracy of measurement of severity of illness in ICU patients

Measurement of severity of illness requires methods of measuring both severity of disease
and functional reserve13. Ideally an evaluation of illness severity should incorporate the
measurement of physiological disturbance caused by the disease, its degree of reversibility and
the subsequent effect on health status and quality of life. However the latter requirement poses
considerable difficulty in measurement, encompassing both individual and social valuations. It
is this difficulty in incorporating 'quality of life' variables into severity scores which has led to
current systems concentrating on the risk of a single outcome, namely death in hospital.
The validated scoring systems in use have been constructed using mathematical models of
the most relevant variables correlating with mortality in databases of thousands of patients.
Accuracy of these models at providing an estimate of risk of death in particular situations, such
as in specific populations of patients, or in different ICUs in different countries and in the
individual patient has been carefully assessed. Current scoring systems such as APACHE,
92

SAPS and MPM have been found to be highly specific (i.e. ability to predict survival - 90%)
but not very sensitive (i.e. ability to predict death only 50-70%). For example, if 100 patients
each had a probability of death of 0.2, and the model was well calibrated, 20 of these patients
would be expected to die. No information is given as to which individual patients will die. The
prediction of outcome is based upon a decision rule whereby the full range of probabilities of
death is reduced to a dichotomous prediction of either death or survival. Typically a cut-off
point of 50% is used. In the above example this would mean that all 100 patients with a
probability of mortality of 20% would be predicted to live. If 20 died as expected, the
prediction of 'no deaths' would be incorrect. This illustrates the distinction of the difference
between discrimination (i.e. how well does the model discriminate between patients who will
live or die?) and calibration (i.e. how closely do predictions correlate with actual outcome
across the entire range of risk (0-100%) permitting the calculation of a standardised mortality
ratio?). The choice of a 50% cut-off is arbitrary and may be altered, for example to 90%, to
reduce the number of false-positives but there remains a continuous trade-off between
sensitivity and specificity best described by the construction of a receiver operating
characteristic (ROC) curve14.
When establishing the required level of accuracy for any scoring system it is important to
know the previous standards of clinical assessment without the score, and also the proposed
situation in which the score is to operate. Obviously a high level of accuracy will be required
when a scoring system is used to facilitate an irrevocable decision with high costs (human or
material). Criticism of general severity scores may be directed at the potential error
incorporated by subjective judgement (e.g. choosing the primary diagnosis in a complex
patient, scoring the Glasgow Coma Scale when the patient is intubated or sedated). Pre-ICU
therapeutic intervention may also effect the accuracy of current severity scores giving rise to
so-called 'lead time bias'15. Different diseases may also have an influence upon the accuracy of
severity scoring. Urosepsis, for instance, has a much better outcome than other forms of sepsis.
Currently available disease-specific scoring systems (Ranson Score, ISS, TRISS, Sepsis Score),
however, have less predictive power than general severity scores, possibly because of their age,
and new scores are required for a variety of specific conditions. In neonates and children,
severity scoring systems developed for adults (SAPS, APACHE and MPM) have not been
evaluated and are not appropriate. Specific paediatric scoring systems (paediatric SAPS, PSI,
PRISM and CRIB) require improvement and evaluation in large populations.
In conclusion, independent comparative evaluation of the three most commonly used
severity scoring systems is required to increase our understanding of the advantages and
disadvantages of each. Until then, since their accuracy is similar, the choice of which system to
use may depend upon availability, familiarity, systems in use in neighbouring units, the
prospects for future developments and costs.
Severity of illness measurement and the prediction of outcome in groups of patients verses
individual cases
Scoring systems developed for use in large ICU populations may be used to evaluate
groups of patients for audit, quality assurance and clinical evaluation. Outcome data such as
mortality rates may be used to monitor performance of one particular ICU over time (internal
audit) or to compare the performance of several different ICUs (external audit). For
comparisons to be valid, standardisation of case mix is essential and severity of illness scores
have an important role in classifying patients16. An SMR may be calculated to show whether
the ICU is performing better or worse than predicted by the model. The SMR may be
misleading if the casemix is substantially different between the populations being considered;
this was illustrated by the failure of APACHE II to calibrate when applied to a Japanese
93

population17. Whether an SMR not equal to 1 is due to poor calibration or to a real difference in
ICU performance may therefore be difficult to determine, lead time bias being an important
influence. In combination with the therapeutic intervention scoring system used to estimate
costs18, judgements can be made about the efficiency of the use of resources within an ICU. A
criticism that the TISS model developed in the USA two decades ago requires updating and
evaluating in European and Australasian ICUs is no longer valid since many units have now
had experience of using the system which allows the allocation of costs to individual patients.
This becomes important in the establishment of efficiency based medicine, ie. that form of
intensive care which is associated with an acceptable cost per life year gained and cost per
quality adjusted life year - acceptable in the sense that they are not dissimilar from many other
medical activities whiich have been traditionallly funded.
Since current scoring systems have been designed for prediction in large populations they
should only be used in groups of patients. Prediction in individual patients is difficult, if not
impossible. The only system in which individual prediction of death has been emphasised is
Chang's Riyadh Intensive Care Program (RIP)7,8,9. This is a dynamic system based upon
changes in the daily organ failure score which in our experience, is highly specific (99.5%)
with a sensitivity of 23%8. Yet it is associated with a false positive diagnosis rate of 4% which
is probably still too high for routine clinical use. Nevertheless, such a system alerts the medical
and nursing staff that an individual patient is unlikely to survive (mortality rate > 95%) and the
opportunity of costs of gaining such a survivor (ie. a blocked ICU bed) are considerable.
The implications of treating patients in the ICU who have a very high risk of death or
severe disability
The point at which a patient becomes too severely ill or disabled, or has too poor a
prognosis to justify the high costs of treatment in the ICU, is a value judgement and will differ
from society to society. The costs and burdens associated with intensive care are of various
types and fall on different people (table 3). It is the duty of the ICU team to minimise the
suffering experienced by the patient and his previous wishes, if known, should be taken into
consideration. The participation of the family in the decision-making process is also extremely
important but promotion of advance directives or living wills may move the decision-making
further towards the individual patient. Undoubtedly, further research into patient preferences, as
well as cost effectiveness and cost utility studies, are necessary to develop guidelines for the
use of scarce ICU resources.
Measurement of illness severity and the provsion of appropriate intensive care
ICU practice demands complex daily decision making regarding the commencement and
continuation of therapy and also withholding and withdrawing life support. These decisions are
based on clinical judgement but could be aided by the use of severity of illness scores. Careful
selection of patients for admission to the ICU allows appropriate treatment of those who may
benefit, and avoids futile treatment in those who will not. Scoring systems may be used to
identify patients who are able to survive without intensive care and those who will retain a poor
chance of survival despite maximal treatment. Triage decisions which are necessary when
resources are insufficient, may be helped by a scoring system but none have been formerly
validated. Withholding or with drawing treatment is a clinical responsibility and cannot be
replaced by a scoring system. but an accurate system could provide additional information and
be used as an aid rather than a rule.
94
Table 3. Costs and burdens associated with Intensive Care

Costs for the patient
death with physical discomfort, social isolation, psychological suffering, loss of
dignity
risk of survival with an unacceptable quality of life.
Costs for the family of the patient
psychological costs of having a relative in the ICU
financial costs of visiting, loss of income and possible long-term support for the
survivor.
Costs for health care personnel
psychological costs (frustration, guilt, loss of job satisfaction - especially in the
setting of clinical conflict)
Costs for the community
economic consequences - opportunity costs
ethical conflict between distributive justice and value of an individual.
Another application is in the field of clinical trials. Recent studies in septic shock suggest
that only patients with scores in the middle range benefited from certain therapies, while less
severely ill patients being adversely affected. Stratification of patients into bands of severity
before randomisation may be useful and a comparison of predicted risk with observed mortality
may also enable evaluation of the effectiveness of a treatment.
Conclusions
At present, illness severity scores are not recommended for routine use in clinical decision
making. Computerised probabilities of outcome may support clinical decisions in the future, but
this process must be under the control of medical personnel who understands the possible
benefits and limitations of applying these probabilities in the clinical setting. Currently
available scoring systems are not designed for, nor are appropriate for making triage decisions.
Prediction of outcome in individuals remains difficult even using a dynamic daily score.
Research on quality of life after discharge should be initiated with social scientists and patient
associations so that the development of scoring systems for the estimation of post-ICU
disability can be explored.
REFERENCES
1. Knaus WA, Draper EA, Wagner DP and Zimmerman JE. APACHE II - a severity of
disease classification system. Crit Care Med 1985;13:818-829.
2. Knaus WA, Wagner DP, Draper EA et al. The APACHE III prognostic system - risk
prediction of hospital mortality for critically ill hospitalised adults. Chest 1991;100:161936.
3. Legall JR, Lemeshow S, Saulnier F. A new simplified acute physiology score (SAPS II)
based on a European - North American multicentre study. JAMA 1993;270:2957-2963.
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Lemeshow S, Teres D, Klar J et al. Mortality prediction models (MPM II) based on an
international cohort of intensive care unit patients. JAMA 1993;270:2478-2486.
Lemeshow S, Lar J, Tere D et al. Mortality probability models for patients in the intensive
care unit for 48 and 72 hours - a propective multicentre study. Crit Care Med
1994;22:1351-1358.
Consensus Conference - Predicting outcome in ICU patients. Intensive Care Medicine
1994;20:390-397.
Chang RWS. Individual outcome prediction models for intensive care units. Lancet
1989;ii:143-146.
Atkinson S, Bihari D Smithies M et al. Identification of futility in Intensive Care. Lancet
1994;344:1203 - 120.
Silvester W, Bihari D. Overtime scoring systems. Curr Opinion Crit Care 1995;1:228 232.
Petros AJ, Marshall JC and van Saene HKF. Should morbidity replace mortality as an end
point for clinical trials in intensive care ? Lancet 1995;345:369-371.
Zimmerman JE, Wagner DP, Draper EA and Knaus WA. Improving intensive care unit
discharge decisions: supplementing physician judgement with predictions of next day risk
for life support. Crit Care Med 1994;22:1373-1384.
Cullen D, Civetta J, Briggs B, Ferrara L. Therapeutic intervention scoring system; a
method for quantitative comparison of patient care. Crit Care Med 1974;2:57-61.
Steingrub JS, Teres D. Comorbidities and organ failure assessment. Current Opinion in
Lemeshow S, Klar J and Teres D. Outcome prediction for individual intensive care
patients: useful, misused or abused ? Intensive Care Med 1995;21:770-776.
Boyd O, Grounds RM. Physiological scoring systems and audit. Lancet 1993;341:15731574.
Rowan K. The reliability of case mix measurement in intensive care. Current Opinion in
Sirio CA, Kimitaka T, Choichiro T et al. An initial comparison of intensive care in Japan
and the United States. Crit Care Med 1992;20:1207.
Malstam J, Lind L. Therapeutic intervention scoring system (TISS) - a method for
measureing workload and calculating costs in the ICU. Acta Anaesthesiol Scan
1992;36:758-763.
96
PULMONARY EMBOLISM
INTRODUCTION
Pulmonary embolism is the partial or complete obstruction of pulmonary arterial blood flow
by an intravascular embolus. While any material may traverse the venous system to embolize in
the pulmonary vasculature, thrombus, air, fat or amniotic fluid are the only materials that
commonly cause clinical symptoms. Massive pulmonary embolus is defined as an embolus
which obstructs greater than 50% of the pulmonary vasculature.
THROMBOEMBOLISM
Cause. Pulmonary thromboembolism occurs in 1%-2% of hospital patients1, and originates
from the lower limbs (two thirds of which have no signs or symptoms) in 95% of cases. An
upper limb thrombus is almost never responsible for a pulmonary thromboembolism2.
Clinical features3. Virtually all patients who have a pulmonary embolism have dyspnoea
that is sudden in onset. The dyspnoea may be transient, although with severe embolism it is
usually persistent and also often out of proportion to the degree and extent of the objective
abnormal findings. The common clinical features of a minor pulmonary thromboembolism
include dyspnoea, pleuritic chest pain, tachycardia, pyrexia and tachypnoea. The common
clinical features of a massive pulmonary thromboembolism include diaphoresis, syncope,
pallor, abdominal pain and a sudden need to evacuate bowels (due to a sudden increase in
venous pressure with splanchnic engorgement), and signs of tachycardia, hypotension, right
ventricular heave, prominent right atrial a waves, and splitting of the second heart sound.
Haemoptysis is a late sign associated with pulmonary thromboembolism and only occurs if
pulmonary infarction has occurred4. As the lung has three sources of oxygen (pulmonary
circulation, bronchial circulation and airways) pulmonary infarction occurs in only 30% of
patients with pulmonary thromboembolism and more often in those patients who have cardiac
failure. The incidence of symptoms and signs associated with pulmonary thromboembolism are
listed in Table 1.
Investigations: The investigations include:
1. Plasma biochemistry: analysis reveals an increase in LDH in 60% of cases and an
increase in bilirubin in 30% of cases.
2. Plasma XDPs (D-dimer). These are increased in patients with pulmonary
thromboembolism. The sensitivity of this test is 97% (when measured by enzyme-linked
immunosorbent assay). However, the specificity of the test is low, so while venous thrombosis
and pulmonary embolism may be unlikely in a patient with normal plasma D-dimer
concentrations (i.e. it is useful in ruling out pulmonary embolism), a positive result requires
confirmation by more specific imaging techniques5.
97
Pulmonary Embolism
Table 26.1 The incidence of symptoms and signs of pulmonary thromboembolism
Symptoms
Incidence %
Dyspnoea
Chest pain
Pleuritic
Non pleuritic
Apprehension
Cough
Haemoptysis
Diaphoresis
Syncope
A need to evacuate
bowels
80
70
10
60
50
30
30
10
10
Signs
Incidence %
Tachypnoea (respiratory rate > 16)

Auscultation: Crepitations, wheezing
Accentuation of P2
S3 or S4
Pleural friction rub
Elevated jugular venous pressure
Tachycardia (pulse rate > 100)
Pyrexia (greater than 37.8o C)
Diaphoresis
Thrombophlebitis
Cyanosis
Hypotension (Systolic pressure < 80 mmHg)
90
60
50
30
10
50
40
40
40
30
20
5
3. Arterial gas analysis: this reveals a low PaCO2 and PaO2 in 90% of cases of pulmonary
thromboembolism, due to hyperventilation and ventilation perfusion mismatch6. The end
expired CO2 is also reduced.
4. ECG: a transient rSR pattern in the anterior chest leads, S1, Q3-T3, clockwise rotation
and right axis deviation are the classical ECG findings of an acute pulmonary embolism,
although they are found in only 5-10% of cases. Commonly there is sinus tachycardia and T
wave inversion in the right precordial leads. Atrial flutter or fibrillation may also occur. While
the ECG may contribute very little to the diagnosis of pulmonary embolism, it often contributes
by excluding other disorders (e.g. myocardial infarction, pericarditis).
5. Chest X-ray: this may reveal oligaemic areas (reduced vascular markings) within the
lung fields, pulmonary artery hilar attenuation, and an elevated hemidiaphragm on the side of
the embolism. Atelectasis and pleural effusion are usually only seen with pulmonary infarction.
A normal chest X-ray, however, is the commonest finding in a patient with pulmonary
thromboembolism.
6. Echocardiography: an echocardiographic finding of a dilated right ventricle, mild to
moderate tricuspid regurgitation and a small (and often actively contracting) left ventricle, is
characteristic of pulmonary embolism, particularly when associated with shock. An
oesophageal echocardiograph may also demonstrate thrombus in the pulmonary artery.
7. Ventilation perfusion scan7. this may reveal a lung scan which is8,
- normal, which does not exclude the diagnosis of pulmonary emboli (i.e. there is a 9%
chance of pulmonary embolism)
- low probability (16% chance of pulmonary embolism)
- intermediate probability (33% chance of pulmonary embolism)
- high probability (greater than 88% chance of a pulmonary embolism)
8. Angiography: this has been used as the only precise method of diagnosing pulmonary
thromboembolism and should be performed in patients who have a high clinical probability for
pulmonary embolism associated with an intermediate, or low ventilation perfusion scan
probability9, and is mandatory if pulmonary embolectomy is to be performed. Pulmonary
angiography demonstrates pulmonary artery intravascular filling defects or 'cut-off' in patients
with pulmonary thromboembolism.
9. Swan-Ganz catheterization: special balloon catheters have been developed which enable
angiography to be performed at the bedside10. These may then be replaced by standard Swan98
Pulmonary Embolism
Ganz catheters which are used for fibrinolytic treatment and haemodynamic monitoring to
guide therapy. In one study of patients with a previously normal cardiovascular system, a mean
pulmonary arterial pressure of 22 mmHg correlated with a 30% pulmonary vascular
obstruction, and a mean pulmonary arterial pressure of 36 mmHg correlated with a 50%
pulmonary vascular obstruction11. The mean pulmonary arterial pressure rarely exceeded 40
mmHg, even with massive pulmonary thromboembolism (unless pulmonary hypertension
existed previously).
10. CT and MR Imaging: Spiral volumetric CT and pulmonary MR angiography are recent
techniques that have been used to detect pulmonary emboli in second to fourth division
pulmonary vessels with specificities and sensitivities approaching that of pulmonary
angiography12.
11. Ultrasound of iliac and femoral veins: As venous thromboembolism is one disorder
which may be asymptomatic or present with features of pulmonary embolism, with or without
deep vein thrombosis13, ultrasonography is often performed to assess the integrity of the lower
limb veins when the diagnosis of pulmonary thromboembolism is being considered.
Treatment. Pulmonary thromboembolism will either undergo natural fibrinolysis (and
resolve), or organisation. Resolution may be enhanced by administering heparin to allow
fibrinolysis to continue without thrombogenesis. Substantial angiographic resolution normally
occurs within the first 24 h, with further resolution being complete within 4-6 weeks.
Approximately 10% of patients with pulmonary thromboembolism undergo organization and
retain the pulmonary defect after 6 weeks14, and 1-2% of patients develop recurrent pulmonary
emboli with progressive pulmonary hypertension, hypoxaemia and right ventricular failure15.
Management of a patient with pulmonary embolism requires:
1.
2.
3.
Oxygen: inspired oxygen concentrations between 40 and 80% are administered by

facemask.
Cardiovascular resuscitation: this is usually needed only in massive thromboembolism,
unless cardiac failure has existed previously, and may require,
a. Intravascular fluid: a moderate increase in intravascular volume (i.e. 500 ml of 5%
albumin) may be beneficial, although an increase in right atrial pressure to greater
than 20 mmHg may be associated with a reduction in left ventricular filling as well
as an acute tricuspid regurgitation, due to an acute right ventricular dilation and
septal shift.
b. Inotropic agents: adrenaline is often considered the inotropic agent of choice as it
provides a positive inotropic effect, systemic vasoconstriction and adequate coronary
and cerebral perfusion16.
Anticoagulation: unless there is a contraindication, intravenous heparin and oral warfarin,
are initiated as soon as the diagnosis is suspected17. Therapy is begun as soon as possible
because untreated pulmonary thromboembolism has a mortality of 15%, which is reduced
to 8% (i.e. two-fold) if it is treated with anticoagulants, whereas haemorrhage from
heparin occurs in only 4% of patients (causing death in less than 0.5%). Heparin is
discontinued, usually after 2-3 days, when the prothrombin ratio is in the therapeutic
range (i.e. an international normalized ratio between 2.0-3.0), warfarin is then continued
for 3 months18, although it may be discontinued after 1 month in uncomplicated cases
(e.g. following surgery)19. The diagnosis of pulmonary embolism should always be
confirmed with objective tests, because anticoagulants need to be discontinued if
pulmonary embolism is not confirmed.
99
Pulmonary Embolism
4.
5.
Fibrinolytic therapy: while thrombolytic therapy clears the pulmonary arteries of clot, and
improves the blood pressure and cardiac output more rapidly than heparin, the mortality of
groups of patients treated by either thrombolysis or heparin is the same after 1 month20.
However, as the improvement in right ventricular function is greater and the pulmonary
artery perfusion defect is less 24 h later21, and one year later22, in patients treated with
fibrinolytic therapy when compared to those treated with heparin, the long term morbidity
(e.g. pulmonary hypertension and right ventricular failure) may be less with fibrinolytic
therapy. Fibrinolytic therapy is usually reserved for patients in whom the haemodynamic
effects and the reduction in pulmonary artery cross-section area due to the
thromboembolism are severe, although some believe that it is the therapy of choice for
any patient who has a high clinical suspicion and a high probability lung scan, for
pulmonary embolism, and in whom there is no contraindications for thrombolytic
therapy23.
One of three agents may be used; streptokinase (250,000 IU over 30 min, followed by
100,000/h for 12-24 h, then continuous heparinization), urokinase (4,400 IU/kg in 15 min
followed by 4,400 IU/kg/h for 12-24 h, then continuous heparinization) or rt-PA (100 mg
over 2 h followed by continuous heparinization)24. The latter may be the treatment of
choice25, as rt-PA has a short half-life (i.e. the coagulation defect may be rapidly reversed
and an embolectomy may be performed without delay), it has a more rapid effect when
compared to urokinase26, it does not cause hypotension (c.f., streptokinase), and it may be
more effective in fibrinolysing older clots27.
Pulmonary embolectomy: as 66% of patients who have massive pulmonary
thromboembolism die within the first hour28 and 80% die within 2 h, the remaining
patients are often able to be managed with inotropic, fibrinolytic and anticoagulant agents
without the need for surgery. Embolectomy should be considered in patients who have
more than 50% occlusion of the pulmonary arteries (i.e. massive pulmonary embolism),
with continuing deterioration 1 h after the onset of thrombolytic treatment29.
AIR EMBOLISM
The introduction of air into the venous system and into the pulmonary artery, produces an
acute obstruction to pulmonary blood flow and an associated pulmonary vasoconstriction due
to platelet aggregation and release. Air may also enter the systemic circulation through
pulmonary arteriovenous anastomoses or through a patent foramen ovale when the right atrial
pressure rises to levels greater than left atrial pressure. In humans, an intravenous bolus of 100
ml of air (1.5 ml/Kg) has been reported to be fatal30, although in critically ill patients 20-50 ml
may be lethal.
Causes. Causes of air embolism include, cardiopulmonary bypass, central venous line
insertion or disconnection, cerebral venous or sagittal sinus trauma during head up anaesthesia
for neurosurgery, and barotrauma (e.g. decompression, positive pressure ventilation,
pneumothorax, diagnostic or therapeutic procedures requiring insufflation with an inert gas,
laparoscopy, diving accident and orogenital sexual activity)31.
Clinical features. The symptoms include, dyspnoea, altered state of consciousness, itching,
abdominal pain, chest pain, and paraesthesia. The signs include, mill-wheel murmur, cyanosis,
agitation, diaphoresis, dyspnoea, wheezing, hypotension, pulmonary oedema, hemiparesis,
paraplegia, and seizures.
Investigations. The arterial gas analysis reveals severe hypoxia and hypocapnia. The end
expired carbon dioxide is decreased, and echocardiography reveals air in the right ventricle.
Treatment. As soon as an air embolism is suspected, the patient is placed head down in the
left lateral decubitus position (so that air will float to the apex of the right ventricle, a
100
Pulmonary Embolism
manoeuvre which has been shown to improve survival30). The head-down position may also
reduce the incidence of cerebral embolism if gas appears in the arterial system because the
cerebral vessels arise from the upper part of the aortic arch32. Blood and air is aspirated through
a Swan-Ganz or central venous catheter, accompanied by closed-chest compression if the
patient is pulseless. Inhalation of 100% oxygen and hyperbaric oxygen33 (even if it is delayed
for 12 h) may be of benefit.
FAT EMBOLISM
Fat embolism may be defined as a blockage of blood vessels by intravascular fat globules
ranging from 3-40 in diameter34. Histological fat deposition in the pulmonary capillaries
occurs in all patients who have long bone and pelvic fractures, although only 1-2% of these
patients develop a clinical syndrome known as the fat embolism syndrome. Histological
evidence of fat embolism may also be found following external cardiac compression, hepatic
injury, gas gangrene, pancreatitis, burns, prolonged high-dose corticosteroid therapy, diabetes
mellitus, joint reconstruction, liposuction, and with lipid infusions. However, in these
conditions the finding is usually a post mortem histological finding of no clinical significance.
Intramedullary fat is the source of the fat embolism in patients who have fractures. The fat
enters torn venules which are kept patent in the Haversion canals and enter the circulation at the
site of injury35.
Clinical syndromes
Fulminant fat embolism syndrome
This is a massive pulmonary fat embolism which produces severe right heart failure, shock
and often death within the first 12-24 h of injury36. The disorder is due largely to an acute
cardiovascular pulmonary obstruction by fat, although platelet aggregation and release may
also contribute to the pulmonary hypertension and oedema. The average lethal dose of fat is 2050 ml. The volume of marrow fat from a femur is approximately 70-100 ml.
Fat embolism syndrome
Cause. Fat collects in the pulmonary or systemic capillary network and is acted upon by
lipoprotein lipases (activated by catecholamine release) liberating high concentrations of toxic
free fatty acids (FFAs) locally, causing platelet aggregation, a mild DIC and disruption of the
pulmonary and cerebral capillary wall. Pulmonary histology reveals intra-alveolar
haemorrhage, fat within pulmonary capillaries and oedema. Cerebral histology reveals diffuse
cerebral oedema with multiple haemorrhagic petechiae37. The capillary disruption causes a
subacute syndrome known as the fat embolism syndrome.
Clinical features. The fat embolism syndrome is characterised by an asymptomatic period
following bony injury of 12-72 h (commonly 36 h, although up to 6 days has been described)
after trauma or manipulation of the trauma site, followed by a symptomatic period with
petechiae, respiratory effects and cerebral effects. The symptoms include dyspnoea, chest
discomfort, wheeze and haemoptysis. The signs include tachypnoea, haemoptysis, tachycardia,
pyrexia, crepitations, rhonchi, petechiae, pallor, somnolence, restlessness, agitation,
disorientation, seizures, coma, decerebration, extensor plantar responses, expressive aphasia,
choreoathetoid movements, rigidity, hemiparesis, scotomas and failure to regain consciousness
following a general anaesthetic.
The petechial rash is the only feature pathognomonic of the fat embolism syndrome and
usually appears on the second or third day after injury, with crops of petechiae being visible for
1-2 days before they fade38. They appear bilaterally in the axilla, neck, front of the chest,
101
Pulmonary Embolism
mouth, palate and conjunctiva. Petechiae only rarely appear on the legs and they are never seen
on the face or the posterior aspect of the body. The latter may be due to the fact that fat
globules float and therefore distribute to branches of the aorta that arise from the top of the
arch, and to the side of the body that is uppermost39. While fat globules may be found in
sputum, urine or blood, they are nonspecific findings that may be observed in conditions
unrelated to fat embolism.
Investigations. The investigations include:
1. Plasma biochemistry and haematology: this may reveal hypocalcaemia (due to binding
of the FFA to calcium40), and an elevated serum lipase, anaemia, and thrombocytopenia (the
platelet count is < 150,000 in 50-80%).
2. Chest X-ray: this usually shows signs of generalized interstitial and alveolar
opacification with no pleural effusion.
3. Arterial gas analysis: the blood gas analysis often reveals hypoxia and hypocapnia. If an
arterial gas analysis is performed regularly in patients with long bone fractures, hypoxia is often
the first sign of the development of the fat embolism syndrome. Cyanosis is usually not
associated with hypoxia as the patient is often anaemic.
4. ECG: apart from sinus tachycardia, the ECG is usually normal. Although it may reveal
nonspecific T wave inversion (particularly in early precordial leads, indicating right ventricular
strain) or RBBB.
5. Cerebral CT scan: this may show generalized cerebral oedema in patients with severe
cerebral fat embolism41.
6. Cerebral magnetic resonance imaging: this may be useful in detecting cerebral lesions
in patients with neurological clinical features of fat embolism and a normal CT scan42.
Treatment. There is no specific therapy for the fat embolism syndrome. Heparin, aspirin,
alcohol, glucose, clofibrate, alpha-blockers, corticosteroids, albumin, dextran and aprotinin
(Trasylol) have not been shown to reduce its incidence or mortality when given either to reduce
the incidence (i.e. as prophylaxis) or as treatment for fat embolism syndrome43. The fat
embolism syndrome is a self-limiting condition, its mortality being related to the degree of
respiratory failure44. Therefore, treatment is aimed at maintaining satisfactory pulmonary gas
exchange throughout the course of the disease, and follows the same principles of management
of ARDS. To prevent continued embolization, all long bone fractures should be promptly
immobilized, because fracture mobility exacerbates liberation of fat into medullary venous
sinusoids45. Recovery from the fat embolism syndrome is usually complete within 2-4 weeks,
although some neurological signs may remain for 3 months46. While complete neurological
recovery from cerebral fat embolism often occurs (e.g. full recovery from decerebrate
posturing47), in some cases permanent neurological disorders may persist48.
AMNIOTIC FLUID EMBOLISM
As amniotic fluid embolism often appears in the pulmonary circulation of peripartum
women who are asymptomatic49, the aetiology of an amniotic fluid embolism syndrome is
probably multifactorial (e.g. due to amniotic fluid, placental tissue, meconium or an excessive
maternal reaction to these products).
The amniotic fluid embolism syndrome occurs characteristically during labour, although it
has been described during first trimester curettage abortion, uncomplicated second and third
trimester pregnancy, amniocentesis, abdominal trauma in pregnancy, vaginal or caesarean
section delivery, and postpartum period. The clinical features include an abrupt onset of a 'bad
taste' in the mouth, cough, dyspnoea, cyanosis, tachycardia and hypotension which is usually
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Pulmonary Embolism
out of proportion to the blood loss. While acute right ventricular failure is the classical
haemodynamic defect, a global left ventricular dysfunction has also been described.50
Alteration in conscious state with agitation, seizures and coma may also occur. If the patient
survives, an ARDS and DIC often develop. The diagnosis of the amniotic fluid embolism
syndrome is a clinical one and based on the exclusion of other causes of ARDS. As amniotic
fluid embolism commonly occur during the peripartum period, the value of tests used to
demonstrate this (using a monoclonal antibody51 or zinc coproporphyrin52), in diagnosing the
amniotic fluid embolism syndrome, are yet to be determined. Treatment is aimed at maintaining
a satisfactory circulation and pulmonary gas exchange throughout the course of the disease, and
follows the same principles of management of shock and ARDS.
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AM, Come PC, Lee RT, Parker JA, Mogtader A, McDonough TJ, Braunwald E. Alteplase
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105
106
MANAGEMENT OF ACUTE ASTHMA

D. J. Cooper, MD, FRACP, FANZCA, FFICANZCA
Intensive Care Department,
Alfred Hospital,
Commercial Rd, Prahran,
VICTORIA 3181
Most patients with acute asthma respond to standard management in the Emergency
Department1. A small subset fail to respond despite therapy, deteriorate and require admission
to Intensive Care. Some of these patients will require intubation and mechanical ventilation2.
Others present after respiratory arrest, having been intubated outside hospital or in general
hospital wards3.
ASSESSMENT OF SEVERITY
Patients with severe asthma are typically breathless, anxious, sitting up in bed and focusing
on breathing. The general appearance of the patient is a good indicator of asthma severity and
must be carefully assessed. Important indicators are the use of accessory muscles, inability to
lie supine, diaphoresis, impaired sensorium and inability to speak. Of these, the last two may
signal patient exhaustion - a key reason for intubation and mechanical ventilation. Other
clinical signs of severe asthma include a respiratory rate of greater than 30 breaths per minute,
tachycardia greater than 120 breaths per minute, and a pulsus paradox of more than 12 mmHg
(normal being 4-10 mmHg)4. None of these latter signs, however, assist with deciding which
patient is coping well with their severe asthma and which is tiring. Wheezing may be a good
indicator of the presence of bronchospasm but is a poor indicator of severity. A quiet or silent
chest may indicate severe obstruction.
Direct measurement of the degree of airflow obstruction should be done using PEFR or
FEV1 unless the patient is so dyspnoeic or exhausted that the procedure might precipitate
respiratory arrest. Severe obstruction is indicated by a PEFR of less than 30-50% of predicted
or of the patients known personal best. This is usually a PEFR of less than 100-120 L/min.
PEFR measurements should not be performed in patients in extreme distress, because the result
is effort dependent and the attempt may precipitate respiratory arrest. When possible, repeated
measurements over time are of value as a failure to respond (or deterioration) after initial
therapy is one of the best ways to predict need for hospitalisation and intubation/mechanical
ventilation. Arterial blood gases have little role in patient assessment because hypoxemia is
rarely a problem, and hypercapnia is a late sign of impending respiratory arrest which should be
identifiable from the patients appearance. Decisions about hospitalisation and/or intubation
should be taken based on clinical assessment and the response to therapy.
STANDARD THERAPIES
1. Oxygen: Although hypoxemia is not usually a major problem in acute asthma, oxygen
should be given by face mask at a flow rate sufficient to maintain oxygen saturation above 9095% using a pulse oximeter. The 95% target is safer in patients at risk of rapid clinical
deterioration. When it occurs, hypoxemia is due to peripheral airway obstruction caused by
inflammation, mucus, and bronchoconstriction producing V/Q mismatch.
2. Inhaled Beta-adrenergic agonists: Inhaled beta-agonists are the mainstay of acute
therapy. The onset is rapid and they are usually well tolerated. Salbutamol is preferred, having
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Management of Acute Asthma

a greater beta-2 selectivity than alternatives and so resulting in less tachycardia. The dose is 2.5
-5 mg administered 0.5-1.0 hourly by a nebuliser. Dose frequency is usually altered depending
on asthma severity, and on the response to the first doses. When patients fail to respond, or
deteriorate, continuous nebulisation should be commenced until there is clinical improvement
or unless side effects (tachycardia, tremor, arrhythmias) are limiting. Larger and more frequent
doses are needed in acute asthma than in stable patients. Long acting beta agonists are not
indicated.
Metered dose inhalers (MDIs) combined with a spacing device are reported to be equally
effective as nebulisers5, but require better patient cooperation and are not successful in
exhausted patients. MDIs are not effective in ventilated patients6 although MDIs with spacers
during mechanical ventilation may be more effective.
3. Corticosteroids: The importance of early corticosteroids in acute asthma is being
increasingly appreciated. Corticosteroids decrease airway inflammation and swelling, potentiate
the beneficial effects of beta agonists, decrease beta agonist tachyphylaxis, and decrease mucus
production7. In a recent meta-analysis8, early corticosteroids reduced hospital admission rates
and the number of early relapses. The route of administration is not important with large oral
doses being as effective as parenteral. However, in patients at risk of intubation the parenteral
route is preferred.
Our practice is to commence hydrocortisone 250 mg iv as soon as possible after patient
presentation. There is no reason not to use other parenteral corticosteroids (methylprednisolone,
dexamethasone) instead, provided that the doses are equivalent. There are however, compelling
reasons not to use very large steroid doses as these have now been closely implicated in the
aetiology of acute necrotising myopathy. McFadden9 has carefully considered the minimum
dose of corticosteroid to achieve maximal efficacy in acute asthma (an important question
given the potential patient morbidity associated with the development of acute myopathy) and
recommends 150-225 mg/day of prednisolone or equivalent (180-250 mg hydrocortisone 6
hourly). Our practice is to commence 250 mg hydrocortisone 6 hourly iv and to dose reduce to
100 mg 6 hourly after 24 hours. Oral prednisolone may be commenced (60 mg 6 hourly
initially) when the patient is improving and the intubation risk has lessened.
4. Anticholinergics: Anticholinergics are synergistic with beta agonists in acute asthma.
Ipratropium bromide by nebuliser is preferred because the side effects of parenteral
anticholinergics are avoided. Although the optimum dose is not known, accepted doses are
0.25-0.5 mg by nebuliser 1 - 4 hourly. More frequent doses have also been reported to be more
effective in children10. Most authors consider that anticholinergics are second line agents which
nevertheless have clear clinical value.
5. Intravenous beta adrenergic agonists: Salbutamol may be given by intravenous
infusion when inhaled salbutamol is ineffective. The optimum dose range is 1-10 g/min, and
side effects are more effectively avoided by using continuous intravenous infusion than by
bolus dosing (100- 300 g iv).
The use of intravenous beta-adrenergic agonists is controversial, with serious toxicity
sometimes reported (cardiac arrythmias, myocardial necrosis) and less severe toxicity (lactic
acidosis) almost inevitable if doses of salbutamol greater than 10 g/min are used. Our practice
is to commence intravenous salbutamol infusions in patients who have not responded to inhaled
salbutamol or in those in whom respiratory arrest is imminent or has already occurred.
6. Adrenaline: Use of adrenaline in acute asthma is also controversial. Compared to
salbutamol, adrenaline has the theoretical advantage of providing alpha-adrenergic agonist
activity which may cause mucosal vasoconstriction and decrease airway oedema. The dose is
adrenaline 0.3-0.5 mg (0.3 - 0.5 ml of 1: 1,000) sc or im which are equally effective in patients
rapidly deteriorating outside hospital and who do not have intravenous access. In hospital,
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intravenous adrenaline is best, but great care should be given to use small doses (0.1 mg or 1 ml
of 1:10,000 adrenaline iv every 2-3 minutes) followed by an infusion of 0-10 g/min. ECG
monitoring is mandatory. Larger doses are very commonly followed soon after by
supraventricular tachyarrythmias. Adrenaline also is preferred in patients with acute
bronchospasm due to anaphylaxis. This distinction can be difficult and is sometimes made in
retrospect after a complete history, sensitivity testing and/or blood tryptase concentrations
become available.
Some clinicians use intravenous adrenaline as the next therapy after failure of intravenous
salbutamol, and there are many anecdotal reports of success. My practice is often to use
adrenaline either down the ET tube (5-10 ml of 1:10,000 solution), or by intravenous infusion
when other therapies including intravenous salbutamol have failed. A well designed,
prospective, controlled trial of intravenous adrenaline versus intravenous salbutamol in patients
failing to respond to standard therapy is required. Intravenous adrenaline is also the treatment
of choice if respiratory arrest is complicated by bradycardia and/or hypotension. The important
side effects include cardiac arrythmias and lactic acidosis.
7. Aminophyline: The place of intravenous aminophyline in the management of acute
asthma is even more controversial. Clinical benefit has been difficult to demonstrate (when
used in addition to standard therapy) and side effects (e.g. tremor, nausea, vomiting,
palpitations and major arrythmias) are not uncommon. A reasonable conclusion from the
available literature is that aminophyline does not have any measurable benefit in addition to
standard therapies when it is given to all patients with acute asthma presenting to the
emergency department11,12. This is most likely to be the case, because most patients with acute
asthma respond rapidly after nebulised salbutamol and steroids. However, in patients who have
not responded well to initial standard therapy, evidence suggests that aminophyline does have
additional benefit13. This benefit has been well demonstrated in children14. The dose is
aminophyline 5 mg/kg iv loading dose followed by 0.5 mg/kg/hour. Blood theophyline
concentrations should be repeatedly checked and toxic blood levels avoided.
ALTERNATIVE THERAPIES
There are many anecdotal reports of patients having acute asthma improving after another
therapy has been added to conventional drugs. These reports are almost impossible to interpret
because the natural history of severe asthma is of rapid (but unpredictably timed) improvement
in most patients.
1. Magnesium: There are many anecdotal reports of benefit although there are also two
prospective studies15,16 which show no benefit for magnesium sulphate in acute asthma.
Therefore, although magnesium sulphate is a very safe drug and although blood magnesium
concentrations are often low in patients with acute asthma, magnesium is not recommended for
routine therapy. However, because it is safe and cheap it is my practice to magnesium to
patients in respiratory arrest or to those who have failed standard therapy. The dose is 2 gm
magnesium sulphate iv over 15-20 minutes. Blood concentrations of about twice baseline will
result.
2. Ketamine: Ketamine is a bronchodilating sedative and analgesic agent which has
been suggested for intubation and for post intubation sedation. The dose is 1 - 2 mg/kg iv. by
slow injection. The disadvantages are that it is less predictable than conventional induction
agents and the side effects including tachycardia, decreased seizure threshold, and mood
disturbance including delirium are all potentially dangerous in acute asthma.
3. Volatile anaesthetics: All volatile anaesthetics are bronchodilators and improvement
in cases of acute asthma have been reported using ether, halothane, enflurane, and isoflurane.
Of these alternatives there has been most clinical experience with ether and halothane, but
109

isoflurane is preferred because of the decreased risk of myocardial depression and arrythmias,
and owing to the ease of administration17,18.
Use of volatile anaesthetics requires intubation, an anaesthesia machine, and a system for
scavenging. If these requirements are available then isoflurane may be a practical
bronchodilating anaesthetic in the poorly responsive patient.
4. Heliox: Heliox is a blend of helium and oxygen (80:20, 70:30, 60:40) which, being
less dense than air decreases airway resistance and may decrease work of breathing, muscle
fatigue, and lung hyperinflation. All studies to date in intubated and non intubated patients have
been uncontrolled, so although some quoted improvements have been extremely rapid19, these
are impossible to separate from the natural history of the disease. One problem with heliox is
that oxygen concentration and tidal volume measuring devices require recalibration to give
meaningful results due to the different density of the gas. We do not use or recommend heliox
at this time but instead view it as a promising but unproven therapy.
INTUBATION
Patients with acute asthma who require intubation are commonly exhausted, hypercapnic,
and may also be hypoxic. The addition of endogenous catecholamines, hypercapnia and
arrythmogenic drugs makes these patients liable to arrythmias. Intubation should be performed
before respiratory arrest when the patient is tiring and is no longer able to maintain a minute
volume sufficient to prevent a rising PCO2. Intubation must then be fast and efficient. This is
not an occasion to teach intubation. In most patients a standard rapid sequence induction is best
as alternative methods all carry risks. Blind nasal intubation in the sitting patient has also been
recommended.
MECHANICAL VENTILATION
Mechanical ventilation of patients with acute asthma has a high risk of complications. The
primary problem is worsening gas trapping which progressively increases intrathoracic pressure
and causes cardiovascular compromise and pulmonary barotrauma. Controlled mechanical
hypoventilation is essential to allow trapped gas to escape and to avoid these complications.
Hypercapnia is the inevitable consequence of hypoventilation, but is well tolerated. Hypoxia is
rarely a problem. During stabilisation and initial assessment patients should be sedated and
paralysed. Paralysis is often essential to get initial control, but thereafter should be minimised.
(1) First ventilator settings
Respiratory rate: A slow respiratory rate is essential to allow time for exhalation of the
tidal volume and trapped gas. Rates of 6-8 breaths per minute are appropriate. When intubation
and mechanical ventilation has been followed by hypotension and cardiovascular collapse the
best first action is to cease mechanical ventilation altogether for 20-30 seconds. This allows
time for intrathoracic pressure to decrease, cardiac preload to return, and cardiac output to
restore. The sometimes quoted Lazarus Phenomenon occurs when a patient with acute
asthma is intubated for respiratory arrest. Excessive ventilation is followed by loss of cardiac
output and apparent cardiac arrest. Such patients may rapidly recover after resuscitation
attempts (including assisted ventilation) have ceased.
Tidal Volume (VT): High tidal volumes are associated with increased peak airways
pressure (PIP). Many clinicians therefore include small tidal volumes in their asthma
management strategies. We prefer to commence management with a standard VT of 10 ml/kg
(about 700 ml) and to alter minute volume when necessary by altering respiratory rate.
110

Inspiratory Flow rate: A fast inspiratory flow rate produces a long expiratory time
(beneficial by allowing time for exhalation) but is directly related to the peak airways
pressure20. A high flow will always be associated with high PIP but may have less trapped gas
than a low flow strategy. We therefore commence with a standard flow of 80-100 L/min and do
not use PIP to assess gas trapping.
PEEP: The use of PEEP in patients with gas trapping on mechanical ventilation is neither
logical nor effective.
Summary: First ventilator settings; RR=8, VT = 10 ml/kg, VI = 80-100 L/min.
(2) Assessment of gas trapping.
Listening to the chest for bronchospasm provides very little information.
Four techniques are available. All require the patient to be paralysed for the initial
measurements.
Plateau airway pressure. This is measured by inserting a 0.5 sec end-inspiratory occlusion
and measuring the pressure at this time. Plateau pressure is directly proportional to the degree
of hyperinflation and should be maintained less than 20 cm H2O.
Autopeep. This is the pressure measured by airway occlusion at the end of exhalation and
is proportional to the trapped gas volume. Maintain less than 12 cm H2O.
Waveforms. Observation of the flow graphics available on many ventilators provides an
indicator of whether flow and volume have returned to baseline before the next breath.
Unfortunately this rapid indicator is not quantitative.
VEI. Addition of a bellows to the expiratory limb of the ventilator enables the
measurement of all exhaled gas during a period of apnoea long enough for the bellows to cease
rising (about 20 secs). This measured volume at end inspiration (called VEI by Tuxen20)
comprises the sum of the tidal volume and the trapped gas. Being a direct measurement of
volume it has advantages over the other techniques. Tuxen has demonstrated that if the VEI is
maintained less than 20 ml/kg then hypotension and barotrauma are eliminated as
complications during mechanical ventilation of patients with acute asthma.
Peak airways pressure (PIP). A single value for PIP is not a good indicator of gas trapping,
because of the dependence of the measure on inspiratory flow rate. Some clinicians maintain
PIP less than 50 cm H2O but this does not eliminate the risk of gas trapping and is less logical
than the other measures. However, during early patient assessment and ventilator adjustment, a
useful rapid technique can be to commence ventilation at a very slow RR (of about 4
breaths/min) and then to slowly increase RR while keeping flow and VT constant. A sharp rise
in PIP indicates gas trapping and the point where further increases in RR should be avoided.
(Plateau pressure and VEI will then also increase).
PERMISSIVE HYPERCAPNIA
Controlled hypoventilation causes hypercapnia, and the acceptance of hypercapnia to
enable prevention of more important complications has been termed Permissive
hypercapnia21. Hypercapnia is surprisingly well tolerated in patients with asthma.
Although acute respiratory acidosis decreases myocardial contractility, in patients with
asthma and hypercapnia, cardiac output is instead markedly increased, probably due to the
combined effects of catecholamines (endogenous and administered) and of vasodilation from
hypercapnia. A controlled study of bicarbonate therapy in patients with acute asthma and
hypercapnic acidosis found no evidence of cardiac compromise and no beneficial effects of the
bicarbonate22. Therefore our practice is to tolerate the gradual development of hypercapnia
111

regardless of the PCO2 (sometimes greater than 100 mmHg), and not to use bicarbonate
infusions unless renal failure prevents normal renal compensation.
MYOPATHY
There have now been many reports of patients on mechanical ventilation who have
developed acute necrotising myopathy (ANM), quite different to the critical illness
polyneuropathy often described in other critically ill patients. Many of these patients had
asthma, but an identical myopathy has also been described in heart/lung transplant patients and
neurosurgical patients. Unlike other types of myopathy, ANM is associated with increased
blood CPK concentrations (and routine blood CPK measurements in predisposed patients may
provide an early warning for the development of overt myopathy). A current review of the
literature23 indicates that this condition is predominantly iatrogenic and is due to high dose
corticosteroids combined with muscle inactivity from muscle relaxants. Many other causative
factors have been proposed but are less likely. Muscle inactivity due to muscle relaxants
appears to sensitise muscle to the development of acute steroid myopathy. Associations with
specific muscle relaxants has been suggested (eg. vecuronium) but ANM has now been
reported after many different relaxants.
The most important measures to decrease the incidence of this often severely incapacitating
condition are (1) use the minimum corticosteroid dose known to be effective for the condition,
(2) paralyse only when absolutely necessary and use heavy sedation instead when possible, (3)
use bolus rather than infusions of muscle relaxants, to minimise total dose and provide periods
of partial skeletal muscle activity, (4) avoid renally excreted muscle relaxants in patients with
renal failure because not only will the duration of action be prolonged but the duration of
complete muscle inactivity will also be prolonged, predisposing to ANM, (5) use peripheral
nerve stimulators routinely to monitor neuromuscular blockade and decrease the risk of relative
overdose.
REFERENCES
1.
Corbridge TC, Hall JB. The assessment and management of adults with status
asthmaticus. Am J Respir Crit Care Med. 1995;151:1296-1316.
2.
Worthley LIG. Synopsis of Intensive Care Medicine. 1994;357-368.
3.
Oh TE. Intensive Care Manual. 3ed. 1990;192-201.
4.
Fitzgerald JM, Hargreave FE. The assessment and management of acute life threatening
asthma. Chest 1989;95:888-894.
5.
Idris AH, McDermott MF, Raucci JC, Morrabel A, McGorray S, Hendeles L.
Emergency department of severe asthma:metered dose inhaler plus holding chamber is
equivalent in effectiveness to nebulizer. Chest 1993;103:665-672.
6.
Newhouse MT, Fuller HD. Rose is a rose is a rose? Aerosol therapy in ventilated
patients: nebulizers versus metered-dose inhalers - a continuing controversy. Am Rev
Respir Dis 1993;148:1444-1446.
7.
Barnes NC. Effectiveness of corticosteroids in acute severe asthma. Thorax
1992;47:582-583.
8.
Rowe BH, Keller JL, Oxman AD. Effectiveness of steroid therapy in acute
exaccerbations of asthma: a meta-analysis. Am J Emerg Med. 1992;10:301-310.
9.
McFadden ER. Dosages of corticosteroids in asthma. Am Rev Respir Dis
1993;147:1306-1310.
10. Schuh S, Johnson DW, Callahan S, Canny G, Levison H. Efficacy of frequent nebulised
ipratropium bromide added to frequent high dose albuterol therapy in severe asthma. J
Pediatr 1995;126:639-645.
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23.
Murphy DG, McDermott MF, Rydman RJ, Sloan EP, Zalenski RJ. Aminophyline in the
treatment of acute asthma when beta-2 adrenergics and steroids are provided. Arch
Intern Med 1993;153:1784-1788.
Coleridge J, Cameron P, Epstein J, Teichtahl H. Intravenous aminophylline confers no
benefit in acute asthma treated with intravenous steroids and inhaled bronchodilators.
Aust NZ J Med 1993;23:348-353.
Pierson WE, Bierman CW, Stamm SJ, VanArsdel PP. Double blind trial of
aminophyline in status asthmaticus. Pediatrics 1971;48:642-646.
Yung M, South M. Severe acute asthma in children: is it time to stop using
aminophylline? Anaesth Intens Care 1997 (in press).
Green SM, Rothrock Sg. Intravenous magnesium for acute asthma: failure to decrease
emergency treatment duration or need for hospitalisation. Ann Emerg Med 1992;21:260265.
Tiffany BR, Berk W, Todd IK, White S. magnesium bolus or infusion fails to improve
expiratory flow in acute asthma exaccerbations. Chest 1993;104:831-834.
Johnston RG, Noseworthy TW, Friesen EG, Yule HA, Pharm M, Shustack A. Isoflurane
therapy for status asthmaticus in children and adults. Chest 1990;97:698-701.
Bierman MI, Brown M, Muren O, Keenan RL, Glauser FL. Prolonged isoflurane
anesthesia in status asthmaticus. Crit Care Med 1986;14:832-833.
Gluck EH, Onorato DJ, Castriotta R. Helium-oxygen mixtures in intubated patients with
status asthmaticus and respiratory acidosis. Chest 1990;98:693-698.
Tuxen DV, Lane S. The effects of ventilatory pattern on hyperinflation, airway
pressures, and circulation in mechanical ventilation of patients with severe airflow
obstruction. Am Rev Respir Dis. 1987; 136:872-879.
Tuxen DV. Permissive hypercapnic ventilation. Am J Respir Crit Care Med. 1994; 150:
870-874.
Cooper DJ, Cailes JB, Scheinkestel CD, Tuxen DV. Does bicarbonate improve cardiac
or respiratory function during respiratory acidosis and acute severe asthma. Am Rev
Resp Dis 1993; 147(4):A614
Nates JL, Cooper DJ, Day B, Tuxen DV. Acute severe weakness syndromes in critically
ill patients - a review. Anaesth Intensive Care (submitted).
113
114
POSTOPERATIVE MANAGEMENT OF CARDIAC SURGERY

PATIENTS
INTRODUCTION
Management of any acute postoperative cardiac surgical patient (i.e. coronary artery bypass
grafting, cardiac valve replacement, aneurysectomy, ventricular or atrial septal defect repair)
usually follows common principles which involve monitoring and correcting abnormalities
created by surgery, anaesthesia and cardiopulmonary bypass. Postoperative cardiac
performance will largely depend on the surgical result (e.g. effective revascularization or valve
repair) and the cardiopulmonary bypass time. If the cardiopulmonary bypass time is greater
than 150 min there is a greater risk of myocardial dysfunction (causing hypotension and
difficulty in weaning from cardiopulmonary bypass), clotting defects, air and cellular aggregate
microembolism, and ARDS from activation of inflammatory mediators. Postoperative
complications may also arise from surgical trauma which may cause atheromatous (cholesterol)
cerebral emboli, dissection of the aorta and damage to cardiac conducting pathways.
Postoperative management includes monitoring and treatment of haemodynamic instability
(i.e. hypotension and hypertension), cardiac arrhythmias, hypothermia, electrolyte and acidbase disturbances, respiratory insufficiency, bleeding disorders, renal impairment, and
neurological dysfunction, and (apart from specific surgical problems), is best performed using a
system oriented approach1.
MANAGEMENT
Postoperative transfer and ICU handover
As with any patient transfer from theatre to the ICU this period is hazardous. Before leaving
theatre, blood pressure, pulse, arterial saturation, oxygen supply, suction, mechanical
ventilation, and intravenous infusions (e.g. inotropes, vasodilators, blood) must be maintained
and adequately monitored.
On arrival to ICU a handover is performed and the patient's ventilation, wound drainage and
monitoring are reestablished and a chest X-ray, ECG, APTT, INR, complete blood picture and
a plasma biochemical screen are performed.
Circulation
Blood pressure, pulse and central venous pressure are monitored continuously. During the
first 30-60 min, if the peripheral perfusion is poor, femoral artery pressure measurement may be
required as there can be up to 30 mmHg difference between mean aortic and radial artery
pressure2. For long and complex procedures, or if the patient has a previously known poor
cardiac function, Swan-Ganz catheterization is performed to provide complex haemodynamic
monitoring. Temporary ventricular and atrial pacing wires may be inserted if cardiac surgery is
performed in and about the junctional tissue, to allow cardiac pacing if complete heart block
occurs. The blood pressure should be regulated between a MAP of 70 - 100 mmHg3, and blood
is usually administered if the haemoglobin value is 10 g/100 ml or less.
115
Postoperative Management of Cardiac Surgery Patients

Hypotension: severe hypotension (i.e. MAP less than 60 mmHg) should be treated
immediately as coronary perfusion is compromised at these levels and often leads to a further
reduction in blood pressure, graft occlusion (signalled by ST segment elevation), bradycardia
and ventricular fibrillation. Immediate treatment includes intravenous fluids (i.e. blood, 5%
albumin), pacing, inotropic agents (e.g. adrenaline at 2 - 10 ug per min or i.v. calcium chloride
3.4 mmol, if the ionized plasma calcium < 1.20 mmol/l), intra-aortic balloon counterpulsation
(often initiated if the patient has been difficult to wean from cardiopulmonary bypass)4 and
reoperation if cardiac tamponade or graft occlusion is deemed to be present.
As FFAs require more oxygen to generate ATP than glucose, infusions of glucose, insulin
and potassium may reduce the oxygen requirement in an ischaemic myocardium5. In patients
with refractory left ventricular failure after cardiopulmonary bypass, infusions of glucose,
insulin and potassium (80 mmol potassium chloride and 80 u insulin, in a litre of 50% glucose
infused at 0.5 - 1.0 ml/kg/h) have been reported to be of benefit by increasing cardiac output,
renal perfusion and skeletal muscle perfusion and reducing systemic vascular resistance6,7.
Triiodothyronine administration immediately following coronary artery bypass surgery does
not alter mortality or morbidity8.
Hypertension: if the MAP is greater than 95 mmHg the patient is given some intravenous
sedation (e.g. midazolam 1-2 mg, morphine 1-2 mg) ventilation may be increased if the PaCO2
is greater than 40 mmHg, and glyceryl trinitrate (150 mg in 500 ml 5% dextrose, i.e 300 g/ml)
is administered at 25 - 200 g/min (i.e. 5 - 40 ml/h). Sodium nitroprusside (50 mg in 50 ml of
5% dextrose, i.e. 1000 g/ml) is added (10 - 166 g/min, i.e. 0.6 -10 ml/h) if hypotension
becomes resistant to glyceryl trinitrate. Intravenous magnesium sulphate (2 - 8 mmol bolus over
2 - 5 min, up to 30 - 40 mmol during the first 12 h post operative period) may also be used to
control hypertensive episodes; it also reduces the postoperative analgesic requirement and
appears to promote normal sleep9.
Arrhythmias: ECG monitoring is continued for 48 h. Apart from ventricular or
supraventricular ectopic beats, the commonest arrhythmias are atrial flutter and atrial
fibrillation which are treated along conventional lines (e.g. intravenous digoxin, amiodarone,
verapamil, sotalol or cardioversion, depending on the blood pressure and ventricular rate).
Hypokalaemia and hypomagnesaemia should be corrected as they may provoke ventricular and
supraventricular tachyarrhythmias. Bradycardias are best treated with AV sequential pacing
although atropine or isoprenaline may be used acutely in the absence of temporary pacing
wires. Cardiac arrest (i.e. asystole, ventricular fibrillation or pulseless electrical activity) is also
managed along conventional lines, although external cardiac compression is usually not
performed as defibrillation is often available within 20-30s of the cardiac arrest in most
instances. If cardiac compression is required, internal cardiac compression is performed during
the cardiac arrest if an emergency sternotomy is required to diagnose and manage acute
tamponade, cardiac rupture or bleeding problems. In one study, internal cardiac compression
was used successfully to resuscitate 75% (i.e 18 of 24) postoperative cardiac patients in whom
resuscitation with external cardiac compression had failed to revive the patient within 5 min.
By comparison, 20% (5 of 15) of patients were successfully resuscitated, when external cardiac
compression only was performed10.
Respiration
Routine postoperative cardiac cases may be extubated after 6-8 h (i.e. at the termination of
the anaesthetic)11, although more complex cases are usually sedated and ventilated for a further
12-18 h (i.e. overnight). PEEP is not used routinely because of its cardiovascular depressant
and barotrauma (e.g. higher incidence of pneumothorax particularly in patients who have
internal mammary grafts) effects.
116

Post operative atelectasis and reduction in air entry particularly to the basal segments of the
left lung are observed in up to 90% of postoperative cardiac surgical patients, and is usually of
little clinical significance12. Pulmonary oedema (cardiogenic and non cardiogenic) may also
complicate the postoperative period particularly if poor left ventricular function, prolonged
bypass time and a difficult 'redo' has occurred. Phrenic nerve paralysis may complicate post
bypass surgery in 1.5% of patients13 (particularly if topical iced slush is poured into the
pericardial sac during surgery14) and may lead to postoperative respiratory failure if it is
bilateral.
Shivering
While the patient may return to the intensive care unit with a core temperature of 33 - 35oC,
episodes of shivering or rigidity usually occur 2-4 h postoperatively and often when the
temperature has almost returned to normal (particularly if volatile anaesthetic agents or high
dose fentanyl have been used). These episodes are often accompanied by sinus tachycardia and
hypertension and are controlled by either magnesium sulphate (8-10 mmol i.v.) or pethidine (25
mg i.v.). If the shivering and rigidity reoccur a further dose of pethidine or magnesium may be
administered or if it becomes resistant, a nondepolarizing muscle relaxant (e.g. vecuronium 4
mg i.v.) may be given.
Vomiting
When extubated within 6-8 h after cardiac surgery the incidence of nausea and vomiting is
approximately 37%15 (i.e similar to other types of surgery16). As dopaminergic (DA2),
cholinergic (muscarinic), histaminic (H1) and serotonergic (5-HT3), receptors appear to play an
important role in mediating the emetic response, antiemetic agents that act on one or more of
these receptors17 (e.g. metoclopramide, prochlorperazine, droperidol, ondansetron) are often
used postoperatively.
Renal and electrolytes
The urine volume is measured and recorded hourly. Post bypass surgery is often associated
with a 4-6 h diuresis in the postoperative period which is then followed by an antidiuresis with
urine outputs varying between 0.25 to 0.5 ml/kg/h for approximately 12 h. Potassium and
magnesium requirements are variable and depend on the patient's preoperative electrolyte
status, the amount of cardioplegia used and the postoperative diuresis. Correction regimens for
hypokalaemia and hypomagnesaemia are similar to those recommended for acute myocardial
infarction. For example, hypokalaemia, particularly in association with ectopic beats or
tachycardia, is corrected with intravenous potassium chloride infused at 10 mmol/h and
repeated as necessary (rechecking the potassium level every hour) until the serum potassium is
4.0 - 4.5 mmol/l (or plasma potassium is 3.5 - 4.0 mmol/l)18. Hypomagnesaemia may be
corrected with magnesium sulphate administered as an 8 mmol intravenous bolus (over 5 min),
followed by an infusion of 65 mmol in 50-500 ml of 5% dextrose over 24 h19, although some
infuse 20 mmol of magnesium sulphate in 500 ml of 5% dextrose over 6-8 h in all patients as
the serum magnesium levels may be of little use in determining the post cardiac surgery
patient's magnesium requirements20. In one study, an intravenous infusion of 8 mmol of
magnesium chloride (over 20 min) decreased the incidence of ventricular arrhythmias and
increase the cardiac index in post cardiac surgery patients21.
Postoperative intravenous fluids for the first 24 h are usually administered at 1.2 ml/kg/h
(i.e. approximately 2 l/70 kg/24 h) containing 0-1 mmol of sodium/kg/24 h. The intravenous
fluid intake is often halved for the next 24 h and ceased for the third and following
postoperative days as the patient is then able to drink.
117
Surgical problems
Bleeding: Continuous bleeding may be due to poor surgical haemostasis, coagulation
abnormalities (e.g. partial heparin reversal, heparin rebound, warfarin therapy, hepatic failure,
DIC), or platelet abnormalities (aspirin or other NSAID therapy, uraemia). Heparin rebound
(i.e. heparin effect returns after 4 h due to release of stored heparin22) or partial heparin reversal
(APTT is usually greater than 40 s) is treated with 50 mg i.v. of protamine. While a large
excess of protamine can act as an anticoagulant a small amount of protamine excess has no
effect on bleeding23 and is often desirable to prevent heparin rebound. Fresh frozen blood and
platelet transfusions may also be used to correct coagulation abnormalities, and intravenous
desmopressin (0.3 g/kg over 30 min) are also effective in decreasing postoperative bleeding in
cardiac surgical patients, particularly those who have platelet dysfunction (e.g. uraemia,
preoperative NSAID therapy)24,25. Aprotinin has also been used to reduce postoperative
bleeding after cardiopulmonary bypass surgery26, although it may be associated with an
increased risk of graft occlusion and myocardial infarction27.
Reoperation may be necessary if bleeding continues at 200 ml/h or greater for three hours,
or is more than 400 ml in 1 h as it usually indicates poor surgical haemostasis.
Chest tubes: these are left in until drainage is less than 20 ml/h for three hours (usually 24-48
h postoperatively) and there is no air leak.
Prophylactic antibiotics: as the commonest postoperative infection is caused by
Staphylococcus aureus, prophylactic postoperative antibiotic therapy (cephalothin 1 g 6-hourly
for 48 h) for coronary artery bypass surgery or prosthetic valve surgery is often used to reduce
the incidence of infection. Administration of antibiotics for a longer than 2 days is of no added
benefit28.
Neurologic dysfunction
Postoperative cerebral dysfunction occurs in many cardiac surgery patients. The defects are
often subtle and usually transient varying from an acute confusional state (in up to 28% of
patients29, due to sleep deprivation, pain, alcohol or sedative withdrawal), to a hemiparesis due
to cerebral hypoperfusion, thrombosis or embolism (air, calcium or cholesterol particles).
Peripheral neuropathies may also occur due to interoperative injury to the brachial plexus
(more often with mammary artery grafting) or femoral or peroneal nerve.
REFERENCES
1.
2.
3.
4.
5.
6.
Worthley LIG. A system structured medical record for intensive care patient
documentation. Crit Care Med 1975;3:188-191.
Mohr R, Lavee J, Goor DA. Inaccuracy of radial artery pressure measurement after
cardiac operations. J Thorac Cardiovasc Surg 1987;94:286-290.
Editorial. Anaesthesia for patients with coronary disease. Br Med J 1980;281:341.
Scheidt S, Collins M, Goldstein J, Fisher J. Mechanical circulatory assistance with the
intraaortic balloon pump and other counterpulsation devices. Prog Cardiovasc Dis
1982;25:55-76.
Oliver MF, Opie LH. Effects of glucose and fatty acids on myocardial ischaemia and
arrhythmias. Lancet 1994;343:155-158.
Gradinak S, Coleman GM, Taegtmeyer H., Sweeney MS, Frazier OH. Improved cardiac
function with glucose-insulin-potassium after coronary bypass surgery. Ann Thorac Surg
1989;48:484-489.
118
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
Report of a Meeting at University of Texas Houston Health Science Center, Texas Heart
Institute, Houston. Metabolic support for the postischaemic heart. Lancet 1995;345:15521555.
Bennett-Guerrero E, Jiminez JL, White WD, et al. Cardiovascular effects of intravenous
triiodothyronine in patients undergoing coronary artery bypass graft surgery: a
randomized, double-blind, placebo-controlled trial JAMA 1996;275:687-692.
Tramr MR, Schneider J, Marti R-A, Rifat K. Role of magnesium sulfate in postoperative
analgesia. Anesthesiology 1996;84:340-347.
Raman J, Saldanha RF, Branch JM, Esmore DS, Spratt PM, Farnsworth AE, Harrison
GA, Chang VP, Shanahan MX. Open cardiac compression in the postoperative cardiac
intensive care unit. Anaesth Intens Care 1989;17:129-135.
Chong JL, Grebenik C, Sinclair M, Fisher A, Pillai R, Westaby S. The effect of a cardiac
surgical recovery area on the timing of extubation. J Cardiothorac Vasc Anesth 1993;7:15.
O'Donohue WJ Jr. Prevention and treatment of postoperative atelectasis. Chest
1985;87:1-2.
Markland ON, Moorthy SS, Mahomed Y, et al. Postoperative phrenic nerve palsy in
patients with open-heart surgery. Ann Thorac Surg 1985;39:68.
Marco JD, Hahn JW, Barner HB. Topical cardiac hypothermia and phrenic nerve injury.
Ann Thorac Surg 1977;23:235.
Grebenik CR, Allman C. Nausea and vomiting after cardiac surgery. Br J Anaesth
1996;77:356-359.
Palazzo MGA, Strunin L. Anaesthesia and emesis. I: aetiology. Can Anaesth Soc J
1984;31:178-187.
Grunberg SM., Hesketh PJ. Control of chemotherapy-induced emesis. N Engl J Med
1993;329:1790-1796.
Standards and guidelines for cardiopulmonary resuscitation (CPR) and emergency
cardiac care (ECC). JAMA 1992;268:2172-2288.
Woods KL, Fletcher S, Roffe C, Haider Y. Intravenous magnesium sulphate in suspected
acute myocardial infarction: results of the second Leicester Intravenous Magnesium
Intervention Trial (LIMIT-2). Lancet 1992;339:1553-1558.
Vyvyan HAL, Mayne PN, Cutfield GR. Magnesium flux and cardiac surgery. A study of
the relationship between magnesium exchange, serum magnesium levels and
postoperative arrhythmias. Anaesthesia 1994;49:245-249.
England MR, Gordon G, Salem M, Chernow B. Magnesium administration and
dysrhythmias after cardiac surgery. A placebo-controlled, double-blind randomised trial.
JAMA 1992;268:2395-2402.
Pifarre R, et al. Management of postoperative heparin rebound following cardiopulmonary
bypass. J Thorac Cardiovasc Surg 1981;81:378.
Ellison N, Ominsky AJ, Wollman H. Is protamine a clinically important anticoagulant? A
negative answer. Anesthesiology 1971;35:621.
Czer LSC, Bateman TM, Gray RJ, Raymond M, Stewart ME, Lee S, Goldfinger D, Chaux
A, Matloff JM. Treatment of severe platelet dysfunction and hemorrhage after
cardiopulmonary bypass: reduction in blood product usage with desmopressin. J Am Coll
Cardiol 1987;9:1139-1147.
Harker LA. Bleeding after cardiopulmonary bypass. N Engl J Med 1986;314:1446-1448.
119
26. Pocha E, Hidalgo F, Llorens R, Melero JM, Arroyo JL, Paramo JA. Randomised study of
aprotinin and DDAVP to reduce postoperative bleeding after cardiopulmonary bypass
surgery. Circulation 1994;90:921-927.
27. Van der Meer J, Hillege HL, Ascoop CAPL, Dunselman PHJM, Mulder BJM, van
Ommen GVA, Pfisterer M, van Gilst WH, Lie KI, for the CABADAS Research Group of
the Interuniversity Cardiology Institute of the Netherlands. Aprotonin in aortocoronary
bypass surgery: increased risk of vein-graft occlusion and myocardial infarction?
Supportive evidence from a retrospective study. Thromb Haemost 1996;75:1-3.
28. Goldmann DA, et al. Cephalothin prophylaxis in cardiac valve surgery. A prospective,
double blind comparison of two-day and six day regimens. J Thorac Cardiovasc Surg
1977;73:470.
29. Kornfield DS, Heller SS, Frand KA, et al. Delirium after coronary artery bypass surgery. J
Thorac Cardiovasc Surg 1978;76:93.
120
TRAINEE PRESENTATIONS
Each registrant has prepared a five minute talk and a one page summary (with one reference
only), on the topics listed below. The one page summaries that were received in time for
publication have been included (unedited).
List the;
1. actions, indications and complications of intravenous
verapamil.
2. indications and complications of intravenous NaHCO3.
3. actions, indications and complications of aspirin and
compare them with ticlopidine.
4. beneficial and adverse effects of permissive
hypercapnea and define permissive hypercapnea.
5. clinical features and management of a patient with
Burkholderia (pseudomonas) pseudomallei infection.
amiodarone.
7. indications and complications of intra-aortic balloon
counterpulsation.
8. actions, indications and complications of inhaled nitric
oxide.
ondensadron.
lignocaine.
11. indications and complications of intravenous calcium
chloride during a cardiac arrest.
hypophosphataemia.
Cryptococcus neoformans meningitis.
heparin induced thrombocytopenia.
15. differences between Haemaccel and 5% albumin
solutions.
16. complications associated with massive blood
transfusion.
17. clinical features and management of a patient who has
carcinoid syndrome.
18. differences in clinical features and investigations
between septic shock and toxic shock syndrome.
19. causes and management of a ventilated critically ill
patient who develops muscle weakness
milrinone.
21. causes and treatment of torsades de pointes.
22. actions, indications and complications of warfarin.
121
Dr. C. Bhringer.
page
123
Dr. B. Venkatesh.
Dr. P. W. Cheung.
124
125
Dr. D. Stephens.
127
Dr. D. Green.
128
Dr. C. Woolfe.
130
Dr. C. Edibam.
132
Dr. M. Pinder.
134
Dr. C. Nolan.
135
Dr. M. Parmar.
136
Dr. C. Motherway.
137
Dr. C. A. Cheng.
138
Dr. P Nair.
140
Dr. J. Evans.
142
Dr. V. Pellegrino.
144
Dr. D. Chu.
145
Dr. B. Dixon.
147
Dr. H. L. Chee.
148
Dr. J. Awad.
149
Dr. R. Calcroft.
151
Dr. D. Corbett.
Dr. J. Liang.
152
153
23. determinants of plasma sodium concentration and the

clinical features and treatment of hyponatraemia.
24. clinical features and management of a patient who has a
phaeochromocytoma.
25. differences in aetiology, clinical features, and
management of the serotonin syndrome and the
neuroleptic malignant syndrome.
26. differences between pulmonary embolism and acute
cardiac tamponade.
digoxin.
28. clinical features and management of a patient with fat
embolism.
29. causes and treatment of a metabolic acidosis.
30. differences between the cardiovascular response to
intravenous dopamine and intravenous adrenaline
haemolytic uraemic syndrome.
32. causes and treatment of a metabolic alkalosis.
33. the actions, indications and complications of intravenous
propranalol.
omeprazole.
Wegners granulomatosis
36. actions, indications and complications of hiruidin
37. clinical features and management of a patient with air
embolism.
122
Dr. F. Colreavy.
Dr. N. Kavanagh.
Dr. P. Frost.
Dr. H Opdam.
Dr. E. Wheatley.
Dr. P. Lam.
Dr. C. Hill.
Dr. K. OConnor.
Dr. T. Williams.
Dr. T. Duke.
Dr. P. Seal.
Dr. N. Widdicombe.
Dr. D. Mullany.
Dr. M. Gopalakrishnan.
Dr. A. Purdon.
LIST THE ACTIONS, INDICATIONS AND COMPLICATIONS OF INTRAVENOUS

VERAPAMIL
Dr. C. Bhringer, Intensive Care Unit, John Hunter Hospital, Newcastle, New South Wales
ACTIONS:
Heart:
Circulation: -
slows conduction and increases refractory period of AV node

negative dromotrope
negative chronotrope (slows discharge rate of the sinus node)
negative inotrope
vasodilation
INDICATIONS: termination of paroxysmal SVT (if adenosine not available)

further rate control in atrial fibrillation or flutter following digitalization
Prinzmetal angina
Hypertrophic cardiomyopathy
Raynauds phenomenon when oral administration not available
COMPLICATIONS: bradycardia, AV block
hypotension, decreased cardiac output, heart failure
cardiovascular collapse (especially if used with i.v. beta blockers or in the
presence of digoxin toxicity
other: dizziness, headache, constipation
Reference
Nademanee K. Control of cardiac arrhythmias by calcium antagonism. Ann NY Acad Sci
1988;522:536-562.
123
LIST THE INDICATIONS AND COMPLICATIONS OF INTRAVENOUS NAHCO3

Dr. B. Venkatesh, Intensive Care Unit, Royal Brisbane Hospital, Queensland
Indications for NaHCO3 therapy
1. Treatment of hyperkalaemia.
2. Certain groups of metabolic acidoses.
a) Renal tubular acidosis.
b) Acidosis due to GI bicarbonate loss.
c) Diabetic ketoacidosis: if pH < 6.9, or if < 7.1 and associated with shock and
hyperkalaemia.
3. Urinary alkalinization to
a) prevent uric acid precipitation in tumour lysis syndrome
b) enhance salicylate and barbiturate elimination in cases of intoxication
c) prevent myoglobin precipitation in myoglobinuria
Situations in which sodium bicarbonate is of little or of no proven value
a) During cardiopulmonary resuscitation
b) Routine treatment of the acidosis in diabetic ketoacidosis
c) Lactic acidosis
Complications of sodium bicarbonate therapy
1) Hypernatraemia and hyperosmolality (8.4% NaHCO3 = 1000 mOsm/l, 1 ml = 1 mmol of
Na+ and HCO3-)
2) Worsening of intracellular acidosis due to transfer of CO2 into the cell, when NaHCO3 is
used to treat acid-base defects in cardiac arrest and states of hypoperfusion (at 37C, 100
ml of 8.4% NaHCO3 will generate 2.5 l of CO2 when it buffers 100 mmol of H+). The
transfer of CO2 is immediate, while NaHCO3 takes 10 minutes to equilibrate across the
cell membrane.
3) Intracellular alkalosis may worsen lactic acidosis because of increase in glycolysis
4) Extracellular alkalosis will lead to hypokalaemia and left shift of the ODC resulting in
decreased oxygen delivery
5) Decrease in ionized calcium
6) Precipitation of calcium when administered into the same i.v. line
In practical terms sodium bicarbonate is effective as an alkalizing agent only when the
generated CO2 is eliminated from the body.
Reference
Hindman BJ. Sodium bicarbonate in the treatment of subtypes of acute lactic acidosis:
Physiological considerations. Anesthesiology 1990;72:1064-1076.
124
LIST THE ACTIONS, INDICATIONS AND COMPLICATIONS OF ASPIRIN AND

COMPARE THEM WITH TICLOPIDINE
Dr. P. Cheung, Intensive Care Unit, Queen Elizabeth Hospital, Hong Kong
Actions
Mechanism of antiplatelet action
Site of action
Reversibility of action
Effect on vascular prostacyclin formation
Effect on granule secretion
Effect on atherosclerosis and mitogenic
responses of vascular smooth muscle
Inhibition of shear induced platelet
aggregation and secretion
Effect on GP IIb/IIIa receptor
Effect on thrombolysis induced platelet
activation
In vitro action
Active metabolites
Indications
Anti-inflammation and analgesia and antipyrexia
Role in anti-platelet treatment
Cerebrovascular thrombosis
Secondary prevention
Effectiveness in women
Acute myocardial infarction
Primary and secondary prevention
Treatment before PTCA
Aortocoronary bypass grafting
Unstable angina
Reduction in frequency of death and
myocardial infarction
Additional beneficial effects
Nonproliferative diabetic retinopathy
Sickle cell disease
Prevention of A-V shunt thrombosis
Aspirin
Ticlopidine
Inhibition of
thromboxane
A2 generation
Non-selective inhibition
of cyclo-oxygenase
No
Yes (dose dependent)
Inhibition of ADP
action via 2methylo-thio-ADP
Unknown
No
No
Yes
Yes
No
Yes
No
Less
Yes (indirect effect)

Less
Active
No
Inactive
Yes
Yes
No
First line
Second line
Yes
Controversial
More effective
Equal in males
Yes
Higher dose (500 mg
/day) may be required
Yes
Yes
Yes
More effective
Yes
Yes
Yes
No
Yes
125
No
No
Complications
Major adverse effects
Minor adverse effects
Costs
GI bleeding (25%-30%)
Reyes syndrome (< 12
year old)
Hypersensitivity
Provoke renal
impairment, papillary
necrosis or interstitial
nephritis
Thrombocytopenia
GI intolerance
Dizziness
Tinnitus
Deafness
Low
Neutropenia (2.4%)
severe if < 0.44 x
109/l (0.85%)
within first 3
months
Thrombocytopenia
Aplastic anaemia
Reversible
Diarrhoea (20%)
GI intolerance
GI pain
Increased total
cholesterol by 9%
High
Reference
Karsten Shror. Antiplatelet drugs: a comprehensive review. Drugs 1995;50:7-28.
126
DEFINE AND LIST THE BENEFICIAL AND ADVERSE EFFECTS OF PERMISSIVE

HYPERCAPNEA.
Dr. Dianne Stephens. Intensive Care Unit, Royal Childrens Hospital. Victoria
DEFINITION OF PERMISSIVE HYPERCAPNIA
Permissive hypercapnia is a ventilator strategy which allows for respiratory acidosis to occur in
order to avoid ventilation induced lung injury. In general an arterial pH above 7.25 and a
PaCO2 below 80 mmHg are acceptable though at times these levels need to be exceeded. The
ventilation parameters are guided by the avoidance of;
1. Hyperinflation (VEI < 20 ml/kg, TV < 10 ml/kg)
2. High airway pressures (Pplat < 35 cmH2O)
3. Repetitive opening and closing of recruitable alveoli (optimal PEEP)
BENEFITS OF PERMISSIVE HYPERCAPNIA
1. Allows ventilator strategy designed to reduce the incidence of ventilator induced lung injury
including worsening of acute lung injury and pulmonary barotrauma.
2. Avoids the circulatory depression associated with hyperinflation and high airway pressures.
3. May improve morbidity and mortality in ARDS and obstructive airways disease.
ADVERSE EFFECTS OF PERMISSIVE HYPERCAPNIA
1. Intracellular and extracellular acidosis
2. Cardiovascular effects a) Direct myocardial depression with increased risk in;
* pre-existing LV dysfunction
* hypovolaemia
* blockade
* other cardiodepressant drugs
* impaired sympathetic response
b) Increased sympathetic activity results in;
* hypertension
* increased risk of arrhythmias
* reduced RBF and GFR
* reduced splanchnic blood flow
c) Direct peripheral vasodilation resulting in hypotension
d) Increased PVR resulting in increased RV work and may
produce RV failure
3. CNS effects
a) Cerebral vasodilation, increased cerebral blood volume,
increased cerebral oedema and raised ICP
b) Convulsions with increased risk in;
* PaCO2 > 150 mmHg
* known epilepsy
* cerebral injury
4. Respiratory effects
Tachypnoea, dyspnoea, respiratory distress and increased work of
breathing are alleviated by sedation
5. Biochemical effects
a) Hyperkalaemia
b) Reduced O2 uptake by haemoglobin
c) Altered drug pharmacokinetics
d) Reduced aminoglycoside activity
Reference
Principles and Practice of Mechanical Ventilation. Tobin 1994.
127
LIST THE CLINICAL FEATURES AND MANAGEMENT OF A PATIENT WITH

BURKHOLDERIA (PSEUDOMONAS) PSEUDOMALLEI INFECTION
Dr. D. Green. Intensive Care Unit, Royal Prince Alfred Hospital, New South Wales
PSEUDOMONAS PSEUDOMALLEI
First isolated 1911 by Captain Whitmore (Whitmores Bacillus)
1921 infection termed melioidosis (from Greek word melis meaning a distemper of asses)
Epidemiology
Gram-negative, motile, aerobic bacillus with occasional filamentous chains.
Natural saprophyte isolated from soil, stagnant streams, ponds, rice paddies in endemic
areas (mainly between latitudes 20 degrees north and south)
Capable of causing epizootic disease (sheep, goats, swine, horses and seals)
Human infection usually caused by direct contact with contaminated soil or water through
cutaneous inoculation. Less commonly by inhalation or ingestion of contaminated soil or
water.
There is adequate documentation that the disease can occur after many years of latency or
recur after months or years after apparent cure.
Clinical presentation
There are four clinical forms of the disease: Acute fulminant septicaemia, subacute illness,
chronic infection, and subclinical disease.
Characteristics
Progression
Shock
Radiograph
Incubation
period
2 days
Acute
Infection at localised
site (only minority
present with
pneumonia). Symptoms
of localised abscess.
Septicaemic shock
(endemic areas only)
Rapid
Mortality
high
Frequent
Unilobar or
bilobar infiltrates
(mostly upper
lobes) and/or
nodular lesions
that coalesce
Subacute
Recrudescent disease
often involving lungs:
Chronic febrile wasting
condition resembles
reactivation TB
Mixed
Infrequent
Cavity formation
in upper lobes
resembling TB
Reports of
up to 26
years after
initial
infection
Chronic
Long-standing
suppurative abscesses
involving numerous
anatomic sites. Chronic
febrile wasting
condition with
occasional periods of
remission.
Slow
Rare
Cavity formation
in upper lobes
resembling TB
Weeks to
years after
initial
exposure
128
Subclinical
Characteristics
Progression
None or minimal
symptoms. Chronic
carrier state
None
Reactivation
if decreased
immunocompetence
occurs
Shock
Never
Radiograph
Incubation
period
Normal
Diagnosis
Clinical suspicion and history of travel in endemic area at any time
P pseudomallei grow on most laboratory media in 12 - 48 hours.
Bipolar safety pin pattern observed on Wayson or Wright stain.
Diagnosed presumptively using serological testing by indirect haemagglutination test
(IHA).
IHA titre > 1:40 generally regarded as evidence of melioidosis
Acute septicaemic form may have titres < 1:40)
IHA titres 1:40 to 1:160 in many subclinical carriers.
IHA > 1:640 highly suggestive of active melioidosis.
Fourfold rise in IHA titre is suggestive of active infection
Elevation in C-reactive protein (CRP) levels may be helpful in ascertaining active infection
in patients with low IgM antibody titres
Gram stain of infected tissue or pus may occasionally show no Gram-negative rods.
Prevention
No active immunisation available
Protective clothing in at-risk areas. Thorough cleansing of skin abrasions in endemic areas.
Infected persons or animals isolated and bodily fluids handled with biohazard precautions to
prevent spread.
Treatment
People with low-titre positive serological test responses but without other evidence of
infection do not require therapy.
Large abscesses should be surgically drained under antibiotic cover.
Acute melioidosis: Ceftazidime (120 mg/kg/day) plus Co-trimoxazole (20/100 mg/kg/day) or
doxycycline (40 mg/kg/day) or chloramphenicol (40 mg/kg/day) advocated.
Optimum duration of treatment undetermined. Recrudescence after apparent successful
antibiotic therapy reported.
Increase in CRP to more than 10 mg/dl suggests reactivation of infection
Regimen of choice: Combination i.v. chemotherapy followed by 6 - 12 months of oral
tetracycline or co-trimoxazole until further studies reveal a more efficacious
protocol
Reference
Sanford JP. Pseudomonas species (including melioidosis and glanders). In: Mandel GL,
Douglas RD, Bennet JE, eds. Principles and practice of infectious diseases 4th ed. New York
Churchill Livingstone, 1995;2003-2009.
129

AMIODARONE
Dr. C. Woolfe. Intensive Care Unit, Liverpool Hospital, New South Wales
Actions: Antiarrhythmic and antianginal
Electrophysiologic actions and pharmacologic properties
Antiarrhythmic:
Class III actions, with weak class I, class II ( block), and class IV (ie.
calcium channel block or CCB) actions
Direct effect:
Depression of automaticity of the SA and AV nodes
blockade:
Noncompetitive
Antithyroid:
Interferes with thyroid metabolism and with the effects of thyroxine in
the heart
Haemodynamic effects
Coronary vasodilation: direct effect on smooth muscle, CCB and block
Peripheral vasodilation: decreased BP, afterload reduction
Negative inotrope:
offset by decreased afterload; CO and SV maintained
Slows sinus rate:
direct effect on automaticity, antisympathetic, CCB
Indications: Balance risks of amiodarone toxicity versus benefits
Atrial fibrillation and flutter
Completely or partially effective for prevention in 60-80% at 1 year (cf 50% with class I drugs)
Prevents episodes of paroxysmal AF, and recurrence after cardioversion (unrelated to LA size)
Post myocardial infarction
Reduced mortality, especially high risk patients (nonsustained VT, frequent PVCs)
Cardiomyopathy and ventricular arrhythmia
Effective in controlling arrhythmias and reducing mortality (data from non controlled trials)
Sustained VT
Efficacy equivalent to AICD: AICD preferred to amiodarone in patients with significant LV
dysfunction
Complications 80% of patients, 10-15% require amiodarone withdrawal
CVS:
Accentuation of electrophysiological actions: bradycardia, heart block,

prolonged QT
CCF (negative inotropic action) 2-3%
Hypotension (28% following intravenous administration, unrelated to dose)
Increases threshold energy for defibrillation
RS:
Eosinophilic lung infiltrate: early, fever, SOB cough

Pulmonary fibrosis: months-years, 6-8%, insidious, cough, fatigue, low grade
fever, SOB (CXR)
Thyroid:
Interferes with conversion of T4 to T3

Hypothyroidism (5-8%) and hyperthyroidism (2%)
130
GIT:
Nausea and vomiting, anorexia, abdominal pain, constipation, altered taste:

common, early, dose related.
Abnormal LFTs (25%), hepatitis and liver failure (rare)
Dermatological: Allergic rash, photosensitivity, blue grey discolouration (common)

Neurological:
Dose related, usually during loading: tremor, ataxia, peripheral neuropathy,

fatigue, weakness
Opthalmologic: Corneal microdeposits, secretion of amiodarone by lacrimal glands (may lead

to cysts)
Drug
interactions:
Warfarin, decreased metabolism, increase PT x 3
Digoxin, elevates level x 2
Other antiarrhythmics, increased serum levels (including phenytoin)
Potentiation of anaesthetic agents
blockers and CCB: synergy - negative chronotropic and inotropic effect
Reference
Podrid PJ. Amiodarone: reevaluation of an old drug. Ann Intern Med 1995;122:689-700.
131
LIST THE INDICATIONS AND COMPLICATIONS OF INTRA-AORTIC BALLOON

COUNTERPULSATION.
Dr. C Edibam. Intensive Care Unit, Royal Perth Hospital, Western Australia
1. Physiological goals of counter pulsation are to reduce impedance to left ventricular ejection
and augment aortic diastolic pressure via timed balloon deflation and inflation respectively.
The overall desired effect is to reduce myocardial oxygen demand to supply imbalance and
improve cardiac output and vital organ blood flow.
2. Clinical indications
2.1 Ischaemic heart disease
- Unstable angina refractory to medical therapy/support during balloon angioplasty or
while awaiting CABG
- Myocardial infarction associated with cardiogenic shock if,
: amenable to revascularization (CABG/PTCA). Massive infarction with loss of > 40%
of myocardium that cannot be salvaged is associated with an extremely poor
prognosis and thus use of IABP here is not beneficial
: associated with acute mitral incompetence or VSD
- Critical left main coronary artery stenosis; insertion of IABP pre-operatively may
reduce the frequency of ischaemic events in the immediate prebypass period.
: support during angioplasty
- Failed angioplasty (support prior to emergency CABG)
- Refractory ventricular arrhythmias associated with ischaemia
2.2 Post cardiopulmonary bypass pump failure
- expected (poor preop LV/RV function) or unexpected difficulties in weaning from
CPB (prolonged clamp, bypass times, inadequate myocardial protection, graft
failure/spasm/air embolism)
2.3 Cardiac transplant recipients
- ventricular dysfunction associated with prolonged ischaemic times, acute rejection
2.4 Any other potentially reversible cause of cardiogenic shock
- myocardial contusion
- acute viral myocarditis
- acute mitral incompetence associated with endocarditis
- severe poisoning with negative inotropes
3. Contraindications
3.1 Absolute : aortic regurgitation, aortic dissection/aneurysm
3.2 Relative : coagulopathy, occlusive peripheral vascular disease, extreme tachycardia/
arrhythmias where timing is difficult
: irreversible ventricular dysfunction
: untrained staff (nursing, medical)
4. Complications
4.1 Arterial cannulation
: haematoma/haemorrhage, damage to surrounding structures, false aneurysm, a-v
fistula
4.2 Passage of wire/dilator/IABP
: arterial perforation, dissection
132
4.3 Presence of IABP

: limb ischaemia (diabetics, females, PVD, sheathed insertion)
: infection (rare but high mortality)
: thrombosis/embolism from balloon or aorta
: thrombocytopenia/haemolysis (rare)
: balloon rupture and gas embolism
: incorrect timing, positioning
Reference
Lancey R. Mechanical assistance of failing ventricle. In Rippe et al. Intensive Care Medicine
3rd ed 1996, Little Brown & Co. Boston:pp116-120.
133
LIST THE ACTIONS, INDICATIONS AND COMPLICATIONS OF INHALED

NITRIC OXIDE
Dr. M. Pinder. Intensive Care Unit, Alfred Hospital, Victoria
Actions
1. Selective pulmonary vasodilation
decreased PAP and PVR
improved V/Q matching
increased PaO2
reduced RV afterload
2. Bronchodilator effect - small and inconsistent effect noted at 80ppm in asthmatics
Indications
1. Pulmonary hypertension
1
2 - hypoxic lung disease, cardiac disease
persistent PHT of the newborn
post cardiac surgery
2. V/Q mismatch
ARDS
post lung transplant
3. Acute RV dysfunction associated with acute PHT in severe sepsis
4. ?Acute severe asthma - current studies using NO as a bronchodilator show conflicting
results
Complications
1. Toxicity
occurs with high concentrations and long-term exposure
nitrates and peroxynitrite radicals formed with effects including severe pulmonary
oedema, acid pneumonitis and death
2. Methaemoglobinaemia
3. Increased capillary permeability
4. Local atmospheric effects - NO is a recognised air pollutant
5. Delivery - the ideal delivery system must ensure continuous, predictable concentration of
gas, monitor NO content in delivered gas, be leak-proof and have scavenging
Reference
Barnes PJ, Belvisi MG. Nitric oxide and lung disease. Thorax 1993;48:1034-1043.
134
LIST THE ACTIONS, INDICATIONS, AND COMPLICATIONS OF ONDANSETRON

Dr. C. Nolan. Intensive Care Unit, Liverpool Hospital, New South Wales
Actions
Pharmacology
Ondansetron belongs to a relatively new class of drugs known as 5-HT3 antagonists. This
group acts by highly selective and potent antagonism of 5-hydroxytryptamine receptors in the
brain. A high density of these receptors occurs in the area postrema and the chemoreceptor
trigger zone (CTZ). Also an increase turnover and release of 5HT from enterochromafin cells
in the SI suggests a peripheral emetic action of 5-HT and therefore a peripheral action of the 5HT3 antagonists.
Pharmacokinetics
May be administered orally or intravenously. Intravenous administration of 8 mg produces
peak plasma levels of 30 ng/ml. Plasma protein binding is moderate (i.e. 70-76%), and the
volume of distribution (Vd) is 160 l. The terminal elimination half-life is 3 hours and 5% is
excreted unchanged in the urine with the major route being hydroxylation and glucuronidation
by the liver. The intravenous preparation is compatible with all crystalloid solutions.
Indications
Chemotherapy: in studies comparing ondansetron with metoclopramide, ondansetron has a
consistently superior anti-emetic effect (91% cf 42%)
Radiotherapy: especially in whole body or upper abdominal irradiation, ondansetron is better
in relieving emesis.
Anaesthesia: in postoperative patients, postoperative nausea and vomiting (PONV) occurs in
30%, despite prophylaxis with agents such as droperidol, lorazepam or
antihistamines. PONV is worse depending on the surgery (e.g. gynaecological,
strabismus correction in children). Ondansetron 8 mg i.v. is better than placebo
in treating PONV with 66 - 78% experiencing no emesis vs 30%
Complications
Common reactions
Headache, light headedness, a warm sensation in the epigastrium, flushing constipation
with prolonged whole gut transit time.
Rare hypersensitivity reactions
- Self-limiting LFT abnormalities with bilirubin levels 2 x normal and aminotransferase
levels 3 x normal.
- ?? 5-HT3 receptors mediate vasodilation so 5-HT3 antagonism may cause VC.
- No effect on the respiratory system and does not exacerbate opioid-induced ventilatory
depression.
- No impairment of psychomotor function
- No effect on histamine, dopamine, cholinergic receptors and therefore no effect on
motion sickness or on emesis produced by dopamine agonists.
Reference:
Russel D, Kenny GNC. 5-HT3 antagonists in postoperative nausea and vomiting. Br J Anaesth
1992;69 (Suppl 1):63S-68S.
135
LIST THE ACTIONS INDICATIONS AND COMPLICATIONS OF INTRAVENOUS

LIGNOCAINE
Dr. M. Parmar. Intensive Care Unit, St George Hospital, New South Wales
Actions:
Cardiac:
Class IB (membrane stabilizing) antiarrhythmic. Combines with fast sodium channels.
Reduces rate of dV/dt of phase 0 of the action potential. Reduces the action potential
duration and effective refractory period. Reduces automaticity and excitability of the
His-Purkinje system. Little effect on the sinus and atrioventricular node in normal tissue
at therapeutic concentrations.
Neurological:
Peripheral nervous system anaesthetic and analgesic. Central nervous system depressant
with sedative, analgesic and anticonvulsive effects.
Indications:
Cardiac:
Treatment of stable ventricular tachycardia.
Management of ventricular fibrillation.
Treatment of ventricular premature contractions.
Prevention of primary ventricular fibrillation post myocardial infarction
Treatment of digitalis-induced ventricular arrhythmias.
Anaesthetic:
Suppression of the cough, gag and hypertensive reflexes associated with endotracheal
intubation.
Intravenous regional anaesthesia (previously)
Analgesic:
Acute pain associated with burns
Some chronic pain syndromes.
Antiepileptic:
Status epilepticus
Complications: Uncommon. If occur, involves CNS and is of short duration and dose related.
Neurological:
Early signs are manifest by drowsiness, dizziness, disorientation, agitation, tinnitus,
visual disturbances, nausea and vomiting, circumoral paraesthesia, and slurred speech.
This can progress to muscle twitching, seizures, unconsciousness coma and respiratory
arrest.
Cardiac:
With high plasma concentrations, hypotension, arrhythmias, heart block and bradycardia
leading to cardiac arrest may occur. Cardiac arrest due to lignocaine is, however, usually
secondary to respiratory arrest.
Hypersensitivity:
May be manifest by rash, urticaria and anaphylactoid reactions.
Local phlebitis:
May occur with prolonged intravenous infusion.
Reference
AHFS Drug information 96. Cardiac Drugs: Lignocaine Hydrochloride. 24:04;p1176-1179.
136
LIST THE INDICATIONS AND COMPLICATIONS OF INTRAVENOUS CALCIUM

CHLORIDE DURING A CARDIAC ARREST.
Dr. C Motherway. Intensive Care Unit, Queen Elizabeth Hospital, South Australia
Indications
1. Cardiac arrest secondary to hyperkalaemia
2. Documented hypocalcaemia
3. Calcium channel blocker toxicity
Complications
1.
2.
3.
4.
5.
Hypercalcaemia
Bradycardia/asystole
Sclerosis/tissue injury
Potentiation of digoxin toxicity
Increased extracellular calcium may lead to;
a) worse neurological outcome
b) increased stiffness of damaged and ischaemic myocardium with reduced contractility.
Reference
Standards and guidelines for cardiopulmonary resuscitation (CPR) and emergency cardiac care
(ECC). JAMA 1992;268:2172-2288.
137

HYPOPHOSPHATAEMIA
Dr. C. Cheng. Intensive Care Unit, Prince of Wales Hospital, Hong Kong
Definition:
Normal serum phosphate range = 0.84 - 1.58 mmol/l (2.6 - 4.9 mg/dl)
Hypophosphataemia < 0.8 mmol/l (i.e. < 2.5 mg/dl); severe hypophosphataemia
< 0.32 mmol/l (i.e. < 1 mg/dl).
Clinical features:
I. Impaired muscle function.
a) Myocardial depression.
b) Respiratory muscle weakness, impaired diaphragm contractility.
c) Skeletal muscle weakness.
d) Rhabdomyolysis.
II Carbohydrate metabolism.
a) Hyperinsulinaemia.
b) Decreased glucose metabolism, glycosuria.
III Haematological alterations
a) Red blood cells.
1. Decreased 2,3-DPGdecreased P50, impaired O2 delivery to tissues.
2. Decreased life span.
3. Haemolysis
4. Spherocytosis
b) Leukocytes
1. Decreased phagocytosis
2. Decreased chemotaxis
3. Decreased bactericidal activity.life-threatening infections in critically ill.
c) Platelets
1. Impaired clot retraction
2. Thrombocytopaenia
3. Megakaryocytosis
4. Decreased life span.
IV Neurologic manifestations (impaired nerve conduction, metabolic encephalopathy)
a) Anorexia, irritability, confusion.
b) Paresthesias, dysarthria, ataxia
c) Seizures
d) Coma
V Skeletal abnormalities
a) Bone Pain
b) Radiolucent areas (on X-ray)
c) Pseudofractures
d) Rickets or osteomalacia
Management:
Monitor serum phosphate of at risk patients (e.g. glucose administration/hyperalimentation
in alcoholic or nutritionally compromised, DKA, burns, diuretic therapy, unexplained heart
failure, difficulty in weaning off ventilator)
138
For severe hypophosphataemia/symptomatic patients: intravenous potassium phosphate

(0.08 - 0.16 mmol/kg body weight) over 6 hours; stop when serum phosphate > 0.65 mmol/l
(i.e 2.0 mg/dl)
Moderate hypophosphataemia: oral phosphate 1-4 g/day in divided doses (S/E: diarrhoea).
Mild/asymptomatic: ensure adequate diet, halt renal losses.
Maintenance: ensure 500 mg/day P in nutrition, add to enteral formulas, i.v. fluids.
Correct hypocalcaemia: monitor serum calcium and magnesium.
Reference
Slatoposky et al. Disorders of phosphorous, calcium and magnesium metabolism. In: Schrier
RW, Gottschalk eds. Diseases of the Kidney. New York: Little Brown and Company, 1993
pp2604-2611.
139

CRYPTOCOCCUS NEOFORMANS MENINGITIS.
Dr. P. Nair, Intensive Care Unit, Illawarra Regional Hospital, New South Wales
Introduction:
There are two varieties of Cryptoccus Neoformans: (a) var. neoformans - found in Europe and
North America, mainly affects immunocompromised hosts. (b) var. gatti - found in the tropics
and subtropics, affects apparently healthy individuals.
Infection occurs through inhalation and systemic spread arises from lungs. Cryptococcal
meningitis is commonly associated with HIV infection/AIDS, sarcoidosis, Hodgkins
lymphoma, collagen vascular diseases, carcinomas, transplants & systemic steroid therapy.
However in the pre-AIDS era, 50% had no apparent immunological deficiencies.
It is one of the most common life threatening invasive fungal infection in patients with
AIDS. It may occur early or late in the course of AIDS and is often the first opportunistic
infection to be diagnosed although in two large treatment trials, the median CD4 count was <
50/cubic mm.
Symptoms:
Onset may be insidious. Acute manifestations are commoner in patients with AIDS and those
on steroids or treatment for lymphoreticular malignancy. Those with chronic courses may have
waxing or waning manifestations over weeks or months often with completely asymptomatic
periods leading to a delay of several weeks before diagnosis. The average duration of
symptoms is 31 days. Non-specific symptoms include malaise, nausea, vomiting, dizziness,
irritability, somnolence, clumsiness, confusion, obtundation, impaired memory and judgement,
psychiatric and speech abnormalities. Headaches and fever occur in 60-80%, typical meningism
and photophobia are rare, especially in AIDS patients, occurring in 30% and 19-28%
respectively. Focal neurodeficit and convulsions are uncommon (< 10%) and suggest the
presence of abscess/granuloma formation or cortical venous sinus thrombosis. Cranial nerve
palsies, hyperreflexia, clonus, extensor plantars, choreoathetoid movements and myoclonic
jerks may also be seen. Pre-AIDS patients may show a sudden stroke syndrome due to
vasculitis, arteritis and/or cerebral infarction. Increased intracranial pressure has been reported
in cases of progressive deterioration or relapsed meningitis and presents with decreased visual
acuity, papilloedema and increase in blind spot. Visual impairment can occur due to direct
invasion of the optic nerve.
There is no significant difference between symptoms of primary infection and those of
symptomatic relapse.
Extraneural manifestations like pulmonary infiltrates, skin lesions, prostatic abscess or
hepatitis may be seen.
Diagnosis:
CSF- Increased opening pressures, raised proteins, low sugars (15-35 mg), lymphocytic
pleocytosis (in immunocompetent patients) - 40-400 cells/cubic mm. Indian ink preparation
positive in 70-75%, Cryptococcal antigen positive in 95-98%. False positive results may occur
making cultures mandatory. CSF culture has a high detection rate. Latex agglutination titres 1:2
- 1:64 000 in CSF and 1:1000 - 1:2000 000 in serum. Blood, sputum and stool should also be
cultured. CT scan is recommended to look for mass lesions, ring enhancing lesions, cerebral
oedema, infarct and haemorrhage.
140
Differential diagnosis:
Tubercular meningitis, other opportunistic infections like toxoplasma, CMV and herpes
simplex. In HIV infection, CNS lymphoma, HIV encephalopathy and progressive multifocal
leukoencephalopathy should be considered.
Treatment:
a) Of acute infection
- Severe infection (altered sensorium, CSF WBC count < 20/cubic mm, Ag titre > 1:1024,
positive blood culture)
Amphotericin B 0.5 - 0.7 mg/kg/day i.v. + flucytosine 100-150 mg/kg/day i.v. or orally
for 2 weeks followed by fluconazole 400 mg/day for 8-10 weeks.
Alternatives to amphotericin B like high dose fluconazole and liposomal amphotericin B
have been tried
- Mild infection Fluconazole 800 mg loading dose, then 400 mg/day + flucytosine 100150 mg/kg/day orally. Clinical response is observed in 1-2 weeks, 50-60% relapse
within 6 months without maintenance therapy.
b) Of elevated ICP
Repeated lumbar punctures to drain CSF, acetazolamide or shunt surgery.
c) Prevention of relapse
Fluconazole 200 mg/day orally lifelong, especially with HIV infection. Found to be
more effective than weekly amphotericin B therapy. No evidence for use of
anticryptococcal prophylaxis in patients with low CD4 counts. May induce cryptococcal
and candida resistance.
Prognosis
Acute mortality rates are 10-30% usually in the first few weeks. Poor prognostic
indicators are age <35 years, CSF - raised opening pressures, low glucose, WBC <
20/cubic mm, Ag titre > 1:32, altered mental status, absence of headaches,
hyponatraemia, extraneural positive cultures, steroid therapy or chemotherapy for
haematological malignancy, abnormal CT scan.
Reference:
Jones GA, Nathwani D. Cryptococcal meningitis. Br J Hosp Med 1995;12:54 (9).
141

HEPARIN INDUCED THROMBOCYTOPENIA.
Dr. J. Evans, Intensive Care Unit, Princess Alexandra Hospital, Queensland
Cause
Heparin - platelet factor 4 (PF4) induced IgG
antibody
Clinical features for diagnosis

Thrombocytopenia (< 150 x 109/l) or rapid
fall in platelet count > 5 days exposure to
heparin (usually unfractionated)
PLUS
Heparin induced platelet antibody assay
(HIPAA) or ELIZA to IgG/PF4
Thrombocytopenia occurs much more rapidly on subsequent exposure to unfractionated

heparin and with 90% cross reaction to low mol. Wt. Heparin.
Clinical features of complications
Painful, swollen, oedematous leg/s.
Cause
Proximal lower limb DVT.
Painful, swollen, oedematous arm/s.
Upper limb DVT.
Cold pale painful pulseless limb.
Arterial embolism.
Tachypnoea, dyspnoea, cyanosis,

cough/haemoptysis.
Pulmonary embolism or ARDS from

inflammatory reaction.
Chest pain/diaphoresis/collapse/cardiac arrest.
Coronary artery ischaemia/infarction.
Focal neurological deficit/hemiplegia.

Altered level of consciousness.
Amnesia.
CVA from myocardial/prosthetic valve

embolism, venous sinus thrombosis or
cerebral artery thrombosis.
Oliguria/anuria/abdominal pain.
Renal vein embolism/thrombosis.
Abdominal pain-rigidity/ileus/melaena.
Mesenteric embolism/thrombosis.
Paraplegia/incontinence.
Spinal artery/vein thrombosis.
Hypotension, hyponatraemia, hyperkalaemia.
Addisons - from adrenal artery thrombosis.
Skin eruptions- erythematous papules,

necrosis, gangrene.
Local skin reactions to endothelial damage,

platelet aggregation.
Management
Cease heparin and exclude other causes of thrombocytopenia
Re-evaluate need for anticoagulation.
TED stockings and sequential calf compression
142
Alternate anticoagulation:
Org 10172 (Danaparoid sodium): which inhibits Xa, can be used. Beginning with a 25
000 u bolus followed by an infusion of 400 u/hour for 4 hours then 300 u/hour for 4
hours then 200 u/hour.
Anacrod (defibrinating snake venom): 1 u/kg over 12 hours i.v. then titrated to
fibrinogen level 0.5 - 2 g/l
Warfarin:
Treat complications e.g. thrombolysis/PTCA/surgery
Continue monitoring platelet count
Reference
Warkentin TE, et al. Heparin-induced thrombocytopenia in patients treated with low molecular
weight heparin or unfractionated heparin. N Engl J Med 1995;332:1330-1335.
143
LIST THE DIFFERENCES BETWEEN HAEMACCEL AND 5% ALBUMIN

SOLUTIONS
Dr. V. Pellegrino. Intensive Care Unit, Monash Medical Centre, Victoria
HAEMACCEL
Bovine collagen hydrolysed to
polypeptides (12 000-15 000)
Urea linked circular
polypeptides
Sterile
5% ALBUMIN
Pooled volunteer donor
plasma. Cohn cold
fractionation and
chromatographic separation.
Viral removal and inactivation
procedures (limited against
non-enveloped viruses)
Composition:
Average m.w. 35 000

Pyrogen free
Isotonic: Na/Cl/K/Ca
Stable 8 years at room temp
m.w. 70 000
Negligible other proteins
Isotonic: Na/Cl/ Octanoate
Stable up to 1 year at room
temperature
Effects:
500 ml increases the

circulating blood volume by
350 ml.
Oncotic press = 25-28 mmHg
Nil
Infused volume equals the

increase in blood volume.
Redistribution half-life = 4 h
80% excreted in 48 h (renal)
Redistribution half-life = 16 h
Metabolic half-life = 20 days
(hepatic)
Not common
Nil
Rare
Rare
Not
Fibronectin
Yes
Nil
$17.50
$100.00 (production costs)
Preparation:
Metabolism:
Side effects:
Allergy and anaphylactoid
Transmission infection
Compatibility with blood
products
Immune/Opsonisation
Cost:
Oncotic press = 14-15 mmHg

Transporter and scavenger role
Reference
Cone A. The use of colloids in clinical practice. Br J Hosp Med 1995;54.
144
LIST THE COMPLICATIONS ASSOCIATED WITH MASSIVE BLOOD

TRANSFUSION
Dr. D. Chu. Intensive Care Unit, Princess Alexandra Hospital, Queensland
Massive blood transfusion is defined as replacement of more then one circulation blood volume
within 24 hours.
Complications are related to the underlying cause of hypovolaemia, rate of transfusion, timing
and method of stored blood.
Immediate
Immunological
Haemolytic
ABO incompatibility
Non-haemolytic
Leucocyte antibody reaction
Platelet antibody reaction
IgG anti-IgA antibody reaction
Non-Immunological
Hypothermia
Citrate toxicity - acute hypocalcaemia
Hyperkalaemia
Metabolic acidosis
Hyperammoniaemia
Hyperphosphataemia
Left shift of oxygen dissociation curve
Dilutional thrombocytopaenia
Factor V and factor VIII related coagulopathy
DIC
Microaggregate (40 -160 ug) related pulmonary dysfunction
Endogenous and exogenous pyrogen
Vasoactive compound: Kinins and histamine
Delayed
Immunological
Graft vs host disease
Transfusion related acute lung injury (TRALI)
Post-transfusion purpura
Immunomodulation
Extravascular haemolysis (Rh incompatibility or anamnestic reaction)
Non-immunological
Infective
Bacterial (psycotrophic)
Pseudomonas, Yersinia, Campylobacter
Staphylococcal, Streptococcal, Syphilis
Brucellosis
145
Viral
HIV1, HIV2, HTLV1 & HTV2
HAV, HBV, HCV, HDV, NANBHV
CMV, EBV, Parovirus B19
Protozoal
Malaria, toxoplasmosis gondii
Parasitic
T cruzi, Microfilarisis
Non-infective
Iron overload
Metabolic alkalosis and hypokalaemia
Thrombophlebitis
Reference
Mollisin PL, Engelfriet CP, Contreras M. Transfusion in clinical medicine. 1993 Chapter 15 &
16: pp 677-784.
146

CARCINOID SYNDROME
Dr. B. Dixon. Intensive Care Unit, St Vincents Hospital, Victoria
Clinical Features
Symptoms do not arise from carcinoid tumours in the gut until the tumour has metastasized to
the liver. Rarely primary tumours may occur outside the gut and therefore be symptomatic
without metastases.
Flushing involving the head and neck associated with tachycardia, fall in systolic blood
pressure and rise in temperature
Telangiectasia
Bronchospasm
Right sided heart failure due to fibrosis of the tricuspid and pulmonary valves with pulmonary
stenosis and tricuspid regurgitation.
Cushingoid features due to release of ACTH
Painful hepatomegaly due to metastatic disease
Diarrhoea which may be profuse, associated with abdominal pain and vomiting
Weight loss
Pellagra
Management
Raised urinary 5-HIAA (hydroxy indole acetic acid) levels confirm the diagnosis
Serial 24 hour urinary samples can give an index of tumour progression
Other serum markers may also be raised including: 5-HT, histamine, pancreatic polypeptide,
motilin, gastrin, glucagon, insulin, ACTH, parathyroid hormone, and calcitonin
Isotopic liver scans and abdominal CT scans to document both liver metastases and primary
tumours which most commonly arise in the terminal ileum
Echocardiogram to investigate cardiac involvement
Liver biopsy to obtain histological confirmation
Somatostatin 200 ug s/c 8-hourly
Surgery for localised tumours and metastases
Hepatic artery embolization for liver metastases
Generally insensitive to chemotherapy
Reference:
Holst JJ. Gut endocrine tumour syndromes. Clin Endocrinol Metab 1979;8:413-432.
147
LIST THE DIFFERENCES IN CLINICAL FEATURES AND INVESTIGATIONS

BETWEEN SEPTIC SHOCK (SS) AND TOXIC SHOCK SYNDROME (TSS)
Dr. H. L. Chee. Intensive Care Unit, The St. George Hospital, New South Wales
SS
TSS
Clinical features
Temperature
Fever
Hypothermia
common
occasionally
> 38.9C
rare
Dermatologic
Rash
Desquamation
Mucous membranes
rare
rare
rare
diffuse macular erythema

after 1 to 2 weeks
common
Gastrointestinal
Ileus
Vomiting
Diarrhoea
common
uncommon
uncommon
rare
common
common
Musculoskeletal
Myalgia
rare
common and severe
Multiorgan involvement
variable number
3 or more
Age/gender
all
menstruating females
Focus of infection
not always identifiable
Systemic diseases
immunocompromised
diabetes
advanced malignancy,
trauma, burns
vagina (tampons used), abscesses,

cellulitis, other staph infections
uncommon
Investigations
Positive blood cultures
Common organisms cultured
40 - 45% of cases
not common
E coli
Klebsiella pneumoniae
Enterobacter spp.
Pseudomonas aeruginosa
Staphylococcus aureus
Reference:
Tolte RW, Williams DM. Clinical and laboratory manifestations of toxic shock syndrome. Ann
Intern Med 1982;96:843.
148
LIST THE CAUSES AND MANAGEMENT OF A VENTILATED CRITICALLY ILL

PATIENT WHO DEVELOPS MUSCLE WEAKNESS
Dr. J. Awad, Intensive Care Unit, Westmead Hospital, New South Wales
CAUSES:
Systemic illness
Malnutrition
Sepsis, cardiac failure, respiratory failure, hepatic failure,

renal failure, anaemia, malignancies
Inadequate energy and nitrogen intake, alcoholism
Vitamin deficiencies (e.g. vitamin B1, B12 and E)
Electrolyte abnormalities Na, K, Mg, Ca, PO4

Endocrine
Diabetes mellitus - polyneuropathy, hypoglycaemia

Steroid related myopathies
Thyroid disease
Adrenocortical insufficiency, panhypopituitarism
Encephalopathy
Sepsis, ischaemia, encephalomyelitis, metabolic
Myelopathy
Trauma, ischaemia, abscess, haematoma, myelitis
Polyneuropathy
Critical illness polyneuropathy

Guillain Barre syndrome
Motor neurone disease
Systemic diseases - diabetes, uraemia, hypothyroidism, porphyria,
carcinomata
Vitamin deficiencies - B1, B12, E; pyridoxine abuse
Drugs: vecuronium, penicillin & aminoglycoside toxicity
Poisons: heavy metals, arsenic, thallium
Myopathy
Primary e.g. muscular dystrophy

Disuse (cachectic myopathy)
Systemic diseases - hyper & hypothyroidism, polymyositis
malignancies
Drugs: steroids, vecuronium, pancuronium
Water and electrolyte disturbances
Necrotising myopathy (e.g. trauma, sepsis)
Neuromuscular
transmission defects
Drugs: muscle relaxants, aminoglycosides

Myasthenia gravis
Eaton-Lambert syndrome
Ca & Mg
Organophosphate poisoning
Botulism
Envenomation & poisonings
149
MANAGEMENT:
FBC, UEC, LFT, Ca, Mg, PO4, CK, glucose, thyroid function tests
Imaging - CXR, spine Xrays, CT/MRI head & spine as clinically indicated
Nerve conduction studies, electromyography
Lumbar puncture
Muscle and nerve biopsies
Treat underlying cause
Nutrition, vitamins, fluids and electrolytes
Physiotherapy, prevent bed sores and contractures
Tracheostomy where appropriate
Prophylaxis against venous thromboembolism
Supportive care
Reference
Bolton CF. Sepsis and the systemic inflammatory response syndrome: neuromuscular
manifestations. Crit Care Med 1996;24:1408-1416.
150

MILRINONE
Dr. C. Calcroft, Intensive Care Unit, Prince of Wales Hospital, Hong Kong
Milrinone: is a bipyridine derivative, originally synthesized by modification of amiodarone.
Actions:
Inhibits phosphodiesterase III, leading to;
levels of cAMP, and then,
intracellular calcium activity.
May act directly on calcium channels to facilitate entry.
May also act at the level of the sarcoplasmic reticulum, modulating re-uptake of
calcium
These actions lead to positive inotropy without concomitant chronotropic action.
Peripheral vasodilation; seems to be related to inhibition of phosphodiesterase
activity, but may also be related to a direct modulation of
calcium handling.
Pulmonary vasodilation.
Electrophysiological: Increases number of L-type channels open during
diastole in myocytes
Most significant are enhanced automaticity, and arrhythmogenesis
Other: positive lusitropic effect
Slight increase in coronary blood flow, and
No increase in oxygen consumption.
Indications:
Acute exacerbations of congestive heart failure, especially secondary to volume
overload
Chronic heart failure
Complications:
Acute: Hypotension
Ventricular arrhythmias
Sudden death
Chronic: as above
Reference
Shipley JB, Tolman D, Hastillo A. Milrinone: basic and clinical pharmacology and acute and
chronic management. Am J Med Sci 1996;311:286-291.
151
LIST THE CAUSES AND TREATMENT OF TORSADES DE POINTES

Dr. D. Corbett, Intensive Care Unit, Griffith Base Hospital, New South Wales
CAUSES:
Common:
1. Toxicity due to class 1(a) anti-arrhythmic drugs (e.g. quinidine, procainamide,
disopyramide)
2. Hypokalaemia
3. Hypomagnesaemia
Other predisposing causes:
1. Phenothiazines, tricyclic anti-depressants.
2. Bradyarrhythmias - especially 3rd degree atrio-ventricular block.
3. Some intracranial pathology.
4. Idiopathic - congenital or acquired prolonged QT interval
TREATMENT:
1. Remove the precipitating factors - e.g. withdraw anti-arrhythmic drugs.
2. Correct electrolyte disturbance - e.g. administer potassium or magnesium.
3. For drug induced torsades de pointes
- magnesium and or atrial or ventricular overdrive pacing
4. For congenital prolonged QT interval:
- -blockers are the mainstay of treatment. Phenytoin can also be used to shorten the
QT interval
- Cervico-thoracic sympathectomy may be considered but is rarely effective as the
sole treatment.
Beware of polymorphic tachycardia with normal QT interval in ischaemic heart disease where
the tachycardia is initiated by R on T stimulus. This is not true torsades de pointes and is
probably a re-entry phenomenon. The treatment is totally different and quinidine-like drugs in
full doses may be effective. However, severe ischaemia will only respond to abolition of the
ischaemia by revascularisation.
Reference
Harrisons principles of internal medicine, 13th Ed. 1994. McGraw Hill Co.
152
LIST THE ACTIONS, INDICATIONS AND COMPLICATIONS OF WARFARIN.

Dr. J. Liang, Intensive Care Unit, Starship Childrens Hospital, New Zealand
Actions
inhibition of cyclic conversion of vitamin K to its 2,3 epoxide - the non epoxide form is
the activator.
leads to the decreased activation (whether pro or anti coagulant) of:
- factors II, VII, IX, X
- protein C
- protein S
protein C is converted to active form via thrombin
protein C binding to thrombomodulin on endothelium increases this
active protein C inhibits activated V + activated VIII i.e. procoagulant
VII concentration will fall first as it has the shortest half-life
anticoagulant effects first seen at 24 hr
Peak anticoagulant effects not seen till 96 hr (i.e. II, IX, X inhibition)
But protein C activity also falls, + can do so rapidly with large starting doses of warfarin
(i.e. procoagulant effect)
Indications
anticoagulation
- DVT/PE prophylaxis and treatment
- prevention of arterial thromboembolism in AF, other cardiac conditions (e.g.
cardiomyopathy, CHF), presence of prosthetic valves
- ? treatment of cerebral embolic stroke
- treatment of extracranial arterial dissection (internal carotid or vertebral)
Complications
bleeding (most common adverse reaction)
relates to:
dosage (note many drugs alter warfarin pharmacokinetics)
underlying systemic disease (especially hepatic dysfunction)
other factors (e.g. trauma, drugs, age)
minor bleeding in 18%, major in < 5%
skin reactions:
warfarin necrosis
bleeding into skin (ecchymoses)
in pregnancy : foetal wastage + teratogenic effects
Reference:
Chernow B. The pharmacologic approach to the critically ill patient. 3rd edn, 194 Williams &
Willkins, p680.
153
154
INDEX
Abbreviated injury score, 37
Acute fatty liver of pregnancy, 56
treatment, 57
Acute phase proteins, 18
Acute renal failure, 39
adenosine antagonists, 46
atrial natriuretic peptide, 47
blood pressure augmentation, 45
calcium channel blockers, 46
dopamine, 47
endothelin antagonists, 47
frusemide, 45
intra-abdominal pressure and, 42, 44
mannitol, 47
mechanisms, 41
pathophysiology of, 39
prevention of, 42
prostaglandins, 46
solute loading, 45
theophylline, 46
treatment, 45
Acute respiratory distress syndrome
mechanical ventilation, 87
Adenosine, 41
Adenosine antagonists, 46
Adenyl cyclase, 1, 2
Adrenaline, 3, 108
Adrenergic receptors
alpha, 1
beta, 1
Air embolism, 100
causes, 100
clinical features, 100
investigations, 101
treatment, 101
Airway
acute management, 29
assessment, 29
devices, 29
Albumin, 144
Aminophyline, 109
Amiodarone, 130
Amniotic fluid embolism, 103
Angiotensin converting enzyme inhibitors,
7
Anticholinergics, 108
ARDS. See Acute respiratory distress

syndrome
Aspirin, 125
Asthma, 107
mechanical ventilation in, 88, 110
myopathy, 112
severity, 107
treatment
alternative, 109
standard, 107
Asymmetrical chest movement
causes of, 31
Atrial natriuretic peptide, 47
Auto-peep, 111
Benzodiazepine antagonists, 67
Benzodiazepines, 66
dosage, 66
indications, 66
side-effects, 67
Beta blocking drugs, 2
Beta-endorphin, 62
Beta-receptor stimulation
immunomodulatory effects, 3
metabolic effects, 3
Brain
cerebral perfusion pressure, 5
Calcium
inotropic effect of, 7
Calcium chloride, 137
Calorie
nitrogen ratio, 19
Carcinoid syndrome, 147
Cardiac arrest, 137
Cardiac failure
digoxin and, 7
Catabolic disease
metabolic effects of, 18
Chlorpromazine, 68
Circulation
assessment of, 33
Coronary blood flow, 6
Coronary perfusion pressure
dopamine and, 6
isoprenaline and, 6
noradrenaline and, 6
155
Corticosteroids
inhaled, 108
Cricothyroid insufflation, 30
Cricothyrotomy, 30
Critically ill
energy requirements of, 19
nitrogen requirements of, 19
Cryptococcus Neoformans, 140
dopamine and, 5
Glasgow coma score, 36
G-protein, 1, 2
Haemaccel, 144
Haemofiltration, 76
Haemorrhage
classification, 33
treatment, 35
Haemothorax
management of, 32
Haloperidol, 69
Heart failure, 2
Helium, 110
HELLP syndrome, 54
Heparin induced thrombocytopenia, 142
Hydrocortisone, 108
Hypertension in pregnancy, 53
Hypophosphataemia, 138
Hypovolaemia
management of, 33
Hypoxia
lactic acidosis and, 12
Delirium tremens, 69
Diacyl glycerol, 1, 2
Digoxin, 7
Dopamine, 2, 47
'low dose', 5
Dopaminergic receptors, 1
Dynorphins, 61
Early Management of Severe Trauma, 27
EMST. See Early management of severe
trauma
airway assessment, 30
definitive care, 28
primary survey, 27
resuscitation, 27
secondary survey, 28
Endorphins, 61
Endothelin, 42
Endotracheal intubation, 29
Enkephalins, 61
Enteral nutrition
immunonutrients and, 23
indications for, 20
paediatric, 78
Ethyl alcohol
withdrawal, 69
Infection
Injury severity score, 37
Inositol triphosphate, 2
Inotropic agents
treatment with, 7
Intensive care patient
sedation, 69
Interleukin-10, 3
Intra-aortic balloon counterpulsation, 132
Intravenous therapy
paediatric, 75
Fat embolism, 101

fulminant, 101
investigations, 102
syndrome, 101
treatment, 102
Flail chest, 32
Flumazenil, 67
Juxtamedullary glomeruli, 40
Ketamine, 68, 109
Kidney
autoregulation, 5
pressure-flow regulation, 5
Lactate/pyruvate ratio, 11
Lactic acid
metabolism of, 11
Lactic acidosis
buffer therapies and, 13
Gas trapping
assessment of, 111
Gastric mucosal blood flow, 5
dobutamine and, 5
156
cardiac dysfunction and, 13

classification of, 11
combined types A and B, 12
critically ill patients and, 12
definition of, 11
phenformin and, 12
l-aminoacid decarboxylase, 2
Lignocaine, 136
Lipid emulsions
immunosuppressive effects of, 21
Lipopolysaccharide, 3
Norpethidine, 63
NSAIDs. See Non-steroidal antiinflammatory drugs
dosage, 65
indications, 64
side-effects, 65
Nutrition
paediatric, 77
Nutritional assessment, 17
Nutritional support, 19
economic considerations, 24
glutamine in, 23
Magnesium, 55, 109

Malnutrition, 17
diagnosis, 17
Mannitol, 47
Mechanical ventilation, 81
airway pressure-release ventilation, 86
assist/control, 85
complications, 82
controlled mechanical ventilation, 84
inspiratory/expiratory ratio, 87
intermittent mandatory ventilation, 85
modes, 84
objectives of treatment, 82
pressure support ventilation, 86
sigh, 87
weaning, 88
Melanocyte-stimulating hormone, 62
Melioidosis, 128
Milrinone, 6, 151
Multiple organ failure, 21
Myocardial contractility, 1
Myocardial depression, 3
Myocardial ischaemia
inotropic drugs and, 5
Myocardial perfusion
intraortic balloon and, 5
Myopathy in critical illness, 149
Ondansetron, 135
Opioid antagonists, 64
Opioid peptides, 61
Opioid receptors, 61
Opioid withdrawal, 64
Opioids, 61
clinical effects, 62
CNS effects, 62
cutaneous effects, 63
CVS effects, 62
GIT effects, 63
musculoskeletal effects, 63
respiratory effects, 63
side effects, 63
Ovarian hyperstimulation syndrome, 57
Paracetamol, 65
Parenteral Nutrition
bacterial translocation in, 21
gut atrophy in, 21
indications for, 19
paediatric, 78
PEEP. See Positive end-expiratory
pressure
Peritoneal dialysis, 77
Permissive hypercapnea, 127
Permissive hypercapnia, 112
Pethidine, 63
Phenobarbitone, 67
Phenothiazines, 68
phosphoinositol, 1
Phosphoinositol biphosphate, 2
Phospholipase C, 1
Plateau airway pressure, 111
Pneumothorax
management of, 31
Na+/K+-ATPase, 2
Naloxone, 64
Nephrotoxins, 41
Nitric oxide, 3, 134
Non-invasive ventilation, 86
Non-protein calories, 19
Non-steroidal anti-inflammatory drugs, 64
Noradrenaline, 3
157
tension
management of, 32
Positive end-expiratory pressure, 86
Post-operative cardiac surgery, 115
arrhythmias, 116
bleeding, 118
hypertension in, 116
hypotension in, 116
neurological dysfunction, 118
prophylactic antibiotics, 118
shivering, 117
Pre-eclampsia, 53
magnesium, 55
mild, 54
pathophysiology, 54
severe, 54
treatment, 55
Pro-opiomelanocortin, 61
Propofol, 68
Protein kinase C, 2
Pulmonary embolism, 97
Purine A2 receptor, 40
Pyruvate
formation of, 11
accuracy, 92
predictive power, 93
Sedation
scale, 70
Selective phosphodiesterase inhibitors, 6
Sepsis, 3
Septic inflammatory response syndrome, 5
Septic shock, 148
Sodium bicarbonate, 124
Splanchnic
perfusion pressure, 5
Surgery
Sympathomimetic amines, 1
Systemic inflammatory response
syndrome, 21
Tertiary Survey, 28
Theophylline, 6
Thiopentone, 67
Thromboembolism
causes, 97
embolectomy, 100
investigations, 97
treatment, 99
Thrombolytic therapy, 100
Ticlopidine, 125
Torsades de pointes, 152
Torso injuries
treatment, 36
Toxic shock syndrome, 148
Transfusion
complications, 145
Trauma score, 36
Tubuloglomerular feedback, 40
Tumour necrosis factor, 3, 55
Receptors
down regulation of, 2
Renal dose dopamine, 47
Renal physiology
blood flow, 39
cortical blood flow, 40
outer medullary blood flow, 40
oxygen consumption, 39
vasoregulatory hormones, 40
Revised trauma score, 37
Right ventricular coronary perfusion
pressure, 6
Right ventricular failure, 6
Verapamil, 123
Volatile anaesthetics, 110
Salbutamol, 108
Scoring systems, 36, 91
Warfarin, 153
158

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Inotropic drugs in the intensive care unit

Nutrition in the critically ill

Acute trauma management

Acute renal failure

Intensive care obstetrics

Sedation, analgesia and relaxants in the intensive care patient

Paediatric fluid, renal and nutritional support

Principles of mechanical ventilation

Management of acute asthma

Postoperative management of cardiac surgery patients

1997 SHORT COURSE PROGRAMME

J.M M.B P.T D.C

M.OF A.H C.K T.C

A.V L.W A.B A.H

FMC = Flinders Medical Centre

D.C J.M M.B P.T

QEH = Queen Elizabeth Hospital

(D.B) Dr. J. Cooper

INOTROPIC DRUGS IN THE INTENSIVE CARE UNIT

Inotropic Drugs in the ICU

Legend: Dopamine is an important component of sodium (Na+) homeostasis. Circulating l-dopa

Inotropic Drugs in the ICU

Inotropic Drugs in the ICU

& ) is determined by perfusion pressure (PP), mean blood pressure

Inotropic Drugs in the ICU

Inotropic Drugs in the ICU

Inotropic Drugs in the ICU

Inotropic Drugs in the ICU

Inotropic Drugs in the ICU

LACTIC ACIDOSIS: A GENERATION OR A CLEARANCE

Walley K, Lewis T, Wood L. Acute respiratory acidosis decreases left ventricular

NUTRITION IN THE CRITICALLY ILL

Identification of Malnourished Patients.

Nutrition in the Critically Ill

Nutrition in the Critically Ill

Energy and Nitrogen Requirements in the Critically Ill.

Indications for Nutritional Support.

Nutrition in the Critically Ill

Adams et al 198619 46 trauma patients

Early post-operative jejunostomy feeding is

Moore, Jones et al 198920 63 patients with

Reduced septic complications in TEN group.

Moore et al21 Meta analysis of 8 trials 1992

High risk post operative surgical patients will

Kudsk et al 199222 96 trauma patients

Significantly lower incidence of septic

Wicks et al 199428 24 patients undergoing

Enteral feeding after liver transplantation is

Route of Nutritional Support

Nutrition in the Critically Ill

Nutrition in the Critically Ill

Formulation of the nutritional support

Nutrition in the Critically Ill

TABLE 2 ROUTES OF ACCESS FOR DELIVERY OF ENTERAL NUTRITION

via nasopharynx or at laparotomy

endoscopy, image intensification

open surgical procedure or via the

Nutrition in the Critically Ill

Economical considerations in the provision of nutritional support

Nutrition in the Critically Ill

Nutrition in the Critically Ill

ACUTE TRAUMA MANAGEMENT

Acute Trauma Management