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Introduction
Osmolality = Solute or particle concentration of fluid Posm =2[Na+] + [glucose]/18 + [BUN]/2.8 The major ECF particles ; Na+ and its accompanying anions Cl and HCO3 The major ICF particles ; K+ and organic phosphate esters Plasma osmolality: 275290 mosmol/kg Water intake must equal water excretion Disorders of water homeostasis result in hypo- or hypernatremia
8590% of all Na+ is extracellular ECF volume is a reflection of total body Na+ content Na+ excess or deficit ; edematous or hypovolemic states Tubule Na+ reabsorption ; the major regulatory mechanism controlling Na+ excretion
water metabolism
Thirst Arginine vasopressin hormone (AVP) Renal function AVP: Hypothalamus posterior pituitary gland Osmoreceptor (hypothalamus): osmolarity Baroreceptor (carotid artery, aortic arch, left atrium): BP
Hyponatremia
Most common electrolyte disturbance 15-22% of hospitalized patients Hyponatremia increased mortality, length of hospital stay and costs
In critically ill, severe hyponatremia (Na<120 mmol/L ) independent predictor of hospital mortality, estimated risk for death 40% Definition: serum Na < 135 mmol/L
Isotonic hyponatremia
Normal plasma osmolarity Pseudohyponatremia Hyperlipidemia, Hyperproteinemia TG 100 mg/dl ~ Na 2 mEq/l TP 1 g/dl ( from 8 g/dl ) ~ Na 0.25 mEq/l Flame photometry: dilute method Corrected by ion specific electrode
Hypertonic hyponatremia
High plasma osmolarity Translocational hyponatremia: Water shift from intracellular compartment to extracellular compartment: osmotic agents Hyperglycemia: PG 100 mg/dl ~ Na 1.6 mEq/l, if BS>400: PG 100 mg/dl ~ Na 2.4 mEq/l Mannitol, sorbitol Radiocontrast
Hopotonic hyponatremia
Plasma osmolarity < 275 mOsm/Kg H2O True hyponatremia, dilutional hyponatremia Excess of water in relation to existing sodium stores (decreased, essentially normal, or increased) Common: impair renal excretion of water
Water excretion
1. Normal water excretion: Uosm<100 mmol/L 2. Abnormal water excretion: Uosm >100 mmol/L Hypovolemic hyponatremia Normovolemic hyponatremia Hypervolemia hyponatremia
Extrarenal sodium loss Diarrhea Vomiting Blood loss Excessive sweating: e.g., in marathon runners Fluid sequestration in third space: Bowel obstruction, peritonitis, pancreatitis, muscle trauma, burns 2. Increased volume of extracellular fluid Congestive heart failure Cirrhosis Nephrotic syndrome Renal failure (acute or chronic)
3. Essentially normal volume of extracellular fluid Thiazide diuretics Hypothyroidism Adrenal insufficiency Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) Decreased intake of solutes Beer potomania Tea-and-toast diet
Normal capacity of renal water excretion: Uosm<100 mosm/L: 1.Water intoxication Primary polydipsia Dilute infant formula Sodium-free irrigant solutions: hysteroscopy, laparoscopy, TURP Accidental intake of large amounts of water Multiple tap-water enemas 2.Reset osmostat
SIADH
Syndrome of Inappropriate Antidiuresis (SIAD) Most frequent cause of hyponatremia First described in pts with bronchogenic CA Common causes of SIAD: brain lesions D/Dx: cerebral salt wasting
Causes of SIAD
1. Malignancy 1.1 Carcinoma Lung: SCLC, Mesothelioma Oropharynx GI: stomach, duodenum, pancreas GU tract: ureter, bladder, prostate, endometrium Endocrine: thymoma 1.2 Lymphomas 1.3 Sarcomas Ewings sarcoma 2. Pulmonary diseases 2.1 Infections Bacterial pneumonia Viral pneumonia Pulmonary abscess Tuberculosis Aspergillosis 2.2 Asthma 2.3 Cystic fibrosis 2.4 Respiratory failure associated with positivepressure breathing
Causes of SIAD
3. CNS disorders 3.1 Infection Encephalitis Meningitis Brain abscess Rocky Mountain spotted fever AIDS 3.2 Bleeding and masses SDH SAH CVA Brain tumors Head trauma Hydrocephalus Cavernous sinus thrombosis 3.3 Other Multiple sclerosis GuillainBarre syndrome ShyDrager syndrome Delirium tremens Acute intermittent porphyria
Causes of SIAD
4. Drugs 4.1 Drugs that stimulate release of AVP or Cyclophosphamide NSAIDs MDMA (ecstasy) 4.2 AVP analogues Desmopressin (DDAVP) Oxytocin Vasopressin
Chlorpropramide SSRIs Tricyclic antidepressants Clofibrate Carbamazepine Vincristine Narcotics Antipsychotic drugs Ifosfamide
Causes of SIAD
5. Others 5.1 Hereditary (Gain of function mutations in V2 receptor) 5.2 Idiopathic 5.3 Transient Endurance exercise General anesthesia Nausea Pain Stress Senile atrophy
Diagnosis of SIAD
Essential features Decreased effective osmolality (<275 mOsm/kg ) Uosm >100 mOsm/kg during hypotonicity Clinical euvolemia No clinical signs of volume depletion of ECF No clinical signs of excessive volume of ECF UNa >40 mmol/L with normal dietary salt intake Normal thyroid and adrenal function No recent use of diuretic agents
Supplemental features Suric <4 mg/dl BUN <10 mg/dl FENa >1%; FEUrea >55% Failure to correct hyponatremia after 0.9% NSS infusion Correction of hyponatremia through fluid restriction Abnormal result on test of water load (<80% excretion of 20 ml/Kg of water in 4hrs or Uosm < 100 mOsm/kg ) Elevated plasma AVP, despite the presence of hypotonicity and clinical euvolemia
Approach to hyponatremia
1. Exclude isotonic and hypertonic hyponatremia 2. True hyponatremia: evaluate ECF volume status Low ECFV: loss of sodium (renal, extrarenal) Normal ECFV: SIAD, hypothyroid, glucocorticoid deficiency High ECFV: NS, CHF, cirrhosis, renal failure
Diagnostic Approach
Isotonic Hyponatremia
Hyponatremia
True Hyponatremia Hypertonic Hyponatremia
History, Physical examination, Labs*
Euvolemia
>20 - 40
Hypervolemia
> 20
Acute or chronic Renal failure
> 20
Renal loss
< 20
Extrarenal loss Clinical equivocal (hypo- or euvolemia) Response to NSS* Yes No
< 20
Edematous State (CHF, liver cirrhosis, NS)
Uosm
mOsm/Kg <100 >100
Primary polydipsia Low solute intake Reset osmostat *Try NSS 2 liters within 1-2 days
Treatments
1. Correct causes of hyponatremia 2. Increased level of plasma Na Fluid Rate Calculation for Na requirement
TREATMENT
Asymptomatic Symptomatic
Acute(<48hr)
No immediate correction
Long-term Rx
quadriparesis
Dx by CT scan / MRI Risk factors Chronic & severe hyponatremia Alcoholism Post liver transplantation Chronic thiazide used Malnutrition Hypokalemia
Monitor
Closed monitor of SNa post Rx q 2-4 hr Additional bolus doses may be needed in Seizures are known to increase SNa concentration because internal water shift into muscle cells caused by intracellular solute In water toxicity Delayed water reabsorption from intestinal tract
Chronic Hyponatremia
Overcorrection CPM or ODS Goal in Rx keep patient safe from complication of hypoNa + avoid iatrogenic injury Target setting is lower in the present: 25 mmol/L in 48 hr 18-25 mmol/L in 48 hr Most accepted: 12 mmol/L in 24 hours No therapeutic target is absolutely safe
Vasopressin Antagonists
Blockade of vasopressin receptors Increased electrolyte free water clearance
Conivaptan is potent inhibitor of CYP3A4, interact with many medication including statin US FDA approve only IV form
Vasopressin Antagonists
Indication
Contraindication Hypovolemic HypoNa Euvolemic HypoNa HypoNa caused by HypoNa caused by CHF cirrhosis HypoNa caused by (conivaptan) cirrhosis (not conivaptan) No data Acute hyponatremia Extremely low serum Na conc. Hypervolemic hypoNa not from CHF, cirrhosis
Hypernatremia
Hypernatremia
Plasma Na > 145 mEq/L
< 1% of hospitalized patients Common in elderly patients: thirst abnormality Classification 1. Hypovolemic hypernatremia 2. Normovolemic hypernatremia 3. Hypervolemic hypernatremia
Etiology
ECV : Na overload ECV : renal or nonrenal hypotonic volume loss ECV : essential hypernatremia, primary hypodipsia, DI
>20
<20 >700
Uosm BW
(mOsm/kg)
~300-700
<150
>700
vary
Extrarenal loss
Renal loss
- DI
or -1ohypodipsia
(thirst testing)
1o hyperaldosteronism
Treatment
DDAVP in central DI
Treatment
Treat underlying disease
Treatment of hypernatremia
Net water loss patient
Route :
PHYSIOLOGY
Adult body K = 50 55 mEq/kg (3,000 4,000 mEq) 98% intracellular Function : Membrane excitability Cell metabolism : protein & glycogen synthesis Serum level : 3.5 5 mEq/L
3Na+
2K+
K BALANCE
Intake : 60 100 mEq/day Distribution : Intracellular anabolism : glucose, insulin, folic, B12 Cell membrane factor : Na+K+ATPase, insulin,
GI : secretion upper 5 15 mEq/L lower 90 mEq/L Renal excretion**: 40-120 mEq/day depend on K intake K depletion renal K ~ 5-25 mEq/day
Hypokalemia
Plasma K < 3.5 mEq/L
Diagnosis
CLINICAL SIGNS & SYMPTOMS SERUM K+ Exclude : spurious hypokalemia Wbc > 100,000/mm3 Plt > 500,000-1,000,000/mm3
LVH
Digitalis intoxication
Intake
Shift
1.Intracellular anabolism
B12 , folic acid , GM-CSF
2. Cell membrane
insulin , 2 adrenergic agonist , FPP , hyperthyroidism
3. Extracellular
metabolic alkalosis
Extra-renal loss
Renal loss
Intake Body K loss 100-200 mEq PK 1mEq/L Tissue UGI loss metabolic alkalosis Amount of K loss : minor Renal loss : major LGI loss metabolic acidosis GI loss K Renal loss
Extra-renal loss
Renal loss
Clinical
Lab
- Asymptomatic Hypokalemia - EKG change - Proximal muscle weakness - Rhabdomyolysis
How to approach
History : diuretic uses, vomiting, diarrhea, drugs, Hx of muscle weakness ECF volume: JVP Blood pressure : HT / orthostatic hypotension
Algorithm
Exclude redistribution Extrarenal or Renal loss: Urine K+ excretion rate Urine K+ Urine Na+ (mEq/day) Renal > 20 Extrarenal < 20 > 200 if urine Na+ < 100
repeat after diet Na > 100/day
HypoK 24hr UK K (mmol/day) Spot UK K mmol/L **Spot UK/UCr <mmol/L:mmol/L> Cr mg/dL mmol/L 0.088 FEK TTKG: mineralocorticoid activity < 20 < 20 < 1-1.5
<5 <2(>4)
> 20 >10(<5)
Normal
Inappropiate response
Hypokalemia
[acid-base, ECF volume, hypertension, urine K+]
Metabolic acidosis
urine K+ low high (urine Na+ > 100 mEq/day)
Normal acid-base
Metabolic alkalosis
urine K+ low high + (urine Na > 100 mEq/day)
Intracellular shift insulin -agonist extracellular pH thyrotoxicosis periodic paralysis cell production intoxication other drugs (see text)
loss gastric secretion (late) (urine pH<5.5, low urine Cl-) remote diuretic use (thiazide, loop diuretics) laxative abuse
normotension
hypertension
mineralocorticoid excess or effects
loss gastric secretion (early) (urine pH>7, low urine Cl-) recent diuretic use (thiazide, loop diuretics) Bartters syndrome Gitelmans syndrome Mg2+ depletion
PRA PAC
Secondary hyperaldosteronism renovascular hypertension diuretic use renin producing tumor malignant hypertension coarctation of the aorta
Mineralocorticoid-like effects exogenous (licorice, see text) congenital adrenal hyperplasia DOC-producing tumor cushings syndrome 11-HSD deficiency altered aldosterone metabolism Liddles syndrome
Treatment
Evaluation : EKG and weakness Emergency : arrhythmia, respiratory failure, paralysis IV KCl (1 cc : K+ and Cl- 2 mEq) 40 60 mEq/ IV 1 L without glucose rate <10 20 mEq/hr 40 60 mEq/day
Oral : KCl (general) > Kcitrate (RTA) Check serum K+ q 60 mEq iv replacement Causes : Mg2+ depletion
Treatment
IV K+ 15%KCl (1cc = K+ 2 mEq) , 8.7%K2HPO4 (1cc = K+ 1 mEq) Oral K+ KCl : elixir (15 cc 20 mEq) tablet (wax matrix, microencapsulated) K citrate (15 cc 10 mEq)
Hyperkalemia
Plasma K > 5.5mEq/L
Renal (E=F-R+S)
Extrarenal
Etiology
Factitious hyperkalemia Metabolic acidosis Potassium load : exogenous / endogenous Renal failure Impaired RAAS Inhibition of tubular secretion : spironolactone, triamterene, amiloride
Mechanism
Increased K intake
Inhibit renin release Inhibit conversion of Angiotensin I to Angiotensin II Inhibit activation of AT1 receptor by Angiotensin II Inhibit aldosterone synthase, rate limiting enzyme for aldosterone synthesis
Example
KCl
Propanolol Captopril Losartan
Mechanism
Block aldosterone receptor activation Block collecting duct apical Na channel, decreasing gradient for K secretion Inhibit prostaglandin stimulation of collecting duct K secretion, inhibits renin release
Example
Spironolactone Amiloride, Triamterene, Trimethoprim Pentamidine Ibuprofen, Rofecoxib Digoxin
Cyclosporine, Tacrolimus
Diagnosis
Clinical: S&S Serum K+ Exclude : spurious hyperkalemia WC > 100,000/mm3 Plt > 1,000,000/mm3 Hemolysis Clenching
Diagnosis
Rule out factitious hyperkalemia
K+ load
Cause of shift Decrease renal K+ excretion advanced renal failure severe congestive heart failure
Treatments
Emergency Abnormal EKG Serum K+ > 6.5 (or acute > 6.0) Severe paralysis, respiratory failure
EKG monitoring
Specific treatments
Antagonize membrane effect Decrease K+ level Remove K+ from the body
Intracellular K+ shift
Insulin : most effective and reliable Beta2 agonist : modest, tachycardia (IV) HCO3- : ineffective in advanced renal failure, use in metabolic acidosis cases
Remove K+
Hemodialysis : most rapid Anion exchange resin + laxative Kayexalate : Na polystylene sulfonate 0.6 0.7 mEq K+/1 g resin Complication : intestinal necrosis, Na+ overload
Adjunctive treatments
Restrict K+ 2 g/day Stop risk factors Diuretics : increase ECF Fludrocortisone : decrease ICF Long term kayexalate with meal Avoid fasting without glucose