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Piyarat Rojsanga Udornthani Hospital

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

Abnormal of plasma osmolarity = abnormal of

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

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

Classification: plasma osmolarity 1.Isotonic hyponatremia 2.Hypertonic hyponatremia 3.Hypotonic hyponatremia

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

Causes of hypotonic hyponatremia

Impaired capacity of renal water excretion: Uosm>100 mosm/L 1.Decreased volume of extracellular fluid Renal sodium loss Diuretic agents Osmotic diuresis: glucose, urea, mannitol Adrenal insufficiency Salt-wasting nephropathy Bicarbonaturia: RTA, disequilibrium stage of vomiting Ketonuria

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

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

enhance its action

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

Signs and symptoms

Depend on Rapidity: <48hr = acute hyponatremia > 48 hr = chronic hyponatremia Level: plasma Na < 120 mmol/L Abnormal mental status: confusion, consciousness, hallucinations, coma Convulsions Fatigue Headache Irritability Loss of appetite Muscle spasms or cramps Muscle weakness Nausea, vomiting

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

Investigation (before treatment)

Volume status : JVP, BP Spot urine Na Volume status Spot urine osmolality ADH effect Serum osmolality Osmolality stage BUN, serum uric acid, FE urea, uric

Diagnostic Approach
Isotonic Hyponatremia

True Hyponatremia Hypertonic Hyponatremia
History, Physical examination, Labs*

Assess ECF Volume

U [Na]

>20 - 40

> 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)

mOsm/Kg <100 >100

Primary polydipsia Low solute intake Reset osmostat *Try NSS 2 liters within 1-2 days

Glucocorticoid def. Hypothyroidism

SIADH Drugs, stress

1. Correct causes of hyponatremia 2. Increased level of plasma Na Fluid Rate Calculation for Na requirement

Asymptomatic Symptomatic

Chronic or Undetermine onset


Chronic(>48hr) or undetermine onset

No immediate correction

Emergency Rx until clinically improved

Immediate Rx & avoid over correction

Long-term Rx

Osmotic demyelination syndrome

Biphasic pattern: onset 1-3 days EPM: personality change, abnormal movement, akinetic mutism CPM: dysarthria, dysphagia, pseudobulbar palsy,


Dx by CT scan / MRI Risk factors Chronic & severe hyponatremia Alcoholism Post liver transplantation Chronic thiazide used Malnutrition Hypokalemia

Acute/Severe Symptomatic Hyponatremia

Risks of electrolyte disturbance exceed risks of excessive treatment Fear of ODS should not deter aggressive Rx

Correction 1-2 mmol/L/hr by infusion 3%NaCl at rate 1-2 cc/kg/hr

Bolus infusion of IV hypertonic saline

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

Calculation for Na requirement = Na * TBW ( 3%NaCl = 514 mEq/L = 0.5 mEq/ml)


Increase PNa( for 1 litre of infusate)

= {Infusate[Na]-PNa}/{TBW+1}
(Infusate[Na] = Fluid Na concentration)

Treatment of Chronic Hyponatremia

Fluid restriction Salt: Isotonic saline, Hypertonic saline Furosemide, Demeclocycline, Lithium Correction of hypokalemia V2 receptor antagonists

Restrict free water

Normovolemic or hypervolemic hyponatremia 500-1000 cc/day Calculate: Urine electrolyte ratio= (Una+UK)/Pna 0.5 recommended fluid intake <1L /day 0.5 1.0 recommended fluid intake <500 ml/day 1 avoid free water intake

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
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


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

Risk factors for hypernatremia

Advanced age Mental or physical impairment Hospitalization: decreased baseline levels of consciousness Uncontrolled DM (solute diuresis) Tube feeding Hypertonic infusions Osmotic diuresis Lactulose Mechanical ventilation Medication: diuretics, sedatives

Signs and symptoms

7.5% NaHCO3 Hypertonic saline


Sweating Osmotic diarrhea

ECV : Na overload ECV : renal or nonrenal hypotonic volume loss ECV : essential hypernatremia, primary hypodipsia, DI

Hypernatremia (Serum Na >145 mEq/L)

Hypovolemia (loss of hypotonic soln) UNa


Euvolemia (free water loss) vary

Hypervolemia (Na gain) >20


<20 >700

Uosm BW






Renal loss - GI : diarrhea

-Osmotic glucose urea mannitol - Burn - Excessive sweating - Fistula

Extrarenal loss

Renal loss
- DI

Extrarenal loss -insensible loss

Respiratory, dermal

or -1ohypodipsia
(thirst testing)

Hypertonic - NaCl - NaHCO3

1o hyperaldosteronism


Hypotonic fluid replacement

DDAVP in central DI

Free water + Furosemide, Dialysis

Treat underlying disease
Treatment of hypernatremia
Net water loss patient

Free water or hypotonic solution (5%D/W<300 ml/min BS<180 mg/dL)

Isotonic solution in case of ECF volume & hemodynamic instability) Calculate Water Deficit Insensible loss Plus continuous loss

Route :

prefers enteral if no contraindication

Rate : Acute or symptomatic serum Na 1 mEq/L/hr

Chronic serum Na 0.5 mEq/L/hr,

increase serum Na not more than 10 mEq/L/day

Water deficit = ( PNa 140 ) x TBW 140 Type of fluid : oral route > IV route

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



Intake : 60 100 mEq/day Distribution : Intracellular anabolism : glucose, insulin, folic, B12 Cell membrane factor : Na+K+ATPase, insulin,

adrenergic receptor (-out, 2-in) Extracellular factor : acidosis-out, alkalosis-in

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

Plasma K < 3.5 mEq/L

CLINICAL SIGNS & SYMPTOMS SERUM K+ Exclude : spurious hypokalemia Wbc > 100,000/mm3 Plt > 500,000-1,000,000/mm3


3.0 - 3.5 mEq/L : no symptoms

2.5 - 3.0 mEq/L : non-specific symptoms, constipation

< 2.5 mEq/L < 2.0 mEq/L : proximal muscle weakness, muscle necrosis : ascending paralysis, respiratory muscle weakness


Cardiac conduction defects Ischemia Heart failure

Digitalis intoxication

ST depress, U wave, Peak P, PR prolong, Widening QRS



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


- Asymptomatic Hypokalemia - EKG change - Proximal muscle weakness - Rhabdomyolysis

Pseudohypokalemia FPP, Hyperthyroidism UGI loss , LGI loss Renal loss

How to approach
History : diuretic uses, vomiting, diarrhea, drugs, Hx of muscle weakness ECF volume: JVP Blood pressure : HT / orthostatic hypotension

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

HyperK >100,150 >?? >10-15

<5 <2(>4)

> 20 >10(<5)

Limitation of TTKG -UNa>25 -Uosm Sosm pathophysiology K


Inappropiate response

[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)

Lower GI loss diarrhea laxative abuse villous adenoma

Renal loss RTA DKA acetazolamide

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


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

Hypokalemia, Hypertension, Metabolic alkalosis, renal K+ loss (screening test)

[plasma renin activity (PRAng/ml/hr), plasma aldosterone concentration (PAC,ng/dl)]


PRA (<1) PAC (>9) >25 24 hr urine aldosterone >14 g


Secondary hyperaldosteronism renovascular hypertension diuretic use renin producing tumor malignant hypertension coarctation of the aorta

Confirmatory test NaCl loading test Fludrocortisone suppression test

Primary hyperaldosteronism GRA

Mineralocorticoid-like effects exogenous (licorice, see text) congenital adrenal hyperplasia DOC-producing tumor cushings syndrome 11-HSD deficiency altered aldosterone metabolism Liddles syndrome

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

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)

Plasma K > 5.5mEq/L

Intake Tissue ECFK

Renal (E=F-R+S)


Factitious hyperkalemia Metabolic acidosis Potassium load : exogenous / endogenous Renal failure Impaired RAAS Inhibition of tubular secretion : spironolactone, triamterene, amiloride

Medications associated with hyperkalemia

K-containing medicines -adrenergic receptor blockers ACEI
ARB Heparin

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

Propanolol Captopril Losartan

Medications associated with hyperkalemia

Aldosterone receptor antagonist K-sparing diuretic

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

Spironolactone Amiloride, Triamterene, Trimethoprim Pentamidine Ibuprofen, Rofecoxib Digoxin

NSAID and COX-2 inhibitors Digitalis glycosides Calcineurin inhibitors

Inhibit Na-K-ATPase necessary for collecting duct K secretion

Inhibit Na-K-ATPase necessary for collecting duct K secretion

Cyclosporine, Tacrolimus

Clinical: S&S Serum K+ Exclude : spurious hyperkalemia WC > 100,000/mm3 Plt > 1,000,000/mm3 Hemolysis Clenching

Signs & symptoms

Proximal muscle weakness Cardiac conduction defect

Flat P, Prolong PR, AV block, Widening QRS, Sine-wave

Rule out factitious hyperkalemia

K+ load
Cause of shift Decrease renal K+ excretion advanced renal failure severe congestive heart failure

decrease aldosterone effect

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