HYPOKALEMIA

Dr.P.Sharath Chandra

Definition

Hypokalemia is defined as a persistently low levels of serum potassium lower than 3.6 mEq/L.

Normal serum levels are 3.5-5mEq/L. 98% of body potassium is intracellular

(150mEq/L) whereas only 2% of it is intracellular (3.5-5mEq/L)

Potassium It is the major intracellular cation,essential for the

maintainance of acid-base balance, isotonicita and electrodynamic cellular function.

Essential for transmission of nerve impulse,contraction of skeletal,cardiac and smooth muscle cells, gastric secretion, renal function, tissue synthesis and carbohydrate metabolism.

Reduces mean SBP and DBP Glucose-Insulin-Potassium/GIK therapy is benificial on

ischemic myocardium by decreasing circulating FFAs and myocardial uptake of FFAs shown to be toxic to ischaemic myocardium. It stimulates myocardial potassium uptake and provides glucose as a substrate for glycolytic ATP production.

Potassium excretion Potassium excretion is chiefly renal. 20mEq of k is lost daily regardless of levels of dietary intake. Potassium excretion is determined by regulated secretion in

the cortical collecting duct(CCD) and the connecting segment(CNT) of the distal nephron by principal cells.

Na is reabsorbed and K+ is secreted in the amiloride sensitive ENaC and is dependent on adequate delivery of luminal Na+ to the CNT and CCD and k+ secretion ceases when luminal Na+ drops below 8mmol/L.

Dietary restriction of sodium decreases K+ secretion and is enhanced by excess intake.

Other channels like the small conductance SK ,ROMK, maxi-k channels are also present in the distal nephron.

Potassium reabsorption

The proximal tubule and loop of henle mediate the bulk of potassium reabsorption and a considerable fraction is reabsorbed prior to entering the distal tubules.

In addition to secretion, distal nephron can reabsorb K+ during dietary restriction in the outer medullary collecting ducts via the H+-K+ATPase pumps

Importance Occurs in 20% of hospitalised patients. 10 fold increase in mortality rates by its adverse

effects on cardiac rhythm,BP, Respiratory depression. Precipitates hepatic encephalopathy in patients with

liver disease. Worsens BP in HTN patients on treatment with

diuretics. Leads to AKI and ESRD in longstanding hypokalemia. Hypokalemic myopathy leading to rhabdomyolysis. Increased risk of arrythmias in patients on digitalis

therapy.

Causes Decreased intake Redistribution / intracellular shifts Non renal losses(urinary k <15mEq/L) Renal losses (urinary K >15mEq/L) Spurious hypokalemia: Delay in sample

analysis may cause hypokalemia due to time dependent intracellular shift of K+.

Rarely profound leukocytosis due to acute leukemia may cause artefactual hypokalemia without any clinical or ECG manifestations. This can be avoided by analysing sample immediately after venepunture.

Decreased intake

K+ deficit I.V fluids,TPN. Decreased dietary intake when on

diuretic therapy, anorexia nervosa, hypo-caloric protein diets for rapid weight loss.

Redistribution of potassium Due to intracellular shift of K. Exogenous Insulin glucose infusion

increases K+ entry into skeletal and hepatic cells by promoting Na-K-ATPase activity. This effect is more prominent when administered in settings of DKA or nonketotic hyperglycemia.

Carbohydrate load in malnourished patient leading to endogenous insulin release can cause the same effects.

Redistribution of potassium Increased beta-adrenergic activity: Promote

Na-K-ATPase activity.

-Beta adrenergic agonists like salbutamol, ritodrine.

-Caffeine and theophylline intoxication by downstream activation of cAMP.

-Occult sources of sympathomimetics like cough syrup and slimming agents contain pseudoephedrine and ephedrine, which are commonly overlooked.

-Stress induced release of epinephrine and cortisol in Alcohol withdrawal, head injury,MI leads to transient hypokalemia.

Redistribution of potassium Metabolic alkalosis: Extracellular K+

exchanged by intracellular H+ ions to maintain pH. Administration of sodium bicarbonate to treat metabolic acidosis can cause this condition.

Increased hematopoiesis: GM-CSF used to treat neutropenia and B-12 and folic acid to treat megaloblastic anemia may cause sharp rise in cell production and increased K+ entry into cell causes hypokalemia.

Redistribution of potassium Hypokalemic periodic paralysis(HOKP):

HOKP type-1 is commoner and is due to AD mutations in the CACNA1S gene encoding the alpha subunit of L-type calcium channels.

HOKP type-2 is due to mutations in SCN4A gene encoding the skeletal Na channel.

Andersen syndrome: AD mutations in the KCNJ2 gene encoding for the inwardly rectifying K+ channel cause periodic paralysis, arrythmias, and dysmorphic features.

Hypokalemic periodic paralysis(HOKP)

Reversible attacks of hypokalemia with paralysis, typically precipitated by rest after exercise or carbohydrate rich meal as insulin potentiates muscle weakness by inhibiting ATP sensitive inward rectifying K+ (K-ATP) channels.

Acute attacks lower Sr.K+ levels to 1.5-2.5 mEq/L.

Paralysis usually starts in the lower limbs and progresses to quadriparesis.

Often accompanied by hypophosphatemia and hypomagnesemia.

Thyrotoxic periodic paralysis Excess thyroid hormone increases Na-K-ATPase

activity , increased B-adrenergic response and predisposes to paralytic attacks with profound hypokalemia, Sr.K+ ranging between 1.1-2.5 mEq/L.

Typically presents between 1AM to 6AM with weakness of limb girdles and extremities.

High dose propranolol @ 3mg/Kg rapidly reverses dyselectrolytemia and paralysis with no rebound hyperkalemia whereas K+ replacement in TPP is associated with 25% risk of rebound hyperkalemia.

A case report of HOKP

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Redistribution of potassium Barium toxicity: Barium is a potent inhibitor if passive K+

efflux channels. It occurs in suicidal or accidental ingestion of barium carbonate (rodenticide),barium containing shaving cream and hair remover. Treatment with K+ repletion serves to both rising serum K+ and to displace barium from efflux channels. Hemodialysis is also effective.

Chloroquine toxicity: Causes intracellular shift of K+ by an unclear mechanism and this can be exacerbated by use of epinephrine to treat intoxication.

Hypothermia: Results In a drive of K+ into cells which is reversible on rewarming.

Increased k+ excretion

Increased K+ excretion

GI tract

Upper GIT-vomiting

-Ryles aspiration

Lower GIT-laxatives

-villous adenoma

-VIPoma

-ileostomy

Renal

RTA, diuretics, Mineralocorticoid

excess,salt wasting nephropathies.

Skin

-Burns-eczema-psoriasis

Non-renal losses Urinary k<15mEq/L or TTKG <3 Sweating in extremes of physical exertion. Gastric losses (vomiting, ryles aspiration)-

ensuing hypochloremic alkalosis results in persistent kaluresis due to secondary hyperaldosteronism and bicarbonaturea.

Diarrhoea is a known cause of K+ loss and may present with acute complications like myopathy and flaccid paralysis.

Non anion gap acidosis with negative urinary anion gap suggests diarrhoea as a cause.

Non-renal losses

Non-infectious processes like ileostomy villous adenoma,laxative abuse celiac disease can present with acute hypokalemic syndromes or with chronic complications like ESRD.

Bowel cleansing agents like oral sodium phosphate can cause GI losses of K+.

Renal losses

Diuretics: Diuretics are an important cause of

hypokalemia by increasing distal delivery of Na and increasing distal flow.

Thiazides cause more hypokalemia than loop diuretics despite their lower natriuretic effect due to their differential effect on calcium excrtetion.

Hypercalciurea caused by loop diuretics increases luminal calcium which inturn inhibitd ENaC in the principal cells.

Renal losses

Non-reabsorbable anions: Non-reabsorbable anions in the distal nephron like penicillin, nafacillin, dicloxacillin,ticarcillin,oxacillin,carbencillin and other anions like bicarbonate increase obligatory K+ excretion and thereby kaliuresis.

K+ excretion Increases to balance negative charge of these anions.

Renal losses

Tubular toxins: Several tuular toxins can cause combined K+ and Magnesium wasting that can masquerade as Bartter’s syndrome.

Eg:gentamycin,amphoterecin, foscarnet, cisplatin, ifosfamide.

Hpokalemia is refractory to K+ repletion unless concomitant Mg supplementation is given.

Hyperaldosteronism

Primary

genetic

Familial hyperaldosteronism

FH-1/GRA

Dexamethasone supression test +ve

FH-2

Congenital adrenal hyperplasia

11-B hydroxylase(virilism),7- alpha hydroxylase

deficiency(hypogonadism)

AcquiredIHA(B/L)

PAH(U/L), APA, adrenal carcinomas.

Secondary

HTN, RAS, RST, Page kidney.

Syndromes of apparent minerakocorticoid excess(SAME)

Loss of function mutation in the 11-BHSD-2 gene cause defective peripheral conversion of cortisol to inactive cortisone.

Cortisol has similar effects on the mineralocorticoid receptor as aldosterone.

11-BHSD2 converts cortisol to cortisone and prevents this illicit activation of MLR.

Pharmacological inhibition of 11-BHSD2 is seen with consumption of liquorice which contains glycyrrhizinic acid and carbenoxolone.

Rarely, gain of function mutations on the MLR can cause SAME.

Liddle syndrome

Liddle syndrome

Autosomal dominant gain in function mutation of amiloride sensitive ENaC leading to overactivity and overexpression on the cell membrane.

Presents with severe HTN, hypokalemia unresponsive to spironolactone but responsive to amiloride and triamterene.

Blunted aldosterone response to ACTH and decreased urinary aldosterone excretion.

Familial hypokalemic alkalosis

Includes Bartter’s and Gitelman syndromes. Bartter’s syndrome:

Mimics loop diuretic effect-defect in TALH Na-K-2Cl cotransport.

Polyuria, polydypsia with hypokalemic hypochloremic alkalosis, hypercalcuria and 20% are hypomagnesemic.

Raised serum AT-2, aldosterone, rennin. Antenatal BS presents early in life with electrolyte wasting,

polyhydramnios, hypercalcuria with nephrocalcinosis. Increased prostaglandin synthesis amplify the inhibition on urinary concentrating ability and COX inhibition with indomethacin is proven to be benificial.

Pseudobartter syndrome: Furosemide abuse, laxative abuse,Bulimia.

Familial hypokalemic alkalosis

Gitelman syndrome: Mimics thiazide diuretic effect-defective thiazide sensitive Na-Cl cotransport in DCT.

Hypocalciuria is seen and hypomagnesemia is universal in contrast to BS.

Pseudo Gitelman syndrome: chemotherapy with cisplatin,sjogrens syndrome, tubulointerstitial nephritis may cause hypokalemic alkalosis with hypomagnesemia and hypocalciuria.

Clinical features Non severe hypokalemia is usually asymptomatic. Common acute manifestations are muscle weakness and

ECG changes. Prolonged and profound hypokalemia may cause arrythmias,

rhabdomyolysis, renal abnormalitiess. History may reveal the cause like

exertion,vomiting,diarrhoea,drugs,B-12 therapy etc. Asymptomatic or growth retardation should prompt the

suspicion of RTA. S/O volume depletion. Kussumal breathing may suggest metabolic acidosis with

respiratory compensation. Presence of oedema and HTN may indicate mineralocorticoid

excess.

Clinical features

• Cardiac arrythmias like sinus bradycardia, premature beats, ventricular fibrillation, AV blocks.

• Skeletal muscle weakness or paralysis usually do not develop unless hypokalemia develops slowlyand levels are <2.5mEq/L.

• Constipation and ileus due to smooth muscle involvement.

• Nausea/vomiting, abdominal cramps. • Polyuria, nocturia, or polydipsia • Psychosis, delirium, or hallucinations • Depression

Clinical features Signs of ileus Hypotension Ventricular

arrhythmias Cardiac arrest Bradycardia or

tachycardia Premature atrial or

ventricular beats

• Hypoventilation, respiratory distress

• Respiratory failure • Lethargy or other

mental status changes • Decreased muscle

strength, fasciculations, or tetany

• Decreased tendon reflexes

• Cushingoid appearance (eg, edema)

Investigations Sr.Electrolytes,BUN,creatnine. ECG Urine electrolytes to differentiate non-renal from renal

causes. Exclude associated electrolyte abnormalities especially in

alcoholism. ABG to detect acidosis or alkalosis when cause is not

apparent. Urinalysis and urine pH if RTA is suspected. Urinary calcium to exclude Bartters syndrome. Aldosterone supression test if aldosterone producing

adenoma is suspected. CT abdomen to R/O other pathologies.

ECG changes

Flat “T” wave Prominent “U” wave ST depression QT prolongation

PR prolongation Wide QRS Ventricular arrythmias Decreased voltage

Effects on kidney

Raised bicarbonate and salt retention Polyuria by secondary polydypsia and

nephrogenic DI Increased ammonogenesis. Structural:vacuolising proximal tubule

injury,interstitial nephritis,renal cysts.

Diagnostic approach History(drugs,diet,diarrhoea/vomiting) Physical examination(BP,s/o

hyperthyroidsm,cushings) Lab tests(serum

electrolytes,BUN,Sr.creatnine,CBP,urinary pH) ECG

Treatment goals

Prevent hypokalemia Correct hypokalemia Prevent complications Minimize losses Correct underlying etiology

Prevention

Especially important in patients on digitalis,hepatic failure,previous MI,DM.

Normal daily intake of 60mEq/day Supplementation in patients on

digitalis,diuretics and long term steroids,hepatic failure.

When to treat?

3.5-5mEq/L: No supplement needed

Potassium rich foods

Change diuretics 3-3.5mEq/L: Treatment needed in high

risk patients(h/o MI,CHF) <3mEq/L: Needs definitive treatment.

Precautions

Oliguria/anuria Patients on ACE inhibitots,k-sparing

diuretics,renal failure. Digitalis (slower infusions <20mEq/hr) Continuous ECG monitoring if infusion

rates >20 mEq/hr. Deficit should be corrected slowly over

four days.

Treatment Oral supplementation preferred if patient tolerates oral K+ and if there is

no DKA or non-ketotic hyperglycemia. Serum K+ can raise by 1-1.5 mEq after an oral dose of 40-50mEq of K+. I.V KCL may be used as an adjunct if large doses are required as higher

oral doses cause gastric irritation. Oral potassium phosphate in patients with associated hypophosphatemia. Oral potassium bicarbonate/potassium citrate in patients concomitant

acidosis. Correct Mg deficiency. Oral supplements are best taken after meal with a glass of water. Usually dose of 20mEq 3-4 times a day is given and should not exceed

200mEq/day in adults and it should not exceed 3mEq/kg/day in pediatric patients.

In severe/symptomatic hypokalemia, upto 40mEq/6hrs can be given under close ECG monitoring.

Oral KCL solutions contain 20mEq/15ml of solution and a KCL tablet contains 8mEq of K+.

Treatment I.V supplementation:IV replacement carries a higher

risk of hyperkalemia and is required if patient is unable to tolerate oral supplements or in the settings of DKA and non-ketotic hyperglycemia.

Maximum recommended rate is 10 – 20 mEq/hr with a daily maximum of 240mEq/day.

Faster rates may be considered in presence of ECG manifestations, muscle weakness or paralysis.

Solutions more than 60mEq/L are painful and may cause phlebitis and larger veins preferably femoral vein is used.

Normal saline is preferred dilutent as dextrose preparations cause insulin release and isolyte and RL have potassium added.

Isolyte-M has maximum k concentration.1. Isolyte-M --- 35mEq/L

2. Isolyte-P----20mEq/L

3. Isolyte-G---17mEq/L

4. Isolyte-E----10mEq/L

5. R/L-----------4mEq/L

Interactions: ACE inhibitors like captopril and enalapril, K+ sparing diuretics like amiloride, spironolactone and triamterene cause increased risk of hyperkalemia. Concomitant use with corticosteroids and corticotropins is not recommended.

Thank you