HYPERTENSION AND HYPOKALEMIA

HYPERTENSION AND HYPOKALEMIA 3 : 5 Sekhar Chakraborty, Siliguri INTRODUCTION Hypertension and Hypokalemia are two distinct clinical entities, whenever present in a single clinical setting of an individual, may or may not be related to each other. However it is mandatory for a treating physician to search for this clinical correlation. Detection of the underlying cause not only guides the treatment protocol but also dictates further steps for prevention of hypertension & hypokalemia, prevention for life threatening conditions like arrhythmias, sudden cardiac death, respiratory failure etc. & provides the insights for prognosis. Simple reason like diuretic induced hypokalemia for the treatment of hypertension may be overshadowed with complicated genetic disorders, channelopathies or endocrine disorders which need prolonged biochemical & genetic workup. Therefore careful & vigilant approach is warranted in this clinical setting. Potassium Homeostasis Approximately 98 % of total body stores are intracellular Normal Serum [K + ] ranges from 3.5 5 mmol/ L Insulin, aldosterone, catecholamine & acid base status influence movement of [K + ] into the cells. K + excretion is regulated at the distal nephron. K + excretion is related to (Urine flow rate) The marked discrepancy between intracellular & extracellular content of potassium is illustrated Fig. 1. Total body potassium content in healthy adult is approx 50mEq/ kg, so a 70 kg adult will have 3500 meq as 2% of total amount is in extracellular fluid, therefore ECF contain 70 meq K+. As plasma 4000 Total Body K (meq) 3000 353500 2000 70 meq 1000 0 Intracellular Potassium Extracellular Potassium Fig. 1 : Intracellular & extracellular content of potassium 128

accounts for approx 20% of ECF volume, the potassium content of plasma is about 15 meq which is about 0.4% of total body potassium. This suggests that plasma potassium is an insensitive marker of changes in total body potassium stores. Serum level of K+ is regulated by- Uptake of K+ into cells by altering activity of Na K- ATP s pump in the cell membrane. Renal excretion mainly controlled by aldosterone. 10 8 Serum K+ (meq/ L) 6-4 - 2 - ACIDOSIS -900-600 -300 +300 0 Fig. 2 : Relationship between the Serum potassium concentration & changes in total body potassium content. Hypertension and Hypokalemia (70 kg Adult) K+ Deficit (meq) K+ Excess (meq) Hypokalemia: High K+ excretion Extra renal loss e.g. gastrointestinal. Definition of Hypokalemia Hypokalemia has been defined as Serum [K + ] is < 3.5 meq/ L. Severe hypokalemia where Serum [K + ] = < 2.5 meq / L (Figs. 3 and 4). HYPERTENSION Hypertension, more specifically systemic arterial hypertension is defined as the elevation of blood pressure (BP) to such a level that place patients at increased risk of target organ damage in several vascular beds including the retina, brain, heart, kidneys and large condict arteries. In demographic studies the level has been observed above 120/80mHg. Hypertension has been staged as High normal stage I & II, Hypertensive crisis, isolated systolic HTN according to level of elevation of BP, rapidity of development of HTN, threat to vascular bed, etc. Prevalence Recent studies have reported a high prevalence of hypertension in both urban & rural areas, in India In urban area the prevalence varies from 30-45 % in ALKALOSIS different regions, which is consistent with the findings with other developing countries in Asia where prevalence is 50% Epidemiological studies report that currently 70% of hypertension in India is Stage I (140 159 / 90 99 mmhg.) & rest of are Stage II. Mechanism of hypokalemia Prevalence of resistant hypertension in India is unknown. Reason? (Can be both) Osmoles? High Flow Rate High [K + ] CCD ECFV? Lytes Organics Not low = Low = Faster Na + Slower Cl - * High NaCl input * Glucose * Primary high * Bartter * Diuretics loop, * Urea aldosterone * Gitelman Thiazide, or * Mannitol * AME syndrome * Bicarbonaturia Cal types * GRA * Low Cl - delivery * Liddle * Amphotericin B Hypokalemia Fig. 3 : Mechanism of hypokalemia 129 Faster Na + Slower Cl -

Hypokalemia * Liddle * Amphotericin B Medicine Update 2012 Vol. 22 Faster Na + Slower Cl - Na + Electro -negative Electronegative Cl - K * TTKG * TTKG Na * ECFV * ECFV * Urine [Na + + Cl - ] * Urine [Na + + Cl - ] if ECFV low not Fig. 4 : Hypokalemia 50 40 30 20 10 0 Prevalence Awareness Treatment Control Urban Rural Fig. 5 : Status of hypertension prevalence, awareness, treatment & control in India. Status of hypertension prevalence, awareness, treatment and control in India. (4608 middle aged women, 35 70 years, in 4 urban and 5 rural cites.) What is the relation between Hypertension & Hypokalemia? Hypertension & hypokalemia are two distinct clinical syndromes which may or may not be associated. Relation between these two clinical syndromes can be established as follows. 1. Aetiology of hypertension is associated with hypokalemia. 2. Treatment of HTN may lead to hypokalemia Aetiology of HTN associated with hypokalemia. Among all the causes of HTN, the following are related to hypokalemia. Extrarenal (Urine K+ < 20mmol/ day) Inadequate intake Copious perspiration Gastrointestinal losses Diarrhoea Laxative abuse Villous adenoma Table 1 : Causes of K + depletion Endocrine cause Primary hyperaldostronism Secondary hyperaldostronism Cushing Syndrome. Congenital adrenogenital syndrome Renal (Urine K+> 20mmol/day) Renal tubular acidosis Diabetic ketoacidosis Chloride depletion Vomiting/gastric suction Diuretics Bartter s syndrome Gitelman s syndrome Mineralocorticoid excess states Liddle s syndrome Glucocorticoid excess Magnesium depletion Antibiotic therapy Leukaemia Interstitial nephritis immune related Diuretic conditions. 130

High aldosterone Hypertension and Hypokalemia Table 2 : Mineralocorticoid Excess States 131 Low aldosterone and PRA Low PRA High PRA Normal cortisol Low cortisol High cortisol Primary hyperaldosteronism Glucocorticoid-remediable Aldosteronism (GRA) Renovascular disease Main renal arteries Small vessels Renin secretory tumour Exogenous Mineralocorticoid 11-β-HSD deficiency Congenital Liquorice Carbenoxolone Liddle s syndrome MR activation mutation. Adrenogenital syndrome 17-α- Hydroxylase deficiency 11-β-Hydroxylase deficiency Familial Glucocorticoid resistance Algorithm depicting the diagnostic approach to hypokalemia ileus occurs when smooth muscle function is affected. Exclude spurious/transcellular shift More severe hypokalemia my lead to complete paralysis, hypoventilation or rhabdomyolysis Urine K+ < 25 meq/d Acid-base status Decreased total body K+ Urine K+ > 30 meq/d Acid-base status Normal acid-base Metabolic acidosis Metabolic alkalosis Normal acid-base * Profound Lower GI loses Post ATN/post sweating obstructive diuresis * Prolonged Osmotic diuresis decreased intake Gentle diuretic use * Remote diuretic, Urine [Cl - ] < 20mEq/L Urine [Cl - ]> 20mEq/L [Mg ++ ] NG suction, High-dose penicillin or vomiting Polydipsia/DI * NG suction Blood pressure * Vomiting Hypertensive Normotensive/ Metabolic acidosis hypotensive Normal/low aldosterone High aldosterone Aggressive diuretic use Type 1 or 2 RTA Bartter s or Amphotericin B Gitelman s DKA Syndrome Acetazolamide * Cushing syndrome * Apparent Mineralocorticoid excess * Primary hyperaldosteronism * Liddle s syndrome * Secondary hyperaldosteronism * CAH Algorithm depicting the diagnostic approach to hypokalemia, ATN, acute tubular necrosis; CAH, congenital adrenal hyperplasia; DI,diabetes insipidus; DKA, diabetic ketoacidosis; GI, grastrointestinal;ng, nasogastric;rta, renal tubular acidosis. Fig. 6 : Algorithm depciting the diagnostic approach to hypokalemia Renal Renal parenchymal disease. Renovascular hypertension } Secondary hyperaldosteronism Renin producing tumors. Clinical Presentation 1. Clinical presentation may be related to both of hypertension & hypokalemia. Features of K + depletion vary greatly & their severity depends in part on the degree of hypokalemia. Symptoms seldom occur unless the plasma [K + ] is < 3/mEq/L. 2. Fatigue, myalgia, muscular weakness or cramps of lower extremities are common. Constipation or paralytic 3. K + depletion is associated with increased risks of arrhythmias leading to palpitation or Syncope. 4. Polydipsia & Polyuria may result for hypokalemia induced NDI. 5. Possible causes of transcellular shift should be sought, such as use of bronchodilators in COPD. Diuretic & laxative abuse & recurrent vomiting should be excluded. 6. Sign of hypovolemia or hypervolemia, hypotension/ hypertension provides the clue to the aetiology. 7. ECG changes of hypokalemia do not correlate well with the plasma [K + ]. Early changes may include flattening or inversion of T waves a prominent U wave (more than 1 mm in height) S.T.segment depression and a prolonged Q u interval. Severe K + depletion may result in a prolonged PR interval, decreased voltage and widening of QRS complex. We approach these patients by check there Urinary K + excretion & look for TTKG (transtubular potassium gradient) TTKG = (Urinary K+ /plasma K + ) Urinary osm/plasma osm Increased loss 24 hrs UK, TTKG UK > 30mEq/day, TTKG >7 Renal loss Check BP

Algorithm for diagnosis 24 hrs free cortisol Normal <4 x increase >4 x increase No Cushing s syndrome Low dose DST to confirm the diagnosis Diagnosis of Cushing s syndrome ACTH increased MRI pituitary Measure ACTH Fig. 7 : Algorithm for diagnosis Primary Hyperaldosteronism Definition: - Diastolic hypertension without oedemn, decreased renin & increased aldosterone secretion Aetiology 1. Aldosterone producing adrenal adenoam (Conn s syndrome) 75 % 2. Adrenal hyperplasia (25%) Clinical features: Hypertension Polyuria polydipsia - nocturia Fatigue weakness paresthesia Headache Severe case Tetany Intermittent paralysis Investigations: Urea & electrolytes hypokalemia, mild hypernatremia, hypomagnesaemia High 24 hrs or plasma aldosterone + low random plasma renin. CT or MRI (to differentiate adenoma from hyperplasma) Treatment: Medical Spironolactone (aldosterone antagonist or Amiloride.) ACEI might be added for better control of BP Surgical Removal of adenoma Medicine Update 2012 Vol. 22 ACTH decreased CT Scan of Adrenal 132 Secondary hyperaldosteronism Definition:-Increase in the level of aldosterone in response to activation of renin-angiotensin system. Renovascular hypertension: This is hypertension secondary to Renovascular disease. It is suspected if:- Negative family history of HTN Spontaneous hypokalemia Sudden onset of exacerbation of HTN. Difficult to control with antihypertensive therapy. Pathophysiology: - There is decreased in renal perfusion in one or both kidneys leading to increased renin release & subsequent Angiotension II production. It is two types Atherosclerotic plaque prox ⅓ rd of renal artery involved, usually male> 55 years. Fibromuscular hyperplasia distal ⅔ rd of renal artery involved usually in young females. Cushing Syndrome Definition:-Clinical syndrome results from chronic Glucocorticoid excess. Aetiology ACTH dependant a. ACTH secreting pituitary adenoma (Cushing s disease 80 %) b. Ectopic ACTH secreting tumor (SCLC) ACTH independant a. Long term use of exogenous Glucocorticoid b. Primary adrenocortical Tumor. Treatment: Pituitary Transphenoidal resection Irridiation only 50 % Effective Adrenal Adenoma Unilateral adrenalectomy Carcinoma palliative Ectopic ACTH Chemotherapy, Radiation Ketoeonazole, Metyrapone. Laboratory Tests for Evaluation of Hypertension BASIC TEST FOR INITIAL EVALUATION 1. Always included

Hypertension and Hypokalemia a. Urine for protein, blood, and glucose b. Microscopic urinalysis c. Hematocrit d. Serum potassium e. Serum creatinine and /or blood urea nitrogen. f. Fasting glucose g. Total cholesterol h. Electrocardiogram 2. Usually included, depending on cost and other factors a. Thyroid-stimulating hormone b. White blood cell count c. HDL and LDL cholesterol and triglycerides d. Serum calcium and phosphate e. Chest x-ray; limited echocardiogram. SPECIAL STUDIES FOR SECONDARY HYPERTEN- SION 1. Renovascular disease: angiotension-converting enzyme inhibitor radionuclide renal scan, renal duplex. Doppler flow studies and MRI angiography. 2. Pheochromocytoma: 24-h urine assay for creatinine, metanephrines, and catecholamines. 3. Cushing s syndrome: overnight dexamethasone suppression test or 24-h urine cortisol and creatinine. 4. Primary aldosteronism: plasma aldosterone: renin activity ratio. Management Treatment of hypertension & hypokalemia includes the following- 1. To identify the cause & treat the cause. 2. Treatment of hypertension & prevention of hypokalemia. 3. Treatment of hypokalemia Treatment of hypertension & prevention of hypokalemia a. Life style modification. b. Diet & exercises. Advised to consume fruits & fruit juice & K + containing salt preparation c. Antihypertensive medication i. Avoid use of diuretics. ii. ACEI/ARB preferred. iii. Potassium sparing diuretics may be prescribed carefully to avoid hyperkalemia Treatment of Hypokalemia Therapeutic goalsa. Prevent life threating complication (Arrhythmias, Respiratory failure.) b. Correct K+ deficit. c. Minimize ongoing loss through treatment of underlying cause. Assessment of K+ deficit- If the hypokalemia is due to potassium depletion (where transcellular shift e.g. alkalosis is excluded)- Every 1mmEq/ L [K + ] depletion = 10 % Reduction of total body K + store. [Total body K + content = 50mEq/ KG] For a 60 kg person, total body K + store = 60 x 50= 3000 meq. Therefore, 1 meq/ L [K + ] depletion = 3000 x 10% = 300 meq. = Total K+ deficit. Oral therapy: i. It is generally safer to correct hypokalemia via oral route. KCl is usually preparation of choice for hypokalemia + Metabolic alkalosis. ii. Potassium bicarbonate & citrate tend to alkalize the blood, may be useful in correcting hypokalemia associated with chronic diarrhea or RTA. iii. Potassium phosphate may be preferred for DKA. IV therapy: Imminently life threating hypokalemia (unable to take KCl orally.) Concentration of K+ administration 40 meq/ L in peripheral vein 100 meq/ L in central vein. K+ solutions are hyperosmotic, therefore should be diluted with NS always (Dextrose should be avoided to prevent transcellular shift of K +. Rate of infusion - 20mEq/ hour. Hypomagnesaemia should be sought in all hypokalemic patients and corrected to allow effective K+ repletion. Conclusion Hypertension & hypokalemia are distinct clinical Syndromes which can be correlated clinically & biochemically. Both the conditions are widely prevalent among different groups of 133

Medicine Update 2012 Vol. 22 patients. Prevention and treatment of these clinical states depends on proper history taking & examination, clinical suspects, laboratory investigations & its adequate proper management. Though these two conditions are mild in most of the instances these can be life threatening & should be managed aggressively & adequately in ICU setup. References: 1. Rose BD, POST tw. Potassium homeostasis In: Clinical physiology of acid-base and electrolytes disorders 5 th edition. NewYork. Mc Graw- Hill, 2001: 372 402 2. Schaefer TJ, Wolford RW. Disorders of potassium. Emerg Med Clin North America 2055; 23:723-747 3. Grover P. Hypokalemia. Crit care Rescue 1999; 1 :239-251 4. Kamel S. Kamel, Mn S. Oh & Mitchell L. Halperin Treatment of hypokalemia & hyperkalemia, Therapy in Nephrology 7 Hypertension A companion to Brenner and Rector s 5. The kidney: 35: 349-364. 2 nd edited by H.R.Brady & C.S.WILCOX edn. 6. Richard L. Tannen and Kenneth R. Hallows Hypo Hyperkalemia 2.3: 269 286. Oxford Textbook of Clinical Nephrology volume 1. 3 RD Edn 2005. 7. Anbry Morrision & Anitha Vijayan Hypertension 102 The Washington Manual of Medical Therapeutics. 32 ND Edn 2007. 8. Rajeev Gupta: Resistant hypertension: A clinical perspective 51-60. Medicine update, API, Volume 21, 2011 9. Paul L. Marino Renal and Electrolytes disorder Potassium 33: 611-624. The ICU Book 3 rd Edn 2007 10. Kamlanathat Sambandham and Anitha Vijayan Fluid and Electrolyte Management. Potassium 69-76. The Washington Manual of Medical Therapeutics 32 nd Edn 2007. 134