albumin. Urine [Na+] concentration and osmolality. \200 Adrenal and thyroid function tests (in sel ected cases). SIADH is a diagnosis of exclusion. Essential diagnostic fea- tures are: \200 Low plasma osmolality (<275 mOsmol/kg H2O). \200 Elevated urine osmolality (>100 mOsmol /kg H2O in the face of a low plasma osmolality). Presence of clinical euvolemia. \200 Urine [Na+] >40 mmol/L with normal dietary salt inta ke. \200 Normal thyroid, adrenal, and kidney function. \200 No recent diuretic use. \200 Hypouricemia (<238 mol/L) and low [urea] (<3.5 mmol/L) are supplementary features o f SIADH. A diagnostic algorithm for hypo-osmolal hyponatremia is shown in Fig. 2.1.1. In a euvolemic patient with hyponatremia, a urine osmolal- ity <100 mosm/L indicates the presenc e of primary poly- dipsia, reset osmostat or beer potomania. Treatment Treating the underlying cause and restricting \202 uid intake is suf \201 cien t in most cases. Morbidity and mortality are related to neurologic com- plications of eithe r acute cerebral edema in severe, acute cases or central pontine myelinolysis (CPM) due to improper management (too rapid correction or overcorrection). Treatment choices are depende nt on the rapidity of onset of hyponatremia, the severity of symptoms and the ECF volume st ate. Asymptomatic hyponatremia Treatment should focus on underlying causes. \200 In the hypovo lemic patient, prevent further \202 uid loss and replace the ECF volume de \201 cit with normal saline. Once euvolemia is established, ADH production will be sup- pressed and exce ss water will be excreted. For hypervolemic patients, treat the underlying disorder. Restrict salt and water intake an d administer diuretics if necessary. Ultra \201 ltration and dialysis may be required in t hose with resistant heart failure or renal failure. M. ARICI 44 In euvolemic patients, \202 uid restriction (<800 \200\2231000 mL/ day) is the treatment of choice. Some patients may need pharmacologic antagonism of ADH with demeclocycline or li thium. Supplementation of the diet with additional sol- ute in the form of protein, salt or urea may also be helpful. Hypervolemic hypernatremia indicates net sodium gain. Most cases are iatrogenic. Signs and symptoms High serum osmolality results in water movement out of cells, leading to cellular dehydration and cell shrinkage, particularly in brain cells. This osmolar shift o f water is pri- marily responsible for the neurologic symptoms and potentially life-threate ning complications. Brain cells compensate for hyperosmolality by increasing intracellular electrolyte and osmolyte concentrations over a 24 \200\22348 h period. Symptoms of hypernat remia depend on the absolute level of serum [Na+] and the rapidity of onset of hyperosmolal ity. In severe, acute hypernatremia (duration <48 h) brain shrinkage may be substantial, re sulting in cerebral and sub- arachnoid hemorrhage. In less severe chronic hypernatremia, ma nifestations are nonspeci \201 c (nausea, muscle weakness, and alterations in mental statu s ranging from lethargy to coma). Elderly patients have generally few symptoms unless serum [Na+] is >160 mmol/L. Diagnosis Hypernatremia is rarely suspected from the clinical pres- entation; the diagnosis is made by measurement of the serum [Na+]. Take a careful history ( for water intake and loss, polyuria, medications, underlying diseases). Clinically assess t he ECF volume status and perform a neu- rologic evaluation. Laboratory studies: \200 seru m electrolytes and osmolality; \200 glucose, urea, creatinine, calcium; \200 urine sodi um concentration and osmolality. Most patients have signs and symptoms of hypovolemia. Euvo lemic patients are usually mildly hypernatremic, but complain of polyuria. Polyuria is de \201 ned as a urine output of >3 L/day. The water deprivation test followed by administrati on of ADH helps to differentiate central from nephrogenic DI (Chapter 5.5 for details). A d iagnostic algorithm for hypernatremia is shown in Fig. 2.1.2. In a hypo- or euvolemic patie nt with hypernatremia, a urine osmolality >700 mOsm/L indicates the presence of an extraren al source for water loss. A new class of drugs known as vasopressin receptor antag- onists induces free water diuresi s without natriuresis or kaliuresis (aquaretics) by antagonizing V2 receptors in the collec ting duct. Conivaptan (V1a and V2 antagonist) has been approved by the Food and Drug Admini stration for IV treatment of euvolemic and hypervolemic hyponatremia. Several orally active drugs that are speci \201 c to V2 receptors are still being investigated. Prevention Avoid hypotonic \202 uid use in high risk hospitalized patients, especially in the postoperative period. Be cautious with thiazide use in the elderly. Hypernatremia Serum [Na+] >145 mmol/L. Epidemiology In hospitalized patients the prevalence of hypernatremia is 0.5 \200\2233.5%. The highest risk is in patients with altered mental status, the elderly, intubated patients and infants. Pathophysiology Hypernatremia is generated by net water loss or hyper- tonic Na+ gain, but maintained by a failure to sense thirst and/or an inability to access water. Normally the d evelop- ment of thirst prevents the maintenance of hypernatremia. A defect in urine concent ration with an inadequate water intake will cause hypernatremia. A decrease in the level or activity of ADH prevents maximal urinary concentration. Hypernatremia is most often due to net water loss in excess of sodium. This may be due to renal or extrarenal water loss. Etiology Hypernatremia is always associated with hyperosmolality. Hypernatremic conditions are classi \201 ed according to the ECF volume status (Fig. 2.1.2) Hypernatremia with decr eased ECF volume indicates renal or extrarenal salt and water losses in which the loss of w ater exceeds that of sodium. Euvolemic hypernatremia is usually caused by diabetes insipidu s (DI). In DI, there is either an abnormality in ADH secretion (central DI) or resistance t o ADH action in the kidney (nephrogenic DI). Table 2.1.1 Formulas used in calculating initial therapeutic targets of hypo- and hypernatr emia Formula 1: Sodium requirement = TBW \227 (Desired serum [Na+] \200\223 Actual serum [Na+] ) Formula 2: Water excess (in L) = TBW \227 {1 \200\223 (Actual serum [Na+]/Desired serum [Na+])} Formula 3: Serum [Na+] change (after 1 L of IV \202 uid) = ([Na+] concentration in IV \202 uid \200\223 Actual serum [Na+])/(TBW + 1) Formula 4: Water de \201 cit (in L) = TBW \227 {(Actual serum [Na+]/Desired serum [Na+]) \200\223 1} TBW: total body water (in L) is estimated as body weight \227 0.6 in men and \227 0.5 in women. CHAPTER 2.1 Hypo-/hypernatremia 45 Prevention Administering adequate \202 uid avoids hypernatremia in high risk settings. Be cautious with hypertonic solution (such as sodium bicarbonate) administration. Treatment Treating the underlying cause and giving water is suf \201 cient in most cases. Acute symptomatic hypernatremia In this situation rapid correction of the water de \201 ci t is required. Water should be administered (usually as IV 5% dextrose solution) at a rate that reduces the serum [Na+] by 1 mmol/L/h until symptoms have resolved. The total magnitud e of correction should not exceed 8 \200\22310 mmol/ day. During treatment close monitoring of the patient, the serum [Na+], \202 uid intake, urine output and neurologic symptoms a re necessary and should preferably be done in an intensive care unit. Several formulas can be used to calculate the water de \201 cit (Formula 4) or to estimate the effect on serum [Na+] con- centration of any infused solution (Formula 3) (Table 2.1.1). Further reading Adrogue HJ, Madias NE. Hypernatremia. N Engl J Med 2000; 342: 1493 \200\2231499. Adrogue HJ, Madias NE. Hyponatremia. N Engl J Med 2000; 342: 1581 \200\2231589. Cawley MJ. Hyponatremia: current treatment strategies and the role of vasopressin antagonis ts. Ann Pharmacother 2007; 41: 840 \200\223850. Ellison DH, Berl T. The syndrome of inappro priate antidiuresis. N Engl J Med 2007; 356: 064 \200\2232072. Kumar S, Berl T. Sodium. Lancet 1998;352:220 \200\223228. Reynolds RM, Pad \201 eld PL, Se ckl JR. Disorders of sodium balance. Br Med J 2006; 332: 702 \200\223705. Chronic asymptomatic hypernatremia Rapid correction of chronic hypernatremia can cause cere bral edema. The rate of correction should not exceed 0.5 mmol/L/h. Water may be administere d orally, by nasogastric tube or IV (as 5% dextrose in water). In hypovolemic patients with circulatory compromise, nor- mal saline should be given until euvolemia is restored. In eu volemic patients, oral tap water, 5% dextrose in water or hypotonic saline (0.45% sodium ch loride) may be given to correct hypernatremia. In hypervolemic patients, diuretics plus 5% dextrose in water are administered to remove the excess sodium. In massive volume overload or renal failure, dialysis may be needed. For chronic treatment of central DI, desmopressin is the drug of choice. In nephrogenic DI, treatment involves: reducing solute intake to re duce the obligate urinary sol- ute excretion; administering thiazide diuretics to induce mi ld volume contraction; and administering nonsteroidal anti-in \202 ammatory drugs to suppr ess prostaglandin-medi- ated antagonism of ADH. Smellie WSA, Heald A. Hyponatremia and hypernatremia: pitfalls in testing. Br Med J 2007; 334: 473 \200\223476. Verbalis JG, Goldsmith SR, Greenberg A, Schrier RW, Sterns RH. Hyponatremia treatment guide lines 2007: expert panel recom- mendations. Am J Med 2007; 120(11 Suppl 1): S1 \200\22321. Internet resources Overview of \202 uid physiology: http://www.anaesthesiamcq.com/FluidBook/ index.php Review of diseases of water metabolism: http://www.kidneyatlas.org/book1/ADK1_01.pdf Review of diseases of sodium balance: http://www.kidneyatlas.org/book1/ADK1_02.pdf See also Nephrogenic diabetes insipidus, p. 220 Measure serum [Na+] Hypernatremia Serum [Na+] >145 mmol/l Assess clinical volume state Hypovolemia Euvolemia Hypervolemia Total body Na+ \206\223 Total body water \206\223 \206\223 Total body Na+ \206\221 \206\221 Total body water \206\221 Total body Na+ normal Total body water \206\223 Pathophysiological condition Urine [Na+] >20 mmol/L Urine [Na+] <20 mmol/L Urine [Na+] variable Urine [Na+] variable Urine [Na+] >20 mmol/L Urine [Na+] <20 mmol/L Measure urine [Na+] Excess mineralocorticoid activity (mild hypernatremia) Renal loss Diuretics Osmotic divresis Extrarenal loss GI loss Skin loss Respiratory loss Iatrogenic Hypertonic saline Hypertonic tube feeding Excessive salt ingestion Renal water loss Extrarenal water loss (Insensible losses) Underlying disease process \206\223 ADH Central DI \206\221 ADH Nephrogenic DI Water replacement Diuretics Isotonic saline & water or hypotonic saline Treatment Water administration and specific treatment Fig. 2.1.2 M. ARICI 46 Hypo-/hyperkalemia Potassium (K+) is the major intracellular cation. 98% of total body K+ is in the cells. The intracellular/extracellular K+ ratio is the major determinant of the resting membrane pote ntial, and is therefore critical for the proper function of excitable tissues, such as hear t and neuromuscular cells. Potassium balance and serum K+ concentration ([K+]) is controlle d: \200 in the short term by transcellular shift of potassium: Total potassium depletion Poor dietary intake is an uncommon cause. Alcoholics, the elderly and poor, and patients with eating disorders are prone to inadequate dietary intake. Incre ased K+ loss may be due to renal or extrarenal losses. Urinary indices of K+ (Table 2.2.1), acid \200\223base status, blood pressure, urinary chloride (Cl \200\223) and plasma renin and aldosterone levels are helpful in determining the source of potassium loss (Figure 2.2. 1). This is commonly seen in patients who either are on diu- retics (thiazide or loop diure tics) or have gastrointestinal diseases (most commonly with diarrhea). Vomiting and nasogas tric suctioning are also common causes. These result in volume depletion, metabolic alkalos is, and increased urinary K+ loss. Endogenous or exogenous mineralocorticoid excess (primar y or secondary) is also a frequent cause Hypomagnesemia often accompanies hypokalemia. Hypo kalemia cannot be reversed until the magnesium de \201 cit is corrected. Rare causes of re nal K+ loss are renal tubular acidosis and the hypokalemic tubulopathies (Gitelman \200\231 s, Bartter \200\231s, and Liddle \200\231s syndromes). this is controlled by insulin, epinephrine (via B2 adren- ergic receptors( ), acid \200\223 base status and serum [K+]; in the longer term by renal K+ handling: this is mainly regulated by distal K+ secretion; - distal K+ secretion is augmented by aldo sterone, high distal sodium delivery, high urine \202 ow rate, and high intracellular [K+ ] in the tubule cells. Serum [K+] disorders can alter membrane excitability, thus causing serious complications, i ncluding fatal cardiac arrhythmias, paralysis and respiratory failure. Hypokalemia Serum [K+] <3.5 mmol/L. This increases the morbidity and mortality risk in pati ents with cardiovascular disease. Epidemiology Hypokalemia is found in >20% of hospitalized patients. The frequency increases with age. It is found in 10 \200\22340% of patients treated with non-K+-spar- ing diuretic s. Signs and symptoms Mild hypokalemia (3.0 \200\2233.5 mmol/L) is often asymptomatic. Symptom s are more common in patients with moderate (2.5 \200\2233.0 mmol/L) or severe (<2.5 mmol/L ) hypokalemia. Most signs and symptoms involve the cardiovascular, neu- romuscular, renal a nd endocrine systems (Table 2.2.2). Cardiac arrhythmias are common in patients with underly - ing heart disease (acute myocardial infarction, left ventricu- lar hypertrophy, heart fai lure) and may be fatal. In digoxin-treated patients, hypokalemia of any degree can precipit ate arrhythmias. Pathophysiology Hypokalemia may develop because of either: \200 increased shift of K+ int o the cells (redistribution hypoka- lemia; total body K+ is usually normal); or total body K+ depletion due to either decreased intake or increased renal or extrarenal losses. Increased K+ loss is the major cause of hypokalemia. Etiology Pseudohypokalemia (spurious h ypokalemia) Diagnosis Measure serum [K+]; exclude spurious or redistribution hypokalemia. Undertake a d etailed history (for dietary intake, medica- tion history, severe diarrhea) and physical ex amination par- ticularly for blood pressure and neuromuscular signs. Perform an ECG to dete rmine the effects on cardiac con- duction (Figure 2.2.2) and to detect evidence of digoxin toxicity. Laboratory studies: \200 Measure serum electrolytes, glucose, urea and creatini ne. \200 Assess urine K+ indices (Table 2.2.1). \200 Assess acid \200\223base status. \200 Measure magnesium, renin, aldosterone and cortisol in This is seen in patients with leukocyte counts >50 \200\223 100 \227 109/L, particularly i f the sample is stored at room temperature. This can be avoided by prompt centrifugation of the specimen. Redistribution hypokalemia This is a relatively uncommon cause but when it coexists with mi ld K+ depletion it can lead to severe hypokalemia. Most common causes are: \200 Alkalosis (serum [K+] decreases 0.2 \200\2230.3 mmol/L per 0.1 unit increase in pH). selected cases. Excess insulin (acute glucose load, exogenous insulin or insulinoma). Treatment Treat the underlying cause; stop ongoing K+ losses. Replete K+ according to: 1. U nderlying pathophysiology (redistribution vs K+ loss). 2. Severity of hypokalemia (actual l evel of [K+] neu- romuscular symptoms ECG alterations presence of cardiac disease) . Increased B-adrenergic activity (e.g. acute myocardial infarction, head trauma) or exogenou s administration of B-adrenergic agonists (adrenaline, salbutamol, terbutaline, fenoterol). Rare causes are hypokalemic periodic paralysis, hypother- mia, chloroquine intoxication, an d rapid cell synthesis during B12 therapy. CHAPTER 2.2 Hypo-/hyperkalemia 47 Table 2.2.1 Urinary indices of potassium excretion Index Equation Hypokalemia Hyperkalemia Caution i Load d Renal excretion Extrarenal loss Renal loss Spot urinary [K+] (mmol/L) Spot urine K+/Creat (mmol/mmol) \200\223 <15 \200\22320 >15 \200\22320 >100 <200 Convenient, but less accurate \200\223 <1 >2 >15 <15 Convenient, but with a large \200\230gray \200\231 area 24 h urinary K+ (mmol/day) \200\223 <15 \200\22320 >15 \200\22320 >100 <200 Accurate but inconvenient, needs 24 h urine collection Fractional excretion of potassium (FEK) <5% >5% >20% <20% \200\223 + \227 100% +/S K UK UCre/SCre +/S K UK Uosm/Sosm + <3 >7 >10 <5 \200\2237 Not useful when Uosm < Sosm Transtubular potassium gradient (TTKG) Extrarenal losses (urine [K+] <15 \200\22320mmol/L) With normal pH Poor K+ intake Excessive perspiration Geophagia Laxative abuse With metabolic acidosis Diarrhea Lower GI losses Laxative abuse With metabolic alkalosis Congenital chloride losing diarrhea Villous adenoma Renal losses (urine [K+] >15 \200\22320mmol/L With normal pH Magnesium deficiency Cisplatin therapy Aminogycosides Amphotericicn B With metabolic acidosis Renal tubular acidosis Diabetic ketoacidosis With metabolic alkalosis \210\222 \210\222 ] <10 mmol/L Urine [Cl ] >10 mmol/L Urine [Cl Prior diuretic use Vomiting Upper gastrointestinal losses Normal BP Diuretic use Bartter \200\231s syndrome Gitelman \200\231s syndrome High BP High renin Renal artery stenosis Hypertension with diuretic use Malignant hypertension Reni n-secreting tumor Low renin Low aldosterone Cushing \200\231s syndrome Apparent mineralocorticoid excess Licorice inges tion Liddle \200\231s syndrome High aldosterone Primary aldosteronism Glucocorticoid remediable aldosteronism Fig. 2.2.1 Causes of increased potassium loss. M. ARICI 48 In redistribution hypokalemia, treating the underlying cause is suf \201 cient. Potassium supplementation is not indicated and can even be dangerous. Serum [K+] decreases by 0.25 \200\2230.30 mmol/L for every 100 mmol reduction in total body K+. In acute, life-threateni ng conditions (paralysis, malignant ventricular arrhythmias and digoxin intoxication), pota s- sium chloride (KCl) should be given IV in a nondextrose- containing solution (10 \200 \22320 mmol/h into a peripheral vein or 20 \200\22340 mmol/h (never >40 mmol/h) into a cent ral vein) with continuous ECG monitoring. Serum [K+] should be checked every 2 \200\2233 h. Asymptomatic and mild hypokalemia (3.0 \200\2233.5 mmol/L) can simply be treated with a K+ -rich diet. The only exception is following myocardial infarction when K+ supplementation i s recommended to keep the serum [K+] >4.5 mmol/L. In all other cases of hypokalemia (modera te hypokalemia with no indications for urgent treatment), K+ supplementa- tion should be un dertaken orally. Potassium chloride (KCl) should be used in most circumstances (in divided doses of 20 \200\223160 mmol/day). KCl can be administered IV (<10 mmol/h) if the oral rout e is not possible. Replete magnesium if it is low. Patients with hyperaldosteronism may req uire K+-sparing diuretics (spironolactone 25 \200\223400 mg/day, amiloride 5- 40 mg/day, or triamterene 100 \200\223400 mg/day) until the underlying disorder can be corrected. Overtr eatment of hypokalemia leading to hyperkalemia is a life-threatening complication. A conser vative approach is recommended in most situations and where active treat- ment is institute d, close monitoring of the response to treatment is mandatory. Etiology Pseudohyperkalemia (spurious hyperkalemia) Prolonged tourniquet application, dif \201 cult venepuncture, hemolysis, marked leukocytosis (>50 \200\223100 \227 109/L) and th rombocytosis (>1000 \227 109/L) may cause pseudohyper- kalemia. In marked leukocytosis or thrombocytosis, parallel meas- urements of serum and plasma (sample with heparin) [K+] will identify spurious hyperkalemia. Redistribution hyperkalemia This is rarely an important cause of hyperkalemia unless it is accompanied by impaired K+ excretion. Most common causes are: \200 metabolic acidosis (se rum [K+] rises 0.7 mmol/L per 0.1 unit decrease in pH during a mineral acidosis, i.e. hyper chloremic acidosis); \200 insulin de \201 ciency or resistance; \200 hyperosmolality ( e.g. hyperglycemia, mannitol infusion); \200 B-adrenergic antagonist treatment (e.g. prop ranolol, labetolol, carvedilol, etc.). Rare causes are hyperkalemic periodic paralysis, digoxin toxicity and succinylcholine admin istration. Increased total body potassium Since the excretory capacity of the kidneys for potassium is so great, excessive K+ ingestion causes hyperkalemia only rarely. A massive potassium load in a short time (e.g. 300 mmol as a single dose orally or >40 mmol/h IV; or massive cell l ysis, such as in tumor lysis or rhabdomyolysis) may overwhelm the renal excretory capacity and cause hyperkalemia. Impairment of renal K+ excretion is the cause of hyperka- lemia in >80 \200\22390% of cases (Table 2.2.3). Patients with a GFR of <5 \200\22310 ml/min have an intrinsic risk of developing hyperkalemia. If hyperkalemia develops in a patient with less severe renal failure (i.e. GFR >20 mL/min), there is usually an associated condition which further impairs K+ excretion. These are: 1. Effective circulating volume depletion (conges tive heart Prevention Check serum [K+] regularly in patients treated with thiazide diuretics and in th ose with ongoing sources of K+ loss. Hyperkalemia Serum [K+] >5.0 mmol/L. This is the most common electrolyte disorder associate d with life-threatening cardiac arrhythmias and sudden death. failure). 2. Diminished aldosterone activity (primary adrenal insuf- ficiency, hyporeninemic hypoaldo steronism, drug- induced hypoaldosteronism). Epidemiology Reported incidence is between 1 and 10% of hospitalized patients. Most cases a re related to drugs interfering with K+ excre- tion (renin \200\223angiotensin \200\223aldo sterone inhibitors) in combi- nation with pre-existing or acute renal failure. Advanced age , presence of diabetes, renal failure, conges- tive heart failure and polypharmacy are the main risk factors. 3. Decreased tubular secretion (tubulointerstitial diseases, pseudohypoaldosteronism, potas sium sparing diuretics). Signs and symptoms Hyperkalemia may be classi \201 ed as mild (5.5 \200\2236.0 mmol/L), moderate (6.0 \200 \2236.5 mmol/L) and severe (>6.5 mmol/L or any [K+] associated with muscle symptoms or ECG changes). Pathophysiology Hyperkalemia may develop because of: \200 decreased shift of K+ into the cells (redistribution hyper- kalemia, the total body K+ is usually normal); increased total body K+ due to either excessive potas- sium ingestion or, more commonly, de creased renal excretion. In most situations, persistent hyperkalemia is associated with impairment of urinary K+ exc retion. CHAPTER 2.2 Hypo-/hyperkalemia 49 Table 2.2.2 Major clinical manifestations of hypo- or hyperkalemia System Hypokalemia Hyperkalemia ECG alterations (Fig. 2.2.2) ECG alterations (Fig. 2.2.2) Cardiovascular Ventricular tachycardia/ \201 brillation, long QT syndrome, torsade de pointes, hypertensi on Life-threatening ventricular arrythmias including sudden death, hypotension Muscular weakness, paresthesias, ascending paralysis, respiratory impairment Muscular weakness, cramps, rhabdomyolysis, ileus, constipation, bladder dysfunction, ascend ing symmetric paralysis, respiratory impairment Neuromuscular Reduced ammoniagenesis, type IV renal tubular acidosis, natriuresis Nephrogenic diabetes insipidus, increased ammonia production, metabolic alkalosis, hypokale mic nephropathy (vacuolization in proximal tubules, medullary cyst formation and interstiti al \201 brosis) Renal Increased renin, decreased aldosterone, decreased insulin secretion, growth retardation Decreased renin, increased aldosterone, increased insulin secretion Endocrine/metabolic Table 2.2.3 Causes of impaired potassium excretion Glomerular \201 ltration rate <5 \200\22310 mL/min Oliguria of any cause Endogenous potas sium load Glomerular \201 ltration rate >20 mL/min Low aldosterone Low renin Gastrointestinal bleeding Hemolysis Rhabdomyolysis Catabolic state Hyporeninemic hypoaldosteronism Diabetes mellitus NSAIDs High renin Exogenous potassium load Dietary intake Salt substitutes Stored blood Drugs Aldosterone ant agonists K+-sparing diuretics ACEIs ARBs Beta-blockers NSAIDs Trimethoprim Heparin Addison \200\231s disease Heparin ACEIs ARBs Normal \200\223high aldosterone Aldosterone antagonists K+-sparing diuretics Trimethoprim Tubulointerstitial nephritis Syst emic lupus erythematosus Amyloidosis Sickle cell disease Pseudohypoaldosteronism types I an d II (Gordon \200\231s syndrome) M. ARICI 50 Tall peaked T wave ST depression U wave Tall peaked T wave Loss of P wave Widened QRS with tall T wave Flat T wave Normal serum K 3.5-5.0 mmol/L Decreasing K+ from 3.0 to 2.0 mmol/L Increasing K+ from 6.0 to 10 mmol/L Peaked T wave Prolonged PR interval Shortened QT interval Wide QRS complex Widening of QRS complex Loss of P wave Sine wave pattern Ventricular fibrillation Ventricular tachycardia Flat T wave Prominent U wave Depressed ST segment Fig. 2.2.2 Typical electrocardiographic changes in a spectrum of potassium disorders from h ypo- to hyperkalemia. (ECG tracings from Slovis C, Jenkins R. ABC of clinical electrocardio graphy: conditions not primarily affecting the heart. BMJ 2002;324:1320-1323, with permissi on.) If urgent treatment is required, continuous cardiac moni- toring should be instituted. The aims of treatment are to: 1. Antagonize the cell membrane actions of hyperkalemia Most signs and symptoms involve the cardiovascular, neuromuscular, renal and endocrine syst ems (Table 2.2.2). Cardiac toxicity is enhanced by hypocalcemia, hyponatremia, acidosis and a rapid rise in [K+]. Cardiac toxicity usually precedes neuromuscular manifes- tations. Mu scle weakness usually only becomes apparent when [K+] >8.0 mmol/L. Patients with hypoaldost eronism may also complain of weight loss and symptoms related to salt wasting. to protect the heart and respiratory muscles. \200 Infuse 10 mL of 10% calcium gluconate or chloride over 2 \200\2233 min; action starts in 1 \200\2233 min, but the effect is transient. Repeat the dose after 5 \200\22310 min if ECG c hanges persist. Use calcium cautiously in patients taking digoxin as it may precipitate tox icity. 2. Increase K+ entry into the cells. Diagnosis Measure serum [K+], exclude pseudohyperkalemia and look for potential causes of r edistribution hyperkalemia. A thorough history (for dietary intake, history of kidney disea se, medication history including K+ supplements, K+- sparing diuretics, renin \200\223angio tensin \200\223aldosterone system inhibitors) and physical examination (for blood pressure and muscle weakness) should be undertaken. Perform an ECG to determine the effects on cardi ac con- duction and the need for urgent treatment (Figure 2.2.2). Laboratory studies: \200 Measure serum electrolytes, glucose, urea and creatinine. \200 Calculate the estimated GFR. \200 Assess urine K+ indices (Table 2.2.1). \200 Assess acid \200\223base status. \200 Measure renin, aldosterone and cortisol levels in selected Administer 10 U of soluble insulin with 50 mL of 50% dextrose in water (DW) as an intraveno us bolus, followed by an insulin infusion (1 \200\2234 U/h) with 5% DW. The effect is appar ent in 15 \200\22330 min and lasts 2 \200\2234 h. Blood glucose must be monitored because of the risk of hypoglycemia. Administer high-dose B2-adrenergic agonist (salbutamol (albut erol) 0.5 mg IV in 5% DW for 10 \200\22315 min or 10 \200\22320 mg by nebulized inhaler for 10 min). Action of IV and nebulized salbutamol begins in 20 \200\22330 min and lasts 2 \200\2234 h. Patients treated with this will also become very tremulous. Combining insulin \200\223dextrose with salbutamol proba- bly leads to greater reductions in potassium than e ither alone. Administer sodium bicarbonate (50 \200\223100 mmol IV for 5 min) only if there is a metabolic acidosis. Onset of action may be delayed by hours, so the ef \201 cacy is questionable. In addition caution should be used in patients with renal failure since the s odium load may precipitate pulmonary edema. cases. Treatment Treat urgently if: \200 there are ECG abnormalities and signs of neuromuscular dysfunction, or the serum [K+] is >6.5 mmol/L without any ECG abnormalities. CHAPTER 2.2 Hypo-/hyperkalemia 51 renin \200\223angiotensin system (RAS) inhibitors in heart failure patients. In chronic kid ney disease patients, if hyperkalemia develops during RAS inhibitor treatment, other measur es (dietary K+ restriction, stopping contributory drugs, adding a diuretic or reducing the dose of RAS inhibitors) should be tried before discontinuing the RAS inhibitors. 3. Eliminate excess potassium from the body. Volume expand with saline followed by furosemide (20 \200\22340 mg IV) administration once volume replete. This may be helpful if there is prerenal acute renal fail- ure or residual renal function. Onset of action is within 1 h; however, it is unlikely to work in patients with advanced renal failure. Resin exchanger sodium or calcium polystyrene sul- fonate (kay exalate or calcium resonium respectively) mixed with sorbitol can be given orally (30 g) or as a retention enema (50 g). Each gram of resin removes 0.5 \200\2231.0 mmol of potassium. The onset of action is within 1 \200\2232 h. The dose may be repeated every 3 \200\2234 h (oral) or 2 \200\2234 h (rectal). Dialysis is indicated if all of the above measures fail t o correct hyperkalemia. Further reading Alfonzo AVM, Isles C, Geddes C, et al. Potassium disorders \200\223 clinic al spectrum and emergency management. Resuscitation 2006; 70: 10 \200\22325. Gennari FJ. Hypokalemia. N Engl J Med1998; 339: 451 \200\223458. Halperin ML, Kamel KS. Pot assium. Lancet 1998; 352: 135 \200\223140. Mahoney BA, Smith WAD, Lo DS, et al. Emergency i nterventions for hyperkalemia. Cochrane Database Syst Rev 2005; CD003235. Rastergar A, Sole imani M. Hypokalaemia and hyperkalaemia. Most patients with mild hyperkalemia (5.5 \200\2236.0 mmol/L) can be treated by eliminating the underlying cause (such as discontinuing K+ supplements or aldosterone antagonists) and restricting dietary potassium. In patients with moderate hyperkalemia (6.0 \200\2236.5 mmo l/L) consider additional maneuvres such as loop diuretics (provided that renal function is relatively maintained), resin exchanger or synthetic mineralocorticoids (in cases of minera locorticoid de \201 ciency). Postgrad Med J 2001; 77: 759 \200\223764. Smelli WSA, Shaw, Bowlees R, et al. Best practice in primary care pathology: Review 9. J Clin Pathol 2007; 60: 966 \200\223974. Internet resources Review of disorders of potassium metabolism: http://www.kidneyatlas.org/book1/adk1_03.pdf See also Hypo-/hypermagnesemia, p. 60 Hypokalemic tubular disorders, p. 214 Clinical acid \200\223base disorders, p. 64 Renal tubular acidosis, p. 208 Prevention Check [K+] regularly in susceptible patients, especially those taking drugs that impair K+ excretion. An increasing incidence of hyperkalemia is observed with combined use of aldosterone antagonists with P. GUPTA AND W. MADIRA 52 Hypo-/hypercalcemia Calcium is the most abundant mineral in the body. 98% of the total body calcium is stored i n bone and the rest is in the soft tissues and extracellular \202 uid. Calcium circulates in the plasma in the bound and free form. The normal range for total calcium is 2.25 \200 \2232.65 mmol/L. Approximately 40% of plasma calcium is bound to proteins (mainly albumin), and 10% is complexed to anions such as bicarbonate, citrate, sulfate, phosphate and lactat e. The remaining 50% of plasma calcium is in the ionized form and is physiologically active . With 1,25-(OH)2 vitamin D de \201 ciency and/or hyperpar- athyroidism, osteoclastic activi ty may be enhanced result- ing in increased bone resorption. There is a steep inverse relat ionship between the serum ionized calcium concentration and PTH release that is mediated by the calcium-sensing receptor (CaSR) on the chief cells of the parathyroid gland. Kidney Sixty- \201 ve percent of \201 ltered calcium is reabsorbed in the proximal tubul e. This is not under hormonal regulation but is closely associated with sodium and water ba lance. Approximately 25% of the \201 ltered calcium is reabsorbed in the loop of Henle an d 10% in the distal convoluted tubule under the in \202 uence of PTH. PTH also stimulates 1A-hydroxylase activity in the kidney, leading to increased formation of 1,25-(OH)2 vitami n D and thus indirectly regulates intestinal calcium and phos- phate absorption. There is a lso evidence that vitamin D may independently increase renal calcium reabsorption. Functions of calcium The functions of calcium in the body include: \200 maintenance of sk eletal and dental structure; \200 muscle contraction and relaxation; \200 stimulation o f blood clotting; \200 maintenance of cell membrane integrity; \200 nerve transmission; \200 regulation of intracellular signaling; \200 stimulation of hormone secretion; \200 augmentation of enzyme activity (enzyme cofactor). Hypocalcemia Hypocalcemia is regarded as mild when the serum calcium concentration (adjuste d for albumin) is 1.75 \200\2232.10 mmol/L, and severe when it is <1.75 mmol/L. Calcium homeostasis The serum calcium concentration is maintained in a very narrow range wi th <2% variability. The three key organs involved in calcium homeostasis are the gut, bone, and kidney. The main calcium regulators are parathyroid hormone (PTH) and 1,25-(OH)2 vitam in D. A critical level of serum magnesium concentration is required for PTH secretion, thus severe hypomagnesemia may impair PTH release even in the presence of signi \201 cant hypo calcemia. Causes of hypocalcemia \200 25-(OH) vitamin D de \201 ciency Nutritional de \201 ciency in Asians, the elderly in nursing homes or those who are home-b ound and vegetarian. Malabsorption of fat soluble vitamins, e.g. Crohn \200\231s dis- ease, chronic pancreatitis, hepatobiliary disorders. In renal diseases such as nephrotic syndrom e, vitamin D binding proteins may be lost leading to vitamin D de \201 ciency. Antiepilept ic drugs such as phenytoin and phenobarbital. Gut Gastrointestinal absorption of calcium can be passive or active. About 40% of the daily dietary calcium intake ( 25 mmol) is absorbed in the gut (10 mmol). The absorption can be greatly increased if the body is in negative calcium balance. Passive absorption is by the paracellular junctions driven by the concentration gradients between the gut lumen and the serosal surfaces. Active transportation is mediated by entry of luminal calcium through api cal calcium channels, binding to the calcium binding protein, calbindin, and extrusion by a n active Na/ Ca-ATPase and Na/Ca exchanger. This is a saturable proc- ess which is tightly regulated by 1,25-(OH)2 vitamin D. Calcium absorption can be inhibited by citrates, phytate s, and drugs such as colchicine and theophylline. 1,25-(OH)2 vitamin D de \201 ciency Chronic renal failure with GFR <30 mL/min. Inherited disorders, e.g. vitamin D-dependent ri ckets type I due to 1-A-hydroxylase de \201 ciency; and vitamin D dependent rickets type I I due to end-organ unrespon- siveness to 1,25-(OH)2 vitamin D. Hypoparathyroidism Postoperative. Autoimmune. Congenital (e.g. activating mutations of the CaSR, par- athyroid aplasia). In \201 ltrative disorders. Pseudohyperparathyroidism. Hyperphosphatemia (resulting in increased calcium \227 phosphate (Ca \227 P) product caus ing ectopic calci \201 cation) Renal failure. Tumor lysis syndrome. Rhabdomyolysis. Intrav enous phosphate administration. \200 Severe magnesium de \201 ciency/depletion. \200 A cute pancreatitis. \200 Hungry bone syndrome. \200 Sepsis, burns or severe illness. Bone Both PTH and 1,25-(OH)2 vitamin D play a key in bone metabolism through regulation of both bone formation and resorption. Under normal circumstances in adults, bone formation an d resorption are in balance and there is no net movement of calcium from bone. CHAPTER 2.3 Hypo-/hypercalcemia 53 If hyperphosphatemia is present (e.g. in renal failure), saline infusions should be adminis tered cautiously since this may worsen the hypocalcemia. Dialysis may be nec- essary in sev ere hyperphosphatemia. Drugs, e.g. bisphosphonates, cinacalcet. \200 Artefactual, e.g. chelation with EDTA. Clin ical manifestations of hypocalcemia Both the rate of fall and the severity of hypocalcemia determine the severity of the signs and symptoms. Patients may be asymptomatic or have subt le symptoms and signs but they may also present acutely with life-threat- ening manifestati ons. Hypomagnesemia, hypokalemia and alkalosis may coexist and worsen the clinical picture. Oral calcium and vitamin D supplements may be given concurrently with IV infusions. Once th e patient can tol- erate adequate oral supplements, the infusions may be stopped. Chronic hypocalcemia \200 In patients with CKD the goal is to prevent metabolic bone dise ase and vascular mineralization. Serum calcium should be maintained within the target range and Ca \227 P kept at <4.8 mmol2/L2 and ideally <4.2 mmol2/L2. Neuromuscular \200 Tetany and seizures. \200 Trousseau \200\231s and Chvostek \200\231s sign. \200 Muscle cramps/tenderness/myopathy. \200 Laryngeal stridor, bronchospasm and respiratory arrest. \200 Perioral numbness and paresthesias. \200 Calcifications of th e basal ganglia, cerebrum and In dialysis patients, serum calcium should ideally be kept at <2.5 mmol/L. PTH measurement is not routinely required in the absence of suspected disorder of bone and mineral metabolism in CKD stages 1 and 2 or in nonprogressive stage 3, although PTH levels should be maintained within normal reference ranges. cerebellum. Depression and irritability. \200 Dementia and movement disorders. \200 Papilloedema. C ardiovascular \200 Syncope, rarely congestive heart failure and angina. \200 Prolongati on of QT interval, ventricular \201 brillation and PTH needs to be routinely measured 3-monthly in patients with CKD 5. Measurement of PTH sho uld also be considered in earlier stages of CKD (CKD 4 and possibly CKD 3) although opinion varies about the required frequency and utility of this. In stage 4, the PTH should be bet ween the upper limit and two times the upper limit of the normal range, and in stage 5 pati ents not on dialysis it should be between two and four times the upper limit of the normal range. If neces- sary, surgical treatment for hyperparathyroidism may be considered. heart block. Other manifestations \200 Biliary and intestinal cramps. \200 Resistance to digoxin the rapy. \200 Cataracts. \200 Poor dentition (age of \211 5 years). \200 Dry, coarse sk in, brittle nails, alopecia. \200 Bone changes (rickets) and osteodystrophy. Investigatio n of hypocalcemia Measure: \200 Serum urea, creatinine and electrolytes, calcium, phospha te, albumin, alkaline phosphatase and magnesium. In patients with hypocalcemia and CKD stages 3 \200\2235, ther- apy with active oral vitami n D sterols (calcitriol, alfacal- cidol) is indicated with close monitoring of serum calciu m and phosphate, and to maintain plasma PTH within the de \201 ned limits.