Management of severe hyperkalemia


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Management of severe hyperkalemia

  1. 1. Concise Definitive Review R. Phillip Dellinger, MD, FCCM, Section EditorManagement of severe hyperkalemiaLawrence S. Weisberg, MD Background and Objectives: Hyperkalemia is one of the few Results and Conclusions: A more complete understanding ofpotentially lethal electrolyte disturbances. Prompt recognition and potassium homeostasis in recent years has led to new ap-expeditious treatment of severe hyperkalemia are expected to proaches to the management of severe hyperkalemia. The phys-save lives. This review is intended to provide intensivists and iologically based sequential approach still applies. The efficacy,other interested clinicians with an understanding of the patho- pitfalls, and risks of the agents available for use at each step inphysiology that underlies hyperkalemia, and a rational approach the sequence are critically reviewed. Rational use of the availableto its management. tools will allow clinicians to successfully treat severe hyperkale- Methods: This article reviews and analyzes literature relevant mia. (Crit Care Med 2008; 36:3246 –3251)to the pathophysiology and management of severe hyperkalemia. KEY WORDS: hyperkalemia; treatment; critical illnessMethods include search of MEDLINE, and bibliographic search ofcurrent textbooks and journal articles.H yperkalemia is common in rium is modulated by insulin (3–5), cat- panies acute kidney injury, particularly in hospitalized patients, and echolamines (6, 7) and, to a lesser extent, the setting of mineralocorticoid defi- may be associated with ad- by acid-base balance (8 –10), plasma to- ciency (13–15). Such mineralocorticoid verse clinical outcomes (1, nicity, and several other factors (3). The deficiency is often induced by drugs that2). Its prevalence and clinical impact in other system governs K homeostasis over interfere with the renin-angiotensin-critically ill patients are unknown. There the long-term by regulating external bal- aldosterone axis and commonly causesis no doubt, however, that severe hyper- ance: the parity between K intake and hyperkalemia in patients with chronickalemia can be fatal. Proper treatment of elimination. In individuals with normal kidney disease, as well (16, 17). Sustainedhyperkalemia depends on an understand- renal function, the kidneys are responsi- hyperkalemia is always attributable to in-ing of the underlying physiology. ble for elimination of about 95% of the adequate renal K elimination. A detailed The ratio of extracellular to intracel- daily K load with the remainder exiting discussion of the causes of hyperkalemialular potassium (K) concentration largely through the gut. External K balance is in critically ill patients is beyond thedetermines the cell membrane resting maintained largely by modulating renal K scope of this article, but may be found inelectrical potential that, in turn, regu- elimination. a recent review (18).lates the function of excitable tissues Almost all the K excreted by the kid-(cardiac and skeletal muscle, and nerve) ney comes from K secreted in the distal Clinical Manifestations of(1). Small absolute changes in the extra- nephron (connecting tubule and collect- Hyperkalemiacellular K concentration will have large ing duct) (11). Virtually all regulation ofeffects on that ratio, and consequently on Alterations in PK have a variety of ad- K excretion takes place at this site in thethe function of excitable tissues. Thus, it verse clinical consequences, the expres- nephron, under the influence of two prin-is not surprising that the plasma K con- sion of which may be magnified in the ciple factors: the rate of flow and solutecentration (PK) normally is maintained critically ill patient. The most serious of (sodium and chloride) delivery through these manifestations are those involvingwithin very narrow limits. This tight reg- that part of the nephron; and the effect of excitable tissues.ulation is accomplished by two coopera-tive systems. One system defends against aldosterone (11). K secretion is directly Cardiac Effects. Hyperkalemia depo-short-term changes in PK by regulating proportional to flow rate and sodium de- larizes the cell membrane, slows ventric-internal balance: the equilibrium of K livery through the lumen of the distal ular conduction, and decreases the dura-across the cell membrane. This equilib- nephron, and to circulating aldosterone tion of the action potential. These levels in the setting of an aldosterone- changes produce the classic electrocar- sensitive epithelium. This explains, in diographic (EKG) manifestations of hy- part, why the use of diuretic drugs that perkalemia including (in order of their From the Division of Nephrology, Department ofMedicine, UMDNJ-Robert Wood Johnson Medical work proximal to the K secretory site usual appearance) peaked T waves, wid-School, Cooper University Hospital, Camden, NJ. (loop and thiazide diuretics) often is ac- ening of the QRS complex, loss of the P The author has not disclosed any potential con- companied by hypokalemia. K secretion wave, “sine wave” configuration, or ven-flicts of interest. is inversely proportional to the chloride For information regarding this article, E-mail: tricular fibrillation and asystole (19, 20) concentration of the luminal fluid and is These EKG changes may be modified by a Copyright © 2008 by the Society of Critical Care stimulated, for example, by luminal deliv- multitude of factors such as extracellularMedicine and Lippincott Williams & Wilkins ery of sodium bicarbonate (12). Con- fluid pH, calcium concentration, sodium DOI: 10.1097/CCM.0b013e31818f222b versely, hyperkalemia commonly accom- concentration, and the rate of rise of PK3246 Crit Care Med 2008 Vol. 36, No. 12
  2. 2. Table 1. Emergency treatment of hyperkalemia Agent Dose Onset Duration ComplicationsMembrane stabilization Calcium gluconate (10%) 10 mL IV over 10 min Immediate 30–60 min Hypercalcemia Hypertonic (3%) sodium chloride 50 mL IV push Immediate Unknown Volume overload hypertonicityRedistribution Insulin (short acting) 10 units IV push, with 25–40 g dextrose 20 min 4–6 hrs hypoglycemia (50% solution) Albuterol 20 mg in 4 mL normal saline solution, 30 min 2 hrs Tachycardia inconsistent nebulized over 10 min responseElimination Loop diuretics Furosemide 40–80 mg IV 15 min 2–3 hrs Volume depletion Bumetanide 2–4 mg IV Sodium bicarbonate 150 mmol/L IV at variable rate Hours Duration of infusion Metabolic alkalosis volume overload Sodium polystyrene sulfonate 15–30 g in 15–30 mL (70% sorbitol orally) Ͼ2 hrs 4–6 hrs Variable efficacy intestinal (Kayexalate, Kionex) necrosis Hemodialysis Immediate 3 hrs Arrhythmias (?) IV, intravenously.(19). Hospitalized patients with hyperka- and, thus, prevent correction of a meta- as arbitrary. Nonetheless, since the treat-lemia are reported to have a higher mor- bolic acidosis (29). ment for acute hyperkalemia is safe iftality rate than those without hyperkale- applied properly and hyperkalemia is po-mia (21, 22), but the high prevalence of Treatment of Severe tentially and unpredictably lethal, it iscoexistent renal insufficiency in this pop- prudent to maintain a low threshold for Hyperkalemiaulation is a significant confounding vari- instituting emergency therapy. Becauseable that prevents attribution of the in- In general, the initial treatment of se- most patients manifest hyperkalemiccreased mortality to the hyperkalemia vere hyperkalemia is independent of the EKG changes at PK greater than 6.7itself. cause of the disturbance, whereas the ra- mmol/L (20), hyperkalemia should be EKG changes may not accompany tional therapy of chronic hyperkalemia treated emergently for 1) P K Ͼ6.5changes in PK. The sensitivity of the elec- depends on an understanding of its mmol/L or 2) EKG manifestations of hy-trocardiogram to reveal changes of hy- pathogenesis. perkalemia regardless of the PK (30).perkalemia is quite low (23). It does in- In considering when hyperkalemia Therapy of acute or severe hyperkale-crease in proportion to the severity of the constitutes an emergency, several points mia is directed at preventing or amelio-hyperkalemia (23), but normal electro- should be kept in mind. First, the elec- rating its untoward electrophysiologic ef-cardiograms have been seen even with trophysiologic effects of hyperkalemia are fects on the myocardium. The goals ofextreme hyperkalemia (24) and the first directly proportional to both the absolute therapy, in chronologic order, are as fol-cardiac manifestation of hyperkalemia PK and its rate of rise (19). Second, con- lows (Table 1):may be ventricular fibrillation (25). (The current metabolic disturbances may ame-explanation for a normal electrocardio- liorate (e.g., hypernatremia, hypercalce- 1. Antagonize the effect of K on excitablegram in the setting of extreme hyperka- mia, alkalemia) or exacerbate (e.g., cell membranes.lemia is not entirely clear, but may relate hyponatremia, hypocalcemia, acidemia) 2. Redistribute extracellular K into a slow rate of rise in the PK ͓20, 24͓). the electrophysiologic consequences of 3. Enhance elimination of K from theGiven this insensitivity of the electrocar- hyperkalemia (20, 24). Third, although body.diogram, EKG changes should not be the EKG manifestations of hyperkalemiaconsidered necessary for the emergency are generally progressive and propor- Membrane Antagonismtreatment of severe hyperkalemia. tional to the PK, ventricular fibrillation Neuromuscular Effects. Hyperkalemia may be the first EKG disturbance of hy- Calcium. Calcium directly antago-may result in paraesthesias and weakness perkalemia (25); conversely, a normal nizes the myocardial effects of hyperkale-progressing to a flaccid paralysis, which EKG may be seen even with extreme hy- mia without lowering PK (31, 32). It doestypically spares the diaphragm. Deep ten- perkalemia (24). so by reducing the threshold potential ofdon reflexes are depressed or absent. Cra- With this in mind, it is apparent that cardiac myocytes, thereby restoring thenial nerves are rarely involved and sen- neither the EKG nor the PK alone is an normal gradient with the resting mem-sory changes are minimal (26, 27). adequate index of the urgency of hyper- brane potential, which is distorted by hy- Metabolic Effects. Hyperkalemia de- kalemia, and that the clinical context perkalemia (19, 20, 33). Calcium is ben-creases renal ammoniagenesis which by must be considered when assessing a hy- eficial even in patients who areitself may produce a mild hyperchloremic perkalemic patient. Thus, any pro- normocalcemic. Calcium for injection ismetabolic acidosis (28), and will limit the nouncement on an absolute PK value available as the chloride or gluconatekidney’s ability to excrete an acid load constituting an emergency must be seen salt, both 10% by weight. The preferredCrit Care Med 2008 Vol. 36, No. 12 3247
  3. 3. agent is the gluconate salt, since it is less dextrose has been shown to be inadequate hypokalemic effect of albuterol (42, 48).likely than calcium chloride to cause tis- to prevent hypoglycemia at 60 mins (42). The mechanism for this resistance is un-sue necrosis if it extravasates (34). The It is interesting to note that when insulin known, and there is currently no basis forrecommended dose is 10 mL intravenous was given by continuous intravenous in- predicting which patients will respond.over 10 mins. The onset of action is Ͻ3 fusion for 4 hrs to normal volunteers, PK For that reason, albuterol should nevermins. The EKG should be monitored fell over the first 90 mins and rose there- be used as a single agent for the treat-continuously. The dose may be repeated after (45). Based on that observation, ment of urgent hyperkalemia in patientsin 5 mins if there is no improvement in there seems to be no advantage of a con- with renal failure.the EKG, or if the EKG deteriorates tinuous infusion over a bolus injection. Bicarbonate. The putative benefits of aafter an initial improvement. The dura- Insulin should be used without dex- bolus injection of sodium bicarbonate intion of action is 30 – 60 mins, during trose in hyperglycemic patients; indeed, the emergency treatment of hyperkale-which time further measures may be the cause of the hyperkalemia in those mia pervaded the literature until the pastundertaken to lower PK (30). patients may be the hyperglycemia itself decade. Ironically, this dogma was based There are several case reports of sud- (46). The administration of hypertonic on studies using a prolonged (4 – 6 hrs)den death in patients given intravenous dextrose alone for hyperkalemia is not infusion of bicarbonate (53). It has nowcalcium while also receiving digitalis gly- recommended for two reasons: first, en- been clearly demonstrated that short-cosides (35, 36). Although these anec- dogenous insulin levels are unlikely to term bicarbonate infusion does not re-dotes do not provide clear guidance, it is rise to the level necessary for a therapeu- duce PK in patients with dialysis-depen-wise to administer intravenous calcium tic effect; and second, there is a risk of dent kidney failure, implying that it doesunder very close supervision to patients exacerbating the hyperkalemia by induc- not cause K shift into cells. Infusion of aknown or strongly suspected to have ing hypertonicity (46). hypertonic or an isotonic bicarbonate so-toxic levels of digitalis glycosides. ␤-adrenoceptor Agonists. An appreci- lution for 60 mins has been shown to Hypertonic Saline. Intravenous hy- ation for the effect of catecholamines on have no effect on PK in dialysis patients,pertonic sodium chloride has been shown internal potassium balance recently has despite a substantial increase in serumto reverse the EKG changes of hyperka- been applied to the clinic. Patients with bicarbonate concentration (40, 54 –56).lemia in patients with concurrent hypo- renal failure given the selective ␤2- Only after a 4-hr infusion was a small (0.6natremia (37). This effect seems to be adrenoceptor agonist, albuterol, by intra- mmol/L) but significant decrease in PK ismediated by a change in the electrical venous infusion (0.5 mg over 15 mins) detectable (57). Whether bicarbonate in-properties of cardiomyocytes rather than show a significant decline in PK (about 1 fusion might enhance insulin-mediatedby a reduction in PK (38). Whether hy- mmol/L) that is maximal between 30 and cellular K uptake remains unresolved bypertonic saline is effective in the treat- 60 mins (47). Because injectable albu- two contradictory studies (54, 56). Thement of eunatremic patients has not been terol is unavailable in the United States, absence of a demonstrable effect of bicar-established. Until such benefit has been it is encouraging to note that nebulized bonate to shift K into cells over the shortdemonstrated, the use of hypertonic (3%) albuterol in a high dose, administered to term is not to imply that bicarbonatesaline should be restricted to hyponatre- patients with end-stage renal disease, has might not be useful in the emergencymic patients with hyperkalemia, with an a similar effect: P K declines by 0.6 treatment of hyperkalemia; rather, thatawareness of the volume overload that mmol/L after inhalation of 10 mg of al- its onset and mechanism of action aremay ensue. buterol, and by about 1.0 mmol/L after 20 quite different from what conventional mg (41, 42, 48, 49). Note that the effec- wisdom has held (see below). Further-Redistribution of Potassium into tive dose is at least four times higher than more, the foregoing is not meant to im-Cells that typically used for bronchodilation ply that sodium bicarbonate should be (50), although a smaller decline in PK withheld from the hyperkalemic patient Insulin. Insulin reliably lowers PK in (about 0.4 mmol/L after 60 mins) is seen with metabolic acidosis; rather, that nopatients with end-stage renal disease even with a metered-dose inhaler (51). short-term effect on the PK should be(39 – 43), confirming its effect to shift K The effect of high-dose therapy is appar- anticipated.into cells. The effect of insulin on potas- ent at 30 mins and persists for at least 2sium is dose dependent from the physio- hrs (48). The effect of insulin is additive Elimination of Potassium fromlogic through the pharmacologic range with that of albuterol, with the combina- the Body(5). It is mediated by activation of Na, tion reported to result in a decline in PKK-ATPase, apparently by recruitment of by about 1.2 mmol/L at 60 mins (42). Enhanced Renal Elimination. Hyper-intracellular pump components into the More recently, subcutaneous terbutaline kalemia occurs most often in patientsplasma membrane (4, 44). An intrave- (7 ␮g/kg body weight) has been shown to with renal insufficiency. However, renalnous dose of ten units of regular insulin reduce PK in selected dialysis patients by K excretion may be enhanced even ingiven as a bolus along with an intrave- an average of 1.3 mmol/L within 60 mins patients with significant renal impair-nous bolus of dextrose (25 g as a 50% (52). Mild tachycardia is the most com- ment by increasing the delivery of sol-solution) to anephric adult patients low- mon reported side effect of high-dose ute to the distal nephron, the site of Kers the PK by about 0.6 mmol/L (42). The nebulized albuterol or terbulatine. Pa- secretion.onset of action is Ͻ15 mins and the effect tients taking nonselective ␤-adrenocep- Studies using acetazolamide showis maximal between 30 and 60 mins after tor blockers will be unlikely to manifest that bicarbonate delivery to this site ina single bolus (41, 42). After the initial the hypokalemic effect of albuterol. Even the nephron has a particular kaliureticbolus, a dextrose infusion should be among patients not taking ␤-blockers, as effect (58), even in patients with renalstarted, since a single bolus of 25 g of many as 40% seem to be resistant to the insufficiency (59). It would be unwise to3248 Crit Care Med 2008 Vol. 36, No. 12
  4. 4. administer acetazolamide alone to most be 1.8% among postoperative patients re- kidney function, although it use for thispatients with hyperkalemia, since they ceiving SPS (75). Thus, the slow onset of purpose has not been systematically eval-tend to present with a concomitant met- action and serious, albeit infrequent, toxic- uated. SPS resin has a slow onset of ac-abolic acidosis that would be exacerbated ity make SPS a poor choice for the treat- tion and debatable efficacy. Furthermore,by the drug. But a sodium bicarbonate ment of urgent hyperkalemia. it carries the small risk of intestinal ne-infusion administered during 4 – 6 hrs at Dialysis. Hemodialysis is the method crosis. Hemodialysis remains the mosta rate designed to alkalinize the urine of choice for removal of potassium from reliable tool for removing K from themay enhance urinary K excretion (53), the body. PK falls by over 1 mmol/L in the body in patients with kidney failure.and would be desirable especially in pa- first 60 mins of hemodialysis and a totaltients with metabolic acidosis. The risk of of 2 mmol/L by 180 mins, after which it REFERENCESvolume expansion with the bicarbonate reaches a plateau (3, 76). Rebound alwaysinfusion can be mitigated by the use of occurs after dialysis, with 35% of the re- 1. Gennari FJ: Disorders of potassium ho-loop-acting diuretics, which would be duction abolished after an hour and meostasis. Hypokalemia and hyperkalemia.likely to further enhance the kaliuretic nearly 70% after 6 hr; the magnitude of Crit Care Clin 2002; 18:273–288, vieffect. Loop-acting diuretics alone or in the postrebound PK is proportional to the 2. Stevens MS, Dunlay RW: Hyperkalemia in hospitalized patients. Int Urol Nephrol 2000;combination with a thiazide diuretic will predialysis PK (77). 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