Wednesday, December 7, 2016

Debates in the Management of Hyperkalemia

At the 2016 Midyear Clinical Meeting of the American Society of Health-Systems Pharmacists (ASHP), my colleague Bryan Hayes (@PharmERToxGuy) and I presented a continuing education program on debates in the management of hyperkalemia.

The learning objectives from our session are below:
  1. Evaluate recommendations for dosing and administration of parenteral calcium in the treatment of hyperkalemia. 
  2. Apply practical methods for co-administration of insulin and dextrose in the management of hyperkalemia.
  3. Discuss evidence-based literature surrounding administration of sodium bicarbonate and sodium polystyrene sulfonate in the treatment of hyperkalemia. 
  4. Appraise literature related to clinical trials evaluating novel and newly approved agents for hyperkalemia.
This blog post serves as a summary of the key points of the presentation, and we created this resource as an active and living reference of the educational material shared in the session that can be shared at any point following the session.



An elevated calcium concentration decreases the depolarization effect of an elevated K+ concentration. IV calcium antagonizes the cardiac membrane excitability thereby protecting the heart against dysrhythmias. (Hoffman BF, et al. Am J Physiol 1956;186:317-24) (Treatment of Acute Hyperkalemia in Adults - Clinical Practice Guideline. UK Renal Association 2014)

  • Life-threatening ECG changes, dysrhythmias, & cardiac arrest - YES 
  • Peaked T waves - PROBABLY 
    • ECG can be normal, but in some cases is an insensitive marker for assessing severity in hyperkalemia (Parham WA. Tex Heart Inst J 2006;33:40-7) (Szerlip HM, et al. Am J Kidney Dis 1986;7:461-5) (Bandyopadhyay S, et al. Int J Clin Pract 2001;55:486-7) 
  • Optimal dose unclear. Start with at least 1 gm CaCl2 or 2 gm calcium gluconate IV 
  • Starts to work in about 3 minutes 
  • Redose in 5-10 minutes if no effect seen from first dose 
  • Effects last 30-60 minutes (may need to redose if further treatment needed while awaiting emergent hemodialysis) 
  • Does calcium gluconate act slower than calcium chloride because it needs hepatic activation? No! 
    • Serum ionized calcium levels were measured in 15 hypocalcemic patients during the anhepatic stage of liver transplantation. Half received CaCl 10 mg/kg, the other half received calcium gluconate 30 mg/kg. Serum concentrations of ionized calcium were determined before and up to 10 min after calcium therapy. Equally rapid increases in calcium concentration after administration of CaCl and gluconate were observed, suggesting that calcium gluconate does not require hepatic metabolism for the release of calcium and is as effective as CaCl in treating ionic hypocalcemia in the absence of hepatic function. (Martin TJ, et al. Anesthesiology 1990;73:62-5) 
    • A weird randomized prospective study in both children and dogs compared ionization of CaCl and calcium gluconate. The authors conclude that equal elemental calcium doses of calcium gluconate (10%) and CaCl (10%) (approximately 3:1), injected over the same period of time:
      • Are equivalent in their ability to raise calcium concentration during normocalcemic states in children and dogs 
      • The changes in calcium concentration following calcium administration are short-lived (minutes)  
      • The rapidity of ionization seems to exclude hepatic metabolism as an important factor in the dissociation of calcium gluconate (Cote CJ, et al. Anesthesiology 1987;66:465-70) 
    • In ferrets and in vitro human blood, equimolar quantities of CaCl and calcium gluconate produced similar changes in plasma ionised calcium concentration when injected IV into anaesthetised ferrets or when added to human blood in vitro. In vivo changes were followed with a calcium electrode positioned in the animal’s aorta, and this showed that the ionisation of calcium gluconate on its first pass through the circulation is as great as that of CaCl. This does not support the common suggestion that CaCl is preferable to calcium gluconate because of its greater ionisation. (Heining MP, et al. Anaesthesia 1984;39:1079-82)
Calcium in Digoxin Overdose
  • There are only 5 case reports suggesting a temporal relationship between calcium administration and death in the setting of digoxin toxicity (primarily from the 1930s and 1950s); symptoms of digoxin toxicity are not described, no digoxin levels were taken and only 2 cases had a strong temporal relationship (which does not imply causation).There are also case reports of calcium use in patients with digoxin toxicity without any ill effects. 
  • Original animal models flawed - toxic effects only occurred when animals were made severely hypercalcemic prior to digoxin administration. Subsequent animal models mimicking digoxin toxicity failed to demonstrate adverse effects. 
  • The most recent study retrospectively reviewed 159 dig toxicity cases, 23 of which received calcium (Levine M, et al. J Emerg Med 2011; 40:41-46). Death rate was same in both groups and no dysrhythmias were noted. The problem is all except 1 were chronic digoxin overdose. Hyperkalemia is more problematic in the acute overdose.
  • Stone heart theory is probably false. Calcium appears safe, but we don’t even know if it would work the same as in hyperK from other causes. Little evidence in acute overdose where hyperkalemia may be more problematic. If known digoxin-induced hyperkalemia, give antidote. Otherwise give calcium.
Insulin and Dextrose

Treating Hyperkalemia with Insulin

  • Insulin remains one of the cornerstones of early severe hyperkalemia management. Insulin works via a complex process to temporarily shift potassium intracellularly. 
  • Insulin lowers serum potassium by activating Na+-K+ ATPase and by recruitment of intracellular pump components into the plasma membrane. Insulin binding to specific membrane receptors results in extrusion of Na+ and cellular uptake of K+. (Hundal HS, et al. J Biol Chem 1992;267:5040-3)
  • Doses of 5 units boluses up to 20 unit/hr infusions have been used. The most common dose studies is 10 units IV regular insulin as a bolus. This lowers the potassium level by about 1 mEq/L. Neither of these regimens provides sustained effect.
  • Based on what is known of physiology and drug kinetics, one group suggests the most logical regimen for a 70-kg subject (with weight adjustment of dosages for others) would be an infusion of short-acting insulin at 20 U/h after a 6-U loading dose, given with 60 g of glucose per hour (Sterns, Kidney Int 2016). This needs to be studied before it can be recommended.
Preventing Hypoglycemia
  • Though insulin certainly lowers plasma potassium concentrations, we often underestimate the hypoglycemic potential of a 10 unit IV insulin dose in this setting.
  • Incidence of Hypoglycemia
    • A 10 unit dose of IV regular insulin has an onset of action of about 5-10 minutes, peaks at 25-30 minutes, and lasts 2-3 hours. Herein lies the problem in that IV dextrose only lasts about an hour (at most). Allon et al reported up to 75% of hemodialysis patients with hyperkalemia developed hypoglycemia at 60 minutes after insulin administration (Kidney Int 1990;38:869-72). A retrospective review of 219 hyperkalemic patients reported an 8.7% incidence of hypoglycemia after insulin treatment (Schafers S, et al. J Hosp Med 2012;7:239-42). More than half of the hypoglycemic episodes occurred with the commonly used regimen of 10 units of IV insulin with 25 gm of dextrose. A more recent study of 221 end-stage renal disease patients who received insulin for treatment of hyperkalemia reported a 13% incidence of hypoglycemia (Apel J, et al. Clin Kidney J 2014;0:1-3) 
    • The overall incidence of hypoglycemia appears to be ~10%, but could be higher. 
  • Risk Factors for Developing Hypoglycemia
    • The study by Apel et al identified three factors associated with a higher risk of developing hypoglycemia:
      1. No prior diagnosis of diabetes [odds ratio (OR) 2.3, 95% confidence interval (CI) 1.0–5.1, P = 0.05]
      2. No use of diabetes medication prior to admission [OR 3.6, 95% CI 1.2–10.7, P = 0.02]
      3. A lower pretreatment glucose level
        • In mg/dL: mean 104 ± 12 mg/dL vs 162 ± 11 mg/dL, P = 0.04
        • In mmol/L: mean 5.8 ± 0.7 mmol/L vs 9.0 ± 0.6 mmol/L, P = 0.04
    • Renal dysfunction in and of itself may also be a risk factor for developing hypoglycemia. Some evidence suggests that insulin is metabolized by the kidneys to some extent. Furthermore, patients with acute kidney injury (AKI) have clinically relevant changes in insulin metabolism, as evidenced by increased hypoglycemic events and lower insulin requirements upon developing AKI (Dickerson RN, et al. Nutrition 2011;27:766-72).
  • Strategies for Avoiding Hypoglycemia
    • Preventing hypoglycemia is important. Some clinicians use up to 20 units of IV regular insulin as the hypokalemic effect is dose dependent (Blumberg A, et al. Am J Med 1988;85:507-12). Here is a suggested strategy for administering enough dextrose to counter the initial insulin bolus of 10 or 20 units: It is loosely based on the Rush University protocol (Apel 2014).
Sodium Bicarbonate

  • History has not been on our side when it comes to understanding and appreciating the role of sodium bicarbonate in the management of hyperkalemia.
  • In one survey of directors of nephrology training programs, respondents indicated that sodium bicarbonate was among their top choices as an agent for treating hyperkalemia, with over 30% indicating that this agent should be used either alone or in conjunction with calcium gluconate. (N Engl J Med 1989; 320:60-61)
  • This attitude has been perpetuated across decades of training, but it is essential to understand the mechanism that sodium bicarbonate holds in the management of hyperkalemia.
  • It has often been said that sodium bicarbonate is effective in hyperkalemia due to its effects on enhancing the excretion of potassium, shifting potassium into the intracellular space, and/or decreasing the amount of hydrogen ions in the extracellular fluids.
  • However, one little known fact related to the role of sodium bicarbonate is its influence on the sodium-bicarbonate co-transport system as well as the exchange system for sodium and hydrogen within the skeletal muscles in promoting uptake of potassium. (Clin J Am Soc Nephrol 2015; 10:1050-1060)
  • By increasing sodium in the intracellular space, the activity of the enzyme sodium-potassium adenosine triphosphatase also increases.
  • One of the key influences of promoting the activity of the sodium-hydrogen exchange system is the presence of intracellular acidosis, which is thought to account for the purported efficacy of sodium bicarbonate in the treatment of hyperkalemia. (Kamel et al. Nephrol Dial Transplant 2003; 18:2215-2218)
  • One of the earliest evaluations of sodium bicarbonate in the management of hyperkalemia occurred in the setting of chronic kidney disease and severe acidosis with administration as a continuous infusion. (Circulation 1959; 19:215-220) For every 10 mmol/L increase in serum sodium bicarbonate, serum potassium levels decreased by 2 mmol/L.
  • A few caveats:
    • This evaluation was conducted in was conducted in four patients.
    • In addition, this is not generally the way we typically administer sodium bicarbonate in the emergency department; oftentimes, we administer it as a one-time IV bolus dose of 50 mEq.
Myths Debunked
  • One thing that we do know that within the literature, there are several controlled studies that have indicated that sodium bicarbonate will not work within the first 60 minutes of administration for the treatment of hyerpkalemia. (Am J Med 1988; 85:507-512) (Nephron 1996; 72:476-482) (Am J Kidney Dis 1996; 28:508-514) (Korean Med Sci 1997; 12:111-116)
    • Its onset is within 4 to 6 hours, with a duration of activity of the same time frame. The effects have reportedly been “variable” at best.
  • Even in the stetting of worsening metabolic acidosis and concomitant hyperkalemia, sodium bicarbonate has not been shown to be more effective that other common therapies used for this condition.
  • Some have said that perhaps the effect is more of dilutional in nature, simply because of the volume of sodium bicarbonate that is infused when administered as a continuous infusion as opposed to a bolus dose. (Miner Electrolyte Metab 1991; 17:297-302) (Kidney Int 1992; 41:369-374)
Concomitant Agents
  • Most of us who manage hyperkalemia in the health-system setting will often see orders for several agents to be administered simultaneously, with common agents being calcium gluconate or chloride, insulin with dextrose, sodium bicarbonate, and potentially other medications.
  • This is the origin of the hyperkalemia cocktail as we know it today:
    • Not surprisingly, this was described in 1954, and it was used in the military, specifically on the battlefield in soldiers who experienced traumatic acute kidney injury. (J Am Med Assoc 1954; 155:877-883)
    • The cocktail consisted of 400 mL of D25, 50 units of regular insulin, 50 mmol of sodium bicarbonate, and boluses of calcium administered as an as needed basis, but generally incorporating 100 mL of 10% solution of calcium gluconate.
    • When all the agents were compounded in an isotonic solution of sodium chloride at a rate of 25 mL/hr, this was a means to control hyperkalemia in soldiers on the battlefield for several days. 
  • However, there is little to suggest that the use of sodium bicarbonate within so-called hyperkalemia treatment cocktails actually effectively enhances the effects of other agents used to decrease serum concentrations of potassium. (Am J Kidney Dis 1996; 28:508-513) (East Afr Med J 1997; 74:503-509)

More to the Story: Thinking Beyond All About That Base

Utility of Hypertonic Saline
  • Case series of four patients who received a 5% solution of hypertonic saline for managing hyperkalemia in the setting of profound hyponatremia. (Am Heart J 1962; 64:483-488)
  • The study has been replicated a few times, but mostly in animal models, not in clinical practice with humans. (Am J Med 1953; 14:504) (Acad Emerg Med 1997; 4:93-99) (Acad Emerg Med 2000; 7:965-973)
Sodium-Loading Agent?
  • Activity at a specific voltage-gated sodium channel known as Nav1.5. (Am J Physiol 1975; 229:935-940)
    • It has been suggested that this sodium channel is antagonized in the setting of hyperkalemia, preventing the entry of sodium across the ventricular myocytes, which leads to a subsequent stalling of Phase 0 of the action potential, and may manifest in cardiac arrhythmias. The sodium load with sodium bicarbonate may allow for entry of sodium at the level of ventricular myocytes, which can normalize any manifestations in abnormalities in cardiac conduction. (Kidney Int 2016; 90:450-451)
Other Potential Mechanisms
  • Improved cellular perfusion in cardiac pacemaker cells
  • Decrease in systemic vascular resistance leading to reduction in afterload and induction of reflex tachycardia
  • Dilutional effect of extracellular potassium with rapid expansion of the volume of the plasma. (Acad Emerg Med 2000; 7:965-973)
Sodium Polystyrene Sulfonate (SPS)

  • SPS made its way onto the market in 1958, nearly four years before the passage of the Kefauver-Harris amendments requiring proof of both effectiveness and safety prior to medications being potentially approved by the Food and Drug Administration.
  • SPS has the claim to fame of serving as an ion-exchange resin. By design, it exchanges sodium for ammonium, calcium, and magnesium in addition to potassium as a means to facilitate fecal elimination of potassium. It generally works in the lower portion of the gastrointestinal tract, specifically in the distal colon, which contains the greatest proportion of potassium. At acidic pH, SPS cannot function as hydrogen ions occupy the sulfonate groups with the general structure of the compound. (Lancet 1953; 265:791-795) (Gastroenterology 1994; 107:548-571)
  • In the “pivotal” studies of SPS, 33 patients were evaluated and were deemed to be successfully treated with SPS for hyperkalemia.
  • One evaluation was a case report (N Engl J Med 1961; 264:111-115.), and the other study included the remaining 32 patients. (N Engl J Med 1961; 264:115-119.)
    • The latter reflected a decrease in serum potassium of 0.9 mEq/L in the first 24 hours with effects noted at 1 to 5 days post-administration.
    • There was no control for concomitant agents that could potentially be administered, and so it is difficult to attribute that this effect occurred due to the influence of the resin or the presence of other cathartic agents such as hypertonic glucose.
Controversies of SPS
  • SPS possesses many other properties that deem several questions related to its use in treating hyperkalemia: (J Am Soc Nephrol 2010; 21:733-735.)
    1. Sodium Load: 100 mg of sodium is contained per gram of SPS, which is equivalent to 4 mEq of sodium. The Heart Failure Society of America recommends exercising the use of caution of SPS in patients with congestive heart failure. 
    2. Many times, SPS is used in patient with chronic, end-stage renal disease (ESRD). However, for those with ESRD, colonic excretion is actually enhanced due to the actions of aldosterone. So whether SPS is truly beneficial in patients with ESRD is questionable.
    3. Fatal colonic perforation associated with SPS formulated with and without sorbitol.
    4. Based on a Cochrane review of studies evaluating the role of SPS in hyperkalemia, SPS has never been found to be effective within the first few hours of treatment, and fecal elimination of potassium has never been found to be significantly enhanced with use as well as no demonstrated benefit in reduction of serum potassium. (Coch Data Syst Rev 2005 Issue 2. CD 003235)

This agent is a non-absorbable synthetic polymer that acts as a “me-too” resin, in that similar to SPS, it facilitates fecal potassium excretion in the distal colon in exchange for calcium. It has been evaluated primarily in patients with chronic kidney disease with concomitant cardiovascular disease (N Engl J Med 2015; 372:211-221.) (JAMA 2015; 314:151-161.)(Eur Heart J 2011; 32:820-828.). It has a black box warning for separation from other orally administered medications by at least six hours due to demonstration of in vitro binding. One of its major adverse drug event is hypomagnesemia, which was observed in over 8% of patients in clinical trials; however, no neuromuscular abnormalities nor cardiac arrhythmias have been reported as manifestations.

Sodium zirconium cyclosilicate (ZS-9)

This agent is a crystal structure with high selectivity for potassium and ammonium ions. Hydration shells of these ion shells must be shed to induce thermodynamic stability, which requires energy (PLoS One 2014;9(12):e114686.) A binding pore within its structure traps potassium due to the size of pocket, which prevents binding of other smaller and larger cations. It is highly specific in that it entraps more than nine times the amount of potassium than SPS. Upon binding, sodium zirconium cyclosilicate facilitates excretion of potassium in exchange with sodium and hydrogen through the entire GI tract (not restricted to distal colon). It has been suggested to be effective in the long-term maintenance of normokalemia (Kidney Int 2015; 88:404-411.) (N Engl J Med 2015; 372:222-231.)

  • The publication of a subgroup analysis of two phase 3 trials that led to its approval is somewhat controversial (N Engl J Med 2015; 372:1577-1578.) This article was published as a correspondence to the journal and it described 45 patients with baseline serum potassium concentrations ranging between 6.1 and 7.2 mmol/L, demonstrating a somewhat rapid reduction in potassium at 1, 2, and 4 hours post-administration. 
  • Taking a closer look at patient populations, namely, among those excluded consisted of:
    • Hemodialysis
    • Outpatient treatment with phosphate binders (ergo end-stage renal disease)
    • Outpatient treatment for hyperammonemia (ergo end-stage liver disease)
    • Diabetic ketoacidosis
    • Life-threatening cardiac arrhythmias
  • These excluded patient populations consists of the majority of the patients that we encounter in the acute care setting such as the emergency department with hyperkalemia. We cannot confidently state that sodium zirconium cyclosilicate has a role in managing hyperkalemia acutely due to exclusion of these patient populations. (Hypertension 2015; 66:731-738) (Pharmacotherapy 2016; 36:922-923)