Insulin Dosing in Hyperkalemia – Is It a One Size Fits All?

Authors: Kayvan Moussavi, PharmD, BCCCP (Assistant Professor- Department of Pharmacy Practice, Marshall B. Ketchum University College of Pharmacy), Scott Fitter, PharmD, BCCCP (Clinical Pharmacy Specialist- Emergency Department, Loma Linda University Medical Center) // Edited by: Alex Koyfman, MD (@EMHighAK) and Brit Long, MD (@long_brit)

Acknowledgements

The authors would like to thank Joshua Garcia, PharmD, BCPS (Assistant Professor, Marshall B. Ketchum University College of Pharmacy) for editing this article.

Case

A 58-year-old, 90 kg female with history of hypertension, obesity, and ESRD on dialysis three times weekly presents to the Emergency Department (ED) from her dialysis clinic for hypertension.  The patient was scheduled for dialysis today, but the clinic noted the patient’s blood pressure was 200/120 and requested the patient be treated for hypertensive crisis in ED.  The patient did not receive dialysis today.  The patient does not have any complaints but states she did not take her medications this morning.  Upon assessment you note the following:

  • Vitals: BP 210/120, HR 100 (sinus tachycardia), RR 16, Sat 97% on RA, T 98.8 F, GCS 15
  • EKG: within normal limits
  • Labs of interest: potassium 6.5 mmol/L, glucose 71 mg/dL
  • Home medications: metoprolol, nifedipine, losartan, hydrochlorothiazide, aspirin, sevelamer, cinacalcet, iron sulfate, and B-complex vitamin

Examination reveals a patient without signs of distress.  Because the patient is hypertensive but does not appear to have new or worsening organ damage, you order the patient’s home doses of metoprolol, nifedipine, losartan, and hydrochlorothiazide.  You would also like to treat the patient’s hyperkalemia.  You place a nephrology consult for urgent dialysis and consider ordering calcium gluconate 1000 mg intravenously (IV), albuterol 10 mg nebulized, insulin regular 10 units IV with dextrose 50% 25 grams IV; however, you wonder if the insulin may cause hypoglycemia in your patient.  The patient’s blood glucose is 71 mg/dL, bordering on hypoglycemia.

Should you modify your insulin or dextrose dose in this patient?

Introduction

Hyperkalemia is a common, potentially lethal clinical condition that often affects patients with chronic kidney disease (CKD), acute kidney injury (AKI), cardiovascular disease, diabetes mellitus, or those taking various medications, such as angiotensin-converting-enzyme (ACE) inhibitors or angiotensin-receptor blockers (ARB).1-4  Options for treatment include calcium, beta-2 agonists (e.g. albuterol), sodium bicarbonate, ion-exchange resins (e.g. sodium polystyrene sulfonate or Kayexalate®), loop diuretics, dialysis, and insulin.2,4  These options have different onsets of action, durations of clinical effects, adverse effect profiles, and ease of initiation.2  Insulin is a popular option due to its quick onset of action (~20 minutes), moderate duration of effect (4-6 hours), and ability to be administered IV.2 Insulin regular 10 units IV with 25 grams of dextrose IV is a common regimen utilized for hyperkalemia treatment.2,5-7  However, insulin is not risk free and can put patients at risk of developing hypoglycemia even after co-administration with dextrose.5,6,8-13

Let’s examine insulin use for hyperkalemia and discuss considerations that should be made when deciding how to use it.

Insulin mechanism of action in hyperkalemia14,15

Insulin causes an intracellular shift of potassium by stimulating Na+-H+antiporters, promoting sodium influx.  Increased intracellular sodium concentrations trigger the activation of the Na+-K+ATPase transporter, which exchanges intracellular sodium for extracellular potassium.  A dose of 10 units IV insulin regular has been estimated to lower serum potassium levels by 0.6 to 1.2 mEq/L in 1hour.16

Risk factors for hypoglycemia during treatment with insulin

Hypoglycemia secondary to IV insulin administration is a well-documented complication in the treatment of hyperkalemia. In one study involving patients with End Stage Renal Disease (ESRD) given insulin regular 10 units with 25 grams of dextrose, 75% of patients experienced blood glucose <55mg/dL one hour post treatment.16More recent studies have reported hypoglycemia rates between 8.7% and 28.6%.5,9,11Potential risk factors for hypoglycemia due to IV insulin administration include:

  • Lower patient weight (e.g. less than 60 kg)11,17
  • Patients without a diagnosis of diabetes mellitus17
  • Lower pretreatment glucose (e.g. less than 140 mg/dL)13,17
  • Female Gender13

ESRD also contributes to hypoglycemic events after IV insulin administration due to decreased insulin clearance, prolonging its duration of action.17 Patients with ESRD also have reduced renal gluconeogenesis, predisposing them to fasting hypoglycemia, as well as reductions in glucagon release.17

Insulin dosing evaluation in hyperkalemia

Several studies have compared insulin dosing strategies in hyperkalemia.8-10,13,18  These studies compared patients receiving 10 units to lower doses, such as 5 units or 0.1 unit/kg, and assessed for potassium-lowering ability and incidence of hypoglycemia.8-10,13,18  Hypoglycemia was generally defined as blood glucose less than 70 mg/dL; however, there were varying definitions of severe hypoglycemia and duration of monitoring for hypoglycemia after insulin administration.8-10,13,18

To summarize:8-10,13,18

  • There are currently no prospective trials examining efficacy or safety of different insulin dosing regimens for hyperkalemia.
  • Several studies have compared 10 unit dosing to 5 units or 0.1 units/kg IV.
  • Patients in these studies were typically given 25 to 50 grams of dextrose concurrently with insulin.
  • Mean pre-insulin potassium levels were generally between 6 to 6.5 mmol (or meq) per liter.
  • Mean post-insulin potassium levels were not different between higher or lower insulin dosing strategies and generally ranged from a decrease of 0.5 to 1.4 mmol (or meq) per liter.
  • One study found that in patients with baseline potassium 6 mmol/L or greater, 10 unit dosing provided greater mean potassium reduction than 5 units (1.08 vs. 0.83 mmol/L; p=0.018).18
  • Patients receiving lower insulin doses experienced similar or lower rates of hypoglycemia compared to higher insulin doses.Rates of severe hypoglycemia were similar across all studies.
  • Across all studies, rates of hypoglycemia in lower insulin dose groups ranged from 6.67% to 22.6% versus 5.8% to 33% in higher dose groups.

Dextrose dosing evaluation in hyperkalemia

Another consideration during insulin treatment is dextrose administration.  Traditionally, dextrose 25 grams (usually as dextrose 50% solution) as an IV bolus has been recommended to be given alongside insulin if pre-treatment blood glucose is less than 250 mg/dL.2,7  A potential problem of this approach is that the hyperglycemic effects of a dextrose bolus may not have the same duration as the hypoglycemic effects of insulin. Dextrose boluses typically last 60 minutes while the effects of insulin may last 4 to 6 hours or longer in some patients.2  This gap in glycemic coverage is demonstrated in the following studies:

According to these studies, hypoglycemia tends to occur 2.5 to 3.5 hours after insulin administration.10-12,19 This suggests the duration of action for dextrose is shorter than the duration of action for insulin and that patients may require repeat dextrose doses several hours after insulin even if dextrose was given concurrently.

The approaches to dextrose dosing by Wheeler et al. and Coca et al. offer guidance on strategies to prevent hypoglycemia after insulin.  Wheeler et al. noted that when patients were given 50 grams as a bolus and 0.1 units/kg of insulin, hypoglycemia was observed in 10.6% of patients.13 Coca et al. noted that when patients were given 50 grams as a four hour infusion, hypoglycemia was observed in 6.1% of patients.19  Of note, patients in this study also received 10 units of insulin as a four hour infusion.19  The rates of hypoglycemia in these two studies were noticeably lower than hypoglycemia rates in other studies (e.g. 28.6% in those given insulin 10 units in LaRue et al.).9,13,19  Another approach is to administer repeat dextrose boluses several hours after the initial dextrose bolus as described by LaRue et al. (e.g. 25 grams one hour after initial dextrose dose).9  However, rates of hypoglycemia in this study ranged from 19.5% (insulin 5 units) to 28.6% (insulin 10 units) and were higher than rates reported in other studies.9

Monitoring after treatment

As described previously, hypoglycemia after insulin treatment appears to most often occur 2.5 to 3.5 hours after insulin administration even if dextrose was given concurrently.10-12,19  Some patients may even experience hypoglycemia 6 to 7.5 hours after insulin.10,19  Based on these findings, it is reasonable to monitor blood glucose hourly up to 4 to 6 hours after insulin administration.  This is even more important in patients unable to communicate that they are experiencing symptoms of hypoglycemia (e.g. dementia, mechanically ventilated, altered mental status).  Proactively ordering dextrose as needed for hypoglycemia could help ensure rapid treatment for patients noted to have hypoglycemia after insulin treatment (e.g. dextrose 50% 25 grams IV as needed for blood glucose less than 70 mg/dL).          

Patients without risk factors for hypoglycemia after insulin

If patients do not have any risk factors for hypoglycemia after insulin, no modification to traditional practice is needed. Some sources recommend holding dextrose if pre-treatment blood glucose is greater than 250 mg/dL.7 However, monitoring blood glucose every hour for 4 to 6 hours after insulin is still recommended regardless of the number of risk factors the patient has for hypoglycemia.  

Case resolution

Due to the patient’s low pretreatment glucose, lack of diabetes mellitus history, and poor renal function you decide to give insulin regular 5 units IV with dextrose 50% 50 grams IV once now and order point-of-care glucose checked hourly for 6 hours.  You also order dextrose 50% 25 grams IV as needed for blood glucose less than 70 mg/dL.

6 hours later the following vitals and labs are noted: BP 150/100, HR 85, potassium 5.5 mmol/L, glucose 99 mg/dL. The patient did not experience any hypoglycemic episodes during this period, although there was a glucose reading of 183 mg/dL one hour after insulin.  Repeat glucose readings ranged from 95 to 140 mg/dL, and none required intervention.  The patient is then admitted to the internal medicine service for dialysis.  Excellent work!

 

Take home points:

  • Insulin is an excellent option for management of hyperkalemia due to its rapid onset, moderate duration of action, and ability to be given IV.
  • Patients at increased risk for hypoglycemia during hyperkalemia treatment with insulin include those with low pretreatment glucose (e.g. less than 140 mg/dL), no history of diabetes mellitus, female gender, abnormal renal function (AKI or CKD), lower body weight (e.g. less than 60 kg), and those receiving higher amounts of insulin (e.g. 10 units or higher).
  • Strategies for decreasing risk of hypoglycemia can include giving less insulin (e.g. 5 units instead of 10 units), more dextrose (e.g. 50 grams instead of 25 grams), or infusing dextrose over a longer period (e.g. 4 hour infusion instead of a rapid bolus).
  • In most studies, giving less insulin (e.g. 5 units) does not appear to provide less potassium lowering effect when compared to higher doses (e.g. 10 units); however, one study found greater potassium reduction after 10 units versus 5 units in patients with baseline potassium 6 mmol/L or greater.
  • Because insulin can have a prolonged duration of action in those with kidney dysfunction, patients should be monitored for hypoglycemia for at least 4 to 6 hours after receiving insulin.

 

References/Further reading

  1. Kovesdy CP. Updates in hyperkalemia: Outcomes and therapeutic strategies. Rev Endocr Metab Disord. 2017. 18(1):41-47.
  2. Weisberg LS. Management of severe hyperkalemia. Crit Care Med. 2008;36(12):3246-51.
  3. Palmer BF. Managing hyperkalemia caused by inhibitors of the renin-angiotensin-aldosterone system. N Engl J Med. 2004;351:585-92.
  4. Mahoney BA, Smith WA, Lo DS, et al. Emergency interventions for hyperkalaemia. Cochrane Database Syst Rev. 2005(2):CD003235.
  5. Scott NL, Klein LR, Cales E, et al. Hypoglycemia as a complication of intravenous insulin to treat hyperkalemia in the emergency department. Am J Emerg Med. 2018; S0735-6757(18)30379-6.
  6. Harel Z, Kamel KS. Optimal Dose and Method of Administration of Intravenous Insulin in the Management of Emergency Hyperkalemia: A Systematic Review. PLoS One. 2016;11(5):e0154963.
  7. Weiner DI, Wingo CS. Hyperkalemia: a potential silent killer. J Am Soc Nephrol. 1998. 9: p. 1535-1543.
  8. Brown K, Setji TL, Hale SL, et al. Assessing the Impact of an Order Panel Utilizing Weight-Based Insulin and Standardized Monitoring of Blood Glucose for Patients With Hyperkalemia. Am J Med Qual;2018:1062860618764610.
  9. LaRue HA, Peksa GD, Shah SC. A Comparison of Insulin Doses for the Treatment of Hyperkalemia in Patients with Renal Insufficiency. Pharmacotherapy. 2017;37(12):1516-1522.
  10. Pierce DA, Russell G, Pirkle JL. Incidence of Hypoglycemia in Patients With Low eGFR Treated With Insulin and Dextrose for Hyperkalemia. Ann Pharmacother. 2015;49(12):1322-6.
  11. Schafers S, Naunheim R, Vijayan A, et al. Incidence of hypoglycemia following insulin-based acute stabilization of hyperkalemia treatment. Journal of Hospital Medicine. 2012;7(3):239-242.
  12. McNicholas BA, Pham MH, Carli K, et al. Treatment of Hyperkalemia With a Low-Dose Insulin Protocol Is Effective and Results in Reduced Hypoglycemia. Kidney Int Rep. 2018;3(2):328-336.
  13. Wheeler DT, Schafers SJ, Horwedel TA, et al. Weight-based insulin dosing for acute hyperkalemia results in less hypoglycemia. J Hosp Med. 2016;11(5):355-7.
  14. Li T, Vijayan A. Insulin for the treatment of hyperkalemia: a double-edged sword? Clin Kidney J. 2014;7:239-241.
  15. Sterns RH, Grieff M, Bernstein PL. Treatment of hyperkalemia: something old, something new. Kidney Int. 2016; 89(3):246-54.
  16. Allon M, Copkney C. Albuterol and insulin for treatment of hyperkalemia in hemodialysis patients. Kidney International. 1990;38:869-872.
  17. Apel J, Reutrakul S, Baldwin D. Hypoglycemia in the treatment of hyperkalemia with insulin in patients with end-stage renal disease. Clin Kidney J. 2014;7(3):248-50.
  18. Garcia J, Pintens M, Morris A, et al. Reduced versus conventional dose insulin for hyperkalemia treatment. Journal of Pharmacy Practice. 2018;XX(X):1-5.
  19. Coca A, Valencia AL, Bustamante J, et al., Hypoglycemia following intravenous insulin plus glucose for hyperkalemia in patients with impaired renal function. PLoS One. 2017;12(2):e0172961.

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