What causes persistent hyperkalemia (elevated potassium levels) unresponsive to calcium gluconate, insulin, and dextrose?

From the Guidelines

Continued hyperkalemia unresponsive to standard treatments like calcium gluconate, insulin, and dextrose is most likely caused by underlying factors such as severe renal failure, ongoing tissue breakdown, acidosis, or medication effects, particularly from potassium-sparing diuretics, ACE inhibitors, ARBs, or NSAIDs, as highlighted in the expert consensus document on hyperkalaemia management 1. The most common causes of continued hyperkalemia include:

• Severe renal failure with minimal remaining kidney function
• Ongoing tissue breakdown (rhabdomyolysis, tumor lysis syndrome, or severe hemolysis)
• Acidosis
• Medication effects (particularly potassium-sparing diuretics, ACE inhibitors, ARBs, or NSAIDs)
• Adrenal insufficiency
• Pseudohyperkalemia from hemolyzed blood samples In cases of true refractory hyperkalemia, additional interventions should be considered, including:
• Sodium bicarbonate (50-100 mEq IV over 5-10 minutes) if acidosis is present
• Loop diuretics like furosemide (40-80 mg IV) if kidney function permits
• Additional doses of insulin/glucose
• Urgent hemodialysis for severe cases
• Potassium binders such as sodium polystyrene sulfonate (15-30g orally or rectally), patiromer (8.4-25.2g daily), or sodium zirconium cyclosilicate (10g three times daily initially) may be needed, as discussed in the clinical management of hyperkalemia study 1. Identifying and addressing the underlying cause is crucial for effective management, such as stopping potassium-containing medications, treating adrenal insufficiency with hydrocortisone, or addressing tissue breakdown. Persistent hyperkalemia despite these measures requires immediate nephrology consultation for possible dialysis, as severe hyperkalemia can lead to life-threatening cardiac arrhythmias.

From the Research

Causes of Continued Hyperkalemia

• Certain medical conditions, such as chronic kidney disease (CKD), diabetes mellitus, and others, can lead to hyperkalemia 2
• Inadequate treatment or insufficient doses of insulin, glucose, and calcium gluconate may contribute to continued hyperkalemia 3, 4
• The effectiveness of calcium gluconate in treating hyperkalemia may be limited, and it may only be effective in main rhythm disorders due to hyperkalemia 5
• The use of bicarbonate and calcium may not have a significant effect on potassium levels, and evidence does not support their clinical beneficial effect in treating hyperkalemia 6

Factors Affecting Treatment Response

• Hypoglycemia after insulin use is a frequent complication during hyperkalemia management, and certain factors such as low pretreatment glucose, no history of diabetes mellitus, female gender, abnormal renal function, and lower body weight may increase the risk of hypoglycemia 4
• The duration of action of insulin may exceed that of dextrose, and patients receiving insulin for hyperkalemia should be monitored for hypoglycemia hourly for at least 4-6 hours after administration 4

Alternative Treatment Options

• Insulin in combination with glucose, inhaled salbutamol, intravenous salbutamol dissolved in glucose, or a combination of these may be effective in reducing potassium levels 6
• New medications such as sodium polystyrene sulfonate (SPS), sodium zirconium cyclosilicate (SZC), and patiromer may also be useful in managing hyperkalemia 2, 3