Reference: Jessen et al. Pharmacological interventions for the acute treatment of hyperkalaemia: A systematic review and meta-analysis. Resuscitation 2025

Date: August 6, 2025

Guest Skeptic: William Toon is a paramedic who, this past May achieved over 50 years of continuous EMS certification. His professional path has taken him from front-line paramedic to national presenter, expert witness, flight medic, EMS program director, and senior training executive with a doctorate in Higher Education.

Case: A 65-year-old patient presents to the emergency department (ED) with general weakness, mild abdominal cramping, and nausea over the past 12 hours. The patient has poorly controlled type 2 diabetes, heart failure with reduced ejection fraction, and chronic kidney disease stage 4 on hemodialysis. The patient missed their last dialysis appointment two days ago. The patient takes several medications for kidney disease and blood pressure, including a potassium-sparing diuretic. His ECG shows peaked T-waves. Stat chemistry reveals a serum potassium of 6.5 mmol/L. He is not yet oliguric and is hemodynamically stable. The team must initiate pharmacologic treatment immediately while preparing for possible escalation to dialysis.

Background: Hyperkalemia is a potentially life-threatening electrolyte abnormality frequently encountered in the ED. It’s common in patients with chronic kidney disease, diabetes, or those on renin-angiotensin-aldosterone system (RAAS) inhibitors. While treatments like insulin, beta-agonists, and calcium gluconate are well-known, the comparative efficacy and safety of pharmacologic agents used to rapidly reduce serum potassium remain uncertain.

Clinicians must balance rapid action with safety when choosing treatment for hyperkalemia. Understanding which pharmacologic interventions work best and how quickly they act is vital to optimizing care. Unfortunately, much of the existing data on hyperkalemia treatment is derived from small or methodologically limited trials.

Clinical Question: What is the effectiveness of pharmacological interventions in the acute treatment of hyperkalemia compared to standard care, placebo, or other interventions in adults?

Reference: Jessen et al. Pharmacological interventions for the acute treatment of hyperkalaemia: A systematic review and meta-analysis. Resuscitation 2025

  • Population: Adult patients with hyperkalemia (typically defined as serum potassium ≥5.0 mmol/L). Studies included varied populations such as those with CKD, dialysis patients, and acutely ill inpatients.
    • Exclusions: Patients under 18 and those receiving non-pharmacologic interventions (dialysis) were excluded.
  • Intervention: Any acute pharmacological intervention to mitigate the harmful effects of hyperkalemia or to lower potassium levels.
  • Comparison: Placebo, standard care, or head-to-head comparisons of other pharmacologic interventions.
  • Outcome:
    • Primary Outcome: Change in serum potassium from baseline at specific time points (1, 2, 4, and 6 hours).
    • Secondary Outcomes: Proportion of patients achieving normokalaemia, adverse events (hypoglycaemia), need for rescue therapy (dialysis), and all-cause mortality.
  • Type of study: Systematic review and meta-analysis

Authors’ Conclusions: “Evidence supports treatment with insulin in combination with glucose, inhaled or intravenous salbutamol, or the combination. No evidence supporting a clinical effect of calcium or bicarbonate for hyperkalaemia was identified.”

Quality Checklist for Therapeutic Systematic Reviews:

  1. The clinical question is sensible and answerable. Yes
  2. The search for studies was detailed and exhaustive. Yes
  3. The primary studies were of high methodological quality. No
  4. The assessment of studies were reproducible. Yes
  5. The outcomes were clinically relevant. Yes
  6. There was low statistical heterogeneity for the primary outcomes. No
  7. The treatment effect was large enough and precise enough to be clinically significant. Yes
  8. Who funded the trial? No financial support was provided for the study.
  9. Did the authors declare any conflicts of interest? No relevant conflicts of interest disclosed.

Results: Studies included adult patients with hyperkalemia from EDs, inpatient wards, and dialysis units. Ages ranged widely, with a predominance of patients with chronic kidney disease (CKD) and cardiovascular comorbidities.

Key Result: Sodium zirconium cyclosilicate and insulin-glucose regimens were most effective in lowering serum potassium within four hours, while other agents had limited short-term impact.

  • Primary Outcome: At four hours, insulin-glucose reduced potassium by an average of 0.8 mmol/L, and sodium zirconium cyclosilicate by 0.67 mmol/L. SPS (sodium polystyrene sulfonate) and patiromer showed smaller and delayed effects.
  • Secondary Outcomes: Hypoglycemia occurred in 17% of insulin-treated patients. Dialysis was needed in 6.2%. Mortality rates were not significantly different among treatment groups.

  1. Substantial Clinical and Methodological Heterogeneity: One of the most important limitations of this SRMA was the considerable heterogeneity in study design, patient populations, baseline potassium levels, and definitions of hyperkalemia. For example, some studies included only CKD patients, while others focused on acutely ill hospitalized individuals or dialysis-dependent populations. Furthermore, the timing of outcome measurements varied, making direct comparisons difficult. This heterogeneity undermines the consistency of pooled estimates and limits the applicability of the findings to specific ED populations.
  2. Risk of Bias in Primary Studies: Many of the included trials had methodological weaknesses, including poor allocation concealment, lack of masking, and incomplete outcome data. Several studies did not clearly describe their randomization procedures. These issues increase the risk of performance and detection bias, especially when subjective outcomes or clinician decisions like the need for dialysis. The GRADE framework used by the authors appropriately rated much of the evidence as “low” or “very low” certainty for key comparisons. These biases raise doubts about the internal validity of the SRMA conclusions and highlight the need for better-quality trials in this domain.
  3. Co-Interventions and Protocol Variability: A recurring issue was the use of multiple simultaneous treatments across arms, such as combining insulin, beta-agonists, and calcium gluconate in varying doses and sequences. This practice, while clinically realistic and pragmatic, muddled the attribution of treatment effect to any single agent. In real-world ED settings, polytherapy is common, but in research, this confounds the estimation of the independent effectiveness of each drug. Without stratified analyses that control for such co-interventions, it is difficult to know whether observed reductions in potassium were due to one agent or the combination of agents. This limits the SRMA’s ability to inform what might be the best therapeutic option.
  4. Sample Sizes and Few Events: Despite including over 100 studies, many of the comparisons within the SRMA were based on small individual trials with limited numbers of participants and few outcome events. As an example, data on adverse effects like hypoglycemia or need for dialysis were inconsistently reported and often underpowered to detect differences. The lack of data leads to wide confidence intervals and imprecise point estimates, which weaken the clinical significance and reproducibility of the findings.
  5. Lack of Focus on ED-Specific Contexts: Though the SRMA is highly relevant to emergency medicine, only a minority of included studies were conducted in ED settings. Many trials were hospital-based or conducted in specialized units like nephrology wards, and some included stable outpatient populations. This matters because ED patients often present with more acute symptoms, comorbidities, and a need for rapid intervention. Additionally, drug availability and workflow constraints in the ED differ from other settings. Therefore, the external validity of the findings to ED practice is limited, and the SRMA may not fully capture the nuances of time-sensitive decision-making in the ED environment.

Comment on Authors’ Conclusion Compared to SGEM Conclusion: We agree with the authors’ conclusions but would emphasize the limited certainty and highlight the need for better patient-oriented outcome data before changing practice broadly. 

SGEM Bottom Line: Insulin-glucose remains a reliable first-line agent for acute hyperkalemia management, but newer agents like sodium zirconium cyclosilicate show promise and may play a complementary role.

Case Resolution: You administer 10 units of IV insulin with an amp of D50 and initiate inhaled albuterol. You consult nephrology and start sodium zirconium cyclosilicate, which is available in your ED. Repeat potassium at four hours drops to 5.4 mmol/L. No dialysis is needed.

William Toon

Clinical Application: This SRMA reaffirms insulin-glucose as the first-line treatment for hyperkalemia in the ED. It also supports adding beta-agonists when needed, de-emphasizing bicarbonate and sodium polystyrene sulfonate in acute settings, and suggests newer agents like SZC for future integration into your ED’s hyperkalemia protocol.

However, it does not mean we should not use calcium gluconate or chloride in patients with hyperkalemia. These agents are not meant to lower potassium levels, and it would be inappropriate to have expected them to do so. The SRMA did not demonstrate a patient-oriented outcome (POO) of benefits. We should interpret the findings cautiously. The absence of evidence of benefit is not the same as evidence of no benefit. Therefore, calcium should not be abandoned for the acute treatment of hyperkalemia solely based on this SRMA.

What Do I Tell the Patient? We’re treating your high potassium levels quickly to protect your heart. We’ve given insulin and another medicine to bring the levels down safely. We’ll keep monitoring you closely over the next few hours.

Keener Kontest: Last week’s winner was David Michaelson. He knew that TENS units are thought to reduce pain through the gate control mechanism and the release of endorphins.

Listen to the SGEM podcast for this week’s question. If you know, then send an email to thesgem@gmail.com with “keener” in the subject line. The first correct answer will receive a shoutout on the next episode.

Remember to be skeptical of anything you learn, even if you heard it on the Skeptics’ Guide to Emergency Medicine.