Pharmacological Interventions for the Acute Treatment of Hyperkalemia: ALS 3403 TF SR

Conflict of Interest Declaration-

The authors report no conflicts of interest.

CoSTR Citation

Pharmacological Interventions for the Acute Treatment of Hyperkalemia: a systematic review. Granfeldt A, Holmberg M, Andersen LW, Ng KC, Jana Djakow on behalf of the Advanced Life Support and Pediatric Life Support Task Forces.

Methodological Preamble and Link to Published Systematic Review

The continuous evidence evaluation process for the production of Consensus on Science with Treatment Recommendations (CoSTR) started with a systematic review on pharmacological Interventions for the Acute Treatment of Hyperkalemia (PROSPERO CRD42023440553, registered on June 29th, 2023) with involvement of the Advanced Life Support Task Force and the Pediatric Lie Support Task Force groups.

Systematic Review

Webmaster to insert the Systematic Review citation and link to Pubmed using this format when it is available if published

PICOST

The PICOST (Population, Intervention, Comparator, Outcome, Study Designs and Timeframe)

Population: Adults and children with hyperkalemia in any setting (both with and without cardiac arrest)

Intervention: Any acute pharmacological intervention with the aim of mitigating the harmful effect of hyperkalemia or with the aim of lowering potassium levels

Comparators: No intervention, a different intervention (including a different dose), or placebo

Outcomes: Any clinical outcome, including change in potassium, use of dialysis, ECG changes/arrythmias, survival/survival with a favorable neurological outcome at hospital discharge/28 days/30 days/1 month, survival/survival with a favorable neurological outcome at later times (e.g., 90 days, 180 days, and 1 year), health-related quality of life, and cost-effectiveness.

Study Designs: We included original studies and trials including randomized trials, non-randomized trials, observational studies (cohort studies and case-control studies), and experimental animal studies. We also included original studies and trials without a control group including single-arm interventional trials, observational studies, and experimental animal studies. Reviews, abstracts only, and unpublished studies were not included. Case reports and case series (generally defined as < 10 non-consecutive patients) were not included. All years and all languages were included if there was an English abstract, or an English full-text article was available. Non-English articles were translated using online translation tools such as Google Translate.

Timeframe: No date restriction, and search was updated to September 9, 2024.

PROSPERO Registration CRD42023440553

Consensus on Science

The number of studies reporting patient-centered outcomes such as mortality were low, and no formal synthesis of the results for these outcomes could be performed. The consensus on science therefore relates to changes in potassium levels and ECG changes.

Insulin for hyperkalemia^a

We identified low-certainty evidence (downgraded for risk of bias) from 8 studies (parallel group studies, cross-over studies, one before and after study and one observational study) including 645 patients showing that administration of intravenous 8-12 IU insulin in combination with glucose results in a mean change in potassium of -0.7 mmol/L (95%CI: -0.9, -0.6).

Salbutamol for hyperkalemi^b

We identified very low-certainty evidence (downgraded for risk of bias) from 7 studies (parallel group study, cross-over studies and before and after studies) including 87 patients showing that administration of 10-20 mg inhaled salbutamol results in a mean change in potassium of -0.9 mmol/l (95%CI: -1.2, -0.7).

We identified very low-certainty evidence (downgraded for risk of bias and imprecision) from 6 studies (parallel group studies and one before and after study) including 100 patients showing that administration of 0.5 mg intravenous salbutamol dissolved in glucose/dextrose results in a mean change in potassium of -1.0 mmol/l (95%CI: -1.4, -0.6).

Insulin compared to salbutamol

We identified very low-certainty evidence (downgraded for risk of bias and imprecision) from 3 studies (parallel group studies) including 64 patients showing that administration of 0.5 mg intravenous salbutamol^c compared to 10 IU insulin results in a mean change in potassium of -0.3 mmol/l (95% CI: -0.5, 0.0)

Bicarbonate for hyperkalemia

We identified very low-certainty evidence (downgraded for risk of bias) from 5 studies (before and after studies, one parallel group study and one cross over study) including 44 patients showing that administration of intravenous 50-390 mmol of bicarbonate resulted in a -0.1 mmol/l (95%CI: -0.3, 0.1) change in potassium.

Combination of insulin and salbutamol for hyperkalemia

We identified very low-certainty evidence (downgraded for risk of bias and imprecision) from 3 studies (parallel group studies) including 25 patients showing that administration of 0.5 mg of intravenous salbutamol^c, 10 IU insulin, and 25 g or 40 g glucose results in a mean change in potassium of -1.2 mmol/l (95% CI: -1.5, -0.8).

We identified very low-certainty evidence (downgraded for risk of bias and imprecision) from 3 studies (parallel group studies) including 64 patients showing that administration of 10 IU of insulin intravenously and 0.5mg intravenous salbutamol compared to 0.5 mg salbutamol^c results in a mean change in potassium of -0.22 mmol/l (95% CI: -0.5, 0.1).

We identified very low-certainty evidence (downgraded for risk of bias and imprecision) from 3 studies (parallel group studies) including 50 patients showing that administration of 10 IU of insulin intravenously and 0.5 mg of intravenous salbutamol compared to 10 IU of insulin^c results in a mean change in potassium of -0.5 mmol/l (95% CI: -0.7, -0.2) based on 3 parallel group studies. (Very low certainty of evidence)

Calcium for ECG changes

We identified very-low-certainty evidence (downgraded for risk of bias and imprecision) from one retrospective observational study including 111 patients showing that administration of calcium did not show statistically significant improvements in any rhythm disorder.

Calcium and cardiac arrest

We identified very-low-certainty evidence (downgraded for risk of bias and imprecision) from one retrospective observational study including 109 adult patients showing that administration of calcium was associated with an absolute higher mortality.

Notes

1. As very few studies included a comparison group, we describe a study intervention or exposure group as a study e.g. if a single study includes 4 different interventions this will be described as 4 studies.
2. Salbutamol is the generic name used in many parts of the world. Albuterol is the name used primarily in the United States.
3. Insulin was given in combination with glucose/dextrose and salbutamol was dissolved in glucose/dextrose.
   

Treatment Recommendations

Non-cardiac arrest

For the treatment of acute hyperkalemia, we suggest intravenous insulin in combination with glucose or inhaled or intravenous beta2-agonists or the combination of insulin and glucose with inhaled or intravenous beta2-agonists (weak-recommendation, low certainty of evidence).

For the treatment of acute hyperkalemia, we suggest against the routine use of intravenous bicarbonate (weak-recommendation, low certainty of evidence).

For the treatment of acute hyperkalemia, there is insufficient evidence to recommend for or against the use of calcium for the treatment of hyperkalemia (weak-recommendation, very low certainty of evidence).

Cardiac arrest

For the treatment of cardiac arrest suspected to be caused by acute hyperkalemia, we suggest intravenous insulin in combination with glucose (weak-recommendation, very low certainty of evidence).

For the treatment of cardiac arrest suspected to be caused by acute hyperkalemia there is insufficient evidence to make a recommendation for or against the use of intravenous sodium bicarbonate (weak-recommendation, very low certainty of evidence).

For the treatment of cardiac arrest suspected to be caused by acute hyperkalemia there is insufficient evidence to recommend for or against the use of calcium (weak-recommendation, very low certainty of evidence).

Justification and Evidence to Decision Framework Highlights

This topic was prioritized by the ALS and PLS Task Force because calcium is a recommended treatment for ECG changes and arrhythmias caused by hyperkalemia. As the ILCOR CoSTR for Calcium During Cardiac Arrest, recommends against the routine administration of calcium for the treatment of cardiac arrest (CoSTR Calcium During Cardiac Arrest: ALS), the role of calcium as a treatment for cardiac arrest caused by hyperkalemia was questioned. Additionally, the topic has not been reviewed previously.

In making these updated recommendations, the Task Force considered the following:

Treatment recommendations were divided into non-cardiac arrest and cardiac arrest, as physiology differs between the two conditions, making the treatment effects likely different in each group. Additionally, all the evidence identified was in non-cardiac arrest patients, except for two observational studies. The treatment recommendations don’t differentiate between treatment out-of-hospital and in-hospital.

Non-cardiac arrest

Despite limited evidence for clinical outcomes, an initial treatment strategy aimed at acutely lowering extracellular potassium levels, in combination with more permanent potassium-lowering strategies seems logical.

The rationale for combining insulin and glucose with inhaled or intravenous beta2-agonists is based on a meta-analysis of 50 patients, which demonstrated a greater reduction in potassium levels when insulin and salbutamol were combined, compared with insulin alone.

Only a limited number of studies have compared different treatment strategies and doses, which is why recommendations on specific dosing and a ranking of specific interventions are not included.

The rationale for recommending against the routine use of sodium bicarbonate in non-arrest patients is based on a meta-analysis of five studies, which showed no reduction in potassium levels with sodium bicarbonate.

For calcium, there is insufficient evidence to support routine use. Only one study was identified that investigated the effects of calcium on ECG changes in patients without cardiac arrest (low certainty of evidence)¹. Despite the lack of evidence, the Task Force decided not to recommend against routine calcium use in patients without cardiac arrest, due to the absence of any signal of harm and the fact that current guidelines generally recommend treatment with calcium.

Cardiac arrest

For cardiac arrest caused by hyperkalemia the Task Force prioritized treatments focused on lowering potassium levels.

The recommendation for insulin in combination with glucose is based on indirect evidence from non-cardiac arrest patients. The reason for not recommending beta2-agonists during a cardiac arrest was based on the following considerations:

• Beta-adrenergic activation is already provided by the administration of epinephrine
• The theoretical potential for harmful effects from excessive beta-stimulation during cardiac arrest
• The difficulty of dose titration of intravenous beta2-agonists during a cardiac arrest
• The general recommendation against tracheal administration of drugs during cardiac arrest due to unpredictable drug delivery

As only two observational studies addressing the effect of calcium administration, one in pediatrics and one in adults, have been identified, treatment recommendations for patients with cardiac arrest are also based on indirect evidence from hyperkalemia patients without cardiac arrest. The Task Force acknowledges the general lack of evidence in patients with cardiac arrest due to hyperkalemia. Cardiac arrest due to suspected hyperkalemia refers to a cardiac arrest suspected to be caused by hyperkalemia, rather than a coincidental finding of elevated potassium levels during cardiac arrest, as potassium levels naturally increase during cardiac arrest.²

The recommendation of insufficient evidence to make a recommendation for or against the routine use of bicarbonate in cardiac arrest suspected to be caused by acute hyperkalemia was based on the lack of studies addressing this question and the general lack of effect of bicarbonate in cardiac arrest³(CoSTR Buffering agents ALS TF 483). The decision not to recommend against bicarbonate was based on the lack of evidence for harm in the general cardiac arrest population.

The recommendation of insufficient evidence to recommend for or against the use of calcium in cardiac arrest suspected to be caused by acute hyperkalemia was based on a number of considerations.

• Only anecdotal evidence of a protective effect of calcium during hyperkalemia.⁴
• Current guidelines recommend the use of calcium for the treatment of hyperkalemia
• Two observational studies demonstrated a higher mortality in patients receiving calcium (Critical risk of Bias).^5,6
• The potential harm of routine administration of calcium during out-of-hospital cardiac arrest.⁷
• The potential harm of calcium administration in out-of-hospital cardiac arrest patients with pulseless electrical activity and electrocardiographic characteristics potentially associated with hyperkalemia⁸.
• The general recommendation against routine use of calcium during cardiac arrest (CoSTR Calcium During Cardiac Arrest: ALS).⁹

The Task Force acknowledges that not recommending calcium administration in cardiac arrest suspected to be caused by acute hyperkalemia challenges current guidelines. This was taken into account during the drafting of the recommendation. The Task Force is acquainted with case reports, reporting a potential beneficial effect of calcium, but regarded the quality of these case reports insufficient to be included in the treatment recommendation. Furthermore, the Task Force recognizes that distinguishing between non-cardiac arrest and cardiac arrest can be clinically challenging, especially for patients in the peri-arrest phase. Additionally, the evidence for harm of calcium is based on out-of-hospital cardiac arrest, whereas the recommendation for in-hospital cardiac arrest patients is based on indirect evidence

Knowledge Gaps

• The effect of different treatments of hyperkalemia on patient-centered outcomes such as mortality
• How calcium affects clinical outcome when used for hyperkalemia
• The optimal doses or combinations of drugs (e.g. insulin, glucose and salbutamol) used for the treatment of hyperkalemia
• The optimal treatment of hyperkalemia during cardiac arrest
• Time to effect interventions applied during cardiac arrest.
• The optimal ratio between insulin and glucose for treatment of suspected hyperkalemia during cardiac arrest

ETD summary tables:

ALS 3403 evidence to decision table Insulin and salbutamol

ALS 3403 evidence to decision table Calcium

ALS 3403 evidence to decision table bicarbonate

References

1. Celebi Yamanoglu NG, Yamanoglu A. The effect of calcium gluconate in the treatment of hyperkalemia. Turk J Emerg Med. 2022;22:75-82. doi: 10.4103/2452-2473.342812

2. Martin GB, Nowak RM, Cisek JE, Carden DL, Tomlanovich MC. Hyperkalemia during human cardiopulmonary resuscitation: incidence and ramifications. J Emerg Med. 1989;7:109-113. doi: 10.1016/0736-4679(89)90253-9

3. Xu T, Wu C, Shen Q, Xu H, Huang H. The effect of sodium bicarbonate on OHCA patients: A systematic review and meta-analysis of RCT and propensity score studies. The American Journal of Emergency Medicine. 2023;73:40-46. doi: https://doi.org/10.1016/j.ajem.2023.08.020

4. Chamberlain MJ. Emergency Treatment of Hyperkalaemia. Lancet. 1964;1:464-467. doi: 10.1016/s0140-6736(64)90797-4

5. Cashen K, Sutton RM, Reeder RW, Ahmed T, Bell MJ, Berg RA, Burns C, Carcillo JA, Carpenter TC, Michael Dean J, et al. Calcium use during paediatric in-hospital cardiac arrest is associated with worse outcomes. Resuscitation. 2023;185:109673. doi: 10.1016/j.resuscitation.2022.109673

6. Wang C-H, Huang C-H, Chang W-T, Tsai M-S, Yu P-H, Wu Y-W, Hung K-Y, Chen W-J. The effects of calcium and sodium bicarbonate on severe hyperkalaemia during cardiopulmonary resuscitation: A retrospective cohort study of adult in-hospital cardiac arrest. Resuscitation. 2016;98:105-111. doi: 10.1016/j.resuscitation.2015.09.384

7. Vallentin MF, Granfeldt A, Meilandt C, Povlsen AL, Sindberg B, Holmberg MJ, Iversen BN, Mærkedahl R, Mortensen LR, Nyboe R, et al. Effect of Intravenous or Intraosseous Calcium vs Saline on Return of Spontaneous Circulation in Adults With Out-of-Hospital Cardiac Arrest: A Randomized Clinical Trial. JAMA. 2021. doi: 10.1001/jama.2021.20929

8. Vallentin MF, Povlsen AL, Granfeldt A, Terkelsen CJ, Andersen LW. Effect of calcium in patients with pulseless electrical activity and electrocardiographic characteristics potentially associated with hyperkalemia and ischemia-sub-study of the Calcium for Out-of-hospital Cardiac Arrest (COCA) trial. Resuscitation. 2022;181:150-157. doi: 10.1016/j.resuscitation.2022.11.006

9. Hsu CH, Couper K, Nix T, Drennan I, Reynolds J, Kleinman M, Berg KM. Calcium during cardiac arrest: A systematic review. Resusc Plus. 2023;14:100379. doi: 10.1016/j.resplu.2023.100379