Conflict of Interest Declaration
The ILCOR Continuous Evidence Evaluation process is guided by a rigorous ILCOR Conflict of Interest policy. The following Task Force members and other authors were recused from the discussion as they declared a conflict of interest: none applicable
The following Task Force members and other authors declared an intellectual conflict of interest and this was acknowledged and managed by the Task Force Chairs and Conflict of Interest committees: none applicable
CoSTR Citation
Djakow J, Ng KC, Raymond T, Atkins D, Acworth J, Scholefield B. on behalf of the International Liaison Committee on Resuscitation Pediatric Life Support Task Force. Pharmacological Interventions for the Treatment of Hyperkalaemia in Paediatric Patients with Cardiac arrest – Paediatric Consensus on Science and Treatment Recommendations [Internet] Brussels, Belgium: International Liaison Committee on Resuscitation (ILCOR) Paediatric Advanced Life Support Task Force, 2024 November xxxxx. Available from: http://ilcor.org
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 nodal systematic review of Jessen MK, 2024, PROSPERO CRD42023440553. Evidence for adult and pediatric literature was sought and considered by the Advanced Life Support Task Force and the Pediatric Task Force groups respectively. The above mentioned systematic review considered literature for patients both in cardiac arrest and also all pharamacological interventions for acute hyperkalaemia. Non-pharmacological interventions (e.g. dialysis or hyperventilation in ventilated patients) were not studied in this systematic review. Based on the discussion in the PLS TF the Treatment Recommendations will be issued by the PLS TF only for the situation of cardiac arrest associated with or caused by hyperkalaemia and not for acute hyperkalemia. Therefore, only limited data were taken into account when formulating the Treatment Recommendations as most of the studies identified were considering the patients in the peri-arrest acute hyperkalaemia.
Systematic Review
Jessen MK, Andersen LW, Holmberg MJ, Djakow J, Chong KC, Stankovic N, Staer C, Vammen L, Petersen AH, Munch Johannesen C, Eggertsen MA, Mortensen SO, Hoybe M, Norholt C, Valentin MF, Granfeld A. for the ILCOR Advanced and Paediatric Life Support Task Forces. Submitted to Resuscitation. In 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 (≥18 years) and children (<18 years) with hyperkalemia in any setting (both with or without cardiac arrest)
Intervention: Acute pharmacological intervention with the aim of mitigating the harmful effect of hyperkalemia or with the aim of lowering potassium levels
Comparators: Compared to either no intervention, a different intervention (including a different dose), or placebo
Outcomes: Outcomes included, but were not limited to, 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. For potassium levels, we have reported the pre-intervention potassium level and the post-intervention value closest to 60 min. if possible. In the meta-analyses, we only included potassium values measured within 2 hours of the intervention.
Study Designs: Original studies and trials including randomized controlled trials (RCTs) and non-randomized studies (non-randomized controlled trials, cohort studies and case-control studies), ale also original studies and trials without a control group including single-arm interventional trials, and experimental animal studies were eligible for inclusion.
Timeframe: All years and all languages were included as long as there was an English abstract; unpublished studies (e.g., conference abstracts, trial protocols) were excluded. Literature search was performed on 29th of June 2024 and again on 9th of September.
PROSPERO Registration on June 29th, CRD42023440553
Bias was assessed per outcome using version 2 of the Cochrane RoB tool for randomized trials and cross-over studies, the ROBINS-I tool for observational studies and a modified SYRCLE’s RoB tool for animal studies.
Consensus on Science
The results bellow from the original systematic review concerning the paediatric patients. For all the results including the results in adults, see the original systematic review.
- For the outcome of post-intervention potassium levels:
- a. Insulin and dextrose/glucose - five neonatal studies tested insulin and glucose in weigh-based approach.[1-5] Two studies reported decrease while two reported no change and the studies were not eligible for the meta-analyses due to differences in methodology.
- b. Intravenous beta2-agonists (4-5 ug/kg) compared to no treatment for the treatment of acute hyperkalemia in neonatal or paediatric population (53 patients): meta-analysis of 4 studies – mean decrease in potassium was 1.0 mmol lower (1.5 lower to 0.6 lower 95% CI) (follow-up range 60 mins).[6-9] One paediatric study investigated combination therapy of intravenous beta-agonists and insulin with glucose.[10]
- c. Inhaled beta2-agonists (400 ug salbutamol as inhalation) compared to no treatment for the treatment of acute hyperkalaemia in neonatal population (51 patients in total): meta-analysis of 3 studies – mean decrease in potassium was 0.9 mmol lower (1.2 lower to 0.5 lower 95%CI) (follow up range 120 mins).[2, 5, 11]
- d. Bicarbonate – no study in paediatric population. In adults no change in potassium levels after administration of 50-390 mmol was found in the meta-analysis of 5 adult studies.
- Other outcomes – are reported in the original systematic review. Most frequently reported outcomes were changes in heart rate, blood glucose or hypoglycemic events, as well as ECG changes. Treatment with insulin resulted frequently in decrease in glucose levels, while beta-2 agonists in general caused an increase in heart rate. Seven (adult) studies reported disappearance of the ECG changes concomitant with the reduction of potassium levels.
- Outcomes after cardiac arrest studies: Two studies investigated the treatment of hyperkalaemia during cardiac arrest. Both studies investigated the use of calcium; one in adult patients and one in neonatal and paediatric patients. The adult study found a lower unadjusted rate of ROSC with the administration of calcium, sodium bicarbonate or the combination.[12] In the paediatric study, calcium was frequently used during cardiac arrest and was associated with worse outcomes.[13] Both studies were assessed as high risk of bias.
Based on the current systematic review, there is evidence that treatment with insulin and glucose or inhaled or intravenous beta2-agonists causes an acute reduction in potassium levels. For all interventions, the reduction in potassium was consistently in the range of 0.7 to 1.2 mmol/l. Whether this acute decrease in potassium translates to an improvement in clinical outcomes is unclear based on the current evidence. Only a limited number of studies has compared different treatment strategies, adding little help to clinicians in prioritizing interventions. In one meta-analysis including three studies, treatment with intravenous salbutamol and intravenous salbutamol in combination with 10 IU of insulin was more effective in lowering potassium when compared to 10 IU of insulin alone (evidence in adult patients). This suggests prioritizing treatment with intravenous salbutamol either alone or in combination with insulin. However, the certainty of evidence was very low, and future studies are needed to investigate different treatment strategies. Although the certainty of evidence was from very-low to low, the treatment effect in paediatric and neonatal studies is similar to studies in adults. The choice of treatment must consider potential side effects in the neonatal and pediatric population such as tachycardia and hypo- and hyperglycaemia. In premature neonates, changes in glucose levels (both hypo-and hyper-glycaemia) have previously been associated with increased risk of intraventricular haemorrhage. Therefore, inhaled or intravenous salbutamol might be a safer first-choice treatment than insulin and glucose in this population. Hyperkalaemia is less prevalent in older infants and children than in premature newborns, neonates and adults. There is a need for high-quality studies to address questions in pediatric populations at high risk of hyperkalemia (e.g., children with acute or chronic renal failure, tumor lysis syndrome), particularly regarding the preferred treatment, appropriate dosing, and timing of interventions.
The rationale for administering calcium during cardiac arrest caused by hyperkalemia is based on the presumed ability to prevent arrhythmias. Although calcium is widely recognized and used for this indication, the current review did not find any clinical evidence to support this. One study in patients without cardiac arrest tested the effect of intravenous calcium gluconate on ECG pathology. The study was considered to have critical risk of bias and found no important effect of calcium gluconate on ECG changes.
One cardiac arrest animal study tested the effect of bicarbonate and calcium. The study demonstrated increased survival with bicarbonate but no effect of calcium chloride. This challenges the recommendation to use calcium during cardiac arrest in patients with suspected hyperkalaemia, especially in light of potential harm of routine calcium administration in patients with out-hospital cardiac arrest. For bicarbonate, studies included in the meta-analysis in this systematic review did not find any potassium lowering effect in non-cardiac arrest adult patients with hyperkalaemia and there were no studies identified in pediatric patients.
Treatment Recommendations
For pediatric patients in cardiac arrest associated with hyperkalaemia, there is insufficient evidence to suggest for or against the use of calcium
For pediatric patients in cardiac arrest associated with hyperkalaemia, there is insufficient evidence to make a treatment recommendation for or against the use of sodium bicarbonate
Good practice statement:
We suggest using intravenous salbutamol or insulin with glucose or combination of both to lower the potassium levels in paediatric patients with cardiac arrest associated with hyperkalaemia with the aim to lower the potassium levels during the concurrently ongoing high-quality resuscitation efforts.
Justification and Evidence to Decision Framework Highlights
After the discussion, the PLS TF decided not to make any statements about the treatment of the pediatric patients not in cardiac arrest, although some evidence for this group of patients exists and is summarized above.
Use of bicarbonate: There is no existing evidence in paediatric patients looking at the potassium lowering effect in paediatric patients. In adult patients bicarbonate did not lead to lowering of potassium levels, neither to improved outcomes. Therefore, the ALS TF decided to suggest against the use of sodium bicarbonate in patients with acute hyperkalemia. However, as no studies were identified for the population in cardiac arrest, they also decided to not make a treatment recommendation about its use in cardiac arrest patients.
Use of the calcium: The very low certainty evidence suggests association of calcium with worse outcomes but there are critical risks of bias and high uncertainty of associated effects mainly due to resuscitation time (duration of resuscitative efforts) bias. However, even in patients without cardiac arrest, any evidence of calcium having effect on ECG pathology was not shown in the systematic review performed. Therefore, the rationale behind the use of calcium for the assumed myocardial protecting effect is being questioned.
Use of salbutamol and insulin with glucose: The effects on potassium levels in the cardiac arrest patients were not studied so it is not clear whether the potassium-lowering effect would be present also in cardiac arrest patients. However, the Task Force agreed that the potential benefits of these pharmacological interventions outweigh potential risks in the cardiac arrest patients and their use is therefore justified.
Despite limited evidence for clinical outcomes, an initial treatment strategy aiming at acutely lowering extracellular potassium levels simultaneously with more permanent potassium lowering strategies seems logical when hyperkalaemia is a suspected reversible cause of cardiac arrest. Only beta2-agonists were proven to have potassium lowering effect in paediatric patients by meta-analysis in the systematic review. Inhalation administration is generally not recommended in cardiac arrest. Insulin with glucose for the potassium lowering effect was studied in the pediatric patients but the high heterogeneity of the studies precluded the meta-analysis. PLS TF agreed that they would use insulin with glucose in case of suspected hyperkalemia despite the lack of high quality studies in pediatric patients. The insulin with glucose was used in this indication and it has proven potassium lowering effect in adult population.
Knowledge Gaps
Further examination of potential strategies for reduction of potassium including the combination strategies need to be studied to better understand the best possible treatment regimes for paediatric patients in cardiac arrest associated with hyperkalaemia.
It is also not clear whether any decrease in potassium levels (in both intra-arrest and peri-arrest patients) translates into meaningful patient-centred outcomes such as survival to discharge or survival with good neurological outcomes.
The role of calcium as a protection of myocardial cells from hyperkalaemia is recently questioned and the published studies do not support its presumed usefulness. More studies are needed to better understand this topic.
There is a need for high-quality studies to address questions in pediatric populations at high risk of hyperkalemia (e.g., children with acute or chronic renal failure, tumor lysis syndrome or others), particularly regarding the preferred treatment, appropriate dosing, and timing of interventions.
EtD Tables: PLS 4160 17 Hyperkalaemia Et D1 Calcium vs no calcium, PLS 4160 17 Hyperkalaemia Et D2 Bicarbonate vs no bicarbonate docx, PLS 4160 17 Hyperkalaemia Et D3 Insulin with glucose or salbutamol vs no insulin with glucose no salbutamol
References
1. Lui, K., et al., Treatment with hypertonic dextrose and insulin in severe hyperkalaemia of immature infants. Acta Paediatr, 1992. 81(3): p. 213-6.
2. Mu, S.C., et al., Salbutamol in the treatment of neonatal hyperkalemia. Clinical Neonatology, 1997(4): p. 9-12.
3. Hu, P.S., et al., Glucose and insulin infusion versus kayexalate for the early treatment of non-oliguric hyperkalemia in very-low-birth-weight infants. Acta Paediatr Taiwan, 1999. 40(5): p. 314-8.
4. Hung, K.C., et al., Glucose-insulin infusion for the early treatment of non-oliguric hyperkalemia in extremely-low-birth-weight infants. Acta Paediatr Taiwan, 2001. 42(5): p. 282-6.
5. Saw, H.P., et al., Nebulized salbutamol diminish the blood glucose fluctuation in the treatment of non-oliguric hyperkalemia of premature infants. J Chin Med Assoc, 2019. 82(1): p. 55-59.
6. Murdoch, I.A., R. Dos Anjos, and G.B. Haycock, Treatment of hyperkalaemia with intravenous salbutamol. Arch Dis Child, 1991. 66(4): p. 527-8.
7. McClure, R.J., V.K. Prasad, and J.T. Brocklebank, Treatment of hyperkalaemia using intravenous and nebulised salbutamol. Arch Dis Child, 1994. 70(2): p. 126-8.
8. Noyan, A., et al., Treatment of hyperkalemia in children with intravenous salbutamol. Acta Paediatr Jpn, 1995. 37(3): p. 355-7.
9. Kemper, M.J., et al., Effective treatment of acute hyperkalaemia in childhood by short-term infusion of salbutamol. Eur J Pediatr, 1996. 155(6): p. 495-7.
10. Arias-Reyes, J.A., et al., [Correction of hyperkalemia with intravenous salbutamol in children with chronic renal insufficiency]. Bol Med Hosp Infant Mex, 1989. 46(9): p. 603-6.
11. Singh, B.S., et al., Efficacy of albuterol inhalation in treatment of hyperkalemia in premature neonates. J Pediatr, 2002. 141(1): p. 16-20.
12. Wang, C.H., et al., 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: p. 105-11.
13. Cashen, K., et al., Calcium use during paediatric in-hospital cardiac arrest is associated with worse outcomes. Resuscitation, 2023. 185: p. 109673.