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

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: Dr. Grunau was a contributing author on the Kawano 2017 manuscript.

CoSTR Citation

Lavonas EJ, Grunau B, Drennan IA, on behalf of the International Liaison Committee on Resuscitation (insert) Life Support Task Force(s). Buffering Agents for Cardiac Arrest in Adults: Consensus on Science with Treatment Recommendations [Internet] Brussels, Belgium: International Liaison Committee on Resuscitation (ILCOR) Advanced Life Support Task Force, 2024 Nov 1. Available from: http://ilcor.org

Methodological Preamble and Link to Published Systematic Review

In the course of developing this Consensus on Science with Treatment Recommendations (CoSTR) statement, the Advanced Life Support Task Force identified a recently published systematic review and meta-analysis on the topic of sodium bicarbonate / buffering agent administration for out-of-hospital cardiac arrest (OHCA) which included randomized controlled trials and propensity score-matched cohort studies (Xu 2023 40),¹ The systematic review was registered in PROSPERO (CRD42023407579). This systematic review was assessed using the AMSTAR 2 appraisal tool (Shea 2017 358; PMID 28935701),² using the on-line checklist (https://amstar.ca/Amstar_Checklist.php). The published systematic review was assessed to be of high quality. Two deficiencies were identified and corrected: Drs. Xu and Huang provided the search strategies used in their systematic review, and the ILCOR authors searched clinical trials registries.

The ALS Task Force decided to proceed with adolopment of the systematic review of Xu et al., using the ILCOR adolopment process (available at https://ilcor.org/documents/continuous-evidence-evaluation-guidance-and-templates). The systematic review identified three clinical trials (Dybvik 1995 89, Vukmir 2006 229, and Ahn 2018 2295)^3-5 and three propensity score-matched observational studies (Kawano 2017 63, Chen 2018 1998, Niederberger 2023 109641)^6-8 which form the basis for this CoSTR. After verifying the data extraction, we used the calculations contained in the Xu meta-analysis as the basis of this CoSTR. In keeping with the methodology used by Xu and colleagues, we pooled the short-term endpoints of ROSC, survival to emergency department admission, and survival to hospital admission.

One additional clinical trial (Weaver 1990 2027)⁹ was identified by Xu et al which compared patients with OHCA who were treated with epinephrine to those receiving lidocaine. Sodium bicarbonate was administered to patients in a historical control group, which was compared with both experimental groups. This study therefore has a retrospective observational design with regard to bicarbonate administration, did not compare bicarbonate to similar treatment without bicarbonate, and was therefore excluded from the systematic review.

An updated literature search of PubMed was performed on 27 September 2024 which identified no additional articles published subsequent to the search date of the Xu systematic review, and a search of the clinical trials registries clinicaltrials.gov and ICTRC conducted on 27 September 2024 identified no additional completed clinical trials. The updated literature search identified an observational study analyzing outcomes associated with bicarbonate use during in-hospital cardiac arrest (IHCA).(Holmberg 2023 109958)¹⁰ This study used an instrument-variable analysis to reduce resuscitation-time bias, but could not measure time to bicarbonate administration. Although the study was not included in this review because it does not meet our prespecified inclusion criteria, the results were aligned with those of the three propensity score-matched studies.

Xu and colleagues reported results in the form of Mantel-Haenzel odds ratios using a fixed effects meta-analytic model. The Task Force re-calculated effect estimates using GRADEPro GDT and Cochrane RevMan to calculate absolute risk differences and odds ratios, also using a Mantel-Haenzel fixed effects model. Risk of bias was also re-assessed for the included clinical trials using GRADEPro GDT. These tables are available as supplemental materials.ALS 3205 Evidence Profile Table Buffering Agents 2024 10 30;

The systematic review on which this CoSTR is based studied only OHCA. To review data pertaining to buffering agent use in IHCA, we conducted a focused literature review, searching PubMed (from inception through 27 Sep 2024), clinical trials registries, and the findings of published systematic reviews that included IHCA (Wu 2020 856, Wongtanasarasin 2021 24).^11,12 In this search, we did not identify any clinical trials or propensity score-matched observational studies conducted on buffering agent use for adults the IHCA setting. One adult IHCA observational study (Wang 2021 12380)¹³ was identified which used the dichotomous variable of sodium bicarbonate ≥ 20 min in logistic regression analysis; this study also found no benefit associated with sodium bicarbonate administration. We did not include this study because it fell outside our prespecified inclusion criteria for study design. A propensity score-matched study in pediatric IHCA, (Cashen 2022 784)¹⁴ which accounted for resuscitation duration but not time of bicarbonate administration, found sodium bicarbonate administration was associated with decreased survival to hospital discharge and decreased survival to hospital discharge with favorable neurologic outcome. Because of double indirectness (different population, different setting), we did not combine these data with the other propensity score-matched observational studies; a sensitivity analysis doing so found little change in the results.

Systematic Review

This CoSTR is based on adolopment of the following systematic review:

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. Am J Emerg Med 2023; 73:40-46. PMID 37611525. DOI: https://doi.org/10.1016/j.ajem.2023.08.020

PICOST

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

ALS 483: Buffering Agents

Population: Adults with cardiac arrest in any setting (in-hospital or out-of-hospital)

Intervention: The use of buffering agents alone or in combination with other drugs.

Comparators: Standard resuscitation

Outcomes: Return of spontaneous circulation (important); survival to hospital admission (important); survival at 30-days, hospital discharge, or any subsequent time point (critical), survival with favorable neurological outcomes at 30-days, hospital discharge, or any subsequent time point (critical).

Study Designs: Randomized clinical trials and propensity score-matched observational studies

Timeframe: All years.

Risk of Bias: Risk of bias assessment was performed by Xu and colleagues using the Cochrane Collaboration tool for RCTs and the Newcastle Ottawa Scale for cohort studies. The Cochrane Risk of Bias assessment was repeated by the ILCOR authors. The clinical trials were judged to have serious limitations in confidence of the estimates of effect due to issues with imprecision (Ahn 2018 2295)³ (N = 50) and indirectness (Dybvik 1995 89 and Vukmir 2006 156)^4,5 (trials conducted prior to major changes in resuscitation that were implemented circa 2010).

The propensity-matched cohort studies were all determined to have critical risk of bias due to failure to account for duration of resuscitation or timing of buffering agent administration (resuscitation-time bias).(Andersen 2018 79)¹⁵

Consensus on Science

For the critical outcome of 1-month survival with favorable neurologic outcome (FNO) (Cerebral Performance Category 1 or 2 at the time of hospital discharge or later), we identified low certainty evidence (downgraded for imprecision and blinding of outcome assessment) from one RCT enrolling 50 patients (Ahn 2018 2295)³ (Risk Difference: -0.4; 95% confidence interval (CI): -0.14 to 0.06) (4 fewer (CI: 14 fewer to 6 more) patients surviving with FNO at 1 month per 100[ID1] patients receiving buffering agent (bicarbonate)). No patient in either group (0/25, 0/25) survived with FNO at 6 months (Risk difference: 0.00; CI: -0.07 to 0.07) (0 fewer; CI: 7 fewer to 7 more surviving with FNO at 6 months per 100 patients randomized to buffering agent (bicarbonate)).

For the critical outcome survival to hospital discharge, we identified moderate certainty evidence (downgraded for indirectness) from two RCTs enrolling 552 subjects (Ahn 2018 2295, Dybvik 1995 89)^3,5, which showed no benefit from the administration of buffering agents when compared with standard care alone (Risk Difference: -0.04 (CI: -0.09 – 0.01) (4 fewer (CI: 9 fewer to 2 more) survivors per 100 patients receiving buffering agent (bicarbonate or Tribonat). This is supported by very low certainty evidence (downgraded due to critical risk of bias) from two propensity-matched cohort studies enrolling 15,228 subjects (Kawano 2017 63, Niederberger 2023 109641),^7,8 which showed no benefit from buffering agent administration compared with standard care alone (Risk difference: 0.00; CI: -0.02 – 0.03) (0 fewer (CI: 2 fewer – 3 more) patients with long-term survival per 100 patients receiving buffering agents).

For the important outcome of short-term survival (combining ROSC, survival to emergency department arrival, or survival to hospital admission), we identified moderate certainty evidence (downgraded for indirectness) from three RCTs enrolling 1344 subjects (Ahn 2018 2295, Dybvik 1995 89, Vukmir 2006 156),^3-5 which showed no benefit from the administration of buffering agents when compared with standard care (Risk Difference: -0.01; CI: -0.05 to 0.04 (1 fewer (CI: 5 fewer to 4 more) patients with short term survival per 100 receiving buffering agents (bicarbonate or Tribonat). This is supported by the very low certainty evidence (downgraded due to critical risk of bias) from three propensity score-matched observational studies enrolling 10,035 subjects (Chen 2018 1998, Kawano 2017 63, Niederberger 2023 109641)^6-8 which showed no benefit from the administration of buffering agents, compared with standard care alone (RD: 1.05; CI: 0.98 – 1.13) (1 more (CI: 0 fewer to 2 more) patients with short-term survival per 100 receiving buffering agents).

Treatment Recommendations

We suggest against the administration of buffering agents such as sodium bicarbonate in the treatment of out-of-hospital cardiac arrest, unless a special circumstance for its use is present (weak recommendation, low certainty of evidence).

We suggest against the administration of buffering agents such as sodium bicarbonate in the treatment of in-hospital cardiac arrest, unless a special circumstance for its use is present (weak recommendation, very low certainty of evidence).

Justification and Evidence to Decision Framework Highlights

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

• This CoSTR does not address the use of buffering agents / sodium bicarbonate in special circumstances, such as for the treatment of hyperkalemia (covered by PICO ALS 456) or sodium channel blocker / tricyclic antidepressant poisoning (ALS 429).

• This topic was prioritized by the ALS Task Force based data showing frequent use of buffering agents (particularly sodium bicarbonate) in resuscitation in both the IHCA and OHCA settings (Bar-Joseph 2002 47; Bar-Joseph 2005 6; Moskowitz 2019 194),^16-18 despite current and previous guidelines from the ILCOR (Morrison 2010 S345)¹⁹ and major resuscitation organizations (Panchal 2020 S366 PMID 33081529; Link 2015 S444 PMID 26472995, Neumar 2010 S729, PMID 20956224, Soar 2021 115 PMID 33773825, Soar 2015 100 PMID 26477701, Deakin 2010 P1305 PMID 20956049)^20-25 that recommend against routine administration of buffering agents in cardiac arrest.

• In making this recommendation we placed a higher value on not allocating resources to an ineffective intervention, which may divert rescuer time from more beneficial interventions.

• The Task Force cautions against drawing conclusions from observational studies of this topic, even with propensity score matching, if the study does not account for resuscitation-time bias. Given the tendency of resuscitation providers to administer sodium bicarbonate late in resuscitation as a last resort medication,(Bar-Joseph 2002 47)¹⁷ any observational study that does not account for resuscitation-time bias is considered to have critical risk of bias.

• Given the availability of comparative data from multiple RCTs and propensity-matched observational studies, we did not include observational studies without propensity matching.

EtD: ALS 3205 Et D table Buffering Agents 2024 10 30

Knowledge Gaps

• All identified studies had significant risk of bias and/or were conducted prior to the major changes in standard resuscitation that happened circa 2010.

• To our knowledge, no recent systematic review and no RCTs have been published about buffering agent therapy for IHCA, nor about pediatric OHCA or IHCA. A clinical trial examining buffering agents for IHCA (NCT05564130) is currently enrolling patients.

• The identified studies did not attempt to identify sub-populations, such as people with prolonged cardiac arrest (Wang 2021 12380)¹³, who might have different outcomes from buffering agent administration than cardiac arrest patients in general.

References

1. 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. Am J Emerg Med. 2023;73:40-46. doi: 10.1016/j.ajem.2023.08.020

2. Shea BJ, Reeves BC, Wells G, Thuku M, Hamel C, Moran J, Moher D, Tugwell P, Welch V, Kristjansson E, Henry DA. AMSTAR 2: a critical appraisal tool for systematic reviews that include randomised or non-randomised studies of healthcare interventions, or both. BMJ. 2017;358:j4008. doi: 10.1136/bmj.j4008

3. Ahn S, Kim YJ, Sohn CH, Seo DW, Lim KS, Donnino MW, Kim WY. Sodium bicarbonate on severe metabolic acidosis during prolonged cardiopulmonary resuscitation: a double-blind, randomized, placebo-controlled pilot study. J Thorac Dis. 2018;10:2295-2302. doi: 10.21037/jtd.2018.03.124

4. Vukmir RB, Katz L, Sodium Bicarbonate Study G. Sodium bicarbonate improves outcome in prolonged prehospital cardiac arrest. Am J Emerg Med. 2006;24:156-161. doi: 10.1016/j.ajem.2005.08.016

5. Dybvik T, Strand T, Steen PA. Buffer therapy during out-of-hospital cardiopulmonary resuscitation. Resuscitation. 1995;29:89-95. doi: 10.1016/0300-9572(95)00850-s

6. Chen YC, Hung MS, Liu CY, Hsiao CT, Yang YH. The association of emergency department administration of sodium bicarbonate after out of hospital cardiac arrest with outcomes. Am J Emerg Med. 2018;36:1998-2004. doi: 10.1016/j.ajem.2018.03.010

7. Niederberger SM, Crowe RP, Salcido DD, Menegazzi JJ. Sodium bicarbonate administration is associated with improved survival in asystolic and PEA Out-of-Hospital cardiac arrest. Resuscitation. 2023;182:109641. doi: 10.1016/j.resuscitation.2022.11.007

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11. Wongtanasarasin W, Srisurapanont K. Efficacy of bicarbonate therapy for adults with cardiac arrest: A systematic review and meta-analysis of randomized-controlled trials. Turk J Emerg Med. 2021;21:24-29. doi: 10.4103/2452-2473.301917

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[ID1]100 or 1000?