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: (Markus B Skrifvars is a co-author of the systematic review being considered for adolopment)
CoSTR Citation
Insert citation for ILCOR.org posting of CoSTR
McGuigan PJ, Pauley E, Bergh K, Drennan I, Skrifvars MB. Neuroprotective drug therapy versus placebo or usual care for comatose survivors of cardiac arrest. Consensus on Science with Treatment Recommendations [Internet] Brussels, Belgium: International Liaison Committee on Resuscitation (ILCOR) Advanced Life Support Task Force, 2024, Oct XX. Available from: http://ilcor.org
Methodological Preamble and Link to Published Systematic Review
The topic was prioritized for GRADE-ADOLOPMENT by the ALS task force following the ILCOR scientific statement which examined why therapeutic interventions have failed to translate to improved outcomes in clinical trials (Perkins 2024); that statement identifyied the effect of any specific drug therapies for neuroprotection in comatose survivors of cardiac arrest as a significant knowledge gap. The ALS Task Force was aware of a systematic review addressing this question, which was deemed suitable for GRADE-ADOLOPMENT to inform Consensus on Science with Treatment Recommendations (CoSTR). It was registered on the International Prospective register of Systematic Reviews (PROSPERO) funded by the NIHR, on 29th November 2023 (CRD42023488043).
Systematic Review
McGuigan PJ, Pauley E, Eastwood G, Hayes LMC, Jakobsen JC, Moseby-Knappe M, Nichol AD, Nielsen N, Skrifvars MB, Blackwood B, McAuley DF. Drug therapy versus placebo or usual care for comatose survivors of cardiac arrest: a systematic review with meta-analysis. Submitted to Resuscitation.
Webmaster to insert the Systematic Review citation and link to Pubmed using this format when it is available if published
PICOST
Population: Comatose patients aged ≥ 16 years who suffered either an out-of-hospital cardiac arrest (OHCA) or in-hospital cardiac arrest (IHCA).
Intervention: Neuroprotective drug administration irrespective or route of administration.
Oxygen and fluid therapy interventions were excluded. The intervention may have commenced during the cardiac arrest but must have continued after return of spontaneous circulation. Otherwise, there was no restriction on the timing of initiation or duration of the intervention.
Comparators: Placebo or usual care.
Usual care was defined as the standard of care expected at the time the study was conducted. Trials which compared anti-arrhythmic medication with defibrillator / cardioversion / ablation therapies / angioplasty / surgery therapies were excluded.
Outcomes: Critical outcomes were mortality and functional outcome at 30 days / hospital discharge.
Outcomes reflected those of the Core Outcome Set for Cardiac Arrest (COSCA).
- Mortality at 30 days / hospital discharge (critical)
- Mortality from > 30 days / hospital discharge to < 180 days
- Mortality from 180 days to 1 year
- Functional outcome at 30 days / hospital discharge (critical)
- Functional outcome from > 30 days / hospital discharge to < 180 days
- Functional outcome from 180 days to 1 year
- Health related quality of life
- Serious adverse events
Study Designs: Only randomised clinical trials (RCTs) were eligible for inclusion. Results published as abstracts only were not included. Studies with results published on trial registries (but which were not published in peer reviewed journals) were included.
Timeframe: No date range or language restriction was applied. Searches were completed on 12th April 2024 prior to final analysis.
A risk of bias assessment was conducted independently by two reviewers using Cochrane Risk-Of-Bias Version 1 (ROB-1) tool for randomized trials.
Where sufficient studies that were clinically homogenous were found, meta-analyses were undertaken (i.e. for steroids, coenzyme Q10 and thiamine with ≥ 3 trials reporting mortality at 30 days / hospital discharge).
Consensus on Science
Initially a total of 44 studies (5,640 participants) were included in the systematic review. Of these 3 studies were related to drugs already included in separate CoSTR documents, two on antiobiotic use after cardiac arrest and one on vasopressors choice to manage blood pressure, and these are not included in the current CoSTR. The majority of studies (n=24, 55%) were single centre. The median (interquartile range, IQR) sample size was 63 (40-156) patients. Studies were grouped thematically as supportive drug therapy (10 studies), neuroprotective agent (18 studies), and anti-inflammatory / antioxidant (16 studies) to facilitate narrative reporting of systematic review results.
PRISMA: ALS 3507 PRISMA Neuroprotective Drugs Flow chatrt 31 10 24
Grade Tables: ALS 3507 NEUROPROTECTIVE DRUG GRADE tables
Supportive Drug Therapies
In the supportive drug therapies category, we found 5 randomized controlled trials investigating three separate therapies antiplatelets (Llitjos 2016, Steblovnik 2016), sedation (Bjelland 2012) and neuromuscular blockade (Lee 2018, Moskowitz 2020) that reported the critical outcome of mortality at 30 days / hospital discharge. There was no evidence of an effect on mortality at 30 days / hospital discharge between intervention and control in any of the studies. No study reported mortality between 30 days / hospital discharge and < 180 days. One study reported mortality between 180 days and 1 year; this found no evidence of an effect at 1 year with neuromuscular blockade (Stockl 2017).
For the critical outcome of good functional, no study reported an effect in the supportive drug therapies category at any time point. No study of supportive drug therapies reported health related quality of life outcomes. There was no evidence of an effect on serious adverse events between intervention and control arms in the supportive drug therapies category.
Neuroprotective Agents
In the neuroprotective agent category, 14 studies of 13 therapies reported the critical outcome of 30 day / hospital mortality. These therapies included thiopental (Abramson BRCT I 1986), the dopamine agonist amantadine (Coppler 2024), calcium channel blockers nimodipine (Gueugniaud 1990, Roine 1990) and lidoflazine (Abramson BRCT I 1991), inhaled xenon (Arola 2013), nitric oxide (Dezfulian 2020) or hydrogen (Tamura 2023), the glucagon-like peptide-1 agonist exenatide (Wiberg 2016), epoetin alfa (Cariou 2016), sodium nitrite (Dezfulian 2018), magnesium (Thel 1997), MLC901 which is a combination of 9 herbal components (Pakdaman 2023), and the anticholinergic penehyclidine hydrochloride (Wang 2018).
Thirteen of the 14 studies reported no effect on mortality at 30 days / hospital discharge. One single-centre study from China (80 participants) reported reduced 30 day / hospital mortality in patients treated with the anticholinergic penehyclidine hydrochloride compared with those treated with hyoscine hydrobromide; RR 0.17, 95% CI 0.04 - 0.70 (high ROB in two domains) (Wang 2018).
One multicentre study from Japan comparing inhaled hydrogen with nitrogen placebo reported reduced mortality between 30 days / hospital discharge and < 180 days; RR 0.39, 95% CI 0.17 - 0.91 (low or unclear ROB) (Tamura 2023). However, this study was terminated early due to the COVID-19 pandemic having recruited 73 of a planned 360 patients and was thus underpowered, reducing the certainty of this finding. There was no evidence of an effect on mortality between 180 days and 1 year in any study.
For the critical outcome of good functional outcome, no study reported an effect in the neuroprotective agent category at any time point. No study of neuroprotective agents reported health related quality of life outcomes. Studies of thiopental, lidoflazine, and epoetin alfa all reported increased serious adverse events in the intervention arm (Abramson BRCT I 1986, Abramson BRCT II 1991, Cariou 2016).
Anti-inflammatory / antioxidant agents
In the anti-inflammatory / antioxidant category, 16 studies of 9 therapies reported the critical outcome of 30 day / hospital mortality. These therapies included steroids (Donnino 2016, Mentzelopolous 2022, Obling 2023), vasopressin in conjunction with steroids (Mentzelopolous 2009, Mentzelopolous 2013), thiamine (Berg 2024, Donnino 2024, Pradita-Ukrit 2020), coenzyme Q10 (Cocchi 201, Damian 2004, Holmberg 2021), vitamin C (Privšek 2024), the interleukin-6 inhibitor tocilizumab (Meyer 2021), the prostacyclin analogue iloprost (Meyer 2020), the neutrophil elastase inhibitor urinastatin (Gando 1995), and the traditional Chinese medicine Shenfu (Zhang 2017).
Three studies reported reduced mortality at 30 days / hospital discharge. The first, a single centre study from Greece (100 participants) compared intra-arrest vasopressin and methylprednisolone plus hydrocortisone for post resuscitation shock with placebo; RR 0.84, 95% CI 0.73 - 0.98 (low ROB) (Mentzelopoulos 2009). The second, a multicentre study from Greece (268 participants) also comparing intra-arrest vasopressin and methylprednisolone plus hydrocortisone for post resuscitation shock with placebo; RR 0.89, 95% CI 0.81 – 0.98 (low ROB) (Mentzelopoulos 2013). The third, a study from 50 centres in China (978 participants), compared the traditional Chinese medicine, Shenfu, with usual care; RR 0.81, 95% CI 0.74 – 0.90 (high ROB in four domains) (Zhang 2017). These three studies also reported reduced mortality between 30 days / hospital discharge and < 180 days. In addition, a trial comparing coenzyme Q10 with placebo reported reduced mortality between 30 days / hospital discharge and < 180 days; RR 0.45, 95% CI 0.24 – 0.85 (low ROB) (Damian 2004). Whereas, 1 study reported increased mortality between 180 days and 1 year when comparing iloprost with placebo; RR 2.54, 95% CI 1.21 – 5.32 (low or unclear ROB) (Meyer 2020).
For the critical outcome of good functional outcome at 30 days / hospital discharge, 2 studies reported improved outcomes in the anti-inflammatory / antioxidant category. The first was a multicentre study that compared intra-arrest vasopressin and methylprednisolone plus hydrocortisone for post resuscitation shock with placebo; RR 2.73, 95% CI 1.18 – 6.32 (low ROB) (Mentzelopolous 2013). The second compared the traditional Chinese medicine, Shenfu, with usual care; RR 1.70, 95% CI 1.34 – 2.16 (high ROB in four domains) (Zhang 2017). No study reported an effect on good functional outcome in the neuroprotective agent category between 30 days / hospital discharge and < 180 days or between 180 days and 1 year.
No study of anti-inflammatory / antioxidant agents reported health related quality of life outcomes. There was no evidence of an effect on serious adverse events between intervention and control arms in the supportive drug therapies category.
Mortality Meta-Analysis and TSA: Steroids, Coenzyme Q10 and Thiamine
There were sufficient clinically homogenous studies of steroids, coenzyme Q10 and thiamine which presented mortality data at 30 days / hospital discharge to allow meta-analyses.
For the critical outcome of mortality at 30 days / hospital discharge five studies (739 participants) provided low certainty evidence (downgraded for imprecision and indirectness) showing no evidence of an effect on mortality with steroids compared to placebo (risk ratio (RR), 0.93; 95% CI 0.83-1.04. ARD 56 fewer deaths/1000; 95% CI 136 fewer to 32 more deaths/1000) (Donnino 2016, Mentzelopolous 2009, Mentzelopolous 2013, Mentzelopolous 2022, Obling 2023). Trial sequential analysis demonstrated that the required information size had not been met.
For the critical outcome of mortality at 30 days / hospital discharge three studies (107 participants) provided low certainty evidence (downgraded for imprecision) showing no evidence of an effect on mortality with coenzyme Q10 compared to placebo (RR, 0.91; 95% CI 0.61-1.37. ARD 40 fewer deaths/1000; 95% CI 173 fewer to 248 more deaths/1000) (Damian 2004, Holmberg 2021, NCT01319110). A trial sequential analysis was not performed for trials of coenzyme Q10 due to the low number of participants.
For the critical outcome of mortality at 30 days / hospital discharge three studies (149 participants) provided low certainty evidence (downgraded for imprecision) showing no evidence of an effect on mortality with thiamine compared to placebo (RR, 1.11; 95% CI 0.88-1.40. ARD 67 more deaths/1000; 95% CI 73 fewer to 242 more deaths/1000) (Berg 2024, Donnino 2024, Pradita-Ukrit 2020). A trial sequential analysis was not performed for trials of thiamine due to the low number of participants
Treatment Recommendations
There is insufficient evidence to recommend the use of any specific drug therapy for comatose survivors of cardiac arrest (weak recommendation, low to very low certainty of evidence).
Justification and Evidence to Decision Framework Highlights
In making these changed recommendations, the ALS Task Force considered the following:
- At present ILCOR do not recommend the use of any specific drug therapies in comatose survivors of cardiac arrest. This recommendation is echoed by current European Resuscitation Council (ERC) and European Society of Intensive Care Medicine (ESICM) guidelines (Nolan 2021). The American Heart Association (AHA) have identified knowledge gaps relating to the use of analgesics, sedatives, neuromuscular blockade, anti-seizure medication, steroids, neuroprotective agents, vasoactives, anti-arrhythmics, antibiotics and sodium bicarbonate in survivors of cardiac arrest (Panchal 2020, Hirsch 2024).
- No review of drug therapy of comatose survivors of cardiac arrest had previously been conducted.
- The task force recognized that the majority of evidence was derived from single centre trials with a low number of participants in each trial.
- Trials of the anticholinergic penehyclidine (Wang 2018), the traditional Chinese medicine Shenfu (Zhang 2017) and inhaled hydrogen (Tamura 2023) reported reduced mortality. However, a high risk of bias (Wang 2018, Zhang 2017), small sample size (Wang 2018, Tamura 2023) and lack of supporting body of evidence mean we do not recommend the use of these agents at the present point in time.
- Two further trials of intra-arrest vasopressin and methylprednisolone plus hydrocortisone for post resuscitation shock reported a reduction in the critical outcome of mortality at 30 days / hospital discharge (Mentzelopolous 2009, Mentzelopolous 2013). These trials were included in the systematic review of steroids due to the administration of hydrocortisone for post resuscitation shock. It was impossible to separate treatment effect of steroids for post resuscitation shock from co-interventions commenced during cardiac arrest which included vasopressin. A CoSTR review which specifically examined the effect of vasopressin and corticosteroids during cardiac arrest recommended the following:
- “IHCA: We suggest against the use of the combination of vasopressin and corticosteroids in addition to usual care for adult in-hospital cardiac arrest, due to low confidence in effect estimates for critical outcomes. (weak recommendation, low to moderate-certainty evidence).”
- “OHCA: We suggest against the use of the combination of vasopressin and corticosteroids in addition to usual care for adult out-of-hospital cardiac arrest (weak recommendation, very low to low-certainty evidence).”
The TF realizes that there are trials ongoing using intra-arrest vasopressin and steroids with and without post arrest steroids and the results of these trials may change these CoSTRS. If this is the case the current also needs to be updated. The TF nonetheless decided to include steroid use after ROSC in the current CoSTR on neuroprotective drugs as this is not been covered specifically in a perate CoSTRS
- A systematic review, meta-analysis and trial sequential analysis of randomized control trials has been conducted to examine the efficacy and safety of corticosteroids in cardiac arrest (Penn 2023). This review found that corticosteroids administered during or immediately following successful resuscitation from cardiac arrest had an uncertain efect on mortality (RR 0.96, 95% CI 0.90–1.02, very low certainty). The different time point of administration limits applicability of findings to comatose survivors of cardiac arrest. In addition, of the 2213 patients included, 814 were enrolled in a trial of methylprednisolone following acute myocardial infarction (where the mortality rate was 11.5%) as opposed to cardiac arrest (Metz 1986). Nevertheless, the results were consistent with the current review.
- The task force recognized the low certainty of evidence for steroids and that the trial sequential analysis had demonstrated the required information size had not been met.
- One study of coenzyme Q10 reported reduced mortality between 30 days / hospital discharge and < 180 days (Damian 2004). However, the meta-analysis of coenzyme Q10 found no evidence of an effect on mortality at 30 days / hospital discharge. The task force recognized the low certainty of evidence for coenzyme Q10 and that a trial sequential analysis was not performed due to the low number of participants.
- The task force recognized the very low certainty of evidence for thiamine and that a trial sequential analysis was not performed due to the low number of participants. In addition, the task force noted that two studies were stopped early due to concerns of harm in a subgroup of patients with lactate > 5mmol/L at study inclusion.
- Prior CoSTR treatment recommendations relating to prophylaxis and treatment of seizures remain unchanged as follows:
- “We suggest against the use of prophylactic anti-seizure medication in adults post-cardiac arrest (weak recommendation, very low-certainty evidence).”
- “We suggest treatment of clinically apparent and electrographic (EEG) seizures in adults post-cardiac arrest (Good practice statement).”
- “We suggest treatment of rhythmic and periodic EEG patterns that are on the ictal-interictal continuum in comatose adults post-cardiac arrest (weak recommendation, low-certainty evidence).”
Knowledge Gaps
- Previously identified knowledge gaps relating to the use of analgesics, sedatives, neuromuscular blockade, anti-seizure medication, steroids, neuroprotective agents, vasoactives, anti-arrhythmics, antibiotics and sodium bicarbonate remain unanswered (Panchal 2020, Hirsch 2024).
- The therapeutic window for drug interventions remains uncertain and may vary depending on the mechanism of action of the drug.
- There are inadequate data about the timing, duration, dosing, and choice of steroid in comatose survivors of cardiac arrest.
- The role of steroid in those with and without shock following return of spontaneous circulation remains unknown.
- There is inadequate data regarding the use of prophylactic antibiotics in comatose survivors fo cardiac arrest.
- The task force considered that the role of sedation and neuromuscular blockade is likely to be influenced by trials of temperature management following cardiac arrest.
- Whilst the effect of antiplatelet agents and vasoactive medication following cardiac arrest remain uncertain, their evidence base is likely to be derived from best practices in primary percutaneous coronary intervention and cardiogenic shock populations, respectively.
ETD summary table: ALS 3507 Et D
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