Prophylactic antibiotics after cardiac arrest (ALS): Systematic Review

Conflict of Interest Declaration

The ILCOR Scientific Advisory Committee process is guided by a rigorous ILCOR Conflict of Interest policy.

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: Keith Couper and Joyce Yeung were first and last author of the systematic review that forms the basis of this treatment recommendation.

CoSTR Citation

Couper K, Yeung K, Soar J, Berg K, Andersen LW, Böttiger BW, Callaway CW, Deakin CD, Donnino M, Drennan I, Hsu CH, Morley PT, Neumar RW, Nicholson TC, O’Neil BJ, Paiva EF, Parr MJ, Reynolds JC, Sandroni C, Wang TL, Welsford M, Nolan JP. Prophylactic antibiotics following return of spontaneous circulation in adults: Consensus on Science with Treatment Recommendations [Internet] Brussels, Belgium: International Liaison Committee on Resuscitation (ILCOR) Advanced Life Support Task Force, 3 January 2020 Available from: http://ilcor.org

Methodological Preamble

The continuous evidence evaluation process for the production of Consensus on Science with Treatment Recommendations (CoSTR) started with a detailed review of a recently published systematic review/guideline based on a recently published systematic review (Couper 2019 166). Key changes to the original review were exclusion of a randomised controlled trial published only as an abstract (authors contacted)(Bongaerts 2013 S287), exclusion of five observational studies assessed as being at critical risk of bias (Skrifvars 2003 319, Kocjancic 2014 1364, Gagnon 2015 154, Kim 2016 17, Ribaric 2017 103 (observational cohort)), replacement of an abstract of a randomised controlled trial with the full-text paper (Daix 2018 P061, Francois 2019 1831), and removal of the outcome of positive bacterial cultures (categorised as not important). Additional scientific literature published after the completion of the published systematic review was identified by a subsequent search of the relevant literature, conducted by Keith Couper and Joyce Yeung with involvement of clinical content experts. The totality of this identified evidence was considered by the Advanced Life Support Task Force, and used to create/update bias assessment tables and evidence profile tables. These data were then used to formulate the Consensus on Science and Treatment Recommendations

PICOST

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

Population: Adult patients following return of spontaneous circulation from cardiac arrest in any setting (in-hospital and out-of-hospital)

Intervention: Early/ prophylactic antibiotics

Comparators: Delayed/ clinically-driven administration

Outcomes: Survival; Survival with good neurological outcome; Critical care length of stay; Infective complications (for example, pneumonia); Duration of mechanical ventilation; Duration of antibiotic administration.

Study Designs: Randomized controlled trials (RCTs) and non-randomized studies (non-randomized controlled trials, interrupted time series, controlled before-and-after studies, cohort studies) are eligible for inclusion. Observational studies were eligible only if they were not at critical risk of bias.

Timeframe: All years and all languages are included as long as there is an English abstract. Initial search run 8th May 2018. Searches re-run October 2019.

NOTE FOR RISK OF BIAS: In most cases bias was assessed per comparison rather than per outcome, since there were no meaningful differences in bias across outcomes. In cases where differences in risk of bias existed between outcomes this was noted.

Consensus on Science

For the critical outcome of survival with good neurological outcome (up to day 30) at last recorded time point (O), we identified:

• Low certainty evidence (downgraded for serious risk of bias and serious imprecision) from two randomized controlled trials (Francois 2019 1831, Ribaric 2017 103) enrolling 254 patients (P), which showed no benefit from the intervention (I) when compared with standard care (C) (risk ratio 0.89 [95% CI 0.71, 1.12], p=0.31; risk difference -0.06 [95% CI -0.19, 0.06], p=0.30).

Francois 2019 measured neurological outcome at 30-days. Ribaric 2017 measured neurological outcome at ITU discharge.

• No evidence from observational studies.

For the critical outcome of survival (up to day 30) at last recorded time point (O), we identified:

• Low certainty evidence (downgraded for serious risk of bias and serious imprecision) from two randomized controlled trials (Francois 2019 1831, Ribaric 2017 103) enrolling 254 patients (P), which showed no benefit from the intervention (I) when compared with standard care (C) (risk ratio 0.95 [95% CI 0.79, 1.14], p=0.60; risk difference -0.03 [95% CI -0.15, 0.08], p=0.58).

Francois 2019 measured survival at 30-days. Ribaric 2017 measured survival at ITU discharge.

• Very low certainty evidence (downgraded for serious indirectness) from two observational studies (Tagami 2016 89, Davies 2013 616) enrolling 1742 patients (P). Data presentation precluded pooling of data. One study (Tagami 2016 89) enrolling 1604 patients (P) showed no benefit from the intervention (I) when compared with standard care (C) (odds ratio 1.16, 95% CI 0.94, 1.13], p=0.18). The other study (Davies 2013 616) enrolling 138 patients (P) showed benefit from the intervention (I) when compared with standard care (C) (data presentation precludes reporting of odds ratio, p=0.01).

For the important outcome of infective complications (pneumonia) we identified:

• Low certainty evidence (downgraded for serious risk of bias and serious imprecision) from two randomized controlled trials (Francois 2019 1831, Ribaric 2017 103) enrolling 254 patients (P), which showed no benefit from the intervention (I) when compared with standard care (C) (risk ratio 0.75 [95% CI 0.43, 1.32], p=0.32; risk difference -0.12 [95% CI -0.23, 0.00], p=0.05).

N.B. Differences in how pneumonia was diagnosed between studies.

• Very low certainty evidence (downgraded for serious risk of bias, serious indirectness and serious imprecision) from two observational studies (Tagami 2016 89, Perbet 2011 1048) enrolling 2245 patients (P), which showed no benefit from the intervention (I) when compared with standard care (C) (odds ratio 0.61 [95% CI 0.61, 1.62], p=0.98).

N.B. Differences in how pneumonia was diagnosed between studies.

For the important outcome of critical care length of stay we identified:

• Low certainty evidence (downgraded for serious risk of bias and serious imprecision) from two randomized controlled trials (Francois 2019 1831, Ribaric 2017 103) enrolling 248 patients (P), which showed no benefit from the intervention (I) when compared with standard care (C) (mean difference 0.47 days [95% CI -1.31, 2.24], p=0.61).
• No evidence from observational studies.

For the important outcome of duration of mechanical ventilation we identified:

• Very Low certainty evidence (downgraded for very serious risk of bias and serious imprecision) from one randomized controlled trials (Ribaric 2017 103) enrolling 60 patients (P), which showed no benefit from the intervention (I) when compared with standard care (C) (mean difference 0.20 days [95% CI -1.53, 1.93], p=0.82).
• No evidence from observational studies.

For the important outcome of antibiotic duration we identified:

• No evidence from randomized controlled trials.
• No evidence from observational studies.

Treatment Recommendations

We suggest against the use of prophylactic antibiotics in patients following return of spontaneous circulation. (weak recommendation, low certainty of evidence).

Justification and Evidence to Decision Framework Highlights

• This topic was prioritized by the ALS Task Force based on a recent systematic review (Couper 2019 166).
• This topic has not previously been considered by ILCOR.

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

• This treatment recommendation refers to prophylactic antibiotic use following return of spontaneous circulation, and does not cover situations where antibiotics are used for confirmed or suspected infections.
• Both the meta-analyses of both randomized controlled trials and observational studies which identified no overall benefit to the use of prophylactic antibiotics
• The findings of one randomized controlled trial at low overall risk of bias that reported reduced incidence of early pneumonia in patients treated with prophylactic antibiotics (Francois 2019 1831). Whilst this demonstrates the potential efficacy of prophylactic antibiotics, this finding did not translate to an effect on other clinical outcomes, such as survival or critical care length of stay.
• Pneumonia affects approximately 50% of intensive care unit patients following cardiac arrest (Nielsen 2013 2197), but this is unlikely to contribute to mortality as most deaths are attributable to neurological failure, cardiovascular failure or multi-organ failure (Nielsen 2013 2197, Francois 2019 1831). The incidence of pneumonia following cardiac arrest means a strategy of prophylactic antibiotic use will expose a large number of patients to antibiotics with no specific benefit.
• Both included randomized controlled trials included only out-of-hospital cardiac patients who were treated with targeted temperature management (32-34°C). One study limited inclusion to patients with a cardiac cause of cardiac arrest (Ribaric 2017 103) and the other limited inclusion to patients that presented in a shockable rhythm (Francois 2019 1831).
• The diagnosis of infection following cardiac arrest is challenging as standard indicators of infection, such as fever, are unreliable in the context of post-cardiac arrest syndrome and treatment with targeted temperature management (Nolan 2008 350).
• The decision to commence antibiotics following cardiac arrest, particularly in the context of gastric aspiration, is challenging and clinicians may have different clinical thresholds for prescribing antibiotics.
• We note that both randomized controlled trials were undertaken in Europe and the selected prophylactic antibiotic was amoxicillin/ clavulanic acid. This may not be the most appropriate antibiotic in all settings.
• We did not identify any randomized controlled trials for in-hospital cardiac arrest.
• We did not identify evidence in relation to patients that do not require intensive care admission following cardiac arrest. Such patients are likely to be at lower risk of infection than patients admitted to intensive care units.

Knowledge Gaps

There were no studies identified that evaluated this question in the in-hospital setting.

There were no randomized controlled trials that evaluated this question in patients treated with targeted temperature management at temperatures other than 32-34°C.

There were no studies that were powered to determine the effect of prophylactic antibiotics on outcomes such as critical care length of stay or duration of mechanical ventilation.

Attachments

Evidence-to-Decision Table: Post ROSC antibiotics

References

Bongaerts D, Hendriks B, Gordts B, Malbrain M, Rogiers P and Nieuwendijk R. Antibiotic prophylaxis is superior to selective antibiotic therapy in patients treated with therapeutic hypothermia after out-of-hospital cardiac arrest. Intensive Care Med. 2013;39:S287.

Daix T, Cariou A, Meziani F, Dequin PF, Guitton C, Deye N, Plantefeve G, Quenot JP, Desachy A, Kamel T, Bedon-Carte S, Diehl JL, Chudeau N, Karam E, Renon-Carron F, H, ez Padilla A, Vignon P, Le Gouge A and Francois B. Short term antibiotics prevent early VAP in patients treated with mild therapeutic hypothermia after cardiac arrest. Critical Care Conference: 38th International Symposium on Intensive Care and Emergency Medicine, ISICEM. Crit Care. 2018;22(Supp1):82.

Davies KJ, Walters JH, Kerslake IM, Greenwood R and Thomas MJC. Early antibiotics improve survival following out-of hospital cardiac arrest. Resuscitation. 2013;84:616-619.

François B, Cariou A, Clere-Jehl R, Dequin P-F, Renon-Carron F, Daix T, Guitton C, Deye N, Legriel S, Plantefève G, Quenot J-P, Desachy A, Kamel T, Bedon-Carte S, Diehl J-L, Chudeau N, Karam E, Durand-Zaleski I, Giraudeau B, Vignon P and Le Gouge A. Prevention of Early Ventilator-Associated Pneumonia after Cardiac Arrest. NEJM. 2019;381:1831-1842.

Gagnon DJ, Nielsen N, Fraser GL, Riker RR, Dziodzio J, Sunde K, Hovdenes J, Stammet P,

Friberg H, Rubertsson S, Wanscher M and Seder DB. Prophylactic antibiotics are associated with a lower incidence of pneumonia in cardiac arrest survivors treated with targeted temperature management. Resuscitation. 2015;92:154-159.

Kim SJ, Lee JK, Kim DK, Shin JH, Hong KJ and Heo EY. Effect of Antibiotic Prophylaxis on Early-Onset Pneumonia in Cardiac Arrest Patients Treated with Therapeutic Hypothermia. Korean J Crit Care Med. 2016;31:17-24.

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Perbet S, Mongardon N, Dumas F, Bruel C, Lemiale V, Mourvillier B, Carli P, Varenne O, Mira JP, Wolff M and Cariou A. Early-onset pneumonia after cardiac arrest: characteristics, risk factors and influence on prognosis. Am J Respir Crit Care Med. 2011;184:1048-54.

Ribaric SF, Turel M, Knafelj R, Gorjup V, Stanic R, Gradisek P, Cerovic O, Mirkovic T and Noc M. Prophylactic versus clinically-driven antibiotics in comatose survivors of out-of-hospital cardiac arrest-A randomized pilot study. Resuscitation. 2017;111:103-109.

Skrifvars MB, Pettila V, Rosenberg PH and Castren M. A multiple logistic regression analysis of in-hospital factors related to survival at six months in patients resuscitated from out-of-hospital ventricular fibrillation. Resuscitation. 2003;59:319-328.

Tagami T, Matsui H, Moroe Y, Kaneko J, Unemoto K, Fushimi K and Yasunaga H. Early antibiotics administration during targeted temperature management after out-of-hospital cardiac arrest: A nationwide database study. BMC Anesthesiol. 2016;16:89.