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: Jerry Nolan and Markus Skrifvars were each authors on one of the randomized trials considered as part of this systematic review.
CoSTR Citation
Berg KM, Holmberg M, Nicholson T, Nolan J, Reynolds J, Schexnayder S, Nation K, Soar J, on behalf of the International Liaison Committee on Resuscitation Advanced Life Support Task Force. Oxygenation and Ventilation Targets in Adults with Return of Spontaneous Circulation after Cardiac Arrest, Consensus on Science with Treatment Recommendations; 4 January 2020 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 systematic review of oxygen and carbon dioxide targets in adults and children with return of spontaneous circulation (ROSC) after cardiac arrest (Holmberg et al, 2020, PROSPERO registration number pending, registered on September 24, 2019) conducted by the designated Expert Systematic Reviewer and Systematic Reviewer mentee, with involvement of clinical content experts from the Advanced Life Support and Paediatric task forces. Evidence for adult and paediatric literature was sought and considered by the Advanced Life Support Task Force and the Paediatric Task Force groups respectively. All data found were taken into account when formulating the Treatment Recommendations.
Systematic Review
Webmaster to insert the Systematic Review citation and link to Pubmed using this format when it is available.
Holmberg et al, Oxygen and Carbon Dioxide Targets after Cardiac Arrest: A Systematic Review and Meta-Analysis. (submitted)
PICOST
The PICOST (Population, Intervention, Comparator, Outcome, Study Designs and Timeframe)
Population: Unresponsive adults with sustained return of spontaneous circulation (ROSC) after cardiac arrest in any setting.
Intervention: A ventilation strategy targeting specific SpO2, PaO2, and/or PaCO2 targets.
Comparators: Treatment without specific targets or with an alternate target to the intervention.
Outcomes: Clinical outcome including survival/survival with a favorable neurological outcome at hospital discharge/30 days, and survival/survival with a favorable neurological outcome after hospital discharge/30 days (e.g. 90 days, 180 days, 1 year).
Study Designs: Randomized trials, non-randomized controlled trials, and observational studies (cohort studies and case-control studies) with a control group (i.e. patients treated with no specific SpO2, PaO2, and/or PaCO2 targets or an alternative target to the intervention) will be included. Animal studies, ecological studies, case series, case reports, reviews, abstracts, editorials, comments, and letters to the editor will not be included. There were no limitations on publication period or study language, as long as there is an English abstract. The population includes patients suffering from IHCA or OHCA of any origin. Unpublished studies (e.g., conference abstracts, trial protocols) were excluded. The cited systematic review was done without age restriction, and the evidence from adult studies (generally defined as >16 or ³18) is included here.
Timeframe: All years and all languages were included. Literature search updated to August 22, 2019.
PROSPERO Registration (registered Sept 24, 2019. Final registration number pending)
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. In studies that looked at both survival and survival with favorable neurologic outcome and outcome assessors were not blinded, for example, risk of bias was assessed separately for each outcome as good neurologic outcome is more susceptible to bias.
Consensus on Science
Lower oxygen target compared to higher oxygen target in the pre-hospital setting:
For the critical outcome of survival to hospital discharge we have identified low certainty evidence (downgraded two levels for imprecision) from two RCTs {Kuisma 2006 199; Bray 2018 211} enrolling 89 patients showing no benefit (RR 0.97 [95% CI 0.68 to 1.37], 18 fewer survivors per 1,000 [95% CI from 194 fewer to 224 more]). We found very low certainty evidence (downgraded for inconsistency and two levels for imprecision) from one cluster randomized trial {Thomas 2019 16} enrolling 35 patients and finding a benefit (RR 3.15 [95% CI 1.04-9.52], 379 more survivors per 1,000 [95% CI from 7 more to 1,000 more]).
For the critical outcome of survival to discharge with favourable neurologic outcome, we found low certainty evidence (downgraded two levels for imprecision) from one RCT {Kuisma 2006 199} enrolling 28 patients showing no benefit (RR 1.33 [95% CI 0.63 to 2.84], 141 more per 1,000 [95% CI from 159 fewer to 789 more]), and very low certainty evidence (downgraded for indirectness and two levels for imprecision) from one RCT {Young 2014 1686} enrolling 17 patients showing no benefit (RR 0.56 [95% CI 0.14 to 2.29], 196 fewer per 1,000 [95% CI from 382 fewer to 573 more]).
Lower oxygen target compared to higher oxygen target after admission to the ICU:
For the critical outcome of survival to hospital discharge we have identified moderate certainty evidence (downgraded for imprecision) from one RCT {Jakkula 2018 2112} enrolling 120 patients and showing no benefit (RR 1.07 [95% CI 0.84 to 1.36], 46 more per 1,000 [95% CI from 106 fewer to 238 more]), and very low certainty evidence (downgraded for indirectness and two levels for imprecision) from one RCT {Young 2014 1686} enrolling 17 patients and finding no benefit (RR 1.13 [95% CI 0.41 to 3.08], 58 more per 1,000 [95% CI from 262 fewer to 924 more]). For the critical outcome of survival to 90 days we found low certainty evidence (downgraded two levels for risk of bias) from a subgroup analysis of 164 patients within an RCT {Mackle 2019} finding a benefit (RR 1.39 [95% CI 1.01 to 1.92], 160 more per 1,000 [95% CI from 4 more to 377 more]).
For the critical outcome of discharge to home we found very low certainty evidence (downgraded for indirectness and two levels for imprecision) from one RCT {Young 2014 1686} enrolling 17 patients showing no benefit (RR 0.56 [95% CI 0.14 to 2.29], 196 fewer per 1,000 [95% CI from 382 fewer to 573 more]). For the critical outcome of favorable neurologic outcome at 6 months we found moderate certainty evidence (downgraded for imprecision) from one RCT {Jakkula 2018 2112} enrolling 120 patients showing no benefit (RR 1.13 [95% CI 0.87 to 1.47], 79 more per 1,000 [95% CI from 79 fewer to 287 more]). We also found very low certainty evidence (downgraded for risk of bias and imprecision) from a subgroup analysis of an RCT {Mackle 2019}, including 164 patients, showing no benefit (RR 1.40 [95% CI 0.93 to 2.13], 128 more per 1,000 [95% CI from 22 fewer to 361 more]).
In the observational data, results across the ten studies in adults rated as having only serious risk of bias were inconsistent. Four studies {Janz 2012 3135; Elmer 2015 49; Roberts 2018 2114; Wang 2017 113} found an association between hyperoxia and either worse survival or worse survival with neurologic outcome, while the other six studies {Johnson 2017 36; Humaloja 2019 185; Von Auenmueller 2017 134; Ebner 2019 30; Eastwood 2016 108; Vaahersalo 2014 1463} found no such association. Hypoxemia was found to be associated with worse outcome in adjusted analysis in one of these studies {Wang 2017 113}.
Ventilation targeting moderate hypercapnia compared to ventilation targeting normocapnia or low normal PaCO2 after ROSC:
For the critical outcome of survival to hospital discharge we identified low certainty evidence (downgraded for inconsistency and imprecision) from two RCTs {Jakkula 2018 2112; Eastwood 2016 83} enrolling 203 patients and finding no benefit (RR 0.94 [95% CI 0.78 to 1.14], 42 fewer per 1,000 [95% CI from 155 fewer to 99 more]).
For the critical outcome of survival to discharge with favorable neurologic outcome at six months, we found low certainty evidence (downgraded for inconsistency and imprecision) from two RCTs {Jakkula 2018 2112; Eastwood 2016 83} showing no benefit (RR 0.96 [95% CI 0.77 to 1.21], 24 fewer per 1,000 [95% CI from 138 fewer to 126 more]).
In the observational data, results across the six studies in adults with serious risk of bias were inconsistent. Two studies {Vaahersalo 2014 1463; Hope Kilgannon 2019 212} found higher PaCO2 to be associated with improved outcomes, two studies {Wang 2017 113; Roberts 2013 2107} found an association with worse outcomes, and two studies {Von Auenmueller 2017 134; Ebner 2018 196} found no association. Results were similar for hypocapnia although no studies found an association with benefitreatment
Recommendations
We recommend avoiding hypoxemia in adults with ROSC after cardiac arrest in any setting (strong recommendation, very low-certainty evidence).
We suggest avoiding hyperoxia in adults with ROSC after cardiac arrest in any setting (weak recommendation, low-certainty evidence).
We suggest the use of 100% inspired oxygen until the arterial oxygen saturation or the partial pressure of arterial oxygen can be measured reliably in adults with ROSC after cardiac arrest in any setting (weak recommendation, very low-certainty evidence).
There is insufficient evidence to suggest for or against targeting mild hypercapnia compared with normocapnia in adults with ROSC after cardiac arrest.
We suggest against routinely targeting hypocapnia in adults with ROSC after cardiac arrest. (weak recommendation, low-certainty evidence).
Justification and Evidence to Decision Framework Highlights
Narrative Reporting of the Evidence to Decision Framework Incorporating Values and Preferences and other domains included in the framework, by Task Force Chairs. Technical Remarks refers to details that helps to provide specificity for the recommendation based on the current science i.e. dosing or timing.
Oxygen targets:
In making the recommendation to avoid hypoxemia, the task force acknowledges that the evidence is of very low certainty. The task force concluded that the physiologic basis for hypoxia being harmful justifies its avoidance, and detection of hypoxemia may be the best surrogate for true hypoxia.
The suggestion to avoid hyperoxia is based on very low to moderate certainty evidence that showed either harm or no benefit from hyperoxia. In light of the possible benefit and lack of evidence for harm, the task force suggests targeting normoxia and avoiding hyperoxia. The task force acknowledges that the primary randomized trial evidence suggesting benefit from avoiding hyperoxia is from a subgroup analysis only, and more trials (three currently recruiting) will be helpful. It is also important to consider that the trials generally compare a strategy of more conservative (lower) oxygen administration strategy with a higher oxygen administration strategy. The higher oxygen arm varies across trials from being usual care (as determined by clinical teams) to a defined intervention of 100% oxygen. Observational studies, which compare oxygen levels rather than strategies, generally defined the hyperoxia group as those with PaO2 ³300mmHg, a level above what many would consider usual care. The trials enrolling currently will provide much-needed information on this question.
The task force felt that titration of oxygen should not be attempted until oxygen levels (peripheral oxygen saturation or partial pressure of oxygen in arterial blood) could be measured reliably. This is most likely to be an important consideration in the pre-hospital setting where arterial blood gas analysis is rarely available and peripheral oxygen saturation may be difficult to obtain. Some of the randomized trials conducted in the pre-hospital setting, although very small, reported more desaturation of arterial blood in the lower oxygen group, which reinforces the task force suggestion to administer 100% oxygen until reliable measurement of oxygen level is possible. This is likely to be more important in the pre-hospital setting.
Carbon dioxide targets:
Evidence from existing randomized trials and observational studies is very inconsistent. Both randomized trials failed to show any effect from different CO2 targets. Observational studies were evenly distributed in showing benefit, harm, or no effect associated with hypercapnia. Hypocapnia results were also inconsistent, although no studies found an association with benefit. In light of the lack of evidence for benefit, and lack of consistent evidence for harm from CO2 levels higher than normal, the task force did not think there was sufficient evidence to suggest for or against targeting mild hypercapnia compared with normocapnia. For hypocapnia, very limited evidence suggests either no benefit or harm, supporting the task force’s suggestion against targeting hypocapnia. As with all critically ill patients, there may be specific scenarios in which a patient’s CO2 level may need to be higher or lower than normal to compensate for other illness (e.g. severe lung injury or metabolic acidosis).
Although the task force discussed whether patients with baseline chronic lung disease and chronic CO2 retention might respond differently to different CO2 targets, no evidence addressing this subgroup was found. The task force agreed it would be reasonable to adjust PaCO2 targets in patients with known chronic CO2 retention, but this is expert opinion only as no evidence was identified on this topic.
The prior treatment recommendation (2015) was a suggestion to maintain normocapnia. The updated treatment recommendation allows for continuing this approach, while emphasizing that we do not currently know if targeting normocapnia is beneficial, harmful, or equal in comparison to targeting hypercapnia. The task force discussed the possible complication of acidemia from hypercapnia. The presence or absence of metabolic acidosis requires consideration when choosing a ventilation strategy and PaCO2 target, and metabolic acidosis is common in post-arrest patients. The PaCO2 targets or ranges also differed somewhat between studies. For this reason, the task force chose not to define specific numeric targets as no optimal target or range has been made clear. Additionally, opinions vary on whether arterial blood gas analysis in patients receiving targeted temperature management should be adjusted for temperature. Once again, trials differed in their approach. Approaches to blood gas interpretation regarding temperature also varied across the observational studies. These variations in methodology and in definitions of target ranges prohibit the task force from being able to recommend specific numbers or a specific method for blood gas analysis for systems implementing these recommendations.
Knowledge Gaps
- Published randomized trials comparing lower oxygen strategies with higher oxygen strategies or usual care in post-arrest patients have thus far been small and therefore inconclusive. More trials are needed, and three trials are underway currently.
- Published randomized trials comparing strategies targeting mild hypercapnia with strategies targeting normocapnia have thus far been small and therefore inconclusive. A much larger randomised trial is currently underway.
- How PaCO2 targets should be adjusted in those with chronic CO2 retention is unknown.
- Whether adjusting arterial blood gas analysis to 37 °C or to a patient’s current temperature is preferred is unknown.
Attachment: ALS-448-Et D
References
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