Oxygen and carbon dioxide targets in patients with return of spontaneous circulation after cardiac arrest: ALS SR

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: (not 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: Janet Bray, Bridget Dicker, Theresa Olasveengen, Gavin Perkins, Markus Skrifvars, and Asger Granfeldt were all involved in clinical trials of oxygen or ventilation strategies after cardiac arrest.

CoSTR Citation

Holmberg MJ, Ikeyama T, Garg R, Drennan I, Lavonas E, Bray J, Olasveengen T, and Berg KM, on behalf of the Advanced Life Support and Basic Life Support Task Forces. Oxygenation and Ventilation Targets After Cardiac Arrest: An Updated Systematic Review and Meta-Analysis.

Methodological Preamble and Link to Published Systematic Review

The continuous evidence evaluation process to produce the Consensus on Science with Treatment Recommendations (CoSTR) started with a systematic review (Holmberg 2020 107) with involvement of clinical content experts. Considering new evidence becoming available on this topic, the decision was made to update the systematic review (PROSPERO CRD42022371007). Evidence for adult literature was sought and considered by the Advanced Life Support and Basic Life Support Task Forces. These data were accounted for when formulating the Treatment Recommendations.

Systematic Review

Holmberg et al, Oxygen and Carbon Dioxide Targets after Cardiac Arrest: An Updated Systematic Review and Meta-Analysis (in preparation)

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). The final included outcomes will depend on the available data and subsequent outcome prioritization by the ILCOR ALS Task Force.

Study Designs: This was an update of the previous ILCOR systematic review addressing oxygen and carbon dioxide targets after cardiac arrest (Holmberg 2020 107). Controlled trials including RCTs and non-randomized trials (e.g., pseudo-randomized trials) were included. Observational studies, animal studies, ecological studies, case series, case reports, reviews, abstracts, editorials, comments, letters to the editor, and unpublished studies were excluded. All languages were included if there was an English abstract or full-text article.

Timeframe: Studies already identified in the previous ILCOR systematic review and new controlled trials published from August 22, 2019 – June 30, 2023.

PROSPERO Registration CRD42022371007

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

The updated systematic review identified 5 new RCTs in adult patients. These studies add to the previous systematic review {Holmberg 2020 107} which identified 7 RCTs and 36 observational studies in adult patients.

Given that evidence was available from 12 RCTs and because the observational studies identified in the previous systematic review were limited by a critical risk of bias, only RCTs were considered for the updated consensus on science. Details of the observational studies are provided in the previous systematic review {Holmberg 2020 107}.

Oxygenation strategy targeting lower oxygen levels compared with higher oxygen levels in the prehospital setting:

Four RCTs were included in meta-analyses comparing lower oxygen targets to higher oxygen targets in the prehospital setting. Oxygen targets were defined as a fraction of inspired oxygen (FiO₂) of 30% vs. 100% {Kuisma 2006 199}, administration of 2-4 L/min vs. >10 L/min oxygen {Bray 2018 211}, an oxygen saturation of 94-98% vs. a FiO₂ of 100% {Thomas 2019 16}, and an oxygen saturation of 90-94% vs. 98-100% {Bernard 2022 1818}.

For the critical outcome of survival to hospital discharge, we found moderate certainty evidence (downgraded for imprecision) from four RCTs {Kuisma 2006 199; Bray 2018 211; Thomas 2019 16; Bernard 2022 1818} enrolling 549 patients showing no benefit of targeting lower oxygen levels compared with higher oxygen levels (RR, 0.98 [95% CI, 0.70 to 1.37]; 10 fewer survivors per 1,000 patients [95% CI, from 143 fewer to 177 more]).

For the critical outcome of survival with a favorable neurological outcome at hospital discharge, we found moderate certainty evidence (downgraded for imprecision) from two RCTs {Kuisma 2006 199; Bernard 2022 1818} enrolling 451 patients showing no benefit of targeting lower oxygen levels compared to higher oxygen levels (RR, 0.92 [95% CI, 0.70 to 1.21]; 34 fewer survivors per 1,000 patients [95% CI, from 126 fewer to 88 more]).

For the critical outcome of survival to 3 months, we found very low certainty evidence (downgraded for inconsistency and imprecision) from one cluster RCT {Thomas 2019 16} enrolling 35 patients showing a benefit of targeting lower oxygen levels compared with higher oxygen levels (RR, 3.15 [95% CI, 1.04 to 9.52]; 379 more survivors per 1,000 patients [95% CI, from 7 more to 1,000 more)].

For the critical outcome of survival to 12 months, we found moderate certainty evidence (downgraded for imprecision) from one RCT {Bernard 2022 1818} enrolling 401 patients showing no benefit of targeting lower oxygen levels compared with higher oxygen levels (RR, 0.82 [95% CI, 0.64 to 1.06]; 76 fewer survivors per 1,000 patients [95% CI, from 151 fewer to 25 more]).

For the critical outcome of survival with a favorable neurological outcome at 12 months, we found moderate certainty evidence (downgraded for imprecision) from one RCT {Bernard 2022 1818} enrolling 389 patients showing no benefit of targeting lower oxygen levels compared with higher oxygen levels (RR, 0.85 [95% CI 0.62 to 1.17]; 47 fewer survivors per 1,000 patients [95% CI, from 118 fewer to 53 more]).

Oxygenation strategy targeting lower oxygen levels compared with higher oxygen levels after admission to the ICU:

Five RCTs were included in meta-analyses comparing lower oxygen targets to higher oxygen targets in the ICU setting. Oxygen targets were defined as a partial pressure of oxygen (PaO₂) of 10-15 kPa vs. 20-25 kPa (approximately 75-113 mm Hg vs. 150-188 mm Hg) {Jakkula 2018 2112}, an oxygen saturation of 90-97% vs. standard of care {Young 2020 2411}, a PaO₂ of 9-10 kPa vs. 13-15 kPa (approximately 68-75 mm Hg vs. 98-105 mm Hg) {Schmidt 2022 1467}, an oxygen saturation of 88-96% vs. 96-100% {Semler 2022 1759}, and a PaO₂ of 60 mm Hg vs. 90 mm Hg (approximately 8 kPa vs. 12 kPa) {Crescioli 2023 109838}.

For the critical outcome of survival to hospital discharge, 28 days, or 30 days, we found low certainty evidence (downgraded for risk of bias and imprecision) from two RCTs {Jakkula 2018 2112; Schmidt 2022 1467} and two RCT subgroup analyses {Young 2020 2411; Semler 2022 1759} enrolling 1409 patients showing no benefit of targeting lower oxygen levels compared with higher oxygen levels (RR, 1.10 [95% CI, 0.95 to 1.27]; 60 more survivors per 1.000 patients [95% CI, from 30 fewer to 163 more]).

For the critical outcome of survival with a favorable neurological outcome at hospital discharge, we found moderate certainty evidence (downgraded for imprecision) from one RCT {Schmidt 2022 1467} enrolling 789 patients showing no benefit of targeting lower oxygen levels compared with higher oxygen levels (RR 1.03 [95% CI 0.93 to 1.14], 20 more survivors per 1,000 patients [95% CI from 46 fewer to 93 more]).

For the critical outcome of survival to 3 months or 6 months, we found moderate certainty evidence (downgraded for risk of bias and imprecision) from two RCTs {Jakkula 2018 2112; Schmidt 2022 1467} and two RCT subgroup analyses {Young 2020 2411; Crescioli 2023 109838} enrolling 1405 patients showing no benefit of targeting lower oxygen levels compared with higher oxygen levels (RR, 1.05 [95% CI, 0.92 to 1.20]; 29 more survivors per 1,000 patients [95% CI, from 47 fewer to 116 more]).

For the critical outcome of survival with favorable neurological outcome at 3 or 6 months, we found low certainty evidence (downgraded for risk of bias and imprecision) from two RCTs {Jakkula 2018 2112; Schmidt 2022 1467} and one RCT subgroup analysis {Young 2020 2411} enrolling 1059 patients showing no benefit of targeting lower oxygen levels compared with higher oxygen (RR, 1.07 [95% CI, 0.96 to 1.20]; 43 more survivors per 1,000 patients [95% CI, from 24 fewer to 122 more]).

In the observational data identified in the systematic review published by ILCOR in 2020 (Holmberg 2020 107), results across ten studies in adults rated as having 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 the 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:

Three RCTs were included in meta-analyses comparing moderate hypercapnia to normocapnia in the prehospital setting. Ventilation targets were defined as a partial pressure of carbon dioxide (PaCO₂) of 50-55 mm Hg vs. 35-45 mm Hg (approximately 6.7-7.3 kPa vs. 4.7-6.0 kPa) {Eastwood 2016 83; Eastwood 2023 45} and a PaCO₂ of 5.8-6.0 kPa vs. 4.5-4.7 kPa (approximately 44-45 mm Hg vs. 34-35) {Jakkula 2018 2112}.

For the critical outcome of survival to hospital discharge, we found moderate certainty evidence (downgraded for imprecision) from three RCTs {Eastwood 2016 83; Jakkula 2018 2112; Eastwood 2023 45} enrolling 1866 patients showing no benefit of targeting moderate hypercapnia compared with normocapnia (RR, 0.95 [95% CI, 0.82 to 1.10]; 30 fewer survivors per 1,000 patients [95% CI, from 108 fewer to 60 more]).

For the critical outcome of survival to 6 months, we found moderate certainty evidence (downgraded for imprecision) from one RCT {Eastwood 2023 45} enrolling 1648 patients showing no benefit of targeting moderate hypercapnia compared with normocapnia (RR, 0.96 [95% CI, 0.88 to 1.05]; 22 fewer survivors per 1,000 patients [95% CI, from 65 fewer to 27 more]).

For the critical outcome of survival with favorable neurological outcome at 6 months, we found moderate certainty evidence (downgraded for imprecision) from three RCTs {Eastwood 2016 83; Jakkula 2018 2112; Eastwood 2023 45} enrolling 1751 patients showing no benefit of targeting moderate hypercapnia compared with normocapnia (RR, 0.96 [95% CI, 0.85 to 1.10]; 19 fewer survivors per 1,000 patients [95% CI, from 70 fewer to 46 more]).

In the observational data identified in the systematic review published by ILCOR in 2020 (Holmberg 2020 107), 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 benefit.

Treatment Recommendations

Oxygen targets:

We recommend 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 the pre-hospital setting (strong recommendation, moderate certainty evidence) and in-hospital setting (strong recommendation, low certainty evidence).

We recommend avoiding hypoxemia in adults with ROSC after cardiac arrest in any setting (strong recommendation, very low certainty evidence).

We suggest avoiding hyperoxemia in adults with ROSC after cardiac arrest in any setting (weak recommendation, low certainty evidence).

Following reliable measurement of arterial oxygen levels, we suggest targeting an oxygen saturation of 94-98% or a partial pressure of arterial oxygen of 75-100 mm Hg (approximately 10-13 kPa) in adults with ROSC after cardiac arrest in any setting (good practice statement).

When relying on pulse oximetry, health care professionals should be aware of the increased risk of inaccuracy that may conceal hypoxemia in patients with darker skin pigmentation (good practice statement).

Carbon dioxide targets:

We suggest targeting normocapnia (a partial pressure of carbon dioxide of 35-45 mm Hg or approximately 4.7-6.0 kPa) in adults with ROSC after cardiac arrest (weak recommendation, moderate certainty evidence).

Justification and Evidence to Decision Framework Highlights

Oxygen targets:

The task forces felt that oxygen titration should not be attempted until oxygen levels (arterial oxygen saturation with a pulse oximeter or partial pressure of oxygen in arterial blood) can be measured reliably. This is most likely to be an important consideration in the prehospital setting where arterial blood gas analysis is rarely available and peripheral oxygen saturation may be difficult to obtain consistently. Some of the RCTs conducted in the prehospital setting reported more desaturation of arterial blood in the lower oxygen target groups, and the largest RCT to inform oxygenation targets (comparing oxygen saturation targets of 90-94% to 98-100%) suggests that early titration to a lower oxygen target is harmful {Bernard 2022 1818}. Most patients in the standard care arm of that RCT received 100% oxygen prior to hospital arrival, rather than titrated levels, due to the introduction of air-mix mechanical ventilators. Hence, the task forces deemed it acceptable to temporarily target a higher oxygen range to mitigate the risk of hypoxemia. The task forces discussed whether the evidence favored avoiding any titration of oxygen in the prehospital setting since most patients in the EXACT trial {Bernard 2022 1818} received 100% oxygen without titration. However, most thought that once reliable measurement of oxygenation was available, the evidence only supported not titrating to a lower target range of 90-94%. The separate recommendations for different settings, with a stronger recommendation for the prehospital setting, were influenced by the evidence of harm from that same RCT as well as the differing certainty of evidence in the prehospital and ICU studies.

In making the recommendation to avoid hypoxemia, the task forces acknowledges that the evidence is of very low certainty from observational studies. The task forces 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 hyperoxemia is based on very low to moderate certainty evidence that showed either harm (in observational studies included in the 2020 systematic review) or no benefit (in RCTs) from hyperoxemia. It is important to consider that the RCTs generally compared a conservative oxygen strategy with a liberal oxygen strategy. Observational studies, which compared oxygen levels rather than strategies, generally defined the hyperoxemia group as those with PaO₂ ³ 300 mm Hg, a level above what many would consider usual care.

The variability in oxygenation targets across RCTs and observational studies makes it difficult to identify an evidence-based optimal range. However, the task forces recognized the need for more precise guidance than what has previously been provided. The most comprehensive RCTs in the prehospital {Bernard 2022 1818} and hospital {Schmidt 2022 1467} settings, which compared an oxygen saturation of 90-94% to 98-100% and a PaO₂ of 9-10 kPa to 13-15 kPa, don’t identify a specific optimal arterial oxygen saturation or partial pressure of oxygen but support normoxemia being safe. Given the absence of conclusive evidence for specific oxygen levels outside the normoxemia range, the task force agreed that targeting an oxygen saturation of 94-98% or a PaO2 target of 75-100 mm Hg (10-13 kPa) is reasonable.

While studies evaluating the accuracy of pulse oximetry in people with different degrees of skin pigmentation were not part of this systematic review, the systematic review team and task forces are aware of and considered several such studies that have found a slightly higher risk of occult hypoxemia (pulse oximetry reading of greater than 90% saturation while arterial oxygen saturation by blood gas is < 88%) in people with darker skin. {Sjoding 2020 2477; Won 2021 e2131674; Jamali 2022 1951} While none of these studies were done in cardiac arrest patients, the task forces felt that this issue was important to make medical professionals treating cardiac arrest patients aware of, as this knowledge could inform decision making about whether to titrate supplemental oxygen. The task forces provided a good practice statement to highlight this issue, while acknowledging that this evidence was not formally evaluated as part of this systematic review.

Carbon dioxide targets:

The evidence from RCTs and observational studies is inconsistent. RCTs have failed to show any effect from different CO₂ targets. The largest RCT to inform ventilation targets in the hospital setting found no significant differences in outcomes from targeting normocapnia (PaCO₂ of 35-45 mm Hg) and mild hypercapnia (PaCO₂ of 50-55 mm Hg) {Eastwood 2023 45}. Observational studies have been evenly distributed in showing benefit, harm, or no effect associated with hypercapnia. Results for hypocapnia have also been inconsistent, although no studies have found an association with benefit.

Considering the lack of evidence for benefit or harm from targeting CO₂ levels above or below the normal range, the task forces deemed it reasonable to target normocapnia, generally defined as a PaCO₂ of 35-45 mm Hg in both RCTs and observational studies. Notably, the task force is aware of unpublished data from one RCT {Bernard 2022 1818} and observational studies not included in this review {Moon 2007 219; Mueller 2022 120; Kim 2019 1; Abrahamowicz 2022 3} suggesting that ETCO₂ levels may not accurately reflect PaCO₂ levels, which may be an important consideration in the prehospital setting. As with all critically ill patients, there may be specific scenarios in which CO₂ levels may need to be higher or lower than normal to compensate for other illnesses (e.g., severe lung injury or metabolic acidosis).

The task forces discussed whether cardiac arrest patients with baseline chronic lung disease and chronic CO₂ retention might respond differently to different CO₂ targets, however, no evidence addressing this subgroup was found. The task forces agreed that it would be reasonable to adjust PaCO₂ targets in patients with known chronic CO₂ retention (expert opinion).

The task forces 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. Additionally, opinions vary on whether arterial blood gas analysis in patients receiving targeted temperature management should be adjusted for temperature. Approaches to blood gas interpretation regarding temperature varied across RCTs and observational studies. These variations in methodology and in definitions of target ranges prohibit the task forces from being able to recommend specific numbers or a specific method for blood gas analysis for systems implementing these recommendations.

Knowledge Gaps

Knowledge Gaps Template for Task Force chairs

1. The optimal oxygen target for post-cardiac arrest patients
2. Whether there is a threshold at which hypoxemia and hyperoxemia become harmful
3. The optimal duration for specific oxygen strategies
4. The optimal carbon dioxide target for post-cardiac arrest patients
5. Whether there is a threshold at which hypocapnia and hypercapnia become harmful
6. The accurate correlation of ETCO₂ with PaCO₂ levels
7. The effects of manipulating PaCO₂ on cerebral blood flow in post-cardiac arrest
8. How PaCO₂ targets should be adjusted in those with chronic CO₂ retention
9. Whether arterial blood gas analysis should be adjusted to 37°C or to a patient’s current temperature

Attachment:

ALS Et D O2

ALS Et D CO2

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