Oxygen and carbon dioxide targets in patients with return of spontaneous circulation after cardiac arrest. ALS 3305, 3506, 3516, 3517 TF 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: 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

Holmberg M, Berg KM, Ikeyama T, on behalf of the International Liaison Committee on Resuscitation Advanced Life Support and Basic Life Support Task Forces.

Oxygenation and Ventilation Targets in Adults with Return of Spontaneous Circulation after Cardiac Arrest, Consensus on Science with Treatment Recommendations.

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 CRD42022371007). The review was updated for the 2024 CoSTR, and was updated again for this 2025 COSTR due to awareness of new trial data. Evidence for adult and paediatric literature was sought and considered by the Advanced Life Support, Basic Life Support and Pediatric Life Support Task Forces respectively. All adult data found were taken into account when formulating these 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.(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).

Study Designs: Randomized clinical trials (RCTs) only were included. Non-randomized studies animal studies, ecological studies, case series, case reports, reviews, abstracts, editorials, comments, and letters to the editor were excluded. Unpublished studies (e.g., conference abstracts, trial protocols) were excluded. All relevant publications in any language were included if there was an English abstract.

Timeframe: The original search included all years and was conducted in August of 2019. The search was subsequently updated in June 2023. The search for the present update includes studies published from June 1 2023-May 14 2024. RCTs already included in the previous review and new RCT data published after the previous search in June 2023 will be included.

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 favorable neurologic outcome is more susceptible to bias.

Consensus on Science

The updated search identified 529 studies. Of these, only one was included¹. This study reported longer-term outcomes from a previously included trial ². Therefore, the section on oxygen targets in the ICU setting is the only section of the consensus on science which has been updated since the 2024 CoSTR.

Lower oxygen target compared to higher oxygen target in the pre-hospital 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% ³, administration of 2-4 L/min vs. >10 L/min oxygen ⁴, an oxygen saturation of 94-98% vs. a FiO₂ of 100% ⁵, and an oxygen saturation of 90-94% vs. 98-100% ⁶.

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 ⁶ 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]).

For the critical outcome of survival to 12 months, we found moderate certainty evidence (downgraded for imprecision) from one RCT ⁶ 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 to 3 months, we found very low certainty evidence (downgraded for inconsistency and imprecision) from one cluster RCT ⁵ 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 with a favorable neurological outcome at hospital discharge, we found moderate certainty evidence (downgraded for imprecision) from two RCTs ^3,6 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 hospital discharge, we found moderate certainty evidence (downgraded for imprecision) from four RCTs ^3-6 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]).

Lower oxygen target compared to higher oxygen target after admission to the ICU:

Five RCTs were included in meta-analyses comparing lower oxygen targets to higher oxygen targets in the ICU setting ^2,7-10. One additional study reporting one-year outcomes of a previously-included trial was added.¹ 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) ⁷, an oxygen saturation of 90-97% vs. standard of care ⁸, a PaO₂of 9-10 kPa vs. 13-15 kPa (approximately 68-75 mm Hg vs. 98-105 mm Hg) ^1,2, an oxygen saturation of 88-96% vs. 96-100% ⁹, and a PaO₂ of 60 mm Hg vs. 90 mm Hg (approximately 8 kPa vs. 12 kPa) ¹⁰.

For the critical outcome of survival with favorable neurologic outcome at 1 year, we found low-certainty evidence (downgraded for risk of bias and imprecision) from a secondary publication of one RCT ^1,2 including 771 patients showing no benefit from targeting lower oxygen levels compared with higher oxygen levels (RR 1.06 [95% CI 0.94-1.18]; 36 more survivors per 1,000 [95% CI from 36 fewer to 109 more]).

For the critical outcome of survival at 1 year, we found low-certainty evidence (downgraded for risk of bias and imprecision) from a secondary publication of one RCT ^1,2 including 789 patients showing no benefit from targeting lower oxygen levels compared with higher oxygen levels (RR 1.04 [95% CI 0.94-1.16]; 25 more survivors per 1,000 [95% CI from 38 fewer to 101 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 ^2,7 and one RCT subgroup analysis ⁸ enrolling 1059 patients showing no benefit of targeting lower oxygen levels compared with higher oxygen levels (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]).

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 ^2,7 and two RCT subgroup analyses ^8,10 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 a favorable neurological outcome at hospital discharge, we found moderate certainty evidence (downgraded for imprecision) from one RCT ² 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 hospital discharge, 28 days, or 30 days, we found low certainty evidence (downgraded for risk of bias and imprecision) from two RCTs ^2,7 and two RCT subgroup analyses ^8,9 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]).

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)^7,11,12 and a PaCO₂ of 5.8-6.0 kPa vs. 4.5-4.7 kPa (approximately 44-45 mm Hg vs. 34-35) ⁷.

For the critical outcome of survival to hospital discharge, we found moderate certainty evidence (downgraded for imprecision) from three RCTs^7,11,12 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 ¹² 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^7,11,12 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]).

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

Since the prior review, the only new evidence identified was a reporting of one-year outcomes from a previously included trial. These results were consistent with the shorter-term outcomes included in the prior CoSTR. Therefore, the ALS Task Force did not think any change to the treatment recommendations was indicated. The main discussion points informing these treatment recommendations are included below.

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 ⁶. 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 ⁶ 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 > 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 ⁶ and hospital ² 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. ^13-15 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) ¹². 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 CO₂levels 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 ⁶ and observational studies not included in this review ^16-19 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

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 CO₂retention
9. Whether arterial blood gas analysis should be adjusted to 37°C or to a patient’s current temperature

ETD summary table: ALS 3305 Et D O2 October 2024 F Inal; ALS 3305 Et D CO2 2 Ocrtober 2024 final

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