Mild Hypercapnia Does Not Lead to Better Neurological Outcomes at 6 Months Compared to Normocapnia in Resuscitated Patients With Coma


Despite prior studies showing less brain injury biomarkers in patients with targeted mild hypercapnia, findings from a new trial suggest it does not improve neurological outcomes at 6 months.

In resuscitated patients who were in a coma after out-of-hospital cardiac arrest, targeted mild hypercapnia did not lead to better neurological outcomes at 6 months in comparison to targeted normocapnia, according to the results of a new study published in The New England Journal of Medicine.

Human brain digital illustration. Electrical activity, flashes and lightning on a blue background. | Image Credit: Siarhei -

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The international, investigator-initiated, open-label, randomized trial had 1700 patients from 17 different countries between March 2018 and September 2021, with 847 (49.8%) assigned to targeted mild hypercapnia and 853 (50.2%) assigned to targeted normocapnia, the study authors explained.

During the study, the primary outcome was a favorable neurological outcome, which was defined as a Glasgow Outcome Scale-Extended (GOS-E) score of 5 to 8 at 6 months. The secondary outcomes included death of the patient within the 6-month time period and poor neurological function, which was defined as a Rankin Scale score of 4 to 6 at 6 months, according to the investigators.

Data for the primary outcome of the trial was available in 1548 of 1676 patients (92.4%), and a dichotomized neurological outcome, either favorable or unfavorable, was available for 1594 of 1676 (95.1), according to investigators.

Results of the trial showed that, at 6 months, 332 of 764 (43.5%) patients in the mild hypercapnia-assigned group had a favorable neurological outcome, in comparison to the normocapnia group, in which 350 of 784 (44.6%) patients had a favorable neurological outcome (relative risk with mild hypercapnia, 0.98; 95% CI, 0.87 to 1.11; P = 0.76).

At 6 months, 393 of 816 patients (48.2%) in the mild hypercapnia group had died, in addition to 382 of 832 patients (45.9%) in the normocapnia group (relative risk with mild hypercapnia, 1.05;

95% CI, 0.94 to 1.16), the trial results showed.

Continuing, 407 of 762 patients (53.4%) in the mild hypercapnia group had a poor functional outcome at 6 months, compared to 400 of 779 patients (51.3%) in the normocapnia group, according to the study authors.

The most frequent adverse events in the patients included pneumonia, arrhythmias resulting in hemodynamic compromise, sepsis, and bleeding. The incidence of these events did not differ significantly between the 2 groups. Further, there were no significant differences between the 2 groups in the incidence of death before neurologic prognostication, death due to cerebral causes, or the occurrence of myoclonic seizure and tonic–clonic seizures, the study authors explained.

In a prior observational study and a phase 2 trial, the investigators found an association between treatment with mild hypercapnia in the first 24 hours in the intensive care unit (ICU) and an increased likelihood of being discharged home among adults with coma who were resuscitated after out-of-hospital cardiac arrest.

In a separate phase 2 trial, despite lacking statistical power to predict the primary outcome at 6 months, mild hypercapnia was shown to decrease the levels of brain injury biomarkers. These findings, however, suggest that mild hypercapnia does not in fact improve outcomes at 6 months and that research around the subject is incomplete, the study authors discussed.

The investigators noted multiple potential limitations to their study, including the fact that emergency department and ICU staff members were aware of the intervention assignments, and the study only included patients with out-of-hospital cardiac arrest of a presumed cardiac or unknown cause, which could limit applicability in patients with in-hospital cardiac arrest or those who had cardiac arrest due to different causes.

“Our results were consistent across the individual and dichotomized neurologic outcome categories of the GOS-E,” the study authors wrote. “The large sample size, pragmatic eligibility criteria, separation in mean PaCO2 values and in the incidence of hypocapnia, and the numerous hospitals and countries represented in this trial increase the robustness of our findings.”


Eastwood G, Nichol AD, Hodgson C, Parke RL, et al. Mild hypercapnia or normocapnia after out-of-hospital cardiac arrest. N Engl J M. 2023;10.1056/NEJMoa2214552. doi:10.1056/NEJMoa2214552

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