Targeted Therapeutic Mild Hypercapnia after Resuscitated Cardiac Arrest

Eastwood. NEJM 2023. DOI: 10.1056/NEJMoa2214552

Clinical Question

  • In patients resuscitated from out-of-hospital cardiac arrest (OOHCA) does targeted mild hypercapnia compared to targeted normocapnia improve 6-month neurological outcomes?


  • Ischaemia-reperfusion injury following cardiac arrest can further exacerbate the initial ischaemic insult and lead to worsening organ function
  • Sustained cerebral vasoconstriction and hypoxia has been demonstrated in this cohort of patients
  • It is hypothesised that mild targeted hypercapnia and the resultant vasodilatation may ameliorate some of these changes and thus improve outcomes
  • Small trials assessing mild hypercapnia have shown improved cerebral oxygenation and decreased neuron specific enolase levels and an observational cohort study of patients after OHCA showed an association of mild hypercapnia with improved outcomes
  • There is, however, no high-quality randomised evidence to guide CO2 targets


  • International, multi-centre, investigator-initiated, open label RCT
  • Co-enrolment with other trials (e.g. TTM2) allowed
  • Randomized as soon as possible following hospital admission by clinician using web-based software in a 1:1 ratio
    • Random permuted block sizes used and stratified by site and co-enrolment in TTM2
  • Unblinded for bedside clinicians but outcome assessors unaware of allocation
  • Data for primary outcome collected in person, via telephone or videoconference interviews
  • Outcome assessors provided with standardized training materials and pre-specified and ad-hoc checks carried out by study personnel
  • Pre-publication of protocol and statistical analysis plan
  • Sample Size Calculation
    • 1624 patients needed to provide 90% power to detect or reject an 8 percentage-point difference in favourable neurological outcome (50% in normocapnia and 58% in mild hypercapnia) at an alpha of 0.05
    • Based on earlier trials of hypercapnia in cardiac arrest


  • March 2018 – September 2021
  • 63 ICUs in 17 countries


  • Inclusion:
    • Age ≥ 18
    • OHCA of presumed cardiac or unknown cause
    • < 180 minutes since ROSC
    • Sustained ROSC (> 20 minutes without chest compressions)
    • Unconsciousness and unable to obey verbal commands
  • Exclusion:
    • Unwitnessed OHCA
    • Asystole as initial rhythm
    • Temperature < 30°C
    • ECMO
    • Pregnancy
    • Intracranial bleeding (suspected or confirmed)
    • Severe COPD with long term home O2
  • 1700 randomised
    • 847 to mild hypercapnia and 853 to normocapnia
    • 5779 assessed for eligibility, 3732 excluded and 347 eligible but not randomised
  • Balanced baseline characteristics
    • Comparing mild hypercapnia vs normocapnia group
    • Age: 61 vs 62
    • Male: 77 vs 81%
    • Witnessed cardiac arrest: 88 vs 89%
    • Bystander CPR: 81 vs 81%
    • First Rhythm shockable: 70 vs 73%
    • Median time from arrest to sustained ROSC: 26 vs 25 mins
    • Median time from arrest to randomisation: 154 vs 151 mins
    • Median arterial pH: 7.20 vs 7.22
    • Arterial lactate level: 6.79 vs 7.00 mmol/L
    • First measured PaCO2: 52.8 vs 52.5 mmHg
    • STEMI: 41 vs 42%
    • PCI: 35 vs 36%


  • Targeted Therapeutic Mild Hypercapnia
    • 24 hours targeting PaCO2 50 – 55 mmHg
    • Normocapnia restored over following 24-48 hours
    • Any severe metabolic acidosis (pH < 7.1 or BE > -6 mmol/L treated prior to commencement of hypercapnia)


  • Normocapnia
    • 24 hours targeting PaCO2 35 – 45 mmHg

Management common to both groups

  • Clear protocol if above or below target CO2
    • 4 hourly ABG if in range, or 30 minutes post ventilator change
    • Changes in ETCO2 also used to guide ABG measurement (if changes > 5 mmHg then ABG required)
  • Deep sedation targeted in both groups (-4 on RASS)
  • All other management at discretion of treating teams but should be guided by best local practice and ILCOR guidelines
  • Blinded prognosticator performs neurological assessment on those deemed free of sedatives at > 96 hours post ROSC
    • Based on ERC and ESICM guidelines
    • Withdrawal of life sustaining treatment (WLST) not allowed prior to this for presumed poor neurological outcome, however decisions regarding WLST at discretion of treating team not prognosticator


  • Primary outcome: 
    • Favorable neurological outcome (GOSE ≥ 5)
    • 43.5% (mild hypercapnia) vs 44.6% (normocapnia)
      • Adjusted relative risk 0.98 (95% CI 0.87 to 1.11)
  • Secondary outcomes:
  • Comparing mild hypercapnia vs. normocapnia group
    • No significant difference in:
      • Poor functional outcome at 6 months (mRS of 4-6): 53.4 vs 51.3%
      • Death at ICU discharge: 38.0 vs 35.6%
      • Death within 6 months: 48.2 vs 45.9%
  • Subgroups
    • No difference in any subgroup (age, sex, time from ROSC, initial rhythm or shock on admission)
  • Adverse Events
    • No difference in adverse events

Authors’ Conclusions

  • The use of targeted mild hypercapnia in patients with OOHCA did not improve neurological outcomes at 6 months


  • International, multi-centre RCT
  • Large numbers of patients recruited
  • Excellent and rapid separation of PaCO2 which was maintained at target levels for duration of intervention
    • Median 2 hours to first achieve target (Figure S4)
    • Time weighted PaCO2 averages across first 24 hours were 49.8 mmHg vs 40.8 mmHg (Figure S4)
  • High adherence to protocol with detailed description of protocolized PaCO2 measurements in supplementary material
    • Acknowledging the real-world challenges and complexities of keeping ventilatory parameters within strict targets in trials of this magnitude, a large proportion of measurements in range
      • 76% of all measurements in mild hypercapnia group > 45 mmHg, and 65% of all measurements in normocapnia group 35 – 45 mmHg
  • Comprehensive screening log kept
  • Standardized approach to WLST (withdrawal of life-sustaining therapies)
  • Pre-published statistical analysis plan and blinded manuscript written


  • Clinicians unblinded
  • CO2 target abandoned in 5.6% of patients: 8% in mild hypercapnia group and 3% in normocapnia group (Table S3)
  • 7% missing data for primary outcome
    • Authors used different methods to account for missing of data with no change in outcome

The Bottom Line

  • There appears to be no benefit (or harm) to targeting mild hypercapnia and I will continue to target normocapnia in the absence of ventilatory challenges

External Links


Summary author: George Walker @hgmwalker89
Summary date: 16th June 2023
Peer-review editor: Celia Bradford

Picture by: GiorgioTrovato/Unsplash


Leave a Reply

Your email address will not be published. Required fields are marked *

This site uses Akismet to reduce spam. Learn how your comment data is processed.