ARTICLE: Eastwood G, Nichol AD, Hodgson C, et al., for the TAME Investigators. Mild Hypercapnia or Normocapnia after Out-of-Hospital Cardiac Arrest. N Engl J Med. 2023;389(1):45-57.
To compare the effect of maintaining normocapniaia versus hypercapnia regarding favorable neurologic outcome at 6 months in patients who have been resuscitated after out-of-hospital cardiac arrest.
The main goal of resuscitative measures in cardiac arrest is to preserve neurologic function. Many trials have investigated different variables and interventions to maximize favorable neurologic outcomes for patients in cardiac arrest. Hypoxic-ischemic encephalopathy is the leading cause of death and disability among patients resuscitated from out-of-hospital cardiac arrest.1 Many factors contribute to hypoxic-ischemic encephalopathy after cardiac arrest including but not limited to significantly decreased cardiac output, inadequate oxygenation, and dysregulation of vascular resistance. Despite resuscitative efforts, cerebral hypoperfusion is a major contributor to anoxic brain injury and poor neurologic outcomes.2
Current guidelines recommend patients who have been resuscitated after cardiac arrest to be maintained with normocapnia (PaCO2 35 to 45 mmHg).2-3 This is in part because the partial pressure of arterial carbon dioxide (PaCO2) is a major physiologic regulator of cerebrovascular resistance. Some studies suggest that cerebral perfusion increases by up to 2 ml per 100 g of brain tissue for each increase of 1 mmHg in PaCO2.4-5 This mechanism appears to remains intact after cardiac arrest.6
The question remains as to whether normocapnia is sufficient for this patient population or whether there might be benefits to hypercapnia as a means to increase brain perfusion. A physiologic study showed that intentional hypercapnia increases cerebral oxygenation saturation when compared to normocapnia.7 A small, underpowered multicenter phase 2 randomized trial showed that hypercapnia may reduce the release of neuro-specific enolase, a biomarker of brain injury.8 In two separate observational studies, exposure to hypercapnia was associated with a significantly increased rate of discharge home and better neurologic outcomes at 12 months.9-10 The most beneficial PaCO2 target for patients in cardiac arrest has not been studied in randomized trials yet. The authors who designed the TAME Trial theorized that neurologic outcome and mortality at 6 months would improve if patients resuscitated after out-of-hospital cardiac arrest were maintained with hypercapnia as compared to targeted normocapnia.
This was an international multicenter, investigator-initiated, open-label, randomized superiority trial that ran also concomitantly with the Targeted Hypothermia versus Targeted Normothermia after Out-of-Hospital Cardiac Arrest (TTM2) trial. It was conducted from March 2018 through September 2021 and enrolled patients from 63 ICUs in 17 countries.
As soon as possible after hospital admission, patients were randomly assigned in a 1:1 ratio to either the hypercapnia or the normocapnia group. In each group, the attending clinician was aware of the intervention assignment and followed the assigned protocol for 24 hours after randomization. The hypercapnia group had a PaCO2 target of 50 to 55 mmHg whereas the normocapnia group had a PaCO2 target of 35 to 45 mmHg.
The protocol recommended deep sedation (a target Richmond Agitation-Sedation score of -4); serial arterial blood gases every 4 hours without adjustment in blood pH for hypothermia-mediated effects on blood gases; and the use of end-tidal carbon dioxide levels by clinicians to guide ventilation management. Ventilation settings, sedation agents, and use of paralyzing agents were at the discretion of the treating clinician.
Neurologic assessments were made by a clinician who was blinded by the intervention using a protocol-guided neurologic assessment. This was done at 96 hours after randomization or later for patients who remained in the ICU.
Hospitalized adults (≥ 18 years of age) with coma who had been resuscitated after out-of-hospital cardiac arrest of a presumed cardiac or unknown etiology and had sustained return of spontaneous circulation for ≥20 minutes without chest compressions.
- Patients with interval time of greater than 180 minutes from screening to achieving return of spontaneous circulation (ROSC)
- Patients with unwitnessed cardiac arrest with an initial detected rhythm of asystole
- Limitations of care
A favorable neurologic outcome defined as a Glasgow Outcome Scale—Extended (GOS-E) score of 5-8 at 6 months. For reference, a GOS-E score:
- 1: Death
- 2: Vegetative state
- 3-4: Severe disability
- 5-6: Moderate disability
- 7-8: Good recovery
If a GOS-E could not be done at 6 months, a dichotomized neurologic outcome of “favorable” or “unfavorable” was made on the basis of all available data including medical and interview records by an assessor who was blinded to the intervention assignment.
- Death within 6 months
- Poor functional outcome defined as a modified Rankin scale score of 4 to 6 at 6 months. For reference, a modified Rankin scale score:
- 0: No symptoms
- 1: No clinically significant disability
- 2: Slight disability
- 3: Moderate disability
- 4: Moderately severe disability
- 5: Severe disability
- 6: Death
- Patient-perceived health-related quality of life by means of the visual-analogue scale on the EuroQol Group 5-Dimension Self-Report Questionnaire which ranges from 0 to 100 mm, with a score of 0 mm indicating “the worst health you can imagine” and a score of 100 mm as “the best health you can imagine.”
- The authors also considered pre-specified adverse events including pneumonia, sepsis, bleeding, arrhythmia resulting in hemodynamic compromise, skin complications related to the device used for targeted temperature management, and suspected or confirmed raised intracranial pressure or seizures necessitating normocapnia.
A total of 1700 patients were enrolled with 847 patients (49.8%) assigned to the hypercapnia group and 853 (50.2%) to the normocapnia group. Informed consent was withdrawn in 24 patients. Patients in both groups had similar baseline characteristics (see Table 1) and baseline PaCO2 prior to randomization. Death before neurologic prognostication or confirmed brain death leading to organ donation were similar in the two groups. Additional sensitivity analysis displayed no interaction between the intervention assignments of this study and the intervention study of the TTM2 trial for any outcomes for the 370 patients who were enrolled in both trials.
At 6 months, 332 of 764 patients (43.5%) in the hypercapnia group had a favorable neurologic outcome as compared with 350 of 784 patients (44.6%) in the normocapnia group (relative risk [RR], 0.98; 95% CI, 0.87 to 1.11; P=0.76).
- By 6 months, 393 of 816 patients (48.2%) in the hypercapnia group and 382 of 832 patients (45.9%) in the normocapnia group had died (RR, 1.05; 95% CI, 0.94 to 1.16).
- At 6 months, 407 of 762 patients (53.4%) in the hypercapnia group had a poor functional outcome compared with the 400 of 779 patients (51.3%) in the normocapnia group (RR, 1.05; 95% CI, 0.95 to 1.15).
- The incidence of the prespecified adverse events did not differ significantly between the two groups. There were 4 expected serious and possibly intervention-related adverse events: one cerebral edema in the hypercapnia group and three noncerebral events in the normocapnia group.
- This was an unblinded study: ED and ICU staff were aware of the intervention assignments.
- Sedation, paralytics, and ventilator settings were not protocolized and left to the clinician’s discretion.
- There were 139 of 4464 (3.1%) PaCO2 measurements in the mild hypercapnia group that were hypocapnic (PaCO2 <35 mmHg) while there were 696 of 4397 (15.8%) in the normocapnia group, possibly attenuating the magnitude of difference between the two groups.
- The study ran in parallel with the concomitant TTM2 hypothermia study. Temperature variations may affect arterial blood gases and other parameters.
- The study population consisted of patients with out-of-hospital arrest of presumed cardiac or unknown cause, most of which were witnessed cardiac arrests with initial shockable rhythms and bystander resuscitation. The study results therefore are less generalizable to inpatient cardiopulmonary arrests, unwitnessed cardiac arrests, arrests with non-shockable initial rhythms, or other causes of arrest such as trauma or anaphylaxis.
- Intracranial pressure and cerebral edema was not routinely monitored and therefore the proportion of patients who may have had these findings is unknown.
- Study happened during COVID-19 pandemic, which may limit protocol implementation and follow up.
- Patients who are generally hypercapnic at baseline (e.g., patients with COPD or obesity hypoventilation syndrome) were not addressed in this study. Maintaining a normocapnia target for these patients may decrease cerebral perfusion and portend poor neurologic outcomes.
This trial did not show a significant difference in favorable neurologic outcome, mortality at 6 months, or harm between targeted mild hypercapnia (PaCO2 50 to 55 mmHg) versus normocapnia (PaCO2 35 to 45 mmHg) for patients who achieved ROSC after out-of-hospital cardiac arrest.
- Perkins GD, Callaway CW, Haywood K, et al. Brain injury after cardiac arrest. Lancet. 2021;398(10307):1269-1278.
- Nolan JP, Sandroni C, Böttiger BW, et al. European Resuscitation Council and European Society of Intensive Care Medicine guidelines 2021: post-resuscitation care. Intensive Care Med. 2021;47(4):369-421.
- Panchal AR, Bartos JA, Cabañas JG, et al. Adult basic and advanced life support: 2020 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation. 2020;142:Suppl 2:S366-S468.
- Reich T, Rusinek H. Cerebral cortical and white matter reactivity to carbon dioxide. Stroke. 1989;20:453-457.
- Battisti-Charbonney A, Fisher J, Duffin J. The cerebrovascular response to carbon dioxide in humans. J Physiol. 2011;589:3039-48.
- Bisschops LL, Hoedemaekers CW, Simons KS, van der Hoeven JG. Preserved metabolic coupling and cerebrovascular reactivity during mild hypothermia after cardiac arrest. Crit Care Med. 2010;38(7):1542–1547.
- Eastwood GM, Tanaka A, Bellomo R. Cerebral oxygenation in mechanically ventilated early cardiac arrest survivors: the impact of hypercapnia. Resuscitation. 2016;102:11-6.
- Eastwood GM, Schneider AG, Suzuki S, et al. Targeted therapeutic mild hypercapnia after cardiac arrest: a phase II multi-centre randomised controlled trial (the CCC trial). Resuscitation. 2016;104:83-90.
- Schneider AG, Eastwood GM, Bellomo R, et al. Arterial carbon dioxide tension and outcome in patients admitted to the intensive care unit after cardiac arrest. Resuscitation. 2013;84:927-34.
- Vaahersalo J, Bendel S, Reinikainen M, et al. Arterial blood gas tensions after resuscitation from out-of-hospital cardiac arrest: associations with long-term neurologic outcome. Crit Care Med. 2014;42:1463-70.