Oxygen targets and 6-month outcome after out of hospital cardiac arrest: a pre-planned sub-analysis of the targeted hypothermia versus targeted normothermia after Out-of-Hospital Cardiac Arrest (TTM2) trial

Chiara Robba, Rafael Badenes, Denise Battaglini, Lorenzo Ball, Filippo Sanfilippo, Iole Brunetti, Janus Christian Jakobsen, Gisela Lilja, Hans Friberg, Pedro David Wendel-Garcia, Paul J Young, Glenn Eastwood, Michelle S Chew, Johan Unden, Matthew Thomas, Michael Joannidis, Alistair Nichol, Andreas Lundin, Jacob Hollenberg, Naomi Hammond, Manoj Saxena, Annborn Martin, Miroslav Solar, Fabio Silvio Taccone, Josef Dankiewicz, Niklas Nielsen, Anders Morten Grejs, Florian Ebner, Paolo Pelosi, TTM2 Trial collaborators

Abstract

Background: Optimal oxygen targets in patients resuscitated after cardiac arrest are uncertain. The primary aim of this study was to describe the values of partial pressure of oxygen values (PaO2) and the episodes of hypoxemia and hyperoxemia occurring within the first 72 h of mechanical ventilation in out of hospital cardiac arrest (OHCA) patients. The secondary aim was to evaluate the association of PaO2 with patients' outcome.

Methods: Preplanned secondary analysis of the targeted hypothermia versus targeted normothermia after OHCA (TTM2) trial. Arterial blood gases values were collected from randomization every 4 h for the first 32 h, and then, every 8 h until day 3. Hypoxemia was defined as PaO2 < 60 mmHg and severe hyperoxemia as PaO2 > 300 mmHg. Mortality and poor neurological outcome (defined according to modified Rankin scale) were collected at 6 months.

Results: 1418 patients were included in the analysis. The mean age was 64 ± 14 years, and 292 patients (20.6%) were female. 24.9% of patients had at least one episode of hypoxemia, and 7.6% of patients had at least one episode of severe hyperoxemia. Both hypoxemia and hyperoxemia were independently associated with 6-month mortality, but not with poor neurological outcome. The best cutoff point associated with 6-month mortality for hypoxemia was 69 mmHg (Risk Ratio, RR = 1.009, 95% CI 0.93-1.09), and for hyperoxemia was 195 mmHg (RR = 1.006, 95% CI 0.95-1.06). The time exposure, i.e., the area under the curve (PaO2-AUC), for hyperoxemia was significantly associated with mortality (p = 0.003).

Conclusions: In OHCA patients, both hypoxemia and hyperoxemia are associated with 6-months mortality, with an effect mediated by the timing exposure to high values of oxygen. Precise titration of oxygen levels should be considered in this group of patients.

Trial registration: clinicaltrials.gov NCT02908308 , Registered September 20, 2016.

Keywords: Cardiac arrest; Hyperoxemia; Hypoxemia; Mortality; Neurological outcome.

Conflict of interest statement

Dr. Saxena is receiving consulting fees from Bard Medical; Dr. Young is receiving lecture fees from Bard Medical; Dr. Taccone is receiving grant support from Bard Medical and ZOLL Medical; Dr. Nichol is receiving grant support, paid to University College Dublin, from AM Pharma and grant sup-port, paid to Monash University, from Baxter Healthcare; Dr. Chew is receiving lecture fees from Edwards Lifesciences; Dr. Friberg is receiving fees for academic advising from TEQCool; and Dr. Nielsen is receiving lecture fees from Bard Medical and consulting fees from BrainCool. Dr Badenes is supported by INCLIVA. Dr Robba received fees for lectures from Masimo, and GE. Dr. Battaglini received fees for lectures from Baxter. No other potential conflict of interest relevant to this article was reported.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Frequency distribution of arterial partial pressure of oxygen (PaO2) classes (conventional thresholds). Number of hypoxemia (PaO2 < 60 mmHg) or severe hyperoxemia (PaO2 > 300 mmHg) episodes per patient during the first 72 h after intensive care unit admission. This figure was based on all patients included in the cohort, with a percent distribution as follow: Episodes of Hypoxemia = 0 (n = 1372 (75.01%), 1 (n = 304 (16.62%), 2 (n = 88 (4.81%), 3 (n = 39 (2.13%), 4 + (n = 26 (1.42%). Episodes of Hyperoxemia = 0 (n = 1689 (92.35%), 1 (n = 130 (7.11%), 2 (n = 9 (0.49%), 4 (n = 1 (0.05%)
Fig. 2
Fig. 2
Adjusted hourly trajectories of partial pressure of oxygen according to 6-month survival status. Left panel shows the predicted partial pressure of oxygen (PaO2) trajectories according to survival status. Right panel shows the PaO2 differences between survivors and non-survivors at each time point. For this analysis, mixed regression model included a random intercept on patients ID and a random coefficient on the time variable (time elapsed between measurements). These predicted trajectories were adjusted for TTM2 randomization arms, age (year), gender, Charlson comorbidity index, state of shock at admission, return to spontaneous circulation-ROSC- time, initial cardiac rhythm (shockable vs non-shockable), witnesses of cardiac arrest, respiratory rate (breath/min), plateau pressure (cmH2O),positive end expiratory pressure (cmH2O), arterial partial pressure of carbon dioxide, PaCO2 (mmHg), pH, Base excess (mEq/L), and fraction of inspired O2 (%). Right panel confirmed that the differences between these two trajectories (survivors/non-survivors) are statistically significant up to the first 32 h of measurement (omnibus p value = 0.0074). ICU, Intensive Care Unit
Fig. 3
Fig. 3
Arterial partial pressure of oxygen (PaO2) mortality risk profile. In this Cox regression, PaO2 was modeled with a fractional polynomial (FP) of second degree FP [0–1], and included the following covariates: TTM2 randomization group, tympanic temperature at admission, age (years), gender, Charlson comorbidity index, cardiac arrest witnessed, time to return to spontaneous circulation, ROSC (min), bystander performed cardiopulmonary resuscitation, CPR, shockable rhythm, cardiac arrest location (home, public place, other), shock diagnosis on admission, ST-Elevated myocardial infarction (STEMI) diagnosis on admission, respiratory rate (breath/min), positive end-expiratory pressure, arterial partial pressure of carbon dioxide (PaCO2) (mmHg), pHa, and Base excess (mEq/L), Driving pressure (cmH20), and mechanical power (J/min). Along the PaO2 continuum, values before and after its median (108.7 mmHg and used as reference—see vertical line in red) were statistically associated with mortality if the 95% confidence interval (CI) did not cover the y-line of 1 (horizontal line in red)
Fig. 4
Fig. 4
Relative distribution analysis for the definition of the best cut-off of arterial partial pressure of oxygen (PaO2) associated with mortality. Best cutoff point along the continuum of the marker that separated survivors versus non-survivors at the end of the follow-up. In this analysis, the quantile (or proportion) distribution of the marker survivors (plotted on the x-axis plus the corresponding marker values at the top) is plotted against the proportion ratio of the marker distribution for non-survivors
Fig. 5
Fig. 5
Frequency distribution of arterial partial pressure of oxygen (PaO2) classes (according to best threshold). Numbers of hypoxemia/hyperoxemia episodes per patient during the first 72 of mechanical ventilation. This figure was based on all patients included in the cohort, with a percent distribution as follow: Episodes of Hypoxemia = 0 (n = 805 (44.01%), 1 (n = 439 (24.00%), 2 (n = 239 (13.07%), 3 (n = 142 (7.76%), 4 + (n = 204 (11.05%). Episodes of Hyperoxemia = 0 (n = 1431 (76.90%), 1 (n = 339 (18.53%), 2 (n = 43 (2.35%), 3 (n = 10 (0.55%), 4 + (n = 6 (0.33%)

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