Hyperoxia during extracorporeal cardiopulmonary resuscitation for refractory cardiac arrest is associated with severe circulatory failure and increased mortality

This study was approved by our ethical committee (Commission Cantonale d’Ethique de la Recherche sur l’Etre Humain/CER-VD-Nr: 2017–01,184), as a retrospective use of clinical data with waiver of consent (CER-VD-Nr: 2017–011,184), and conforms to the STROBE statement for the report of observational studies. All methods were performed in accordance with the relevant guidelines and regulations. The cohort included 44 consecutive patients hospitalized in our 35-bed multidisciplinary ICU for refractory, non-traumatic and non-hypothermic, OHCA and IHCA treated with ECPR from June 2017 to June 2019. During this period, our internal recommendations for starting ECPR were: refractory OHCA or IHCA; no flow < 5 min; low flow < 80 min; age < 75 years; absence of major co-morbidities; absence of Do Not Resuscitate order. A subset of patients of the current cohort were also included in an unrelated study evaluating automated pupillometry during Veno-Arterial ECMO (VA-ECMO) for various indications [15].

The insertion of venous and arterial femoral cannulas was performed in the hospital by a cardiac surgeon. Initial VA-ECMO settings included a sweep fraction of oxygen (F_SO2) of 100% and a pump setting for a target blood flow of 40–60 ml/kg, using the Maquet Cardiohelp ECLS system®. Sweep gas flow was adapted to maintain normal PaCO₂. Systemic anticoagulation (intravenous heparin) initiated at the end of surgery was maintained to achieve an anti-Xa activity of 0.3–0.5. A coronary angiography was performed at the discretion of the in charge physicians, when an ischemic origin of cardiac arrest was strongly suspected, according to internal recommendations. Noradrenaline (NA) and Adrenaline (Adre) were given to maintain mean blood pressure (BP) ≥ 65 mmHg. Intravenous (IV) fluids were administered to maintain the target blood flow. Mechanical ventilation was performed with a tidal volume of 6 ml/kg, rate of 10–15/min and PEEP of 6–10 cm H₂O. Both FiO₂ and FsO₂ were set by default at 100% on ECPR initiation. Following these initial settings, decisions to reduce FiO₂ or/and FsO₂ were entirely at the discretion of the treating physicians, without specific recommendation. Sedation was maintained with Propofol (2–4 mg/kg/h) or Midazolam (0.05–0.15 mg/h). Targeted temperature management at 35–36 °C for 24 h was implemented in all patients. Criteria for discontinuing VA-ECMO were the absence of cardiac function recovery, intractable circulatory shock, or evidence of severe neurological injury (major stroke on cerebral imaging or evidence of severe anoxic brain injury according to a multimodal outcome prediction, combining neurological examination, electrophysiological data, and plasma levels of serum neuron-specific enolase (NSE), as described in [16]). Criteria for weaning of VA-ECMO included a mean BP > 65 mmHg, left ventricle ejection fraction > 20% and aortic velocity time integral (VTI) > 10 cm on transthoracic echocardiography, under minimal vasopressor (Norepinephrine ≤ 0.1 μg/kg/min) and inotropic (Dobutamine < 4 μg/kg/min) support and ECMO flow (1L/min).

Demographic variables included age, sex, location of CA (OHCA, IHCA), initial rhythm, duration of no flow and low flow (total duration of CPR before ECMO initiation), SAPS 2 score, ICU and hospital length of stay, duration of ECMO treatment, proportion of patients undergoing coronary angiography and angioplasty (PTCA), as well as the causes of death.

Hemodynamic variables included: (A) Mean arterial blood pressure (mean BP, obtained via an arterial catheter in all but 3 patients), from which we computed the average from all measurements performed each 2 h during the first 24 h (or until death if it occurred before 24 h). (b) Pulse pressure (systolic minus diastolic blood pressure), determined during the first 24 h as an indirect indicator of native cardiac output recovery [17], which was averaged from values obtained at 2, 6, 12 and 24 h (or until death if it occurred before 24 h). (C) The amount of catecholamines, fluids, packed red blood cells and fresh frozen plasma administered (first 72 h).

Blood gas data were obtained from an indwelling intra-arterial catheter, whose position was recorded (right radial, left radial or femoral). The values of PaO₂ measured at 5 different times of ECPR (first 15 min, 2 h, 6 h, 12 h and 24 h) were averaged as the mean 24 h PaO₂ (in patients dying before 24 h, mean PaO₂ was computed from values obtained during the time spent under ECPR until death). Arterial blood lactate was determined in the first arterial blood sampling (first 15 min of ECPR).

Continuous variables are expressed as means ± SD, or medians and interquartile ranges (IQR), and categorical data as absolute numbers and percentages. All comparisons were done using the Wilcoxon’s rank sum test for continuous variables and the chi-square test for categorical variables. We determined which variables were associated with survival using univariate logistic regression analysis for continuous variables and contingency analysis with Pearson’s test for categorical variables. To evaluate the association of hyperoxia with mortality, multivariable logistic regression was applied. We first considered a model including only co-variables significantly associated with mortality in univariate analysis (low flow duration, first arterial lactate, mean BP and mean PaO₂). We next applied a model including co-variables commonly considered as important clinical predictors of poor outcome, including age, low flow and no flow duration, shockable rhythm, the duration of ECMO, as well as mean PaO₂. In both models, hospital mortality was the response binomial variable. Odds ratios (ORs) with 95% CI were calculated (for continuous variables, ORs were calculated per unit change of each variable), and Wald statistics was used to assess the significance of each variable. Furthermore, due to the relatively low number of events in our cohort and the inherent risk of overestimating regression coefficients [18], we complemented this analysis by running several logistic regressions using only mean PaO₂ and a second co-variable at a time (including co-variable with a p value < 0.2 in the multivariable logistic regression: no flow, low flow, and shockable rhythm). To control for possible type I error, we introduced a Bonferroni adjustment for assessing significance in these 3 models (thus, a p value of 0.05/3 = 0.016 was used as the significance limit in these analyses). To determine a possible association between PaO₂ and circulatory failure, we performed bivariate analyses and simple linear regressions between mean PaO₂ and mean blood pressure and between mean PaO₂ and the amount of vasopressive catecholamines administered, with calculation of the Pearson r coefficient. To determine the influence of the arterial catheter position on PaO₂, PaO₂ values obtained in the different catheter positions were compared using Wilcoxon rank test. The JMP software, version 15, was used for all the analyses, and a p value < 0.05 was considered statistically significant.

The restoration of systemic oxygenated blood flow after a prolonged period of hypoxia may trigger widespread reperfusion injury. A key mechanism of reperfusion injury is the generation of oxidants and free radicals [19], whose flux increases in proportion with the local PO₂ [20‐22], implying an increased risk of oxidant-mediated damage at higher PO₂ during reperfusion [23]. In the setting of ECPR, the risk of hyperoxia is particularly elevated, due to the ease of oxygenating blood through the membrane oxygenator [5, 12], and a few retrospective studies have indeed reported a negative impact of hyperoxia on survival after ECPR [13, 14, 24]. In a retrospective cohort of 291 ECPR patients, Chang et al. reported that a first PaO₂ value during the first 24 h after ECPR initiation between 77 and 220 mmHg, was significantly associated with neurologically intact survival in comparison to higher values [14]. In a retrospective cohort of 66 patients undergoing ECPR for refractory OHCA, Halter et al. reported a significant association between PaO₂ measured at 30 min after ECPR initiation and 28 days mortality. Using a threshold value of PaO₂ of 300 mmHg to define hyperoxia, the odds ratio for 28 days mortality was 4.07 [13]. In our study, non survivors displayed a higher mean 24 h PaO₂, lower mean blood pressure, higher needs in vasopressors, and profound circulatory shock was the primary cause of death in a majority of non survivors. Taken together, these findings suggest that severe vascular failure with refractory circulatory shock may represent an important mechanism of hyperoxia toxicity during ECPR.

Hyperoxia results in an increased vascular generation of superoxide (O₂^.−), which reacts rapidly with nitric oxide (NO^.) to form peroxynitrite, that can trigger significant vascular contractile failure through a number of processes [25‐27]. In addition, oxidants such as peroxynitrite promote the expression of multiple inflammatory cytokines and mediators [28‐31], which also reduce vascular tone and may precipitate hypotension. These effects may contribute to foster a sepsis-like state, characterized by an irreversible loss of vascular contractility and refractory hypotension with negative prognostic impact after prolonged resuscitation and ECPR, as recently reported by Jouffroy et al. [32]. Obviously, the formation of peroxynitrite and other oxidants, together with the generation of inflammatory mediators, at different levels of PaO₂ during ECPR, should be evaluated in future investigations to explore these mechanisms.

A critical aspect in the interpretation of arterial blood gases during peripheral VA-ECMO is the localization of arterial blood sampling and right radial artery sampling is recommended [33], owing to the risk of upper body hypoxia in case of cardiac recovery and impaired pulmonary gas exchange [34]. Accordingly, we found that PaO₂ was lower when measured from a right radial artery than from a femoral artery, while it did not differ from values obtained from the left radial artery. One could therefore argue that the lower PaO₂ in survivors might reflect an earlier recovery of native cardiac function, but this appears unlikely in view of the similar values of pulse pressure, an indirect, real-time measure of native cardiac output during extracorporeal support [35], in survivors and non survivors.

The two main causes of death were early circulatory failure and delayed neurological damage. Patients dying from either cause had similar durations of low flow and mean PaO₂, but initial lactate levels were lower in patients dying from neurological damage, pointing to less profound systemic anoxia. These patients also had higher mean blood pressure and required significantly less vasopressors. Overall, these findings suggest that patients with more severe anoxia (higher lactate levels) might develop more severe reperfusion injury under hyperoxic conditions, leading to predominantly vascular failure and early deaths, whereas those with less severe anoxia would survive the early stage and develop delayed hyperoxic neurological damage. This hypothesis should require validation in larger cohorts of patients treated with ECPR for refractory cardiac arrest.

We did not find significant association between the initial rhythm and survival, which differs from the notion that survival under ECPR is better in patients with an initial shockable rhythm [36]. This discrepancy most likely reflects the small sample size in our study. Only 52% of patients had an initial shockable rhythm, and among those with a non-shockable rhythm, all patients with asystole died, whereas 3 out of 14 patients (21%) with pulseless electrical activity (PEA) survived to hospital discharge. Interestingly, these 3 patients had the lowest mean PaO₂ (152, 162 and 184 mmHg, respectively) among the 14 PEA patient, which may suggest that the avoidance of hyperoxia during ECPR could be critical to determine outcome in PEA patients undergoing ECPR.

Besides PaO₂, survival in our cohort was significantly associated with the duration of low flow in univariate analysis, in line with previous investigations [37‐39]. However, this association was not observed in a multivariable analysis evaluating several co-variates commonly associated with poor outcome after CA and ECPR, such as no flow, low flow, initial rhythm, localization of CA (IHCA vs OHCA) and age, together with mean 24 h PaO₂. We also included the duration of ECMO as a co-variate, given that the initial sweep gas oxygen fraction was set at 100%, which could have favored persisting hyperoxia in these patients. With the exception of mean PaO₂, none of these variables displayed a significant association with mortality. Although these findings may suggest a particularly negative prognostic implication of hyperoxia in ECPR, they warrant cautious interpretation. Owing to the relatively small sample size in our study, the results of multivariate analysis may be subject to some bias related to an overestimation of regression coefficients [18]. For this reason, we performed additional analyses using only one co-variate with mean PaO₂, including no flow, low flow and initial rhythm, which confirmed the association of mean PaO₂ with mortality. In addition, due to the retrospective nature of our study, the association of PaO₂ with mortality could represent a surrogate for the sickness of patients. Physicians would indeed be inclined to maintain high levels of administered O₂ to the most severely affected patients, and hyperoxia would therefore be a side effect of such management.

Our study has several limitations. First, we must acknowledge the usual limitations related to the retrospective design of our study [40] and to its relatively small sample size. Second, although we established an association between hyperoxia and mortality, as well with refractory circulatory failure, such associations do not necessarily mean a causal relationship. Third, the absence of internal recommendations for the management of arterial oxygen levels during ECPR may have favored the development of hyperoxia, which could have been avoided with a dedicated clinical protocol. Fourth, we relied on pulse pressure as an indirect evaluation of native cardiac output, which may be of limited reliability under conditions of varying cardiac loading conditions, especially afterload [41]. Direct assessment of native cardiac function using echocardiography would have been more appropriate in this setting, but we do not routinely perform echocardiography in the first 24 h after ECPR initiation. Fifth, we did not measure circulating mediators related to oxidative stress and inflammation, which could have given important insights on the effects of hyperoxic reperfusion during ECPR. Such measurements will be the matter of additional future investigations.