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 (18), whose flux increases in proportion with the local PO2 (19–21), implying an increased risk of oxidant-mediated damage at higher PO2 during reperfusion (22). 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, 23). In our study, non survivors displayed a higher mean 24h 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 (24–26). In addition, oxidants such as peroxynitrite promote the expression of multiple inflammatory cytokines and mediators (27–30), 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. (31). 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 (32), owing to the risk of upper body hypoxia in case of cardiac recovery and impaired pulmonary gas exchange (33). 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 (34), 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 (35). 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 (36–38). 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 24h 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 (17). 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 (39) 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 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.