Among 595 patients with severe ARDS from COVID 19 supported by V-V ECMO, the incidence of stroke within 90 days was 7.2%. Development of stroke was associated with substantially higher in-hospital mortality (79% at 90-days) which is higher than the reported mortality in patients without stroke (45%). We identified several risk factors associated with stroke development, including obesity, pre-ECMO use of vasoactive medication, high SOFA score, low platelet count, higher PaCO2 levels before ECMO support, and the higher ΔPaCO2. These findings emphasize several clinically relevant points and spark the need for future studies. Since obesity and the use of vasoactive medications were associated with increased risk of stroke, mainly hemorrhagic, this finding emphasizes the need for more robust hemodynamic monitoring of those patients to assess the degree of hypovolemia and not relying solely on parameters that could be influenced by patient body habitus such as central venous pressure. Also, it emphasizes the risk of ischemic-reperfusion injury that represents impairment of cerebral autoregulation associated with these risk factors. Whether gradual correction of pre-ECMO hypercarbia and hypoxemia when starting V-V ECMO will reduce the risk of stroke is an important research question for both animal studies and prospective clinical research [17].
The frequency of stroke in this study is consistent with the previously published studies either in COVID-19 or severe ARDS due to other etiologies [11, 18, 19]. The predominant stroke type was hemorrhagic (83.7%), which contrasts sharply with the type of strokes reported in COVID-19 patients who did not receive V-V ECMO support [4]. In a meta-analysis of sixteen studies of COVID-19 patients, the incidence of stroke was 1.1% and 96.6% were ischemic in nature [20]. The higher overall frequency of stroke and the hemorrhagic nature of most of the strokes in COVID-19 patients on V-V ECMO may reflect the severity of illness, the intensity of the inflammatory response, and the need for systemic anticoagulation [4]. Once stroke developed, the outcome is worse than expected for COVID-19 patients on ECMO. In a systematic review of 1,322 patients from twelve case reports and cohort studies of COVID-19 patients supported by V-V ECMO, the mortality of patients who suffered neurological complications was 92% [21]. This is consistent with other studies of patients who have strokes during ECMO. In a meta-analysis of twenty-five studies for different modes of ECMO, the development of hemorrhagic stroke was associated with a relative risk of mortality of 1.27–4.43 [22]. Similarly, in H1N1 patients supported with VV ECMO, hemorrhagic stroke was the most common cause of death [23].
There are multiple factors that could predispose COVID-19 patients on ECMO to stroke. The results of our analysis showed that obesity and pre-ECMO use of vasopressors are independent risk factors for stroke. Obesity may predispose patients to well established mechanisms underlying stroke, such as atherosclerotic and hypercoagulable pathophysiology [24]. In COVID-19 patients, obesity is associated with poor outcomes [25]. This may be due to the deleterious effects of obesity on pulmonary mechanics as well as a higher basal metabolic rate [26]. Also, adipose tissue has proinflammatory characteristics that intensify the systemic inflammatory response and obese patients could have impaired adaptive immune responses [27]. Hence, the higher tendency for stroke in COVID-19 on ECMO patients could be reflective of the intense inflammatory response that predisposes patients to coagulation and metabolic derangements [28]. Also, lung involvement in severe ARDS causes hypoxemia and hypercapnia which impair the autoregulatory mechanisms of the nervous system.
Our study highlighted that the use of vasopressors before initiation of V-V ECMO is a risk factor for stroke development. The need for the vasopressors could be reflective of the severity of illness in the stroke patients, however in our study there was no significant difference in the severity of illness in stroke and the non-stroke populations as conveyed by the APACHE II or SOFA scores. More importantly, the use of vasopressors reduces cerebral blood flow by increasing the cerebral vascular resistance and increases the cerebral oxygen requirements [29]. In addition, COVID-19 infection induces systemic inflammation, disrupts the cerebral microcirculation by inducing endothelial dysfunction and increased production of nitric oxide and inflammatory cytokines, which further exacerbate the pre-existing neuroinflammation and induce thrombotic events [30].
An abrupt reduction in PaCO2 around the time of ECMO initiation may be mechanistically linked to cerebrovascular complications [31]. Cerebral vascular tone and autoregulation is sensitive to hyper- and hypocapnia. Hypercapnia causes cerebral vasodilation and edema, while hypocapnia cause vasoconstriction and decrease in cerebral blood flow [32]. Also, hypocapnia increases cerebral excitability and metabolic rate which predispose patients to seizure activity and increased cerebral oxygen demand [33]. In a retrospective study of 11,972 patients enrolled in ELSO registry, a large relative reduction (> 50%) in PaCO2 in the first 24-hours after ECMO initiation was associated with neurological complications [11].
Similarly, the level of PaO2 has significant clinical importance. Hypoxemia causes an increase in cerebral blood flow to maintain adequate oxygen delivery [34]. Subsequent hyperoxia after placement on ECMO increases the risk of neurological complications. In a study of 765 patients on V-V ECMO, the presence of moderate hyperoxia (PaO2 101–300mm Hg) was associated with increased mortality [35]. The proposed mechanisms were the increase in reactive oxygen species and the accompanying vasoconstriction that will diminish the end-organ perfusion [36]. Regarding stroke, a multicenter retrospective analysis of 2,894 patients with ischemic stroke, and hemorrhagic stroke on mechanical ventilation, revealed that hyperoxia was associated with increased mortality [37].
Our study showed that ECMO configurations (double-lumen versus dual-cannulas) had minimal effect on stroke development. Despite the theoretical risk of impaired cerebral venous drainage by the ECMO cannulas, and results from analysis of 6,834 patients enrolled in the ELSO registry, points toward minimal effect of cannulation strategy on neurological complications [19]. The current analysis was not powered to elucidate the effect of anticoagulation and cannulation strategy on the frequency of stroke development given the amount of missing data. In addition, there are multiple limitations intrinsic to the retrospective nature of the study. It is an observational study with potential presence of many unmeasured confounders. Moreover, some of our estimates for the hazard of stroke development had wide 95% confidence intervals indicating uncertainty in the effect size. We tried to overcome these challenges through a staged approach using univariable analysis followed by multivariable and joint modelling including data with less than 20% missingness and conducting sensitivity analyses. We could not conduct stroke subtype analysis because of the small number of patients who had stroke.