Our study revealed the high frequency of acute neurological events in patients with cardiogenic shock and supported with VA-ECMO (mostly postcardiotomy), and these CNS events were associated with significant morbidity and in-hospital mortality. Ischaemic stroke was diagnosed in 14.9% of patients while ICH was diagnosed in 11.9% of patients and was associated with higher mortality.
Brain injury is a well-known complication of ECMO support. Nasr et al. reviewed 23,951 patients from the Nationwide Inpatient Sample and found 4.1% ischaemic stroke and 3.6% intracranial bleeding . Although that study included a large number of patients, they assessed both VV- and VA-ECMO together and did not examine the risk factors for neurological complications. Gray et al. studied 2000 ECMO-treated adult patients for acute heart failure and found that there was 8% ischaemic stroke and intracranial bleeding with a 43% survival rate . That study combined ischaemic and haemorrhagic strokes and did not evaluate risk factors for the neurological injury. Our study revealed VA-ECMO-treated patients developed 14.9% ischaemic stroke and 11.9% ICH with 76.3% in-hospital mortality compared to patients without acute neurological events. Our study revealed a significant mortality difference between patients with neurological events and those without events, and the patients with ICH had a significantly higher mortality than those with ischaemic stokes.
Lorusso et al. evaluated 4522 ECMO-treated patients included in the registry of Extracorporeal Life Support Organization, detected 15.1% neurological complications occurred during VA-ECMO and identified pre-ECMO cardiac arrest, use of inotrope on ECMO and hypoglycaemia as risk factors for brain injury. The reported hospital mortality of patients with brain injury reached 89% and was significantly higher than those without brain injury 57% .
Recently, Le Guennec et al. studied retrospectively 878 VA-ECMO-treated patients and detected 5.3% ischaemic strokes and 2.8% intracranial bleeding and ICH rather than ischaemic stroke that was associated with higher mortality. Also, that study found that ischaemic strokes occurred after 1 week on ECMO support without specific risk factors and without increased mortality while ICH occurred earlier and was associated with female sex, central VA-ECMO, low platelet count and rapid CO2 change at ECMO start and high mortality .
In our work, there was no significant difference between onset of stroke or ICH and ECMO initiation, and the higher incidence of neurological manifestations in our study may be explained by the higher rates of cardiac surgeries in our studied patients. ECMO was not the only risk factor for neurological events in our patients; cardiac surgery, atrial fibrillation, intracardiac thrombi, haemodynamic instability before ECMO initiation, low cerebral blood flow due to advanced heart failure or other conditions may be also incriminated. Thus, it is very difficult to know the respective effect of the underlying disease(s) and ECMO itself on the development of neurological complications.
In our study, ICH was associated with low body mass index without sex differences, central more than peripheral ECMO, cardiothoracic surgeries, longer cardiopulmonary bypass and aortic cross-clamping times, thrombocytopenia and higher aPTT and INR while ischaemic strokes were associated with atrial fibrillation, diabetes mellitus, intracardiac thrombi and use of IABP.
Regarding analysis of the haemostasis and anticoagulation parameters of our patients, aPTT and PTT ratio were significantly higher at those with CNS events and those who developed ICH had significant thrombocytopenia during initiation of ECMO. Patients who developed ICH had significant thrombocytopenia and higher aPTT and INR compared to those with ischaemic strokes. Few studies have analysed the risk factors for ICH in VA-ECMO patients. Le Guennec et al.  did a multivariable analysis and found that at ECMO initiation, platelet count less than 100 (109/L) was associated with ICH while platelet count > 350 (109/L) was associated with ischaemic strokes and no relation between other haemostatic parameters or anticoagulation with brain injury. Sandersjöö et al.  reported ICH in 21% of 253 VV- and VA-ECMO-supported patients and that pre-ECMO antithrombotic treatment and low platelets on ECMO were associated with ICH. Kasirajan et al.  studied 78 VA-ECMO-treated patients, among whom 18.9% had ICH and the ICH was associated with female sex, renal failure and thrombocytopenia.
Regarding the analysis of the metabolic profile of our studied patients, the patients who developed CNS complications had significant hyperlactataemia (peak and after 24 h), hyperglycaemia and hypoalbuminaemia. Omar et al. evaluated risk factors in a combined VA- and VV-ECMO patients among whom 5.8% developed ischaemic strokes; their multivariable analysis detected pre-ECMO blood lactate > 10 mmol/L as being independently associated with strokes .
In our work, the peak lactate level over 15.5 mmol/L measured after VA-ECMO insertion had a 65.8% sensitivity and 69% specificity for predicting CNS complications (p = 0.05) while lactate level over 3.5 mmol/L measured after 24 h of VA-ECMO support had a 73.7% sensitivity and 62.1% specificity for predicting CNS complications (p = 0.006 ). The impact of hyperlactataemia on mortality has been documented in patients with cardiogenic shock and in those with cardiac arrest even if there is no cut-off value to be associated with worse outcomes or to guide haemodynamic and resuscitation management [16, 17].
We found significant hyperglycaemia in those who developed acute neurological manifestations especially in the ischaemic stroke while there was no significant difference regarding low blood sugar levels. We do not know if this finding was related to the cardiac surgeries and cardiopulmonary bypass or the extracorporeal circulation and inotropes used. Previous studies concluded that high glucose levels during and after CPB is an independent predictor of morbidity and mortality in both diabetic and non-diabetic patients . Patients with persistently elevated glucose levels have increased post-operative mortality and risk of cerebrovascular strokes [19, 20].
In our study, we assessed our patients at admission and after 48 hours with SOFA score to assess clinical severity and degree of organ failure due to its simplicity and validity in reflecting progressive organ failure and increased mortality [21,22,23]. SOFA score at admission was higher in patients who developed acute brain injury than those who did not have clinical neurological events. Also, it was higher in patients with ICH than those who developed ischaemic strokes. SOFA score after 48 h of admission increased in those with CNS complications especially in those who had ICH.
Finally, acute neurological complications were frequent in patients supported with VA-ECMO and associated with significant morbidity and hospital mortality, but it was not confirmed if these CNS complications were related to ECMO itself as a supportive modality or related to underlying diseases and critical conditions of patients, the cardiac surgeries or the deteriorated metabolic and haemostatic parameters.