Discussion
The major finding of this study is that VA-ECMO cannulation location did
not appear associated with stroke risk. Ischemic stroke was the most
common stroke subtype, followed by hemorrhagic transformation, and
intracranial hemorrhage. Lesions were most common in the right
hemisphere, followed by the left hemisphere lesions, bilateral lesions,
and vertebrobasilar lesions.
Current literature suggests that 10-50% of VA-ECMO patients suffer
neurological complications 6,8,12. Variable incidence
rates may be attributed to inconsistent definition of what constitutes a
neurological complication, with some studies including brain death,
diffuse anoxic brain injury, and coma under the scope of neurological
complications while other studies do not. Neurological complications
include subclinical cognitive impairment, seizures, paraplegia,
peripheral neuropathy, and ischemic and hemorrhagic strokes. Ischemic
stroke and hemorrhagic stroke are catastrophic complications associated
with ECMO. Incidence rates for stroke range from 4.2-7.8% among VA-ECMO
patients6-8. The true stroke incidence rate may be
higher as stroke events are likely unrecognized. Neurological diagnosis
is often difficult due to deep sedation and systolic and metabolic
derangements encountered in intensive care unit patients. In a
prospective study, Mateen et al. found that despite a lack of clinical
diagnosis of stroke, autopsy studies of 9 of 10 brains showed
hypoxic-ischemic and hemorrhagic lesions of vascular
origin12.
The specific pathophysiology leading to ischemic or hemorrhagic stroke
during VA-ECMO is poorly understood. There are multiple proposed stroke
risk factors in patients undergoing VA-ECMO. Such risk factors may
include cardiac arrest, cardiac surgery, myocardial infarction, heart
failure, need for renal replacement therapy, sepsis, duration of ECMO,
presence of bleeding at other sites, and non-pulsatile cerebral
perfusion7, 13, 14. Small studies have suggested that
certain risk factors are independently associated with stroke: Omar et
al. found that high pre-ECMO blood lactic acid levels (lactic acid
> 10 mmol/L) were independently associated with ischemic
stroke9. In a retrospective, single-center study,
Saeed et al. found a strong association between early low-level
hemolysis (i.e. 48-hour plasma-free hemoglobin 11-50 mg/dL) with
subsequent non-hemorrhagic stroke15. However, both
studies were limited by small number of cases with the main outcome
variable. As such, assessing the relative impacts of the underlying risk
factor and ECMO itself is challenging.
Cannulation site is a potentially modifiable risk factor that has not
been extensively studied. The association between outflow cannulation
site and neurological complications has been studied among pediatric
VA-ECMO patients with mixed results. Incidence rate of neurological
complications in neonatal VA-ECMO patients has been estimated to be
20%16. A study of pediatric VA-ECMO patients by Werho
et al.17 did not find association between stroke risk
and cannulation site in neonates. Another study by Pinto et
al.19 found that peripheral cannulation was associated
with higher incidence of stroke in pediatric patients. Few studies have
studied such associations among adult VA-ECMO patients. Laterality of
lesions have not been extensively studied in adult VA-ECMO patients, and
reports in pediatric patients have been conflicting19,
21.
This study is subject to limitations particular to non-randomized
studies. Due to the small number of cases with the main outcome
variable, a main study limitation is the low statistical power of the
analysis. In order for our study to have 80% power at alpha = 0.05, the
effect size, as demonstrated by the odds ratio, would have to be at
least 6 (compared to our findings, where OR=1.05 for both axillary vs.
femoral cannulation and central vs. femoral cannulation, and OR=1 for
axillary vs. central cannulation). Therefore, our study was underpowered
to detect a difference in stroke rates based on cannulation site, if
such a difference existed. Second, selection bias may have been
introduced in terms of choice of cannulation strategy due to
accessibility. For example, most patients who received central
cannulation had underlying etiology of postcardiotomy shock for ease of
access, and patients with femoral cannulation were more likely to have
acute myocardial infarction as underlying cardiogenic shock etiology, as
shown by pairwise comparisons with p<0.01 of Bonferroni
correction. Larger, multi-center studies are needed to confirm these
findings. In order to lower the risk of information bias, all documented
stroke outcomes were verified with a CT scan of the head. Therefore,
overall incidence of stroke is likely underestimated. Furthermore, the
long study period (12 years) introduces technological advances that may
have changed patient management during the study period (see
Supplementary Table S2).