In this ELSO Registry analysis of 9,807 peripheral VA-ECMO patients, we found that a low PP (≤ 10 mmHg) measured at 24-hours of ECMO support was independently associated with greater occurrence of ABI in peripheral VA-ECMO patients after adjusting for pre-selected clinically relevant covariates. Additionally, low PP was associated with CNS ischemia but not ICH. We also identified other risk factors for ABI in peripheral VA-ECMO patients: higher delta PaCO2, pre-ECMO cardiac arrest, and on-ECMO hemolysis, cardiac arrhythmia, and renal replacement therapy.
There may be multiple mechanisms at play that can lead to PP influencing ABI in this cohort. One potential mechanism relates to the loss of pulsatility that occurs inherently with VA-ECMO and is enhanced by adjustment of pump speeds,18–20 as nonpulsatile flow is associated with elevated vascular resistance, increased muscular sympathetic nervous system activity, coronary artery disease, limited oxygen consumption, and interruption of cerebral autoregulation.21–23 These factors have been associated with increased incidence of ABI24–29 in non-ECMO patients. Additionally, patients undergoing coronary artery bypass graft with IABP and cardiopulmonary bypass (i.e., nonpulsatile flow) have been shown to have less endothelial activation30–33 and to observe a reduction in nitric oxide34, 35 due to systemic inflammatory response syndrome.9, 36, 37 Patients on the ECMO circuit frequently experience extreme changes in hemodynamic parameters such as PaO217 and PaCO2,38–40 which were previously shown to be associated with ABI. These blood gas derangements, combined with already compromised endothelium function and nonpulsatile cerebral blood flow,41 may lead to ABI. Additionally, as left ventricular (LV) venting may lower PP and further predispose VA-ECMO patients to ABI, future research is warranted to investigate the effects of tMCS such as IABP and Impella® on the association between PP and ABI.
Our results demonstrated that low PP was associated with CNS ischemia but not ICH in peripheral VA-ECMO. Induced by ECMO circuit, the absence of pulsatility is associated with reduced O2 consumption and impaired cerebral autoregulation, potentially contributing to CNS ischemia.21 Furthermore, low PP can indicate inadequate cardiac contractility, and thus systemic hypoperfusion, which may increase the risk of CNS ischemia. Interestingly, in contrast to previous literature describing that a larger delta PaCO2 was associated with ICH,42 our study demonstrated that delta PaCO2 was associated with CNS ischemia rather than ICH. These results did not persist in central VA-ECMO which may be due to different hemodynamic states between both cohorts.13 Other additional key factors such as the use of systemic anticoagulation, duration of ECMO support, hemolysis, and platelet imbalance may also be involved in the pathophysiology of ICH.43 Overall, these findings suggest that additional research is necessary to clarify how certain risk factors lead to either CNS ischemia or ICH in peripheral VA-ECMO patients.
Interestingly, unlike a previous study suggesting severe hyperoxia is associated with ABI,17 an increase in PaO2 was a protective factor for ABI in our analysis. One explanation is that aggressive oxygen therapy helps mitigate the effects of potential hypoxemia during ECMO support as hypoxemia in ECMO patients is well documented.44, 45 Furthermore, a higher PaO2 may help increase regional brain oxygen tension46 and accordingly improve the cerebral metabolic rate of oxygen. We also note we did not “bin” PaO2 values (continuous variable) by groups as this previous study did which may increase their risk of bias.47 Overall, these results suggest that additional research with methodically rigorous study design is necessary to elucidate the mechanisms regarding how these physiological variables lead to ABI in continuous blood flow under the ECMO circuit.
Early assessment and recognition of myocardial function using low PP during the first 24 hours of ECMO support has important clinical implications. Recognizing low PP may allow providers to promptly develop appropriate management techniques, including fine-tuning ECMO settings and using inotropes/vasopressors,48 LV venting,49 or pulsatile ECMO flow50 to improve hemodynamics. Notably, our analysis showed that the use of vasopressors before ECMO support was protective of ABI, supporting our speculation. Additionally, upon recognizing low PP, clinicians can consider more vigilant and standardized neuromonitoring strategies to ensure adequate cerebral perfusion and prevent occurrence/worsening of ABI, which is especially important in peripheral VA-ECMO due to the potential for differential oxygenation.51
Limitations
Our analysis was retrospective and observational, thus limiting our ability to determine causation effects. Additionally, the ELSO Registry lacks granular ABG data, only allowing us to extract one pre-ECMO and one on-ECMO data point for each patient in our analysis. Similarly, for PP we are limited to a single value at 24 hours, however, it is unclear if there is significant variance over the first 24 hours that would influence interpretation. This methodology has also been previously validated in an ELSO Registry analysis of PP and mortality in 2,400 VA-ECMO patients.52 Furthermore, it is unclear how such variance would systematically bias our results as any variation should be at random and thus favor the null hypothesis. Additionally, low PP may represent a population with higher severity of illness which may explain the higher occurrence of ABI despite attempting to account for this with statistical modeling. The ELSO Registry also does not contain specific anticoagulation data, which is a known risk factor for ABI. Nevertheless, we adjusted for many ECMO-specific and clinically relevant covariates in our analysis, and low PP was still independently associated with ABI. Additionally, our study represents the largest and most comprehensive analysis to-date investigating the association between PP and ABI in VA-ECMO patients. We also used methodically rigorous methods in our analysis including multiple imputation to handle missing data, thus minimizing bias and invigorating the validity of our analysis53 and cubic spline analysis when identifying a PP threshold to abate the loss of information and poor predictions when using continuous variables.54 We also excluded ECMO patients simultaneously on LV venting devices as LV venting can directly modulate the PP in ECMO and thus could potentially confounding our findings.3 Finally, the optimum ECMO pump flow rate based on body surface area for each patient was not able to be determined in the ELSO Registry and should be noted.