This systematic review and meta-analysis quantitatively summarised the evidence for survival of adult patients with septic shock requiring VA-ECMO. Pooled survival across 14 studies and 438 patients was 36.4%. Subgroup analyses revealed that pre-ECMO LVEF and ECPR significantly influenced survival rates of patients with septic shock initiated on ECMO in addition to variations in survival by geographic region of study origin.
While data are scarce, studies investigating VA-ECMO adult patients with preserved LVEF have reported dismal outcomes.[40, 46, 49] It has been proposed that septic patients who have hyperdynamic left ventricular function on echocardiography have poorer outcomes than those with normo- or hypo-kinetic profiles, and this stratification may permit better patient selection for VA-ECMO in septic shock. A propensity-score weighted analysis found that select patients with severe myocardial dysfunction (very low LVEF) receiving VA-ECMO during the first four days of septic shock had significantly lower mortality than those without ECMO, with similar findings among observational case series reporting on VA-ECMO for adult and paediatric septic cardiomyopathy.[11, 12, 47] Concordant with these observations, our analysis found that survival among patients with LVEF > 35% was significantly lower than those with LVEF < 20% (62.0 % Vs 32.1%). Patients with LVEF between 20% and 35% had intermediate survival (42.3%), suggesting a possible graded effect of LVEF on outcomes. While plausible, further research investigating pre-ECMO LVEF and its relation with mortality on VA-ECMO for adult septic shock is needed to conclusively substantiate our findings.
Currently, the diagnostic criteria for adult septic cardiomyopathy are not fully established, due to the complexity and variations in the cardiovascular response to infection.[52, 53] It is also difficult to determine how well myocardial dysfunction correlates with organ dysfunction in general, and how much it independently contributes to poorer outcomes. This is compounded by the lack of longitudinal echocardiography data to ascertain cardiac function at premorbid, disease, and recovery states. Nonetheless, it is understood that transient and reversible myocardial depression is common in septic patients, and is associated with low or normal LV filling pressures despite depressed systolic function.[54, 55] Three broad criteria were proposed to characterise septic cardiomyopathy: LV dilatation with normal- or low-filling pressure, reduced ventricular contractility, and ventricular dysfunction with reduced response to volume infusion. While increasing perfusion and cardiac output can improve survival among these patients,[56, 57] the use of very high-dose vasopressors might contribute to a vicious circle of vasoconstriction and refractory cardiovascular failure. By providing mechanical circulatory support, VA-ECMO can potentially restore systemic perfusion pressure and increase oxygen delivery. This corrects the cellular hypoxia and metabolic acidosis during septic cardiomyopathy, ameliorating vasopressor dependence and potentially improving the chances of survival.
In septic patients with preserved cardiac function, VA-ECMO may be contraindicated as it reduces preload, increases afterload, and increases capillary leakage, eventually decreasing cardiac output. Of note were 6 patients from the study by Falk and colleagues, who underwent VV-ECMO and then converted to VA-ECMO. All 6 patients had LVEF > 35% and none of them survived to discharge. This might also explain why survival reported by studies from Europe was higher than those from Asia. While patients in European studies presented with severe myocardial depression, Asian studies described patient profiles of distributive shock and relatively preserved LV function. Apart from this, the proportion of patients undergoing ECPR, which is associated with greater mortality (RR survival = 0.403, p = 0.01), was higher in studies from Asia. While ECPR may be construed as a version of VA-ECMO, factors contributing to poor survival on ECPR are manifold and may not be similar to VA-ECMO.
Strengths of this study include the broad inclusion criteria and relevant exclusion criteria. Our review included 14 studies, pooling data from 8 different countries across 3 regions. We elucidated factors correlating with survival via subgroup analysis and meta-regression, reducing confounding. Coupled with non-significant results from Egger’s test, we sourced for unpublished data for IPD meta-analysis, limiting publication bias. Nonetheless, we recognise several limitations of this study. The absence of randomised studies increases the risks of confounding and bias, in particular, confounding by indication. Furthermore, there are different initiation thresholds and varying protocols and practices between individual institutions, which can introduce confounding factors given the lack of risk adjustment or propensity-scoring techniques. Finally, the need for VA-ECMO in adult septic cardiomyopathy is uncommon, which makes these results applicable to a narrow spectrum of patients in clinical practice. While it would be most appropriate to perform a prospective randomized clinical trial in this patient population, there would be considerable challenges in doing so, including the low incidence of patients with septic shock and septic cardiomyopathy, and the ethical challenges surrounding randomization in ECMO studies.[60–62]