Background
Sepsis is a leading cause of death among critically ill patients and a global public health burden, leading to high healthcare costs [
1,
2]. In 2017 alone, there were 48.9 Million cases of sepsis and 11.0 Million deaths (19.7% of all global deaths) related to sepsis [
3]. The burden of sepsis is highest in early childhood, followed by a second peak in incidence in late adulthood [
4]. Recognising sepsis as a global health priority, the World Health Assembly adopted a resolution to reduce its burden through better awareness, early diagnosis, and aggressive management [
2]. This is reflected in national healthcare efforts, one example being the German Quality Network Sepsis which aims to decrease sepsis-related mortality [
5].
Approximately, 15% of patients with sepsis develop septic shock, defined as persistent hypotension requiring vasopressors and elevated lactate levels despite adequate fluid resuscitation, where hospital mortality is in excess of 40% [
3]. A subset of adult patients with septic shock develops concomitant left ventricular dysfunction, often described as septic cardiomyopathy [
6]. However, septic cardiomyopathy is poorly defined in the literature and may be an underdiagnosed entity due to a lack of formal diagnostic criteria [
6‐
10]. Adult patients with septic cardiomyopathy have 2–3 times increased mortality compared with those with septic shock alone [
7]. Single-centre studies have shown dismal survival rates (10–30%) when severe left ventricular (LV) dysfunction coexisted in patients with septic shock [
11].
Unlike many aetiologies of cardiomyopathy, septic cardiomyopathy is reversible, and early detection and intervention of septic cardiomyopathy in patients with septic shock may reduce mortality [
11]. The encouraging outcomes of extracorporeal membrane oxygenation (ECMO) in paediatric septic shock have led to it being recommended as a potential therapy in some societal guidelines [
12‐
18]. However, the haemodynamic pattern of septic shock is markedly different across age groups: new-born infants typically present with pulmonary hypertension and right heart failure, young children with left heart failure, and adolescents and adults with distributive shock [
16]. Given the contrast in haemodynamic status between adult and paediatric shock, the use of ECMO, and in particular venoarterial ECMO (VA ECMO), in adult septic shock remains controversial.
VA ECMO has been found to be a risk factor for mortality when compared to venovenous ECMO (VV ECMO) in patients with sepsis [
19‐
21]. This might be due to the differing indications for ECMO in sepsis (concomitant hypoxemia and right ventricular dysfunction in VV ECMO vs. cardiomyopathy and vasoplegia in VA ECMO), potentially reflecting less severe disease for patients supported with VV ECMO. Nonetheless, single-centre observational studies have shown that a subset of septic adults (specifically those with septic cardiomyopathy) may benefit from VA ECMO for mechanical circulatory support [
22‐
24]. We conducted a systematic review of literature on the outcomes and complications of VA ECMO as mechanical circulatory support in adult patients with septic shock.
Discussion
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 468 patients was 36.4%. Subgroup analyses revealed that pre-ECMO LVEF 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 [
6]. 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 [
50], with similar findings among observational case series reporting on VA ECMO for adult and paediatric septic cardiomyopathy [
12,
13,
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 [
53]. This is compounded by the lack of longitudinal echocardiography data to ascertain cardiac function at premorbid, disease, and recovery states [
9]. 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 [
8]. 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 [
22]. 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, and increases afterload, eventually decreasing cardiac output [
58]. Of note were six patients from the study by Falk and colleagues, who underwent VV ECMO and then converted to VA ECMO. All six patients had LVEF > 35% and none of them survived to discharge. Similarly, patient profiles described by studies from Asia were characterised by distributive shock and relatively preserved LV function. On the other hand, patients in studies from Europe typically presented with severe myocardial depression, which might explain why survival reported by studies from Europe was higher than those from Asia. Apart from this, the proportion of patients undergoing CPR prior to or during ECMO, that is associated with greater mortality, was also higher in studies from Asia.
Strengths of this study include the broad inclusion criteria and relevant exclusion criteria. Our review included 14 studies, pooling data from eight different countries across three 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. In addition, there was limited data on vasopressor scores or cardiac index in most of the studies. Some of the pertinent sequelae to VA ECMO such as differential oxygenation and its impact on organ dysfunction in adult septic patients could not be fully elucidated due to lack of granular data. 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 randomised 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 randomisation in ECMO studies [
59‐
61].
Conclusions
Our systematic review and meta-analysis of the current literature suggests that VA ECMO may be a viable salvage therapy among select patients with septic shock and concomitant myocardial depression, characterised by persistently low cardiac output refractory to inotropes. By contrast, ECMO is associated with especially poor outcomes among patients with septic shock but without severe ventricular dysfunction. Overall pooled survival in our meta-analysis was 36.4%. Patients with septic cardiomyopathy had considerably better survival than those with normal LV function. While the results of this review might only be translatable to a small population of patients with septic shock and concomitant cardiomyopathy, judicious selection of these patients for VA ECMO could improve mortality.
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