Renal Recovery in Critically Ill Adult Patients Treated With Veno-Venous or Veno-Arterial Extra Corporeal Membrane Oxygenation: A Retrospective Cohort Analysis

The use of extracorporeal membrane oxygenator (ECMO) has risen for adults and children with severe cardiac and pulmonary dysfunction. Of the two types of ECMO, veno-venous (VV) ECMO is used for respiratory support. In contrast, veno-arterial (VA) ECMO is used for cardiac support [1, 2]. Generally, patients receiving ECMO therapy are critically ill. These patients receive aggressive treatments with nephrotoxic medications, vasopressor support, antibiotics, and intravenous contrast agents that put them at high risk for acute kidney injury (AKI) [3].

Additionally, patients are also exposed to risk factors specific to the ECMO circuit’s mechanics that may affect renal recovery [4]. The incidence of AKI in patients on ECMO is about 75 to 80% [3, 5, 6]. Several factors related to the intervention of ECMO treatment could contribute to AKI. First, ECMO initiation and subsequent vasopressors’ adjustments can cause rapid hemodynamic fluctuations with resultant ischemiareperfusion-induced AKI [7]. Second, blood exposure to artificial surfaces within the ECMO circuit can cause systemic inflammation [8], hypercoagulation, haemolysis or haemoglobinuria [9]. Finally, hormonal variations, including renin-angiotensin-aldosterone dysregulation, occur in patients receiving ECMO, leading to impaired renal homeostasis and maladaptive hemodynamic fluctuations [4].

Differences in hemodynamic flows and molecular changes between the two types of ECMO circuits may pose different risks of developing or recovering from AKI. Cardiac output in VA ECMO is a varying mixture of pulsatile (native cardiac) and non-pulsatile (ECMO flow) based on the residual function of the heart [10]. On the other hand, patients on VV ECMO have only pulsatile, native cardiac, blood flow [11]. Veno-arterial ECMO is closely related to cardiopulmonary bypass (CPB) [12]. Several studies suggested that the systemic inflammatory response in patients on CPB depends on the nature of the blood flow with pulsatile blood flow having reduced inflammatory response compared to non-pulsatile blood flow in extracorporeal circulation [13]. It has been further theorised that end-organ microcirculation is improved with pulsatile blood flow [14].

Development of AKI is associated with significant morbidity and mortality. Dialysis dependence at ninety-days is as high as 30% and a five-year cumulative risk for developing end-stage renal disease (ESRD) of 11.7% [15]. Mortality of patient developing AKI in an ICU can be greater than 50% [16]. Garzotto et al. showed that out of 576 patients in the ICU 379 developed AKI, 59.4% had a complete renal recovery, 13.5% had a partial renal recovery, and 27.2% of patients did not recover their renal functions at the time of death or ICU discharge. Their study also showed that when AKI patients were compared with non-AKI patients, they had a higher crude ICU mortality (28.8 vs 8.1%; p<0.001) and longer ICU length of stay [17]. Given these findings maximising the chance of renal recovery after AKI is of prime importance. Hence, knowledge about the prevalence of renal recovery in patients on ECMO with AKI is valuable in predicting morbidity and mortality.

Renal replacement therapy (RRT) is sometimes required in patients who develop AKI to assist with volume management and metabolic derangements [3]. The combination of ECMO and AKI requiring RRT portends a poorer prognosis, with an in-hospital mortality rate 3.7-fold higher as well as a high risk for the long-term development of CKD or dialysis-dependent renal failure [18, 19]. Antonucci et al. found no significant difference in the intensive care unit (ICU) mortality in ECMO patients with AKI requiring or not requiring RRT. They also found no significant differences in the ICU mortality between VA and VV ECMO patients with AKI [20]. Significantly, short-term renal outcomes in patients who develop AKI have not been compared by type of ECMO support.

The study aimed to analyse and compare renal outcomes in critically ill patients who develop AKI and receive VA or VV ECMO support.

Specifically, the association of complete renal recovery, partial renal recovery, and dialysis dependence at the time of discharge in adult critical care patients with the type of ECMO was assessed.

AKI is a common complication in critically ill patients. It portends a significant risk for short- and long-term mortality, CKD development, and cardiovascular events [15]. After an episode of AKI, the rate of dialysis dependence requiring RRT ranges from 0 to 40% [24, 25]. Hence, it is crucial to reduce the exposure to factors that may contribute to the development of AKI and focus on maximising the chance of renal recovery after AKI. In our study, of the 122 critically ill patients treated with ECMO, 109 (89%) developed AKI during the hospitalisation, which is similar to the reported incidence of 75 to 80% AKI in patients on ECMO [3]. Chen et al. evaluated long term outcomes in 3251 patients with AKI who received ECMO. In their cohort, complete renal recovery, partial renal recovery, and dialysis dependence occurred in 48.4%, 32.6% and 19% of the patients [19]. Our study is the first to evaluate the renal outcomes by type of ECMO support. We found that the overall AKI incidence and renal recovery rate did not differ by type of ECMO support.

In regards to AKI, the baseline serum creatinine was identified as the most recent serum creatinine before admission or serum creatinine at the time of admission if no previous labs were available and the estimated glomerular filtration rate (eGFR) was reported using the CKD-EPI equation [26]. The presence of other risk factors for AKI and their association with a renal outcome such as the use of IV contrast [27], NSAIDs [28], CPB machine [29], nephrotoxic antibiotics [30], sepsis [31], CHF [32] and vasopressors-dependent hypo-tension were also evaluated in the present study [33]. The diagnosis of sepsis was statistically more common in the VV ECMO group. This could account for the higher incidence of stage 3 AKI and RRT’s need in this group. The higher RRT rates in VV ECMO group are due to the higher number of Stage 3 AKI compared to the VA ECMO group. It was noted that patients in the VV ECMO group had longer ICU length of stay, likely related to differences in the primary clinical indication for ECMO initiation. There was no significant difference between the two ECMO groups concerning the distribution of AKI risk factors such as use IV contrast, NSAIDs, nephrotoxic antibiotics, CHF, hypotension and vasopressor-dependent hypotension. Though the baseline serum creatinine was similar between the groups, patients in the VV ECMO group had higher peak serum creatinine levels before RRT initiation (Figure 1). This might be related to the indication for RRT; those with VA ECMO may have had more volume overload as the indication for dialysis instead of solute clearance, making it difficult to draw firm conclusions on kidney injury potential between ECMO groups based on comparison of serum peak creatinine values alone.

In the present study, the complete renal recovery rate was not statistically different between the two ECMO groups. Though VV ECMO group had higher APACHE II scores, stage 3 AKI, and need for RRT; 43% in the VV ECMO group had complete renal recovery relative to 26% of patients in the VA ECMO. The cardiac output in VA ECMO is non-pulsatile or a mixture of pulsatile and non-pulsatile flow. The VA setting improves the total cardiac output. It facilitates renal blood flow [34].

On the other hand, in VV ECMO, systemic oxygenation and delivery are improved, contributing to better renal metabolism [3]. The rates of partial renal recovery and dialysis dependency at the discharge time were similar in both ECMO groups. The difference in the rate of complete renal recovery could be related to our primary hypothesis that the pulsatile blood flow with VV ECMO renders renal hemodynamics closer to physiologic [14]. These findings need to be interpreted with caution, given the smaller sample size. The results serve as preliminary data for more extensive studies.

We noted that serum lactic acid levels were significantly higher in the VA ECMO. Previous studies showed that higher lactic acid levels are directly associated with higher hospital mortality [35]. Though in-hospital mortality for patients who developed AKI on ECMO was not statistically different between the groups possibly due to small sample size, the VA ECMO group had 66% mortality rate compared to 49% in the VV ECMO group. Serum lactic acid levels did not correlate with renal outcomes in our cohort. We noted overall in-hospital mortality of 57% for patients who developed AKI and were treated with ECMO, similar to that reported by Antonucci et al. [20]. The use of CPB machine is also a known risk factor for AKI [29]. In the present study, although CPB was more commonly used in the VA ECMO group, as these patients had a primary cardiac need for ECMO support, renal outcomes were not impacted by CPB use.

No significant differences in the extent of renal recovery, varying from complete to partial and dialysis dependency between the patients who develop AKI and treated with VV or VA ECMO, were observed.

While clinicians should be cautious interpreting this data, future research in this field on larger collaborative multi-institutional cohorts is needed to understand renal outcomes in patients undergoing extracorporeal oxygenation.