The AminoECMO Pilot Trial

Acute kidney injury (AKI) is common in critically ill patients, especially in those requiring extracorporeal membrane oxygenation (ECMO). AKI is associated with significant morbidity and mortality. The current management for the prevention of AKI is supportive, such as treating underlying causes, avoiding nephrotoxins, and optimising fluid status. Despite optimal care, more than half of ECMO patients develop severe AKI requiring renal replacement therapy (RRT), including 46% in venovenous (V-V) ECMO, and 61% in venoarterial (V-A) ECMO. Severe AKI is associated with significantly worse outcomes and higher mortality, and there is a strong need to identify therapies that can improve renal function in ECMO.

It has already been established that glomerular filtration rate (GFR) increases in response to (IV or enteral) protein administration. The precise mechanism for increased GFR is not completely understood, however recruitment of dormant renal function (called functional renal reserve RFR) has been hypothesised. Amino acid delivery is associated with a renal vasodilation mediated increase renal blood flow by >30%. Different metabolic, endocrine, and paracrine factors have been implicated. It has been suggested that recruitment of RFR could prevent or manage AKI.

Amino Acids Infusions and Preventing AKI The impact of amino acids on renal function has been investigated in clinical trials. This has predominantly occurred in the perioperative setting, in patients with stable renal function undergoing operations associated with a significant risk of developing an AKI. In cardiac surgery, several early-phase studies have demonstrated an improvement in measures of renal function with the perioperative infusion of amino acids. These findings are not isolated to the cardiac surgery population, which may have unique pathological mechanisms for AKI, as a recent pilot RCT in patients undergoing major urology surgery demonstrated a reduction in the incidence of postoperative AKI. Recently a large RCT published in the New England Journal of Medicine showed that the peri-operative administration of amino acids in patients undergoing cardiac surgery significantly decreased the incidence of AKI. Importantly, in a sub group analysis of 232 patients who underwent perioperative mechanical cardiac support, the rate of AKI was lower in the group randomized to amino acids: 44.6 vs 60.8% relative risk 0.73 (0.57-0.94 P=0.01 NNT =6) suggesting a potentially important benefit in this group.

Despite the increasing interest and quantity of research surrounding the association between amino acid infusion and kidney function, several unanswered questions remain. Firstly, although amino acid infusion has been demonstrated to reduce the incidence of AKI when administered before an insult, the impact on renal function in critically ill patients receiving ECMO therapy is unclear, particularly as the insult may have already started to occur prior to ECMO initiation. Secondly, several recent studies of high dose protein have suggested potential harm in patients randomised to a higher dose of protein (2.2g/kg/day vs <1.2g/kg/day) when given over prolonged periods.

The intervention in this pilot differs as it is will commence <24hours post ECMO initiation, and it is given short term only (up to 48 hours). It remains unclear if this will translate to improve renal and patient outcomes.

In summary, ECMO therapy is associated with an increased risk of acute kidney injury. The current management for prevention of AKI is supportive with no current therapies that can decrease the risk of AKI and improve clinical outcomes. Given the physiologically and clinically demonstratable impact of amino acid infusion on renal function, further research is logical and desirable.

Inclusion criteria

• Aged ≥18 years
• Enrolled in the EXCEL Registry

Exclusion criteria

• Urea level ≥30 mmol/L
• Requirement for renal replacement therapy
• Chronic hemodialysis or peritoneal dialysis
• ECMO for ≥24 hours
• Pre-admission CKD with an eGFR <30 ml/min
• Previous enrolment in this study
• Pregnant or Lactating
• Known contraindication to AA infusion
• ECMO expected to cease ≤24 hours
• Expected to be transferred to another hospital ≤24 hours
• Treating clinical team deems study is not in the patient's best interest