Effect of Vasopressin on Kidney and Cardiac Function in Previously Hypertensive Patients With Septic Shock: A Randomized Clinical Trial

A) Theoretical foundations and state of the art A.1 Introduction Septic shock is a syndrome characterized by tissue hypoperfusion and hypotension secondary to an uncontrolled infection. It is a frequent cause of admission to the intensive care unit (ICU) and has an associated mortality around 40%(1). Several infectious diseases may lead to septic shock including different agents (bacteria, virus or fungi) and different sites (e.g. Pneumonia, abdominal infections, or urinary tract infections). Even Covid-19 may cause septic shock in a significant proportion of patients admitted to ICU(2).

Acute kidney injury (AKI) is a major complication associated to septic shock. Around 50 % of septic shock patients exhibit early AKI and 30 to 40% will require renal replacement therapy(3, 4), both factors associated with worse outcomes. Until now, there are no specific treatments to prevent AKI or renal failure. The current approach is based on optimizing systemic hemodynamics and promptly correcting hypoperfusion by the administration of fluids and vasopressors.

Tissue hypoperfusion is often present in septic shock patients due to several mechanisms including systemic vasodilatation, relative hypovolemia, myocardial depression, endothelial and microcirculatory dysfunction, and low arterial pressure with impaired global perfusion pressure. The hemodynamic treatment of septic shock is aimed at both, maintaining oxygen delivery above a critical threshold, while keeping a MAP at a level that allows adequate organ perfusion(5). Organ auto-regulation plays an important role to maintain organ blood flow over a range of perfusion pressures(6). There is evidence that that local auto-regulation may be impaired in septic shock(7). The optimal perfusion pressure may vary, especially in previously hypertensive patients as they may have a shift to the right in their kidney auto- regulatory curve(8). This concept was highlighted by a landmark study performed by Asfar and cols.(4), which compared the use of a higher target of MAP (80-85 mmHg) vs the usual target (65-70 mmHg) in septic shock patients treated with NE as the sole vasopressor. Although the study found no differences in the whole study group, among patients with chronic hypertension, those assigned to the higher MAP target had an improved renal function. A Consensus on circulatory shock and hemodynamic monitoring of the European Society of Intensive Care medicine (ESICM 2014) recommended to titrate NE to higher MAP goals in previously hypertensive patients(9). However, in the study of Asfar the incidence of atrial fibrillation increased in the group assigned to the high MAP target, associated to the higher NE doses required, which has raised some concerns about the safety of this strategy(4). In this context, the addition of exogenous vasopressin (AVP), a drug used as a vasopressor but with cathecholamine independent mechanisms, may prevent this side effect by decreasing NE dose requirements.

Low doses of AVP in septic shock appear to be safe and when combined with NE to maintain a conventional target of MAP, it resulted in increased creatinine clearance and decreased use of renal replacement therapy, compared to NE alone (10). Theoretically, AVP can improve glomerular filtration rate(11). Therefore, the addition of AVP to NE to target a higher MAP goal in previously hypertensive septic shock patients may be a reasonable strategy to preserve renal function while avoiding the side effects of high doses of cathecolamines. However, in contrast to NE, AVP increases systemic vascular resistance (afterload) without a parallel inotropic effect. Myocardial dysfunction is highly prevalent in septic shock and it may contribute to persistent hypoperfusion and to worse outcomes(12, 13). Therefore, there is a reasonable concern regarding the impact of AVP on cardiac performance and stroke volume when targeting higher blood pressures.

A.2 Renal dysfunction in septic shock Around 80% of septic shock patients develop AKI throughout their evolution and 30 to 40% require renal replacement therapy (4, 14). According to severity, AKI is usually graded in 3 stages(15). A large epidemiologic study showed that critically ill patients meeting stage 3 AKI criteria have an associated mortality of 51.1%, and in those patients who required renal replacement therapy (RRT) it was 55.3%(16). A large clinical trial of septic shock revealed that 50.4% of patients already had stage 2-3 AKI at ICU admission. Among patients without AKI at enrollment, 37.8% developed AKI during their evolution and the requirement of RRT was around 6%. Moreover, 60-day mortality was three to five times higher in those who developed AKI, independent of whether AKI was present at admission or developed later (3). In addition, AKI adversely impacts short- and long-term clinical outcomes, and healthcare costs (17, 18).