Selepressin in septic shock: A wake-up call for new drugs
Résumé
Editorial Selepressin in septic shock: A wake-up call for new drugs Despite more than three decades of intensely investigating patients with septic shock, their mortality rate remains unacceptably high, particularly when the use of high-dose norepinephrine is required. An observational study reported mortality rates exceeding 80% for patients receiving intravenous norepinephrine doses above 1 mg/kg/min [1], and endogenous elevation of norepineph-rine serum concentrations has also been associated with increased mortality in patients with chronic congestive heart failure [2]. While one may assume that norepinephrine levels rise in response to increasing severity in patient condition, there is no proof of directionality. This association therefore suggests that treating patients with septic shock with exogenous norepineph-rine may in fact be counterproductive. Indeed, norepinephrine may not be the ideal medication for the treatment of septic shock. High-dose norepinephrine generates immunosuppression, thereby potentially contributing to the infectious process [3-5]. Norepinephrine increases blood pressure by triggering contraction of vascular smooth muscle. This effect is mediated through a-receptors that activate the inositol triphos-phate cascade, resulting in a massive release of intracellular calcium into the systemic circulation. However, a-receptors undergo downregulation in patients with severe inflammation. These are all good reasons for attempting to identify alternatives to norepinephrine. Vasopressin, one such alternative, is a neuroendocrine mediator released by the posterior hypophy-sis. Vasopressin modulates an intracellular chain of action similar to that of norepinephrine; i.e. a release of intracellular calcium through the phospholipase C signaling cascade [6]. However, it does so by activating V1a, V1b and V2 receptors. Contrary to norepinephrine, vasopressin can maintain activity in acidotic conditions [7]. Experimentally, in low doses, it can also act synergistically with norepinephrine [8]. To date, no randomised controlled trial (RCT) comparing treatment of patients with septic shock with norepinephrine versus vasopressin has revealed a survival difference [9,10]. Similarly , no study has found more deleterious effects when using either one of these vasopressors. Accordingly, vasopressin was endorsed as a second line vasopressor in the 2016 Surviving Sepsis Guidelines [11]. However, the clinical equivalence found in studies thus far has discouraged several European agencies from licensing vasopressin and/or approving reimbursement to healthcare facilities providing this medication, thereby effectively eliminating clinician discretion concerning medication choice. Vasopressin induces intracellular activation via V1a receptors, which triggers vasoconstriction. However, vasopressin also activates V1b and V2 receptors, both of which set in motion eventual extravascular fluid loss [6]. This effect is undesirable in septic shock where less fluid administration has been associated with increased survival. Selepressin, a newly available, short-acting vasopressin analogue, acts selectively on V1a receptors, thereby avoiding fluid retention. Animal models of ovine septic shock consistently show that administration of selepressin is accompanied by less net fluid gain than administration of arginine-vasopressin [12-14]. A pioneer randomised controlled study recently conducted in adult patients with early septic shock (n = 53) also confirmed lower net fluid gain among patients treated with selepressin versus those treated with placebo [15]. Observational studies show a clear and consistent association between net positive fluid balance and poorer outcomes in septic shock [16,17]. Therefore, it is logical to infer that the reduced fluid gain in septic patients treated with selepressin will also improve outcomes. In a well-designed multicentre trial conducted in 63 intensive care units across five countries (Belgium, Denmark, France, the Netherlands and the United States), Laterre et al. randomised 868 patients with septic shock to norepinephrine plus placebo (n = 283) or norepinephrine plus selepressin (n = 585) [18]. The primary endpoint sought was a composite 1.5-day reduction in ventilator-and vasopressor-free days. Assuming the baseline of ventilator-free days was 10 days and that of vasopressor-free days was 20 days, such a difference would represent a 7.5 to 15% improvement (power 91%, 1-tailed a-error 0.2). Treatment allocation and outcomes analyses were blinded. An adaptive platform was used for this study, enabling the analysis of several dosing regimens of selepressin, as well as patient recruitment until the sample sizes required for the study endpoints were met.