Adjunctive terlipressin versus placebo in the treatment of refractory septic shock: a randomized, placebo-controlled trial

1. Terlipressin in the treatment of refractory septic shock is significantly better than placebo at maintaining mean arterial pressure (MAP) but does not improve overall mortality

Evidence Rating Level: 1 (Excellent)

Current guidelines for septic shock where hemodynamics are refractory to norepinephrine infusion recommend beginning vasopressin as it raises blood pressure through a non-adrenergic receptor pathway, minimizing the risk of excessive stimulation. However, there is limited data on the efficacy of adding terlipressin as a second vasopressor. Terlipressin is a vasopressin analog with a longer half-life and greater selectivity for V1 receptors compared to vasopressin. In this prospective, single-center, double-blind, randomized controlled trial, patients aged 18 years or older were included if they had a serum lactate > 2 mmol/L and required norepinephrine doses above 0.2 mcg/kg/min to maintain a MAP of at least 65 mmHg. 130 patients were randomized in a 1:1 ratio to receive up to a maximum of 0.025 mcg/kg/min of terlipressin or 0.9% sodium chloride solution to achieve a MAP above 65 mmHg. The primary outcome was successful septic shock hemodynamic stabilization within 6 hr, defined as maintaining a MAP of at least 65 mmHg with a total catecholamine requirement (norepinephrine dose + epinephrine dose + [dopamine dose]/100 + [dobutamine dose]/100) below 0.2 mcg/kg/min. This outcome occurred significantly more frequently in the terlipressin group compared to the control group (22.7% vs 9.4%; RR = 1.53, 95% CI = 1.09–2.14, P = 0.039); however, there was no significant difference at 24 and 74 hours. There was no significant difference in 28-day mortality (RR = 0.93, 95% CI = 0.66 − 1.31, P = 0.684) or adverse effects such as non-onset atrial fibrillation (RR = 1.05, 95% CI = 0.61 − 1.80, P = 0.848) or fatal arrhythmias (RR = 0.98, 95% CI = 0.43 − 2.23, P = 1.000). Patients with a SOFA score below 12 (adjusted odds ratio [aOR] = 33.33, 95% CI = 3.45–100.0, P = 0.003) and an initial serum lactate level below 4 mmol/L (aOR = 33.33, 95% CI = 3.12–100.0, P = 0.004) were independently associated with responsiveness to terlipressin. Although terlipressin in refractory septic shock may safely improve hemodynamics and reduce catecholamine use, it is unclear whether these benefits translate to overall mortality.

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