Abstract and Introduction
Abstract
Objectives: Vasopressin and corticosteroids are both commonly used adjunctive therapies in septic shock. Retrospective analyses have suggested that there may be an interaction between these drugs, with higher circulating vasopressin levels and improved outcomes in patients treated with both vasopressin and corticosteroids. We aimed to test for an interaction between vasopressin and corticosteroids in septic shock.
Design: Prospective open-label randomized controlled pilot trial.
Setting: Four adult ICUs in London teaching hospitals.
Patients: Sixty-one adult patients who had septic shock.
Interventions: Initial vasopressin IV infusion titrated up to 0.06 U/min and then IV hydrocortisone (50 mg 6 hourly) or placebo. Plasma vasopressin levels were measured at 6–12 and 24–36 hours after hydrocortisone/placebo administration.
Measurements and Main Results: Thirty-one patients were allocated to vasopressin + hydrocortisone and 30 patients to vasopressin + placebo. The hydrocortisone group required a shorter duration of vasopressin therapy (3.1 d; 95% CI, 1.1–5.1; shorter in hydrocortisone group) and required a lower total dose of vasopressin (ratio, 0.47; 95% CI, 0.32–0.71) compared with the placebo group. Plasma vasopressin levels were not higher in the hydrocortisone group compared with the placebo group (64 pmol/L difference at 6- to 12-hour time point; 95% CI, –32 to 160 pmol/L). Early vasopressin use was well tolerated with only one serious adverse event possibly related to study drug administration reported. There were no differences in mortality rates (23% 28-day mortality in both groups) or organ failure assessments between the two treatment groups.
Conclusions: Hydrocortisone spared vasopressin requirements, reduced duration, and reduced dose, when used together in the treatment of septic shock, but it did not alter plasma vasopressin levels. Further trials are needed to assess the clinical effectiveness of vasopressin as the initial vasopressor therapy with or without corticosteroids.
Introduction
Catecholamines remain the primary vasopressors used to treat hypotension during septic shock after IV fluid resuscitation. Vasopressin has been proposed as an adjunctive therapy in septic shock and has been shown to increase blood pressure and reduce catecholamine requirements. Despite some small studies suggesting a beneficial physiological effect on organ function, in particular renal function, a large randomized controlled trial of vasopressin versus norepinephrine (Vasopressin and Septic Shock Trial, VASST) did not provide evidence of a difference in survival in the whole septic shock population (35.4% and 39.3% 28-day mortality, respectively; difference, –3.9%; 95% CI, –10.7 to 2.9).
However, there were some interesting subgroup results from this trial. First, in the a priori defined stratum of less severe shock (defined as patients requiring < 15 μg/min of norepinephrine at baseline), there was a reduced mortality in the vasopressin group compared with the norepinephrine group (26.5% vs 35.7% 28-day mortality; difference, –9.2%; 95% CI, –18.5 to 0.1). In contrast, in the more severe shock stratum (≥ 15 μg/min of norepinephrine at baseline), there was no difference in mortality between the groups (44.0% and 42.5%, respectively; difference, 1.5%; 95% CI, –8.2 to 11.2). Further post hoc subgroup analysis suggested that vasopressin may be more effective at preventing deterioration in renal function, rather than reversing established acute kidney failure.
Another interesting finding in VASST was that there was evidence of an interaction between vasopressin and corticosteroid treatment. The combination of vasopressin and steroids led to a lower mortality compared with norepinephrine plus steroids (35.9% vs 44.7%, respectively; difference, –8.8%; 95% CI, –16.7 to –0.9). In contrast, patients who were treated with vasopressin and did not receive corticosteroids had an increased mortality compared with patients who received norepinephrine and no corticosteroids (33.7% vs 21.3%; difference, 12.3%; 95% CI, –0.2 to 24.9). Interestingly, patients who received corticosteroids and vasopressin had higher levels of circulating vasopressin compared with patients treated with vasopressin alone. Similar findings were observed in other retrospective analyses where plasma vasopressin levels were higher in patients on concomitant hydrocortisone and also survival rates were higher in patients treated with concomitant vasopressin and hydrocortisone.
However, these subgroup analyses must be interpreted cautiously as many are retrospective, and even though the severity of shock strata analysis in VASST was predefined, the original hypothesis was that vasopressin would be more beneficial in the more severe stratum. The earlier use of vasopressin in septic shock and its interaction with corticosteroids needs further investigation in randomized controlled trials.
We undertook a pilot trial to prospectively test our primary hypothesis that there was an interaction between vasopressin and corticosteroids and secondarily to test the feasibility of vasopressin use as initial vasopressor therapy in septic shock (http://www.controlled-trials.com/ISRCTN66727957).