Abstract

Background: In-hospital mortality of cirrhosis patients with septic shock is higher than in other patients and exceeds 70%. These patients have high output cardiac failure secondary to severe systemic vasodilatation which is refractory to catecholamines. Terlipressin, as a second vasopressor, can provide the severe systemic vasodilation and improve macro and microcirculation. Terlipressin has been used either as continuous infusion or boluses in hepatorenal syndrome. However, at present none of studies reveal which would be a better mode of administration considering the reversal of hemodynamic and safety of patients. We aimed to study the efficacy of continuous infusion of terlipressin (T-CON) versus intermittent boluses (T-BOL) in reversal of septic shock in cirrhosis patients.

Methods: In this study, 115 patients requiring noradrenaline more than 0.5 ug/kg/min to maintain mean arterial pressure (MAP) of more than 65 mm Hg were randomized into T-CON (n=55) at 2mg/24`hour continuous infusion and T-BOL (n=57) at intermittent boluses of same dosage. The dose was increased to maximum 4 mg. Primary end-point was reversal of shock over 72 hours. Secondary end-points included rebound hypotension, treatment-related adverse effects, effect on hemodynamic and mortality at 28 days.

Results: Baseline parameters [aged (years) 47.41 ± 9.91 vs. 47.41 ± 9.95; p=0.44, males (%) 93.1 vs. 96.4; p=0.68, alcohol (%) 70.4 vs. 73.9; p=0.73] were comparable in two groups; including serum lactate(µmol/L) [2.32 ± 0.95 vs. 2.55 ± 1.12; p=0.24], SOFA scores [12.43 ± 3.62 vs. 12.48 ± 3.50; p=0.94], MELD Na [33.13 ± 5.27 vs. 31.25 ± 8.01; p=0.16] and MAP [73.88 ± 6.21 vs. 73.35 ± 6.18; p=0.65]. Pneumonia is most common source of sepsis [89.7% vs. 77.2%; p=0.08] in both the groups. On intent to treat analysis, reversal of shock at 72 hours [65.5% vs. 42.1%; p=0.02] was significantly better in T-CON. Better improvement in hemodynamics, systemic vascular resistance [47.8% vs. 23.8%; p=0.04], cardiac index [47.6% vs. 23.5%; p=0.06] and lactate improvement [48.1% vs. 44.7%; p=0.84] was achieved in T-CON. Significantly fewer incidences of rebound hypotension [43.1% vs. 78.9%; p=0.03] and adverse effects of terlipressin [51.7% vs. 75.4%; p = 0.01] were noted in T-CON group. Common terminology criteria for adverse events (CTCAE) grading showed more incidence of Grade 3 [20% vs. 25.6%] and Grade 4 [46.6% vs. 44.2%]. Adverse events causing protocol violation (CTCAE 2-5) [37.9% vs. 57.9%; p=0.04] were significantly higher in the T-BOL. Even on per-protocol analysis, reversal of shock was better in T-CON [69.4% vs. 41.7%; p=0.03]. The duration of ICU stay, mechanical ventilation and 28 days mortality were not different between groups.

Conclusion: Continuous infusion of terlipressin is superior to intermittent boluses as a second vasopressor in cirrhosis patients with septic shock by better improvement of hemodynamic and sustained reversal of shock.