Terlipressin Versus Placebo for Septic Shock Refractory to High Doses Catecholamine Vasopressors: A Randomized-controlled Trial
Overview
- Phase
- Phase 2
- Intervention
- Terlipressin
- Conditions
- Septic Shock
- Sponsor
- Mahidol University
- Enrollment
- 130
- Locations
- 1
- Primary Endpoint
- Achieve target blood pressure with low dose adrenergic agents
- Status
- Recruiting
- Last Updated
- 4 years ago
Overview
Brief Summary
Norepinephrine was recommended as the first vasopressor for septic shock resuscitation.
For the patient who did not response to high dose norepinephrine, epinephrine was recommended.
Vasopressin was also recommended as an alternative vasopressor, in case patient did not response to norepinephrine and or epinephrine.
Terlipressin, a selective V1 receptor binding with long half life, was reported that it main action is to increase blood pressure via the different mechanism from norepinephrine and epinephrine.
To use terlipressin, combine with norepinephrine and or epinephrine among refractory septic shock, could decrease the usage dose of norepinephrine and epinephrine as well as lower the side effects of too high adrenergic stimuli.
Detailed Description
Norepinephrine was recommended as the first vasopressor for septic shock resuscitation. For the patient who did not response to high dose norepinephrine, epinephrine was recommended. Both norepinephrine and epinephrine action via the alpha adrenergic stimuli to increase vascular smooth muscle contraction, induced vasoconstriction and increase arterial blood pressure. It also action via beta adrenergic stimuli, to increase heart rate and myocardial contractility, then increase stroke volume and cardiac output. Too much alpha and beta adrenergic stimulation, especially during received high dose norepinephrine and or epinephrine associated with vasoconstriction induce organs ischemia. The most common organ ischemia included myocardial ischemia, bowel ischemia and limbs ischemia. Cardiac arrhythmia was also the most common complication associated with high dose norepinephrine and or epinephrine. Atrial fibrillation was the most common reported arrhythmia, however, fatal arrhythmia included ventricular fibrillation and tachycardia were also reported. Vasopressin was recommended as an alternative vasopressor, in case patient did not response to norepinephrine and or epinephrine. Terlipressin, a selective V1 receptor binding with long half life, was reported that it main action is to increase blood pressure via the different mechanism from norepinephrine and epinephrine. To use terlipressin, combine with norepinephrine and or epinephrine among refractory septic shock, could decrease the usage dose of norepinephrine and epinephrine as well as lower the side effects of too high adrenergic stimuli. The benefit effect of terlipressin could be demonstrated when prescribe among the septic shock patients who required high dose of adrenergic vasoactive agents. Terlipressin plus norepinephrine and or epinephrine could maintain or even improve blood pressure and tissue perfusion with lower fatal side effects than norepinephrine and or epinephrine without terlipressin.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Septic shock according to Sepsis-3 definition
- •Evidence of adequate fluid
- •Received norepinephrine 0.2 mcg/kg/min or more
- •Received norepinephrine plus epinephrine (any dose)
- •Mean arterial lower than 65 mmHg or lactate \> 2 mmol/liter
Exclusion Criteria
- •Septic shock diagnosis \> 48 hours before
- •Receive intravenous fluid \< 30 mL/kg before enrollment
- •Do-not-resuscitation and terminally ill
- •Refractory to treatment malignancy
- •Chronic renal failure stage 5 with no plan for long term renal replacement therapy
- •Cirrhosis child C
- •Cardiogenic shock
- •Acute decompensated heart failure
- •Evidence of left ventricular ejection fraction (LVEF) \< 35%
- •Acute coronary syndrome within 72 hours
Arms & Interventions
Terlipressin group
Terlipressin acetate 1 mg in 0.9% normal saline (NaCl) 50 mL (0.02 mg/mL) Initial dose 20 mcg/hr (1 mL/hr) titrate increase 1 mL/hr every 30 min to 100 mcg/hr (5 mg/hr) to keep mean arterial blood pressure (MAP) \> 65 mmHg If MAP \> 75 mmHg for \> 30 min, decrease epinephrine and norepinephrine until \< 0.15 mcg/kg/min, then decrease terlipressin until stop
Intervention: Terlipressin
Placebo group
Placebo 0.9% NaCl 50 mL Initial dose 1 mL/hr titrate increase 1 mL/hr every 30 min to 5 mg/hr to keep mean arterial blood pressure (MAP) \> 65 mmHg If MAP \> 75 mmHg for \> 30 min, decrease epinephrine and norepinephrine until \< 0.15 mcg/kg/min, then decrease placebo until stop
Intervention: Placebo
Outcomes
Primary Outcomes
Achieve target blood pressure with low dose adrenergic agents
Time Frame: 6 hours after initiate study drug
Achieve target mean arterial blood pressure 65 millimeter mercury or more with norepinephrine and/or epinephrine dose 0.2 mcg/kg/min or lower
Secondary Outcomes
- 28 day mortality(28 days)
- Hospital mortality(90 days)
- ICU mortality(90 days)
- Mean arterial blood pressure(72 hours)