Terlipressin for Refractory Septic Shock

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

UNKNOWN

Clinical Phase

PHASE2

Total Enrollment

130 participants

Study Classification

INTERVENTIONAL

Study Start Date

2020-04-03

Study Completion Date

2025-07-31

Brief Summary

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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.

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Detailed Description

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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.

Conditions

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Septic Shock Refractory Shock Norepinephrine Adverse Reaction

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Intervention arm: Terlipressin plus Norepinephrine and/or Epinephrine Controlled arm: Placebo plus Norepinephrine and/or Epinephrine for Treatment Refractory Septic Shock

Primary Study Purpose

TREATMENT

Blinding Strategy

QUADRUPLE

Participants Caregivers Investigators Outcome Assessors

Performed a randomization table before enrollment. Prepare the study drug receiving or placebo receiving according to sequential number derived from the randomization table and keep it in a conceal envelop. Prepare study drug and placebo by a pharmacist or an investigation nurse, according to the randomization table number, and keep both study drug and placebo in the identical containment which labeled by a sequential number. Once a patient was enrolled and informed was signed, then study drug or placebo was start according to sequential number.

Study Groups

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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

Group Type ACTIVE_COMPARATOR

Terlipressin

Intervention Type DRUG

Terlipressin (20-100 mcg/hr) plus norepinephrine and/or epinephrine

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

Group Type PLACEBO_COMPARATOR

Placebo

Intervention Type DRUG

0.9% NaCl plus norepinephrine and/or epinephrine

Interventions

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Terlipressin

Terlipressin (20-100 mcg/hr) plus norepinephrine and/or epinephrine

Intervention Type DRUG

Placebo

0.9% NaCl plus norepinephrine and/or epinephrine

Intervention Type DRUG

Eligibility Criteria

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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

1. Septic shock diagnosis \> 48 hours before
2. Receive intravenous fluid \< 30 mL/kg before enrollment
3. Do-not-resuscitation and terminally ill
4. Refractory to treatment malignancy
5. Pregnancy

7\. Chronic renal failure stage 5 with no plan for long term renal replacement therapy 8. Cirrhosis child C 9. Cardiogenic shock 10. Acute decompensated heart failure 11. Evidence of left ventricular ejection fraction (LVEF) \< 35% 12. Acute coronary syndrome within 72 hours 13. Severe valvular heart disease 14. Documented life-threatening tachyarrhythmia before enrollment 15. Diagnosis of acute mesenteric ischemia before enrollment 16. Previous diagnosis of Raynaud's phenomenon 17. Known peripheral arterial disease 18. Refuse to sign the informed consent by patient or representative

Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No