Terlipressin for Refractory Septic Shock (TERESEP)

Mahidol University

Status and phase: Enrolling; Phase 2

Conditions: Norepinephrine Adverse Reaction; Refractory Shock; Septic Shock

Treatments: Drug: Placebo; Drug: Terlipressin

Study type: Interventional

Funder types: Other

Identifiers

NCT04339868

Si 049/2020

Details and patient eligibility

About

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.

Full 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.

Enrollment: 130 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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

6. 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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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130 participants in 2 patient groups, including a placebo group

Terlipressin group

Active Comparator group

Description:

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

Treatment:

Drug: Terlipressin

Placebo group

Placebo Comparator group

Description:

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

Treatment:

Drug: Placebo