Terlipressin for Refractory Septic Shock

Septic Shock Clinical Trial

— TERESEP  

Official title:

Terlipressin Versus Placebo for Septic Shock Refractory to High Doses Catecholamine Vasopressors: A Randomized-controlled Trial

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04339868
• Other study ID #: Si 049/2020
• Status: Recruiting
• Phase: Phase 2
• Start date: April 3, 2020
• Est. completion date: July 31, 2025

Study information

• Verified date: September 2021
• Source: Mahidol University
• Contact: Surat Tongyoo, MD
• Phone: 0820137771
• Email: surat.ton[@]mahidol.ac.th
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 130
• Est. completion date: July 31, 2025
• Est. primary completion date: March 31, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Norepinephrine Adverse Reaction
• Refractory Shock
• Septic Shock
• Shock
• Shock, Septic

Intervention

Drug:
• Terlipressin
Terlipressin (20-100 mcg/hr) plus norepinephrine and/or epinephrine
• Placebo
0.9% NaCl plus norepinephrine and/or epinephrine

Locations

Country	Name	City	State
Thailand	Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University	Bangkok

Sponsors (1)

Lead Sponsor	Collaborator
Mahidol University

Country where clinical trial is conducted

Thailand, 

References & Publications (3)

Permpikul C, Tongyoo S, Viarasilpa T, Trainarongsakul T, Chakorn T, Udompanturak S. Early Use of Norepinephrine in Septic Shock Resuscitation (CENSER). A Randomized Trial. Am J Respir Crit Care Med. 2019 May 1;199(9):1097-1105. doi: 10.1164/rccm.201806-10 — View Citation

Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, Kumar A, Sevransky JE, Sprung CL, Nunnally ME, Rochwerg B, Rubenfeld GD, Angus DC, Annane D, Beale RJ, Bellinghan GJ, Bernard GR, Chiche JD, Coopersmith C, De Backer DP, French CJ, Fujishima — View Citation

Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, Bellomo R, Bernard GR, Chiche JD, Coopersmith CM, Hotchkiss RS, Levy MM, Marshall JC, Martin GS, Opal SM, Rubenfeld GD, van der Poll T, Vincent JL, Angus DC. The Third International C — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Achieve target blood pressure with low dose adrenergic agents	Achieve target mean arterial blood pressure 65 millimeter mercury or more with norepinephrine and/or epinephrine dose 0.2 mcg/kg/min or lower	6 hours after initiate study drug
Secondary	28 day mortality	Proportion of patient who dead before 28 days after enrollment	28 days
Secondary	Mean arterial blood pressure	Mean arterial blood pressure after initiate study drug	72 hours
Secondary	Hospital mortality	Proportion of patient who dead before hospital discharge after enrollment	90 days
Secondary	ICU mortality	Proportion of patient who dead before ICU discharge after enrollment	90 days