Weaning Approaches for Vasopressin in Sepsis

Official title

Weaning Approaches for Vasopressin in Sepsis - a Randomized Controlled Trial of Titrated Versus Abrupt Discontinuation During Stabilization of Septic Shock - WAVES Trial

Overview

In this study, we aim to evaluate the incidence of hypotension during vasopressin weaning by comparing two methods - titrated reduction versus abrupt withdrawal - through the conduct of a randomized clinical trial.

Detailed description

Catecholamine infusions are usually tapered gradually in a titrated manner. However, little is known about how to manage adjunctive therapies such as vasopressin. While catecholamines have a short half-life (2-3 minutes), vasopressin's half-life ranges from 10 to 20 minutes. Although endogenous vasopressin levels are depleted in the early phase of shock, they are restored during recovery. Given its pharmacokinetic profile and the endogenous dynamics across different phases of shock, the optimal approach to vasopressin withdrawal - whether titrated or abrupt - remains unclear.

In 2021, a study was published comparing abrupt versus gradual vasopressin discontinuation. This was a retrospective observational study including 1,318 patients. Using ICU length of stay as the primary outcome, no significant difference was observed between groups (abrupt discontinuation: 7.9 days; gradual discontinuation: 7.3 days; p = 0.6). Similarly, there was no difference in the incidence of clinically significant hypotension (abrupt: 39.7%; gradual: 41.7%; p = 0.53). However, when stratifying patients based on whether catecholamine infusions were still ongoing at the time of vasopressin discontinuation, the results reversed in terms of ICU stay (abrupt: 9.2 days; gradual: 7.6 days), although this difference was not statistically significant (p = 0.24). In 2023, another retrospective observational study was published comparing abrupt versus gradual vasopressin withdrawal, including 74 patients. No difference was found in the incidence of clinically significant hypotension (abrupt: 57.1%; gradual: 52.3%; p = 0.68), nor in ICU length of stay. It is important to note, however, that in this cohort only patients who had already discontinued catecholamines prior to vasopressin withdrawal were included.

Interventions

• Other Titrated weaning of vasopressin.
  The titrated group will follow the vasopressin weaning protocol used in the DOVSS study (reduction of 0.01 U/min per hour).
• Other Abrupt weaning of vasopressin.
  The abrupt group will discontinue the vasopressin infusion at the time of randomization, without dose titration.

Primary outcome measures

• Hypotension within the first 24 hours [Time frame: 24 hours]

Secondary outcome measures (9)

• Hypotension stratified according to vasopressin duration [Time frame: 24 hours]
• Hypotension within the first hour [Time frame: First hour]
• Vasopressor-free days [Time frame: 7 days]
• Vasopressin-free days [Time frame: 7 days]
• Renal replacement therapy [Time frame: 7 days]
• Cardiac arrhythmias [Time frame: 7 days]
• ICU-free days [Time frame: 28 days]
• Ischemic events [Time frame: 28 days]
• All-cause mortality [Time frame: 28 days]

Eligibility criteria

Inclusion criteria

• Age over 18 years
• Admitted to the Intensive Care Unit
• Patients with vasopressor dependent sepsis
• Receiving combined norepinephrine and vasopressin therapy

Exclusion criteria

• Withdrawal/reduction of vasopressin related to a plan of treatment limitation or palliative care
• Withdrawal/reduction of vasopressin associated with the initiation of adrenaline or any other vasopressor

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Brazil · 1 center

• Hospital Nossa Senhora da Conceição — Porto Alegre

Publications

• Murata J, Buckley M, Lehn J, Agarwal SK, Stevenson B, Martinez B, MacLaren R. Incidence of Hypotension Associated With Two Different Vasopressin Discontinuation Strategies in the Recovery Phase of Septic Shock. J Pharm Pract. 2023 Aug;36(4):830-838. doi: 10.1177/08971900221078270. Epub 2022 Mar 25. PMID 35331049
• Lam SW, Sacha GL, Duggal A, Reddy AJ, Bauer SR. Abrupt Discontinuation Versus Down-Titration of Vasopressin in Patients Recovering from Septic Shock. Shock. 2021 Feb 1;55(2):210-214. doi: 10.1097/SHK.0000000000001609. PMID 32842024
• Der-Nigoghossian C, Hammond DA, Ammar MA. Narrative Review of Controversies Involving Vasopressin Use in Septic Shock and Practical Considerations. Ann Pharmacother. 2020 Jul;54(7):706-714. doi: 10.1177/1060028020901521. Epub 2020 Jan 20. PMID 31958982
• Jeon K, Song JU, Chung CR, Yang JH, Suh GY. Incidence of hypotension according to the discontinuation order of vasopressors in the management of septic shock: a prospective randomized trial (DOVSS). Crit Care. 2018 May 21;22(1):131. doi: 10.1186/s13054-018-2034-9. PMID 29784057
• Sacha GL, Lam SW, Duggal A, Torbic H, Reddy AJ, Bauer SR. Hypotension Risk Based on Vasoactive Agent Discontinuation Order in Patients in the Recovery Phase of Septic Shock. Pharmacotherapy. 2018 Mar;38(3):319-326. doi: 10.1002/phar.2082. Epub 2018 Feb 8. PMID 29328496
• Hammond DA, Painter JT, Meena N. Incidence of Clinically Significant Hypotension Stratified by Vasopressin Duration. J Intensive Care Med. 2019 Jan;34(1):77-78. doi: 10.1177/0885066617745809. No abstract available. PMID 30798676
• Landry DW, Levin HR, Gallant EM, Ashton RC Jr, Seo S, D'Alessandro D, Oz MC, Oliver JA. Vasopressin deficiency contributes to the vasodilation of septic shock. Circulation. 1997 Mar 4;95(5):1122-5. doi: 10.1161/01.cir.95.5.1122. PMID 9054839
• Bissell BD, Magee C, Moran P, Bastin MLT, Flannery AH. Hemodynamic Instability Secondary to Vasopressin Withdrawal in Septic Shock. J Intensive Care Med. 2019 Sep;34(9):761-765. doi: 10.1177/0885066617716396. Epub 2017 Jul 28. PMID 28750598

Identifiers

NCT: NCT07067866 · CAAE: 83246724.1.0000.5530

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗