Shorter Weaning From Invasive Ventilation With Levosimendan

Официальное название

Shorter Weaning From Invasive Ventilation With Levosimendan: a Randomized, Double-blind, Multicentre Study in Critically Ill Patients

Обзор

Prolonged weaning from mechanical ventilation is a common and serious challenge in the ICU, associated with increased morbidity, mortality, and length of stay. Diaphragm dysfunction plays a key role in weaning failure, and current strategies to support respiratory muscle function are limited. Levosimendan is a calcium sensitizer that enhances cardiac and skeletal muscle contractility, including the diaphragm, without increasing oxygen demand. The investigators hypothesize that treatment with Levosimendan in difficult-to-wean ICU patients will improve diaphragm function and thereby shorten the duration of mechanical ventilation compared to placebo.

Подробное описание

Objective: To assess the effect of levosimendan on the number of ventilator-free days up until day 28.

Study design: WEANLESS is an investigator-initiated, multicenter, double blind, randomized clinical superiority trial in ventilated adult patients admitted to the ICUs of participating hospitals.

Study population: This study will include 250 patients who are invasively ventilated for more than 48 hours and failed at least one SBT. Patients are enrolled from participating ICUs and randomized within 24 hours after failing their first SBT.

Intervention:

Patients will be randomly assigned in a double-blind manner to receive either levosimendan or placebo. The study medication will be administered as a continuous intravenous infusion over 24 hours, starting at a dose of 0.1 µg/kg/min, with the option to increase to 0.2 µg/kg/min after 4 hours if well tolerated. If weaning is not successful after 7 days, a maximum of four treatment cycles may be given. All patients will continue to receive standard ICU care, including daily assessments of readiness to wean from mechanical ventilation.

In addition to the intervention, health-related quality of life will be assessed using the EQ-5D-5L questionnaire at baseline, 3 months, and 12 months after inclusion. Dyspnea scores will be recorded daily after extubation until ICU discharge.

Main study parameters/endpoints: The primary endpoint of the study is the number of ventilator-free days and alive (VFD) at day 28 from randomization. This is a composite endpoint combining both mortality and the duration of ventilation. Secondary outcomes include ventilator-free days at day 90, dyspnea scores, reintubation rates, ICU readmission, ICU length of stay, hospital length of stay and mortality. Safety outcomes include the occurrence of cardiac arrhythmias, changes in vasopressor requirements and other adverse events related to levosimendan.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness: The burden for participants is minimal. Levosimendan is a registered drug with a known safety profile and is already used in critical care settings. The placebo is an infusion with Soluvit. All other care follows standard ICU procedures. Data will be collected from the electronic medical record and routine monitoring. No additional invasive procedures are required solely for the main study.

Вмешательства

• Препарат levosimendan
  Participants randomized to to the intervention will receive levosimendan. The infusion is administered over 24 hours, starting at a dose of 0.1 µg/kg/min. After 4 hours, the dose may be increased to 0.2 µg/kg/min if tolerated, based on clinical judgment. A maximum of four treatment cycles may be given if the patient is not successfully weaned from mechanical ventilation within 7 days.
• Препарат Soluvit
  Participants randomized to this arm will receive a placebo consisting of Soluvit diluted in glucose 5%, administered as an intravenous infusion over 24 hours. The infusion will mimic the Levosimendan administration protocol, starting at 0.1 µg/kg/min and potentially increasing to 0.2 µg/kg/min after 4 hours, to maintain blinding. A maximum of four placebo treatment cycles may be administered if the patient is not successfully weaned from mechanical ventilation within 7 days.
• Другое Standard care
  All patients in this arm will receive standard ICU care, including daily assessments for readiness to wean from invasive ventilation.

Первичные конечные точки

• The primary endpoint of the study is the number of ventilator-free days and alive (VFD) at day 28 from randomization. This is a composite endpoint combining both mortality and the duration of ventilation. [Срок оценки: From randomization up until day 28.]

Вторичные конечные точки (12)

• The number of ventilator-free days from randomization up until day 90. [Срок оценки: From randomization up until day 90.]
• The number of days from randomization to successful weaning from invasive ventilation. [Срок оценки: From randomization up until day 90.]
• ICU mortality [Срок оценки: From randomization up until day 28.]
• ICU mortality [Срок оценки: From randomization up until day 90.]
• Dyspnea sensation [Срок оценки: From extubation up until day 28 or ICU discharge whichever comes first.]
• Quality of life at baseline and at follow up after 3 and 12 months. [Срок оценки: From randomization up until 3 and 12 months.]
• The number of patients with a reintubation (for endotracheally intubated patients) or reinstitution of invasive ventilation (for tracheostomized patients) within 7 days after liberation. [Срок оценки: From randomization up until day 90.]
• ICU readmission within 90 days. [Срок оценки: From randomization up until day 90.]
• The number of days with non-invasive respiratory support (high flow nasal canula or non-invasive ventilation). [Срок оценки: From randomization up until day 28.]
• The length of stay in the ICU. [Срок оценки: From randomization up until day 90.]
• The length of stay in the hospital. [Срок оценки: From randomization up until day 90.]
• Plasma concentration of levosimendan [Срок оценки: From 24 hours after start of the first dose of medication up until 120 hours after start of the fist dose of medication.]

Критерии участия

Критерии включения

• Invasively ventilated > 48 hours.
• Failed at least one spontaneous breathing trial (SBT).
• Age above 18 years.
• Female patients with age < 60 must have a negative pregnancy test (blood or urine) prior to participation.

Критерии исключения

• Pre-existing neuromuscular disease (congenital or acquired)
• Endotracheally intubated primarily for neurological reason (e.g., traumatic brain injury, intracranial haemorrhage, epilepsy, intracranial infection), or developed severe intracranial haemorrhage/infarction during ICU stay.
• Contra-indications for levosimendan: severe renal failure (creatinine clearance <30mL/min) unless managed with appropriate continuous kidney replacement therapy (such as CRRT), severe liver failure (Child-Pugh class C), history of torsade des pointes; known significant mechanical obstructions affecting ventricular filling/ outflow or both; prolonged QTc interval (QTc > 470ms); breast feeding; known hypersensitivity to levosimendan.
• Treatment with intermittent haemodialysis.
• Treatment limitation decision in place: do not reintubate
• Previous treatment with levosimendan within 30 days.
• Currently in another interventional trial that might interact with study drug or primary outcome.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Четверное слепое

Основная цель

Лечение

Центры проведения

Нидерланды · 8 центров

• Rijnstate Ziekenhuis Stichting — Arnhem
• Intensive Care Medicine, Radboud University — Nijmegen
• Canisius Wilhelmina Ziekenhuis — Nijmegen
• Jeroen Bosch Ziekenhuis Stichting — 's-Hertogenbosch
• Catharina Ziekenhuis Stichting — Eindhoven
• Erasmus Universitair Medisch Centrum Rotterdam (Erasmus MC) — Rotterdam
• Sint Franciscus Vlietland Groep Stichting — Rotterdam
• Maasstad Ziekenhuis Stichting — Rotterdam

Публикации

• De Leijer E, Hofma C, Serpa Neto A, Hunfeld NGM, Schultz MJ, Doorduin J, Heunks L. Weaning from invasive ventilation with levosimendan (WEANLESS): study protocol for a multicentre randomised clinical trial. BMJ Open. 2026 May 20;16(5):e117615. doi: 10.1136/bmjopen-2026-117615. PMID 42161542

Идентификаторы

NCT: NCT07105202 · 2024-518810-23-00 · 2024-518810-23-00

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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