Inhaled Isoflurane for Sedation of Invasively Ventilated Patients With Cardiogenic Shock on Extracorporeal Membrane Oxygenation

Overview

Midazolam and propofol are the most used intravenous (IV) sedative agents, but their use is associated with well-known adverse effects such as accumulation, myotoxicity, tachyphylaxis, and unpredictable wake-up time. For benzodiazepines, an increased tolerance, possible accumulation after long-term use, and an increased risk of acute withdrawal syndrome are reported. In patients on extracorporeal membrane oxygenation (ECMO) for cardiogenic shock, the negative hemodynamic effects of these drugs are a particular matter of concern. Besides the extracorporeal circuit itself may affect the pharmacokinetics of these IV sedatives. Indeed, drug sequestration in ECMO circuits is a well-known phenomenon influenced by drug chemo-physical properties. Given the large surface area of tubing and membrane, considerable quantities of drugs used in ECMO patients may be sequestered over a period, resulting in a significant increase in their volume of distribution. Similarly, frequent hemodilution and organ dysfunction would also contribute to an increase in the volume of distribution. Propofol, which is lipophilic is significantly sequestrated in the circuit. Consequently, it is commonly observed that patients receiving ECMO have substantially higher sedative and analgesic drug requirements than patients without ECMO. To date, there is no ideal concept for analgesia and sedation of patients on ECMO in the ICU. A drug that sedates effectively but with minimal residual sedation after the end of the administration and without the aforementioned drawbacks of the current agents would be valuable. Interestingly, a recent randomized controlled non-inferiority trial that randomized 338 patients showed that, compared with propofol, sedation with inhaled anaesthetics was non-inferior. Sedation with inhaled anaesthetics resulted in a higher rate of spontaneous breathing and a shorter wake-up time after 48h of sedation. Indeed, inhaled sedation, which has been associated with reduced opioid consumption and less delirium in ICU patients, is a promising alternative to IV sedation. Moreover, inhaled anaesthetics might be associated with less myocardial injury and lower doses of inotropic support in patients undergoing cardiac surgery. However, to date, the experience with volatile agents remains limited in patients on ECMO. We hypothesized that the use of inhaled isoflurane with the Sedaconda anaesthetics conserving device (ACD) in cardiogenic shock patients on ECMO will reduce the mortality and increase the number of ventilation-free days at day 28 following ECMO onset compared to usual IV sedation by propofol and/or midazolam.

Interventions

• Drug Inahled Isoflurane
  treatment administration
• Drug Propofol, midazolam
  treatment administration

Primary outcome measures

• A composite hierarchical outcome composed of two components: 1) mortality, 2) number of days alive without invasive mechanical ventilation within 28 days following ECMO initiation [Time frame: Day 28]

Secondary outcome measures (12)

• Overall survival [Time frame: Day 28]
• Number of ECMO-free days [Time frame: Day 14, Day 28]
• Number of inotropes-free days [Time frame: Day 14, Day 28]
• Number of ICU-free days [Time frame: Day 28]
• Number of ventilation-free days [Time frame: Day 14, Day 28]
• incidence of delirium [Time frame: Day 28]
• Opioids daily consumption during invasive mechanical ventilation [Time frame: Day 14]
• Consumption of propofol [Time frame: Day 14]
• Consumption of midazolam [Time frame: Day 14]
• Consumption of Clonidine [Time frame: Day 14]
• Consumption of Haloperidol [Time frame: Day 14]
• Consumption of dexmedetomidine [Time frame: Day 14]

Eligibility criteria

Inclusion criteria

• Cardiogenic shock on VA ECMO support for less than 24 hours
• Patients on invasive mechanical ventilation receiving propofol and/or midazolam at the time of randomization
• Invasive mechanical ventilation for less than 48 hours
• Expected invasive ventilation and sedation for at least 24h, with a prescribed Richmond agitation scale target within the range of -1 to - 4
• Social security registration (AME excluded)

Exclusion criteria

• Age <18 and >75
• Pregnancy or breastfeeding
• Initiation of ECMO >24 hours
• Initiation of mechanical ventilation >48 hours
• Cardiopulmonary Resuscitation >20 minutes before randomization
• Patient moribund on the day of randomization, SAPS II >90
• Suspected or proven intracranial hypertension
• Corrected QT interval > 450ms or with a known or suspected genetic predisposition to malignant hyperthermia
• Chronic liver disease defined as a Child-Pugh score of 12-15
• Patients ventilated with a tidal volume < 4ml/kg predicted body weight
• Participation in another interventional study or being in the exclusion period at the end of a previous study.
• Contraindication or allergies to isoflurane, propofol, midazolam or other halogenated anaesthetics

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

Center list to be confirmed — check the primary protocol.

Publications

• Meiser A, Volk T, Wallenborn J, Guenther U, Becher T, Bracht H, Schwarzkopf K, Knafelj R, Faltlhauser A, Thal SC, Soukup J, Kellner P, Druner M, Vogelsang H, Bellgardt M, Sackey P; Sedaconda study group. Inhaled isoflurane via the anaesthetic conserving device versus propofol for sedation of invasively ventilated patients in intensive care units in Germany and Slovenia: an open-label, phase 3, ran PMID 34454654

Identifiers

NCT: NCT07099014 · APHP230844 · 2023-510261-94-00

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗