5-HT3 Receptor Antagonist and Respiratory Drive in Patients With ARDS

Study Overview
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Brief Summary
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This is a pilot study aimed at acquiring primary physiological data, describing and estimating the effects of a 5-HT3 receptor antagonist (ondansetron) on respiratory drive in patients with acute respiratory distress syndrome (ARDS). The results of this study will determine the interest and feasibility of assessing the clinical applications of ondansetron in reducing patient self-inflicted lung injury (P-SILI) in ARDS, in subsequent studies.

Official Title
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Effect of a 5-HT3 Receptor Antagonist on Respiratory Drive in Spontaneously Breathing Mechanically Ventilated Patients With Acute Respiratory Distress Syndrome (ARDS): a Pilot Proof-of-concept Crossover Non-randomized Controlled Trial

Conditions
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Acute Respiratory Distress Syndrome

Intervention / Treatment
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* Drug: Placebo
* Drug: Ondansetron


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patient (18-75 years old) Berlin Criteria for Acute Respiratory Distress Syndrome (ARDS) (1): Hypoxemic respiratory failure with a patrial pressure of arterial oxygen to fraction of inspired oxygen ratio (PaO2:FiO2 ratio) < 300 Bilateral opacities not fully explained by effusions, lung/lobar collapse, or nodules on chest imaging that appeared within 7 days of a known clinical insult Respiratory failure not fully explained by cardiac failure or fluid overload Has been mechanically ventilated > 48 hours Planned to remain mechanically ventilated for the next 24 hours Currently on Pressure Support Ventilation or planning to go on pressure support ventilation in the next 24 hours Exclusion Criteria: Having received a 5-HT3 antagonist in the last 24 hours, or planning to use one in the next 24 hours Recently treated for bleeding varices, stricture, hematemesis, esophageal trauma, recent esophageal surgery or other contraindication for nasogastric tube placement Severe coagulopathy (platelet count< 10 000 or International Normalized Ratio (INR) > 3) Neuromuscular disease that impairs ability to ventilate spontaneously (including C5 or higher spinal cord injury, amyotrophic lateral sclerosis, Guillain-Barre syndrome or myasthenia gravis) Treating clinician refusal, or unwillingness to commit to pressure support ventilation for at least 6 hours. Pregnancy Liver cirrhosis (Child B or C) or other severe impairment of hepatic function Congestive heart failure Bradyarrhythmia (baseline pulse<55/min) Known long QT syndrome QTc prolongation>450 msec, noted on prior or screening ECG, or who are taking medication known to cause QT prolongation Hypersensitivity or other known intolerance to ondansetron or other 5-HT3 antagonists

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Non-randomized crossover controlled trial with two interventions and one sequence. The sequence of treatment is first placebo and secondly ondansetron.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>All participants will receive a single injection of placebo, followed, three hours later, by a single injection of ondansetron. | Drug: Placebo<br>* Single intravenous dose of 10 mL of sodium chloride (NaCl) 0.9% over 15 minutes.<br>* Other names: Sodium chloride;|
| Active Comparator: Ondansetron<br>All participants will receive a single injection of placebo, followed, three hours later, by a single injection of ondansetron. | Drug: Ondansetron<br>* Single intravenous dose of ondansetron hydrochloride dihydrate 0.15 mg/kg (maximum 16 mg) in 10 mL of NaCl 0.9% over 15 minutes.<br>* Other names: Ondansetron hydrochloride dihydrate;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pressure-time product of the esophageal pressure per minute | Difference in mean pressure-time product of the esophageal pressure per minute between placebo phase and ondansetron phase | Continuous measurement during each 2-hour phase | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Respiratory rate | Difference in mean respiratory rate between placebo phase and ondansetron phase | Continuous measurement during each 2-hour phase | 
| Tidal volume | Difference in mean tidal volume between placebo phase and ondansetron phase | Continuous measurement during each 2-hour phase | 
| Pressure-time product of the esophageal pressure per breath | Difference in mean pressure-time product of the esophageal pressure per breath between placebo phase and ondansetron phase | Continuous measurement during each 2-hour phase | 
| Esophageal pressure swings | Difference in mean esophageal pressure swings between placebo phase and ondansetron phase | Continuous measurement during each 2-hour phase | 
| Transpulmonary pressure swings | Difference in mean transpulmonary pressure swings between placebo phase and ondansetron phase | Continuous measurement during each 2-hour phase | 
| Estimated occlusion pressure at 0.1 msec (P0.1) | Difference in mean estimated occlusion pressure at 0.1 msec (P0.1) between placebo phase and ondansetron phase | Continuous measurement during each 2-hour phase | 
| Peak electrical activity of the diaphragm (Eadi) | Difference in mean peak Eadi between placebo phase and ondansetron phase | Continuous measurement during each 2-hour phase | 
| Area under the Eadi curve | Difference in area under the Eadi curve between placebo phase and ondansetron phase | Continuous measurement during each 2-hour phase | 
| End-tidal CO2 (EtCO2) | Difference in mean EtCO2 between placebo phase and ondansetron phase | Continuous measurement during each 2-hour phase | 
| Volume of expired CO2 (VCO2) | Difference in mean VCO2 between placebo phase and ondansetron phase | Continuous measurement during each 2-hour phase | 
| Oxygen saturation estimated by pulse oximetry (SpO2) | Difference in mean SpO2 between placebo phase and ondansetron phase | Measurement every 5 minutes during each 2-hour phase | 
| Partial pressure of carbon dioxide in arterial blood (PaCO2) | Difference in mean PaCO2 between placebo phase and ondansetron phase | Measurement every 30 minutes during each 2-hour phase | 
| Partial pressure of oxygen in arterial blood (PaO2) | Difference in mean PaO2 between placebo phase and ondansetron phase | Measurement every 30 minutes during each 2-hour phase | 
| Heart rate | Difference in mean heart rate between placebo phase and ondansetron phase | Measurement every 5 minutes during each 2-hour phase | 
| Mean arterial pressure (MAP) | Difference in mean MAP between placebo phase and ondansetron phase | Measurement every 5 minutes during each 2-hour phase | 
| Corrected QT length (QTc) | Difference in QTc between placebo phase and ondansetron phase | Measurement once (at the 1 hour-mark) during each 2-hour phase | 
| Temperature | Difference in mean temperature between placebo phase and ondansetron phase | Hourly measurement during each 2-hour phase | 
| Richmond Agitation and Sedation Scale (RASS) | Difference in mean Richmond Agitation and Sedation Scale (RASS) between placebo phase and ondansetron phase. This scale goes from -5 (unraousable) to +4 (combative). | Hourly measurement during each 2-hour phase | 
| Critical care Pain Observation Tool (CPOT) | Difference in mean Critical care Pain Observation Tool (CPOT) between placebo phase and ondansetron phase. This scale goes from 0 (lowest pain level) to 10 (highest pain level). | Hourly measurement during each 2-hour phase | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ARDS, Ondansetron