Ondansetron for the Prevention of Patient Self-Inflicted Lung Injury in Patients With ARDS - Pilot RCT

BACKGROUND: Acute Respiratory Distress Syndrome (ARDS) is a life-threatening inflammatory lung condition with high mortality and long-term morbidity. Lung-protective ventilation - targeting low tidal volumes and driving pressures - is one of the few proven interventions but often requires deep sedation and neuromuscular blockade (NMB), which are associated with delirium, ICU-acquired weakness, and prolonged ICU stays. Maintaining spontaneous breathing can offer physiological advantages but is frequently limited by excessive respiratory drive, which increases the risk of patient self-inflicted lung injury (P-SILI). Lung inflammation leading to stimulation and sensitization of pulmonary vagal afferent Cfibers could contribute to excessive respiratory effort. Stimulation of pulmonary C-fibers by serotonin increases respiratory rate in animal models through 5-HT receptors. Our previous data suggest that 3 ondansetron, a 5-HT receptor antagonist, attenuates respiratory drive and effort. We hypothesize that 3 this effect may reduce the need for sedation and paralysis, minimize P-SILI, and ultimately improve outcomes in ARDS.

OBJECTIVES: The overarching goal of the OSIRIS research program is to evaluate whether regular intravenous ondansetron can improve patient-important outcomes (survival, ventilator-free days and long term neurocognitive function) in patients with ARDS. With the OSIRIS-1 pilot study, our objective is to assess:

Feasibility:

[RQ1] What is the adherence to the study protocol? [PRIMARY] [RQ2] What is the completeness of the data collection? [RQ3] What is the recruitment rate?

Preliminary mechanistic efficacy and safety:

[RQ4] Does it decrease respiratory effort? [RQ5] Does it reduce exposure to sedatives, opioids and neuromuscular blockers? [RQ6] Is the intervention safe?

METHODS: OSIRIS-1 is a multicenter, double-blind, parallel-group, phase 2 and feasibility pilot RCT. We will enroll 76 invasively mechanically ventilated adults with moderate-to-severe ARDS (PaO :FiO2 < 200). Participants will be randomized to receive ondansetron 8 mg IV or placebo every 8 hours until liberation from invasive mechanical ventilation. Feasibility will be assessed through protocol adherence (defined as scheduled doses administered within ±2 hours), completeness of key clinical outcomes (ventilator-free days, coma/delirium-free days, 90-day survival), and site-level recruitment metrics. For preliminary efficacy, we will estimate respiratory drive using Pmus (derived from occlusion pressure, ΔPocc), measured three times daily by respiratory therapists. We will also measure P0.1, respiratory rate, and other ventilatory parameters. For safety, we will monitor the occurrence of ventricular arrhythmias, serotonin syndrome, and other serious adverse events.

IMPACT: OSIRIS-1 will provide essential data on mechanistic efficacy, safety, and feasibility to inform the design of a future large-scale trial evaluating patient-important outcomes. By targeting respiratory drive pharmacologically, we may enable safer spontaneous breathing, reduce the harms of oversedation and paralysis, and ultimately improve outcomes in ARDS.

Inclusion criteria

• Moderate-to-severe ARDS with all of the following:
• Hypoxemic respiratory failure with PaO2:FiO2 < 200 (on IMV with PEEP ≥ 5)
• Precipitated within 1 week of an acute condition
• Bilateral opacities on chest radiography and computed tomography or bilateral B lines and/or consolidations on ultrasound not fully explained by effusions, atelectasis, or nodules/masses
• Pulmonary edema not exclusively or primarily attributable to cardiogenic pulmonary edema/fluid overload
• Hypoxemia/gas exchange abnormalities not primarily attributable to atelectasis
• IMV initiated < 96 hours
• Extubation not anticipated within 24 hours

Exclusion criteria

• Neuromuscular disease impairing spontaneous breathing
• Pregnancy
• Liver cirrhosis (Child B or C) or other severe impairment of hepatic function
• Bradycardia (baseline pulse<50/min) on screening day
• Known long QT syndrome
• History of sustained ventricular tachycardia
• Active digestive / abdominal infection44
• QTc prolongation > 470 msec in men and > 480 msec in women on screening day
• On a medication at high risk of QT prolongation (Table 5)50
• On two or more serotonergic medications (Table 6)51
• Hypersensitivity / intolerance to 5-HT3 antagonists
• Patient deemed unlikely to survive past 24 hours or being transitioned to a fully palliative philosophy of care