Continuous Flow Ventilation With the Ventijet System in Acute Respiratory Distress Syndrome: a First-in-Human Feasibility and Non-Inferiority Trial

This is a prospective, interventional, single-center clinical study conducted to evaluate the physiological effects and safety of a novel ventilation system-continuous flow ventilation with Ventijet-in adult patients diagnosed with moderate acute respiratory distress syndrome (ARDS). The objective was to compare gas exchange and pulmonary mechanics between conventional pressure-controlled ventilation and the Ventijet system, which delivers continuous flow through a high-velocity nozzle.

Ventijet is a prototype mechanical ventilator developed during the COVID-19 pandemic, motivated by the urgent need for scalable and physiologically effective ventilatory support. The system builds on the concept of continuous-flow extratracheal jet ventilation (VC-ET), originally described and patented by Dr. Lucas Picazo in the 1990s. It generates a high-speed continuous gas stream via a proximally placed nozzle (tobera), which creates an expiratory braking effect. This facilitates alveolar recruitment throughout the respiratory cycle while maintaining low airway pressures and small tidal volumes. Unlike classical jet systems, Ventijet integrates real-time safety monitoring and operates using time-cycled, volume-controlled settings, making it suitable for intensive care unit (ICU) use.

Inclusion and Exclusion Criteria

Patients were screened in the ICU and included if they met all of the following:

• Age ≥ 18 years
• Intubated and on invasive mechanical ventilation
• Diagnosis of moderate ARDS (PaO₂/FiO₂ ratio between 150-200 mmHg, Berlin definition)
• Richmond Agitation-Sedation Scale (RASS) score of -5 (deep sedation)
• Stable hemodynamic and ventilatory parameters

Exclusion criteria included:

• Obstructive pulmonary disease (e.g., chronic obstructive pulmonary disease [COPD], asthma)
• Known intracranial hypertension
• Pregnancy
• Morbid obesity (body mass index [BMI] ≥ 40 kg/m²)
• Contraindication to esophageal balloon catheter placement

Study Protocol and Ventilation Phases

All patients were first stabilized on a conventional ICU ventilator (Puritan Bennett™ 840) with lung-protective settings:

• Tidal volume ≤ 6 mL/kg predicted body weight (PBW)
• Positive end-expiratory pressure (PEEP) titrated to maintain an end-expiratory transpulmonary pressure (PLexp) between 0-2 cm H₂O
• Respiratory rate adjusted to maintain arterial pH > 7.30
• Fraction of inspired oxygen (FiO₂) adjusted to maintain oxygen saturation (SpO₂) > 92%

Once stability was confirmed, patients remained on these settings for 1 hour (Conventional-1h phase), after which a full dataset was collected, including:

• Arterial blood gas (ABG) analysis
• Respiratory and ventilatory parameters
• Hemodynamic variables
• Pulmonary mechanics

Patients were then transitioned to the Ventijet system using end-expiratory clamping to avoid alveolar derecruitment. Ventijet parameters were adjusted to approximate the previous conventional settings. After 1 hour on Ventijet (VJ-1h phase), the same dataset was recorded. This timepoint served as the primary comparison for non-inferiority analysis of oxygenation (PaO₂).

Patients who remained stable on Ventijet continued for up to 24 hours. Additional datasets were collected at 6, 12, and 24 hours (VJ-6h, VJ-12h, VJ-24h). Afterward, they were reconnected to the conventional ventilator (again using end-expiratory clamping), and evaluations were repeated at 1, 12, and 24 hours post-reconnection (Post-VJ-1h, Post-VJ-12h, Post-VJ-24h).

Monitoring and Data Collection Each study phase was supervised continuously by a trained investigator. A CARESCAPE™ B650 monitoring system (General Electric™) was used to capture ventilatory and hemodynamic parameters. Active humidification was maintained throughout. Deep sedation (RASS -5) was ensured during all Ventijet phases.

Variables collected at each phase included:

• Clinical and demographic data
• Age, sex, ICU admission diagnosis
• Comorbidities, corticosteroid use
• Neuromuscular blockers, vasoactive drugs
• Gas exchange
• Arterial partial pressures: oxygen (PaO₂), carbon dioxide (PaCO₂)
• pH, bicarbonate (HCO₃-), arterial oxygen saturation (SaO₂)
• Ventilatory variables
• Tidal volume (VT), respiratory rate (RR), PEEP
• FiO₂, inspiratory time, end-tidal CO₂ (EtCO₂), SpO₂
• Hemodynamics
• Mean arterial pressure (MAP), heart rate (HR)
• Pulmonary mechanics
• Esophageal pressure (Pes)
• Transpulmonary pressures (PLinsp, PLexp)
• Compliance of the respiratory system (Crs), lung (CL), and chest wall (Ccw)
• Driving pressures (airway and transpulmonary)

Outcomes

• Primary outcome: Change in PaO₂ between Conventional-1h and VJ-1h phases. The study was powered as a non-inferiority trial using a predefined margin of ±20 mmHg in PaO₂. Based on an estimated standard deviation of 30 mmHg, the required sample size was 14 patients (α=0.05, β=0.2).
• Secondary outcomes: Change in PaCO₂ across all phases.
• Other prespecified outcomes (collected and reported):
• Changes in respiratory mechanics (compliance, pressures)
• Duration of mechanical ventilation
• ICU and hospital length of stay
• Need for tracheostomy
• ICU, in-hospital, and 1-year mortality

Safety and Oversight

Adverse events were continuously monitored. Protocol mandated immediate reconnection to the conventional ventilator in case of:

• Hemodynamic instability
• Worsening gas exchange
• Equipment malfunction

The study was conducted in compliance with Good Clinical Practice (GCP) guidelines and was externally monitored by the Clinical Research Support Unit (SEIC) at Biocruces Bizkaia.