Surfactant Depletion Combined with Injurious Ventilation Results in a Reproducible Model of the Acute Respiratory Distress Syndrome (ARDS)
April 7th, 2021
A combination of surfactant washout using 0.9% saline (35 mL/kg body weight, 37 °C) and high tidal volume ventilation with low PEEP to cause moderate ventilator induced lung injury (VILI) results in experimental acute respiratory distress syndrome (ARDS). This method provides a model of lung injury with low/limited recruitability to study the effect of various ventilation strategies for extended periods.
The combination of surfactant wash-out with injurious ventilation reduces the recruitability of the lung injury as compared to models with exclusive surfactant wash-out. The model is reproducible and does not require additional techniques. Furthermore, a two-hit model closely mimics the realistic clinical situation.
The low recruitability of this model supports the experimental investigation of new ventilation strategies, paving the way for the translation of experimental lung research into clinical practice. To begin, set the mechanical ventilation parameters as described in the text manuscript, and target an end expiratory partial pressure of carbon dioxide of 35 to 40 millimeters of mercury and an oxygen saturation above 95%Use a continuous intravenous infusion of thiopentone and fentanyl to maintain the anesthesia, and administer a muscle relaxant if required. Cannulate the external jugular vein with a central venous catheter, and insert the introducer sheath of the pulmonary arterial catheter into the same vein.
Then, cannulate the femoral artery for invasive blood pressure monitoring. Calibrate the transducers against the atmosphere, which is zero millimeters of mercury and 200 millimeters of mercury for the arterial line, and 50 millimeters of mercury for the central venous line, and start monitoring by connecting them to the arterial catheter and the central venous line. Connect the pulmonary artery catheter to the pressure transducer system and calibrate the transducer against the atmosphere and 100 millimeters of mercury.
Then, introduce the pulmonary artery catheter through the introducer sheath with a deflated balloon for 10 to 15 centimeters, depending on the sheath length. Once the balloon has left the sheath, inflate it and advance the pulmonary artery catheter further while monitoring the pressure. Push the pulmonary artery catheter forward when the right atrium, the right ventricle, and the pulmonary artery pressure waves appear on the monitor, and stop when the pulmonary capillary wedge pressure wave is seen.
Then, record the pulmonary capillary wedge pressure at end expiration and deflate the balloon. Calculate the pressure parameters described in the text manuscript, and record the required respiratory settings and measurements to complete the dataset. Ventilate the animal with a fraction of inspired oxygen of one, then disconnect the animal from the ventilator.
Fill the lungs with pre-warmed saline using a funnel connected to the endotracheal tube. Stop if the mean arterial pressure decreases below 50 millimeters of mercury. Drain the lavage fluid by lowering the funnel to the ground level, and monitor the wave.
Reconnect to the animal to the ventilator for oxygenation and wait until the animal recuperates, then repeat lavages until the Horowitz index decreases below 100 millimeters of mercury for at least five minutes at a fraction of inspired oxygen of one, and a positive end expiratory pressure above five millibar. Take an arterial blood gas sample after five minutes following each lavage. Keep the fraction of inspired oxygen at one, and set the ventilator on the volume-guaranteed, pressure-controlled ventilation mode.
Increase the alarm threshold for peak inspiratory pressure to 60 millibar. Lower the respiratory rate, and set the inspiration-to-expiration ratio, then increase the tidal volume slowly up to 17 milliliters per kilogram body weight over at least two minutes. Do not increase the tidal volume further if an inspiratory pressure of 60 millibar is reached.
Reduce the positive end expository pressure to two millibar and ventilate the animal for up to two hours. The Horowitz index decreased during the surfactant washout in all animals, but the recruitment maneuver resulted in a notable increase in oxygenation after the surfactant wash-out. The injurious ventilation of two hours diminished lung recruitability with respect to gas exchange and the mean pulmonary arterial pressure.
The gas exchange parameters were improved with high tidal volumes due to the cyclic recruitment, while mean pulmonary arterial pressure was elevated due to high intrathoracic pressures and hypercapnia. Computer tomographic imaging of the lungs showed extensive atelectasis of the dependent areas of the lung during the ventilation, with a positive end expiratory pressure of six millibar, which resolved largely when the ventilation was escalated to a positive end expiratory pressure of 15 millibar. However, the substantial ubiquitous ground glass opacities did not resolve.
The alveolar opacities observed with a positive end expiratory pressure of 15 millibar indicated structural damage of the lungs. They were also observed in the post-mortem examination of the lungs. When attempting this protocol, it is important to adjust the duration of injurious ventilation because structural lung damage cannot be recruited, and an animal might die prematurely if the injury is too extensive.
The combination of surfactant depletion and injurious ventilation supports the investigation of therapies resulting in fast recruitment of atelectatic lung regions, such as ventilation modes with high ventilatory pressures.
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Overview
This article describes a reproducible animal model for acute respiratory distress syndrome (ARDS) that combines surfactant depletion via repeated lung lavage with injurious ventilation (high tidal volume/low PEEP) in anesthetized pigs. This two-hit model closely mimics clinical scenarios, reduces lung recruitability, and supports the investigation of new ventilation strategies relevant to intensive care settings.
Key Study Components
Area of Science
- Respiratory physiology
- Critical care medicine
- Experimental animal models
Background
- ARDS is a complex syndrome with various animal models used to study its pathomechanisms.
- Surfactant depletion via lung lavage is a common method to induce ARDS-like injury but is highly recruitable and reversible with high airway pressures.
- Combining surfactant depletion with injurious ventilation reduces recruitability and better simulates severe clinical ARDS.
- This model allows for standard respiratory and hemodynamic monitoring using clinically relevant devices.
Purpose of Study
- To establish a reproducible ARDS model with low lung recruitability.
- To enable experimental investigation of ventilation strategies that cannot be tested in highly recruitable models.
- To provide a clinically relevant platform for translational lung research.
Methods Used
- Induction of anesthesia and maintenance with thiopentone and fentanyl; muscle relaxant as needed.
- Central venous and arterial catheterization for hemodynamic monitoring.
- Insertion and calibration of pulmonary artery catheter for pressure measurements.
- Repeated lung lavages with pre-warmed saline to deplete surfactant, monitoring oxygenation (Horowitz index) and hemodynamics.
- Application of injurious ventilation: high tidal volume (up to 17 mL/kg), low PEEP (2 mbar), for up to two hours.
- Continuous monitoring of respiratory and hemodynamic parameters, with arterial blood gas analysis after each lavage.
- CT imaging and post-mortem examination to assess lung injury.
Main Results
- The two-hit model produced a rapid and reproducible decrease in oxygenation (Horowitz index) and increased mean pulmonary arterial pressure.
- Recruitment maneuvers temporarily improved oxygenation after surfactant washout, but subsequent injurious ventilation diminished lung recruitability.
- CT imaging revealed extensive atelectasis and persistent ground glass opacities, indicating structural lung damage.
- Post-mortem examination confirmed alveolar damage consistent with ARDS.
Conclusions
- The combined surfactant depletion and injurious ventilation model closely mimics severe, low-recruitability ARDS seen in clinical practice.
- This model is suitable for testing ventilation strategies and therapies aimed at rapid recruitment of atelectatic lung regions.
- Careful adjustment of injurious ventilation duration is necessary to avoid excessive, non-recruitable lung damage and premature animal death.
Frequently Asked Questions
Executive Industry Relevance
The combined surfactant depletion and injurious ventilation model provides a reproducible, low-recruitability ARDS platform that closely mimics severe clinical scenarios. This enables rigorous evaluation of ventilation strategies and therapeutic interventions under conditions relevant to intensive care and translational research. The model supports predictive confidence in preclinical respiratory studies and informs risk-adjusted portfolio decisions for respiratory drug and device development.
Strategic Applications in Biopharma R&D
Early Discovery & Target Validation
- Enables interrogation of ARDS pathomechanisms in a clinically relevant, low-recruitability setting.
- Supports functional validation of respiratory targets under severe injury conditions.
- Facilitates mechanistic de-risking for candidate interventions targeting lung injury and repair.
Screening & Assay Development
- Provides a standardized, reproducible animal model for quantitative assessment of ventilation strategies.
- Enables collection of robust respiratory and hemodynamic data for assay development.
- Supports reproducibility and scalability for comparative evaluation of therapeutic candidates.
Translational & Preclinical Research
- Aligns with disease-relevant ARDS phenotypes observed in critical care settings.
- Enables continuity from discovery through preclinical validation of ventilation and pharmacologic interventions.
- Supports translational biomarker development through integration of imaging and physiological endpoints.
Pipeline & Workflow Integration
This model is positioned at the interface of discovery biology and preclinical validation, bridging mechanistic studies and translational research in ARDS.
- Discovery Biology: Facilitates hypothesis testing and pathway clarification in severe lung injury.
- Screening: Delivers reproducible, quantitative outputs for evaluating ventilation and therapeutic strategies.
- Analytics: Provides continuous respiratory and hemodynamic measurements, including Horowitz index and pulmonary pressures.
- Translational Research: Supports alignment with clinical ARDS features and biomarker endpoints.
- Enterprise Reuse: Offers a reusable, standardized platform for cross-program respiratory research.
Operational & Enterprise Impact
- Scientific Value: Increases predictive confidence and reduces mechanistic ambiguity in ARDS research.
- Operational Value: Enhances standardization, reproducibility, and scalability of preclinical respiratory studies.
- Strategic Value: Informs go/no-go decisions and reduces late-stage biological risk for respiratory portfolios.
- Portfolio Impact: Enables risk-adjusted prioritization and advancement of respiratory drug and device candidates.
Implementation Considerations
- Requires expertise in animal anesthesia, ventilation management, and invasive monitoring.
- Demands access to respiratory and hemodynamic monitoring infrastructure, including CT imaging.
- Necessitates cross-team standardization of injury induction and measurement protocols.
- Adaptation across species or model systems may require protocol optimization.
- Careful control of injurious ventilation duration is critical to avoid excessive, non-recruitable lung damage.
Biopharma FAQs
Chapters in this video
0:05
Introduction
0:44
The Mechanical Ventilation
1:46
Introduction of the Pulmonary Artery Catheter
2:46
Surfactant Depletion
3:41
Injurious Ventilation with High Tidal Volume/Low PEEP (High Tv/low PEEP)
4:25
Results: Effects of the Injurious Ventilation on the Lungs
5:40
Conclusion
