Airway Pressure Release Ventilation in Acute Lung Injury

The purpose of this study is to compare airway pressure release ventilation (APRV) to conventional mechanical ventilation (MV) in patients with acute lung injury (ALI) to determine if APRV can reduce agitation, delirium, and requirements for sedative medications. We will also compare markers of inflammation in the blood and lung to determine if APRV reduces ventilator-induced lung injury (VILI), compared to conventional mechanical ventilation.

The proposed study is a randomized, crossover trial. We plan to enroll 40 patients with ALI and randomize to APRV or conventional MV for 24 hours. After this time the patients will be switched to the alternative mode of ventilation (MV or APRV) for another 24 hours. To assess breathing comfort, at the end of each 24-hour period we will measure the amounts of sedative and analgesic medications used. We will also measure the concentrations of markers of inflammation in the blood and lung as measures of VILI. Finally, throughout the study we will compare the adequacy of gas exchange with APRV compared to conventional MV.

Acute respiratory failure is common in patients with acute lung injury. MV re-establishes adequate gas exchange; it allows time for administration of antibiotics, for the host's immune system to fight infections, and for natural healing. Approximately 60% of ALI patients survive to hospital discharge (1). However, conventional approaches to MV in ALI frequently cause dyssynchrony between a patient's spontaneous respiratory efforts and the ventilator's respiratory cycle (2;3). Dyssynchrony causes discomfort, anxiety, and agitation. To manage dyssynchrony, physicians frequently prescribe large doses of sedative and analgesic medications. These medications contribute to delirium and sleep deprivation during the critical illness, and may delay weaning from MV and discharge from the intensive care unit (2;4). They may also contribute significantly to neuromuscular and neurocognitive sequelae after recovery from ALI (5;6). Moreover, MV may itself cause additional lung injury (ventilator-induced lung injury, VILI) which could, paradoxically, delay or prevent recovery from respiratory failure in some ALI patients (7;9).

Airway pressure release ventilation (APRV) is a mode of MV that is designed to reduce patient-ventilator dyssynchrony and VILI. It differs from most other modes of MV in that it allows patients to breathe spontaneously at any time, independent of the ventilator's cycle. This feature may improve breathing comfort by minimizing patient-ventilator dyssynchrony. Improving comfort and reducing agitation may ultimately curtail the use of sedative and analgesic medications. Since a substantial proportion of ventilation results from the patient's spontaneous efforts independent of the ventilator cycle, the frequency of mechanically assisted breaths can be reduced. This may reduce VILI from the cyclic opening-closing of alveoli and small bronchioles that results from assisted MV breaths. Another feature of APRV that distinguishes it from other modes of MV is that it applies a sustained high pressure during inspiration and a brief period of lower pressure during exhalation. This approach may maximize and maintain alveolar recruitment throughout the ventilatory cycle while limiting high airway pressures, thus further reducing VILI. Moreover, spontaneous contractions of the diaphragm during APRV may open dependent atelectatic lung regions, improving ventilation-perfusion (V/Q) matching and gas exchange. However, these potential advantages of APRV are unproven.

Eligibility Criteria:
Inclusion Criteria:

Acute onset of:

1. Arterial Pressure of Oxygen (PaO2) / FiO2 ≤ 300
2. Bilateral infiltrates consistent with pulmonary edema on frontal chest radiograph. The infiltrates may be patchy, diffuse, homogeneous, or asymmetric
3. Requirement for positive pressure ventilation via endotracheal tube, and
4. No clinical evidence of left atrial hypertension.
5. Receiving conventional MV, or lung-protective ventilation (LPV), in the assist control (AC) mode with positive end-expiratory pressure (PEEP) \> 5 cm H2O Criteria 1-3 must occur within a 24-hour period. "Acute onset" is defined as follows: the duration of the hypoxemia criterion (#1) and the chest radiograph criterion (#2) must be \< 7 days at the time of randomization.

Exclusion Criteria:

1. FiO2 \> 70% or PaO2/FiO2 \< 125 or arterial pH \< 7.25
2. Greater than 6 days since all inclusion criteria are met
3. Anticipated to begin weaning from MV within 48 hours
4. Neuromuscular disease that prevents the ability to generate spontaneous tidal volumes.
5. Glasgow Coma Scale (GCS) \< 15 within 1 week of intubation
6. Acute stroke (vascular occlusion or hemorrhage)
7. Current alcoholism or previous daily use of opioids or benzodiazepines before hospitalization
8. Acute meningitis or encephalitis
9. Pregnancy (negative pregnancy test required for women of child-bearing potential) or breast-feeding.
10. Severe chronic respiratory disease
11. Previous barotraumas during the current hospitalization
12. Clinical evidence of bronchoconstriction on bedside examination (i.e., wheezing).
13. Patient, surrogate, or physician not committed to full support
14. Severe chronic liver disease (Child-Pugh Score B or C)
15. International Normalized Ratio (INR) \> 2.0
16. Platelet level \< 50,000
17. Mean arterial pressure \< 65, or patient receiving intravenous vasopressors (any dose of epinephrine, norepinephrine, phenylephrine, or dopamine \> 5 mcg/kg/min)
18. Age \< 16 years old
19. Morbid obesity (greater than 1kg/cm body weight).
20. No consent/inability to obtain consent
21. Unwillingness of the clinical team to use conventional low tidal-volume protocol for MV.
22. Moribund patient not expected to survive 24 hours.