Reproduced with permission. © 2012 American Thoracic Society. Phua J, Badia JR, Adhikari NK, et al. Has mortality from acute respiratory distress syndrome decreased over time? A systematic review. Am J Respir Crit Care Med. 2009;179:220-227.

The task force focused on feasibility, reliability, validity, and objective evaluation of the new model’s performance. A draft definition was evaluated and validated using 4 multicenter data sets with clinical data and 3 single-center data sets containing additional physiological information. The final classification demonstrates progressive increases in mortality rates as the stage increases from mild to severe (mild, 27%; moderate, 32%; severe, 45%, P < 0.001) as well as increases in median duration of mechanical ventilation in survivors (mild, 5 days; moderate, 7 days; severe, 9 days; P < 0.001). For the overall predictive value for mortality, the area under the receiver operating curve for the Berlin Definition model was 0.577, slightly improved from the AECC model.

Specific clarifications of ambiguities in the prior AECC definition are given in Table 6-2. The changes include definition of acute onset as 1 week or less; requirement for a specific minimal positive end-expiratory pressure (PEEP) for determination of Pao₂/Fio₂ ratio; elucidation of radiographic imaging criteria, with allowance for computed tomography (CT) findings as well as chest radiograph findings; elimination of the pulmonary capillary wedge pressure criteria; and requirement for objective assessment to rule out cardiogenic edema in the absence of a known ARDS risk factor. Disappointingly, analyses that included additional variables suggesting severe disease (radiographic severity, respiratory system compliance <40 mL/cm H₂O, PEEP ≥10 cm H₂O, and higher dead space ventilation) failed to add additional prognostic value to the model. Overall, the Berlin criteria remain very similar in structure to the AECC definition but are updated to reflect current ICU practice, are clearer, and are more specific. The lack of major substantive changes is perhaps expected given the inherent difficulty in applying any more than broad rules to such a multifaceted syndrome.⁷ It is hoped that the additional precision in categorization will help improve care and treatment.

Ventilator Management in ARDS

The pathological lesion in ARDS includes epithelial and endothelial lung injury, alveolar exudate, and increased pulmonary vascular permeability.⁸ Autopsy and radiographic studies demonstrate that injury in ARDS is distributed throughout the pulmonary parenchyma in a heterogeneous fashion.⁹ Gattinoni et al¹⁰ corroborated these findings with CT scanning of ARDS patients, identifying (1) “normal”-appearing lung tissue, (2) patchy consolidation with fluid-filled and/or atelectatic lung, and (3) a “recruitable” component that is collapsed upon expiration but will expand with inspiration. Attempting to ventilate poorly compliant portions of lung simultaneously exposes normal regions to high pressure and risks overdistension, hemodynamic compromise, and further damage to the remaining functional portions of the lung.¹¹ These consequences of mechanical ventilation can compromise the benefits of support by instead promoting a persistent cycle of injury.

The goal of current mechanical ventilation treatment strategies remains optimizing oxygenation and ventilation while further limiting ventilator-induced lung injury (VILI). Of note, all of the approaches discussed here reflect a trend toward higher airway pressures, and the potential for paradoxical worsening of VILI exists. A careful, stepwise approach is recommended; an example is depicted in Figure 6-2.

ARDSNet Lung-Protective Ventilation

Low tidal volume, lung-protective mechanical ventilation has become the standard of care since the publication of the seminal ARDSNet low tidal volume trial in 2000.¹² To date, this trial remains the only randomized, controlled study of mechanical ventilation that demonstrated a mortality benefit; a 9% absolute reduction was seen in patients receiving 6-mL/kg tidal volumes compared with those receiving 12-mL/kg tidal volumes (31.0% vs. 39.8%, P = 0.0007). Lung-protective tidal volumes were set based on predicted body weight (based on patient height), using pressure-limited titration to maintain plateau pressures less than 30 cm H₂O. A standardized PEEP/Fio₂ table was used to guide ventilator changes.

It is not known whether the 6-mL/kg tidal volume setting or use of the standard ARDSNet PEEP/Fio₂ table represents optimal ventilation for all ARDS patients. In patients with larger nonaerated compartments on CT scan, lung-protective ventilation may not completely eliminate tidal hyperinflation in the remaining lung.¹³ Conversely, atelectatic injury may be aggravated by small tidal volumes.¹⁴ The relative contributions of peak, mean, drive, or end-expiratory airway pressures in promoting lung injury are not clearly delineated. Likewise, it is not clear what role active alveolar recruitment and ventilator modes incorporating spontaneous ventilation have in reducing VILI.

Recruitment/Open Lung Ventilation

Ventilator management strategies directed at increasing the fraction of recruitable lung available for gas exchange include recruitment maneuvers and the use of higher PEEP “open lung” ventilation.

Multiple approaches to recruitment maneuvers have been described, including prolonged breath holds, intermittent sighs, and short periods of pressure control ventilation at higher plateau pressures.¹⁵ These interventions usually result in significant but temporary improvement in arterial oxygenation.¹⁶ Serious adverse events are infrequent and include transient hypotension and desaturation during the period of increased pressure. Because near-maximal increases in volumes are likely achieved rapidly and hemodynamic alterations are usually seen after more sustained exposure to higher pressures, the majority of benefit may be achieved in the first 10 seconds of intervention.¹⁷

Controlled application of brief periods of increased airway pressure may bring additional alveolar units to contribute to gas exchange but at the potential cost of overdistension of adjacent normal units. The fraction of collapsed alveoli seen in ARDS, and thus the potential for additional lung recruitment, may vary considerably from patient to patient.¹⁸ The exact benefit or best use of these maneuvers is not clearly established, particularly in patients with minimal recruitable lung seen on imaging, and use should be individualized.¹⁶

The open lung approach attempts to preserve end-expiratory lung volume following recruitment by maintaining end-expiratory pressure above the critical alveolar closing pressure. The optimal PEEP level to prevent derecruitment and alveolar recollapse¹⁹ is not known; however, the required settings are often higher than those present prior to the recruitment maneuver.¹⁵ In determining final PEEP settings, a decremental rather than incremental PEEP trial may more properly identify the expiratory limb inflection point.²⁰ In this construct, a recruitment maneuver is performed followed by application of high PEEP settings, which are then gradually decreased in a stepwise fashion until derecruitment occurs, as manifested by decreases in returned tidal volumes or compliance. Recruitment is then repeated and PEEP set above the level at which derecruitment was identified.

Three separate multicenter, randomized controlled trials^21-23 have not shown a survival advantage to a higher PEEP, open lung strategy over conventional ARDSNet ventilation. A recent meta-analysis of these 3 trials, which included a total of 2,299 patients, found no significant mortality reduction in the full cohort; however, subgroup analysis did suggest improved survival and decreased time to unassisted breathing in patients with Pao₂/Fio₂ ratio less than 200 treated with higher PEEP.²⁴ In the ARDSNet ALVEOLI²¹ trial, the higher PEEP arm achieved higher Pao₂/Fio₂ ratios but showed no difference in the end points of mortality, organ failure–free days, or biomarker levels when compared with ventilation directed by the conventional ARDSNet PEEP table. Recruitment maneuvers were performed in the initial 80 enrolled patients but were then discontinued from the protocol after demonstration of lack of benefit. Interpretation of the trial results is confounded somewhat by baseline differences in age and baseline mean Pao₂/Fio₂ ratio present between groups, despite randomization. The Canadian Critical Care Trials Group LOVS²² trial compared lung-protective ventilation with a strategy including recruitment maneuvers (40-second breath hold, 40 cm H₂O, Fio₂ 1.0) and higher PEEP levels, with plateau pressure limited to less than 40 cm H₂O. Improvements were seen in the secondary outcomes of severe hypoxemia, Fio₂ requirement, and use of rescue therapies, although no clear mortality benefit or decrease in duration of mechanical ventilation was identified. The French ExPress trial²³ titrated a low-PEEP arm between 5 and 9 cm H₂O to achieve minimum oxygenation targets and a high-PEEP arm to as high a level of PEEP as possible while maintaining plateau pressure limits of 28 to 30 cm H₂O. Again, improvements in ventilator and organ failure outcomes were seen, without significant reduction in mortality.

Despite the convincing lack of survival benefit, secondary outcome improvements seen in these trials suggest that benefit from recruitment and a higher PEEP strategy may exist.

Optimizing PEEP, Esophageal Pressure Protocol

An additional consideration in setting PEEP levels is the contribution of chest wall compliance to measured determinations of airway pressures. In patients with chest and abdominal wall restriction, elevated airway pressures may reflect higher contribution from transpleural pressure rather than truly elevated transpulmonary pressure. In a single-center randomized trial, Talmor et al²⁵ used balloon catheter determinations of esophageal pressure to approximate pleural pressure and based ventilator management on calculated estimated transpulmonary pressure (Transpulmonary Pressure (Ptp) = Airway pressure (Paw) – Esophageal Pressure (Pes). Esophageal pressure–guided PEEP titration yielded statistically significant improvements in oxygenation and respiratory system compliance over the standard ARDSNet PEEP/Fio₂ table. Of note, PEEP was increased more than 5 cm H₂O from baseline in 60% of patients in the esophageal manometry group immediately following randomization but in only 3% of the standard of care group. Improvement in oxygenation, rather than mortality, was the prespecified primary end point; however, after investigators accounted for baseline severity of illness, the esophageal pressure-guided protocol was associated with significantly decreased 28- and 180-day mortality. The authors suggest that this strategy may facilitate optimal, safe PEEP titration by individualizing adjustments for a given patient’s specific torso compliance. A National Institutes of Health–sponsored, phase 2 randomized, multicenter clinical trial testing this hypothesis (EPVent 2—A Phase 2 Study of Mechanical Ventilation Directed by Transpulmonary Pressures, NCT01681225) is currently enrolling patients.

Spontaneous Ventilation

The majority of randomized trials in ARDS patients have studied outcomes in the setting of controlled mechanical ventilation, relegating pressure support modes to the weaning portion of the protocol. Nevertheless, spontaneous breathing permits more physiological negative-pressure respiration and reduces dyssynchrony, and patients may need less sedation compared with controlled ventilation modes.²⁶ We must recognize that as a natural consequence of ICU protocols aimed at reduction of pharmacological sedation, it is now not uncommon to have spontaneous ventilation begin before active weaning commences.

Airway pressure-release ventilation (APRV) and bilevel ventilation use high levels of continuous positive airway pressure (CPAP) to provide increased mean airway pressure while allowing spontaneous breathing and facilitating mandatory tidal ventilation with intermittent pressure release to a lower airway pressure. In contrast to synchronized intermittent mandatory ventilation, in APRV and bilevel ventilation spontaneous respiration occurs primarily at the higher PEEP level (Figure 6-3). Settings are accomplished by adjusting high and low pressure levels (P_high and P_low), or time at preset inspiratory and expiratory pressures (T_high and T_low). The inspiratory to expiratory (I:E) ratio is inversed to maintain higher mean airway pressures and to encourage recruitment. If T_low extends beyond time needed for exhalation, significant auto-PEEP and pronounced swings to low or negative transpulmonary pressure may aggravate alveolar collapse and cyclic strain.²⁷ Several small randomized studies comparing APRV to conventional mechanical ventilation have shown improvement in oxygenation, but, to date, no trials of spontaneous ventilator modes have demonstrated a mortality benefit.²⁸ Further studies of the use of these modes in the ARDS population are required.

Sedation and Neuromuscular Blockade

Sedatives and narcotics are administered in at least 80% of ARDS patients,²⁹ with neuromuscular blocking agents used in at least 25%.³⁰ The impact of minimizing sedation on improving ICU outcomes is well known. The recognition that daily interruption of sedation decreases the duration of mechanical ventilation,³¹ the realization that the choice of sedative agent affects late delirium-associated mortality,³² and the finding of long-term functional impairment in ARDS patients³³ all have spurred adoption of sedation reduction and early mobilization protocols for these patients.

Running counter to this trend is a recent multicenter randomized trial finding significant mortality benefit to a short course of neuromuscular blockade in early, severe ARDS.³⁴ The investigators administered high-dose cisatracurium infusion for 48 hours in combination with lung-protective ventilation in patients with early moderate to severe ARDS (Pao₂/Fio₂ ratio <150, presentation within 48 hours of onset of ARDS). The cisatracurium group had an increase in oxygenation, increases in ventilator- and organ failure-free days, and a significant reduction in mortality (hazard ratio 0.68; 95% confidence interval, 0.48-0.98; P = 0.04). No significant increases in functional weakness were identified either at day 28 of the study or at ICU discharge.³⁴

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