By Vibhu Sharma, MD, MS

Assistant Professor of Medicine, University of Colorado, Denver

Dr. Sharma reports no financial relationships relevant to this field of study.

SYNOPSIS: In this randomized trial, daily maximal recruitment trials failed to reduce ventilator-free days in the setting of acute respiratory distress syndrome, but increased the risk of cardiovascular adverse effects.

SOURCE: Hodgson CL, Cooper DJ, Arabi Y, et al. Maximal recruitment open lung ventilation in acute respiratory distress syndrome (PHARLAP). A phase II, multicenter randomized controlled clinical trial. Am J Respir Crit Care Med 2019;200:1363-1372.

The Permissive Hypercapnia, Alveolar Recruitment, and Low Airway Pressure (PHARLAP) trial recruited patients with moderate to severe acute respiratory distress syndrome (ARDS) (PaO2/FiO2 [or P/F] ratio of < 200 with a positive end-expiratory pressure [PEEP] > 5 cm H2O). Patients had to be mechanically ventilated for < 72 hours and diagnosed with ARDS using the Berlin criteria. Patients were randomized in a 1:1 ratio to the PHARLAP intervention or the control strategy of low tidal volume (Vt) per ARDSNet criteria (the PHARLAP intervention is described subsequently). Patients were stratified by site and the etiology of ARDS (pulmonary vs. extrapulmonary).

The PHARLAP intervention consisted of a pressure control (PC) mode with an inspiratory pressure of 15 ± 3 cm H2O targeting a Vt of 4 mL to 6 mL and a plateau pressure maintained at < 28 cm H2O whenever possible. Permissive hypercapnia was allowed. Daily recruitment maneuvers (RMs) were performed (for up to five days) in the PHARLAP intervention group. The protocol for the RMs consisted of two separate recruitment maneuvers: a staircase recruitment maneuver (SRM) and then a brief recruitment maneuver (BRM), if needed. The first step, SRM, involved increasing PEEP to 20 cm H2O all the way up to 40 cm H2O pressure, in 10 cm H2O increments, with two-minute plateaus at each step. A high pressure of 55 cm H2O thus was possible. Hemodynamic instability or marked oxygen desaturation (SpO2 < 85%) were criteria for termination of the PEEP titration maneuver, with the PEEP left at the level prior to the one at which desaturation or hemodynamic instability happened. After completion of the stepwise increase to maximal tolerated PEEP, the PEEP was reduced immediately to 25 cm H2O and subsequently reduced in 2.5 cm H2O decrements every three minutes until a PEEP of 15 was reached or desaturation (SpO2 drop of ≥ 2%) occurred. The point at which desaturation occurred was deemed the derecruitment PEEP. If derecruitment occurred, a second recruitment maneuver (BRM) was performed in the pressure control mode with the inspiratory pressure set at 15 ± 3 cm H2O and PEEP set at the maximal tolerated PEEP during the SRM for two minutes. PEEP then was returned to 2.5 cm H2O above derecruitment PEEP.

In the PHARLAP intervention group, after the RMs (“open lung procedure”) were performed, the PC level was reduced to achieve total pressure (PEEP + PC) to < 28 cm H2O using reductions in targeted Vt to as low as 4 mL/kg as needed. Failure of the recruitment strategies and persistent severe hypoxemia allowed for intervention with rescue strategies (e.g., high-frequency oscillatory ventilation, inhaled nitric oxide [iNO] or prostacyclin, prone positioning, or extracorporeal membrane oxygenation [ECMO]). The control group was ventilated using low Vt strategies per ARDSNet criteria, and rescue strategies as noted earlier were implemented as needed and as available by site.

Most patients recruited had pulmonary ARDS. The mean PEEP and P/F ratios were higher in the PHARLAP group, and pH was lower compared to the control group. Importantly, from day 1 to day 4 of 5 of the PHARLAP intervention, plateau pressures were significantly higher in the PHARLAP group (though still < 28 cm H2O), while driving pressures were not better than the control group beyond day 1. At 28 days, the number of ventilator-free days in the PHARLAP group was not different from the control group.

This study did not find differences in the rates of pneumothorax or mortality. However, the patients randomized to the PHARLAP group did have a reduction in the use of iNO, the need for ECMO, and prone positioning. There were no differences in the proportion of patients on neuromuscular blockade between groups. The PHARLAP strategy was associated with an increase in the risk of cardiac arrhythmias (atrial fibrillation, ventricular tachycardia, and ventricular fibrillation). The trial was terminated prematurely because of “safety concerns and perceived loss of equipoise at the sites” after publication of the Alveolar Recruitment Trial (ART). This resulted in recruitment cessation at 114 patients instead of the originally planned 340, resulting in an underpowered study for the primary endpoint.

COMMENTARY

This trial attempted to revisit the “open lung strategy” in the setting of ARDS, wherein attempts are made to open collapsed alveoli by RMs that transiently increase mean airway pressure up to (and occasionally above) 40 cm H2O. This trial had to be terminated early after publication of another trial (Alveolar Recruitment Trial)1 that showed an increase in cardiovascular adverse effects, barotrauma, and mortality at 28 days with RMs. A meta-analysis of other trials involving RMs and including the patients in this trial performed by the authors suggested no increase in mortality. However, an increased risk of barotrauma persisted. A plateau pressure of < 30 cm H2O is the major determinant of mortality, with lower plateau pressures (even those below 30 cm H2O) associated with decreasing mortality. The intervention group in this trial had a plateau pressure higher than the control group for each of the four out of five days (the duration that RMs were performed). Although plateau pressure remained below 30 cm H2O in the intervention group, lower plateau pressures were achieved in the control group with a simple low Vt strategy, and the differences were significant. The RMs were performed by expert clinicians who were “senior medical staff” and took an average of 18 minutes in my estimation. The authors stated that “the time required at the bedside limited recruitment into the study.” While oxygenation indices were better in the intervention group, oxygenation does not predict mortality in the setting of ARDS.

Prone positioning is an intervention that has a demonstrable mortality benefit, especially when done early in the setting of severe ARDS.2 A recent trial also seemed to suggest a mortality benefit for early use of airway pressure release ventilation (APRV) as a mechanical ventilation strategy in the setting of severe ARDS.3 Animal studies4 suggest a more prolonged benefit of RMs performed while prone, and other smaller clinical studies5,6 suggest a larger benefit for RMs in the prone position compared to the supine position. There are no studies that have compared the effects of an RM in the prone vs. the supine position with respect to endpoints studied in the PHARLAP trial. A low Vt strategy with early proning and possible use of APRV prior to initiating rescue therapies (ECMO/iNO) may be the preferred strategy for ventilating ARDS patients. The significantly higher plateau pressure in the intervention group in this study (albeit still < 30 cm H2O) over the four of five days after randomization is the strongest argument to discard RMs as a routine intervention in moderate to severe ARDS.

REFERENCES

  1. Writing Group for the Alveolar Recruitment for Acute Respiratory Distress Syndrome Trial (ART) Investigators, Cavalcanti AB, Suzumura EA, et al. Effect of lung recruitment and titrated positive end-expiratory pressure (PEEP) vs low PEEP on mortality in patients with acute respiratory distress syndrome: A randomized clinical trial. JAMA 2017;318:1335-1345.
  2. Guerin C, Reignier J, Richard JC, et al. Prone positioning in severe acute respiratory distress syndrome. N Engl J Med 2013;368:2159-2168.
  3. Zhou Y, Jin X, Lv Y, et al. Early application of airway pressure release ventilation may reduce the duration of mechanical ventilation in acute respiratory distress syndrome. Intensive Care Med 2017;43:1648-1659.
  4. Cakar N, der Kloot TV, Youngblood M, et al. Oxygenation response to a recruitment maneuver during supine and prone positions in an oleic acid-induced lung injury model. Am J Respir Crit Care Med 2000;161:1949-1956.
  5. Rival G, Patry C, Floret N, et al. Prone position and recruitment manoeuvre: The combined effect improves oxygenation. Crit Care 2011;15:R125.
  6. Pelosi P, Bottino N, Chiumello D, et al. Sigh in supine and prone position during acute respiratory distress syndrome. Am J Respir Crit Care Med 2003;167:521-527.