Optimal Ventilator Strategies in Acute Respiratory Distress Syndrome

Michael C. Sklar, MD; Bhakti K. Patel, MD; Jeremy R. Beitler, MD, MPH; Thomas Piraino, RRT; Ewan C. Goligher, MD, PhD


Semin Respir Crit Care Med. 2019;40(1):81-93. 

In This Article

Airway Pressure Release Ventilation

Airway pressure release ventilation (APRV) was originally described over 30 years ago by Stock et al as a mode of ventilation that maintained an elevated pressure for most of the respiratory cycle (inverse I:E ratio) with periods of "release" to a lower CPAP to facilitate elimination of CO2.[101] The mode is purely time-cycled, shifting between high-pressure and low-pressure settings at set time intervals while allowing unrestricted breathing by the patient at any time during ventilation. There are four settings that set APRV apart from other modes; high pressure (Phigh) and the length of time Phigh is maintained (Thigh), low pressure (Plow) and the length of time Plow is maintained (Tlow). However, the literature contains major differences in how these settings are used and in the ventilation strategies used as comparators in trials.[102] Older studies of APRV titrated Plow to prevent alveolar collapse, whereas a more modern approach adjusts Tlow based on expiratory flow to maintain auto-PEEP to prevent alveolar collapse. Additionally, there are minor differences between studies of similar methods that may be important, such as the Plow settings used, or how much expiratory flow is limited with Tlow[103] (Table 1).

Setting P low

The traditional method of APRV was to set a Plow level and allow exhalation to that level prior to returning to Phigh.[101] In older studies, Plow was set according to the lower inflection point of the pressure–volume curve and control groups had PEEP set by the same method.[104–106] One of the most widely cited studies using this method was a crossover study of trauma patients by Putensen et al that randomly assigned 30 patients to receive APRV or pressure-controlled ventilation. They reported lower inotropic support requirements, fewer ventilator days, and a shorter length of ICU stay in patients that were initially managed with APRV.[104] However, the control group was paralyzed for the first 72 hours then switched to APRV; it is possible that the observed benefit of APRV was attributable to the protocol design rather than the mode per se. Subsequently, Varpula et al published the first RCT of APRV in ARDS patients using a Thigh of 4 seconds and a Tlow set to 1 second.[106] Similar to the Putensen et al, P low values during APRV and PEEP in the control group were set according to the lower inflection point of the pressure–volume curve. They originally planned to enroll 80 patients but stopped early for futility after an interim analysis of the first 58 patients. They found no significant difference in the primary outcome of ventilator-free days (13.4 vs. 12.2 with APRV and synchronized intermittent mandatory ventilation [SIMV], respectively). Of note, tidal volumes were high in both groups (between 8 and 10 mL/kg).

Limiting Expiratory Flow

In more recent years, studies of APRV have used a different approach where Tlow is set short enough to limit expiratory flow deceleration. With this method, auto-PEEP rather than Plow is used to prevent alveolar collapse. This approach has now been used in three randomized trials (two adult and one pediatric study), with minor differences between them related to setting Plow and the allowable limit of expiratory flow. In an RCT by Maxwell et al, APRV was compared with low VT ventilation (using SIMV) in 63 trauma patients.[107] They set P low to 0 cm H2O with T low set to terminate exhalation when the expiratory flow fell between 75 and 25% of peak expiratory flow. The outcomes were similar in both groups despite worse baseline physiological scores (APACHE II) in the APRV group. Sedation requirements were similar, and the duration of ventilation was not significantly different.

Recently Zhou et al conducted an RCT comparing APRV to conventional low tidal volume ventilation using the ARDSNet trial protocol in 138 patients meeting criteria for ARDS.[108] This was the first RCT comparing APRV to low VT specifically in ARDS. They set Plow to 5 cm H2O and set Tlow to prevent expiratory flow from falling below 50% of the peak expiratory flow. They reported a significant improvement in the primary outcome of ventilator-free days using APRV compared with low VT ventilation (19 vs. 2; p < 0.0001). In contrast to Maxwell et al, they included spontaneous breathing trials in the protocols of both groups. However, the results may be confounded by several cointerventions: sedatives were significantly reduced in APRV patients by protocol design and spontaneous modes were not used in the control arm (patient–ventilator interaction was not assessed or considered). Furthermore, it was a single-center study limiting generalizability, baseline characteristics were not well balanced between groups (more patients with comorbidities were enrolled in the control arm), and there was an abnormally high rate of unsuccessful extubations and tracheostomies in the low VT group.[103,109] Shortly after the Zhou et al publication, an RCT of pediatric ARDS patients comparing APRV with low VT was stopped early after 50% enrollment (n = 52) when an interim analysis demonstrated higher mortality in the APRV group.[110]

APRV With Shorter P high

Another method to use the APRV mode is often referred to as biphasic positive airway pressure. This method uses Phigh and Plow pressures comparable to conventional ventilation with Thigh and Tlow ratios similar to conventional pressure control (1:1 or greater), in contrast to the typical inverse ratio in most APRV studies.[102] The mode simply allows the patient to breathe freely without the need to be synchronous (ventilator breaths are delivered based solely on time and not patient effort). The primary goal of this approach is to limit transpulmonary pressure swings by inducing dyssynchrony (rather than trying to avoid dyssynchrony).[111] This method was recently applied in the largest study to date using the APRV mode, but the results have not been published at the time of this writing [NCT01862016]. Nonetheless, it will address a different question as it deals more with the question of synchrony rather than alveolar recruitment and an open lung approach.

The ability to generate higher mean airway pressure at lower peak airway pressures is the reason why APRV has been discussed in the context of managing ARDS, similar to the story of high-frequency oscillatory ventilation (HFOV).[112] However, in recent years the use of HFOV has fallen out of favor in the management of ARDS due to lack of effect and even potential harm.[113] [114] Other "open lung" approaches using recruitment maneuvers and setting PEEP according to respiratory system compliance have also seen troubling results demonstrating potential for harm.[69] A major concern with widespread adoption of APRV is that it has not been studied nearly as well as these other approaches, which have all produced disappointing and concerning results in recent trials. Clinicians should be cautious in assuming that an open lung approach using APRV would yield different results. Currently the data are insufficient to recommend its use outside of a clinical trial.