Journal of Critical Care 34 (2016) 154–159

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Journal of Critical Care

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Characteristics and outcomes of patients treated with airway pressure

release ventilation for acute respiratory distress syndrome: Aretrospective observational study☆

Jolene Lim, MBBS (Hon) a,1, Edward Litton, MB, ChB, MSs, FCICM b,c,⁎,Hayley Robinson, BMedSci (Hon), MBBS (Hon) d, Mike Das Gupta e,2

a Medical student, Royal Perth Hospital, Perth, Western Australiab Staff Specialist Intensive Care Medicine, Intensive Care Unit, Royal Perth Hospital, Perth, Western Australiac Clinical Senior Lecturer, School of Medicine and Pharmacology, University of Western Australia, Perth, Western Australiad Senior Registrar Intensive Care Medicine, Intensive Care Unit, Royal Perth Hospital, Western Australiae Senior Clinical Respiratory Technician, Intensive Care Unit, Royal Perth Hospital, Perth, Western Australia

a b s t r a c ta r t i c l e i n f o

☆ Conflicts of interest: The authors declare that there ar⁎ Corresponding author at: Staff Specialist Intensive Car

Fiona Stanley Hospital, 11 Robin Warren Drive, MurdoAustralia.

E-mail address: Ed_litton@hotmail.com (E. Litton).1 Present address: Medical Officer, Fiona Stanley Hospit2 Present address: Senior Clinical Respiratory Technic

Stanley Hospital, Perth, Western Australia.

http://dx.doi.org/10.1016/j.jcrc.2016.03.0020883-9441/© 2016 Elsevier Inc. All rights reserved.

Keywords:

Airway pressure release ventilationacute respiratory distress syndromemechanical ventilationECMO

Background: The optimal mode of ventilation in acute respiratory distress syndrome (ARDS) remains uncertain.Airway pressure release ventilation (APRV) is a recognized treatment for mechanically-ventilated patients withsevere hypoxaemia. However, contemporary data on its role as a rescue modality in ARDS is lacking. The goal ofthis study was to describe the clinical and physiological effects of APRV in patients with established ARDS.

Methods: This retrospective observational study was performed in a 23-bed adult intensive care unit in a tertiaryextracorporeal membrane oxygenation (ECMO) referral centre. Patients with ARDS based on Berlin criteriawere included through a prospectively-collected APRV database. Patients receiving APRV for less than sixhours were excluded.Results: Fifty patients fulfilled the eligibility criteria. Prior to APRV initiation, median Murray Lung Injury Scorewas 3.5 (interquartile range (IQR) 2.5–3.9) and PaO2/FiO2 was 99 mmHg (IQR 73–137). PaO2/FiO2 significantlyimproved within twenty-four hours post-APRV initiation (ANOVA F(1, 27) = 24.34, P b .005). Two patients(4%) required intercostal catheter insertion for barotrauma. Only one patient (2%) required ECMO after APRV ini-tiation, despite a majority (68%) fulfilling previously established criteria for ECMO at baseline. Hospital mortalityrate was 38%.Conclusions: In patients with ARDS-related refractory hypoxaemia treated with APRV, an early and sustained im-provement in oxygenation, low incidence of clinically significant barotrauma and progression to ECMO was ob-served. The safety and efficacy of APRV requires further consideration.

© 2016 Elsevier Inc. All rights reserved.

1. Background

The mortality associated with acute respiratory distress syndrome(ARDS) remains high and has changed little in the last twenty years[1]. Despite the advent of lung protective ventilatory strategies, consen-sus on the optimal mode of ventilation in patients with ARDS is lacking.Airway pressure release ventilation (APRV) is an established mode ofventilation based on the open-lung approach, allowing unrestricted

e no conflicts of interest.e Medicine, Intensive Care Unit,ch, WA, 6150, Perth, Western

al, Perth, Western Australia.ian, Intensive Care Unit, Fiona

spontaneous breathing with intermittent mandatory ventilation [2–4].Positive pressure (Phigh) is applied for a prolonged time (Thigh), with arelease phase (Plow) for a short period (Tlow) [2,3].

Potential advantages of using APRV in ARDS include increased re-cruitment of lung units due to an increase in functional residual capac-ity, reduction in atelectrauma through decreased cyclical recruitmentand derecruitment, unrestricted spontaneous breathing improving ven-tilation/perfusion (V/Q)matching and reduction in sedation and neuro-muscular blockade requirements [2,5–10].

Compared with other conventional ventilatory modes, APRV mayimprove oxygenation, length of stay in the intensive care unit (ICU)and ventilator-free days [6–8,11–16]. As such, APRV may represent analternative to extracorporeal membrane oxygenation (ECMO) [17] inpatients with severe hypoxaemic respiratory failure secondary toARDS. However, data investigating the safety and efficacy of APRV as arescue therapy in this group is lacking [9,10].

Fig. 1. Flow chart of the patients included in the study.

155J. Lim et al. / Journal of Critical Care 34 (2016) 154–159

Therefore, the objective of this study was to describe the safety andefficacy of APRV initiation in patients with established ARDS, with theconsideration of its role as a rescue therapy and alternative to ECMO.

2. Materials and methods

This retrospective observational studywas performed at Royal PerthHospital's (RPH) ICU, a 23-bed adult ECMO referral centre in WesternAustralia. Ethical approval and waiver of consent was obtained fromthe RPH Human Research Ethics Committee (approval number REG

Table 1Baseline characteristics of patients. Statistics presented as median and interquartile range(IQR) unless otherwise stated.

Characteristic N = 50

Age 44 (37–55)Male sex, n (%) 29 (58)Admission type, n (%) Medical 36 (72)

General surgical 6 (12)Trauma 5 (10)Other 3 (6)

Source of ICU admission, n (%) 17 (34)10 (20)4 (8)19 (38)

Lung injury mechanism, n (%) Pulmonary 39 (78)Extrapulmonary 11 (22)

Acute Physiology and Chronic Health Evaluation(APACHE) II score

23 (19–29)

Predicted mortality based on APACHE II score 0.39 (0.30–0.60)Hours from intubation to APRV 2 (0–23)ARDS severity (Berlin criteria), n (%) Mild 12 (24)

Moderate 17 (34)Severe 21 (42)

Murray Lung Injury Score 3.5 (2.5–3.9)Mode of ventilation prior to APRV, n (%) Direct to APRV 14 (28)

SIMV VC 6 (12)Bilevel 22 (44)Pressure support 7 (14)Assist control 1 (2)

PaO2/FiO2 ratio prior to APRV (mmHg) 99 (73–137)Spontaneously breathing on initiation of APRV, n (%) 29 (58)Noradrenaline requirement on initiation of APRV(mcg/kg/min), mean (SD)

0.15 (0.28)

14–103). All patients on APRVwere identified prospectively and includ-ed in a database.

Patients aged 18 years and above, receiving APRV ventilation duringtheir index admission to the ICU and diagnosed with ARDS based onBerlin criteria [18] were included. Patients receiving APRV for lessthan six hours, or for an indication other than ARDS were excluded.Data related to oxygenation and ventilationwas not included in analysisif a patient was initiated on ECMO. Ventilator (Puritan Bennett 840)APRV parameters were initially adjusted by the attending intensivecare physician, with reference to previously published guidelines [19].Briefly, release time was adjusted to maintain a peak expiratory flowrate termination of 50–75%, the number of releases was minimized toencourage spontaneous breathing, automatic tube compensation wasset at 100%.

Data for each patient was collected on a pre-specified case reportform and included baseline characteristics such as age, gender, bodymass index, admission time to hospital and ICU, admission source andcategory, acute physiology and chronic health evaluation (APACHE) IIscore, date and time of intubation,mode of ventilation prior to initiationof APRV and date and time of APRV initiation. Radiographic require-ments for the diagnosis of ARDS were derived from the attendingradiologist's final chest x-ray report. Additional Berlin criteria were de-rived from the participant medical notes and ICU observation charts.

Table 2Ventilatory parameters on initiation of APRV and 12 h post-APRV initiation. Statistics pre-sented as median and interquartile range (IQR) unless otherwise stated.

Ventilatory parameter

On initiation of APRV N = 50

Phigh (cmH2O) 30 (26–30)Peak airway pressure (cmH2O) 32 (29–35)Mean airway pressure (cmH2O) 25 (24–26)Set pressure (cmH2O) 30 (26–30)Tidal volume (ml) 500.0 (400.0–600.0)

12 h post initiation of APRV N = 35Phigh (cmH2O) 28 (24–30)Peak airway pressure (cmH2O) 32 (28–35)Mean airway pressure (cmH2O) 25 (24–26)Set pressure (cmH2O) 28 (24–30)Tidal volume (ml) 500.0 (400.0–650.0)

Fig. 2.Median PaO2/FiO2 and FiO2 vs. time on APRV.

156 J. Lim et al. / Journal of Critical Care 34 (2016) 154–159

Process measures included peak airway pressure, mean airway pres-sure, set pressure, total PEEP, Phigh, tidal volume, mandatory respiratoryrate, presence of spontaneous breathing and concurrent therapy re-quirements (nitric oxide, epoprostenol, noradrenaline, ECMO, proning,oscillation). Ventilator parameters were obtained at pre-defined time-points, and averaged over the hour.

Outcome measures included PaO2/FiO2 (PF) ratio, serum pH andPaCO2, CVP (as a surrogatemarker of right heart dysfunction), incidenceof barotrauma, ICU and hospital length of stay and mortality, durationof APRV and requirement for tracheostomy. Incident barotrauma wasdefined as new pneumothorax, pneumomediastinum or surgical em-physema radiologically-diagnosed via chest x-ray or computed tomog-raphy occurring after initiation of APRV. The severity of ARDSwas basedon Berlin criteria and Murray lung injury scores [20] which were de-rived from chest imaging reported by a radiologist.

These outcomeswere also examined in a subgroup of patients fulfill-ing previously published criteria for initiation of ECMO, with MurrayScoreN 3.0 or pH b7.20 [17]. Continuous variables are reported asmean and standard deviation or median and interquartile range forparametric and non-parametric data respectively, and categorical vari-ables as number (%). One-way repeated-measures analysis of variance(ANOVA) was employed to examine the relationship of outcome mea-sures over time. Statistical analyses were performed with Stata Statisti-cal Software Version 13 (StataCorp, College Station, TX) and MicrosoftExcel 2013.

3. Results

3.1. Study Population

Between October 2012 and August 2014 fifty patients fulfilled eligi-bility criteria andwere included in the study (see Fig. 1). The lung injury

Fig. 3.Median PaCO2 and

mechanism for thirty-nine patients (78%) was from pulmonary insults,with pneumonia being themain etiology (fifteen patients (30%)). Medi-an APACHE II score was 23 (IQR 19–29), with a predicted mortality rateof 39% (IQR 30–60). Twenty-one patients (42%) had severe ARDS as perthe Berlin criteria, with a median Murray Lung Injury Score of 3.5 (IQR2.5–3.9) (see Table 1). The median time from intubation to initiationof APRV and subsequent duration of ventilation with APRV were2 hours (IQR 0–23) and 51 hours (IQR 26–106) respectively.

3.2. Aprv Respiratory Parameters

Twenty-eight out of thirty-five patients (80%) were spontaneouslybreathing at 24 hours post-initiation of APRV. Ventilator parameterson initiation of APRV and 12 hours post-initiation are presented inTable 2.

Initiation of APRV, was associated with a significant increase in P/Fratio (F(1, 27)=24.34, P b .005). Similarly, the delivered FiO2 decreasedsignificantly over the same period (F(1, 27) = 20.72, P b .005) (seeFig. 2).

PaCO2 remained stable in the first 24 hours post-initiation of APRV,although a significant improvement in pH was observed (see Fig. 3).

3.3. Safety of APRV

Incident barotrauma occurred in seven (14%) patients whilst receiv-ing APRV. However, only two (4%) required intercostal catheter inser-tion. These events occurred 48 hours and 7 days post-APRV initiationand there was no associated early mortality. Peak airway pressureremained stable in the first 24 hours after initiation of APRV (see Fig. 4).

Central venous pressure (CVP) decreased significantly in the first24 hours after initiation of APRV (F(1, 18) = 44.24, P = .04) (seeFig. 5). Concurrently, mean noradrenaline requirement was observed

pH vs. time on APRV.

Fig. 4. Median peak airway pressure vs. time on APRV.

157J. Lim et al. / Journal of Critical Care 34 (2016) 154–159

to decrease from 0.19mcg/kg/min (SD 0.33) on initiation of APRV to0.15mcg/kg/min (SD 0.28) at 72 hours post-APRV initiation.

3.4. Concurrent Rescue Therapies

Eighteen patients (36%) received concurrent therapies while onAPRV (see Table 3). Three (6%) received nitric oxide only, nine (18%) re-ceived epoprostenol only and three (6%) received both nitric oxide andepoprostenol. Of note, although thirty-four patients (68%) fulfilled pre-viously published criteria for initiation of ECMO [17], only three (6%) re-ceived ECMO, two prior to initiation of APRV and one post-initiation ofAPRV. No patients were proned or received oscillation ventilation.

3.5. Avoidance of VV-ECMO

Thirty-four patients (68%) met criteria for ECMO according to CESARcriteria (Murray Score N 3.0 or pH b7.20) (see Table 4). Ventilator pa-rameters for this group of patients are outlined in Table 5. Comparedwith patients not fulfilling these criteria, patients in this subgroup hada lower baseline PF ratio (85 mmHg (IQR 71–110)), higher APACHE IIscore (25 (IQR 19–29)), longer median ICU length of stay (12 days),and higher hospital mortality (sixteen patients (47%)) (see Table 6).

Fig. 5. Median central venous p

4. Discussion

To our knowledge, this is one of the largest studies describing thecharacteristics and outcomes associated with initiation of APRV in pa-tients with established ARDS using contemporary Berlin Criteria [18].We observed that in a cohort of patients with severe hypoxaemic respi-ratory failure, initiation of APRV was associated with a significant andsustained improvement in oxygenation. In-hospital mortality was sim-ilar to APACHE II-predicted mortality and current comparable ARDSstudies [1,21–23].

Whether the improvement in oxygenation associatedwith initiationof APRV results in improved patient-centered outcomes is uncertainand requires further investigation. The association between improvedoxygenation andmortality has not been apparent in current ARDS liter-ature, with approximately 9% increase in mortality in the higher tidalvolume group in the landmark ARDSNet study despite better oxygena-tion in this group [24]. Notably, higher PEEP and lower FiO2 was utilizedearly in the lower tidal volume group [24]. This aligns with the princi-ples of APRV. Prospective multicentre studies of APRV for patientswith ARDS are warranted, and require precise characterization of theextent and effect of spontaneous ventilation and the profile of the me-chanical breath.

The safety of APRV, in particular the incidence of barotraumaandpo-tential precipitation or exacerbation of right heart dysfunction, require

ressure vs time on APRV.

Table 3Outcomes of patientswith ARDSonAPRV. Statistics presented asmedian and interquartilerange (IQR) unless otherwise stated.

Outcome N = 50

Concurrent therapy requirement, n (%) Nitric oxide 6 (12)Epoprostenol 12 (24)ECMO 3 (6)Proning 0Oscillation 0

Barotrauma, n (%) Pneumothorax 4 (8)Pneumomediastinum 1 (2)Multiple 3 (6)New intercostal catheter 2 (4)

Hours on APRV 51 (26–106)Mechanical ventilation duration (h) 207 (111–363)Tracheostomy, n (%) 11 (22)ICU LOS (days) 12 (8–22)ICU mortality, n (%) 19 (38)Hospital mortality, n (%) 19 (38)

Table 5Ventilatory parameters on initiation of APRV and 12 h post-APRV initiation in the sub-group analysis. Statistics presented as median and interquartile range (IQR) unless other-wise stated.

Ventilatory parameter

On initiation of APRV N = 34

Phigh (cmH2O) 30 (26–30)Peak airway pressure (cmH2O) 32.5 (30–35)Mean airway pressure (cmH2O) 25 (24–27)Set pressure (cmH2O) 30 (26–30)Tidal volume (ml) 500.0 (450–600)

12 h post initiation of APRV N = 25Phigh (cmH2O) 28 (25–30)Peak airway pressure (cmH2O) 32 (30–35)Mean airway pressure (cmH2O) 19 (18–24)Set pressure (cmH2O) 28 (25–30)Tidal volume (ml) 600.0 (400–680)

158 J. Lim et al. / Journal of Critical Care 34 (2016) 154–159

careful consideration. Risk of barotraumamay bemore closely associat-edwith the severity of the underlying lung disease and duration of priorventilation, rather than ventilator mode per se. Furthermore, despite ahigh peak airway pressure, the incidence of barotrauma described inour study is similar to other studies comparing ventilatory strategiesin ARDS [21,22]. Of note, the rate of barotrauma in the control groupof the landmark ARDS Network study was 10% [24]. CVP, whichwas used as a surrogate for right heart failure in the context ofAPRV-associated high intrathoracic pressure, was observed to signifi-cantly decrease. This refutes the suggestion of right heart dysfunctionas a complication of APRV [25]. Similar to the haemodynamic effectsin several experimental models of APRV, we also observed a significantdecrease in noradrenaline requirement associated with the initiation ofAPRV [26,27].

The role of spontaneous respiration in early severe ARDS remainscontroversial. Papazian et al. (2010) demonstrated that early adminis-tration of cisatracurium conferred an improvement in the adjusted 90-day survival rate, although there was no significant improvement inoverall 90-daymortality [22]. It has been hypothesized that this benefitis secondary to a reduction of ventilator-patient dysynchrony [22].APRV allows for unrestricted spontaneous breathing and thus decreasesthe risk of ventilator-patient dysnchrony. As such, it is arguable that thebenefits of neuromuscular blockade may not be applicable to APRVwhereflow is not fixed and lung volume and compliancemay be higher.In our study, changes in tidal volume associated with spontaneousbreathing over the course of delivery of APRV were not studied. The

Table 4Baseline characteristics of patients in the subgroup analysis. Statistics presented asmedianand interquartile range (IQR) unless otherwise stated.

Characteristic N = 34

Age 44 (37–55)Male sex, n (%) 29 (58)Admission type, n (%) Medical 36 (72)

General surgical 6 (12)Trauma 5 (10)Other 3 (6)

Acute Physiology and Chronic Health Evaluation(APACHE) II score

25 (19–29)

Predicted mortality based on APACHE II score 0.44 (0.27–0.66)Hours from intubation to APRV 2 (0–23)ARDS severity (Berlin criteria), n (%) Mild 1 (2.9)

Moderate 12 (35.3)Severe 21 (61.8)

Murray Lung Injury Score 3.5 (3.5–4.0)PaO2/FiO2 ratio prior to APRV (mmHg) 84.7 (71.0–109.7)Spontaneously breathing on initiation of APRV, n (%) 22 (64.7)Noradrenaline requirement on initiation of APRV(mcg/kg/min), mean (SD)

0.19 (0.33)

possible effect of spontaneous breathing on the risk of volutraumashould be examined in future studies.

One of the perceived benefits of APRV is its utility as an ECMO-sparing agent. ECMO is cost and labor-intensive, and logistically chal-lenging in resource-poor and high-demand situations (e.g. epidemics).Although themajority of our study cohort fulfilled previously publishedcriteria for initiation of ECMO [17], only one patient required ECMOafterinitiation of APRV.While themortality rate in the subgroup analysiswashigher than that of the CESAR trial's (47% vs 37% respectively), this sub-group had a significantly higher median APACHE II score as comparedwith the treatment group in the CESAR trial (25 vs 20) [17]. Our ob-served mortality rate was also comparable to the predicted mortalityrate based on APACHE II score (44%).

This study has several strengths, including the selection of a patientcohort with severe hypoxaemic respiratory failure at high risk of deathand therefore the group of patients most likely to benefit from use ofAPRV, and the availability of detailed data on the safety and efficacy ofAPRV therapy. Nonetheless, there are limitations. First, the external va-lidity of findings from a single centre study are uncertain. However, weused consensus criteria to diagnose ARDS and the characteristics of thecohort, including underlying etiology, illness severity and outcomes, arecomparable to those published in multicentre studies [24,28–30]. Sec-ond, this study was conducted with the intent of describing the out-comes of patients with ARDS treated with APRV, and thus there wasno direct comparison with other conventional ventilation methods,nor of the use of APRV as a strategy to prevent ARDS. Third, initiationof APRV and ECMO were based on the decision of the treating clinicianrather than a unit guideline. Fourth, specific data on sedation and neu-romuscular blockade was not obtained, nor was the percentage of

Table 6Outcomes of patients with ARDS on APRV in the subgroup analysis. Statistics presented asmedian and interquartile range (IQR) unless otherwise stated.

Outcome N = 34

Concurrent therapy requirement, n (%) Nitric oxide 6 (17.6)Epoprostenol 9 (26.5)ECMO 2 (5.9)Proning 0Oscillation 0

Barotrauma, n (%) Pneumothorax 2 (5.9)Pneumomediastinum 1 (2.9)Multiple 3 (8.8)New intercostal catheter 0

Duration on APRV (h) 51 (22.1–89.5)Mechanical ventilation duration (h) 196 (97.6–354.9)Tracheostomy while on APRV, n (%) 7 (20.6)ICU LOS (days) 11.5 (7.25–21.75)ICU mortality, n (%) 16 (47.1)Hospital mortality, n (%) 16 (47.1)

159J. Lim et al. / Journal of Critical Care 34 (2016) 154–159

spontaneous ventilation in relation to totalminute ventilation recorded,although amajority of patients were spontaneously breathing on initia-tion of APRV and thus unlikely to be heavily sedated and the principle ofmaximizing spontaneous ventilation in APRV is widely accepted [19].Finally, this study is susceptible to unmeasured confounding factorsand no causal inferences can be made about the association betweenAPRV use and outcomes.

5. Conclusions

In patients with ARDS and severe hypoxaemic respiratory failure,initiation of APRV was associated with an early and sustained improve-ment in oxygenation and low incidence of clinically significant baro-trauma and progression to ECMO. The safety and efficacy of APRV as arescue strategy for patients with ARDS and severe hypoxaemic respira-tory failure requires further consideration.

Acknowledgements

We gratefully acknowledge the contributions of the clinical and ad-ministrative staff of Royal Perth Hospital's Intensive Care Unit.

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