AJRCCM Articles in Press. Published on 14-May-2018 as 10.1164/rccm.

201804-0778ED
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Editorial relating to Blue-201705-0989OC.R2

Airway Pressure Release Ventilation (APRV):

A Therapy in Search of a Disease?

Shekhar Venkataraman, MD1

John P. Kinsella, MD2

1
Division of Pediatric Critical Care Medicine, Department of Critical Care, University of

Pittsburgh School of Medicine

2
Section of Neonatology, Department of Pediatrics, University of Colorado School of Medicine

and Children’s Hospital Colorado.

Corresponding Author:

Shekhar T. Venkataraman MD

4401 Penn Avenue

Children’s Hospital of Pittsburgh

Faculty Pavilion, Room 2117

e-mail-venkataramanst@upmc.edu

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Since the seminal observations of Webb and Tierney on the causes of lung injury during

positive pressure mechanical ventilation, intensivists have sought ways to minimize ventilator-

induced lung injury (VILI). (1-3). Lung-protective strategies have included peak inspiratory

pressure limitation, reduction in tidal volume, optimizing positive end expiratory pressure

(PEEP), controlling the peak inspiratory alveolar pressure below a “safe” threshold, and

numerous alternate modes of ventilation such as high frequency ventilation.

In 1987, Stock et al (4) introduced a concept called airway pressure release ventilation

(APRV) which provided mechanical ventilation by deflating the lungs periodically from a high

level of continuous positive airway pressure (CPAP) rather by inflating the lung to a higher

pressure (4, 5). APRV was envisioned and designed to provide unrestricted spontaneous

breathing using continuous gas flow. Inspiratory times were longer than expiratory times, and

when matched for the same mean airway pressure, APRV provided similar gas exchange in

normal lungs and better oxygenation in injured lungs of dogs without an increase in peak

inspiratory pressure (4). Downs and Stock envisioned that patients with ARDS would at first be

managed with an appropriate level of CPAP, and if needed, could be augmented by APRV (5).

Pilot studies in humans showed that this technique, which was also referred to as CPAP with

release, was feasible (6, 7). Using modern terminology, APRV can be classified as pressure-

controlled, intermittent mandatory ventilation, typically applied using inverse inspiratory-

expiratory (I:E) ratios while permitting spontaneous breathing during and between mandatory

breaths. The amplitude of the mandatory breaths is called Phigh, the duration of inflation is

called Thigh, the deflation pressure is called Plow and the duration of deflation or release time is

called Tlow.

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Since the original reports on the concept and feasibility, numerous laboratory and case

series using APRV have been reported. The results have been reviewed recently (8). The first

randomized, controlled trial (RCT) by Varpula et al (9) used APRV as the primary mode of

ventilation in patients with acute lung injury compared to conventional mechanical ventilation

(SIMV with pressure support). The trial was terminated for futility when an interim analysis

after two-thirds enrollment showed that there was no difference in the primary outcome variable

of ventilator-free days between the two groups (9). APRV did not differ from conventional

ventilation in any other clinically relevant outcomes. A more recent RCT by Maxwell et al (10)

in adult trauma patients showed that while there was no difference in mortality, there was a trend

toward worse secondary outcomes with APRV, including increased ventilator days, ICU length

of stay, and ventilator-associated pneumonia. Recently, Zhou et al reported the results of a

single center trial comparing early application of APRV to conventional support (11). They

found that the APRV group had a higher number of ventilator free days, but there was no

difference in mortality or length of hospital stay. Significant limitations of the study include a

higher rate of comorbid conditions in the control group, internal inconsistencies, and the fact that

the groups were unbalanced (e.g., vasopressor use) (11).

Here, Lalgudi Ganesan et al (12) report on the first RCT in children comparing APRV

with conventional mechanical ventilation. The protocol used in this study is similar to that used

by Maxwell et al (10). APRV was initiated with a Phigh that was equal to the end-inspiratory

plateau pressure or 30 cm H2O, Thigh was set at 4 secs, Plow was set to zero and Tlow was

adjusted to terminate at 75% of peak flow so as to generate some amount of auto-PEEP. All

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other adjustments for both conventional and APRV modes were made in response to changes in

gas exchange and chest radiography. The conventional arm followed the ventilator protocol

described by Curley et al (13) in their study on prone positioning. To match the tidal volumes of

conventional ventilation, the APRV group targeted release volumes of 6-7mL/kg. At baseline,

the APRV group had worse oxygenation than the control group. The study was terminated after

enrollment of approximately 50% of the planned sample size when an interim analysis showed a

trend toward increased 28-day all-cause mortality in the APRV arm (53.8% vs 26.9%). The

primary cause of death was worsening hypoxemia in almost half of the patients and worsening

multi-organ dysfunction syndrome in about another half. It is interesting to note that almost 50%

of the patients died of refractory hypoxemia. The most common reason for mortality from ARDS

in adults is multiorgan system failure. Similarly, children with ARDS die with respiratory failure

rather than because of it (14). It is, therefore, difficult to extrapolate these results to all pediatric

patients.

There are many concerns that have been raised recently regarding APRV (15-23).

Published studies have reported differing Phigh, Plow, Thigh, and Tlow settings leading to

difficulties in interpreting the results. Some have set the Plow to zero and Tlow to a level of

incomplete emptying (usually about 75% of the peak inspiratory flow) so as to create auto-PEEP

to prevent derecruitment (15, 16). The amount of auto-PEEP depends on the initial lung volume

at the start of deflation, the time constant of deflation, and elastic properties of the chest,

abdomen and the lungs. The performance of ventilators differs in the amount of auto-PEEP

generated for the same termination criterion (17). Therefore, auto-PEEP may differ between

patients even though they have the same Tlow termination criterion. Potentially, auto-PEEP

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levels may be below the critical closing pressures leading to derecruitment and atelectotrauma

(17-19). Work of spontaneous breathing and discomfort may be increased during APRV (20, 22).

Also, it is likely that patient-ventilator interactions during APRV are more complex than during

conventional mechanical ventilation and have not been studied adequately. It is possible that

APRV may not achieve better gas exchange than CPAP alone (23).

The theoretical benefits of APRV have so far not been demonstrated in clinical trials. At

the present time, APRV seems to be used as a rescue mode in children (24, 25). It is possible that

a subset of children with hypoxemic respiratory failure might benefit from APRV, but the

available evidence doesn’t support its use. In fact, APRV may increase the risk for adverse

outcomes Indeed, the trial reported by Lalgudi Ganesan et al should give us considerable cause

for concern about the safety and efficacy of APRV in children.

References

1. Webb, H. H., and D. F. Tierney. Experimental pulmonary edema due to intermittent positive

pressure ventilation with high inflation pressures: protection by positive end-expiratory pressure.

Am. Rev. Respir. Dis. 1974;110:556–565.

2. John, E., R. Ermocilla, J. Golden, M. McDevitt, and G. Cassady. Effects of intermittent

positive-pressure ventilation on lungs of normal rabbits. Br. J. Exp. Pathol.1980;61:315–323.

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3. Dreyfuss, D., G. Basset, P. Soler, and G. Saumon. 1985. Intermittent positive-pressure

hyperventilation with high inflation pressures produces pulmonary microvascular injury in rats.

Am. Rev. Respir. Dis. 1985;132:880–884.

4. Stock MC, Downs JB, Frolicher DA. Airway pressure release ventilation. Crit Care Med. 1987

May;15:462-6.

5. Downs JB, Stock MC. Airway pressure release ventilation: a new concept in ventilatory

support. Crit Care Med. 1987 May;15:459-61..

6. Garner W, Downs JB, Stock MC, Räsänen J. Airway pressure release ventilation (APRV). A

human trial. Chest. 1988;94:779-81.

7. Räsänen J, Cane RD, Downs JB, Hurst JM, Jousela IT, Kirby RR, Rogove HJ, Stock MC.

Airway pressure release ventilation during acute lung injury: a prospective multicenter trial. Crit

Care Med. 1991;19:1234-41.

8. Habashi NM. Other approaches to open-lung ventilation: airway pressure release ventilation.

Crit Care Med. 2005;33(3 Suppl):S228-40.

9. Varpula T, Valta P, Niemi R, Takkunen O, Hynynen M, Pettilä VV. Airway pressure release

ventilation as a primary ventilatory mode in acute respiratory distress syndrome. Acta

Anaesthesiol Scand. 2004;48:722-31

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 AJRCCM Articles in Press. Published on 14-May-2018 as 10.1164/rccm.201804-0778ED
Page 7 of 9

10. Maxwell RA, Green JM, Waldrop J, Dart BW, Smith PW, Brooks D, et al. A randomized

prospective trial of airway pressure release ventilation and low tidal volume ventilation in adult

trauma patients with acute respiratory failure. J Trauma 2010;69:501-510.

11. Zhou Y, Jin X, Lv Y, Wang P, Yang Y, Liang G, Wang B, Kang Y. 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.

12. Lalgudi Ganesan S, Muralidharan J, Singhi S, Bansal A. Airway Pressure Release

Ventilation in Pediatric Acute Respiratory Distress Syndrome: a Randomized Controlled Trial.

Amer J Respir Crit Care Med [online ahead of print] 11 April 2018;

www.atsjournals.org/doi/abs/10.1164/rccm.201705-0989OC

13. Curley MAQ, Hibberd PL, Fineman LD, Wypij D, Shih M-C, Thompson JE, Grant MJ, Barr

FE, Cvijanovich NZ, Sorce L, Luckett PM, Matthay MA, Arnold JH. Effect of prone positioning

on clinical outcomes in children with acute lung injury: a randomized controlled trial. JAMA.

2005;294:229–37.

14. Yehya N, Thomas NJ Relevant Outcomes in Pediatric Acute Respiratory Distress Syndrome

Studies. Front Pediatr. 2016; 4:51 pp 1-8.

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 AJRCCM Articles in Press. Published on 14-May-2018 as 10.1164/rccm.201804-0778ED
Page 8 of 9

15. Rose L, Hawkins M. Airway pressure release ventilation and biphasic positive airway

pressure: a systemic review of definitional criteria. Intensive Care Med 2008;34:1766-1773.

16. Jain SV1, Kollisch-Singule M1, Sadowitz B1, Dombert L1, Satalin J2, Andrews P3, Gatto

LA1,4, Nieman GF1, Habashi NM The 30-year evolution of airway pressure release ventilation

(APRV). Intensive Care Med Exp. 2016;4:11 pp 2-18.

17. Baum M, Benzer H, Putensen C, Koller W, Putz G. Biphasic positive airway pressure

(BIPAP): a new form of augmented ventilation. Anaesthesist 1989;38:452-458.

18. Ehab G Daoud MD, Hany L Farag MD, and Robert L Chatburn. Airway Pressure Release

Ventilation: What Do We Know? Respir Care 2012;57:282–292.

19. Mireles-Cabodevila E1, Kacmarek RM. Should Airway Pressure Release Ventilation Be the

Primary Mode in ARDS? Respir Care. 2016;61:761-73.

20. Kallet RH. Patient-ventilator interaction during acute lung injury, and the role of

spontaneous breathing: part 2: airway pressure release ventilation. Respir Care. 2011;56:190-

203.

21. Marini JJ, Crooke PS 3rd., Truwit JD. Determinants and limits of pressure-preset ventilation:

a mathematical model of pressure control. J Appl Physiol 1989;67:1081–1092.

Copyright © 2018 by the American Thoracic Society

 AJRCCM Articles in Press. Published on 14-May-2018 as 10.1164/rccm.201804-0778ED
Page 9 of 9

22. Chiang AA1, Steinfeld A, Gropper C, MacIntyre N. Demand-flow airway pressure release

ventilation as a partial ventilatory support mode: comparison with synchronized intermittent

mandatory ventilation and pressure support ventilation. Crit Care Med. 1994;22:1431-1437.

23. Neumann P, Hedenstierna G. Ventilatory support by continuous positive airway pressure

breathing improves gas exchange as compared with partial ventilatory support with airway

pressure release ventilation. Anesth Analg. 2001;92:950-958.

24. Krishnan J, Morrison W. Airway Pressure Release Ventilation:A Pediatric Case Series.

Pediatric Pulmonology 2007;42:83–88.

25. Yehya N, Topjian AA, Lin R, Berg RA, Thomas NJ, Friess SH. High frequency oscillation

and airway pressure release ventilation in pediatric respiratory failure. Pediatr Pulmonol.

2014;49:707-715.

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