The acute respiratory distress syndrome (ARDS) was first described half a century ago by Ashbaugh et al. (1). They considered several therapeutic options to combat refractory hypoxemia and proposed that appropriate titration of positive end-expiratory pressure (PEEP) may be the sole effective intervention. Ever since the publication of this seminal paper, the pursuit of an adequate level of PEEP has never ceased to intrigue intensivists. Let us consider the physiology behind the application of PEEP and how it may be titrated to an ideal level.
Titration of PEEP to improve oxygenation
PEEP may be targeted to improve oxygenation; many intensivists aim for this easily discernible endpoint by the bedside. PEEP may also be used as part of an overall strategy aimed at lung protection. Conventionally, the inspiratory limb of the pressure-volume curve has been the focus of attention in an attempt to find the optimal pressure that will enable an open lung approach. However, lung recruitment is not confined to a single point such as the lower inflection point of the pressure-volume curve; it occurs throughout the inspiratory limb. The extent of lung recruitment increases with increasing inspiratory pressure. Thus, recruitment is essentially an inspiratory phenomenon. In contrast, PEEP is an expiratory phenomenon that prevents de-recruitment during the expiratory phase. Besides, it is important to note that for any level of airway pressure, the lung volume is higher during expiration compared to inspiration (Fig. 1). Hence, it may be more appropriate to titrate PEEP based on the deflation limb of the pressure-volume curve (2). Aiming for improvement in oxygenation as the sole target may also have several pitfalls. ARDS is a non-homogenous disease process; attempts to recruit non-ventilated regions of the lung invariably leads to overdistension of areas of the lung that are better ventilated. Overdistension may lead to a rise in the pulmonary artery and right ventricular pressures, leading to a fall in cardiac output. Any fall in cardiac output and impaired oxygen delivery may offset the advantage gained by improvement in arterial oxygen levels.
Fig 1. The pressure-volume curve of the lung. For a given level of pressure, the lung volume is higher during expiration compared to inspiration. Green arrow: Lower inflection point; red arrow: upper inflection point
Titration based on compliance
This method involves the upward titration of PEEP until the static compliance ceases to rise. Pintado et al. increased PEEP levels in a step-wise manner based on static compliance (3). The PEEP level that resulted in the highest static compliance was chosen in the intervention group. In the control group, PEEP was applied based on the FiO2, as recommended in the ARDS-net study. Patients who received best compliance-based PEEP levels had significantly more multiorgan dysfunction-free days. There were non-significant improvements in the PaO2/FiO2ratios in the initial 14 days of treatment and the 28-day mortality.
CT and ultrasound-guided lung recruitment
Would CT imaging help to assess recruitability and appropriate titration of PEEP? Cressoni et al. performed CT scans at PEEP levels of 5 and 45 cm of H2O and attempted to calculate the optimal level of PEEP (4). This theory assumes that PEEP constitutes the pressure required to elevate the chest wall and non-dependent lung that leads to compression and gravity-induced collapse of the dependent lung regions. However, no correlation could be found between CT-guided PEEP values and the extent of lung recruitment. Besides, repeated transfer of sick patients for CT makes this an unwelcome option. Repeated ultrasound imaging may also guide the clinician in choosing the appropriate level of PEEP. A progressive reduction in the extent of lung collapse with increasing PEEP is relatively easy to visualize by ultrasonography (Fig. 2). A significant limitation of this strategy may be the relative inability to view deeper regions of the lung by ultrasonography.
Fig 2. Ultrasonography-based titration of PEEP. Progressive recruitment of collapsed lung is seen from panel A to C
PEEP titration based on transpulmonary pressure
Maintenance of positive airway pressure alone may be insufficient to prevent alveolar collapse, especially at end-expiration. A higher pleural pressure compared to applied PEEP may lead to lung collapse. A non-compliant chest wall and increased intra-abdominal pressure may lead to variable pleural pressures in mechanically ventilated patients.
The distending pressure of the lung (which maintains the lung open) is the transpulmonary pressure:
Transpulmonary pressure = airway pressure – pleural pressure
The esophageal pressure is considered to be a reasonable surrogate of the pleural pressure. The transpulmonary pressure needs to be positive throughout the respiratory cycle to prevent derecruitment. Beitler et al. titrated PEEP levels to maintain the end-expiratory transpulmonary pressure equal to or higher than the esophageal pressure (between 0–6 cm H2O higher than the esophageal pressure) and compared it with PEEP settings based on a PEEP–FiO2 table (5). The composite primary outcome of death and ventilation-free survival through day 28 did not differ significantly between groups. Pre-specified secondary outcomes, including 28-day mortality, ventilation-free days, and the need for rescue therapy were also not significantly different. Although titration of PEEP based on end-expiratory pleural pressures is based on strong physiological grounds, it requires further investigation for efficacy in severely hypoxic patients and during prone ventilation.
High vs. low PEEP
Three large randomized controlled studies have compared empirical high vs. low PEEP levels in patients with ARDS (6–8). The ARDS-net study used PEEP/FiO2tables for PEEP adjustment, while the ExPress study adopted a compliance-based PEEP strategy. None of these studies revealed a significant mortality benefit with the application of a higher PEEP level. Briel et al. performed a meta-analysis of the three studies (9). They observed that the treatment effect was variable and depended on the severity of ARDS, with a suggestion that a higher PEEP level may be beneficial in patients with more severe illness, with a PaO2/FiO2ratio < 200.
The bottom line
- The holy grail of optimal PEEP lies in the grey area between maintenance of effective alveolar recruitment and the potential for harmful overdistension.
- Strategies based solely on improving arterial oxygenation are unlikely to be beneficial; a more comprehensive lung-protective approach may be more appropriate.
- Several methods have been studied to choose an optimal level of PEEP; however, no significant improvement in clinical outcomes have been demonstrated with any specific titration strategy.
- Arbitrarily chosen higher levels of PEEP may not benefit in heterogeneous groups of ARDS patients; however, a higher PEEP may improve outcomes in patients with severe ARDS.
- A ballpark PEEP level may be 5–10 cm of H2O in mild to moderate ARDS; a higher level of 15–20 cm of H2O may be more appropriate in severe ARDS.
- Time-consuming and cumbersome techniques in the pursuit of titration of PEEP levels may not lead to a discernible benefit.
- Ashbaugh DG, Bigelow DB, Petty TL, Levine BE. Acute respiratory distress in adults. Lancet Lond Engl. 1967 Aug 12;2(7511):319–23.
- Gattinoni L, Carlesso E, Cressoni M. Selecting the ‘right’ positive end-expiratory pressure level: Curr Opin Crit Care. 2015 Feb;21(1):50–7.
- Pintado M-C, de Pablo R, Trascasa M, Milicua J-M, Rogero S, Daguerre M, et al. Individualized PEEP Setting in Subjects With ARDS: A Randomized Controlled Pilot Study. Respir Care. 2013 Sep 1;58(9):1416–23.
- Cressoni M, Chiumello D, Carlesso E, Chiurazzi C, Amini M, Brioni M, et al. Compressive forces and computed tomography-derived positive end-expiratory pressure in acute respiratory distress syndrome. Anesthesiology. 2014 Sep;121(3):572–81.
- Beitler JR, Sarge T, Banner-Goodspeed VM, Gong MN, Cook D, Novack V, et al. Effect of Titrating Positive End-Expiratory Pressure (PEEP) With an Esophageal Pressure–Guided Strategy vs an Empirical High PEEP-F io2Strategy on Death and Days Free From Mechanical Ventilation Among Patients With Acute Respiratory Distress Syndrome: A Randomized Clinical Trial. JAMA [Internet]. 2019 Feb 18 [cited 2019 Feb 24]; Available from: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2019.0555
- Brower RG, Lanken PN, MacIntyre N, Matthay MA, Morris A, Ancukiewicz M, et al. Higher versus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome. N Engl J Med. 2004 Jul 22;351(4):327–36.
- Writing Group for the Alveolar Recruitment for Acute Respiratory Distress Syndrome Trial (ART) Investigators, Cavalcanti AB, Suzumura ÉA, Laranjeira LN, Paisani D de M, Damiani LP, 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 10;318(14):1335–45.
- Mercat A, Richard J-CM, Vielle B, Jaber S, Osman D, Diehl J-L, et al. Positive end-expiratory pressure setting in adults with acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. JAMA. 2008 Feb 13;299(6):646–55.
- Briel M, Meade M, Mercat A, Brower RG, Talmor D, Walter SD, et al. Higher vs lower positive end-expiratory pressure in patients with acute lung injury and acute respiratory distress syndrome: systematic review and meta-analysis. JAMA. 2010 Mar 3;303(9):865–73.