PEEP titration by the bedside: how do we set it right?

The beneficial effects of mechanical ventilation is closely related to the prevention of ventilator-induced lung injury (VILI). The harmful effects of positive pressure ventilation may be mitigated by the application of appropriate levels of positive end-expiratory pressure (PEEP). In their seminal paper, Ashbaugh et al. observed the beneficial effect of PEEP on arterial oxygenation in patients with acute respiratory distress syndrome (ARDS).¹ However, the potentially harmful effects of excessive PEEP, including hemodynamic compromise and barotrauma, were soon realized. How do we decide on what may be an appropriate level of PEEP among mechanically ventilated patients?

Physiological effects of PEEP

The application of PEEP results in an increase in the end-expiratory lung volume, which leads to higher compliance, thereby reducing the driving pressure (Pplat­–PEEP). Improved compliance and lower driving pressures have been shown to improve survival.² If the airway and alveolar pressures remain low at end-expiration, unstable alveoli may repetitively open and collapse during tidal ventilation. The repetitive opening and closure perpetuates shear injury to the lung parenchyma and distal small airways. Besides, surfactant dysfunction occurs, leading to alveolar collapse.³ Alveolar collapse in diseased areas of the lung leads to preferential ventilation and overdistension of alveoli in the relatively normal areas of the lung, causing strain. Thus, predilection to injury occurs in the better ventilated areas of the “baby” lung. The strain is selectively distributed along the margins of aerated and non-aerated alveoli.⁴ The application of an appropriate level of PEEP attenuates tidal recruitment-derecruitment, thus reducing lung stress. Furthermore, alleviation of lung stress mitigates the inflammatory response and the consequent biotrauma. 

The application of PEEP helps to maintain alveoli open during end-expiration, thus reducing the adverse impact of the tidal recruitment-decruitment cycle. As more alveoli remain open at end-expiration, there is less overinflation of the relatively normal lung. Thus, the effect of stress at the margins of the aerated and collapsed lung is attenuated. Overall, optimal levels of PEEP offer more homogenous ventilation of the lung. Besides, by recruiting collapsed lung, PEEP results in reduction of the intrapulmonary shunt and improved oxygenation. 

Adverse effects of PEEP 

The application of inappropriately high levels of PEEP may lead to increased inspiratory pressure, alveolar overdistension, and perpetuation of VILI. PEEP may not recruit collapsed alveoli as expected; instead, it may overinflate alveoli that are already aerated.⁵ The extent of recruitment of collapsed alveoli compared to overinflation of already aerated alveoli may vary depending on the level of PEEP and the “recruitability” of the collapsed lung. Therefore, the application of PEEP may lead to recruitment, overinflation, or a combination of both. 

Excessively high PEEP levels may also result in high intrathoracic pressures, impeding venous return, and thereby, reduce cardiac output. Pulmonary capillaries may collapse as they are subjected to increased pressure, resulting in an increase in the pulmonary vascular resistance, thus increasing the afterload to the right ventricle. The alveolar pressure may rise above the pulmonary capillary pressure during PEEP application; this may result in closure of pulmonary capillaries, thereby reducing the perfusion relative to ventilation, leading to an increase in the alveolar dead space.⁶

How to titrate PEEP?

PEEP tables 

The ARDS-net trial applied PEEP using a table based on the FiO₂ requirement.⁷ Although simple to use, titration based on FiO₂ levels does not take into account lung recruitability, and no improvement in oxygenation may ensue with incremental levels of PEEP. Indeed, there may be wide variability between patients in the individual response to PEEP.⁸

Oxygenation response 

A commonly adopted approach is titration of PEEP based on the oxygenation response. If the lung is recruitable by PEEP, reduction of the intrapulmonary shunt should result in improved oxygenation. Although the correlation between alveolar recruitment and improved oxygenation may not be constant, improvement in oxygenation in response to PEEP has been shown to improve survival.⁸ An increase in the PaCO₂ levels in response to increasing levels of PEEP suggests alveolar overdistension. 

Compliance 

Improved compliance with PEEP application has been traditionally considered to suggest recruitment. In their landmark paper, Suter et al. demonstrated that maximal oxygen transport occurred when PEEP was titrated to obtain the highest level of static compliance.⁶ Adjustment of PEEP levels targeting static compliance is associated with improved oxygenation and organ function.⁹ However, an increase in the compliance may solely reflect cyclical opening and closure of alveoli, without resulting in recruitment. 

Driving pressure 

Driving pressure is tidal volume/static compliance. Thus, for a constant tidal volume, a decrease in driving pressure with incremental PEEP suggests alveolar recruitment. However, a decrease in driving pressure occurs due to increased compliance. Hence, PEEP adjustment based on driving pressures may have the same limitations as adjustment based on static compliance. Amato et al. performed a multilevel mediation analysis of 3562 patients from nine randomized controlled trials. They demonstrated that driving pressure was most strongly associated with survival; higher driving pressures were associated with increased mortality. Changes in tidal volume and PEEP were associated with survival only through concomitant changes in driving pressure.¹⁰

Esophageal pressure 

During mechanical ventilation, the airway pressure attempts to distend the lung, while the pleural pressure acts as a counterforce in the opposite direction. Thus the true distending pressure applied to the lung is the transpulmonary pressure.

Transpulmonary pressure = airway pressure – pleural pressure

Abnormalities of the chest wall and abdomen (chest trauma, pleural effusion, obesity, abdominal compartment syndrome, etc.) tend to increase the pleural pressure, thus, reducing the transpulmonary pressure. Any increase in the chest wall elastance (increased chest wall stiffness) offsets the transpulmonary pressure, thus opposing lung inflation. Setting the PEEP level at or above the pleural pressure at end-expiration may prevent alveolar collapse during expiration. The esophageal pressure is measured as a close approximation of the pleural pressure to set an appropriate level of PEEP.  

Titration of PEEP guided by measurement of esophageal pressure was compared with empirically set PEEP, based on the FiO₂ requirement, in a randomized controlled trial. In the esophageal pressure-guided group, the PEEP level was set between 0–6 cm H₂O higher than the esophageal pressure, based on the FiO₂ requirement. There was no significant difference between groups in the primary composite outcome of death and mechanical ventilation-free days through day 28.¹¹

Imaging-guided PEEP titration

CT imaging may enable analysis of compressive forces acting on the lung at different levels. However, the utility of CT imaging to guide PEEP levels has not been corroborated in clinical practice.¹² Considering the practical difficulty related to repeated CT imaging in critically ill patients, this approach does not hold promise in most settings. Bouhemad et al. employed lung ultrasonography to evaluate PEEP-induced lung recruitment. They observed a significant correlation between the ultrasonographic reaeration score and lung recruitment measured using pressure-volume curves.¹³Ultrasonography is easily performed by the bedside in the critically ill, and hence, more feasible compared to CT imaging. However, the use of ultrasonography is limited by the inability to identify alveolar overdistension.  

High vs. low levels of PEEP

Several studies have compared high vs. low PEEP levels, using PEEP/FiO₂ tables^4,14 or based on inspiratory plateau pressures,¹⁵ with no difference in mortality rates. However, any beneficial impact of PEEP would occur only among patients with potential for lung recruitment. It is likely that an empirical strategy, without assessment of the potential for recruitment, may result in beneficial effects in patients with recruitable lung; in contrast, it may lead to overdistension-related harmful effects if the lung is non-recruitable. Any high PEEP-related benefit may thus be offset by harm among the subgroup of patients with no potential for alveolar recruitment. Patient heterogeneity may thus confound trials that use fixed levels of PEEP among patients with wide variability in the level of recruitability.

Summary

• An appropriate level of PEEP must be individualized based on the potential for recruitment 
• Empirically applied high PEEP levels are unlikely to benefit 
• Oxygenation response to increasing levels of PEEP may be an appropriate physiological endpoint and has been shown to improve survival
• Improved compliance and a reduction in the driving pressure may be clinically useful indicators of recruitability associated with increasing levels of PEEP 
• Although transpulmonary pressure-guided PEEP application has a strong physiological rationale, clinical outcomes have been disappointing 
• Future research should focus on improved methodology for the assessment of recruitability and more precise titration of PEEP

References

1.         Ashbaugh DG, Bigelow DB, Petty TL, Levine BE. Acute respiratory distress in adults. Lancet Lond Engl. 1967;2(7511):319-323. doi:10.1016/s0140-6736(67)90168-7

2.         Sahetya SK, Goligher EC, Brower RG. Fifty Years of Research in ARDS. Setting Positive End-Expiratory Pressure in Acute Respiratory Distress Syndrome. Am J Respir Crit Care Med. 2017;195(11):1429-1438. doi:10.1164/rccm.201610-2035CI

3.         Muscedere JG, Mullen JB, Gan K, Slutsky AS. Tidal ventilation at low airway pressures can augment lung injury. Am J Respir Crit Care Med. 1994;149(5):1327-1334. doi:10.1164/ajrccm.149.5.8173774

4.         Mead J, Takishima T, Leith D. Stress distribution in lungs: a model of pulmonary elasticity. J Appl Physiol. 1970;28(5):596-608. doi:10.1152/jappl.1970.28.5.596

5.         Chiumello D, Marino A, Brioni M, et al. Lung Recruitment Assessed by Respiratory Mechanics and Computed Tomography in Patients with Acute Respiratory Distress Syndrome. What Is the Relationship? Am J Respir Crit Care Med. 2016;193(11):1254-1263. doi:10.1164/rccm.201507-1413OC

6.         Suter PM, Fairley B, Isenberg MD. Optimum end-expiratory airway pressure in patients with acute pulmonary failure. N Engl J Med. 1975;292(6):284-289. doi:10.1056/NEJM197502062920604

7.         Acute Respiratory Distress Syndrome Network, Brower RG, Matthay MA, et al. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med. 2000;342(18):1301-1308. doi:10.1056/NEJM200005043421801

8.         Goligher EC, Kavanagh BP, Rubenfeld GD, et al. Oxygenation response to positive end-expiratory pressure predicts mortality in acute respiratory distress syndrome. A secondary analysis of the LOVS and ExPress trials. Am J Respir Crit Care Med. 2014;190(1):70-76. doi:10.1164/rccm.201404-0688OC

9.         Pintado M-C, de Pablo R, Trascasa M, et al. Individualized PEEP setting in subjects with ARDS: a randomized controlled pilot study. Respir Care. 2013;58(9):1416-1423. doi:10.4187/respcare.02068

10.       Amato MBP, Meade MO, Slutsky AS, et al. Driving pressure and survival in the acute respiratory distress syndrome. N Engl J Med. 2015;372(8):747-755. doi:10.1056/NEJMsa1410639

11.       Beitler JR, Sarge T, Banner-Goodspeed VM, et al. Effect of Titrating Positive End-Expiratory Pressure (PEEP) With an Esophageal Pressure-Guided Strategy vs an Empirical High PEEP-Fio2 Strategy on Death and Days Free From Mechanical Ventilation Among Patients With Acute Respiratory Distress Syndrome: A Randomized Clinical Trial. JAMA. 2019;321(9):846-857. doi:10.1001/jama.2019.0555

12.       Cressoni M, Chiumello D, Carlesso E, et al. Compressive forces and computed tomography-derived positive end-expiratory pressure in acute respiratory distress syndrome. Anesthesiology. 2014;121(3):572-581. doi:10.1097/ALN.0000000000000373

13.       Bouhemad B, Brisson H, Le-Guen M, Arbelot C, Lu Q, Rouby J-J. Bedside ultrasound assessment of positive end-expiratory pressure-induced lung recruitment. Am J Respir Crit Care Med. 2011;183(3):341-347. doi:10.1164/rccm.201003-0369OC

14.       Brower RG, Lanken PN, MacIntyre N, et al. Higher versus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome. N Engl J Med. 2004;351(4):327-336. doi:10.1056/NEJMoa032193

15.       Mercat A, Richard J-CM, Vielle B, et al. Positive end-expiratory pressure setting in adults with acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. JAMA. 2008;299(6):646-655. doi:10.1001/jama.299.6.646