Pepsin A in Tracheal Secretions From Patients Receiving Mechanical Ventilation

Steven Talbert, PhD, RN; Annette M. Bourgault, PhD, RN, CNL; Kimberly Paige Rathbun, BSN, RN; Bassam Abomoelak, PhD, MT(AAB); Chirajyoti Deb, PhD, Devendra Mehta, MBBS, MSc (dist), MRCP; Mary Lou Sole, PhD, RN, CCNS, CNL


Am J Crit Care. 2021;30(6):443-450. 

In This Article

Abstract and Introduction


Background: In patients in the intensive care unit (ICU) receiving mechanical ventilation, aspiration of gastric contents may lead to ventilator-associated events and other adverse outcomes. Pepsin in pulmonary secretions is a biomarker of microaspiration of gastric contents.

Objectives: To evaluate the association between tracheal pepsin A and clinical outcomes related to ventilator use.

Methods: A subset of 297 patients from a larger clinical trial on aspiration of oral secretions in adults receiving mechanical ventilation consented to have pepsin A measured in their tracheal aspirate samples. A concentration ≥6.25 ng/mL indicated a positive result. Abundant microaspiration was defined as pepsin A in ≥30% of samples. Statistical analyses included analysis of variance, analysis of covariance, and χ 2 tests.

Results: Most patients were White men, mean age 59.7 (SD, 18.8) years. Microaspiration was found in 43.8% of patients (n = 130), with abundant microaspiration detected in 17.5% (n = 52). After acuity was controlled for, patients with tracheal pepsin A had a longer mechanical ventilation duration (155 vs 104 hours, P < .001) and ICU stay (9.9 vs 8.2 days, P = .04), but not a longer hospital stay.

Conclusions: Microaspiration of gastric contents occurred in nearly half of patients and was associated with a longer duration of mechanical ventilation and a longer stay in the ICU. Additional preventative interventions beyond backrest elevation, oropharyngeal suctioning, and management of endotracheal tube cuff pressure may be needed. Also, the timing of pepsin measurements to capture all microaspiration events requires additional exploration.


Microaspiration is a consequence of intubation in which secretions leak past the endotracheal tube (ETT) cuff into the lower airway.[1] Microaspiration of both oral and gastric secretions can occur. Although microaspiration remains difficult to detect accurately, it often occurs in critically ill patients and can be a pathway for the development of complications, such as ventilator-associated pneumonia (VAP)[1–3] or other ventilator-associated events (VAEs).[4]

Microaspiration of oral secretions is often detected by measuring the amount of α-amylase in tracheal secretions.[5] Detection of digestive system biomarkers, including pepsin and pepsin A, in tracheal secretions or in bronchoalveolar lavage specimens indicates microaspiration of gastric secretions.[1,6–8] The focus of this study is on the detection of microaspiration associated with gastric causes.

Pepsin is a protease stored in its inactive form (pepsinogen) in gastric mucosal chief cells. In the acidic pH levels in the stomach, pepsinogen is converted to pepsin.[2] Pepsin refers to any of a group of structurally similar isoenzymes.[9] We measured pepsin A, which is considered a specific marker of gastric reflux aspiration.[6,10,11] When exposed to tissues outside the stomach, pepsin A exhibits cytotoxic properties, induces the inflammatory response, and is responsible for more cellular damage than gastric acid alone.[9,12,13] In an animal model, pepsin-induced damage of the esophagus was irreversible.[13] Much of what is known regarding pepsin's cytotoxic actions is the result of studying gastric reflux disorders and chronic respiratory diseases.[14] Under normal conditions, small amounts of gastric contents that are regularly aspirated into the pulmonary system are efficiently neutralized and removed by existing pulmonary defense mechanisms.[2,6] However, critical illness and mechanical ventilation reduce or inhibit normal defense mechanisms, increasing the risk for adverse outcomes associated with microaspiration.[15] When pepsin A is present in tracheal secretions, gastric aspiration has most likely occurred.[16,17] Detection of pepsin A in oral secretions indicates that gastric reflux has most likely occurred.[18]

In an earlier randomized clinical trial (NCT02284178), we examined the impact of an enhanced oropharyngeal suction intervention on microaspiration of oral contents, which was assessed by measuring tracheal α-amylase levels.[19] Pepsin A was measured as a biomarker of aspiration in a large subset of patients who provided permission for additional study-related analyses. The purpose of this study was to evaluate the association between pepsin A in tracheal secretions and clinical outcomes including lengths of stay (LOS) in the hospital and in the intensive care unit (ICU), duration of mechanical ventilation, mortality, and VAEs. A VAE is a complication of ventilation that results in increased oxygenation needs.[4] There are 3 categories of VAEs: ventilator-associated conditions (VACs), infection-related ventilator-associated conditions (IVACs), and possible VAP.