0
Original Research: Critical Care |

Acid and Weakly Acidic Gastroesophageal Reflux and Pepsin Isoforms (A and C) in Tracheal Secretions of Critically Ill ChildrenGastroesophageal Reflux and Pepsin in ICU Children FREE TO VIEW

Cristiane Hallal, PhD; Veridiana S. Chaves, MD; Gilberto C. Borges, MD; Isabel C. Werlang, PhD; Fernanda U. Fontella, PhD; Ursula Matte, PhD; Marcelo Z. Goldani, PhD; Paulo R. Carvalho, PhD; Eliana A. Trotta, PhD; Jefferson P. Piva, PhD; Sergio G. S. Barros, PhD; Helena A. S. Goldani, MD, PhD
Author and Funding Information

From the Post-Graduate Program Sciences in Gastroenterology and Hepatology (Drs Hallal, Barros, and H. A. S. Goldani); Pediatric Gastroenterology Unit (Drs Hallal, Borges, and H. A. S. Goldani), Pediatric Intensive Care Unit (Drs Chaves, Carvalho, Trotta, and Piva) and Laboratory of Translational Pediatrics (Drs Werlang, Fontella, M. Z. Goldani, and H. A. S. Goldani), Hospital de Clínicas de Porto Alegre; and Post-Graduate Program in Child and Adolescent Health (Drs Matte, M. Z. Goldani, Carvalho, and H. A. S. Goldani), Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, Porto Alegre-RS, Brazil.

CORRESPONDENCE TO: Cristiane Hallal, PhD, Rua Ramiro Barcelos 2350, CEP 90035-903, Porto Alegre-RS, Brazil; e-mail: cris.hallal@yahoo.com


FOR EDITORIAL COMMENT SEE PAGE 300

FUNDING/SUPPORT: This study was conducted using academic funds from the Ministry of Education (Capes), and Fundo de Incentivo à Pesquisa e Eventos do Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2015;148(2):333-339. doi:10.1378/chest.14-1967
Text Size: A A A
Published online

BACKGROUND:  Gastroesophageal reflux (GER) and pulmonary aspiration are frequent in patients in the ICU. The presence of pepsin in airways seems to be the link between them. However, pepsin isoforms A (gastric specific) and C (pneumocyte potentially derived) need to be distinguished. This study aimed to evaluate GER patterns and to determine the presence of pepsin A and C in tracheal secretions of critically ill children receiving mechanical ventilation.

METHODS:  All patients underwent combined multichannel intraluminal impedance-pH (MII-pH) monitoring. Tracheal secretion samples were collected to determine the presence of pepsin. Pepsin A and C were evaluated by Western blot. MII-pH parameters analyzed were number of total GER episodes (NGER); acid, weakly acidic, and weakly alkaline GER episodes; and proximal and distal GER episodes.

RESULTS:  Thirty-four patients (median age, 4 months; range, 1-174 months) were included. MII-pH monitoring detected 2,172 GER episodes (77.0% were weakly acidic; 71.7% were proximal). The median NGER episodes per patient was 59.5 (25th-75th percentile, 20.3-85.3). Weakly acidic GER episodes per patient were significantly more frequent than acid GER episodes per patient (median [25th-75th percentile], 43.5 [20.3-68.3] vs 1.0 [0-13.8], respectively; P < .001). Only three patients had an altered acid reflux index (44.9%, 12.7%, and 13.6%) while not taking antacid drugs. Pepsin A was found in 100% of samples and pepsin C in 76.5%.

CONCLUSIONS:  The majority of GER episodes of children in the ICU were proximal and weakly acidic. All patients had aspiration of gastric contents as detected by pepsin A in tracheal fluid. A specific pepsin assay should be performed to establish gastropulmonary aspiration because pepsin C was found in > 70% of samples.

Figures in this Article

Patients in the ICU experience several disturbances that may cause GI motility abnormality and increase the risk of gastroesophageal reflux (GER) and pulmonary aspiration (PA). Swallowing dysfunction, impaired esophageal clearance, reduced activity of lower esophageal sphincter function, slow gastric emptying, and impairment of small intestinal motility are some of these abnormalities.1,2 In addition, several factors may contribute to the high risk of GER and PA, such as the presence of a nasogastric tube, supine positioning, lower esophageal sphincter relaxing medication, sedation, and mechanical ventilation.3,4

GER is a common problem in patients in the ICU and may lead to erosive esophagitis and PA.4,5 Although the mechanisms that cause GER in critically ill patients receiving mechanical ventilation are well studied,6 the patterns regarding pH (acid, weakly acidic, weakly alkaline) and the height reached by the refluxate (proximal, distal) in the esophagus have not yet been described.

PA of gastric contents may result in a range of lung injuries. Large-volume PA may cause mechanical obstruction and life-threatening pneumonia. Microaspiration may be silent and asymptomatic, but if sustained, it may lead to lung injury as a consequence of chemical damage and release of proinflammatory mediators.7,8 Ventilator-associated pneumonia is the major consequence of PA and one of the most frequent causes of hospital infection in patients in the ICU, increasing the length of hospital stay and use of medical resources.7,9 Early diagnosis of GER and PA is essential to establish treatment and prevent complications.

Pepsin has been regarded as an important biomarker of extraesophageal reflux and gastric content aspiration.10,11 Its presence has been shown in the trachea, lungs, larynx, middle ear, and saliva.1216 Five types of pepsin are known. Pepsinogen A, a precursor of pepsin A, is found exclusively in the stomach. Pepsinogen C, a precursor of pepsin C or gastricsin, is also found in sites distant from the gut, such as lungs, pancreas, and seminal vesicles.17

PA and GER are common problems in patients in the ICU and may worsen clinical outcome.7,12,18 Pepsin seems to be the link between these events, but this association has not been clearly demonstrated. Previous reports did not show a relationship between the presence of pepsin in the airways of critically ill children and the presence of GER. The prevalence of PA in critically ill patients has been assessed by a nonspecific pepsin assay that does not distinguish between pepsin A and pepsin C. The present study aimed to (1) evaluate the GER patterns (acid, weakly acidic, and weakly alkaline; proximal and distal) assessed by multichannel intraesophageal impedance-pH (MII-pH) monitoring in critically ill children receiving mechanical ventilation and (2) to determine the presence of pepsin A and pepsin C in the tracheal secretions of these patients.

This study was approved by the Ethics and Research Committee of the Hospital de Clínicas de Porto Alegre (protocol no. 09/631). Informed and written consent were obtained from all parents or legal guardians.

A prospective observational study was performed in patients requiring mechanical ventilation admitted to the pediatric ICU between January 2011 and December 2012. All patients were under sedation and on full enteral intermittent feeding every 3 h. The majority of patients were on an antacid regimen (proton pump inhibitor or H2 blocker) as prophylaxis for GI bleeding. Enteral feeding was given by gastric or postpyloric tube. Patients who had contraindications for the insertion of a nasogastric tube (orofacial problems, GI bleeding, or severe coagulopathy) or who had previous surgery at the gastroesophageal junction were excluded.

Study Protocol
MII-pH Monitoring:

All patients underwent MII-pH monitoring during a period of at least 20 h. All procedures were performed by the same examiner, with age-appropriate probes with seven impedance sensors 1.5 or 2.0 cm apart and one distal pH sensor (Sandhill Scientific). The pH electrode was calibrated in buffer pH 4 and 7 at the beginning of each study. The catheter was inserted transnasally, approximately positioned according to modified Strobel formula,19 and set at two vertebral bodies above the diaphragmatic angle, as recommended for infants and children.20 The pH probe location was confirmed by chest radiography and adjusted if necessary. The probe was connected to an ambulatory device containing the amplifiers that record data (Sleuth; Sandhill Scientific). An external reference electrode was attached to the patient’s abdomen wall. The recording was uploaded onto a personal computer, and data were manually analyzed independently by two trained examiners (C. H. and H. A. S. G.) using BioVIEW Analysis version 5.6 software (Sandhill Scientific). The MII-pH monitoring data were analyzed following criteria described elsewhere.20 The agreement between examiners was analyzed, and disagreement was resolved by consensus. MII-pH parameters analyzed were number of total GER episodes, height of refluxate (proximal or distal), acid reflux index (ARI) as the percentage of time when pH < 4, and reflux content (acid when pH < 4; weakly acidic when pH 4-7; weakly alkaline when pH > 7).21 Distal reflux was considered as that which reached the two most distal impedance channels (channels 1 and 2), and proximal reflux was defined as that started in channels 1 and 2 and reaching the most proximal channels (channels 3 and up). ARI was considered altered when > 10% in children aged < 1 year and > 5% in children aged > 1 year.20

Tracheal Secretion Samples:

The tracheal secretion samples were collected from each patient by using a 6F or 8F suction catheter throughout the prolonged MII-pH monitoring period. The catheter was passed into the orotracheal tube down to the end of the endotracheal tube without previous saline solution according to local routine standards. After that, the tube was immediately flushed with 1 mL normal saline to collect the residual sample in the catheter. The samples were centrifuged at 4°C for 10 min at 3,000 rpm.18 The supernatant was collected and stored at −80°C for further analysis. Three tracheal secretion samples were collected from each patient: at the beginning, during the mid-MII-pH monitoring period, and at the end of the study period.

Western Blot Analysis

Western blot was performed to test for pepsin A and C. Samples containing up to 80 μg protein were separated on NuPAGE Novex 12% Bis-Tris gel (Life Technologies) using the Xcell SureLock Mini-Cell electrophoresis system (Life Technologies) and then transferred to a polyvinylidene fluoride membrane (EMD Millipore) at 30 V, 400-mA constant current, for 90 min. Briefly, the membrane was blocked with 5% nonfat milk in Tris-buffered saline (pH 7.5) containing 0.1% Tween-20 for 1 h and probed with 1:500 diluted mouse anti-human pepsin C antibody (Santa Cruz Biotechnology, Inc) and 1:500 diluted mouse anti-human pepsin A antibody (Santa Cruz Biotechnology, Inc) for 16 h. The immunoreaction was detected by horseradish peroxidase-conjugated goat anti-mouse antibody (Santa Cruz Biotechnology, Inc) and enhanced chemiluminescence Western blot detection reagents (EMD Millipore). Positive control for pepsin A was a sample of gastric fluid from a normal subject.

Statistical Analysis

Interobserver agreement of MII-pH monitoring analysis was assessed by using the Cohen κ coefficient. Wilcoxon test was used to compare acid and weakly acidic GER. The difference was considered significant at P < .05. SPSS version 18.0 statistical software (IBM Corporation) was used for all analyses.

Thirty-six patients were enrolled in the study; two were excluded due to artifact in the tracings. Thus, 34 children (24 boys and 10 girls) were included in the final sample. Median age was 4 months (range, 1-174 months). Twenty-nine patients had postpyloric feeding tubes, and five had nasogastric feeding tubes. Ten patients were receiving omeprazole and nine ranitidine as antacid treatment. Demographic and clinical data are presented in Table 1. None of the patients had clinical symptoms of nosocomial pneumonia after 1-week follow-up.

Table Graphic Jump Location
TABLE 1 ]  Summary of Study Subjects

Data are presented as counts, median (range), or No. (%).

MII-pH Monitoring

The median distance between the nostril and the correct placement of the pH sensor of the MII-pH catheter in the distal esophagus checked by radiography was 17 cm (range, 13-35 cm). There were 2,172 reflux episodes detected in the study (Fig 1). Of those, 1,672 (77%) were classified as weakly acidic GER, and 1,557 (71.7%) reached the proximal esophagus. The MII-pH parameters of all patients are described in Table 2. From the weakly acidic episodes, 1,199 (71.7%) reached the proximal impedance channels. Similarly, 358 of the acid episodes (71.6%) reached the proximal channels. There were no weakly alkaline reflux episodes.

Figure Jump LinkFigure 1 –  A, Impedance-pH recording of a patient with an acid distal reflux episode: retrograde drop in the two distal impedance channels, with pH < 4. B, Another tracing of a patient with a weakly acidic proximal reflux episode: retrograde drop in impedance up to the proximal impedance channel, with pH > 4.Grahic Jump Location
Table Graphic Jump Location
TABLE 2 ]  Gastroesophageal Reflux Parameters and Presence of Pepsin A and C

AGER = number of acid gastroesophageal reflux episodes; ARI = acid reflux index; DGER = number of distal gastroesophageal reflux episodes; NGER = number of total gastroesophageal reflux episodes; PGER = number of proximal gastroesophageal reflux episodes; WAGER = number of weakly acidic gastroesophageal reflux episodes.

The median (25th-75th percentile) of the total GER (acid and weakly acidic) episodes per patient was 59.5 (20.3-85.3). Weakly acidic GER episodes per patient were significantly more frequent than acid GER episodes per patient (median [25th-75th percentile], 43.5 [20.3-68.3] vs 1.0 [0-13.8], respectively; P < .001) (Fig 2). Only three patients had an altered ARI (44.9%, 12.7%, and 13.6%), all of whom were off antacid drugs. The agreement between the examiners was substantial (κ = 0.704).

Figure Jump LinkFigure 2 –  Analysis of multichannel intraesophageal impedance-pH monitoring values: number of episodes of GER acid vs weakly acidic with significant difference (P < .001). GER = gastroesophageal reflux.Grahic Jump Location
Pepsin Assay

All patients had pepsin A in tracheal secretions on Western blot. Twenty-six patients had pepsin C (76.5%), and eight (23.5%) did not (Fig 3, Table 2).

Figure Jump LinkFigure 3 –  Representative Western blot results to pepsin A and pepsin C. Western blots of samples 23 and 26 (pepsin A+, pepsin C+) and sample 25 (pepsin A+, pepsin C−) probed with pepA and pepC. C+ = positive control for pepsin A; pepA = anti-pepsin A; pepC = anti-pepsin C.Grahic Jump Location

This study assessed the patterns of GER and the presence of pepsin A and C in tracheal secretions of critically ill children receiving mechanical ventilation. We found that GER episodes were predominantly proximal and weakly acidic, and all patients had pepsin A in tracheal secretions. To our knowledge, this study is the first to evaluate GER by prolonged esophageal MII-pH monitoring and to distinguish pepsin A from C in the airways of critically ill, tube-fed children receiving mechanical ventilation.

This study showed a median of 59.5 GER episodes per patient. In another study of critically ill children, only two GER episodes per patient were detected, but these patients were postsurgery and not fed enterally.22 Regarding the height reached by the refluxate, 71% of all GER episodes in the present study were proximal. This might have occurred because of the supine position of and lack of defense mechanisms in these patients. Similarly, other authors have shown a prevalence of proximal reflux in children, and the proximal extent of reflux has been associated with increased risk of PA.11,23,24

Regarding the pH of the refluxate, 77% of GER episodes were weakly acidic. Weakly acidic reflux frequently has been shown in children with GER and respiratory diseases.25 The present finding may be explained by the majority of patients being infants, who may present low acid output. Additionally, the patients received frequent feeding that might have buffered gastric pH, inducing a less-acid refluxate.26 Weakly acidic refluxate can also be aspirated into the lungs, inducing a bronchial inflammatory reaction.27

Pepsin has been considered a biologic marker of PA and is present in both acid and weakly acidic reflux.28 Therefore, it may be detected in refluxate of patients on antacid medications. Pepsin can be detected after a reflux event for at least 24 h, even in a nonacid environment, and may be reactivated in the airways. The reactivation of pepsin may occur by a subsequent acid reflux event or by the acid intracellular environment after endocytosis.14 Another issue regarding pepsin in the airways is that pepsin may induce tissue damage by releasing proinflammatory cytokines and may cause depletion of protective proteins8,14,28,29; however, this explanation needs more evidence. Therefore, we cannot say for sure that the presence of the pepsin in the airways is a marker of pulmonary disease because the cause-effect relationship is not well defined.

PA in patients in the ICU has been evaluated by the detection of pepsin in tracheal secretions or BAL. In ICU neonates, PA is a widespread phenomenon, and pepsin has been detected in up to 100% of patients.12,18 In children in the ICU, previous studies showed 70% prevalence of PA detected by pepsin,29 whereas in adults in the ICU, pepsin prevalence ranged from 16% to 92%.7,9,30 The variability of results may be due to nonstandardization of the assay.

The detection of pepsin in the airways without distinction between pepsin isoforms A and C might not be a specific marker of gastropulmonary aspiration because pepsin C can be expressed from type 2 pneumocytes.31,32 Therefore, identification of pepsin A in the airways is warranted to determine the presence of gastric content in the airways. In the present study, we found that 100% of patients had pepsin A in tracheal secretions. Nonetheless, > 70% of patients also had detectable levels of pepsin C. We could not say for sure that the source of detected pepsin C was produced in the lungs or in the stomach. However, the detection of pepsin A in the airways confirmed the aspiration of gastric content. Previous studies evaluating the prevalence of aspiration in critically ill patients detected the presence of total pepsin, with no distinction between pepsin A and pepsin C.7,12,18,30,33

Regarding the use of antacid medications, Blondeau et al34 showed that the use of a proton pump inhibitor did not prevent nonacid reflux and PA in patients with lung transplants. Furthermore, regarding feeding tube placement, previous studies found that the risk of aspiration pneumonia is not different in patients treated with a gastric or postpyloric tube.35 In the present study, pepsin A was detected in the tracheal fluid of all patients regardless of the type of feeding and acid suppression therapy; however, the sample size did not allow us to investigate the influence of these factors in detail.

The main limitations of this study are the small number of patients and the lack of long-term clinical outcome. Although all patients had pepsin A in tracheal secretions, none had nosocomial pneumonia after a 1-week period. Therefore, it was not possible to associate the presence of pepsin A in the tracheal fluid with further lung complications. Nonetheless, the strength of this study is that it is the first, to our knowledge, to differentiate the presence of pepsin isoforms A and C in tracheal secretions of critically ill patients. The impact of the presence of pepsin A in 100% of patient airways in a clinical setting is unknown.

We found that the majority of reflux episodes in critically ill children are proximal and weakly acidic. All patients had gastropulmonary aspiration detected by gastric-specific pepsin A in the airways. Pepsin C was detected in > 70% samples, suggesting that a more specific pepsin assay should be performed to establish gastropulmonary aspiration. Further studies are needed to better understand, in a clinical context, the role of airway pepsin in aspiration-related lung disease and the contribution of airway pepsin to patient outcome.

Author contributions: C. H. and H. A. S. G. had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. C. H., V. S. C., G. C. B., I. C. W., F. U. F., U. M., M. Z. G., P. R. C., E. A. T., J. P. P., S. G. S. B., and H. A. S. G. contributed to the study concept and design, data interpretation, critical revision of the manuscript for important intellectual content, and final approval of the manuscript.

Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Role of sponsors: The sponsors had no role in the design of the study, the collection and analysis of the data, or the preparation of the manuscript.

Other contributions: This study was performed in the Hospital de Clínicas de Porto Alegre, Porto Alegre-RS, Brazil.

ARI

acid reflux index

GER

gastroesophageal reflux

MII-pH

multichannel intraesophageal impedance-pH

PA

pulmonary aspiration

Kölbel CB, Rippel K, Klar H, Singer MV, van Ackern K, Fiedler F. Esophageal motility disorders in critically ill patients: a 24-hour manometric study. Intensive Care Med. 2000;26(10):1421-1427. [CrossRef] [PubMed]
 
Ritz MA, Fraser R, Tam W, Dent J. Impacts and patterns of disturbed gastrointestinal function in critically ill patients. Am J Gastroenterol. 2000;95(11):3044-3052. [CrossRef] [PubMed]
 
Amantéa SL, Piva JP, Sanches PR, Palombini BC. Oropharyngeal aspiration in pediatric patients with endotracheal intubation. Pediatr Crit Care Med. 2004;5(2):152-156. [CrossRef] [PubMed]
 
Chapman MJ, Nguyen NQ, Deane AM. Gastrointestinal dysmotility: clinical consequences and management of the critically ill patient. Gastroenterol Clin North Am. 2011;40(4):725-739. [CrossRef] [PubMed]
 
Wilmer A, Tack J, Frans E, et al. Duodenogastroesophageal reflux and esophageal mucosal injury in mechanically ventilated patients. Gastroenterology. 1999;116(6):1293-1299. [CrossRef] [PubMed]
 
Nind G, Chen WH, Protheroe R, et al. Mechanisms of gastroesophageal reflux in critically ill mechanically ventilated patients. Gastroenterology. 2005;128(3):600-606. [CrossRef] [PubMed]
 
Metheny NA, Clouse RE, Chang YH, Stewart BJ, Oliver DA, Kollef MH. Tracheobronchial aspiration of gastric contents in critically ill tube-fed patients: frequency, outcomes, and risk factors. Crit Care Med. 2006;34(4):1007-1015. [CrossRef] [PubMed]
 
Bathoorn E, Daly P, Gaiser B, et al. Cytotoxicity and induction of inflammation by pepsin in acid in bronchial epithelial cells. Int J Inflam. 2011;2011:569416. [CrossRef] [PubMed]
 
Metheny NA, Chang YH, Ye JS, et al. Pepsin as a marker for pulmonary aspiration. Am J Crit Care. 2002;11(2):150-154. [PubMed]
 
Samuels TL, Johnston N. Pepsin as a marker of extraesophageal reflux. Ann Otol Rhinol Laryngol. 2010;119(3):203-208. [PubMed]
 
Farrell S, McMaster C, Gibson D, Shields MD, McCallion WA. Pepsin in bronchoalveolar lavage fluid: a specific and sensitive method of diagnosing gastro-oesophageal reflux-related pulmonary aspiration. J Pediatr Surg. 2006;41(2):289-293. [CrossRef] [PubMed]
 
Farhath S, He Z, Nakhla T, et al. Pepsin, a marker of gastric contents, is increased in tracheal aspirates from preterm infants who develop bronchopulmonary dysplasia. Pediatrics. 2008;121(2):e253-e259. [CrossRef] [PubMed]
 
Ward C, Forrest IA, Brownlee IA, et al. Pepsin like activity in bronchoalveolar lavage fluid is suggestive of gastric aspiration in lung allografts. Thorax. 2005;60(10):872-874. [CrossRef] [PubMed]
 
Johnston N, Dettmar PW, Bishwokarma B, Lively MO, Koufman JA. Activity/stability of human pepsin: implications for reflux attributed laryngeal disease. Laryngoscope. 2007;117(6):1036-1039. [CrossRef] [PubMed]
 
Abd El-Fattah AM, Abdul Maksoud GA, Ramadan AS, Abdalla AF, Abdel Aziz MM. Pepsin assay: a marker for reflux in pediatric glue ear. Otolaryngol Head Neck Surg. 2007;136(3):464-470. [CrossRef] [PubMed]
 
Schallom M, Tricomi SM, Chang YH, Metheny NA. A pilot study of pepsin in tracheal and oral secretions. Am J Crit Care. 2013;22(5):408-411. [CrossRef] [PubMed]
 
Kageyama T. Pepsinogens, progastricsins, and prochymosins: structure, function, evolution, and development. Cell Mol Life Sci. 2002;59(2):288-306. [CrossRef] [PubMed]
 
Farhath S, Aghai ZH, Nakhla T, et al. Pepsin, a reliable marker of gastric aspiration, is frequently detected in tracheal aspirates from premature ventilated neonates: relationship with feeding and methylxanthine therapy. J Pediatr Gastroenterol Nutr. 2006;43(3):336-341. [CrossRef] [PubMed]
 
Strobel CT, Byrne WJ, Ament ME, Euler AR. Correlation of esophageal lengths in children with height: application to the Tuttle test without prior esophageal manometry. J Pediatr. 1979;94(1):81-84. [CrossRef] [PubMed]
 
Pilic D, Fröhlich T, Nöh F, et al. Detection of gastroesophageal reflux in children using combined multichannel intraluminal impedance and pH measurement: data from the German Pediatric Impedance Group. J Pediatr. 2011;158(4):650-654. [CrossRef] [PubMed]
 
Sifrim D, Castell D, Dent J, Kahrilas PJ. Gastro-oesophageal reflux monitoring: review and consensus report on detection and definitions of acid, non-acid, and gas reflux. Gut. 2004;53(7):1024-1031. [CrossRef] [PubMed]
 
Solana MJ, Sánchez C, López-Herce J, et al. Multichannel intraluminal impedance to study gastroesophageal reflux in mechanically ventilated children in the first 48 h after PICU admission. Nutrition. 2013;29(7-8):972-976. [CrossRef] [PubMed]
 
Borrelli O, Battaglia M, Galos F, et al. Non-acid gastro-oesophageal reflux in children with suspected pulmonary aspiration. Dig Liver Dis. 2010;42(2):115-121. [CrossRef] [PubMed]
 
Starosta V, Kitz R, Hartl D, Marcos V, Reinhardt D, Griese M. Bronchoalveolar pepsin, bile acids, oxidation, and inflammation in children with gastroesophageal reflux disease. Chest. 2007;132(5):1557-1564. [CrossRef] [PubMed]
 
Condino AA, Sondheimer J, Pan Z, Gralla J, Perry D, O’Connor JA. Evaluation of gastroesophageal reflux in pediatric patients with asthma using impedance-pH monitoring. J Pediatr. 2006;149(2):216-219. [CrossRef] [PubMed]
 
Mitchell DJ, McClure BG, Tubman TR. Simultaneous monitoring of gastric and oesophageal pH reveals limitations of conventional oesophageal pH monitoring in milk fed infants. Arch Dis Child. 2001;84(3):273-276. [CrossRef] [PubMed]
 
Mertens V, Blondeau K, Vanaudenaerde B, et al. Gastric juice from patients “on” acid suppressive therapy can still provoke a significant inflammatory reaction by human bronchial epithelial cells. J Clin Gastroenterol. 2010;44(10):e230-e235. [PubMed]
 
McNally P, Ervine E, Shields MD, et al. High concentrations of pepsin in bronchoalveolar lavage fluid from children with cystic fibrosis are associated with high interleukin-8 concentrations. Thorax. 2011;66(2):140-143. [CrossRef] [PubMed]
 
Samuels TL, Johnston N. Pepsin as a causal agent of inflammation during nonacidic reflux. Otolaryngol Head Neck Surg. 2009;141(5):559-563. [CrossRef] [PubMed]
 
Metheny NA, Schallom L, Oliver DA, Clouse RE. Gastric residual volume and aspiration in critically ill patients receiving gastric feedings. Am J Crit Care. 2008;17(6):512-519. [PubMed]
 
Bohman JK, Kor DJ, Kashyap R, et al. Airway pepsin levels in otherwise healthy surgical patients receiving general anesthesia with endotracheal intubation. Chest. 2013;143(5):1407-1413. [CrossRef] [PubMed]
 
Foster C, Aktar A, Kopf D, Zhang P, Guttentag S. Pepsinogen C: a type 2 cell-specific protease. Am J Physiol Lung Cell Mol Physiol. 2004;286(2):L382-L387. [CrossRef] [PubMed]
 
Gopalareddy V, He Z, Soundar S, et al. Assessment of the prevalence of microaspiration by gastric pepsin in the airway of ventilated children. Acta Paediatr. 2008;97(1):55-60. [CrossRef] [PubMed]
 
Blondeau K, Mertens V, Vanaudenaerde BA, et al. Gastro-oesophageal reflux and gastric aspiration in lung transplant patients with or without chronic rejection. Eur Respir J. 2008;31(4):707-713. [CrossRef] [PubMed]
 
Ho KM, Dobb GJ, Webb SAR. A comparison of early gastric and post-pyloric feeding in critically ill patients: a meta-analysis. Intensive Care Med. 2006;32(5):639-649. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1 –  A, Impedance-pH recording of a patient with an acid distal reflux episode: retrograde drop in the two distal impedance channels, with pH < 4. B, Another tracing of a patient with a weakly acidic proximal reflux episode: retrograde drop in impedance up to the proximal impedance channel, with pH > 4.Grahic Jump Location
Figure Jump LinkFigure 2 –  Analysis of multichannel intraesophageal impedance-pH monitoring values: number of episodes of GER acid vs weakly acidic with significant difference (P < .001). GER = gastroesophageal reflux.Grahic Jump Location
Figure Jump LinkFigure 3 –  Representative Western blot results to pepsin A and pepsin C. Western blots of samples 23 and 26 (pepsin A+, pepsin C+) and sample 25 (pepsin A+, pepsin C−) probed with pepA and pepC. C+ = positive control for pepsin A; pepA = anti-pepsin A; pepC = anti-pepsin C.Grahic Jump Location

Tables

Table Graphic Jump Location
TABLE 1 ]  Summary of Study Subjects

Data are presented as counts, median (range), or No. (%).

Table Graphic Jump Location
TABLE 2 ]  Gastroesophageal Reflux Parameters and Presence of Pepsin A and C

AGER = number of acid gastroesophageal reflux episodes; ARI = acid reflux index; DGER = number of distal gastroesophageal reflux episodes; NGER = number of total gastroesophageal reflux episodes; PGER = number of proximal gastroesophageal reflux episodes; WAGER = number of weakly acidic gastroesophageal reflux episodes.

References

Kölbel CB, Rippel K, Klar H, Singer MV, van Ackern K, Fiedler F. Esophageal motility disorders in critically ill patients: a 24-hour manometric study. Intensive Care Med. 2000;26(10):1421-1427. [CrossRef] [PubMed]
 
Ritz MA, Fraser R, Tam W, Dent J. Impacts and patterns of disturbed gastrointestinal function in critically ill patients. Am J Gastroenterol. 2000;95(11):3044-3052. [CrossRef] [PubMed]
 
Amantéa SL, Piva JP, Sanches PR, Palombini BC. Oropharyngeal aspiration in pediatric patients with endotracheal intubation. Pediatr Crit Care Med. 2004;5(2):152-156. [CrossRef] [PubMed]
 
Chapman MJ, Nguyen NQ, Deane AM. Gastrointestinal dysmotility: clinical consequences and management of the critically ill patient. Gastroenterol Clin North Am. 2011;40(4):725-739. [CrossRef] [PubMed]
 
Wilmer A, Tack J, Frans E, et al. Duodenogastroesophageal reflux and esophageal mucosal injury in mechanically ventilated patients. Gastroenterology. 1999;116(6):1293-1299. [CrossRef] [PubMed]
 
Nind G, Chen WH, Protheroe R, et al. Mechanisms of gastroesophageal reflux in critically ill mechanically ventilated patients. Gastroenterology. 2005;128(3):600-606. [CrossRef] [PubMed]
 
Metheny NA, Clouse RE, Chang YH, Stewart BJ, Oliver DA, Kollef MH. Tracheobronchial aspiration of gastric contents in critically ill tube-fed patients: frequency, outcomes, and risk factors. Crit Care Med. 2006;34(4):1007-1015. [CrossRef] [PubMed]
 
Bathoorn E, Daly P, Gaiser B, et al. Cytotoxicity and induction of inflammation by pepsin in acid in bronchial epithelial cells. Int J Inflam. 2011;2011:569416. [CrossRef] [PubMed]
 
Metheny NA, Chang YH, Ye JS, et al. Pepsin as a marker for pulmonary aspiration. Am J Crit Care. 2002;11(2):150-154. [PubMed]
 
Samuels TL, Johnston N. Pepsin as a marker of extraesophageal reflux. Ann Otol Rhinol Laryngol. 2010;119(3):203-208. [PubMed]
 
Farrell S, McMaster C, Gibson D, Shields MD, McCallion WA. Pepsin in bronchoalveolar lavage fluid: a specific and sensitive method of diagnosing gastro-oesophageal reflux-related pulmonary aspiration. J Pediatr Surg. 2006;41(2):289-293. [CrossRef] [PubMed]
 
Farhath S, He Z, Nakhla T, et al. Pepsin, a marker of gastric contents, is increased in tracheal aspirates from preterm infants who develop bronchopulmonary dysplasia. Pediatrics. 2008;121(2):e253-e259. [CrossRef] [PubMed]
 
Ward C, Forrest IA, Brownlee IA, et al. Pepsin like activity in bronchoalveolar lavage fluid is suggestive of gastric aspiration in lung allografts. Thorax. 2005;60(10):872-874. [CrossRef] [PubMed]
 
Johnston N, Dettmar PW, Bishwokarma B, Lively MO, Koufman JA. Activity/stability of human pepsin: implications for reflux attributed laryngeal disease. Laryngoscope. 2007;117(6):1036-1039. [CrossRef] [PubMed]
 
Abd El-Fattah AM, Abdul Maksoud GA, Ramadan AS, Abdalla AF, Abdel Aziz MM. Pepsin assay: a marker for reflux in pediatric glue ear. Otolaryngol Head Neck Surg. 2007;136(3):464-470. [CrossRef] [PubMed]
 
Schallom M, Tricomi SM, Chang YH, Metheny NA. A pilot study of pepsin in tracheal and oral secretions. Am J Crit Care. 2013;22(5):408-411. [CrossRef] [PubMed]
 
Kageyama T. Pepsinogens, progastricsins, and prochymosins: structure, function, evolution, and development. Cell Mol Life Sci. 2002;59(2):288-306. [CrossRef] [PubMed]
 
Farhath S, Aghai ZH, Nakhla T, et al. Pepsin, a reliable marker of gastric aspiration, is frequently detected in tracheal aspirates from premature ventilated neonates: relationship with feeding and methylxanthine therapy. J Pediatr Gastroenterol Nutr. 2006;43(3):336-341. [CrossRef] [PubMed]
 
Strobel CT, Byrne WJ, Ament ME, Euler AR. Correlation of esophageal lengths in children with height: application to the Tuttle test without prior esophageal manometry. J Pediatr. 1979;94(1):81-84. [CrossRef] [PubMed]
 
Pilic D, Fröhlich T, Nöh F, et al. Detection of gastroesophageal reflux in children using combined multichannel intraluminal impedance and pH measurement: data from the German Pediatric Impedance Group. J Pediatr. 2011;158(4):650-654. [CrossRef] [PubMed]
 
Sifrim D, Castell D, Dent J, Kahrilas PJ. Gastro-oesophageal reflux monitoring: review and consensus report on detection and definitions of acid, non-acid, and gas reflux. Gut. 2004;53(7):1024-1031. [CrossRef] [PubMed]
 
Solana MJ, Sánchez C, López-Herce J, et al. Multichannel intraluminal impedance to study gastroesophageal reflux in mechanically ventilated children in the first 48 h after PICU admission. Nutrition. 2013;29(7-8):972-976. [CrossRef] [PubMed]
 
Borrelli O, Battaglia M, Galos F, et al. Non-acid gastro-oesophageal reflux in children with suspected pulmonary aspiration. Dig Liver Dis. 2010;42(2):115-121. [CrossRef] [PubMed]
 
Starosta V, Kitz R, Hartl D, Marcos V, Reinhardt D, Griese M. Bronchoalveolar pepsin, bile acids, oxidation, and inflammation in children with gastroesophageal reflux disease. Chest. 2007;132(5):1557-1564. [CrossRef] [PubMed]
 
Condino AA, Sondheimer J, Pan Z, Gralla J, Perry D, O’Connor JA. Evaluation of gastroesophageal reflux in pediatric patients with asthma using impedance-pH monitoring. J Pediatr. 2006;149(2):216-219. [CrossRef] [PubMed]
 
Mitchell DJ, McClure BG, Tubman TR. Simultaneous monitoring of gastric and oesophageal pH reveals limitations of conventional oesophageal pH monitoring in milk fed infants. Arch Dis Child. 2001;84(3):273-276. [CrossRef] [PubMed]
 
Mertens V, Blondeau K, Vanaudenaerde B, et al. Gastric juice from patients “on” acid suppressive therapy can still provoke a significant inflammatory reaction by human bronchial epithelial cells. J Clin Gastroenterol. 2010;44(10):e230-e235. [PubMed]
 
McNally P, Ervine E, Shields MD, et al. High concentrations of pepsin in bronchoalveolar lavage fluid from children with cystic fibrosis are associated with high interleukin-8 concentrations. Thorax. 2011;66(2):140-143. [CrossRef] [PubMed]
 
Samuels TL, Johnston N. Pepsin as a causal agent of inflammation during nonacidic reflux. Otolaryngol Head Neck Surg. 2009;141(5):559-563. [CrossRef] [PubMed]
 
Metheny NA, Schallom L, Oliver DA, Clouse RE. Gastric residual volume and aspiration in critically ill patients receiving gastric feedings. Am J Crit Care. 2008;17(6):512-519. [PubMed]
 
Bohman JK, Kor DJ, Kashyap R, et al. Airway pepsin levels in otherwise healthy surgical patients receiving general anesthesia with endotracheal intubation. Chest. 2013;143(5):1407-1413. [CrossRef] [PubMed]
 
Foster C, Aktar A, Kopf D, Zhang P, Guttentag S. Pepsinogen C: a type 2 cell-specific protease. Am J Physiol Lung Cell Mol Physiol. 2004;286(2):L382-L387. [CrossRef] [PubMed]
 
Gopalareddy V, He Z, Soundar S, et al. Assessment of the prevalence of microaspiration by gastric pepsin in the airway of ventilated children. Acta Paediatr. 2008;97(1):55-60. [CrossRef] [PubMed]
 
Blondeau K, Mertens V, Vanaudenaerde BA, et al. Gastro-oesophageal reflux and gastric aspiration in lung transplant patients with or without chronic rejection. Eur Respir J. 2008;31(4):707-713. [CrossRef] [PubMed]
 
Ho KM, Dobb GJ, Webb SAR. A comparison of early gastric and post-pyloric feeding in critically ill patients: a meta-analysis. Intensive Care Med. 2006;32(5):639-649. [CrossRef] [PubMed]
 
NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).

Some tools below are only available to our subscribers or users with an online account.

Related Content

Customize your page view by dragging & repositioning the boxes below.

Find Similar Articles
CHEST Journal Articles
PubMed Articles
  • CHEST Journal
    Print ISSN: 0012-3692
    Online ISSN: 1931-3543