A pilot randomized clinical trial assessing the effect of cricoid pressure on risk of aspiration.

INTRODUCTION: Patients at risk for microaspiration during elective intubation often receive cricoid pressure in the hopes of mitigating such risk. However, there is scarce evidence to either support or reject this practice. The objective of this investigation was to assess the effect of cricoid pressure on microaspiration and to inform the potential feasibility of conducting a larger, more definitive clinical trial. METHODS: This was a pilot randomized clinical trial set in the operating rooms of a tertiary referral hospital between August and October of 2014. Patients with risk factors for microaspiration (obesity, gastroesophageal reflux disease, or diabetes) were enrolled. The patients were randomized to either cricoid pressure or no cricoid pressure during induction of anesthesia with endotracheal intubation. Immediately after intubation, a sample of lower airway secretions was collected and analyzed for pepsin A. MAIN RESULTS: A total of 95 patients were evaluated, randomized and completed the study protocol. 46 were randomized to cricoid pressure and 49 to no cricoid pressure. Seven patients crossed-over treatment arms. A total of 18 (19.6%) patients met the pre-defined criteria for microaspiration. In both the intention-to-treat and per-protocol analyses, there were no statistically significant differences in the rate of microaspiration [OR (95% CI)] = 1.39 (0.49-3.92) and 1.30 (0.44-3.86), respectively. CONCLUSIONS: Utilizing pepsin A as a biomarker of aspiration, this pilot clinical trial did not find evidence for a reduced rate of aspiration or adverse clinical events with the administration of cricoid pressure during elective endotracheal intubation of patients with risk factors for microaspiration.

Detection of gastric pepsin in middle ear fluid of children with otitis media.

OBJECTIVE: We sought to confirm the finding of pepsin/pepsinogen in the middle ear fluid of children with otitis media in a larger sample size using a sensitive and specific pepsin assay. STUDY DESIGN AND SETTING: We evaluated 152 children (225 ear samples) in a prospective study at a tertiary care children's hospital. The presence of pepsin in middle ear aspirates was determined using enzymatic assay. RESULTS: Of the patients, 14.4 percent (22 of 152) had detectable pepsin activity in one or both of the ear samples with no pepsin activity detected in control serum. Average pepsin concentration in the samples was 96.6 +/- 170.8 ng/ml, ranging from 13 to 687 ng/ml. Pepsin concentration in the middle ear of children younger than 1.0 year was significantly higher than in older age groups. CONCLUSION AND SIGNIFICANCE: Results indicate that pepsin/pepsinogen is present in the middle ears of children with otitis media, although not at the high rate previously reported. Gastric reflux may be one causative factor in the pathogenesis of otitis media.

Pepsin, a reliable marker of gastric aspiration, is frequently detected in tracheal aspirates from premature ventilated neonates: relationship with feeding and methylxanthine therapy.

OBJECTIVES: To determine the frequency of pepsin detection in tracheal aspirate (TA) samples of mechanically ventilated premature neonates and its association with feedings and methylxanthine therapy. PATIENTS AND METHODS: Serial TA samples (days 1, 3, 5, 7, 14, 21, 28 and >28 days) were collected from premature neonates receiving ventilatory support. An enzymatic assay with a fluorescent substrate was used to detect pepsin. Pepsin was also measured in 10 serum samples collected in conjunction with the TA samples from 8 neonates. RESULTS: A total of 239 TA samples was collected from 45 premature neonates (mean birth weight, 762 +/- 166 g; mean gestational age, 25.5 +/- 1.5 wk). Pepsin was detectable in 222 of 239 TA samples (92.8%) and in none of the serum samples. Pepsin was significantly lower on day 1 (mean, 170 +/- 216 ng/mL) when compared with all other time points (P < 0.05). Mean concentration of pepsin was significantly lower when infants were unfed (265 +/- 209 ng/mL) compared with levels during feeding (390 +/- 260 ng/mL, P = 0.02). The mean level of pepsin was significantly higher in infants during xanthine therapy (419 +/- 370 ng/mL) compared with no xanthine therapy (295 +/- 231 ng/mL, P = 0.037). CONCLUSION: Pepsin, a marker of gastric contents, was detected in more than 92% of TA samples from premature infants on mechanical ventilation. The level of pepsin was higher in fed infants when compared with unfed infants. Xanthine therapy was also associated with increased pepsin in TA samples. Chronic aspiration of gastric contents may worsen lung disease in premature infants.

The role of gastric pepsin in the inflammatory cascade of pediatric otitis media.

IMPORTANCE: Otitis media is characterized as an ongoing inflammation with accumulation of an effusion in the middle ear cleft. The molecular mechanisms underlying the pathogenesis, particularly the inflammatory response, remain largely unknown. We hypothesize that aspiration of gastric contents into the nasopharynx may be responsible for the initiation of the inflammatory process or aggravate a preexisting condition. OBJECTIVE: To investigate the correlation of gastric pepsin A with inflammatory cytokines, bacterial infection, and clinical outcomes. DESIGN, SETTING, AND PARTICIPANTS: Prospective study of 129 pediatric patients undergoing myringotomy with tube placement for otitis media at a tertiary care pediatric hospital. MAIN OUTCOMES AND MEASURES: Ear samples were tested for pepsin A; cytokines interleukin (IL)-6, IL-8, and tumor necrosis factor; and bacterial culture inoculation. Data were analyzed by descriptive statistics and regression analysis to identify risk factors for the presence of pepsin A and to correlate pepsin A levels with cytokine levels, infection status, and clinical outcomes. RESULTS: Of the 129 patients, 199 ear samples were obtained; 82 samples (41%) and 64 patients (50%) were positive for pepsin A as measured by immunoassay. Pepsin A positivity correlated with age younger than 3.0 years (mean [SD], 2.3 [2.1] years in the positive group vs 3.3 [3.0] years in the negative group) and with all 3 cytokine levels (mean [SD] tumor necrosis factor, 29.5 [45.9] pg/mL in the positive group vs 13.2 [21.6] pg/mL in the negative group; IL-6, 6791.7 [9389.1] pg/mL in the positive group vs 2849.9 [4066.3] pg/mL in the negative group; and IL-8, 6828.2 [8122.3] pg/mL in the positive group vs 2925.1 [3364.5] pg/mL in the negative group [all P < .05]); however, logistic regression analysis showed that only IL-8 (odds ratio, 3.96; 95% CI, 1.3-12.0; P = .02) and age (odds ratio, 3.83; 95% CI, 1.2-12.7; P = .03) were significant independent variables. No statistically significant association was found with other parameters. Multiple linear regressions revealed that the levels of pepsin A were correlated with IL-8 levels (R2 = 0.248; P < .001) and the need for second or third tubes 6 to 12 months after the first (R2 = 0.102; P = .006). The presence of pepsin A in the middle ear was not associated with increased bacterial infection. Interleukin 8 was independent and significantly associated with both pepsin A levels and bacterial infection (R2 = 0.144 and 0.263, respectively; P = .001 for both). CONCLUSIONS AND RELEVANCE: Extraesophageal reflux as indicated by the presence of pepsin A is closely involved in the middle ear inflammatory process and may worsen the disease in some children; however, a proof of cause and effect between extraesophageal reflux and middle ear inflammation requires further investigation.

Detection of pepsin in mouth swab: correlation with clinical gastroesophageal reflux in preterm infants.

OBJECTIVE: To study the relationship between pepsinogen/pepsin in a mouth swab and clinical gastroesophageal reflux (GER) in preterm infants. METHODS: Preterm infants (birth weight ≤ 2000 g) on full enteral feeds were enrolled. Mouth swabs from cheek and below the tongue were collected one, two and three hours after feeding. An enzymatic assay with substrate fluorescein isothiocyanate-casein was used to detect pepsin A and C activities with further confirmation by western blot. Blinded investigators reviewed the infant's medical record to clinically diagnose GER. RESULTS: A total of 101 premature infants were enrolled. Pepsinogen/pepsin was detected in 45/101 (44.5%) infants in at least one sample. A clinical diagnosis of GER was made in 36/101 (35.6%) infants. Mouth swabs were positive in 26/36 (72%) infants with clinical GER and only 19/65 (29%) infants without GER (p < 0.001). Similarly, the levels of pepsinogen/pepsin A and C were higher in the mouth swabs of infants with clinical GER. CONCLUSION: The detection of pepsinogen/pepsin in a mouth swab correlates with clinical GER in premature infants.

Assessment of the prevalence of microaspiration by gastric pepsin in the airway of ventilated children.

AIM: Mechanically ventilated patients are at risk for aspiration of gastric contents. The aim of this observational study was to determine the prevalence of micro-aspiration in children with cuffed and uncuffed endotracheal (ET) tubes and with tracheostomies and to assess the effect of feeding status on aspiration. Micro-aspiration was determined by measuring gastric pepsin in tracheal aspirates. METHODS: We studied 27 children on ventilators in paediatric intensive care unit (PICU) and 10 children undergoing elective surgeries for various indications. Tracheal aspirates were collected from children on ventilatory support in the intensive care unit during medically indicated suctioning and from the group of children undergoing elective surgery in the operation room. Pepsin was detected by enzymatic assay. RESULTS: Overall 70% of cases in PICU were positive for pepsin in at least one of the aspirates. Pepsin positivity was significantly lower in the cuffed group than in the uncuffed and tracheostomy groups. Tube feedings did not significantly influence the prevalence of pepsin positivity. CONCLUSIONS: Measurement of gastric pepsin in tracheobronchial fluid is a sensitive tool to detect aspirations in mechanically ventilated children and to assess the efficacy of preventive measures in PICU settings.

Pepsin, a marker of gastric contents, is increased in tracheal aspirates from preterm infants who develop bronchopulmonary dysplasia.

OBJECTIVE: The objective of this study was to study the association between pepsin in tracheal aspirate samples and the development of bronchopulmonary dysplasia in preterm infants. METHODS: Serial tracheal aspirate samples were collected during the first 28 days from mechanically ventilated preterm neonates. Bronchopulmonary dysplasia was defined as the need for supplemental oxygen at 36 weeks' postmenstrual age. An enzymatic assay with a fluorescent substrate was used to detect pepsin. Total protein was measured by the Bradford assay to correct for the dilution during lavage. Immunohistochemistry using antibody against human pepsinogen was performed in 10 lung tissue samples from preterm infants. RESULTS: A total of 256 tracheal aspirate samples were collected from 59 preterm neonates. Pepsin was detected in 234 (91.4%) of 256 of the tracheal aspirate samples. Twelve infants had no bronchopulmonary dysplasia, 31 infants developed bronchopulmonary dysplasia, and 16 infants died before 36 weeks' postmenstrual age. The mean pepsin concentration was significantly lower in infants with no bronchopulmonary dysplasia compared with those who developed bronchopulmonary dysplasia or developed bronchopulmonary dysplasia/died before 36 weeks' postmenstrual age. Moreover, the mean pepsin level was significantly higher in infants with severe bronchopulmonary dysplasia compared with moderate bronchopulmonary dysplasia. The mean pepsin level in tracheal aspirate samples from the first 7 days was also lower in infants with no bronchopulmonary dysplasia compared with those who developed bronchopulmonary dysplasia or developed bronchopulmonary dysplasia/died before 36 weeks' postmenstrual age. Pepsinogen was not localized in the lung tissues by immunohistochemistry. CONCLUSION: The concentration of pepsin was increased in the tracheal aspirate of preterm infants who developed bronchopulmonary dysplasia or died before 36 weeks' postmenstrual age. Recovery of pepsin in tracheal aspirate samples is secondary to gastric aspiration, not by hematogenous spread or local synthesis in the lungs. Chronic aspiration of gastric contents may contribute in the pathogenesis of bronchopulmonary dysplasia.

The role of extraesophageal reflux in otitis media in infants and children.

OBJECTIVES/HYPOTHESIS: Gastroesophageal reflux disease (GERD) is common in children, and extraesophageal reflux disease (EORD) has been implicated in the pathophysiology of otitis media (OM). We sought to 1) determine the incidence of pepsin/pepsinogen presence in the middle ear cleft of a large sample of pediatric patients undergoing myringotomy with tube placement for OM; 2) compare this with a control population of pediatric patients undergoing middle ear surgery (cochlear implantation) with no documented history of OM; 3) analyze potential risk factors for OM in children with EORD demonstrated by the presence of pepsin in the middle ear cleft; and 4) determine if pepsin positivity at the time of myringotomy with tube placement predisposes to posttympanostomy tube otorrhea. STUDY GROUP: prospective samples of 509 pediatric patients (n = 893 ear samples) undergoing myringotomy with tube placement for recurrent acute OM and/or otitis media with effusion in a tertiary care pediatric hospital with longitudinal follow-up of posttympanostomy tube otorrhea. CONTROL GROUP: prospective samples of 64 pediatric patients (n = 74 ears) with negative history of OM undergoing cochlear implantation at one of the three tertiary care pediatric hospitals. A previously validated, highly sensitive and specific modified enzymatic assay was used to detect the presence of pepsin in the middle ear aspirates of study and control patients. Risk factors for OM and potentially associated conditions, including GERD, allergy, and asthma were analyzed for the study group through review of the electronic medical record and correlated topresence of pepsin in the middle ear space. Study patients were followed longitudinally postoperatively to determine the incidence of posttympanostomy tube otorrhea. RESULTS: The incidence of pepsin in the middle ear cleft of the study group was 20% of patients and 14% of ears, which is significantly higher than 1.4% of control patients and 1.5% of control ears (P < .05). Study patients younger than 1 year had a higher rate of purulent effusions and pepsin in the middle ear cleft (P < .05). Patients with pepsin in the middle ear cleft were more likely to have an effusion at the time of surgery than patients without pepsin in the middle ear cleft (P < .05). There was no statistical association found between the presence of pepsin and clinical history of GERD, allergy, asthma, or posttympanostomy tube otorrhea. CONCLUSIONS: Pepsin is detectable in the middle ear cleft of 20% of pediatric patients with OM undergoing tympanostomy tube placement, compared with 1.4% of controls; recovery of pepsin in the middle ear space of pediatric patients with OM is an independent risk factor for OM. Patients under 1 year of age have a higher incidence of purulent effusions and pepsin-positive effusions. Clinical history of GERD, allergy, and asthma do not seem to correlate with evidence of EORD reaching the middle ear cleft. The presence of pepsin in the middle ear space at the time of tube placement does not seem to predispose to posttympanostomy tube otorrhea.