Therapy with gastric acidity inhibitors increases the risk of acute gastroenteritis and community-acquired pneumonia in children.

Department of Pediatrics, University Federico II of Naples, Naples, Italy. berni@unina.it

OBJECTIVE: Gastric acidity (GA) inhibitors, including histamine-2 receptor antagonists (H2 blockers) and proton pump inhibitors (PPIs), are the mainstay of gastroesophageal reflux disease (GERD) treatment. A prolonged GA inhibitor-induced hypochlorhydria has been suggested as a risk factor for severe gastrointestinal infections. In addition, a number of papers and a meta-analysis have shown an increased risk of pneumonia in H2-blocker-treated intensive care patients. More recently, an increased risk of community-acquired pneumonia associated with GA inhibitor treatment has been reported in a large cohort of adult patients. These findings are particularly relevant to pediatricians today because so many children receive some sort of GA-blocking agent to treat GERD. To test the hypothesis that GA suppression could be associated with an increased risk of acute gastroenteritis and pneumonia in children treated with GA inhibitors, we conducted a multicenter, prospective study. METHODS: The study was performed by expert pediatric gastroenterologists from 4 pediatric gastroenterology centers. Children (aged 4-36 months) consecutively referred for common GERD-related symptoms (for example, regurgitation and vomiting, feeding problems, effortless vomiting, choking), from December 2003 to March 2004, were considered eligible for the study. Exclusion criteria were a history of GA inhibitors therapy in the previous 4 months, Helicobacter pylori infection, diabetes, chronic lung or heart diseases, cystic fibrosis, immunodeficiency, food allergy, congenital motility gastrointestinal disorders, neuromuscular diseases, or malnutrition. Control subjects were recruited from healthy children visiting the centers for routine examinations. The diagnosis of GERD was confirmed in all patients by standard criteria. GA inhibitors (10 mg/kg ranitidine per day in 50 children or 1 mg/kg omeprazole per day in 50 children) were prescribed by the physicians for 2 months. All enrolled children were evaluated during a 4-month follow-up. The end point was the number of patients presenting with acute gastroenteritis or community-acquired pneumonia during a 4-month follow-up study period. RESULTS: We obtained data in 186 subjects: 95 healthy controls and 91 GA-inhibitor users (47 on ranitidine and 44 on omeprazole). The 2 groups were comparable for age, gender, weight, length, and incidence of acute gastroenteritis and pneumonia in the 4 months before enrollment. Rate of subjects presenting with acute gastroenteritis and community-acquired pneumonia was significantly increased in patients treated with GA inhibitors compared with healthy controls during the 4-month follow-up period. In the GA inhibitor-treated group, the rate of subjects presenting with acute gastroenteritis and community-acquired pneumonia was increased when comparing the 4 months before and after enrollment. No differences were observed between H2 blocker and PPI users in acute gastroenteritis and pneumonia incidence in the previous 4 months and during the follow-up period. On the contrary, in healthy controls, the incidence of acute gastroenteritis and pneumonia remained stable. CONCLUSIONS: This is the first prospective study performed in pediatric patients showing that the use of GA inhibitors was associated with an increased risk of acute gastroenteritis and community-acquired pneumonia in GERD-affected children. It could be interesting to underline that we observed an increased incidence of intestinal and respiratory infection in otherwise healthy children taking GA inhibitors for GERD treatment. On the contrary, the majority of the previous data showed that the patients most at risk for pneumonia were those with significant comorbid illnesses such as diabetes or immunodeficiency, and this points to the importance of GA suppression as a major risk factor for infections. In addition, this effect seems to be sustained even after the end of therapy. The results of our study are attributable to many factors, including direct inhibitory effect of GA inhibitors on leukocyte functions and qualitative and quantitative gastrointestinal microflora modification. Additional studies are necessary to investigate the mechanisms of the increased risk of infections in children treated with GA inhibitors, and prophylactic measures could be considered in preventing them.

PMID: 16651285

1: J Perinat Med. 2007;35(2):147-50. Links

Ranitidine and late-onset sepsis in the neonatal intensive care unit.

Bianconi S, Gudavalli M, Sutija VG, Lopez AL, Barillas-Arias L, Ron N.

Department of Pediatrics, New York Methodist Hospital, Brooklyn, NY 11215, USA.

AIMS: The objective of the study was to examine the effect of ranitidine on the incidence of late onset sepsis. METHODS: This study was based on information extracted from charts of 569 infants admitted to the neonatal intensive care unit (NICU) from July 2003 to July 2005. All infants admitted for seven or more days were included. Late-onset neonatal sepsis was defined as a positive blood culture with clinical signs of sepsis after seven days of life. Outcome measures included the use of ranitidine, type of infection and infectious agent, birth weight gestational age, and type of care in the NICU. RESULTS: Of the 569 infants admitted, 53 (9.3%) were treated with ranitidine. Of 74 infants who developed late-onset sepsis, 23 infants received ranitidine and 51 did not. Infants receiving ranitidine were at 7-times greater risk of late-onset sepsis (OR 6.99; 95% CI: 3.78-12.94; P<0.0001). The birth weights and gestational ages of infants with sepsis receiving ranitidine and those not receiving ranitidine were comparable, P=0.59. CONCLUSION: The use of ranitidine in infants admitted to the NICU elevates the risk of late-onset sepsis. The pathological mechanisms need to be further studied. The safety of widespread use of ranitidine in neonates is controversial.

PMID: 17302510 [PubMed – indexed for MEDLINE]

1: Acta Paediatr. 2006 Feb;95(2):176-81. Links

Oral ranitidine and duration of gastric pH >4.0 in infants with persisting reflux symptoms.

Salvatore S, Hauser B, Salvatoni A, Vandenplas Y.

Clinica Pediatrica di Varese, Università dell’Insubria, Varese, Italy.

BACKGROUND: Ranitidine is a drug commonly used in pathological gastro-oesophageal reflux (GOR) in infants. Non-responsiveness has been reported. Data regarding the effect of ranitidine on oesophageal acid exposure and reduction of gastric acid secretion are limited in this age group. OBJECTIVE: To evaluate oesophageal acid exposure, reduction of gastric acid secretion and histology of oesophageal biopsies in infants who clinically do not respond to oral ranitidine. PATIENTS AND DESIGN: 103 infants (mean age 3.3 +/- 1.8 mo) with persisting symptoms of reflux despite administration of ranitidine, prescribed previously by a referring physician, at a mean (SD) dose of 9.4 (+/- 3.3) mg/kg/d for at least 2 wk (mean 30 d), were submitted to a 24-h pH study and oesophageal biopsy (90/103 patients). RESULTS: Histological oesophagitis was present in 21/90 (23%). The oesophageal reflux index (RI) was >5% and >10% in 21/103 (20%) and 6/103 (6%) infants, respectively. Gastric pH was >4.0 during <50%, >50%, >75% and >90% of the duration of pH monitoring in 33/103 (32%), 70/103 (68%), 22/103 (21%) and 7/103 (7%), respectively. By simple regression analysis, the dosage of ranitidine correlated with the oesophageal RI (r = 0.21; p = 0.05), but not with the duration of time gastric pH was >4.0 (r = 0.09; p = 0.39). Histological oesophagitis did not correlate with ranitidine dosage, duration of treatment, duration gastric pH was >4.0 and oesophageal reflux index. CONCLUSION: Some infants presenting with symptoms assumed to be GOR and acid related fail to respond to acid suppression with ranitidine, either because they need better acid suppression or because the symptoms are not acid related.

 

1: J Paediatr Child Health. 2006 Jan-Feb;42(1-2):49-58. Links

Effect of antireflux medication, placebo and infant mental health intervention on persistent crying: a randomized clinical trial.

Jordan B, Heine RG, Meehan M, Catto-Smith AG, Lubitz L.

Mental Health Service, Royal Children’s Hospital, Melbourne, Victoria, Australia. brigid.jordan@rch.org.au

OBJECTIVE: To assess the effect of medical antireflux treatment, and of an infant mental health consultation (IMHC), on persistent crying in infants and maternal distress. METHODS: Infants under 9 months of age with persistent crying, and their mothers, were enrolled in a randomized placebo-controlled trial. At enrollment, a questionnaire on demographic and clinical details was completed by mothers, and maternal distress was measured (Experience of Motherhood Questionnaire; EMQ). Oesophageal 24-h pH monitoring was performed in all infants on day 2. At week 4, the cry chart and EMQ were repeated in conjunction with a final interview. RESULTS: One hundred and three infants (56 under 3 months of age; 55 male) who were randomized to active medication (ranitidine plus cisapride; n = 34), placebo (n = 29) or IMHC (n = 40) completed the trial. There was a significant reduction in crying duration from baseline to week 4 (253 +/- 96.5 min vs 159 +/- 92.3 min per 24 h; P < 0.001), without differences between treatment groups (AVOVA: F = 0.75; P = 0.48). There was a modest improvement in EMQ scores from 44.9 +/- 8.6 at day 1 to 42.8 +/- 9.4 at week 4; P = 0.006. The improvement in maternal stress was similar in all treatment groups (Kruskal-Wallis chi2 = 0.354; P = 0.84), but subsequent admission to a mother-infant unit was significantly less frequent in the IMHC group (P < 0.05). CONCLUSION: Antireflux medications and IMHC were not superior to placebo in treating infants with persistent crying. Although the reduction in maternal distress was similar in all treatment groups, the individualized IMHC reduced the need for subsequent admission to a mother-infant unit.

 

Other Relevant Studies performed on Adults

 

Comment in:

CMAJ. 2005 Feb 1;172(3):331.

JAMA. 2004 Oct 27;292(16):2012-3.

JAMA. 2005 Feb 16;293(7):795-6; author reply 796.

Nat Clin Pract Gastroenterol Hepatol. 2005 Feb;2(2):72-3.

Risk of community-acquired pneumonia and use of gastric acid-suppressive drugs.

Department of Gastroenterology, University Medical Center St. Radboud, Nijmegen, The Netherlands. R.Laheij@mdl.umcn.nl

CONTEXT: Reduction of gastric acid secretion by acid-suppressive therapy allows pathogen colonization from the upper gastrointestinal tract. The bacteria and viruses in the contaminated stomach have been identified as species from the oral cavity. OBJECTIVE: To examine the association between the use of acid-suppressive drugs and occurrence of community-acquired pneumonia. DESIGN, SETTING, AND PARTICIPANTS: Incident acid-suppressive drug users with at least 1 year of valid database history were identified from the Integrated Primary Care Information database between January 1, 1995, and December 31, 2002. Incidence rates for pneumonia were calculated for unexposed and exposed individuals. To reduce confounding by indication, a case-control analysis was conducted nested in a cohort of incident users of acid-suppressive drugs. Cases were all individuals with incident pneumonia during or after stopping use of acid-suppressive drugs. Up to 10 controls were matched to each case for practice, year of birth, sex, and index date. Conditional logistic regression was used to compare the risk of community-acquired pneumonia between use of proton pump inhibitors (PPIs) and H2-receptor antagonists. MAIN OUTCOME MEASURE: Community-acquired pneumonia defined as certain (proven by radiography or sputum culture) or probable (clinical symptoms consistent with pneumonia). RESULTS: The study population comprised 364,683 individuals who developed 5551 first occurrences of pneumonia during follow-up. The incidence rates of pneumonia in non-acid-suppressive drug users and acid-suppressive drug users were 0.6 and 2.45 per 100 person-years, respectively. The adjusted relative risk for pneumonia among persons currently using PPIs compared with those who stopped using PPIs was 1.89 (95% confidence interval, 1.36-2.62). Current users of H2-receptor antagonists had a 1.63-fold increased risk of pneumonia (95% confidence interval, 1.07-2.48) compared with those who stopped use. For current PPI users, a significant positive dose-response relationship was observed. For H2-receptor antagonist users, the variation in dose was restricted. CONCLUSION: Current use of gastric acid-suppressive therapy was associated with an increased risk of community-acquired pneumonia.

PMID: 15507580 [PubMed – indexed for MEDLINE]

1: Arch Intern Med. 2007 May 14;167(9):950-5. Links

Comment in:

Arch Intern Med. 2008 May 26;168(10):1118-9; author reply 1119.

Use of proton pump inhibitors and the risk of community-acquired pneumonia: a population-based case-control study.

Gulmez SE, Holm A, Frederiksen H, Jensen TG, Pedersen C, Hallas J.

Research Unit of Clinical Pharmacology, Faculty of Health Sciences, Institute of Public Health, University of Southern Denmark, Odense, Denmark. egulmez@health.sdu.dk

BACKGROUND: Recently, the use of proton pump inhibitors (PPIs) has been associated with an increased risk of pneumonia. We aimed to confirm this association and to identify the risk factors. METHODS: We conducted a population-based case-control study using data from the County of Funen, Denmark. Cases (n=7642) were defined as all patients with a first-discharge diagnosis of community-acquired pneumonia from a hospital during 2000 through 2004. We also selected 34 176 control subjects, who were frequency matched to the cases by age and sex. Data on the use of PPIs and other drugs, on microbiological samples, on x-ray examination findings, and on comorbid conditions were extracted from local registries. Confounders were controlled by logistic regression. RESULTS: The adjusted odds ratio (OR) associating current use of PPIs with community-acquired pneumonia was 1.5 (95% confidence interval [CI], 1.3-1.7). No association was found with histamine(2)-receptor antagonists (OR, 1.10; 95% CI, 0.8-1.3) or with past use of PPIs (OR, 1.2; 95% CI, 0.9-1.6). Recent initiation of treatment with PPIs (0-7 days before index date) showed a particularly strong association with community-acquired pneumonia (OR, 5.0; 95% 2.1-11.7), while the risk decreased with treatment that was started a long time ago (OR, 1.3; 95% CI, 1.2-1.4). Subgroup analyses revealed high ORs for users younger than 40 years (OR, 2.3; 95% CI, 1.3-4.0). No dose-response effect could be demonstrated. CONCLUSION: The use of PPIs, especially when recently begun, is associated with an increased risk of community-acquired pneumonia.

1: Eur J Surg Suppl. 1998;(583):6-13. Links

Gastro-oesophageal reflux symptoms–clinical findings and effect of ranitidine treatment.

Hallerbäck B, Glise H, Johansson B, Rosseland AR, Hultén S, Carling L, Knapstad LJ.

Department of Surgery, NAL, Trollhättan, Sweden.

BACKGROUND: This study was performed to study the demography, effect of treatment with ranitidine and relapse pattern in patients with reflux symptoms. METHODS: Patients with reflux symptoms were examined by endoscopy and included in a double-blind, comparative trial of placebo and ranitidine 150 mg b.i.d. for two weeks. At two weeks satisfied patients continued the same treatment. Non-satisfied patients were randomised to ranitidine 150 mg b.i.d. or q.i.d for another two weeks. After four weeks medication was stopped and satisfied patients were followed for 24 weeks. No further endoscopy was performed. RESULTS: Four hundred and twenty-seven patients were randomised. At two weeks there was no significant difference between placebo and ranitidine, regarding the proportion of patients with complete relief from symptoms or satisfied with treatment. Ranitidine was superior to placebo in improving symptoms at two weeks. Ranitidine, 150 mg q.i.d. offered no additional advantage in weeks three to four over prolonging treatment with 150 mg b.i.d. after the first two weeks. Patients with oesophagitis at inclusion relapsed more than those with symptoms only, 67% compared with 52%, (p = 0.013). CONCLUSIONS: The effect of ranitidine was marginal compared to placebo. The relapse rate was high after treatment stopped.

Acid-suppressive medication use and the risk for hospital-acquired pneumonia.

Division of General Medicine and Primary Care, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Boston, MA 02215, USA. sherzig@bidmc.harvard.edu

CONTEXT: The use of acid-suppressive medication has been steadily increasing, particularly in the inpatient setting, despite lack of an accepted indication in the majority of these patients. OBJECTIVE: To examine the association between acid-suppressive medication and hospital-acquired pneumonia. DESIGN, SETTING, AND PATIENTS: Prospective pharmacoepidemiologic cohort study. All patients who were admitted to a large, urban, academic medical center in Boston, Massachusetts, from January 2004 through December 2007; at least 18 years of age; and hospitalized for 3 or more days were eligible for inclusion. Admissions with time spent in the intensive care unit were excluded. Acid-suppressive medication use was defined as any order for a proton-pump inhibitor or histamine(2) receptor antagonist. Traditional and propensity-matched multivariable logistic regression were used to control for confounders. MAIN OUTCOME MEASURE: Incidence of hospital-acquired pneumonia, defined via codes from the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM), in patients exposed and unexposed to acid-suppressive medication. RESULTS: The final cohort comprised 63 878 admissions. Acid-suppressive medication was ordered in 52% of admissions and hospital-acquired pneumonia occurred in 2219 admissions (3.5%). The unadjusted incidence of hospital-acquired pneumonia was higher in the group exposed to acid-suppressive medication than in the unexposed group (4.9% vs 2.0%; odds ratio [OR], 2.6; 95% confidence interval [CI], 2.3-2.8). Using multivariable logistic regression, the adjusted OR of hospital-acquired pneumonia in the group exposed to acid-suppressive medication was 1.3 (95% CI, 1.1-1.4). The matched propensity-score analyses yielded identical results. The association was significant for proton-pump inhibitors (OR, 1.3; 95% CI, 1.1-1.4) but not for histamine(2) receptor antagonists (OR, 1.2; 95% CI, 0.98-1.4). CONCLUSIONS: In this large, hospital-based pharmacoepidemiologic cohort, acid-suppressive medication use was associated with 30% increased odds of hospital-acquired pneumonia. In subset analyses, statistically significant risk was demonstrated only for proton-pump inhibitor use.

PMID: 19470989 [PubMed – indexed for MEDLINE]