title: Incompatibility - Neonatal Intensive Care Drug Manual
text: Treatment of gastroesophageal reflux disease (GORD)
  NICE Guidelines1
  1. Do not offer acid-suppressing drugs, such as proton pump inhibitors (PPIs) or H2 receptor antagonists (H2RAs), to treat overt regurgitation in infants and children occurring as an isolated symptom.
  2. Consider a 4-week trial of a PPI or H2RA for those who are unable to tell you about their symptoms (for example, infants and young children, and those with a neurodisability associated with expressive communication difficulties) who have overt regurgitation with 1 or more of the following: Unexplained feeding difficulties (for example refusing feeds, gagging or choking), distressed behaviour, faltering growth.
  3. Consider a 4-week trial of a PPI or H2RA for children and young people with persistent heartburn, retrosternal or epigastric pain.
  4. Assess the response to the 4-week trial of the PPI or H2RA, and consider referral to a specialist for possible endoscopy if the symptoms do not resolve or recur after stopping the treatment.
  5. When choosing between PPIs and H2RAs, take into account: the availability of age-appropriate preparations, the preference of the parent (or carer), child or young person (as appropriate) and local procurement costs.
  6. Offer PPI or H2RA treatment to infants, children and young people with endoscopy-proven reflux oesophagitis and consider repeat endoscopic examinations as necessary to guide subsequent treatment.
  7. Do not offer metoclopramide, domperidone or erythromycin to treat GOR or GORD without seeking specialist advice and taking into account their potential to cause adverse events.
  ESPGHAN and NASPGHAN Guidelines2
  For healing of erosive esophagitis and relief of GERD symptoms, PPIs are superior to H2RAs. Both medications are superior to placebo. Administration of long-term acid suppression without a diagnosis is inadvisable. When acid suppression is required, the smallest effective dose should be used. Most patients require only once-daily PPI; routine use of twice-daily dose is not indicated. No PPI has been approved for use in infants < 1 year of age and there are special concerns pertaining to prescription of PPIs in infants, as described in the Guideline.
  H2RAs exhibit tachyphylaxis or tolerance but PPIs do not. Tachyphylaxis is a drawback to chronic use. H2RAs have a rapid onset of action and, like buffering agents, are useful for on-demand treatment.
  Post-operative prophylaxis in congenital oesophageal atresia and tracheoesophageal fistula
  In a systematic review by Shawyer et al,3 of 25 articles (1,663 patients for analysis), most were single center studies (92 %) and retrospective (76 %); there were no randomised controlld trials. The quality of literature regarding anti-reflux medication for GER post EA-TEF repair is poor.
  Treatment of bradycardias attributed to GOR in preterm infants
  Wheatley et al,12 in a randomised, controlled, masked cross-over study, compared metoclopramide, 0.2 mg/kg/dose q 6 hours, and ranitidine, 2 mg/kg/dose q 8 hours, with saline placebo. Each infant served as his own control. Preterm infants having > 3 bradycardic episodes per 2 days were eligible if the clinician intended to begin anti-reflux medications for bradycardia attributed to GER. Anti-reflux medications did not reduce, and may have increased, bradycardia episodes in preterm infants with GER. Ranitidine is not recommended for this indication.
  Prophylactic therapy to reduce stress ulcers/GI haemorrhage
  In a RCT by Kuusela et al,15 ranitidine was given prophylactically after birth for 4 days to 48 infants mechanically ventilated and treated in the neonatal ICU. The gastric mucosa was both visually and histologically evaluated after 3 to 6 days. In the 23 infants prophylactically treated with ranitidine, the gastric mucosa was visually classified as normal in 14 (61%) infants as compared with five (20%) of 25 controls (p < 0.004). Histological lesions showed parallel results(57% vs. 16%, p < 0.004). Eight gastric ulcers were diagnosed endoscopically in the control group vs. none in the treatment group. The ulcers were all clinically 'silent' at the time of endoscopy. According to logistic regression modelling, the relative risk for gastric mucosal lesions in infants receiving prophylactic ranitidine was 0.03 (95% confidence interval 0.003 to 0.178).
  Pourarian et al,16 in another RCT, evaluated the effects of short-term prophylactic ranitidine in controlling gastric pH and prevention of GI bleeding in 80 neonates. They were randomly divided into case and control groups and their gastric pH, stool occult blood and macroscopic bleeding were determined. Intravenous ranitidine was administrated (5 mg/kg/day) for four days in the case group. Their gastric pH was measured before, one hour and two or three days after injection and prophylactic treatment was considered successful if gastric pH was > 4. Upper GI bleeding was observed in 41% of all patients. After ranitidine, there was a significant increase in gastric pH which was accompanied by a reduction in the frequency of upper GI bleeding. Furthermore, no significant changes were noted in the gastric pH of control group.
  Pharmacokinetics
  Preterm infants need significantly smaller doses of intravenous ranitidine than term neonates to keep their intraluminal gastric pH over 4. The required optimal dose of intravenous ranitidine for preterm infants is 0.5 mg/kg/body weight twice a day and that for term infants 1.5 mg/kg body weight three times a day.20
  Ranitidine (2 mg/kg per dose orally) reduced the time that gastric pH was < 4.0 by 44% when given twice daily and by 90% when given 3 times per day.21
  Target serum ranitidine concentrations effective in reducing gastric acid output probably vary with the gestational and postnatal age of the patient and with the underlying medical disorder (for example, acute stress). Concentrations between 40 and 60 ng/mL were found to suppress unstimulated gastric secretion by 90% in children aged up to 16 years with peptic ulcer disease; Eddlestone et al found the gastric pH to be maintained above 3–5 by serum concentrations greater than 200 ng/mL. Concentrations greater than 100 and 200 ng/mL could be expected for at least 12 hours after a single intravenous bolus of 1.6 and 3.3 mg/kg respectively; the same average concentration range could be obtained at steady state by continuous intravenous infusion at a rate between 0 03–0.06 mg/kg/hour.22
  Safety
  More et al,18 performed a systematic review on the safety of H2-blockers in preterm infants. One case-control and one prospective cohort study (n = 11,346), both evaluating H2-blockers as IGA (inhibitors of gastric acid), were included. Meta-analysis showed a significant association between NEC and IGA (odds ratio [OR]: 1.78, 95% confidence interval [CI]: 1.4; 2.27, p < 0.00001). The prospective cohort study found a higher incidence of infection (sepsis, pneumonia, urinary tract infection) with IGA (37.4% versus 9.8%, OR: 5.5, 95% CI: 2.9 to 10.4, p < 0.001). Meta-analysis concluded that exposure to H2 receptor antagonists may be associated with increased risk of NEC and infections in preterm infants.(LOE ?1 or II, GOR B)
  Terrin G, et al,9 in a multicentre, prospective observational study involving 274 VLBW newborns with birth weight between 401 and 1500 g or gestational age between 24 and 32 weeks showed that risk of NEC was 6.6-fold higher in ranitidine-treated VLBW infants than in control subjects. Mortality rate was also significantly higher in newborns receiving ranitidine (9.9% vs 1.6%, P = 0.003). (LOE II, GOR B) There were other retrospective case series reporting similar increases in NEC.8,10
  Saiman et al, in a multicentre, prospective observational study involving 2157 infants in 6 NICUs in Canada showed that H2 blockers was an independent risk factor for C. parapsilosis.14 (LOEII, GOR C)
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