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H2-Blockers are associated with necrotizing enterocolitis in very low birthweight infants
Translating Best Evidence Into Best Care EDITOR’S NOTE: Journals reviewed for this issue: Archives of Disease in Childhood, Archives of Pediatrics and Adolescent Medicine, British Medical Journal, Journal of the American Medical Association, The Journal of Pediatrics, The Lancet, New England Journal of Medicine, Pediatric Infectious Diseases Journal, and Pediatrics. Heidi Marleau, MLS, Ebling Library for the Health Sciences, University of Wisconsin, contributed to the review and selection of this month’s abstracts. —John G. Frohna, MD, MPH
H2-Blockers are associated with necrotizing enterocolitis in very low birthweight infants Terrin G, Passariello A, De Curtis M, Manguso F, Salvia G, Lega L, et al. Ranitidine is associated with infections, necrotizing enterocolitis, and fatal outcome in newborns. Pediatrics 2012;129:e40-e5. Question Among very low birth weight (VLBW) infants, is the use of ranitidine associated with an increased risk of infections, necrotizing enterocolitis (NEC), and fatal outcome? Design Multicenter, prospective observational study. Setting 4 neonatal intensive care units in Italy. Participants 274 VLBW infants with birth weight between 401 and 1500 g or gestational age between 24 and 32 weeks. Intervention Exposure, or not, to ranitidine. Outcomes The primary outcome was the rate of infectious diseases. Secondary outcomes included NEC, death, and length of hospital stay. Main Results In this population, 91 infants had taken ranitidine and 183 had not. The main clinical and demographic characteristics did not differ between the 2 groups. Thirtyfour (37.4%) of the 91 children exposed to ranitidine and 18 (9.8%) of the 183 not exposed to ranitidine had contracted infections (OR = 5.5, 95% CI, 2.9-10.4, P < .001, number needed to harm = 4). The risk of NEC was 6.6-fold higher in ranitidine-treated VLBW infants (95% CI, 1.7-25.0, P = .003) than in control subjects. Mortality rate was significantly higher in newborns receiving ranitidine (9.9% vs 1.6%, P = .003, number needed to harm = 12). Conclusions Ranitidine therapy is associated with an increased risk of infections, NEC, and fatal outcome in VLBW infants. Caution is advocated in the use of this drug in neonatal age. Commentary Gastroesophageal reflux (GER) is a common physiologic process in infants, and is even more prevalent in preterm infants. Most cases of infantile GER resolve by the age of 24 months. Despite this, the use of inhibitors of gastric acid secretion, including the H2-blocker ranitidine, is commonplace in many preterm infants to treat or as prophylaxis against suspected GER. Multiple observational studies have reported an association between the use of H2-blockers and neonatal sepsis and/or NEC.1-4 This makes sense as gastric acid is a major non-immunologic defense against ingested pathogens, and inhibition of gastric acid can allow pathogenic bacteria to proliferate in the gastroin168
testinal tract leading to bacteremia and infection. The study by Terrin et al is a prospective cohort study that evaluates this association. Unique to most cohort studies, a prospective sample size calculation was done, lending additional credibility to the study. The patient characteristics between the group exposed to ranitidine and the unexposed group are similar with regards to important risk factors for infection and NEC, including birth weight, gestational age, sex, Apgar scores, CRIB scores, persistent ductus arteriosus, duration of endotracheal intubation, and central vascular access duration. Many of these potentially confounding risk factors have not been accounted for in previous studies. Given the multiple studies showing an association between the use of H2blockers and neonatal sepsis and/or NEC, it is unlikely that a randomized controlled trial using H2-blockers in VLBW infants can be performed with equipoise present. As with many clinical decisions, the risks and benefits of acid blockers need to be weighed before they are used. There is no clear benefit of acid blockers in neonates, particularly in preterm neonates, although there continues to be perceived benefits among many subspecialists caring for neonates. As long as acid blockers continue to have perceived benefits in VLBW infants, many clinicians will continue to use them, believing the “benefits” outweigh the increased morbidity. The results from this prospective cohort study provides the most useful and current information regarding the potential risks of H2-blocker use in preterm neonates, and they should be used with care in this population. Jennifer Dalton, MD Robert Schumacher, MD University of Michigan Ann Arbor, Michigan
References 1. Beck-Sague CM, Azimi P, Fonseca SN, Baltimore RS, Powell DA, Bland LA, et al. Bloodstream infections in neonatal intensive care unit patients: results of a multicenter study. Pediatr Infect Dis J 1994; 13:1110-6. 2. Graham PL III, Begg MD, Larson E, Della-Latta P, Allen A, Saiman L. Risk factors for late onset gram-negative sepsis in low birth weight infants hospitalized in the neonatal intensive care unit. Pediatr Infect Dis J 2006;25: 113-7. 3. Guillet R, Stoll BJ, Cotton CM, Gantz M, McDonald S, Poole WK, et al. Association of H2-blocker therapy and higher incidence of necrotizing enterocolitis in very low birth weight infants. Pediatrics 2006;117:e137-42.
Vol. 161, No. 1 July 2012 4. Tijerina-Torres CY, Rodriguez-Balderrama I, Gallegos-Davila JA, et al. Incidence and risk factors associated with in-hospital neonatal sepsis. Rev Med Inst Mex Seguro Soc 2011;49:643-8.
Two cochlear impants are better than one Boons T, Brokx JPL, Frijns JHM, Peeraer L, Philips B, Vermeulen A, et al. Effect of pediatric bilateral cochlear implantation on language development. Arch Pediatr Adolesc Med 2012;166:28-34. Question Among prelingually deaf children, does bilateral cochlear implantation, compared with unilateral implantation, result in improved spoken language outcomes? Design Case-control, retrospective, cross-sectional, multicenter study. Setting Two Belgian and 3 Dutch cochlear implantation centers. Participants 25 children with 1 cochlear implant matched (on 10 auditory, child, and environmental factors) with 25 children with 2 cochlear implants. Both groups of children were selected from a retrospective sample of 288 children who underwent cochlear implantation before 5 years of age. Outcomes Performance on measures of spoken language comprehension and expression (Reynell Developmental Language Scales and Schlichting Expressive Language Test). In those children who had bilateral implants, the authors also evaluated the impact on language development based on the interval between the first and second implants. Main Results On the receptive language tests, children undergoing bilateral implantation performed significantly better than those undergoing unilateral implantation (mean difference [95% CI], 9.4 [0.3-18.6]) and expressive language tests (15.7 [5.9-25.4] and 9.7 [1.5-17.9]). Because the two groups were closely matched, the authors argue that the difference in performance mainly can be attributed to bilateral implantation. In addition, for those children with bilateral implants, a shorter interval between the implants was related to higher standard scores. Children undergoing 2 simultaneous cochlear implantations performed better on the expressive Word Development Test than did children undergoing 2 sequential cochlear implantations. Conclusions The use of bilateral cochlear implants is associated with better spoken language learning. The interval between the first and second implantation correlates negatively with language scores. On expressive language development, there is an advantage to simultaneous versus sequential implantation. Commentary Boons et al address the question, “Are two cochlear implants better than one?” The psychoacoustic literature is clear that normal hearing people and those with hearing aids do better listening with two ears than with one. Why? Binaural hearing allows localization of sound, an important factor in daily communication and safety. By identifying the talker, a listener is able to utilize speech reading, enhancing comprehension with facial expression, lip
position, breath taking, hand gestures, and body language. Listening with two ears also enhances speech recognition in background noise by taking advantage of the head shadow effect (a noise on one side of the skull is partially shielded from the opposite ear and the brain focuses attention to the cleaner signal) and binaural central speech processing. Boons et al provide compelling evidence that, like eye glasses supersede monocles, two cochlear implants are better than one. Thomas J. Balkany, MD, FACS, FAAP University of Miami Ear Institute Miami, Florida
Oral sucrose with facilitated tucking is effective pain control for preterm infants Cignacco EL, Sellam G, Stoffel L, Gerull R, Nelle M, Anand KJS, et al. Oral sucrose and “facilitated tucking” for repeated pain relief in preterms: a randomized controlled trial. Pediatrics 2012;129:299-308. Question Among preterm infants undergoing repeated heel sticks, is the combination of oral sucrose and facilitated tucking for comfort more effective at relieving pain than either intervention alone? Design Multicenter, randomized controlled trial. Setting 3 neonatal intensive care units (NICUs) in Switzerland. Participants 71 preterm infants between 24 and 32 weeks of gestation. Intervention Data were collected during the first 14 days of the infant’s NICU stay. Oral 20% sucrose (0.2 mL/kg) was administered 2 minutes prior to the procedure. For facilitated tucking (FT), the infant was held by placing a hand on his or her hands and feet and by positioning him/her in a flexed midline position while in either a side-lying, supine, or prone position. Three phases of 5 heel stick procedures were videotaped (baseline, heel stick, recovery) for each infant. Outcomes Pain responses were graded by videotape review according to the Bernese Pain Scale for Neonates (BPSN) by four independent, experienced NICU nurses blinded to whether the heel stick was being performed and the heel stick phase with high inter-rater reliability (Cronbach a: 0.900.95). The primary outcome was evaluation of pain response, including total pain response and pain response to each component phase of the heel stick procedure. The secondary outcome was evaluation of pain response based on gestation age groupings. Main Results Sucrose alone was significantly more effective than FT alone at relieving procedural pain (P < .002). FT in combination with oral sucrose seemed to have an added value in the recovery phase (P = .003) as compared with both treatment groups alone. There were no differences in pain responses across gestational age. 169
H2-Blockers are associated with necrotizing enterocolitis in very low birthweight infants Terrin G, Passariello A, De Curtis M, Manguso F, Salvia G, Lega L, et al. Ranitidine is associated with infections, necrotizing enterocolitis, and fatal outcome in newborns. Pediatrics 2012;129:e40-e5. Question Among very low birth weight (VLBW) infants, is the use of ranitidine associated with an increased risk of infections, necrotizing enterocolitis (NEC), and fatal outcome? Design Multicenter, prospective observational study. Setting 4 neonatal intensive care units in Italy. Participants 274 VLBW infants with birth weight between 401 and 1500 g or gestational age between 24 and 32 weeks. Intervention Exposure, or not, to ranitidine. Outcomes The primary outcome was the rate of infectious diseases. Secondary outcomes included NEC, death, and length of hospital stay. Main Results In this population, 91 infants had taken ranitidine and 183 had not. The main clinical and demographic characteristics did not differ between the 2 groups. Thirtyfour (37.4%) of the 91 children exposed to ranitidine and 18 (9.8%) of the 183 not exposed to ranitidine had contracted infections (OR = 5.5, 95% CI, 2.9-10.4, P < .001, number needed to harm = 4). The risk of NEC was 6.6-fold higher in ranitidine-treated VLBW infants (95% CI, 1.7-25.0, P = .003) than in control subjects. Mortality rate was significantly higher in newborns receiving ranitidine (9.9% vs 1.6%, P = .003, number needed to harm = 12). Conclusions Ranitidine therapy is associated with an increased risk of infections, NEC, and fatal outcome in VLBW infants. Caution is advocated in the use of this drug in neonatal age. Commentary Gastroesophageal reflux (GER) is a common physiologic process in infants, and is even more prevalent in preterm infants. Most cases of infantile GER resolve by the age of 24 months. Despite this, the use of inhibitors of gastric acid secretion, including the H2-blocker ranitidine, is commonplace in many preterm infants to treat or as prophylaxis against suspected GER. Multiple observational studies have reported an association between the use of H2-blockers and neonatal sepsis and/or NEC.1-4 This makes sense as gastric acid is a major non-immunologic defense against ingested pathogens, and inhibition of gastric acid can allow pathogenic bacteria to proliferate in the gastroin168
testinal tract leading to bacteremia and infection. The study by Terrin et al is a prospective cohort study that evaluates this association. Unique to most cohort studies, a prospective sample size calculation was done, lending additional credibility to the study. The patient characteristics between the group exposed to ranitidine and the unexposed group are similar with regards to important risk factors for infection and NEC, including birth weight, gestational age, sex, Apgar scores, CRIB scores, persistent ductus arteriosus, duration of endotracheal intubation, and central vascular access duration. Many of these potentially confounding risk factors have not been accounted for in previous studies. Given the multiple studies showing an association between the use of H2blockers and neonatal sepsis and/or NEC, it is unlikely that a randomized controlled trial using H2-blockers in VLBW infants can be performed with equipoise present. As with many clinical decisions, the risks and benefits of acid blockers need to be weighed before they are used. There is no clear benefit of acid blockers in neonates, particularly in preterm neonates, although there continues to be perceived benefits among many subspecialists caring for neonates. As long as acid blockers continue to have perceived benefits in VLBW infants, many clinicians will continue to use them, believing the “benefits” outweigh the increased morbidity. The results from this prospective cohort study provides the most useful and current information regarding the potential risks of H2-blocker use in preterm neonates, and they should be used with care in this population. Jennifer Dalton, MD Robert Schumacher, MD University of Michigan Ann Arbor, Michigan
References 1. Beck-Sague CM, Azimi P, Fonseca SN, Baltimore RS, Powell DA, Bland LA, et al. Bloodstream infections in neonatal intensive care unit patients: results of a multicenter study. Pediatr Infect Dis J 1994; 13:1110-6. 2. Graham PL III, Begg MD, Larson E, Della-Latta P, Allen A, Saiman L. Risk factors for late onset gram-negative sepsis in low birth weight infants hospitalized in the neonatal intensive care unit. Pediatr Infect Dis J 2006;25: 113-7. 3. Guillet R, Stoll BJ, Cotton CM, Gantz M, McDonald S, Poole WK, et al. Association of H2-blocker therapy and higher incidence of necrotizing enterocolitis in very low birth weight infants. Pediatrics 2006;117:e137-42.
Vol. 161, No. 1 July 2012 4. Tijerina-Torres CY, Rodriguez-Balderrama I, Gallegos-Davila JA, et al. Incidence and risk factors associated with in-hospital neonatal sepsis. Rev Med Inst Mex Seguro Soc 2011;49:643-8.
Two cochlear impants are better than one Boons T, Brokx JPL, Frijns JHM, Peeraer L, Philips B, Vermeulen A, et al. Effect of pediatric bilateral cochlear implantation on language development. Arch Pediatr Adolesc Med 2012;166:28-34. Question Among prelingually deaf children, does bilateral cochlear implantation, compared with unilateral implantation, result in improved spoken language outcomes? Design Case-control, retrospective, cross-sectional, multicenter study. Setting Two Belgian and 3 Dutch cochlear implantation centers. Participants 25 children with 1 cochlear implant matched (on 10 auditory, child, and environmental factors) with 25 children with 2 cochlear implants. Both groups of children were selected from a retrospective sample of 288 children who underwent cochlear implantation before 5 years of age. Outcomes Performance on measures of spoken language comprehension and expression (Reynell Developmental Language Scales and Schlichting Expressive Language Test). In those children who had bilateral implants, the authors also evaluated the impact on language development based on the interval between the first and second implants. Main Results On the receptive language tests, children undergoing bilateral implantation performed significantly better than those undergoing unilateral implantation (mean difference [95% CI], 9.4 [0.3-18.6]) and expressive language tests (15.7 [5.9-25.4] and 9.7 [1.5-17.9]). Because the two groups were closely matched, the authors argue that the difference in performance mainly can be attributed to bilateral implantation. In addition, for those children with bilateral implants, a shorter interval between the implants was related to higher standard scores. Children undergoing 2 simultaneous cochlear implantations performed better on the expressive Word Development Test than did children undergoing 2 sequential cochlear implantations. Conclusions The use of bilateral cochlear implants is associated with better spoken language learning. The interval between the first and second implantation correlates negatively with language scores. On expressive language development, there is an advantage to simultaneous versus sequential implantation. Commentary Boons et al address the question, “Are two cochlear implants better than one?” The psychoacoustic literature is clear that normal hearing people and those with hearing aids do better listening with two ears than with one. Why? Binaural hearing allows localization of sound, an important factor in daily communication and safety. By identifying the talker, a listener is able to utilize speech reading, enhancing comprehension with facial expression, lip
position, breath taking, hand gestures, and body language. Listening with two ears also enhances speech recognition in background noise by taking advantage of the head shadow effect (a noise on one side of the skull is partially shielded from the opposite ear and the brain focuses attention to the cleaner signal) and binaural central speech processing. Boons et al provide compelling evidence that, like eye glasses supersede monocles, two cochlear implants are better than one. Thomas J. Balkany, MD, FACS, FAAP University of Miami Ear Institute Miami, Florida
Oral sucrose with facilitated tucking is effective pain control for preterm infants Cignacco EL, Sellam G, Stoffel L, Gerull R, Nelle M, Anand KJS, et al. Oral sucrose and “facilitated tucking” for repeated pain relief in preterms: a randomized controlled trial. Pediatrics 2012;129:299-308. Question Among preterm infants undergoing repeated heel sticks, is the combination of oral sucrose and facilitated tucking for comfort more effective at relieving pain than either intervention alone? Design Multicenter, randomized controlled trial. Setting 3 neonatal intensive care units (NICUs) in Switzerland. Participants 71 preterm infants between 24 and 32 weeks of gestation. Intervention Data were collected during the first 14 days of the infant’s NICU stay. Oral 20% sucrose (0.2 mL/kg) was administered 2 minutes prior to the procedure. For facilitated tucking (FT), the infant was held by placing a hand on his or her hands and feet and by positioning him/her in a flexed midline position while in either a side-lying, supine, or prone position. Three phases of 5 heel stick procedures were videotaped (baseline, heel stick, recovery) for each infant. Outcomes Pain responses were graded by videotape review according to the Bernese Pain Scale for Neonates (BPSN) by four independent, experienced NICU nurses blinded to whether the heel stick was being performed and the heel stick phase with high inter-rater reliability (Cronbach a: 0.900.95). The primary outcome was evaluation of pain response, including total pain response and pain response to each component phase of the heel stick procedure. The secondary outcome was evaluation of pain response based on gestation age groupings. Main Results Sucrose alone was significantly more effective than FT alone at relieving procedural pain (P < .002). FT in combination with oral sucrose seemed to have an added value in the recovery phase (P = .003) as compared with both treatment groups alone. There were no differences in pain responses across gestational age. 169