The Journal of Pediatrics
Volume 155, Issue 4 , Pages 464-465, October 2009

Patience Is a Virtue in the Management of Gastroesophageal Reflux

  • Reese H. Clark, MD

      Affiliations

    • Corresponding Author InformationReprint requests: Reese H. Clark, MD, The Pediatrix Center for Research and Education, Pediatrix Medical Group, 1301 Concord Terrace, Sunrise, FL 33323-2825.

The Pediatrix Center for Research and Education, Pediatrix Medical Group, Inc., Sunrise, Florida

Pediatrix Medical Group, Greenville Memorial Hospital, Greenville, South Carolina

The Pediatrix Center for Research and Education, Pediatrix Medical Group, Inc., Sunrise, Florida

Article Outline

GER, Gastroesophageal reflux, GERD, Gastroesophageal reflux disease, NICU, Neonatal intensive care unit

 

See related article, p 516

In this issue of The Journal, Wheatley et al report the results of a randomized control trial evaluating whether metoclopramide and ranitidine reduce bradycardia attributed to clinically suspected gastroesophageal reflux (GER).1 The conclusions of the study are limited by the sample size (n = 18 neonates). Although the study is under-powered to provide definitive results, this work supports the growing literature that indicates that current medications used to treat reflux do not reduce apnea and bradycardia events or improve the outcomes of preterm infants and may be associated with significant adverse events.2, 3, 4

Our first challenge in evaluating a premature infant with suspected GER is making the correct diagnosis. Determining which premature infant has clinically significant GER (often called gastroesophageal reflux disease [GERD]5) and determining the relationship between GERD and associated morbidity is difficult. For example, it remains unclear whether there is a temporal relationship between apnea of prematurity and GER.6, 7, 8, 9, 10, 11 Our second clinical challenge is defining a safe treatment plan. Two reviews have concluded that there is insufficient evidence to justify the current widespread use of medications (eg, metoclopramide and H2-blockers) to treat GER in infants with symptoms such as recurrent apnea.2, 5 Both reviews offer alternative strategies (eg, positioning) and issue an urgent call for studies that define criteria for identifying premature infants with GERD and how best to treat them. In 2009, there is little new science that changes this message.

Our final and most pressing challenge is to determine how potentially unsafe clinical processes and practices find their way into common place (standard of care) clinical practice.12 Clinical studies demonstrate that the pharmacological management of GER in premature infants is associated with serious adverse events. Hibbs and Lorch in their review of clinical studies of metoclopramide found 4 studies that demonstrated adverse effects of therapy, including irritability, dystonic reactions, drowsiness, oculogyric crisis, emesis, and apnea.2 The US Food and Drug Aadministration recently notified healthcare professionals “that manufacturers of metoclopramide must add a boxed warning to their drug labels about the risk of its long-term or high-dose use—Chronic use of metoclopramide has been linked to tardive dyskinesia, which may include involuntary and repetitive movements of the body, even after the drugs are no longer taken. These symptoms are rarely reversible and there is no known treatment.”13

H2-blocker therapy is also associated with an increased risk of necrotizing enterocolitis in very low birth weight infants and may increase the risk of sepsis.14

Clinical studies demonstrate that the use of GER medications in premature neonates is common and often long term.4, 15 Malcolm et al reported that 24.8% of extremely low birth weight infants were discharged from the hospital with medications to treat GER and that center variations in the use of GER medications at the time of discharge in select populations (those preterm infants being discharged at >42 weeks post menstrual age) varied from 2% to 90%.4 This degree of variation implies a serious lack of evidence to guide practice or ignorance of evidence that would suggest one extreme or the other—use or non use. These extremes (2% versus 90%) cannot be justified in any other way.

At Pediatrix Medical Group, we have an ongoing clinical improvement effort to reduce the use of GER medications. We have had some success; reducing the metoclopramide use rate from 10.4% of neonates admitted to the neonatal intensive care unit (NICU) in 200415 to 5.4% in 2008 (unpublished data from Pediatrix Medical Group Clinical Data Warehouse). However, the 2008 estimated rate of approximately 5.4% of neonates admitted to the NICU means that thousands of neonates were exposed to metoclopramide. When one considers the degree of variation in the management of this ill-defined disease and the potential risk of the drugs being used to treat this disease, it is essential that we take pause and ask, “why are we left with so little evidence to guide practice?” We (the neonatal health care community—doctors, nurses, respiratory therapists, dieticians, etc) must all accept some degree of responsibility and be much more willing to design and support clinical trials.

Although there are serious limitations to the study reported by Wheatley et al, the underlying message appears to be valid. Trials designed to find efficacy (or superiority) must define the degree of difference in the outcome that is clinically meaningful. A study sample size is calculated with the hypothesized event rate (or mean value) and the expected degree of change attributable to the intervention. In the study reported by Wheatley et al, a somewhat arbitrary original sample size of 34 was calculated to detect a mean decrease in bradycardia episodes of 2 per day between the placebo and drug periods with 80% power by using a SD of 4 per day for the difference. Because of slower than anticipated enrollment and a planned replacement of the NICU telemetry system, the study plan was revised to enroll as many infants as feasible before March 2008.1 So the final sample size ended up being one of convenience.

Because of this limitation, however, the authors appropriately state their results by noting that “the number of bradycardic episodes was lower in the placebo period(s) than during the drug period(s).” The authors also correctly point out that this may represent a type 1 (false finding of difference) error. However, the finding was unexpected and should not be disregarded. It took 3.5 years for the authors to show that a therapy that they hypothesized would help appears to make things worse. Therefore this outcome should be carefully considered. In the context of the current evidence,1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 16, 17 neonatologists should cease using GER medications outside the context of clinical trials.

Another important observation made by the authors was that the passage of time alone led to a much more dramatic decline in the frequency of bradycardic events than the study intervention. Thus, for this clinical problem it can be extrapolated that patience is an effective “treatment” that allows us to avoid exposing premature infants to unnecessary and potentially harmful pharmacological interventions. Time and maturation are a cure for many of the diseases associated with prematurity. When we remain patient and avoid the call to “do something” for which we presently have no effective pharmacological treatment, the situation will improve by itself. “Primum non nocere” is never more clearly needed than in use of GER medications. In neonatal medicine, the discipline of patience is a virtue, and the unsupported use of GER medications in the NICU is a dangerous vice.

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References 

  1. Wheatley E, Kennedy KA. Cross-over trial of treatment for bradycardia attributed to gastroesophageal reflux in preterm infants. J Pediatr. 2009;155:516–521
  2. Hibbs AM, Lorch SA. Metoclopramide for the treatment of gastroesophageal reflux disease in infants: a systematic review. Pediatrics. 2006;118:746–752
  3. Slocum C, Hibbs AM, Martin RJ, Orenstein SR. Infant apnea and gastroesophageal reflux: a critical review and framework for further investigation. Curr Gastroenterol Rep. 2007;9:219–224
  4. Malcolm WF, Gantz M, Martin RJ, Goldstein RF, Goldberg RN, Cotten CM. Use of medications for gastroesophageal reflux at discharge among extremely low birth weight infants. Pediatrics. 2008;121:22–27
  5. Poets CF. Gastroesophageal reflux: a critical review of its role in preterm infants. Pediatrics. 2004;113:e128–e132
  6. Peter CS, Sprodowski N, Bohnhorst B, Silny J, Poets CF. Gastroesophageal reflux and apnea of prematurity: no temporal relationship. Pediatrics. 2002;109:8–11
  7. Di Fiore JM, Arko M, Whitehouse M, Kimball A, Martin RJ. Apnea is not prolonged by acid gastroesophageal reflux in preterm infants. Pediatrics. 2005;116:1059–1063
  8. Martin RJ, Hibbs AM. Diagnosing gastroesophageal reflux in preterm infants. Pediatrics. 2006;118:793–794
  9. Magista AM, Indrio F, Baldassarre M, Bucci N, Menolascina A, Mautone A, et al. Multichannel intraluminal impedance to detect relationship between gastroesophageal reflux and apnoea of prematurity. Dig Liver Dis. 2007;39:216–221
  10. Corvaglia L, Zama D, Gualdi S, Ferlini M, Aceti A, Faldella G. Gastroesophageal reflux increases the number of apneas in very preterm infants. Arch Dis Child Fetal Neonatal Ed. 2008;In press
  11. Slocum C, Arko M, Di FJ, Martin RJ, Hibbs AM. Apnea, bradycardia and desaturation in preterm infants before and after feeding. J Perinatol. 2009;29:209–212
  12. Jobe AH. Too many unvalidated new therapies to prevent chronic lung disease in preterm infants. J Pediatr. 1998;132:200–202
  13. FDA. Available at: http://www.fda.gov/medwatch/safety/2009/safety09.htm#Metoclopramide. Accessed June 8, 2009.
  14. Guillet R, Stoll BJ, Cotten 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–e142
  15. Clark RH, Bloom BT, Spitzer AR, Gerstmann DR. Reported medication use in the neonatal intensive care unit: data from a large national data set. Pediatrics. 2006;117:1979–1987
  16. Martin RJ, Di Fiore JM, Hibbs AM. Gastroesophageal reflux in preterm infants: is positioning the answer?. J Pediatr. 2007;151:560–561
  17. Peter CS, Sprodowski N, Ahlborn V, Wiechers C, Schlaud M, Silny J, et al. Inter- and intraobserver agreement for gastroesophageal reflux detection in infants using multiple intraluminal impedance. Biol Neonate. 2004;85:11–14

PII: S0022-3476(09)00495-8

doi:10.1016/j.jpeds.2009.05.014

Refers to article:

  • Cross-Over Trial of Treatment for Bradycardia Attributed to Gastroesophageal Reflux in Preterm Infants , 22 June 2009

    Eva Wheatley, Kathleen A. Kennedy
    The Journal of Pediatrics October 2009 (Vol. 155, Issue 4, Pages 516-521.e1)

The Journal of Pediatrics
Volume 155, Issue 4 , Pages 464-465, October 2009

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