Over-Use of GERD Medications in the NICU

Over-Use of GERD Medications in the NICU Anna Maria Hibbs, MD, MSCE annamaria.hibbs@cwru.edu

GERD Meds: What do nail polish and the laws of physics have to do with it?

Disclosures I have no conflicts of interest to disclose. I will discuss the off-label use of GERD medications in infants.

Objectives Why can t we stop using GERD Meds? General NICU-specific Review (lack of) evidence for efficacy and safety of common GERD medications.

Anti-Reflux Therapies in the NICU Among the most common drugs in the NICU 1 Anti-reflux meds at discharge in the NRN 2 24.8% of ELBW infants Large variation among centers (1) Clark 2006 (2) Malcolm 2008

GER: Passage of gastric contents into esophagus GERD: Symptoms or complications of GER

NASPGN-ESPGHAN Infant Guidelines Happy Spitter with uncomplicated GER No treatment necessary Infant with Complications (GERD) No symptoms can reliably predict tx response Consider anti-acid meds only after diagnostic test and failure of non-pharmacologic measures. Prokinetics not recommended potential risks outweigh potential benefits. No specific recommendations for preterm infants

GER vs. GERD: Implications for Evidence-Based Medicine Best evidence of efficacy = complications physiological measures complications

Putative Complications Pain/Fussiness Apnea Failure to Thrive Food Refusal/Intolerance Exacerbation of Lung Disease

Challenges for NICU Population: What are the complications of GER? Which therapies are effective & safe?

Challenges to Obtaining Evidence in the NICU Population: Heterogeneous Population Small studies Choice of study endpoint Everything changes with development/time Physiology: motility, LES competence, etc. Measurable Outcomes: Symptoms/Complications Response to tx: pharmacokinetics, side-effects, efficacy Long-term harm/benefit after discharge

When asked (away from the bedside) neonatologists say GERD meds are: (1) probably not effective (2) possibly not safe

Choosing Wisely: AAP List 1. Antibiotics should not be used for apparent viral respiratory illnesses (sinusitis, pharyngitis, bronchitis). 6. Don t prescribe high-dose dexamethasone (0.5mg/kg per day) for the prevention or treatment of BPD. 8. Avoid using acid blockers and motility agents such as metoclopramide for physiologic GER that is effortless, painless and not affecting growth. Do not use medication in the so-called happyspitter. http://www.choosingwisely.org/doctor-patient-lists/american-academy-of-pediatrics/

Choosing Wisely SoPPe Survey PPIs & H2-blockers most cited meds. Followed by antibiotics.

Specialists Beliefs: Efficacy GERD Tx Golski, 2010

Specialists Beliefs: Safety GERD Tx Golski, 2010

Why Are We Using GERD Meds? (1) Therapeutic momentum Changing practice is hard Multiple people involved in NICU

Why Are We Using GERD Meds? (2) Therapeutic nihilism is uncomfortable. Can t you do SOMETHING?

Why Are We Using GERD Meds? (3) Extrapolation from other populations

Why Are We Using GERD Meds? (4) The maturation fallacy

The Nail-Polish Paradigm

Step 1: Diagnosis Identify GERD-defining symptoms Step 2: Administer Tx Step 3: Assess Symptoms Step 4: Re-evaluate Tx Improved Continue Tx Not Improved Increase Dose

Nail Polish Initiated Improvement in Symptoms No Improvement in Symptoms Successful therapy Developmental improvement unrelated to nail polish Misdiagnosis: Symptoms not caused by GERD Ineffective therapy for true GERD Consider trialing off drug in weeks to months. Remove Nail Polish

EFFICACY? (With a little bit of safety snuck in)

Acid Suppression: Theoretical Benefits Developed for esophagitis in adults Block symptoms/sequelae of acid reflux

H2-blockers Antagonists of the histamine-2 receptor in the acidproducing gastric parietal cells Parietal cells always produce a basal amount of HCl even when not stimulated by histamine H2-blockers production below physiological basal rates H2-blockers also meal-associated HCl production e.g., ranitidine, cimetidine, famotidine

Famotidine RCT 35 infants, age 1.3-10.5 months 0.5 mg/kg vs. 1 mg/kg x 4 wks double-blind withdrawal w/ placebo x 4 wks Famotidine 0.5 mg/kg improved emesis frequency. 1 mg/kg decreased crying time, emesis frequency & volume. Famotidine may cause agitation & headache (head rubbing). Further studies warranted. Orenstein 2003

Cimetidine RCT Cimetidine is a cytochrome P450 inhibitor (CYP) Postulated to reduce oxidative injury in lung Hypothesis is NOT about GERD! Goal: 288 VLBW s, cimetidine or placebo x 10d Primary outcome: Resp. score at 10 days Stopped at 84 patients by DSMB. Increased death or severe IVH with cimetidine. Minimal chance of difference in 1 outcome. Cotton 2006

Ranitidine + Metoclopramide vs. placebo cross-over trial (n=18) P=0.04 Wheatley, Pediatrics, 2009

Is the Increased Bradycardia Biologically Plausible? Cannot separate effect of 2 drugs Ranitidine can cause bradycardia Histamine receptors are present in the heart In adults, ranitidine assoc. w/ bradyarrhythmias Particularly a problem with the IV form Has been reported in infants Hu 1997, Alliet 1994, Hinrichsen 1995, Nahum 1993, Tanner 1988

Why was the cross-over design important? p=<0.001 Wheatley, Pediatrics, 2009

Proton Pump Inhibitors Irreversibly block the gastric H + /K + ATPase that secretes H + into the gastric lumen e.g., omeprazole, lansoprazole, esomeprazole

PPI use exponentially increasing Prevalence of PPI use among insured infants <12 mo 49% of Rx in infants <4 months old Barron, JPGN, 2007

Lansoprazole RCT 162 infants Failed non-pharmacologic management run-in Randomized to lansoprazole or placebo 44/81 in each group improved symptoms Increased SAE s in tx group (10 vs 2, p=0.032) More Lower Resp. Infections in tx group Orenstein, J Peds, 2009

PPIs should not be prescribed. There is insufficient evidence to support the effectiveness and safety of PPIs in the treatment of GERD.

RCT of infants with recurrent regurgitation unresponsive to conservative tx 69 centers in 10 countries 10 day screening period (n=427) 1-3 week open label 10 mg/day (n=344) If improved, randomized x 5 weeks to placebo, 5mg/day, or 10 mg/day; (n=231).

Hussain, 2014

MOTILITY DRUGS Potential Mechanisms include: Increasing gastric emptying Limits amount of fluid available to reflux Directly improve esophageal motility and lower esophageal sphincter tone

Metoclopramide Systematic Review: infants < 2 yrs old 12 studies, n = 6-77 USPSTF Level of Evidence Scale Quality of literature: Poor Recommendation grade: Inconclusive The level of evidence for both benefit and harm is insufficient to recommend for or against routine use of metoclopramide. *Hibbs 2006

Erythromycin Motilin analog, high affinity for receptor. Motilin normally produced by duodenal and jejunal enterochromaffin cells. Promotes GI migrating motor complexes. Motility doses lower than antibiotic. Infants >32 wks GA may be better able to respond to motilin receptor stimulation. 1 (1) Ng 2008, Patole 2005

Erythromycin Most studies in infants have focused on feeding intolerance, not GERD. No major short-term adverse events reported. In a masked RCT in 24 preterm infants No in GER (secondary outcome) by ph probe Ng 2008, Patole 2005, Ng 2003

SAFETY?

Acid Suppression: Theoretical Risks Acidity s role in digestion Calcium & Magnesium absorption Acidity s action against pathogens

Anti-Acid Therapies: Compromising Host Defense? Pharmacologically decreasing acidity may: Alter gastric colonization in the NICU 1 late-onset sepsis in NICU 2 VAP (MICU, not PICU) 3,4 outpatient pneumonia & gastroenteritis (age 4-36 mo) 5 (1) Cothran 1997 (2) Bianconi 2007 (3) Apte 1992 (4) Yildizdas 2002 (5) Canani 2007

Acid and NEC NICHD NRN Case-Control Study VLBW H2-blocker prophylaxis, not GERD therapy H2-blocker use associated with NEC. Gastric acidification RCT, N=68, blinded Decreased NEC in acidification group. (1) Guillet 2006 (2) Carrion 1990

H2-Blocker Interactions & Side Effects Cimetidine is an inhibitor of CYP3A Can increase drug levels of: theophylline, benzodiazepines, beta-blockers, phenytoin Ranitidine may interact with these meds to a lesser degree. Ranitidine may rarely cause: leukopenia, neutropenia, or thrombocytopenia Usually reversible

PPI Theoretical Risks The FDA released a class label change (2010) Fracture risk in adults on high doses, long courses. Limits over-the-counter use to <14 days, <3x/yr For Rx: limit inappropriate use, trial off Bone effect on preterm infants unknown This population already at risk for osteopenia Vit. B12 absorption also depends on gastric acidity clinical impact of PPIs unknown

PPI Theoretical Risks Acid suppression assoc w/ C. difficile in adults. 1 Effect greater for PPIs than H2-blockers Impact on pathogenic/colonizing C. difficile in infants unknown. In adults, PPIs may increase phenytoin and warfarin levels. 2 Lansoprazole, omeprazole, and pantoprazole are metabolized by CYP2C19. 2 Absent in 3% of Caucasians, 20% of Asians Clinical significance unknown. (1) Howell 2010, Linsky 2010 (2) Flokhart 2000

Acid Suppression & Infection Chung, 2013

Metoclopramide Dopamine D2 receptor antagonist. Crosses the blood-brain barrier Allows anti-emetic action Allows for neurologic side-effects in infants Irritability, drowsiness, oculogyric reaction, dystonic reaction, apnea, emesis in infants. FDA warning: tarditive dyskenesia (2009). Increased risk with prolonged use or high dose.

Metoclopramide: Theoretical Risk Metoclopramide may prolong the duration of neuromuscular blockade during surgery by depressing cholinesterase activity. Interacts with drugs acting on D2 receptor. Anti-emetics, anti-psychotics rarely used in NICU Feldman 1996

Erythromycin Risks Pyloric stenosis in antimicrobial doses. Inhibitor of CYP3A (like cimetidine). May increase serum levels: theophylline, digoxin, some benzodiazepines, sildenafil, phenytoin, warfarin. Has a direct pro-arrhythmic effect. Not only when co-administered with cisapride. May prolong QT, predispose to torsades Ng 2008, Patole 2005, Ng 2003

Concrete Next Steps 1. Educate colleagues and parents 2. Valiant effort not to start GERD meds 3. If you start, be willing to stop a) Within a few days if no improvement b) Within a few weeks if there IS improvement

3 months after brief randomized physician education. Quitadamo, 2014 Rates of PPI Over-Prescription

Combating Momentum The Leed s experience: GERD assessment form Personal communication, Richard Martin

To do nothing is sometimes a good remedy. -Hippocrates

THANK YOU

Reflux and Apnea Immaturity Immaturity Apnea GER Apnea GER Immaturity Immaturity Apnea GER Apnea GER Adapted from Slocum 2007

Fallacy of Results Extrapolated from Other Populations Children are not just small adults Infants are not just small children Preterm infants are not just small infants Term NICU patients may be particularly unique

Common U.S. GERD Therapies Hibbs, 2011

Barron, JPGN, 2007

Metoclopramide Cochrane Review: infants 1 mo - 2 yrs old 6 studies, n = 71-120 Compared to placebo, metoclopramide appears to: - reduce daily symptoms (101 patients in 2 studies) - reduce the reflux index (99 patients in 2 studies) - increase side effects (120 patients in 4 studies) No difference between metoclopramide & placebo: - perceived improvement (71 patients in 2 studies) - # of refluxes > 5 min (99 patients in 2 studies) - # of reflux episodes with ph<4 (99 patients in 2 studies) *Craig 2004