Category Archives: Pediatric Gastroenterology Intestinal Disorder

Do medicines work for GERD infants?

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“Absence of evidence is not evidence of absence.” Carl Sagan

If medicines work for infantile GERD, it is difficult to prove (Winter H, et al. JPGN 2012; 55: 14-20).  The cited study is the latest having difficulty proving that proton pump inhibitors are effective in infants.  In this randomized, double-blind, placebo-controlled multinational study from 33 centers, 98 infants (1-11 months) were enrolled.  My colleague, Dr. Benjamin Gold, was one of the researchers.  Initially, a 2-week open-label treatment was given which was followed by a 4-week randomized phase.   Study participants had to have a clinical diagnosis of GERD with at least one GERD symptom  –at least twice per week in a 4-week period:

  • vomiting/regurgitation
  • irritability
  • supraesophageal manifestations (cough, wheeze, stridor)
  • respiratory symptoms triggered by feedings
  • feeding difficulties

The treatment administered was weight-based dosing of esomeprazole:

  • 3-5 kg:     2.5mg
  • 5-7.5kg    5mg
  • 7.5-12kg  10mg

Daily symptoms were captured with an interactive voice response system.  Among the initial 98 patients enrolled, 80 reached the randomization phase.  During the initial 2-week period, 81 (82.7%) had symptom improvement based on physician global assessment.  During the double-blind phase, 48.8% of placebo-treated patients and 38.5% of esomeprazole-treated patients discontinued therapy due to symptom worsening.  While the time for discontinuing esomeprazole was longer in a posthoc analysis, the primary outcome, discontinuation rate, was not significantly different.

So what is the reason that this was a negative study?  While the reasons are unclear, all of the following are possible:

  • Patient selection/lack of accurate diagnosis.  Mixed-population was recruited for the study –though this type of population is similar to clinical practice.
  • Dose of esomeprazole.
  • Inadequately powered study.  If the effectiveness of PPIs is small, a much larger population is needed.
  • Maybe these agents don’t work in infants.  Infants secrete less acid than children and adults; thus, acid blockers may not work as well. (The Medical Pendulum and Gastroesophageal Reflux)

Why not give PPIs even if they don’t work?  The previous link discusses many of the potential adverse problems that are possible with medical treatment of GERD. However, even if a medicine does not harm does not mean you should do something because it ‘might’ do some good.  An example of this is the apocryphal tale of the famous pianist who died one day in the middle of a recital. (I saw this in a journal article but cannot remember the reference.)  The manager came out to announce his death.  A man in the audience shouts, ‘Give him an enema.’ Initially, the manager tries to ignore him. After the man yells this three times, the manager responds, ‘the poor man is dead…what good will an enema do?’ The voice replies, ‘What harm will it do?

Additional references:

  • -JPGN 2010; 50: 609-18. Pantoprazole helped improve symptoms but there were no significant differences compared to placebo in withdrawal rates due to lack of efficacy. n=128.
  • -NASPGHAN 2009, Abstract#21. Meds/Rx of NICU pts did not shorten hospital stay or promote wt gain, n=1149. Abstract#26. prevacid more effective than ranitidine in infants.
  • -J Pediatr 2009; 155: 601 (letter). Should not be used to treat symptoms unless proven to be reflux.
  • -JPGN 2009; 49: 498. GERD guidelines.  “In infants and toddlers, there is no symptom or symptom complex that is diagnostic of GERD or predicts a response to therapy.” Identical response to placebo (vs prevacid) in largest double-blind randomized study (54% at 4 weeks) (J Pediatr 2009; 154: 514-20.)  Reflux is “not a common cause of unexplained crying. irritability..in otherwise healthy infants.” “There is no evidence to support the empiric use of acid suppression for the treatment of irritable infants.”

“Fatal attraction”

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Today’s 33Charts topic Children and Magnets: a Fatal Attraction gives an update on rare earth magnet ingestions (neodymium) along with some other useful links.

Addendum: Also a link from NY Times on 8/17/12: http://www.nytimes.com/2012/08/17/business/for-buckyballs-toys-child-safety-is-a-growing-issue.html?_r=1&nl=todaysheadlines

Previous posts on this topic:

More on magnet ingestions

Magnet ingestion –urgent removal needed

How helpful are probiotics?

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Nobody really knows.  Claims about their efficacy are often based on poorly designed studies.  Efficacy of each strain for specific conditions and with specific dosing is often lacking.  One recent negative study demonstrates that probiotics are often not beneficial (J Pediatr 2012; 161: 40-3).

In this randomized, double-blind placebo controlled study of 106 Polish children (1-48 months of age), Lactobacillus reuteri had no effect in preventing nosocomial diarrhea in patients admitted for non-diarrheal illnesses.  While the authors contemplate that this could be due to the strain of probiotic chosen or the dose, it is clear that evidence that probiotics prevent infectious diarrhea “is still scant.”

This conclusion is backed by a large meta-analysis (JAMA 2012; 307: 1959-69).  While the study concludes that the use of probiotics is associated with a lower risk of antibiotic-associate diarrhea (RR 0.58), it predicted that the number to treat for one person to benefit would be 13.  The study was based on a systematic review of 82 randomized clinical studies.  Yet, overall the quality of the research was considered low; the studies were often had shortcomings:

  • 59 studies “lacked adequate information to assess the overall risk of bias”
  • 64 did not indicate if treatment randomization was blinded
  • 31 did not report an intent-to-treat analysis
  • 41 did not include a calculation of the study’s statistical power to detect differences
  • 17 trials were industry-sponsored and 52 did not clarify their funding/potential conflicts of interest
  • 59 did not report on adverse events specifically related to probiotic use; few trials addressed the risk of fungemia or sepsis
  • Trials rarely specified antibiotic agents; thus, it is difficult to know if a particular probiotic would be better with certain types of antibiotic therapy or duration.

Additional references/links:

  • Potential and pitfalls of probiotics with necrotizing enterocolitis
  • -JPGN 2010; 51:24. VSL#3 helpful for IBS, n=509 (4-18yr olds). 1 per day for <11yr, 2/day in 12-18yr olds
  • -Pediatrics 2008; 121:e850. Culturelle, during pregnancy and early infancy, not effective in preventing atopic dermatitis. Did increase wheezing.
  • -J Pediatr 2008; 152: 801. Probiotic helped reduce colic sx in 30 preterm infants, Lactobacillus reuteri
  • -Pediatrics 2007; 119; e124. Probiotics reduced colic in breastfed babies more than simethicone. n=83, Lactobacillus reuteri, 10-8th power per day. Decreased crying 18 minutes per day at 1 week compared to simethicone & by 94 minutes/day at 4 weeks (95% response vs 7% of simethicone)
  • -Neurogastroenterol Motili 2007 (Quigley EM, et al), 19: 166-72. Review of probiotics and IBS.
  • -NASPGHAN 2007, author: Brian Dunlap, H. Yu, Y Elitsur. abstract -most commercial yogurts have LOW concentrations of probiotics.
  • -JPGN 2006; 43: 550. Review of probiotics for specific conditions.
  • -J Pediatr 2006; 149: 367. Probiotics reduce risk of antibiotic assoc diarrhea. If 7 pts (on abx) are treated with probiotics, one fewer will develop AAD.
  • -JPGN 2006; 42: 454. Evidenced-based review of probiotics.
  • -Pediatrics 2005; 115: 1-4 & 171 editorial.  Probiotics decreased NEC in this study.
  • -Gastroenterol 2004; 126: 1620-33.  Review of probiotics, prebiotics and antibiotics in IBD.

Comparing diets in EoE

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There remains a limited number of therapeutic options with EoE.  Dietary therapy can be effective as well as burdensome.  A closer look at dietary treatment effectiveness was recently published (J Allergy Clin Immunol 2012; 129: 1570-8 –thanks to Seth Marcus for alerting me to this article).

Due to eligibility requirements, only 98 patients of an initial 513 met criteria.  The findings from this study may be difficult to generalize because of the following:

  • Highly selected patient population
  • Retrospective study.   Dietary therapy was NOT chosen randomly.
  • Study originates from a specialized center (Cincinnati) which attracts atypical cases of EoE

That being said, the study asks some important questions. What is the remission rate for skin test-directed elimination diet in comparison to six food group elimination diet (SFED) and to an elemental diet?  The SFED actually composed two groups (in my opinion, this is a significant flaw in the study design & has a limiting effect on the conclusions).  The ‘classical’ SFED (42% or 11/26) eliminated the six most common food groups (milk, soy, wheat, egg, nuts, fish/shellfish) whereas a ‘modified’ SFED (58% or 15/26)  combined the classical SFED with foods eliciting positive skin-testing.

Some of the authors terminology:

  • Complete remission: 1 or fewer eosinophils/hpf
  • Partial remission: 2-5 eos/hpf
  • Partial resolution: 6-14 eos/hpf
  • Remission: <15 eos/hpf
  • Non-remission: >15 eos/hpf

Skin prick tests (SPFs) were performed to as many as 62 foods and 11 environmental allergens and graded 0-4.  0 equated to negative control & 4 equated to histamine control -all interpreted at 15 minutes after placement.

Atopy patch tests (APTs) were interpreted at 48 hours with scoring between 0-4.  A score of 2 indicated “erythematous with generalized induration.”  Any score of 2 or higher was considered positive.

Food reintroduction process: “Food reintroductions were initiated only when the peak eosinophil count was less than 15 eosinophils/hpf. If symptoms occurred after reintroduction of a food, patients were instructed to discontinue that food, wait approximately 10 to 14 days, and then reintroduce another food…. A food reintroduction was considered successful if no symptoms were reported and the postpeak eosinophil count was less than 15 eosinophils/hpf.”

Why were so many patients excluded?  The main causes were 181 patients did not meet strict EoE criteria, 122 patients received glucocorticoids, and 52 patients had another eosinophilia-associated condition; less common reasons included patient age >21, being part of a separate drug trial, obvious noncompliance, different diet regimen, and not having 2 consecutive EGDs separated by dietary intervention.

How many endoscopies are needed for dietary therapy?   In this study, the average patient had 8.5 EGDs at Cincinnati.  The greatest number of EGDs took place among patients assigned to an elemental diet (average >11); these patients also had a longer followup period compared to the other two groups: 2.9 years compared with 1.1 for SFED and 2.1 for directed diet.

  • All three diets resulted in improvement in eosinophil count.
  • Overall Remission rates: 96% elemental, 81% SFED, 65% directed diet
  • Complete Remission rates:  59% elemental, 39% SFED, 30% directed diet

One interesting set of data is in Table 4.  This gives the pass rate for various foods with single and multiple food reintroductions.  Milk for example had a pass rate of 35% among the 17 patients who had this as a single food reintroduction.  The values ranged from a low pass rate of 29% for strawberries to a high pass rate of 78% for cocoa and 75% for pork. Soy, eggs, and wheat all hovered near 60% pass rate.

Conclusions by authors:

1. “SFED is no less successful than directed diet and consistent with unreliability of skin testing …Our data…undermine the value of skin test-directed dietary management. ” This is due to the fact that the disease mechanism is not an IgE-mediated disease (skin testing primarily detects IgE-mediated allergens).

2. Elemental diet is superior at inducing histologic remission. However, “multiple studies indicate that adherence is inversely related to the number of foods eliminated.”

Previous related posts:

Guidelines for Eosinophilic Esophagitis

Looking better or feeling better in EoE?

Look of improvement on an EoE diet

Eosinophilic Esophagitis -Six Food Group Diet

MicroRNA signature for eosinophilic esophagitis

The undiscovered country

 

More on anti-glycan antibodies in Crohn’s disease

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As noted in recent blog entry (Serology in IBD), anti-glycan antibodies have some usefulness in inflammatory bowel disease.  More data on the utility of these antibodies is available in a study which examined the presence of these antibodies in both a pediatric and adult cohort (Inflamm Bowel Dis 2012; 18: 1221-31).

Anti-L, Anti-C, anti-chitobioside (ACCA), anti-laminaribioside (ALCA), anti-mannobioside and anti-Saccaromyces cervisiae (ASCA) antibodies were tested in 131 pediatric patients (59 CD, 27 UC, 45 controls) and in 728 adult patients (355 CD, 129 UC, 244 controls).  In this study, 78% of pediatric CD patients had at least one serological marker.  ASCA was most accurate for CD diagnosis; it was present in 63% of the pediatric cohort. 

Combined usage of these antibodies helped differentiate CD from UC.  While sensitivity for detecting CD was 78% with the presence of one serological marker, the presence of three (or more) markers increased the specificity to 93% (for CD compared to UC); however, the presence of this many markers occurred in only 28%. Increasing antibody levels also correlated with complicated CD behavior, CD-related surgery and ileal disease location.

Serology in IBD

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Serological antibodies against a number of antigens have shown some utility in differentiating inflammatory bowel disease (IBD) from non-IBD and in distinguishing Crohn’s disease (CD) from ulcerative colitis (UC).  A recent article evaluated 204 articles in a systematic review of these serological markers (Inflamm Bowel Dis 2012; 18: 1340-55).

The study has several useful tables and a long list of references.  In its Table 1, 10 serologies are listed with a range for prevalence in CD, UC, alternative GI conditions, and in healthy population.  Table 2 summarizes the data in terms of sensitivity, specificity, positive predictive value, negative predictive value for these antibodies in determining IBD from non-IBD.

With regard to specific antibodies, the review highlights 10 antibodies:

1. Anti-neutrophil cytoplasmic antibodies (ANCA).  Autoantibody directed against a constituent of neutrophil granules.  With IBD (especially UC), an atypical perinuclear (pANCA) staining pattern with indirect immunofluorescence and DNase-sensitive make this pattern different from ANCA due to vasculitis.

2-7. Anti-glycan antibodies –directed against cell wall microbes and reflect interaction between the immune system and glycosylated cell wall components of microbiota.

2. Anti-Saccharomyces cerevisiae (ASCA IgA and IgG) –antibodies directed against yeast cell wall.  While ASCA antibodies are commonly found in CD patients, 20-25% (or higher in some studies) of healthy relatives will test positive for these antibodies as well.  Approximately 6% of relatives of UC patients will be ASCA-positive.

3. Anti-laminaribioside carbohydrate IgG antibodies (ALCA) –antibodies directed against laminaribioside

4. Anti-chitobioside carbohydrate IgA antibodies (ACCA) –antibodies directed against chitobioside

5. Anti-mannobioside carbohydrate IgG antibodies (AMCA) –antibodies directed against mannobioside

6. Anti-L –antibodies directed against laminarin (large polysaccharide)

7. Anti-C –antibodies directed against chitin (large polysaccharide)

8. Anti-OmpC.  OmpC is a transport protein of E coli

9. Anti-I2.  I2 is a Pseudomonas-associated antigen

10. Anti-CBir1.  CBir1 is a bacterial flagellin antigen

Conclusions:

  • Serology has only limited value for the initial diagnosis of IBD.
  • Serology has ‘better value’ in differentiating CD from UC, though there is substantial variability in serologic responses in both diseases.  Probably, serology is most useful in unclassified IBD (IBD-U) in preoperative setting; serology may help predict risk of developing complications among patients undergoing pouch surgery.
  • Serology is useful in predicting a complicated disease course. The presence and magnitude of these antibodies are strong predictors of disease progression.

Additional references:

  • Pediatrics. 2010 Jun ;125 (6):1230-6.  Shortcomings of the inflammatory bowel disease Serology 7 panel. 
  • -Clin Gastro & Hep 2008; 6: 1105. Increased immune reactivity/markers associated with aggressive disease.
  • -IBD 2006; 12:1122. Expression of I2 antibodies (against a bacterial antigen of psedomonas fluorescens) was highly associated with clinical response to diversion. 15/16 with I2-pos had clinical response; 2/11 I2-neg had clinical response.
  • -IBD 2008; 14: S4 abstract 0010. Practical experience with IBD serology (n=90) much less accurate than reported by Prometheus: overall accuracy of 63% (vs 92%), 66% sensitivity (vs 93%), 59% specificity (vs 95%), 75% PPV (vs 96%), and 49% NPV (vs 90%). In this population, 34% of known IBD were incorrectly predicted. Of 32 who did not have any evidence of IBD after clinical investigation, 40% (13) were seropositive.
  • -Clin Gastro & Hep 2008; 6: 1105. Increased immune reactivity/markers associated with aggressive disease.
  • -IBD 2008; 14; 129. Serologic markers not very useful clinically.
  • -Pediatrics 2007; 119: e193. IBD serology performed poorly in comparison to combination of Hgb/ESR with regard to sensitivity (60% vs. 83%), specificity (92% vs. 96%), positive predictive value (60% vs. 79%) for IBD in children, n=227. Also one third of all positive serology in patients w/o IBD. The positive predictive value in patients w/o rectal bleeding was 35% vs 60% for routine tests.
  • -Gastroenterol 2006; 131: 366. antibodies against laminaribioside, chitobioside, and mannan have predictive value in detecting Crohn’s disease.
  • -Gastroenterol 2006; 130: 1078. Unaffected relatives positive for either OmpC or ASCA in 20% in large cohor (n=619 unaffected relatives. OmpC present in up to 44% of CD pts, up to 24% of UC pts, and 6% of controls.

An unexpected finding with gastroschisis management

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A presumption that paralysis in infants with gastroschisis leads to quicker resolution in silo-assisted closure is not correct (J Pediatr 2012; 161: 125-8).  This presumption had been based on the idea that abdominal muscular relaxation with paralysis would facilitate visceral reduction.

This retrospective Canadian study examined 186 infants with gastroschisis, between 2005-2009.  Standardized data for this study was collected prospectively from 16 perinatal centers in Canada. Findings:

  • 79 had paralysis and 88 did not.  These groups were nearly identical in birth weight, gestational age, and presence of bowel atresia.
  • Paralyzed infants took longer to achieve closure, 8 days versus 5 days.  In addition, the paralyzed group had longer ventilation period, 12 days versus 7 days.
  • These findings persisted after regression analysis/adjusting for other variables.  The analysis included examination of illness severity scores (SNAP-II); it was not simply the sicker infants receiving paralysis.
Besides debunking a false premise with gastroschisis management, this study highlights the necessity of collecting data so that our presumptions can be challenged.

Additional references:

  • -J Pediatr Surg 2011; 46: 801-7.  Outcomes/variation in diaphragmatic hernia and gastroschisis from Canadian Pediatric Surgery network.
  • -J Pediatr Surg 2008; 43: 30-4.  Outcomes in 100 cases of gastroschisis.

What’s the best medical therapy for Clostridium difficile?

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More data on the superiority of fidaxomicin versus vancomycin in adult patients has been published (Lancet 2012; 12: 281-9).  While this study was a ‘double-blind, non-inferiority, randomized controlled trial,’ the data tilt in favor of fidaxomicin.  This study enrolled 535 patients from 45 sites in Europe and 41 sites in U.S.

On an intention-to-treat basis, a clinical cure was noted in 88% of fidaxomicin group (200 mg BID x 10 days) and 86% of vancomycin group (125 mg QID x 10 days).  Clinical cure was defined as resolution of diarrhea and no need for further treatment.  The big difference was in recurrence risk:  13% of patients receiving fidaxomicin compared with 27% of patients receiving vancomycin.  Recurrence was defined as development of three unformed bowel movements in 24 h, a positive stool toxin, and need for retreatment within 30 days of treatment completion.  A sustained response (=”global cure”) was noted in 77% with fidaxomicin compared with 63% of vancomycin group.

Both groups of patients had similar variables: severity of illness, frequency of B1/027 strains, geographic distribution, concomitant antibiotics, previous C difficile infection, age, and inpatient status.  In the group with concomitant antibiotics, fidaxomicin outperformed vancomycin with respect to cure rate: 90% versus 73%.  Adverse reactions were similar as well (Table 7).

To underscore the severity of C difficile in this population, there was a significant mortality rate in both groups.  8% of patients receiving at least one dose of fidaxomicin died compared with 7% of vancomycin-treated patients.

Why does fidaxomicin have a lower recurrence rate?  Probably due to a more narrow antibiotic spectrum and minimal effect on commensal gut flora.  Fidaxomicin also has roughly eight times more potency in vitro than vancomycin against clinical isolates of C difficile.

Previous related blog entries/reference:

Colonoscopy, Split-dosing bowel preps, and Ottawa scores

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Adequate bowel cleansing improves the results of colonoscopy.  Since colonoscopy is a big part of gastroenterology/pediatric gastroenterology, a lot has been written comparing bowel preparations.  A recent study has examined a split-dose polyethylene glycol (PEG) preparation (Gastrointest Endosc 2012; 75: 583-90).

This prospective study from a single center in South Korea examined the effectiveness of a split-dose regimen in 366 patients (18 -65 years).  An interval of 3 to 5 hours between the completion of the last dose of the preparation and the start of the colonoscopy had the highest scores for bowel cleansing.  The authors used the “Ottawa Bowel Preparation Scale” for assessing a quality score.  Favorable odds ratios were noted with optimal preparation interval (OR 1.85), amount of PEG ingested (OR 4.34), and adherence with diet instructions (OR 2.22).

Instructions for preparation in this study:

  • 1. Low-fiber diet for 3 days prior
  • 2. Regular diet for breakfast & lunch day prior; soft diet for dinner, then only clear liquids
  • 3. Two liters of PEG on day prior and then two liters early in morning (5-7 am) on day of procedure –NPO for at least two hours prior to procedure.  While taking PEG, patients were instructed to consume 250 mL every 10 minutes.

Ottawa Scale –score right, mid, and left colon:

  • 0    no liquid
  • 1    minimal liquid –no suctioning required
  • 2    suctioning required to see mucosa
  • 3    wash and suctioning needed
  • 4    solid stool, not washable
  • Plus 0-2 points for overall quantity of fluid.
  • Max score 14 points

In this study, a prolonged interval (> 7 hours) between prep and colonoscopy had increasingly higher scores.  Score for 3-4 hours was 4.25; score for 7-8 hours was 5.20 and score for > 8 hours was 5.92.

As alluded to above, individuals who consumed adequate volume of preparation, had good bowel cleansing.  99% of patients who took at least 75% of PEG (> 3 liters) had a satisfactory preparation.  And, 95% of patients who took less than 75% of PEG had an unsatisfactory preparation.  Compliance with diet instruction was associated with a satisfactory prep in 89% and poor compliance was associated with a poor prep in 81%.

While this study identified these risk factors, it is telling that even in a research study, 141 patients had an unsatisfactory preparation (Ottawa scale 6-14); 225 had a satisfactory preparation (Ottawa scale 0-5).

Additional references –bowel preparations:

  • -JPGN 2011; 53: 71. 2 day prep: Miralax 2 gm/kg, bisacodyl 5mg. n=111.
  • -JPGN 2010; 51: 254. Review of bowel preparations
  • -Gastroenterol 2006; 130: 2240. Oral phospho fleets associated with alarming risk of nephropathy. 21 additional cases identified
  • -J Am Soc Nephrol 2005; 16: 3389-3396
  • -NEJM 2003; 349: 1006. acute phosphate nephropathy after oral phospho fleets in a 71yo woman
Additional references –colonoscopy screening:
  • -Gastroenterol 2010; 138: 73, 27 (ed). Overutilization of colon screening in low risk situations and underutilization in high risk situations in clinical practice.
  • -Clin Gastro & Hep 2009; 7: 1217.  Fewer polyps detected as day progresses at a VA hospital n=477 pts. 27% decline in polyp detection.
  • -NEJM 2009; 361: 1179. Review of screening for colorectal cancer.
  • -Gastroenterol 2009; 137: 792. Use of CT colonography -current appraisal.
  • -Ann Intern Med 2009; 150: 1-8. Says endoscopists miss most cancers on right side & colonosopy reduces cancer by ~60% primarily due to left-sided cancers.  Most, 73%, of colonoscopies not done by GI/colorectal surgery in this study.
  • -Gastroenterol 2008; 134: 1570. Update recommendations from ACS, ACR, US Multi-society task force.
  • -Gastroenterol 2008; 134: 1311. Screening in 40-49 detects similar # of adenomas as in older groups (>50) but fewer advanced Ca.

Other references/links:

1. “Take it easy, Doc, you’re boldly going where no man has gone before.”
2. “Find Amelia Earhart yet?”
3. “Can you hear me NOW?”
4. “Are we there yet? Are we there yet? Are we there yet?”
5. “You know, in Arkansas, we’re now legally married.”
6. “Any sign of the trapped miners, Chief?”
7. “You put your left hand in, you take your left hand out. You do the
Hokey Pokey….”
8. “Hey! Now I know how a Muppet feels!”
9. “If your hand doesn’t fit, you must acquit!”
10. “Hey, Doc, let me know if you find my dignity.” and
11. “Could you write me a note for my wife, saying that my head is not, in fact, up there?”

Avoid ranitidine (acid suppression) in neonates

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More evidence that ranitidine may contribute to necrotizing enterocolitis and fatal outcomes has been published (Pediatrics 2012; 129: e40-45).

In this study (which was reviewed in The Journal of Pediatrics 2012; 161: 168-69), four neonatal intensive care units in Italy performed a multicenter prospective observational study of very low birth weight (VLBW) inants.  There were 274 neonates with gestational ages ranging from 24-32 weeks and birth weights ranging from 401-1500 grams.  The patients receiving ranitidine were similar to the unexposed group in terms of risk factors for infection/NEC, birth weight, gestational age, sex, APGAR scores, PDA, intubation duration, and central vascular access duration.

  • 34 of 91 (37%) exposed to ranitidine developed infections compared with 9.8% of the group not exposed to ranitidine (OR 5.5)
  • Risk of necrotizing enterocolitis (NEC) was 6.6-fold higher among ranitidine-treated neonates
  • Mortality was 9.9% for ranitidine-treated patients compared with 1.6% of control patients
Since gastric acid acts as a defense against ingested pathogens, theoretically inhibition of acid production allows proliferation of these pathogens with subsequent infections and development of necrotizing enterocolitis.  These potential risks and the general lack of benefit of acid suppression in neonates should help guide clinician decision-making.
Another concern with ranitidine has been among acute appendicitis patients (see references below) where it has been associated with an increased likelihood of developing an abscess.

Additional references/previous related blog entries: