Preterm Infants with Increased Infections Following Acid Suppression Therapy

A recent study (P Manzoni et al. J Pediatr 2018; 193: 62-7) provide more data on the detrimental effects of gastric acid inhibitors (eg. proton pump inhibitors, histamine-2 receptor antagonists).  This study was a secondary analysis using prospectively collected data from 235 preterm very low birth weight infants. Key findings:

  • “After multivariate analysis, exposure to inhibitors of gastric acidity remained significantly and independently associated with LOS [late-onset sepsis] (OR 1.03); each day of inhibitors of gastric acidity exposure conferred an additional 3.7% odds of developing LOS.”
  • Acid suppression therapy was associated with gram-negative (P<.001) and fungal pathogens (P=.001)
  • The study showed an association between acid blockers and with necrotizing enterocolitis, which was mitigated in those who received bovine lactoferrin

My take (borrowed, in part, from authors): This data “confirm, strengthen, and expand on previous reports describing an association between inhibitors of gastric acidity and infections.”  Thus, the risks of these medications is likely greater than the benefits in the majority of preterm infants.

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Bright Angel Trail

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When to Check Gastric Residuals in Preterm Infants

A recent study (A Riskin et al. J Pediatr 2017; 189: 128-34) indicates that routine testing of gastric residual volumes is not needed. In this study of preterm infants ≤34 weeks gestation 239 infants were studied prior and 233 studied after dropping routine checks of gastric residuals.

Key findings:

  • Selective evaluation of gastric residuals was associated with achieving full enteral nutrition 1 day earlier
  • The rate of NEC (stage ≥2) was actually lower in the selective evaluation group (1.7% vs 3.3%) compared to the historic control group

Selective checking of gastric residuals was prompted by the following:

  • abdominal distention
  • vomiting or large regurgitation
  • bilious regurgitation or emesis
  • abnormal behaviors: restlessness, somnolence or apathy
  • increased apnea/bradycardia
  • change in vital signs

While checking gastric residuals had been used to determine feeding intolerance and/or development of necrotizing enterocolitis, this study indicates that routine evaluation is not necessary.

My take: This study challenged a common NICU practice and found that routine assessment of gastric residuals is not needed; selective checking of gastric residuals is sufficient.

Vitamin D in Preterm Infants

Vitamin D has garnered a great deal of attention due to concerns that deficiency worsens the outcomes in so many different conditions, including respiratory tract infections, inflammatory bowel disease, diabetes mellitus (type 1), multiple sclerosis, colorectal cancer, schizophrenia, depression, cardiovascular disease, hepatocellular carcinoma and other conditions.  However, evidence of causation is typically inconclusive.

For preterm infants, a study (Onwuneme C, et al. J Pediatr 2015; 166: 1175-80) notes an association between 25-hydroxy vitamin D (25OHD) levels drawn at 24 hours of life and acute respiratory morbidity.

In this study, levels were also drawn at the time of discharge in the 94 preterm infants.  In addition, maternal 25OHD) levels were checked 24 hours after delivery. These preterm infants were either <32 weeks gestation or <1.5 kg.  The study population was predominantly Caucasian.

Key findings:

  • 92% had 25OHD ≤20 ng/mL (=”<20 group”)
  • 64% had 25OHD ≤12 ng/mL (=”<12 group”)
  • Levels of 25OHD ≤12 ng/mL were associated with increased oxygen requirement (P=.008) and greater need for assisted ventilation (P=.013).  The odds of requiring assisted ventilation were approximately 3-fold higher.
  • The authors state that the baseline characteristics for the <12 group were similar to the <20 group.
  • There was statistical difference in the rate of NEC (Bell stage ≥1) based on the 25OHD levels (P=.048)

The authors note in their discussion that they favor supplementation with 400 IU/day which is in agreement with the American Academy of Pediatrics.  Previous ESPGHAN recommendations were 800-1000 IU/day for infants.

The authors note that 25OHD did not affect sepsis outcome.  In addition, antibiotics during labor was virtually identical between the two groups.  However, no data on CRP values were provided.

Bottomline: This study shows an association between 25OHD values and several important neonatal outcomes.  Whether 25OHD is a marker (eg. epiphenomenon) for these outcomes or whether low 25OHD contributes to these outcomes remains unclear.

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Probiotics -Another Positive Study for Prevention of Necrotizing Enterocolitis

The topic of probiotics and necrotizing enterocolitis has been discussed several times on this blog (see some links below).  Here’s an abstract from a recent J Pediatr 2015;166: 545–51.

Objective

To test the efficacy of probiotic and prebiotic, alone or combined (synbiotic), on the prevention of necrotizing enterocolitis (NEC) in very low birth weight (VLBW) infants.

Study design

A prospective, randomized, controlled trial was conducted at 5 neonatal intensive care units in Turkey. VLBW infants (n = 400) were assigned to a control group and 3 study groups that were given probiotic (Bifidobacterium lactis), prebiotic (inulin), or synbiotic (Bifidobacterium lactis plus inulin) added to breastmilk or formula for a maximum of 8 weeks before discharge or death. The primary outcome was NEC (Bell stage ≥2).

Results

The rate of NEC was lower in probiotic (2.0%) and synbiotic (4.0%) groups compared with prebiotic (12.0%) and placebo (18.0%) groups (P < .001). The times to reach full enteral feeding were faster (P < .001), the rates of clinical nosocomial sepsis were lower (P = .004), stays in the neonatal intensive care unit were shorter, (P = .002), and mortality rates were lower (P = .003) for infants receiving probiotics, prebiotics, or synbiotic than controls. The use of antenatal steroid (OR 0.5, 95% CI 0.3-0.9) and postnatal probiotic (alone or in synbiotic) (OR 0.5, 95% CI 0.2-0.8) decreased the risk of NEC, and maternal antibiotic exposure increased this risk (OR 1.9, 95% CI 1.1-3.6).

Conclusions

In VLBW infants, probiotic (Bifidobacterium lactis) and synbiotic (Bifidobacterium lactis plus inulin) but not prebiotic (inulin) alone decrease NEC.

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Current Mortality from Being Born Premature

A recent study (Patel RM et al. NEJM 2015; 372: 331-40) provides prospectively collected data on 6075 deaths among 22,248 live births with gestational ages 22-29 weeks from the U.S NICHD Neonatal Research Network. between 2000 thru 2011:

Key findings:

  • Improved death rate in most recent period of study:  number of deaths per 1000 live births was 275  (2000-2003), 285 (2004-2007), 258 (2008-2011)
  • While there were fewer pulmonary deaths with time, the deaths attributed to necrotizing enterocolitis increased: number of deaths per 1000 live births was 23 (2000-2003), 29 (2004-2007), 30 (2008-2011).  Necrotizing enterocolitis was the leading cause of death between 15-60 days of life (Figure 1).
  • Overall, 40.4% of deaths occurred within 12 hours after birth.  Only 17.3% occurred after 28 days of life.
  • For the entire study period, the rate of death (per thousand) was associated with gestational age: 949 (22 weeks), 730 (23 weeks), 427 (24 weeks), 258 (25 weeks), 157 (26 weeks), 115 (27 weeks), 78 (28 weeks)
  • The authors speculate that the overall reduction in death rate is likely related to more aggressive respiratory care (for bronchopulmonary dysplasia); one marker of this was increased usage of high-frequency ventilation.

Bottomline: While there has been improvement, being born premature is associated with high mortality.

Neonatal Nutrition Lecture -What We Know Right Now

A recent terrific lecture at Northside Hospital’s neonatology conference by Reese Clark highlighted what we know about neonatal nutrition and what we should be striving to achieve.  This blog entry has abbreviated/summarized this presentation. Though not intentional, some important material is likely to have been omitted; in addition, transcription errors are possible as well.

Dr. Clark was willing to share slides from his talk and a related talk on necrotizing enterocolitis:

Here are a couple of key points from his talk regarding postnatal growth and feedings:

  • Every baby needs good nutrition.  While this is an obvious point, a lot of effort is focused on aspects of care needed in only a small number of neonates.
  • New target for weight gain in premature infants should be 20 gm/kg/day.  This growth is associated with better outcomes (Pediatrics 2006; 117: 1253 Ehrenkranz RA).  In this study, which controlled for a large number of variables, those in the top quartile of growth had much lower rates of cerebral palsy and neurologic impairments.  These improvements were also significant when comparing those in the top quartile to those in the 2nd and 3rd quartiles who were not sicker than those in the top quartile.
  • Most premature neonates are not achieving adequate growth with z-scores for weight and height lower at discharge from the NICU than their z-scores at birth. That is, despite advances in enteral and parenteral nutrition, premature neonates are falling behind while in the NICU. (Clark RH, et al. Pediatrics 2003; 111: 986)
  • Recognizing the supremacy of human milk has been the most important advance and has lead to much lower rates of necrotizing enterocolitis.  There is now a great case for exclusive human milk (J Pediatr 2013; 163: 1592-95; BMC Res Notes 2013; 6: 459)
  • With parenteral nutrition, higher amounts of amino acid have been associated with less issues with hyperglycemia. (Pediatrics 2007; 120: 12: 86-96; Pediatrics 2013; 163: 1278-82)
  • Insulin for hyperglycemia has been associated with poorer outcomes.
  • Does carnitine help with lipid metabolism? No one really knows –no randomized trials.
  • Continuous NG feeds are not associated with fewer signs/symptoms (e.g.. apnea, bradycardia, arching) than NG bolus feeds.
  • Acid suppression in neonates is not effective and potentially harmful
  • We need to use the best growth curves for premature infants: Fenton and Olsen growth charts

Since there are not going to be any trials randomizing neonates into groups assigned to poor growth, we will not know with certainty the impact of good nutrition on long-term outcomes.  Issues with reverse causation and selection bias make it difficult to know whether those with poor growth had other factors besides their nutritional plan which contributed to their outcomes.

Bottomline: We need to continue to optimize nutrition in premature infants; this includes using human milk and preventing necrotizing enterocolitis (which includes avoid acid blockers).  Our goal should be to have infants leave the NICU better nourished than when they arrived.

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

 

How Proton Pump Inhibitors Can Cause Infections

In yesterday’s blog, the editorial on “Acid-reducing agents in infants and children: friend or foe?” also commented on an additional study (JAMA Pediatr. 2014. doi: 10.1001/jamapediatrics.2014.696) which addresses the issue of how proton pump inhibitors (PPIs) may contribute to an increased risk of infections.  It is well-known that use of PPIs (and to a lesser extent histamine-2 receptor antagonists) contribute to a significant increased risk of community-acquired pneumonias and gastrointestinal infections (probably including necrotizing enterocolitis in infants).

In this study, (from the editorial) “acid suppression was associated with a positive gastric culture (P =.003) and increased median concentration of gastric bacteria (P<.001). Full-column nonacid reflux was associated with higher concentrations of bacteria in the lung.”

In this era of pioneering microbiome research, it is not surprising that chronic changes in gastric acid production could cause these results.  This is something to consider when calculating risks and benefits, particularly in situations where the benefits are quite minimal.

Here’s the abstract:

Importance  The use of acid suppression has been associated with an increased risk of upper and lower respiratory tract infections in the outpatient setting but the mechanism behind this increased risk is unknown. We hypothesize that this infection risk results from gastric bacterial overgrowth with subsequent seeding of the lungs.

Objectives  To determine if acid-suppression use results in gastric bacterial overgrowth, if there are changes in lung microflora associated with the use of acid suppression, and if changes in lung microflora are related to full-column nonacid gastroesophageal reflux.

Design, Setting, and Participants  A 5-year prospective cohort study at a tertiary care center where children ages 1 to 18 years were undergoing bronchoscopy and endoscopy for the evaluation of chronic cough. Acid-suppression use was assessed through questionnaires with confirmation using an electronic medical record review.

Main Outcomes and Measures  Our primary outcome was to compare differences in concentration and prevalence of gastric and lung bacteria between patients who were and were not receiving acid-suppression therapy. We compared medians using the Wilcoxon signed rank test and determined prevalence ratios using asymptotic standard errors and 95% confidence intervals. We determined correlations between continuous variables using Pearson correlation coefficients and compared categorical variables using the Fisher exact test.

Results  Forty-six percent of patients taking acid-suppression medication had gastric bacterial growth compared with 18% of untreated patients (P = .003). Staphylococcus (prevalence ratio, 12.75 [95% CI, 1.72-94.36]), Streptococcus (prevalence ratio, 6.91 [95% CI, 1.64-29.02]), Veillonella (prevalence ratio, 9.56 [95% CI, 1.26-72.67]), Dermabacter (prevalence ratio, 4.78 [95% CI, 1.09-21.02]), and Rothia (prevalence ratio, 6.38 [95% CI, 1.50-27.02]) were found more commonly in the gastric fluid of treated patients. The median bacterial concentration was higher in treated patients than in untreated patients (P = .001). There was no difference in the prevalence (P > .23) of different bacterial genera or the median concentration of total bacteria (P = .85) in the lungs between treated and untreated patients. There were significant positive correlations between proximal nonacid reflux burden and lung concentrations of Bacillus (r = 0.47, P = .005), Dermabacter (r = 0.37, P = .008), Lactobacillus (r = 0.45, P = .001), Peptostreptococcus (r = 0.37,P = .008), and Capnocytophagia (r = 0.37, P = .008).

Conclusions and Relevance  Acid-suppression use results in gastric bacterial overgrowth of genera including Staphylococcus and Streptococcus. Full-column nonacid reflux is associated with greater concentrations of bacteria in the lung. Additional studies are needed to determine if acid suppression–related microflora changes predict clinical infection risk; these results suggest that acid suppression use may need to be limited in patients at risk for infections.

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