BRUEs in Boston –Two Punch Study

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DR Duncan et al. J Pediatr 2024; 272: 114128. Brief Resolved Unexplained Events Symptoms Frequently Result in Inappropriate Gastrointestinal Diagnoses and Treatment

In this prospective cohort study from Boston Children’s (2017-2022, n=157), the authors examined diagnostic evaluations in children presenting with Brief Resolved Unexplained Events (BRUEs).

Key findings:

  • Only 28% (20% during the hospitalization, 8% afterwards) underwent VFSS with 71% abnormal.
  • 42% of infants had their BRUE attributed to GERD, and 33% were treated with acid suppression during follow-up
  • Provision of GERD diagnosis was associated with a delay in making an aspiration diagnosis. 10% (6/66) of patients with “GERD” diagnosis subsequently had swallow studies –all were abnormal. Mean diagnostic delay was 56 days.

Discussion points:

  • The approach of using symptoms to determine evaluation of BRUEs has been advised by AAP clinical practice guidelines (2016 & 2019); “however, our results suggest that reliance on these clinical characteristics may result in negative outcomes.”
  • Most aspiration in infants is silent aspiration and not detected by clinical feeding evaluation (CFE) in the absence of a VFSS. “It is concerning that 63% of patients had CFE alone without confirmatory VFSS in the present cohort, and it may be that this practice is even more common in other centers.” Silent aspiration can lead to repeat hospital visits and even long-lasting pulmonary damage including bronchiectasis.
  • Establishing a GERD diagnosis likely increases unnecessary (& potentially harmful) acid suppression

My take: The two punches in this study:

  1. Clinicians cannot diagnose aspiration based on history or bedside feeding evaluations. Objective testing (e.g. VFSS) is needed if there are concerns for dysphagia
  2. Inappropriate diagnosis of GERD may cause harm. GERD medications have been associated with increased infections and may increase risk for allergies.

The role of aspiration in causing BRUEs has been well-recognized since 2017 (see below) by the same group in Boston. It is likely that evaluation of dysphagia is even less frequent in other medical centers.

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Markers for Outcomes in Neonates with Acute Liver Failure

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PS Rolfes et al. J Pediatr 2024; 272: 114080. Establishing Neonate-Specific Prognostic Markers in Acute Liver Failure: Admission Alpha Fetoprotein and Novel Neonatal Acute Liver Failure Scores Predict Patient Outcomes

Methods: A single-center, retrospective chart review (n=51) was conducted on neonates ≤ 30 days of life between 2005 and 2022 with ALF (international normalized ratio ≥ 2 or prothrombin time ≥ 20s and liver dysfunction).  This excluded infants who responded to a single dose Vit K injection or fresh frozen plasma. The age at presentation was 4.7 in survival with native liver (SNL) group and 6.9 in the non-SNL group.

Key findings:

  • The most common causes of neonatal ALF included ischemia (22%), infection (20%), and gestational alloimmune liver disease (16%). All three patients with HLH died. Ischemia had the highest survival rate of 64% compared to 40% for infectious ALF, and 50% for GALD-ALF.
  • Overall survival with native liver (SNL) rate was 43% (n = 22).
  • Alpha-fetoprotein levels were higher in SNL group on admission (mean 46,471) compared to transplant/non-survival group (mean 2450). Peak values were 165,000 compared to 17,650. AFP levels remained significant after removing GALD patients with SNL group now with 17,500 mean on admission compared to 1006 in non-SNL group.
  • Ammonia levels were lower in SNL group on admission 48 vs 70 and at peak: 83 vs 172.
  • A neonatal ALF (nALF) model was developed: 1.29 x Admission INR +0.985 x Admission Ammonia (micromol/L). This score was significantly lower (mean 48.1) in SNL group compared to non-SNL group of 76.2.
  • A peak nALF model: 0.982 x Peak PT +0.985 x Peak Ammonia (micromol/L) performed even better than admission nALF model. SNL group had mean value of 118 compared to 223 for non-SNL group (P <0.001)

In the discussion, the authors note that AFP may have high prognostic value at time of admission (similar to neonatal ALF model), especially in Non-GALD patients. AFP Is a “biomarker for hepatic regeneration….Similar to our findings, several adult studies have shown that elevated AFP levels are associated with favorable outcomes in non-oncologic liver diseases…Specifically, it has been shown that in ALF, rising levels of AFP during hospitalization are associated with favorable outcomes.”

My take: Both the AFP and the neonatal ALF score had similar prognostic value for SNL.

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ChatGPT4 Outperforms GI Docs for Postcolonoscopy Surveillance Advice

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PW Chang et al. Clin Gastroenterol Hepatol 2024; 22: 1917-1925. ChatGPT4 Outperforms Endoscopists for Determination of Postcolonoscopy Rescreening and Surveillance Recommendations

Text input of de-identified data into ChatGPT4 from 505 consecutive patients undergoing colonoscopy between January 1 and April 30, 2023. Key findings:

  • ChatGPT4 recommendations were in closer agreement with the USMSTF Panel (85.7%) than gastroenterology practice recommendations with the USMSTF Panel (75.4%) (P < .001).
  • Of the 14.3% discordant recommendations between ChatGPT4 and the USMSTF Panel, recommendations were for later screening in 26 (5.1%) and for earlier screening in 44 (8.7%) cases. 

My take: Incorporating AI in deciding follow-up surveillance is likely to be a helpful tool.

Related article: K-H Yu et al. NEJM 2024; 390: 1895-1904. Medical Artificial Intelligence and Human Values. This article discusses how human values affect the results of AI advice.

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Autoimmune Diseases in Patients with Primary Sclerosing Cholangitis Plus One

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A Lundberg Bave et al. Hepatology 2024; 80: 527-535. Autoimmune diseases in primary sclerosing cholangitis and their first-degree relatives

Methods: Using National Swedish registries, the authors evaluated a matched cohort study, 1378 individuals with PSC and 13,549 general population comparators and their first-degree relatives.

Key findings:

  • After excluding inflammatory bowel disease and autoimmune hepatitis, the prevalence of autoimmune disease was 18% in PSC and 11% in comparators, OR: 1.77
  • Highest odds were seen for celiac disease [OR: 4.3], sarcoidosis [OR: 2.74], diabetes type 1 [OR: 2.91], and autoimmune skin disease [OR: 2.15]
  • First-degree relatives of individuals with PSC had higher odds of developing IBD [OR: 3.25], autoimmune hepatitis [OR: 5.94], and any autoimmune disease than relatives of the comparators [OR: 1.34] 

My take: Keep an eye out for other autoimmune diseases in patients (& their 1st-degree relatives) with PSC.

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Briefly noted: BB Lai et al. Hepatology 2024; 80: 511-526. Genotype correlates with clinical course and outcome of children with tight junction protein 2 (TJP2) deficiency–related cholestasis Key finding: “Patients with the TJP2-C genotype carrying PPTMs [predicted protein-truncating mutation] in both alleles had a rapidly progressive course, leading to early decompensation and death if they did not receive timely liver transplantation.”

Mom, Can We Get a Dog (& a Sibling)? I Don’t Want to Get Crohn’s Disease

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M Xue et al. Clinical Gastroenterology and Hepatology, Volume 22, Issue 9, 1889 – 1897.e12. Open Access! Environmental Factors Associated With Risk of Crohn’s Disease Development in the Crohn’s and Colitis Canada – Genetic, Environmental, Microbial Project

Methods: The authors prospectively followed 4289 healthy first-degree relatives (FDRs) of patients with CD from the Crohn’s and Colitis Canada – Genetic, Environmental, Microbial (CCC-GEM) project. Regression models identified environmental factors associated with future CD onset and their association with pre-disease biological factors, including altered intestinal permeability measured by urinary fractional excretion of lactulose to mannitol ratio (LMR); gut inflammation via fecal calprotectin (FCP) levels; and fecal microbiome composition through 16S rRNA sequencing.

Key findings:

  • Over a 5.62-year median follow-up, 86 FDRs developed CD
  • Living with a dog between ages 5 and 15 (hazard ratio [HR], 0.62; P = .034) was associated with decreased CD risk
  • Living with a dog was associated with reduced LMR, altered relative abundance of multiple bacterial genera, and increased Chao1 diversity.
  • Living with a large family size in the first year of life (HR, 0.43; P = .016) was associated with decreased CD risk
  • Having a bird at the time of recruitment (HR, 2.78; P = .005) was associated with an increased CD risk (though there were relatively few FDRs with birds at baseline, n=136)
  • Limitations: questionnaire-based assessments of environmental exposure can be subject to recall bias

My take (borrowed from authors): “Our findings contribute to the growing evidence supporting the potential health benefits of exposure to pets, particularly dogs, as a potential preventive strategy for individuals at risk of developing CD.” Having a dog during childhood may reduce the later risk of CD by ~40%.

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Blog Case Report: A Persistent Elevated AST in Teen with IBD and ADHD

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A recent case reminded me of the quote by Helena Ravenclaw in Harry Potter: “”If you have to ask, you’ll never know. If you know, you need only ask.”

One of my colleagues recently diagnosed a teenage boy with ulcerative colitis. His past medical history was notable for ADHD. At the time of his evaluation, he was noted to have an elevated AST.

Labs:

  • June: AST 143, ALT 8, Hepatitis B immune
  • August: AST 190, ALT 10, Albumin 4.7, T protein 7.3, T bili 0.4, D bili 0.1, Alk phos 168; GGT 10, CPK 93

The concern at the time was whether his elevated AST should preclude using his ADHD medicine and whether there was an underlying liver disease. Based on the pattern of liver enzyme abnormalities, it was suspected that the patient had macro AST. A blood test was sent to the Mayo clinic and confirmed this diagnosis:

“”The sample was investigated for the presence of macro AST by polyethylene glycol (PEG) precipitation. Serum AST activity = 316 U/L. The AST result post-PEG precipitation = 22 U/L. The results obtained are positive for the presence of macro AST (93% of activity precipitated with PEG). Based on validation studies performed at the Mayo Clinic, a cut-off of >80% AST activity precipitated by PEG indicates the presence of macro AST.” This test is rarely ordered at the Mayo Clinic and is ordered as a miscellaneous test; it is not on the Mayo Clinic’s regular test menu.

Internet description of macro AST: Macro-aspartate aminotransferase (macro AST) is a rare, benign condition that causes a persistent elevation of aspartate aminotransferase (AST) levels in the blood. It’s caused by the binding of AST to immunoglobulins, which results in a high molecular weight macroenzyme that’s excreted from the serum more slowly than normal.

My take: Macro AST diagnosis is useful –it helps eliminate the concern for other conditions. Since it is quite uncommon, it is easier to think of this problem once you have seen it before.

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Dr. Praveen Goday: Tips on Managing Feeding Problems (Part 2)

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Dr. Goday gave our group a great lecture on pediatric feeding disorders. I’ve included many of his slides along with some of my notes. There may be errors in omission and transcription on my part.

Feeding tubes:

  • If taking >75% of feeds orally, only 13% still needing tube feeds 6 months later.  If taking <25%, 81% still needing tube feeds 6 months later (needs a GT)
  • Bridle: Dr. Goday recommends using up to 8 weeks.  If needing longer, GT placement is recommended
  • If needing an NG tube more than 3 months (possibly 6 months), GT placement is recommended
  • Pre-op studies are not predictive of who will need GJ feedings vs GT feedings

Medications:

  • Cyproheptadine -Dr. Goday prefers single night time dose, usually cycles medicine (2 weeks on, 1 week off), uses as early as 8 months of age.  Watch for adverse effects on behavior.
  • Mirtazapine -often used in older children and adolescents though effects on appetite wane with usage.  Dosed as an oral disintegrating tablet.  Typically, 7.5 mg in older children and 15 mg in adolescents.
  • Vitamins -Gummy vitamins are NOT complete vitamins, Nano VM -minimal taste powder (costly)

Choking phobia

  • Can occur with pharyngitis
  • Usually needs EGD and sometimes anxiolytic

Formulas:

  • No clear nutritional role for toddler step-up formulas
  • Dr. Goday often will use infant formula between 1-2 yrs of life rather than pediasure in those without growth concerns.  Pediasure may reduce acceptance of solid foods (due to its sweet taste)
  • Get help from your nutritionists in kids with limited diets

Autism:

  • Avoid adding medication/vitamins to the ‘one food/formula that child will take.’  He may stop taking that food/formula too

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Disclaimer: This blog, gutsandgrowth, assumes no responsibility for any use or operation of any method, product, instruction, concept or idea contained in the material herein or for any injury or damage to persons or property (whether products liability, negligence or otherwise) resulting from such use or operation. These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  Because of rapid advances in the medical sciences, the gutsandgrowth blog cautions that independent verification should be made of diagnosis and drug dosages. The reader is solely responsible for the conduct of any suggested test or procedure.  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.

Dr. Praveen Goday: Tips on Managing Feeding Problems (Part 1)

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Dr. Goday gave our group a great lecture on pediatric feeding disorders. I’ve included many of his slides along with some of my notes. There may be errors in omission and transcription on my part.

Differences between picky eating, pediatric feeding disorder, and ARFID

  • 70% of picky eating is inherited.
  • If there are sequelae from picky eating, this indicates that the child has a pediatric feeding disorder.  There are 4 potential domains to pediatric feeding disorders: medical dysfunction, feeding skills dysfunction, nutritional dysfunction and psychosocial dysfunction (this is more subjective than other domains)
  • Pediatric feeding disorder (PFD) is a better term than “behavior” feeding disorder because many children have underlying contributing disorders like eosinophilic esophagitis (EoE) or aspiration/swallow dysfunction
  • ARFID is a diagnosis used by psychologists. It is when purely psychosocial concerns leads to nutrition dysfunction. The diagnosis is likely best used in older children who are mostly neurotypical and have normal development.  In younger children, it is important to assess for underlying disorders like oromotor discoordination and EoE

Strategies to prevent picky eating:

  • Breastfeeding (varied tastes in breastmilk)
  • Responsive feeding (feeding when hungry)
  • Solids [lumpy] (especially 6-9 months)
  • Multiple-varied exposures
  • Prevention/treatment: Praise at meal times, non-food rewards, Ellyn Satter’s advice (parents decide when, where, and what is offered & child decides how much

Increased risk of developing picky eating: FPIES, multiple allergies

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Disclaimer: This blog, gutsandgrowth, assumes no responsibility for any use or operation of any method, product, instruction, concept or idea contained in the material herein or for any injury or damage to persons or property (whether products liability, negligence or otherwise) resulting from such use or operation. These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  Because of rapid advances in the medical sciences, the gutsandgrowth blog cautions that independent verification should be made of diagnosis and drug dosages. The reader is solely responsible for the conduct of any suggested test or procedure.  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.

Where Will We Be Without Formulas for Premature Babies?

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S.A Abrams, R.J. Shulman. The American Journal of Clinical Nutrition, https://doi.org/10.1016/j.ajcnut.2024.08.028. Open Access! What would happen in the United States if there were no cow milk-based preterm infant nutritional products: Historical perspective and evaluation of nutrient-related challenges

Background: “Recent legal action (1) has raised the possibility that preterm cow milk-based infant nutritional products (PCMBPs) may either not be produced and available in the United States or may require parental consent and warnings making them extremely difficult for caregivers to use and families to accept (2).”

Key points:

  • “Evidence that unfortified human milk is inadequate to meet the nutrient needs of small preterm infants has been present for over 100 years (6). Until the late 1970’s and early 1980’s, there were limited widely available solutions to either fortify or replace human milk for preterm infants and these were often based on providing feedings of concentrated evaporated cow milk; now recognized as woefully inadequate and unsafe (7 ). At that time, specialized formulas that were high in energy, protein, and micronutrients were widely introduced into the market. Early studies confirmed faster growth of infants fed such products compared to unfortified human milk or full-term formula (8) and their use became widespread by by the mid-1980s.”
  • “The availability of PCMBPs as well as a human milk-based human milk fortifier has led to relatively less frequent and severe nutritional failure in very low birth weight, less than 1500 g (VLBW) infants than in earlier eras. Nonetheless growth failure remains a current problem, especially in the smallest of infants, that is, those less than 1000 g birth weight and less than 25 weeks post-menstrual age at birth (12).”
  • “Inadequate growth and mineralization can be expected to lead to long-term developmental disability, bone demineralization, and frank rickets”
  • “Even with such improvements in policy to support breastfeeding and human milk donations, it is unlikely that an all human milk-based diet could be available for many years if ever for most of the preterm infants born in the US each year, either in the NICU or after hospital discharge.”
  • “Supplements for infants who are over a year of age.. are not suitable for preterm infants, especially those in the first 6 to 9 months after birth. They have relatively high osmolality and nutrient levels, would pose substantial risks of intolerance, and would not meet the specific nutrient requirements of this population.”
  • “The process of individualizing or creating multi-component fortification strategies would be daunting and carries risks of contamination, preparation errors, and tolerance issues. Without proper fortification, preterm infants are at a high risk of growth failure and its associated negative impacts on development and even survival.”

My take: Experts in the field of neonatal nutrition are worried that recent litigation will negate decades of nutritional advances in neonatal care. This is a very real threat. In addition to more complications, the litigation will result in much greater expenses for all infants/families.

Related blog post: Proliferation of Formula Lawsuits In Necrotizing Enterocolitis

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GLP-1 Obesity Medication for 6-11 Year Olds

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  • CK Fox et al. NEJM 2024; https://www.nejm.org/doi/full/10.1056/NEJMoa2407379. Liraglutide for Children 6 to <12 Years of Age with Obesity — A Randomized Trial
  • T Barrett et al. NEJM 2024 (editorial);/doi/full/10.1056/NEJMe2410560. Childhood Obesity and GLP-1 Receptor Agonists — A Coming of Age?

Background: The glucagon-like peptide-1 (GLP-1) analogues liraglutide and semaglutide are approved by the Food and Drug Administration and the European Medicines Agency for long-term weight management in adolescents 12 years of age or older with obesity, as adjunct treatments to lifestyle interventions.14-19 These medications act centrally to increase satiety signaling, reduce appetite and energy intake, and decrease food reward; these medications also increase postprandial insulin levels, reduce glucagon secretion, and delay gastric emptying.

Methods: this phase 3a (SCALE kids) trial, which consisted of a 56-week treatment period and a 26-week follow-up period, we randomly assigned children (n=82) (6 to <12 years of age) with obesity, in a 2:1 ratio, to receive either once-daily subcutaneous liraglutide at a dose of 3.0 mg (or the maximum tolerated dose) or placebo, plus lifestyle interventions.

Key findings:

  • At week 56, the mean percentage change from baseline in BMI was −5.8% with liraglutide and 1.6% with placebo
  • A reduction in BMI of at least 5% occurred in 46% of participants in the liraglutide group and in 9% of participants in the placebo group (adjusted odds ratio, 6.3)
  • The most common adverse events were gastrointestinal disorders, which were reported in 45 of 56 participants (80%) in the liraglutide group and in 14 of 26 participants (54%) in the placebo group. Three cases of vomiting in the liraglutide group were considered by investigators to be serious (each required emergency care); however, none of the events required hospitalization and all resolved without sequelae.
  • In the treated group, improvements were also observed in diastolic blood pressure and the glycated hemoglobin level
  • The editorial: “Fox et al. provide much-needed evidence for the effects of a GLP-1 receptor agonist in young children with obesity, offering a therapeutic option in prepubertal children with severe obesity as an adjunct to healthy lifestyle interventions.”

My take: It is good that there are now effective therapeutic pharmaceutical options for obesity, especially for those developing complications. Long term studies are needed as the effects of these medications on weight are not sustained in those who stop them. Given the need for indefinite therapy, other public health measures are needed to try to reverse the high prevalence of obesity.

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