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.

Diagnosing hemophagocytic lymphohistiocytosis (HLH)

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HLH is difficult to diagnose –patients without HLH can meet the established criteria (see links below); and, especially early in the disease, patients with HLH may not meet the established criteria.  A study which will help with this difficulty has been published (J Pediatr 2012; 160: 984-90 and summary pg A1).  For pediatric gastroenterologists, HLH is important because some of our IBD patients may develop HLH and because some patients presenting with liver disease have HLH.

This study examined 756 consecutive patients with fever in Hematology/Oncology unit of China’s Children’s Hospital of Zhejiang between 2005-2010.  Three control groups also were studied: hematology-oncology patients without fever (n=202), healthy children (n=100), and previously-healthy children with bacterial sepsis (n=85).

A highly discriminating cytokine pattern was identified in 71 episodes of HLH.

  • Highly elevated IFN-γ : 94% sensitivity, 97% specificity for HLH using a cutoff of 100 pg/mL
  • Highly elevated IL-10
  • Modestly elevated IL -6
  • Combined use of IFN-γ (>75 pg/mL) & IL-10 (>60 pg/mL) had sensitivity of 93% and specificity of 99% for HLH

Using these cytokines may help establish a more rapid diagnosis of HLH and allow institution of critical therapy while avoiding implementation of the wrong treatment in patients who have other conditions.  In other studies (see below), there are other useful markers that have been identified.

Additional references:

  • -J Pediatr 2011; 159: 808.  HLH increased with Crohn’s Rx.  If fever >5days, can screen for HLH with ferritin (>500mcg/L) & lymphopenia.  Need to discontinue immunosuppression.  100-fold increase risk of HLH.  Diagnostic criteria for HLH pg 809. Newer criteria: molecular, low/absent NK activity & soluble CD-25 (ie. soluble IL-2 receptor) >2400 U/mL.
  • Hemophagocytic Syndrome  Link with powerpoint case presentation including diagnostic criteria for primary and secondary HLH.
  • Hemophagocytic lymphohistiocytosis (HLH) and related disorders  Link with review article by leader in field (A Filipovich, 2009).
  • -J Peds 2006; 149: 134-7.  Aftrican-american infants c HLH often have a specific defect in perforin gene -50delT-PRF1
  • -NEJM 2004; 351: 1120. case of twins c FELS. Impaired NK cell activity is key with absence of NK intracytoplasmic perforin in 20-40%.
  • -JPGN 2002; 34: 3A (pg 433.)  Liver failure with HLH.  mortality 84%, n=25.

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:

BRIC, PFIC, and nasobiliary drainage

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Case reports, when effective, help clinicians understand meaningful differences in disease presentation; in addition, they highlight practical treatment approaches.  An excellent example of one such case report is the following:

  • Zellos A et al.  JPGN 2012; 55: 88-90

These authors present a case with unique features that highlight some of the clinical problems with benign recurrent intrahepatic cholestasis (BRIC) and progressive familial intrahepatic cholestasis (PFIC).  BRIC1 and PFIC1 are associated with mutations in ATP8B1; BRIC2 and PFIC2 are associated with mutations in ABCB11.  The primary difference between BRIC and PFIC is the phenotypic expression.  In BRIC, individuals have episodes of cholestasis; in PFIC, progressive chronic liver disease develops in the first months of life.  PFIC2/ABCB11 mutations cause defective bile salt export pump (BSEP) at the bile-canniculus membrane.

Both ATP8B1 and ABCB11 intrahepatic cholestasis conditions present in a similar fashion with low GGT values.  In this case report, a 5-year-old presented with jaundice, acholic stools and dark urine.  His laboratory values revealed an ALT of 60 U/L, direct bilirubin of 7.6 mg/dL and gamma-glutamyl transpeptidase (GGT) of 10 U/L.  Initially, after exclusion of other liver conditions (eg. NL MRCP, copper studies, α-1 antitrypsin, autoimmune serology, infectious etiologies), the authors suspected ‘a clinicopathologic intergrade between BRIC and PFIC’ likely due to ATP8B1 as there was BSEP expression on liver biopsy immunostaining.  After sequencing did not demonstrate any ATP8B1 mutations, the authors identified two heterozygote mutations in ABCB11.

From a treatment standpoint, once nasobiliary drainage (NBD) was in place, the patient quickly improved.  This occurred after >6 weeks of failure with urosdeoxycholic acid/conservative measures.  As a precaution, the authors cultured the bile once a week and instituted antibiotic treatment when positive cultures were identified.

One other point alluded to by the authors is that the natural history of BRIC2 is poorly described.  Whether this disorder is truly ‘benign’ as the name suggests is unclear.  In patients with similar mutations who develop PFIC2, there is a high risk of hepatocellular carcinoma (HCC).

Intrahepatic Cholestasis Genes/Disorder (Clin Liver Dis 2006; 10: 27-53.)

Gene: Disorder (protein)
ABCB11: PFIC 2, BRIC 2 (BSEP)
ABCB4: PFIC 3, ICP (MDR3)
CFTR: CF (CFTR)
ATP8B1: PFIC1 -Byler’s (FIC1), BRIC, GFC -Greenland Familial
CLDN1: NISCH (Claudin 1) -neonatal sclerosing cholangitis/icthyosis
VPS33B: ARC syndrome (Vascular protein sorting 33) -arthrogryposis-renal dysfn-cholestasis, low GGT
AKR1D1: BAS: Bile acid synthetic defect: neonatal cholestasis with giant cell hepatitis
(5β-reductase)
HSD3B7: BAS (C27-3β-HSD)
CYP7BI: BAS (CYP7BI)
TJP2: (ZO-2) FHC: Familial hypercholanemia (tight junction protein)
BAAT: FHC (BAAT)
EPHX1: FHC (epoxide hydrolase)
JAG1: Alagille (JAG1) JAG1 is transmembrane cell-surface protein important in regulating cell fate during embryogenesis
PKHD1: ARPKD (fibrocystin -important in ciliary function and tubulogenesis)
PRKCSH: ADPLD (hepatocystin)
ABCC2: Dubin-Johnson syndrome (MRP2)
CIRH1A: NAIC -N Amer Indian childhood cirrhosis (Cirhin)

Additional references for BRIC/low GGT PFIC:

  • -JPGN 2010; 51: 494.  Use of biliary diversion –helpful in 18 PFIC2 cases with long-term f/u.
  • -Liver Transplantation 2010; 16: 856.  6 patients developed recurrent low gamma-glutamyl transpeptidase cholestasis, that mimics BSEP disease, following transplantation. All had documented genetic defects in ABCB11 that were predicted to lead to a congenital absence of BSEP protein.
  • -NEJM 2009; 361: 1359. Recurrence of BSEP deficiency p OLT due to antibodies against BSEP
  • -Hepatology 2010; 51: 1645. n=62 children & clinical course.
  • -Gastroenterol 2008; 134: 1203. Severe BSEP –82 different mutations in 109 families. (n=132 patients)
  • -JPGN 2008; 46: 241. Excellent review. FIC1 caused by mutations in ATP8B1, PFIC 2 caused by mutations in ABCB11 which encodes BSEP – bile salt export pump. Increased risk of HCC in PFIC2 especially.
  • -J Pediatr 2007; 150: 556.  Increase risk of HCC in PFIC2.
  • -Hepatology 2006; 44: 478-486. Cases of pediatric HCC in PFIC-2
  • -Gastroenterol 2006; 130: 908. Review of canalicular transport defects.
  • -Hepatology 2005; 42: 222. summary of cholestasis workshop
  • -Gastroenterol 2004; 126: 322. Review of bile salt transporters.
  • -JPGN 2002; 34: 7A. FTT, diarrhea persist p biliary diversion or transplant.

PFIC3 -High GGT

  • -Gastroenterol 2003; 124: 1037-42. MDR3 mutations causing cholelithiasis, cholestasis, biliary cirrhosis, & pregnancy cholestasis.
  • -Gastroenterol 2001; 120: 1448-1458. n=31 cases. MDR3 mutations. ABCB4 gene
  • -Gastroenterol 2001; 120: 1459-67. Gallbladder stones & chronic cholestasis in 6 MDR3+ pts. Avg age of presentation: 2.9yrs. Avg age of Tx: 7.5yrs.  Sx/S : high ggt cholestasis, pruritus, intrahepatic cholestasis of pregnancy in heterozygotes (& c contraception)
  • -Hepatology 1996; 23: 904-8. MDR3 gene assoc c PFIC

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?”

Iron and hepcidin –not just for grownups

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As alluded to in a previous post (Help with hepcidin), hepcidin is integral to iron metabolism.  In a recent study (J Pediatr 2012; 160: 949-53), serum and urine hepcidin concentrations in preterm infants were found to correlate well with iron homeostasis markers in preterm infants.

This study examined 31 preterm infants (23-32 weeks gestational age).

Findings:

  • Serum hepcidin was highest in infants with systemic inflammation.
  • Both serum and urine hepcidin correlated strongly with ferritin (Figure 2 in study) and negatively with soluble transferrin receptor/ferritin-ratio.
  • Infants with lower hemoglobin concentrations and higher reticulocyte counts had lower serum hepcidin.
  • There was good correlation between urine and serum hepcidin (Figure 1 in study). As such, urine hepcidin may become useful non-invasive marker for iron status in sick preterm infants

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:

Helicobacter pylori –useful advice

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Helicobacter pylori (H pylori) infections remain an important cause of gastritis, ulcers, and adenocarcinoma of the stomach.  One new approach in treatment has been the use of sequential therapy.  More data is now available on the effectiveness of this approach and choice of antibiotics (Gastroenterology 2012; 143: 55-61 & editorial 10-12).

In the study, a 10-day sequential regimen (SR) was compared with a 5-day concomitant regimen (CR).

  • CR group (n=90): esomeprazole 40 mg BID, amoxicillin 1 g BID, levofloxacin 500 mg BID, tinidazole 500 mg BID.  Eradication rate (intention-to-treat): 92%
  • SR group (n-90): esomeprazole 40 mg BID, amoxicillin 1 g BID for 5 days, then esomeprazole 40 mg BID, levofloxacin 500 mg BID, tinidazole 500 mg BID for 5 days. Eradication rate (intention-to-treat): 93%
  • Both groups had good results in part due to low resistance rates

Useful advice on this study from the editorial:

  • ‘We prefer concomitant therapy because it is not complex and it may retain its effectiveness at a slightly higher level of resistance compared with sequential therapy.”  Authors prefer 4-drug non-bismuth-containing concomitant treatment.
  • With bismuth therapy (eg. bismuth-metronidazole-tetracycline-PPI), authors prefer a 14 day course.  10-day treatment may be effective when metronidazole resistance is considered unlikely.
  • “Clarithromycin should be abandoned as an empiric regimen” due to resistance in U.S.
  • Fluoroquinolone resistance is increasing rapidly and “prior use virtually ensures resistance.”  Suggested use of fluoroquinolone therapy among adults would be as a rescue therapy (failed 2 different therapies), using dosing regimen as noted in cited study, and in patient without history of prior fluoroquinolone use (&/or proof on susceptibility testing)
What about treatment in kids?
In pediatrics, guidelines for treatment have been recently updated (JPGN 2011; 53: 230-43). (Benjamin Gold, MD -one of my partners is one of the authors and was the lead author of the first guidelines published in 2000.)  NASPGHAN guidelines. PDF of powerpoint slides: H. pylori infection in children: ESPGHAN/ NASPGHAN guidelines … & pdf of text: Evidence-based guidelines from ESPGHAN and NASPGHAN for …
Recommendations for first line treatment are a triple-based therapy with PPI and two antibiotics (eg. amoxicillin and metronidazole).  Alternatives, include bismuth plus two antibiotics, or sequential therapy.  Use of clarithromycin is recommended only after susceptibility testing.

Additional references:

  • -Gut 2010; 59: 1143-53.  Changing treatment recommendations for Helicobacter pylori in the face of resistance.
  • -Am J Gastroenterol 2007;  102: 1808-1825. American College of Gastroenterology Guideline on the Management of Helicobacter pylori Infection.  Doxycycline can be used in place of tetracycline
  • -Gastroenterol 2007; 133: 985. Review. Good article for resistant infections.
  • -Gastroenterol 2005; 129:1414-19.  Sequential Rx (amox + PPI x 5 days, then biaxin, tinidazole, PPI for 5 days) had 97% success.

Clues about constipation and more than 2.5 million views

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A recent article identifies some important factors contributing to constipation in Hong Kong children (JPGN 2012; 55: 56-61).

Using a territory-wide questionnaire in 2318, Hong Kong Chinese elementary school students, the authors identified several factors associated with constipation which was present in 12.2% of this cohort:

  • Refusal to pass bowel movements at school (OR 1.97).  In Hong Kong, students spend >8 hours per day at school.
  • Having dinner with one/both parents <50% of time (OR 1.52).  May indicate less time with parents and less parental prompting.
  • Nighttime sleep <7 hours (OR 1.87).  This is postulated to be related to increased homework and more stress which may affect gut motility.
  • Frequent fast food consumption (OR 1.14).  This may be associated with less fiber intake.

On a tangential note, one of my sons informed me of “bad lip reading” on YouTube; some of these clips are really funny.  Since there was one relevant to the subject at hand, with over 2.5 million views, I’ve provided a link:

“Everybody Poops” – a bad lip reading of the Black Eyed Peas …

Additional blog entries related to constipation:

Stimulants for constipation

Diagnostic tests hardly ever help patients poop

It’s worth the cost

Think twice about checking thyroid

Long-chain polyunsaturated fatty acids, breastmilk, and infant cognition

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A lot has been written about improving infant cognition and breastfeeding, even on this blog (More evidence that breastfeeding improves cognitive development).  Formula companies in their efforts to duplicate the nutritional value of breast milk have supplemented with a number of agents, including long-chain polyunsaturated fatty acids (LCPUFA).  But, does this work?

A meta-analysis of LCPUFA supplementation failed to show any significant effect on early infant cognition (Pediatrics 2012; 129: 1141-49).  Twelve trials with 1802 infants met inclusion criteria.  Included trials were randomized clinical studies that measured cognition with Bayley Scales of Infant Development.

LCPUFAs have been hypothesized to be a potential reason for improved cognition.  LCPUFAs are vital for cell membranes and play a critical role in development and growth.  The two main LCPUFAs are docosahexaenoic acid (DHA) and arachidonic acid (AHA). “An estimated 30-fold increase in the amount of DHA and AA in the infant forebrain occurs between the last trimester of pregnancy and the first 2 years of life.”

The authors note that while breastfed babies tend to have higher intelligence, confounding factors have made it difficult to determine whether actual nutritional differences in breast milk are the reason for this difference.  On average, breastfeeding mothers have higher intelligence, larger incomes, and spend more time with their infants.  Thus, bonding/social interactions as well as other breast milk properties (eg antimicrobial, antiinflammatory, and immunomodulatory) may be important factors.

On the same subject, a second article in the same issue (Pediatrics 2012; 129: 1134-40) also showed that breastfed infants had slightly improved cognitive development compared with formula-fed babies (both cow’s milk and soy formula).  This conclusion was based on Bayley Scales of Infant Development and the Preschool Language Scale-3.  In total, this study examined 391 infants at ages 3, 6, 9, and 12 months.  The authors state that “models were used while adjusting for socioeconomic status, mother’s age and IQ, gestational age, gender, birth weight, head circumference, race, age, and diet history”  –that’s a lot of variables to adjust!

More on breast milk from previous blog entries:

Breastfed babies less likely to develop fatty liver

Breastfeeding: protection from asthma