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Do Enemas Help Nonretentive Encopresis?

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No –according to a recent study (J Pediatr 2013; 162: 1023-7).

In this study, 71 children (76% boys, median age 9 years) with functional nonrententive fecal incontinence (FNRFI) were randomized to receive conventional therapy (control group) or conventional therapy along with daily enemas for 2 weeks.  Conventional therapy was considered education, toilet training, behavioral strategies, and a daily bowel diary with reward system. All children were instructed to defecate on toilet for 5 minutes after each meal.  Treatment success was defined as <2 episodes of fecal incontinence (FI) per month.  Outcomes were measured at 6 weeks, 12 weeks, 6 months, and 12 months after the start of treatment.

Results:

  • At the start, median FI was 6.1 per week and median defecation frequency was 7.0 per week.
  • In both the control group and the treatment group, there was improvement.  After the initial 6 weeks of treatment, FI episodes were 2.0/week in the control group and 1.0/week in the treatment group.
  • The treatment success at long-term followup was 17% for both groups.

In the discussion, the authors note that a longer course of enemas (> 3 months) could be needed to improve long-term outcomes.  They also note a high rate of daytime (31%) and night time (35%) urinary incontinence in these children; “we hypothesize that children with FNRFI not only deny or neglect their urge to defecate but exhibit the same behavior toward micturation.”

Take-home message: Both treatments improved the frequency of FI (and urinary incontinence); however, neither were highly effective.  Short-term use of enemas is not likely to have a meaningful effect.  Better treatment strategies are needed.

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Drug Shortages and Selenium Deficiency

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If you participate in the care of patients who are dependent on parenteral nutrition, then you are familiar with frequent component drug shortages.  Generally, attempts to manage these shortages involve rationing and targeting those with the greatest need.  In one institution, this was not effective in preventing biochemical deficiency of selenium (JPEN 2013; DOI 10.1177/0148607113486005).  Thanks to Kipp Ellsworth for this reference.

The authors describe five pediatric patients who were completely dependent on parenteral nutrition due to intestinal failure.  During a 9-month shortage of intravenous selenium, all five who were previously selenium replete had deficiency identified (level <20 ng/mL).

After these deficiencies were identified, the patients were placed on Multitrace-5 (MTE-5).  This multivitamin contains 20 mcg/mL of selenium.  While patients prior to the shortage typically received 50-75 mcg/day, after instituting MTE-5, they received 10-26 mcg/day.  Nevertheless, this helped prevent any clinical evidence of deficiency.  In patients with selenium deficiency, there is an increased risk of cardiomyopathy, chronic illness, and death.

The authors note that their preference is to individually dose the specific trace elements and that MTE-5 can contribute to elevated levels of manganese and chromium with long-term usage.

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Related references:

  • -Gastroenterol 2009; 137: S61-S69.
  • -J Pediatr 2011; 159: 39.

Overlooking Important Detail$ in Hereditary Angioedema Treatment

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Several approved treatments are now available for Hereditary Angioedema (HAE) attacks. A recent article highlights the effectiveness in 46 children who received 2237 infusions of nanofiltered C1-esterase inhibitor (C1 INH-nf) treatment (J Pediatr 2013; 162: 1017-22).

Background:  HAE prevalence: 1 in 50,000.  Though it is inherited in an autosomal dominant manner, up to 25% of case are de novo. HAE is characterized by recurrent episodic attacks of subcutaneous edema of the skin, GI tract or upper airway.  Symptoms often present between 4 and 11 years of age.  GI tract symptoms are often recurrent colicky abdominal pain. Triggers for attacks may include infections, emotional stress, and trauma (e.g. bodily contact from play).

This manuscript provides data from 4 prospective clinical trials of  C1 INH-nf (Cinryze).  Most children in this study responded within 30 minutes compared with 2 hours for placebo.  Therapy also reduced the rate of attacks.  One interesting aspect of the study was its lack of any mention of cost.

From UptoDate:  “Cost of first-line therapies — All first-line therapies for acute attacks of HAE are costly. In the US, the cost of one treatment with C1INHRP,ecallantide, or icatibant ranged from $5000 to $10,000.”  Hereditary angioedema: Treatment of acute attacks – UpToDate

From a Hereditary Angioedema – RegenceRx website: “As a preventative therapy, C1 esterase inhibitor (Cinryze) is significantly more costly than other formulary alternatives (~$500,000 per year; ~250 times more than danazol). For acute treatment of an HAE attack, C1 esterase inhibitor (Berinert) and ecallantide (Kalbitor) costs approximately $6,000 to $10,000 per attack. Cost may double if re- treatment is needed within 24 hours.”

Additional reference:

  • -Eur J Pediatr 2012; 171: 1339-48.  Consensus of therapeutic strategies for HAE.

Liver Injury from Anti-TNF Agents

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While anti-TNF agents have been associated with drug-induced liver injury (DILI), it has been difficult to get a handle on how much importance to place on this.  A recent study provides more data and some reassurance (Clin Gastroenterol Hepatol 2013; 11: 558-64).

The authors searched the U.S. DILI Network database from 2003 to 2011 and describe 6 cases of anti-TNF DILI; in addition, they searched PubMed for articles related to anti-TNF agent associated hepatotoxicity and identified an additional 28 cases. Other causes of liver disease were excluded in these patients, including reactivation of hepatitis B, and acute viral hepatitis (eg. hepatitis C, hepatitis E).

Results of anti-TNF hepatotoxicity:

  • 26 cases due to infliximab, 4 cases due to etanercept, and 4 due to adalimumab.
  • Based on scoring system, the anti-TNF agent was considered a definite cause of DILI in 1 (3%), very likely in 21 (62%) and probable in 12 (35%).
  • Median latency (duration of therapy before onset of DILI) was 13 weeks with a range of 2-104 weeks.
  • 22 (67%) had positive anti-nuclear and/or smooth muscle antibodies.  15 of 17 of these patients had liver biopsy features consistent with autoimmunity.
  • Among those 22 with autoimmune features, there was a higher peak alanine aminotransferase compared with the 12 without these features (784 vs 528 U/L)
  • Favorable outcome: all but one patient improved after discontinuation of the implicated drug; 12 received corticosteroids. One patient with underlying cirrhosis underwent liver transplantation after infliximab-induced liver injury.

While the authors note the potential for a class effect of anti-TNF agents, in studies from patients with psoriasis, there was a lack of cross-toxicity between etanercept and infliximab.

Take-home messages:

The risk of hepatocellular injury from anti-TNF agents is very low.  DILI due to anti-TNFs often have autoimmune features. The prognosis is favorable, and alternative anti-TNFs can be given after resolution.

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Chronic Care Mode: GJ tube Data

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A lot has changed in the field of pediatric gastroenterology since I completed my training 16 years ago.  One technology that is used frequently now is the gastrojejunal (GJ) tube for feeding neurologically-impaired children.  Previously, GJ tubes were used as a temporary solution.  Part of the rational for short-term usage was that these tubes were often difficult to maintain; they could easily become dislodged or clogged.

A recent study documents the more frequent usage of GJ tubes and their indefinite usage to treat complex feeding issues (JPGN 2013; 56: 523-27).

This retrospective chart review encompassed a 10 year period (1999-2009) at a single academic center.  In total 33 patients were treated with GJ tubes with 160 placements.  The mean age at initial placement was 6 years and the mean weight 19.4 kg. 76% of the patients had cerebral palsy/neurologic disorder, 21% had congenital heart disease, and 9% had chronic lung disease.

Common indications for replacement: dislodgment, obstruction, coiling into stomach, and broken tubing.

Three techniques were used:

  1. Fluoroscopy with guide wire and subsequent GJ
  2. Gastroduodenscopy via gastrostomy site to place guidewire for GJ placement
  3. Tube placement during esophagogastroduodenoscopy

Most procedures (85%) did not require sedation.

Outcomes:

  • 13 (39%) maintained on GJ throughout study period
  • 10 (30%) converted to gastric or oral feeds
  • 5 (15%) surgical intervention
  • 5 (15%) deceased
  • Duration of tube survival: mean 91 days for Mic-Key GJ (low profile) and 177 days for  coaxial PEG-PEJ (e.g. 16 French Corflo gastric tube with 6 French jejunal tube)

When reading the study, it is hard to ignore Figure 3 which shows more than 30 placements per year after 2007 whereas the number was about two per year before 2001. In the discussion, the authors do not focus on how this technology has been embraced so widely.  It is mostly a discussion on the indications, methods, and complications.  Indications included high aspiration risk, intractable vomiting, failed Nissen fundoplication, and gastroparesis.  “Our study showed that long-term jejunal feeding via GJ tubes is possible and safe.”

My preference is generally to avoid GJ feedings as a primary intervention for long-term feeding problems.  That is, when patients need gastrostomy tube feeds but are prone to vomiting, most often a fundoplication is worthwhile.  When a patient has had a fundoplication that is no longer effective, a GJ tube should be considered.

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Spina Bifida, Humility, and Quality of Life

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While a recent article (J Pediatr 2013; 162: 993-98) on spina bifida and its effect on quality of life provide useful information, the accompanying editorial by John Freeman (J Pediatr 2013; 162: 894-95) had much broader implications for me.

The referenced article provides data showing the effects of spina bifida on quality of life QOL), even in those who reported their current health as good.  The tools that the investigators used for 40 youth and 13 young adults were the HUI-3 and AQoL.  Both of these tools correlated health-related QOL (HR-QOL) and the level of the anatomic lesion; those with thoracic/higher lesions had worse HR-QOL.

Some of the points made by Dr. Freeman:

  • Quote at start: “Health: A state of complete physical, mental, and social well-being and not just the absence of sickness or frailty.” –World Health Organization
  • In 2004, he followed up with two patients who he had presumed to be quite successful.  Both “were living at home, wheelchair-bound, with high paraplegias.  Both were community college graduates and employed….When I asked them what I should tell parents delivering a newborn with spina bifida, each replied, ‘I wish I had never been born.’ I was shocked.”
  • He notes that the referenced article had a low participation rate (39%) which could introduce significant biases.  “Were the respondents those with greater or less disability?”
  • Conclusion: “I will not presume to have answers to these questions but propose further discussion of the quality-of-life issues…on decisions regarding early treatment of spina bifida.”

These studies make it clear that some children with spina bifida, particularly those with higher lesions, have poor HR-QOL.  The broader implication is that many children/adults who we think are doing pretty well do not see it that way.  Trying to determine what the future holds for children with chronic health problems in infancy is difficult.  Even in the most severe diseases, most parents want everything done.  Will this type of information change anything?

“Family Feud” for Pediatric Crohn’s Abscess Management

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Initially, this blog entry was titled “What is the best way to manage an intra-abdominal abscess in pediatric Crohn’s disease?”  My answer was simple: it depends on who you ask (Inflamm Bowel Dis 2013; 818-25).  As I thought about this study, the responses reminded me of “Family Feud” minus Richard Dawson.

This survey examined the responses of NASPGHAN members.  Of the initial 1608 emails which were delivered, 248 fully completed surveys.  25% of respondents were in practice for >20 years and 26% treated >50 patients with Crohn’s disease (CD). 87% of respondents were from U.S.

  • What is the best way to image initially?  52% recommended CT scan, 26% MRI, and 21% ultrasound.
  • What is the best modality for followup imaging? 47% ultrasound, 33% MRI, and 13% CT
  • Antibiotics or drainage for abscess <2 cm? 61% recommended antibiotics; 51% would treat for 3-4 weeks, whereas 19% for 1-2 weeks.
  • Antibiotics or drainage for abscess >2 cm? 28% would attempt antibiotics alone
  • When is surgery indicated? 75% said only in select cases after completing antibiotics and interventional radiology drainage.
  • Anti-TNFα therapy?  The survey also questioned the shortest preoperative interval one would prescribe anti-TNFα therapy.  The results ranged from 12% for <1 week to 45% who would not give anti-TNFα therapy at all.

The authors note that there is “a paucity of research and practice guidelines for the optimal management of children with intra-abdominal abscess.”  There were no trends in management identified based on practitioner level of experience.  Some answers to the questions are alluded to by the authors but not expressed definitively. For example, “several studies have reported a lack of association between infliximab and an increased rate of postoperative complications.” “Most infections that occur while on anti-TNFα therapy tend to be opportunistic, not bacterial.”

The study’s conclusions are limited by the low participation rate.  In addition, when physicians are confronted with a specific situation, their response in practice may be different than in a theoretical scenario.  However, it appears that the answers to these important questions are closer to guesses on a game show rather than best care.  More research and collaboration is needed to reduce this highly variable care and determine the most effective approach.

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Norovirus Impact on Young Children

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As noted in a previous blog (Norovirus -now more important than rotavirus | gutsandgrowth), Norovirus has become the most important cause of gastroenteritis in children younger than 5 years.  More data to back up that claim has been published (NEJM 2013; 368: 1121-30).

The authors examined laboratory-confirmed cases of norovirus in children younger than 5 years with acute gastroenteritis in hospitals, emergency departments, and outpatient clinical settings during the years 2009 and 2010.  Using the New Vaccine Surveillance Network (NVSN), the authors undertook a 2-year prospective population-based survey with a catchment population of more than 141,000.  The specific sites included county populations around the University of Rochester, Vanderbilt University, and Cincinnati Children’s.

Results:

  • Norovirus was detected in 21% of children with acute gastroenteritis (2009-2010); it was also detected in 4% of healthy controls.
  • The age group with the highest rates of norovirus infection in this study were 6-18 months of age.
  • The GII.4 Minerva strain was most predominant strain in 2009 and GII.4 New Orleans in 2010. (In 2012, a novel GII.4 Sydney variant has emerged).
  • Rotavirus was identified in 12% of children with acute gastroenteritis (2009-2010).
  • Using this data, the authors extrapolated national estimates (for norovirus) of 14,000  hospitalizations per year (in this age group), 281,000 emergency room visits, and 627,000 outpatient visits.
  • The estimated costs exceed more than $273 million.

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Predicting duration of reflux symptoms in babies

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A recent study identified two factors on multichannel intraluminal impedance pH monitoring (MII/pH) that correlated with the duration of gastroesophageal reflux symptoms in newborns (J Pediatr 2013; 162: 770-5).

This study examined 64 newborns who underwent MII/pH in the first weeks of life and then were enrolled in followup at 1, 3, 6, 9, 12, 18. 24, and 36 months. 53 patients completed the three-year study.

These patients were enrolled consecutively.  All preterm infants had to have a minimum postmenstrual age of 36 weeks.  Other criteria included a MII/pH study with a minimum duration of 19 hours, absence of GERD pharmacology for at least 1 week, and absence of infection, metabolic disease or central nervous system disease.

Results:

  • Impedance bolus exposure index (IBEI) and proximal reflux frequency positively correlated with duration of GERD symptoms.
  • IBEI was 1.45 in the short duration group (0-3 months), 1.85 in the medium duration group (4-9 months) and 2.46 in the long duration group (> 9 months).
  • Proximal reflux frequency (events/hour) was 1.56 in the short duration group (0-3 months), 1.95 in the medium duration group (4-9 months) and 2.38 in the long duration group (> 9 months).
  • Overall, one-half of patients were asymptomatic within the fifth month of age and the vast majority were asymptomatic by one year of age.
  • Weakly acidic events but not acid reflux events were significant in determining the differences in IBEI and proximal reflux.  As such, this study adds weight to the idea that acid blockers have little benefit in the first months of life.

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Global increases in IBD incidence

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Two more studies have shown increasing incidence of pediatric inflammatory bowel disease.

First in Victoria, Australia (mostly Melbourne) (Inflamm Bowel Dis 2013; 19: 1-6).

Over a 60-year span (1950-2009), a retrospective review was undertaken of ulcerative colitis (UC) pediatric patients. In total, 342 children were diagnosed with UC. Key finding: The number of reported cases increased by 11-fold during the study period with a marked increase since 1990 (0.15 –>1.61/100,000).  In addition, recently diagnosed children have had more extensive disease.

Next in Spain (Inflamm Bowel Dis 2013; 19: 73-80).

This retrospective study from hospitals’ databases looked at the incidence between 1996-2009 in the pediatric population (<18 years).  A total of 2107 patients were identified: 1165 with Crohn’s disease, 788 ulcerative colitis, and 154 IBD unclassified. Median age at diagnosis was 12.3 years.  Key finding: in the last 14 years, pediatric IBD incidence has almost tripled (0.9 –>2.8/100,000).

Both of these studies have limitations related to large retrospective reviews in terms of potential problems with capturing all of the patients and the potential for misdiagnosis.  However, the trend is clear.  In addition, these studies show incidence rates comparable to several other Western studies.  The increasing incidence of IBD ‘argue for a common environmental factor in their pathogenesis.’  While interest has focused on microbial factors, the basis for this increased incidence currently remains elusive.

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