Category Archives: Pediatric Gastroenterology Intestinal Disorder

Adalimumab Gains FDA Approval for Use in Children

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Medications used in pediatrics often do not have a “pediatric indication” on their FDA-approved labeling.  Until recently, one of those medications included adalimumab (Humira).

Sept 25, 2014 (From MSN Money):  The Food and Drug Administration cleared Humira as a treatment for moderate to severe Crohn’s disease in children ages 6 and older when those children haven’t been helped by other treatments, AbbVie said. The North Chicago, Illinois, company said Humira can be administered at home, unlike similar drugs used to treat the condition. During the second quarter, revenue from Humira jumped 26 percent to $3.29 billion.

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NASPGHAN “Best Practices Cleanout Regimens”

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The authors of a recent report (JPGN 2014; 59: 409-16) acknowledge that “bowel regimens vary significantly” and “few clinical studies in pediatrics have evaluated the use of various bowel preparation regimens.” Furthermore, “pediatric studies did not have a common efficacy measure.”

Nevertheless, they provide a “NASPGHAN best practices cleanout regimens.”  According to Table 7:

  • Option 1: PEG-3350 (eg. Miralax) -1-day cleanout:  If less than 50 kg, then 4 g/kg/day + bisacodyl 5 mg.  If >50 kg, then 238 g in 1.5 L sports drink + bisacodyl 10 mg.   PEG-3350 administered over 4-6 hours.
  • Option 2: PEG-3350 -2-day cleanout: If <50 kg, then 2 g/kg/day + bisacodyl 5 mg; if >50 kg, then 2 g/kg/day + bisacodyl 10 mg.
  • Option 3: NG cleanout: PEG-ELS (eg. Nulytely) 25 mL/kg/h (max 450 mL/h).  NG cleanouts mainly in those with history of failed preps or other adherence problems (eg. vomiting).
  • Option 4: non-PEG cleanout: Magnesium citrate 4-6 mL/kg/day + bisacodyl 5-10 mg.

My personal opinion is that Table 7 could drop the words “best practices” since the report states “alternative dosing regimens may be entirely reasonable” and the data are quite limited.

With regard to split dosing preparations which are now recommended in adults, their role in pediatrics is a “potential area for future research.” For adults, the U.S. Multi-Society Task Force Consensus Statement on Adequate Bowel Cleansing for Colonoscopy (Johnson DA et al. Optimizing Adequacy of Bowel Cleansing for Colonoscopy: Recommendations from the US Multi-Society Task Force on Colorectal Cancer. Gastroenterology 2014; 147(4):903-924) recommends:

  • Use of a split-dose bowel cleansing regimen is strongly recommended for elective colonoscopy, meaning roughly half of the bowel cleansing dose is given the day of the colonoscopy.
  • The second dose of split preparation ideally should begin four to six hours before the time of colonoscopy with completion of the last dose at least two hours before the procedure time.
  • During a split-dose bowel cleansing regimen, diet recommendations can include either low-residue or full liquids until the evening on the day before colonoscopy. 

Take-home message: This NASPGHAN report summarizes the literature and provides recommendations for effective bowel preparations.

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Brave New World: Psychotropic Manipulation & Pediatric Functional GI Disorders

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A recent review (JPGN 2014; 59: 280-87) provides helpful advice for the use of psychotropic medications in pediatric functional GI disorders.  That being said, a couple key caveats need to be stated first and foremost:

  • “A minority of psychotropic drugs has been studied in children and safety data remain inadequate.  Psychotropic drugs used for gastrointestinal symptoms in pediatric patients will be off-label for the foreseeable future.”
  • “Descriptions of individual drugs in the present review are too brief to provide accurate guidance to someone who is not already familiar with them.”

Given the limited data, the authors, in my opinion, bravely state recommendations regarding these medications.  Despite their common usage, providing explicit recommendations is quite uncommon.  The title of the blog references Aldous Huxley’s book which discusses psychological manipulation.  This book in turn is titled after a line from Shakespeare’s The Tempest, Act V, Scene I (from Wikipedia):

“O wonder!
How many goodly creatures are there here!
How beauteous mankind is! O brave new world,
That has such people in’s.”

Back to the review of psychotropic medications, the authors provide a rationale/pathophysiologic mechanism for the use of these drugs mainly for recurrent abdominal pain and chronic nausea/dyspepsia.  Table 1 lists the authors’ specific suggestions regarding first to fourth choices:

  • For abdominal pain, first choice was amitriptyline, followed by gabapentin, clonidine patch, and SSRI.
  • For nausea/dyspepsia,  first choice was amitriptyline, followed by mirtazapine, buspirone, and clonazepam.
  • For d-IBS,  first choice was amitriptyline, followed by alosetron [not a psychotropic], clonidine patch, and SSRI.
  • For c-IBS (along with polyethylene glycol),  first choice was imipramine, followed by lubiprostone [not a psychotropic], gabapentin, and SSRI.

Table 2 provides dosing suggestions, and common adverse effects.  For example, with amitriptyline, suggested dose is 10-50 mg qhs and “best to begin low dose…titrate up by response.” Other suggestions:

  • SSRIs: “should begin with low dose; titrate up by response.  With SSRIs, benefit is usually apparent after 4 to 6 wk.  Most GI adverse effects disappear in 1 to 2 wk.”
  • Mirtazapine: 7.5 mg dosing for sleep, 15-30 mg qAM for nausea/dyspepsia (higher dose is usually not sedating.  “Few drug interactions; safer than TCAs.” Weight gain is common.
  • Buspirone: 10-60 mg/day, divided twice daily; “may start with half dose in the morning.” Avoid grapefruit juice. Can “used alone or in combination with SSRIs or TCAs.”
  • Gabapentin (100 mg BID to 800 mg TID). “Rare adverse effects include drowsiness and blurred vision…Safe but only effective in about one-third of patients.”
  • Recommends that second-generation antipsychotics (quetiapine, risperidone, and olanzapine) be used only in collaboration with child psychiatry (Figure 2)

Additional pointers:

TCAs:“In RCTs, among children with functional abdominal pain, both amitriptyline and placebo were associated with an excellent therapeutic response.”  It is interesting to note the authors lack of critical comments regarding this statement.  “The usual dose of amitriptyline for chronic functional pain is 1 mg/kg/day up to a maximum of 50 mg/day.”

TCAs and EKGs: “at doses <1 mg/kg/day used to treat chronic pain and nausea, there have been no reports of death or cardiac arrhythmias in >60 years.  An EKG before starting a TCA is unnecessary in otherwise healthy children and adolescents, but may be advisable in those with a personal or family history of corrected QT interval prolongation or heart disease, or in children requiring a dose >50 mg/day.”

TCAs: some tricyclics may be less sedating and constipating including imipramine, doxepin, and nortriptyline.  The later two also come in liquid formulations.

SSRIs: “may be used in combination with TCAs in teens and adolescents…using them simultaneously may increase serum concentrations of both.” “In children there was a single RCT showing citalopram superior to placebo in IBS. Some clinicians obtain an EKG assessing corrected QT interval before initiating citalopram doses >20 mg daily.”

Clonidine has “improved diarrhea-predominant IBS…Common adverse effects include dry mouth, drowsiness, dizziness, and tiredness…checking blood pressure at each clinic visit [is recommended].” It is available as a patch (0.1-0.3 mg/wk).

Melatonin: dosed 3- to 10-mg at bedtime can promote sleep.

Take-home message: This article provides practical advice for the use of these agents.  Discussion with patients and parents regarding the role of these medications in targeting CNS arousal which perpetuates disabling chronic symptoms is crucial as well.  More studies are needed to determine conclusively their effectiveness.

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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.

 

IBS Subtypes in Pediatrics

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A recent study (Clin Gastroenterol Hepatol 2014; 12: 1468-73) examined irritable bowel syndrome (IBS) subtypes among 129 subjects ages 7 to 18 who met Pediatric Rome III IBS criteria.  These children were part of larger studies of functional gastrointestinal disorders and recruited from primary and tertiary care centers.  Participants completed pain and stool diaries.

Key finding:

  • IBS with constipation (IBS-C) was the most common subtype (58.1%); in the other categories IBS unsubtyped (IBS-U) was next at 34.1%, then IBS with diarrhea (IBS-D) at 5.4%, and least common was mixed IBS (IBS-M) at 2.3%

The authors note that in adults with IBS studies tend to yield a more even distribution among the subtypes IBS-C, IBS-D, and IBS-U along with smaller numbers in IBS-M.

Take-home message: IBS with constipation is common in pediatrics.  Among patients who have been labelled as having isolated constipation, many in fact have IBS-C and may have persistent gastrointestinal symptoms despite the use of laxatives.

Related blog post:

Mechanisms of irritable bowel syndrome | gutsandgrowth

More Lessons in TNF Therapy (Part 2)

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Another useful study (Clin Gastroenterol Hepatol 2014; 12: 1474-81, editorial 1482-84 [podcast available: http://www.gastro.org/cghpodcast%5D) on infliximab (IFX) usage addresses the issue of reinitiating IFX therapy after a “drug holiday.”

The authors conducted their retrospective single-center study in Belgium.  This detail is important as interruption of therapy is more common in Europe where agents like IFX are often stopped when patients are doing well.  In the U.S. stopping IFX occurs more commonly when there are antibodies to infliximab (ATIs) or increased clinical symptoms.  In this particularly study, 22% were restarted on IFX after loss of response (despite dose optimization) and the remainder had been stopped either due to remission, pregnancy or patient decision. Also, in their center, patients do not receive IFX unless they were allergic or refractory to steroids and/or immunomodulators for a minimum of 3 months.

In total there were 128 patients (105 with Crohn’s and 23 with ulcerative colitis).

Key findings:

  • Reintroduction of IFX resulted in a clinical response in 84.5% at week 14, 70% at 1 year, and 61% at more than 4 years.
  • Higher response was noted in those who discontinued because of remission: 90% at week 14, 77.5% at 1 year, and 66.6% at more than 4 years.
  • In patients with prior loss of response, 45% had response to reintroduction of IFX at 1 year.
  • 15 patients had acute infusion reactions, seven of these were severe.
  • ATI-positivity was associated with a higher risk of infusion reaction, though most ATI-positive patients did not develop a reaction.  Particularly in ATI-positive patients, the editorial recommends a “slow infusion protocol and possibly steroids before administration of the drug.”
  • The editorial states: “it seems reasonable to check drug levels and antibodies before the second infliximab dose.” Trough levels >2 mcg/mL and undetectable ATIs early after restarting the drug were associated with good responses. “For patients with high ATIs (≥9.1 U/mL), another drug should be considered.”
  • Among those with detectable ATIs, response at 1 year was noted in 54.8%.
  • Immunomodulator cotherapy had a beneficial effect.

Bottomline: This study provides useful insights for patients who need to reinitiate IFX treatment.  In addition, some IFX failures may be able to resume IFX after a drug holiday.

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More Lessons in TNF Therapy (Part 1)

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More data has been published regarding postoperative therapy with infliximab (IFX) in Crohn’s disease (Clin Gastroenterol Hepatol 2014; 12: 1494-1502, editorial 1503-6).

In this prospective, open-label study with at least 5 years of followup, 24 patients who were previously randomly assigned to receive IFX or placebo for 1 year after ileocolonic resection were given the option of continuing IFX or stopping IFX (“watch and wait approach”).  This was a strange study and perhaps mirrors clinical experience in that consistent usage of IFX was not maintained in the majority; in addition, there was not a set pattern with regard to thiopurine usage.

Of 11 patients who received IFX during the first year after surgery, 8 elected to stop IFX and all 8 experienced endoscopic recurrences at a mean of 18.2 months, including 5 who needed surgery.  Of 13 patients who received placebo during the first year after resection, 12 elected to initiate IFX at 1-year entry point;  7 of those responded with endoscopic remission. Overall, the mean percentage of time that a patient received IFX was similar between those initially assigned to IFX or placebo (50.3% vs. 53%).

Key findings:

  • Among those originally assigned to the IFX group, there was a longer mean time to first endoscopic recurrence (1231 days vs. 460 days in placebo group).
  • Colonoscopy identified recurrent disease in 22.2% of patients receiving IFX compared with 93% off IFX.  That is, throughout the study there were 84 colonoscopies.  If one was receiving IFX at the time of the colonoscopy, the adjusted rate ratio for being in remission while on IFX was 13.47.
  • Among patients who received IFX for at least 60% of the full study period, they had fewer surgical recurrences: 20.0% compared with 64.3% (5 of 8).
  • Recurrence was similar for patients receiving IFX monotherapy or in combination (though small numbers preclude a definitive assessment).
  • None of the three patients who continued IFX from the beginning have required an operation in the past 8 years.

One can speculate that the main reason why so many placebo-treated patients (12 of 13) elected to start IFX was that there was evidence of recurrent disease; conversely, many of the patients who received IFX postoperatively were in remission and opted for a watch-and-wait approach subsequently.

Study limitations: small numbers, open-label design, changes in therapy at patient’s physician discretion, and no restrictions on use of concomitant medications.

The associated editorial recommends the use of IFX postoperatively in high-risk patients (perforating disease, smokers, >1 surgical resection) and notes that therapy should be started 2-4 weeks after surgery because IFX is “less effective in preventing medical recurrence if started after endoscopic recurrence.”  The editorial suggests that low-risk patients should undergo a 6- to 12-month endoscopic evaluation.  Though, “we urgently need data from large prospective studies such as the PREVENT trial” (NCT01190839) as well as the POCER study.

Bottomline: Infliximab, administered within 4 weeks of an ileocolonic resection, reduces postoperative recurrence of Crohn’s disease and helps prevent further surgeries.  Studies (like this one) with long followup are essential to determine the effectiveness of anti-TNF (tumor necrosis factor) therapies.  It remains unclear whether only “high-risk” patients should receive anti-TNF therapy or whether these agents should be used more broadly.

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ImproveCareNow Video

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A recent (short ~2:30) ImproveCareNow (ICN) Video explains how ImproveCareNow is a forward-thinking network and how it has the potential to lead to better outcomes for children with inflammatory bowel disease.

If you are part of ICN, this video may help explain to your patients what ICN is all about.

Pattern of Skin Reactions to Anti-TNF Agents

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A recent study indicated a high rate of skin reactions to anti-TNFα in their pediatric inflammatory bowel disease (IBD) population (Inflamm Bowel Dis 2014; 20: 1309-15).

In a two-year prospective study, 84 children with IBD (64 with Crohn’s) who were receiving infliximab infusions were screened for skin changes and had labwork (blood tests and stool calprotectiin).

Key findings:

  • 40 (47.6%) had chronic skin reactions and half of these were considered severe. However, when looking at the “severe” lesions shown in Figure 2, one might question the characterization.
  • Ear lobes and scalp were affected most frequently with psoriasis-like manifestations, followed by eyelids, perioral and pubic areas, trunk, and extremities.
  • Skin reactions were more common in those with a low degree of intestinal inflammation based on calprotectin levels: 133 mg/g in those with skin changes compared with 589 in those without.
  • Seven patients (8.3% of entire cohort) discontinued therapy due to skin reaction.
  • Most patients responded well to topical potent corticosteroids.

Take-home message: In this prospectively-followed cohort, there was a surprisingly high rate of skin reactions.  In patients receiving anti-TNFα therapy, it is a good idea to look closely at their ears and scalp.

Related blog post:

TNF Antagonists and Psoriasis | gutsandgrowth

Is a Continuous IV Proton Pump Inhibitor Really Necessary for GI Bleeders?

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A recent systemic review and meta-analysis (JAMA Intern Med. doi10.10001/jamainternmed.2014.4056) calls into question the practive of using continous intravenous proton pump inhibitor (PPI) for high-risk bleeding ulcers.

“Current guidelines recommend an intravenous bolus dose of a proton pump inhibitor (PPI) followed by continuous PPI infusion after endoscopic therapy in patients wtih high-risk bleeding ulcers.  Substitution of intermittent PPI therapy, if similarly effective as bolus plus continous-infusion PPI therapy, would decrease the PPI dose, costs, and resource use.”

Ultimately, only randomized 13 studies (Table 1) were identified that examined only high-risk ulcers, and used appropriate treatment protocols.  Table 2 lists the results with regard to recurrent bleeding, mortality, surgery, blood transfusions, and length of hospital stay as well as the number of patients; 1691 patients had data for rebleeding within 30 days.  Typically, intermittent PPI dosage was 40-80 mg BID.

Key findings:

  • There was not an increased risk of rebleeding with intermittent vs bolus-continuous; at 7 days, the risk ratio was 0.72 favoring intermittent treatment and the absolute difference was -2.64% (predefined noninferiority was a margin of 3%)
  • The absolute risk difference for all outcomes was less than 1.5% for all rebleeding outcomes.  Using the 95% confidence interval for absolute risk difference, the values were -0.28, 0.17, and 1.49for rebleeding within 7 days, 3 days, and 30 days.

Bottomline: this systemic review indicates that intermittent PPI therapy may be similarly effective as continuous drip PPI for meaningful outcomes in high-risk bleeding ulcers.

Related blog post:

All bleeding stops | gutsandgrowth

Accuracy of ENT diagnosis of Reflux Changes

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Many gastroenterologists suspiciously view a diagnosis of laryngopharyngeal reflux (LPR) as assessed by an Ear, Nose, and Throat (ENT or otorhinolaryngologist) physician.  This is due to a high degree of variability of these visible findings in a number of studies.  A recent pediatric study reaches the same conclusion (J Pediatr 2014; 165: 479-84).

In this study, the authors recruited 52 infants in an effort to establish a reflux finding score for infants (RFS-I).  This infant scale was modified based on a previous RFS developed in adults (Laryngoscope 2001; 111: 1313-7).  In these infants, scored videos were evaluated by 3 pediatric ENTs, 2 adult ENTs, and 2 gastroenterology fellows.

Specific finding:

  • “laryngeal erythema/edema showed the lowest observer agreement…it is often speculated that laryngeal edema is caused by LPR, but no convincing evidence is available to support this theory.”

Bottomline: “Only moderate interobserver agreement [of the RFS-I] was reached with a highly variable intraobserver agreement…the RFS-I and flexible laryngoscopy should not be used solely to clinically assess LPR related findings of the larynx, nor to guide treatment.”

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