Tag Archives: constipation

Prucalopride -Not Better Than Placebo for Children with Constipation

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Background: There were high expectations for prucalopride for the treatment of constipation based on previous small studies as well as a placebo-controlled trial in adults.  In adults, after 12 weeks of treatment, between 19.5-29% were responders compared to 9.6-12.1% in placebo patients. Prucalopride is a 5-hydroxytryptamine receptor-4  (5HT4) agonist which has been shown to accelerate colonic motility and is similar structurally to agents like cisapride and tegaserod; these latter medications have shown effectiveness as prokinetics but were limited by life-threatening cardiovascular side effects.

Design: Large (n=213), multicenter, placebo-controlled trial (Mugie SM, et al. Gastroenterol 2014; 147: 1285-95, editorial 1214-16). Response to medication indicated by >3 spontaneous bowel movements per week and <1 episode of fecal incontinence every 2 weeks.

Findings:

  • 17% of prucalopride subjects and 17.8% of placebo subjects were considered responders.
  • If based solely on bowel movement frequency, 29.2% of prucalopride achieved >3 BMs/week, whereas 35.5% of placebo-treated patients achieved this frequency.
  • Adverse effects were similar

Why did Prucalopride not work?

The authors and editorial make several speculations.  In children, withholding behavior is much more important in the pathophysiology of functional constipation (FC) than in adults.  In addition, slow transit constipation is much more common in adults than in children. In the adolescents (≥12 to <18) there was a mild response noted: 18.5% compared with 14.8% of placebo-treated patients (P=.38). The editorial notes that the short length of the trial (8 weeks) could explain the negative results, though this is unlikely.

The editorial, by Samuel Nurko and Miguel Saps, notes a much higher response to polyethylene glycol which “is the mainstay of treatment.”  “PEG-based solutions achieved a successful outcome in 56% of participants compared with 29% in the lactulose group.”

Take-home message: “This study does not provide new data to justify a change in the indication of PEG as first line of treatment for FC in children.”

In followup to questions regarding Miralax safety, here is a link from NASPGHAN’s Neurogastroenterology and Motility Committee: Miralax FAQ

Related blog posts:

A Sign in Our Office --Needs Clarification

A Sign in Our Office –Needs Clarification

NASPGHAN Postgraduate Course 2014 -3rd Module

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This blog entry has abbreviated/summarized the presentations. Though not intentional, some important material is likely to have been omitted; in addition, transcription errors are possible as well.  All of the speakers had terrific presentations.  The course syllabus is attached:

PG Course Syllabus 2014

The 3rd Module had a “potpourri” of GI problems.

Extraesophageal Manifestations of Gastroesophageal Reflux –Ben Gold, MD (GI Care For Kids, Atlanta) (pg 86)

“Is reflux really the scurge of the earth and the cause of every malady known to human-kind in the head, neck, and lungs…?“

Key points:

Airway protection: “Aerodigestive disease reflexes are intact by 38 weeks gestation.”

Central deglutition apnea: a normal protective mechanism to prevent aspiration during swallowing. (Hasenstab KA, Jadcherla, S. J Pediatr 2014; 165:250-255).  No proof at present that central apnea is caused by reflux though there is a biologic plausibility.

“Although reflux causes physiologic apnea, it causes pathologic apneic episodes in only a very small number of newborns and infants.”  “When reflux causes pathological apnea, the infant is more likely to be awake and the apnea is more likely to be obstructive in nature.”

Laryngeal Reflux:

  • Chronic cough, chronic laryngitis, hoarseness, and asthma may be associated with GERD BUT the data showing a relation between reflux and upper airway disease are weak
  • Airway symptoms attributed to reflux in adults include hoarseness, chronic cough, and globus sensation
  • Affected adults rarely have typical reflux symptoms
  • The sensitivity of laryngoscopic findings to identify reflux disease are poor. Sherman et al. Am J Gastroenterol. 2009;104:1278-95. Vandenplas et al. J Pediatr Gastroenter Nutr. 2009;49:498-547.

Asthma:

“Chronic cough, chronic laryngitis, hoarseness and asthma are multifactorial disease processes and acid reflux can be an aggravating cofactor.” GER is an unlikely contributor to asthma if reflux testing is negative.

“Two NIH-funded blinded, randomized placebo-controlled trials (RCT), one in adults (using esomeprazole), one in children (using lansoprazole) showed NO difference in asthma outcomes comparing placebo and acid suppression therapy”

Multi-Channel Intraluminal Impedance/pH probe studies: Pediatric studies are critically needed to determine if knowing the amount of nonacid reflux changes treatment or outcome

Proton Pump Inhibitors can cause gastric bacterial overgrowth (Rosen R et al JAMA Pediatr 2014; JAMA Pediatr. doi:10.1001/jamapediatrics.2014.696)

Ben Gold (speaker) and Jay Hochman prior to 5K Run

Ben Gold (speaker) and Jay Hochman prior to 5K Run

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EoE: PPI, PPI-REE, TCS, OVB, SFED, 4FED….…Alphabet Distress — Sandeep K Gupta, MD (Indiana University) pg 105 in Syllabus

Treatment endpoints discussed -histologic, symptomatic, fibrosis, etc.

  • Proton pump inhibitor responsive eosinophilic esophagitis (PPI-REE) may work by blocking STAT6 binding to Eotaxin-3 promoter rather than by acid suppression (PLos ONE 2012;7:e50037).  PPIs work (eos <6/hpf) in in 30-40%.  May need high dose to work long-term (Dr Molina-Infante – DDW 2014)
  • Topical corticosteroids (TCS) -higher dose = better response.  (Budesonide. Gupta SK, Vitanza J, Collins, MH Clin Gastro Hepatol 2014 [ePub], Fluticasone. Butz BK. Gastroenterology 2014). Clinical symptoms do not correlate with histologic response. Discussed long term safety concerns.
  • Reviewed diets -elemental, targeted, 4-food elimination and 6-food elimination.

Related blog posts:

“Gotta keep on movin”: New tricks and treatments for motility disorders –Carlo DiLorenzo (Nationwide Children’s Hospital) pg 116 in Syllabus

Key points:

  1. Most important motility study is a normal study.  If normal study, then there is more concern for sensory dysfunction.   Look for significant findings on motility studies not minor changes.
  2. Key to confirm if motility disorder is present. Hx/o small intestinal transplant in medical child abuse/Munchausen syndrome by proxy (Trans Proc 1996; 28: 2790)
  3. New tool: wireless motility capsule (J Pediatr. 2013;162:1181-7)
  4. Easier to obtain full thickness biopsies (Gastrointest Endosc 2011;73:949-54)

Treatments reviewed -“try everything”

  • prucalopride (JPGN 2014; 57: 197-203
  • cisapride -still available
  • lubiprostone (JPGN 2014;58:283–291)
  • linaclotide boxed warning not for <17 years of age –though has been used by motility specialists
  • cyproheptadine (J Pediatr 2013; 163: 261-7) –use in dyspepsia
  • fludrocortisone -used in orthostatic intolerance
  • augmentin -for small bowel motility (JPGN 2012;54: 780–784)
  • octreotide -for bowel motility
  • pyridostigmine (Colorectal Disease 2010 12, 540–548)
  • iberogast
  • botulinum toxin (Gastrointest Endosc. 2012 ;75:302-9)
  • treat bacterial overgrowth
  • surgery: Jube, GJ tube, ileostomy. “Every child with pseudoobstruction on TPN needs a gastrostomy and an ileostomy –(me, now)”
  • gastric electrical stimulation
  • emerging treatment: Elobixibat (for constipation) Expert Opin. Investig. Drugs

Related blog posts:

What’s New in the Diagnosis and Management of Constipation –Manu Sood (Children’s Hospital of Wisconsin) -page 130 in Syllabus

Reviewed recent guidelines from NASPGHAN

“Miralax is considered a 1st line agent”

Outcomes in children with constipation:

  • Almost 50% of patients experienced at least one relapse in first 5 yrs.
  • Almost 20% of children were symptomatic at 10 yrs. follow up (Bongers ME, et al. Pediatrics. 2010)

Pointers:

  • Slow transit is common
  • Rectal compliance does not predict success with treatment. Van den Berg MM, et al. Gastroenterology 2009.  Patients with mega-rectum may have motility disturbance as well.
  • Success rates for antegrade continence enemas (ACE) 65% to 89%. Colon manometry can help predict ACE success.  Up to 40% may be able to stop ACE w/in 2 years

Related blog posts:

Link to NASPGHAN Lectures and Postgraduate Course

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Later this week, our national pediatric GI meeting (North American Society for Pediatric Gastroenterology Hepatology and Nutrition) is starting in Atlanta.  Many in my group are involved and presenting.

The following link (with permission from NASPGHAN) is to the website with links to all of these lectures:

NASPGHAN 2014 Atlanta meeting

For those interested only in the Syllabus for the Postgraduate Course:  NASPGHAN 2014 Postgraduate Course.

Topics include in this 200 page (online) book: primary sclerosing cholangitis, jaundiced infant, acute liver failure, “dreaded” endoscopy wake up calls, endoscopy for biliary tract disease, extraesophageal manifestations of gastroesophageal reflux, constipation, eosinophilic esophagitis, motility disorders, FODMAPs diet, nutrition for neurologically impaired, early onset inflammatory bowel disease, “luminitis” due to non-IBD causes, new IBD treatments, and diet-microbiome.

Should be great!

Also, to plan your meeting -go to NASPGHAN home page and use mobile guidebook: NASPGHAN 2014 has gone mobile using Guidebook!

Naloxegol for Opioid-Induced Constipation

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Opioid narcotics are ubiquitous therapeutic agents for acute and chronic pain.  In the United States, more than 240 million opioid prescriptions are dispensed per year.  One of the most common sided effects is constipation.  The mechanism of this side effect is the binding of opioid agonists to μ-opioid receptors located in the enteric nervous system.

The recognition of this mechanism has allowed the development of μ-opioid receptor antagonists. A recent study has shown that Naloxegol helps treat constipation related to opioids in patients with noncancer pain (NEJM 2014; 370: 2387-96).  Naloxegol is a pegylated derivative of the μ-opioid receptor antagonist naloxone.  Pegylation limits the ability of naloxegol to cross the blood-brain barrier; hence, the central pain effects of narcotics are not blocked whereas the effects on the enteric nervous system are limited.

This study reported the results of two phase 3, double-blind studies with a combined 1352 participants.  Response to treatment was defined as having ≥3 spontaneous BMs/week and an increase in baseline of ≥1 spontaneous BM/week for ≥9 of 12 week study period and for ≥3 of the final 4 weeks.

Key results:

  • Response to Naloxegol at 25 mg dosing: 44.4% in first study and 39.7% in second study (compared with 29% of placebo treated patients in both studies).
  • Most adverse effects were mild to moderate and included increased abdominal pain, diarrhea, nausea, and flatulence.  Major cardiovascular events were rare and not increased compared to placebo.

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What’s Wrong with Ordering an AXR for Constipation in the ER?

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My understanding is that shortly before my twin and I were born, a nurse used a pencil test to predict our genders.  Though my mother is quite smart, she believed the nurse knew what she was doing.  However, shortly thereafter, it turned out that I had a twin brother not a twin sister.

ER doctors often perform a similar service to the pencil test when they use an abdominal radiograph (AXR) to determine if their patients have constipation.  A new pediatric study from Toronto highlights this phenomenon and current recommendations (J Pediatr 2014; 164: 83-8).

Background:  this retrospective cohort study of children <18 years took place between 2008-2010.  As part of the study, a single pediatric radiologist (blinded to participant classification, assigned Leech scores to all misdiagnosis AXRs along with 20% of the remaining AXRs.  From a total of 112,381 ER visits, the review identified 3987 where constipation was the discharge diagnosis (3.5% of all visits).  In the cohort diagnosed with constipation, the mean age was 6.6 years.

Key findings:

  • Only 9% of children returned within 7 days.  20 of these (0.5%) had a significant misdiagnosis based on the authors definition, including 7 with perforated appendix, 2 with intussception, and 2 with bowel obstruction.  Other misdiagnosis included ovarian torsion, thalamic brain tumor, acute lymphoblastic leukemia, cardiomyopathy, ileal volvulus, and pancreatitis.
  • Children with a misdiagnosis had similar amounts of stool on AXR as those who were not misdiagnosed.
  • AXR was performed more frequently in those with a misdiagnosis (75% vs. 46%).
  • Rectal examination was documented in only 9% of those with a diagnosis of constipation (low frequency rectal examination has been shown in other ED-based studies).
  • Abdominal pain and tenderness were more common in those with a misdiagnosis.

Why I think this study is important:

While the authors point out that 1 in 200 children ultimately required a surgical or radiologic  intervention within 7 days, I do not think that this error rate or diagnostic delay is particularly high.  What is important is that this study reiterates the fact that AXRs are not useful for the diagnosis of constipation.  The authors note “reviews have concluded that there is no evidence of an association between clinical symptoms of constipation and fecal loading on AXR.”  Furthermore, AXRs may lead ER physicians to a cognitive diagnostic error.

Also, the misdiagnosis rate is much greater than reported in the study due to the definition adopted by the authors.  The authors did not include treatable infectious diseases (e.g.. pneumonia, urinary tract infection) as well as a large number of other medical diagnosis. Other “incipient” disease processes may have been missed including inflammatory bowel disease and celiac disease.

The authors imply that using a more standard definition of constipation would be useful, namely the Iowa criteria which requires the presence of 2 of the following:

  • ❤ stools/week,
  • ≥1 episoded of fecal incontinence/week
  • large stool palpable on rectal/abdominal examination
  • passing large stool which obstructs toilet
  • withholding posturing
  • painful defecation

The authors reference a study which indicated that AXRs should be restricted to patients with high-yield clinical features: prior abdominal surgery, foreign body ingestion, abnormal bowel sounds, addominal distention, and peritoneal signs.

Bottomline: AXRs do not establish a diagnosis of constipation.  Yet, after families have been told their child is constipated because of an AXR it is not easy to convince them that an AXR is about as useful as a pencil test for this diagnosis.

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What helps kids poop?

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While there are a number of answers to the above title, the answer that I’m looking for is physical activity (JPGN 2013; 57: 768-74).

With regard to the referenced study, a large prospective birth-cohort study (n=347 participants) in Rotterdam showed that preschool children with increased physical activity had about 1/3rd less frequency of functional constipation in the fourth year of life.  Activity measurements at the age of 2 years were accomplished by wearing ActiGraph accelerometers during 1 weekday and 1 weekend day.  Additionally, children who had physical activity of 60 min/day at age 4 had about 1/2 the likelihood of having functional constipation.  There are several limitations to the study; reduced activity and constipation could both be present in some individuals as a consequence of personality or psychologic attributes rather than physical activity having a causal relationship in causing constipation.

Bottomline: Another good reason to encourage physical activity –it might help with regular bowel habits.

Also, on a separate note, a recent blog post by Kipp Ellsworth is a useful reference for lab monitoring (micronutrients and vitamins) in children with short bowel syndrome:

Blog | The Pediatric Nutritionist | Covering the world of infant, child …

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Updated Pediatric Expert Constipation Guidelines

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Updated guidelines for the diagnosis and treatment of constipation by NASPGHAN and ESPGHAN have undergone formal peer review are likely to be published soon (available online with the following link: bit.ly/1geLxrk).  “Evidence-Based Recommendations from ESPGHAN and NASPGHAN for Evaluation and Treatment of Functional Constipation in Infants and Children” by Merti Tabbers, Carlo DiLorenzo et al. The following are some of their recommendations.

Diagnostic recommendations:

  • The ROME III criteria are recommended for the definition of functional constipation for all age  groups.
  • Diagnosis of functional constipation is based on history and physical examination.
  • There is no role for the routine use of an abdominal X-ray to diagnose functional constipation.
  • A plain abdominal  radiography may be used in a child in whom fecal impaction is  suspected but in whom physical examination is unreliable/not possible.
  • Based on expert opinion, a 2-4 weeks trial of avoidance of cow’s milk protein may be indicated in the child with intractable constipation.
  • Routine laboratory testing to screen for hypothyroidism, celiac disease and hypercalcemia is not recommended in children with constipation in the absence of alarm symptoms. 

Treatment Recommendations:

  • We do not recommend the use of biofeedback as additional treatment in childhood constipation.
  • Polyethylene glycol (PEG) with or without electrolytes orally 1-1.5 gr/kg/day for 3-6 days is recommended as first-line treatment for children presenting with fecal impaction
  • An enema once a day for 3-6 days is recommended for children with fecal impaction if PEG is not available.
  • PEG with or without electrolytes is recommended as first-line maintenance treatment. A starting dose of 0.4 gr/kg/day is recommended and the dose should be adjusted according to the clinical response.
  • Addition of enemas to the chronic use of PEG is not recommended.
  • Based on expert opinion, use of milk of magnesia, mineral oil and stimulant laxatives may be considered as additional or second line treatment.
  • Antegrade enemas are recommended in the treatment of selected children with intractable constipation.

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“Poo in You” Video

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New “Poo in You” education video for constipation / encopresis available through YouTube channel: http://www.youtube.com/NASPGHANencopresis

I took a look at this 5 minute video and it explains why kids soil and the basics of treatment; in addition, there is a “wah-wah-wah” sound effect at 2:29 in video when soiling occurs.  Probably worth including this link on an after visit summary:

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Constipation Guidelines:

Data Supporting Miralax

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A summary of the effectiveness of polyethylene glycol for chronic constipation, fecal disimpaction, and as a bowel preparation are presented in a recent article (JPGN 2013; 57: 134-40).

The article provides information on the biochemistry and mechanism of action along with a good number of references –49.

From the summary:

“PEG is an osmotic laxative used in children in the last few years.  It is more effective than lactulose for the treatment of chronic constipation.  It is equally effective compared with milk of magnesia and mineral oil for the long-term treatment of constipation but has a much better acceptance rate…It is a safe medication without any significant adverse effects.  Because PEG can be mixed in a beverage of the patient’s choice, it has excellent long-term patient acceptance.”

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Newsflash: constipation frequently causes abdominal pain

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From the following link (forwarded to me by Mike Hart) http://www.dailyrx.com/abdominal-pain-children-emergency-room-was-most-commonly-constipation:

A recent study found that constipation is the most common reason for abdominal pain among children going to one emergency room.

Appendicitis was diagnosed in only about 4 percent of children who went to the ER.

In addition, the researchers did not find any major differences in the treatment or outcomes of children based on their race.

“Call the pediatrician if your child has severe abdominal pain.”

The study, led by Kerry Caperell, MD, of the Department of Pediatrics at the University of Louisville in Kentucky, looked at the outcomes of children who went to the emergency room for abdominal pain.

The researchers investigated the medical records of 9,424 children, aged 1 to 18, who went to the Children’s Hospital of Pittsburgh emergency department for abdominal pain during a two-year period.

More than half of these children, a total of 5,493, ended up receiving multiple diagnoses for their complaints.

The researchers found that 1.9 percent of the African American children and 5.1 percent of the white children who visited the ER were diagnosed with appendicitis. Overall, 4.3 percent of the children had appendicitis.

Appendicitis was less common among younger children, but constipation was commonly diagnosed for all ages.

Almost 20 percent of the children were diagnosed with constipation, and more than 25 percent of the children aged 5 to 12 had constipation.

Constipation, gastroenteritis and urinary tract infections were more common among the African American patients than the white patients.

“Diagnosing causes of abdominal pain in children can often be difficult, especially the younger they are,” said Chris Galloway, MD, a dailyRx expert who specializes in emergency medicine.

“Fortunately common causes are still common and constipation is a frequent diagnosis we make in the ER, and can be quite distressing for your child,” Dr. Galloway said. “Consult your pediatrician if your child has abdominal pain.”

Older children were more likely to remain in the hospital and have an operation related to the reason they went to the ER.

The researchers did not find any differences in children’s outcomes related to their race. This finding means that all the children who went to the ER received similar evaluation and treatment and had similar outcomes regardless of their ethnicity.

The study was published May 20 in the journal Pediatrics. The research did not receive external funding, and the authors declared no conflicts of interest.

Comment: While constipation is a common entity, many of these children have underlying functional problems that are not addressed in the ER setting.

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