Electrocardiograms -Will We Ever Know If They Are Useful Prior to Tricyclic Antidepressants?

LJ Klein et al. JPGN 2021; 73: 523-528. Electrocardiogram Before Tricyclic Antidepressant Use: Minimal Impact in Pediatric Functional Gastrointestinal Disorders

Key findings from this retrospective review (n=233):

  • TCAs were not started in only 1.7% (4/233) due to ECG results
  • Eight (3.4%) had a cardiology referral; one (0.4%) had a prolonged QTc interval
  • No deaths and no emergency department or hospital visits for arrhythmia or drug overdose occurred

The discussion lists a number of studies generally questioning the utility of pre-medication ECGs while at the same time acknowledging that guidelines in the GI and psychiatric literature support an ECG prior to TCA use. In a large study of sudden cardiac deaths in an adult population, there was no increased risk of death with TCA dosing less than 100 mg/day (Clin Pharmcol Ther 2004; 75: 234-41).

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My take (borrowed in part from authors): While “the benefit of screening ECGs remains elusive,” it is still needed to try to avoid “extremely rare but catastrophic events.” The authors, however, recommend followup ECGs only on “patients on concomitant QT prolonging medications or increases to higher dosing ranges.”

“Turning Purple with Pain”

A recent clinical problem-solving case (TW Fredrick et al. NEJM 2021; 385; 549-554. Turning Purple with Pain) is a good review on episodic pain and acute intermittent porphyria (AIP).

The case presentation regarded a 32 yo with episodic severe pain for 10 years (associated with constipation) that required morphine. Episodes occurred every month or two and lasted for several days. Some clues in this case included the development of hyponatremia, purple urine, and an episode in which she was “out of it.” This episode was attributed to opioid use and providers were concerned about opioid-seeking behavior and a conversion disorder.

She had extensive evaluations including imaging, panendoscopy, and labs. Atypical labs included serum tryptase, cortisol, and C1 esterase inhibitor level. Ultimately, her constellation of findings led to a urine porphyrin levels which disclosed elevated porphobilinogen (PBG) and delta-aminolevulinic acid. The diagnosis of AIP was confirmed with genetic testing.

Key points:

  • AIP results from mutations in HMBS, the gene encoding hydroxymethylbilane synthase which plays an integral role in heme synthesis
  • AIP is rare, affecting about 5 people per million; age of onset is typically 18-45 years of age
  • In a case series, 18% of patients with AIP reported nearly constant abdominal pain symptoms, 73% had nausea/vomiting, 60% have constipation, and 55% had anxiety/depression.
  • Associated conditions included hypertension ((43%), peripheral neuropathy (43%), chronic kidney disease (29%), psychiatric disorders (22%), palpitations (19%), seizures (9%), cirrhosis (2%), and hepatocellular carcinoma (1%)
  • Flares of AIP may be triggered by alcohol, infections, low caloric intake, and medications (especially seizure medications and hormonal contraceptives)
  • The urine can appear red or brown and darkens on exposure to oxygen, light or heat. Purple urine reflects very high urinary PBG levels

My take: This article provides a useful overview. AIP needs to be considered in adolescents with severe abdominal pain that results in hospitalization (especially if episodic).

Related blog post: Liver Shorts -June 2020 (with AIP article)

Also, data supporting COVID-19 effectiveness in reducing the risk of hospitalization–CDC study shows unvaccinated people are 29 times more likely to be hospitalized with Covid (CNBC)

Sterling Pond. Jeffereson, VT

Prospective Pediatric Study of the Persistence and Progression of Recurrent Abdominal Pain

J Sjolund et al. Clin Gastroenterol Hepatol 2021; 19: 930-938. Prevalence and Progression of Recurrent Abdominal Pain, From Early Childhood to Adolescence

Using a prospective, population-based Swedish cohort (1994-1996) (BAMSE project), the authors analyzed data from 2455 children with complete follow-up evaluation at ages 1, 2, 12, and 16 years.

Key findings:

  • RAP was reported by 26.2% of children on at least 1 of 3 assessment points, of which 11.3% reported symptoms more than once
  • Children with RAP at 12 years had persistent symptoms at 16 years in 45% of cases and increased risks for RAP (relative risk, 2.2; 95% CI, 1.7–2.8), any AP-FGID (relative risk, 2.6; 95% CI, 1.9–3.6), and IBS (relative risk, 3.2; 95% CI, 2.0–5.1) at 16 years
  • Figure 3 summarizes the overlap of RAP at different time points:
  • **In early childhood (1-2 years of age), 149 (6%) had RAP per parental reports. Only 27 in this group, had RAP noted at 16 years of age which accounted for 7% of the total 16 year old cohort with RAP
  • **At 12 years of age, 98 (4%) had RAP. 44 (45%) of this group continued with pain at 16 years which accounted for 11% of the total 16 year old cohort with RAP

My take: Most children (84%) with RAP at 16 years of age did NOT report RAP at younger ages; however, in children with RAP at 12 years of age, 45% continued to have RAP at 16 years of age.

Related blog posts:

Narrowing the Workup for Chronic Abdominal Pain –Carlo DiLorenzo Was Right!

In the good old days when we could have large meetings, Carlo DiLorenzo gave a terrific summary of recurrent abdominal pain (#NASPGHAN19 Postgraduate Course -part 3).  One of the slides, shown below, is supported by a new study (J Zeevenhooven et al. J Pediatr 2020; 219: 76-82)

In this recent reterospective study, the authors examined 853 patients, of whom 102 (12%) had an organic disorder; all had abdominal pain >2 months. The authors compared two diagnostic strategies:

  • Group 1: anti-TTG IgA, fecal calprotectin, Giardia, along with blood tests (hemoglobin, CRP, ESR)
  • Group 2: anti-TTG IgA, fecal calprotectin, and Giardia (if diarrhea)

Calprotectin was considered normal if <50 mcg/g,  “gray zone” if 51-250, mildly elevated if 251-1000, and elevated/active inflammation if >1000.

Key findings:

  • Sensitivity of the strategies was 90% and 88% for Group 1 and Group 2 respectively
  • In the presence of 1 or more alarm symptoms, the sensitivity was 92% for both strategies.
  • The sensitivity/specificity of calprotectin varied based on the cutoff value.
    • For >50, the sensitivity 75%, specificity 87%, PPV 44%, and NPV 96%
    • For >250, the sensitivity 48%, specificity 99%, PPV 82%, and NPV 93%
    • For >1000, the sensitivity 38%, specificity 100%, PPV 98%, and NPV 92%

Alarm symptoms

  • Alarm symptoms that were statistically different in the organic group included the following:
    • Chronic diarrhea (P <.001), occurred in 32% organic compared to 6% functional
    • GI blood loss (P <.001) , occurred in 35% organic compared to 5% functional
    • Recurrent vomiting (P=.029), occurred in 10% organic compared to 5% functional
    • Perianal complications (P=.001), occurred in 6% organic compared to 1% functional
    • Impaired growth (P=.023), occurred in 4% organic compared to 1% functional
  • Interestingly, the study found that having a positive family history of IBD/celiac/FMF did not differentiate functional and organic patients, occuring in 12% and 15% respectively.
  • Pain in RUQ or lower region also did not differentiate functional and organic patients, occuring in 3% and 4% respectively.
  • The authors note that 30 (29%) patients with organic disease did not have an identified alarm symptom -this compares to 479 (64%) patients with functional disease did not have an identified alarm symptom

From my experience with our recent study (Digestive Diseases (Full Text): Diagnostic Yield Variation with Colonoscopy among Pediatric Endoscopists) which focused on diagnostic yield with colonoscopy, it is clear that there are significant limitations with data collection in a retrospective study regarding recurrent abdominal pain.  Even the definition of chronic diarrhea may vary considerably among practitioners.  At the same time, we did find that an abnormal calprotectin had the highest diagnostic yield (See related blog post for summary: Our Study: Provider Level Variability in Colonoscopy Yield)

It is surprising to me that only 10 patients (1%) in their cohort were identified as having impaired growth.

My take: This study shows that anti-TTG testing and calprotectin are the most useful tests in children with persistent abdominal pain.  The addition of hemoglobin, CRP, and ESR “can be left out in the clinical evaluation of chronic abdominal pain in children.”  The authors advocate, as well, for a prospective cohort study to confirm their observations.

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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

Probiotics and Recurrent Abdominal Pain

Numerous articles have questioned the effectiveness of probiotics for many of the conditions for which they have been promoted.  A recent systematic review (T Newlover-Delgado, et al. JAMA PediatrPublished online December 28, 2018. doi:10.1001/jamapediatrics.2018.4575) concludes that probiotics “may be effective in the shorter term in improving pain in children with” recurrent abdominal pain (RAP). Thanks to Ben Gold for this reference.

This study extended findings from a 2009 Cochrane review (Huertas-Ceballos AA, et al Cochrane Database Syst Rev 2009; (1):CD003019).  In total, the authors identified 19 eligible studies; of these 15 were not included in the previous review. The most common probiotic studied was Lactobacillus rhamnosus GG in 5 trials.

Key findings:

  • At 0 to 3 months postintervention, ‘based on moderate-quality evidence (odds ratio [OR], 1.63, 95% CI 1.07-2.47; 7 studies, 772 children). The number needed to treat for an additional beneficial outcome was 8.” 
  • There were only 2 studies with results extending 3 to 6 months.  These studies also found reduction in pain in the probiotic-treated children, OR 1.94 (CI 1.10-3.43). 
  • Interestingly, the authors note that fiber-based treatments were not considered more effective than placebo, despite a similar OR of 1.83.  Due to the small number of children in these studies with fiber (n=136), the CI were wide: 0.92-3.65.

The authors discuss some of the limitations such as variations in definitions, choice of probiotic and dosage, and short-term duration.  There is not a discussion of selection bias.  It is quite possible that some negative studies were completed which were not published which could further lower or eliminate the potential benefit.

My take: Probiotics may be helpful for children with recurrent abdominal pain; it is certainly not a panacea.

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Moon over Zabriskie Point, Death Valley -just before sunrise

Almost sunrise at Zabriskie Point, Death Valley


Why Stomach Pain Improves in the Summer

A recent small study (published online: KL Pollard et al. JPGN  doi: 10.1097/MPG.0000000000001886) indicates that the well-recognized phenomenon of improvement in functional abdominal pain during the summer months is associated with lower anxiety.  Here is a link to abstract: Seasonal Association of Pediatric Functional Abdominal Pain Disorders and Anxiety



In a sample of 34 participants who completed both questionnaires, 22 reported improvements during the summer months. These participants reported a significantly higher seasonal decrease in anxiety than participants whose children’s symptoms did not improve from spring to summer (mean decrease 2.21 vs 0.08, P = 0.017). Both groups reported equal improvements in sleep and decreased stress from spring to summer. Neither group experienced statistically significant seasonal change in physical activity or fruit, vegetables, dairy, or caffeine consumption.


This study suggests that amelioration of gastrointestinal symptoms in pediatric patients with AP-FGID during summer months is associated with amelioration of anxiety in the same time period. It is not yet clear whether decreased anxiety is the cause or effect of decreased AP-FGID symptom

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#NASPGHAN17 Selected Abstracts

Some of the abstracts that were presented at this year’s meeting –see below.  For a listing of the titles/authors presented, use this link: NASPGHAN Annual Mtg 2017

For complete abstracts: NASPGHAN 2017 Scientific Abstracts

Using a standardized approach along with a protocol for oral cleanouts and saline enemas if needed, the authors showed a marked decline in admissions for fecal impaction:

In this study, the authors found that low risk patients had a 91% likelihood of a negative scope.  However, on closer inspection, this rate OVERESTIMATES the likelihood of finding anything significant.  Most findings in the low risk group had questionable benefit from being identified on endoscopy including “acute colitis,” and H pylori.

The following abstract showed that in patients with EoE and not PPI-REE that topical steroids alone were as effective as PPI with topical steroids.

The following slides indicate the development of A4250, a bile acid transporter, which reduces pruritus. The presenter stated that this drug essentially is a chemical diversion which could replace biliary diversion for pruritic conditions like PFIC and Alagille syndrome.

Best Tweets from Postgraduate Course: #NASPGHAN15

Since I am not at this year’s national meeting, I have followed some of the information on social media.  Here are some of the best tweets:

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UTI in Infancy–New Risk Factor for Chronic Abdominal Pain?

A recent study (Rosen JM, et al. JPGN 2015; 60: 214-16) identifies a history of a urinary tract infection (UTI) in infancy as a risk factor for development of chronic abdominal pain.

The authors identified 57 patients with a history of UTI during the first year of life and compared them to 58 sibling controls.  Mean age of UTI was 4.8 months and mean time since UTI was 9.3 years.

Key finding:

  • Chronic abdominal pain was noted in 10 (17.5%) of patients with prior UTI compared with 2 (3.4%) of controls (P=0.02)

The authors state that this is the first study showing an infection outside the GI tract could increase the risk of chronic abdominal pain.  It is not clear to me if the UTI would truly be a sensitizing factor or whether other factors like the administration of antibiotics could play a role.

Bottomline: While this is a small study and the incidence of chronic abdominal pain was fairly low in both groups, it suggests that a history of a UTI may be a risk factor for recurrent abdominal pain; a bigger study is needed to validate these findings.

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From Twitter

Trending on Twitter -CampWeeKanEatIt Shoutout

Brave New World: Psychotropic Manipulation & Pediatric Functional GI Disorders

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.