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What to do with ALTEs?

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While apparent life-threatening events (ALTEs) in infants are quite disturbing, the best management for these events is far from clear. A recent systematic review of ALTEs in infants was undertaken and included studies from 1970-2011 (J Pediatr 2013; 163: 94-9). The authors ultimately identified 37 relevant studies: 18 prospective observational studies and 19 retrospective observational studies.

Results:

  • None of the 37 studies yielded “a high level of evidence for diagnostic or prognostic investigations.”
  • Risk factors for ALTE: prematurity, previous ALTEs, and suspected child maltreatment.
  • Routine screening for gastroesophageal reflux, meningitis, bacteremia, and seizures are “highly unlikely to be helpful in patients who are well-appearing and have no other findings suggestive of a diagnosis.”
  • Testing for GERD “is unnecessary in children with ALTEs.”  “A positive test does not necessarily inform management because causation cannot be established.”  Patients with recurrent ALTEs “may benefit from pH monitoring in combination with symptom recording.

Additional references:

NASPGHAN Consensus guidelines on GERD (2009)

Link: Gastroesophageal Reflux Disease in the Pediatric … – NASPGHAN.o

  • In premature infants, a relationship between GER (i.e. reflux) and pathologic apnea and/or bradycardia has not been established.Despite a lack of convincing evidence, if pathological apnea occurs in the face of pre- existing reflux, then the following two statements are the most common features:
  • 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.
  • A diagnosis of an acute life-threatening event (ALTE) warrants consideration of causes other than GER (i.e. reflux).Reflux of gastric acid seems to be related to ALTEs (episodes of combinations of apnea, color change, change in muscle tone, choking, and gagging) in < 5 % of infants with ALTE. 
  • -J Pediatr 2009; 155: 516. Bradycardia not improved in preemies treated for GER. n=18. Editorial 464 urges not using GER Rx in neonates –outside clinical trials.
  • -J Pediatr 2009; 154: 374. Apnea associated with reduction in LES tone in premature infants; therefore, GER may be secondary to apnea rather than the reverse. Small study -12 apneic event in 7 infants.
  • -J Pediatr 2008; 152: 365. Compared risk factors with SIDS. One of 153 (0.6%) with ALTE died.
  • -Pediatrics 2005; 116: 1059 & 1217 (editorial). Apnea in preemies is unrelated to GER.
  • -Pediatrics 2004; 113: e128-132. Apnea is unrelated to GER in most preemies; airway problems due to GERD is hard to establish.
  • -J Pediatr 2000; 137: 321 & 298. Poor temporal association between GER & apnea in ALTE patients.
  • -J Pediatr 2001; 138: 355. Metoclopropramide/cisapride do not help apnea in preemies with GER
  • -Pediatrics 2002; 109: 8-11. GER does not cause apnea of prematurity.

Remission in Crohn’s Disease

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A recent article highlights the issue of remission in Crohn’s disease (CD) (Inflamm Bowel Dis 2013; 19: 1645-53).

As noted in previous blog entries (see links below), improvements in remission with ImproveCareNow and with previous drug trials have several limitations due to the current definition of remission.  Currently, even during periods of clinical remission (defined currently mainly by symptoms), laboratory or endoscopic evidence of persistent inflammation can be seen.  Persistent inflammation is likely to lead to progressive bowel damage. With the advent of more effective treatments as well as better biomarkers, a more objective measure of remission is needed.

“Remission is an evolving concept in CD. At its most fundamental level, remission should be a state with little or no risk of disease progression, likely implying the absence of biological evidence of inflammation.”

The authors proposed definitions of remission based on whether the patient has “early” disease or “late” disease.  Early disease “may be defined as disease duration ≤18 months without previous exposure to immunosuppressants or biologics.”

Early disease:

  • Biologic remission (inflammation control): a) mucosal healing on colonoscopy (no ulcers with the exception of a few aphthous ulcers <5 mm in diameter) and/or b) improvements in serum and fecal biomarkers: CRP < 5 mg/L, fecal calprotectin <250 mcg/g
  • Clinical remission in practice (symptom control): complete absence of symptoms; 1-2 formed stools per day without abdominal pain.  In a clinical trial, CDAI <150 points.
  • Outcomes: no disease progression or complications, normal quality of life

Late disease:

  • Biologic remission (inflammation control): a) mucosal healing on colonoscopy (no ulcers with the exception of a few aphthous ulcers <5 mm in diameter) and/or b) improvements in serum and fecal biomarkers: CRP < 5 mg/L, fecal calprotectin <250 mcg/g
  • Clinical remission (symptom control): a: inflammatory symptom improvement (may have residual symptoms due to previous damage or surgery). In clinical trial, CDAI 150-220 points.
  • Outcome: stabilization of noninflammatory symptoms and no progression of structural damage, improved quality of life

The authors goal is to rework remission to include symptom control and histologic/mucosal healing.  This concept is not novel.  Investigators in the adalimumab EXTEND study coined the term “deep remission.” This term referred to patients with both CDAI remission and complete mucosal healing.  Patients who achieved deep remission had improved outcomes, including fewer hospitalizations and fewer surgical resections (Gut 2010; 59: A80).

Bottomline: Improvements in both objective measures of biologic inflammation along with resolution of clinical symptoms are needed to change the long-term outcome for patients with Crohn’s disease.  The definition of remission should reflect this reality.

“When you can measure what you are speaking about and express it in numbers, you know something about it; but when you cannot express it in numbers, your knowledge is of a meagre and unsatisfactory kind” –Lord Kelvin 1883

Related blog entries:

Rethinking top-down treatment?

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Given the effectiveness of biologic therapy and the potential for disease modification, the threshold for “top-down” treatment has been lower at this time as compared with “step-up” treatment.  What about long-term outcomes, does starting soon increase or decrease the likelihood of doing well?  A recent study suggests that “early biologic therapy did not improve disease activity or quality of life” (Inflamm Bowel Dis 2013; 19: 1397-1403).

In this retrospective chart review involving 93 patient’s with Crohn’s disease (between 2004 and 2010), patients whose data was prospectively maintained were categorized into either early biologic therapy or a step-up group. For these patients, the mean age at diagnosis was 28 years.  There were no apparent differences in demographic variables between the groups; however, the early biologic therapy group had higher disease activity and lower quality of life scores at baseline. 20% were current smokers and 61% never smoked.  Disease location was similar in both groups; overall, 35% had ileal disease, 13% colonic disease, 34% ileocolonic, and 7% isolated upper tract disease.

Results:

  • Mean Harvey-Bradshaw index and Short Inflammatory Bowel Disease Questionnaire scores at 3, 6, and 12 months were not different between the groups.
  • Early biologic therapy group had more hospitalizations.
  • No difference in steroid use or surgeries was noted at one year.

Take-home message: This study suggests that differences in outcomes between “top-down” therapy and step-up therapy are more pronounced early in the treatment course but may wane after 1 to 2 years.  However, early biologic therapy “may be a more effective strategy in patients with Crohn’s disease with higher disease activity.”

Relating blog posts:

Injecting steroids for esophageal strictures -does it work?

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A recent report indicates that steroid injections are not effective in patients with cervical anastomotic strictures (Clin Gastroenterol Hepatol 2013; 11: 795-801).

While this double-blind randomized control multicenter study of 60 patients (mean age 63) dealt with a specific subtype of strictures, the implications may be broader.  In this study, all patients had undergone esophectomy with gastric tube reconstruction.  The treatment group had 4 quadrant injections of 0.5 mL (20 mg) of triamcinolone and the control group had saline injections.  After injections, patients had Savary dilation to 16 mm.  Patients were followed for 6 months subsequently.

Results: In the treatment group 45% remained dysphagia-free for 6 months compared with 36% of controls (RR=12.6, p=0.46).  Median number of dilatations was 2 in treatment group compared with 3 in the controls.  One corticosteroid-treated patient developed a probable perforation and was excluded from final analysis. Four patients in the treatment group, and none in controls, developed Candida esophagitis.

No statistically significant decrease in dilatations or symptoms was demonstrated.

In their discussion, the authors review the effects of intraesophageal corticosteroid therapy and previous studies.  “Thus far, RCTs supporting this…are limited and, if available, are only small-sized and not focused on anastomotic strictures.”  According to the discussion, the evidence for steroid injection may be strongest for peptic strictures, primarily based on a small, sham-controlled RCT (Am J Gastroenterol 2005; 100: 2419) which demonstrated lower redilatation rates in this setting.

To prove that steroids would be effective if there was only a 10-20% improvement would take at least 200-750 patients

Take-home message (from authors): the routine use of corticosteroid injections in patients with benign anastomotic strictures cannot be recommended.

Related references:

  • -Refractory strictures (NASPGHAN 2011): =if not >14 mm after 5 sessions.   Complex strictures: >2 cm long, tortuous, or if scope cannot be passed predilatation. Consider Fluoro for complex strictures. Described technique of endoknife if only one-sided stricture which are hard to dilate.
  • -Am J Gastroenterol 2005; 100: 2419.  Double-blind, randomized trial showed benefit of steroid injection for Rx of recalcitrant peptic strictures. Consider triamcinolone along length of stricture; max ~10mg (2-4 mg/injection)
  • -JPGN 2007; 44: 336. n=16 pts. Mitomycin 0.1mg/mL; apply for 2-3min c pledget.
    -JPGN 2006; 42: 437.  Case report of using indwelling balloon for daily dilatation in refractory patients.
  • -Endoscopy. 2006; 38(4):404-7).  Mitomycin C: an alternative conservative treatment for refractory esophageal stricture in children?
  • -JPGN 2005; 41: 35A (pg503).  Use of stents for refractory benign strictures, n=10.
  • -Gastroenterol 1999; 117: 229 & 233. AGA position statement and technical review.

**Dosing regarding triamcinolone or mitomycin C has not been clearly established for esophageal strictures.  Doses listed above are based on my reading of the references but no specific dose is advocated on this posting.

Cyproheptadine for dyspepsia

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A retrospective open-label study has shown that cyproheptadine can be effective for children with dyspeptic symptoms (J Pediatr 2013; 163: 261-7) –thanks to Mike Hart for suggesting this reference.

Methods: In this study, 80 children (65% female) received cyproheptadine for refractory upper gastrointestinal symptoms, including nausea, early satiety, vomiting, retching after fundoplication, and abdominal pain.  The median age was 9.8 years; 48 children were <12 years.  The median dose was 0.19 mg/kg/day and median duration of treatment was 20 weeks.  All patients had undergone upper endoscopy with biopsy.  Gastric emptying studies were undertaken in 52 patients and antroduodenal manometry in 23 patients.

Results:

  • 33 (41%) had a significant response and symptoms resolved in 11 (14%); thus, 55% in total had improvement
  • In those without response, gastrojejunostomy/jejunostomy was placed in 7 patients, and botulinum toxin intrapyloric injection was undertaken in 3 patients
  • Better responses were more common in children <12 years and in females (P=0.04 and 0.03 respectively)
  • Early vomiting after eating and retching after fundoplication responded more favorably than other symptoms
  • Side effects: somnolence (16%), irritable/behavior change (6%), weight gain (5%)

How does cyproheptadine work? While this is not known, the authors speculate that the antiserotonin effects may improve gastric accommodation.

Take-home message: Cyproheptadine may help dyspeptic symptoms, especially in children <12 years and in those with vomiting and retching after fundoplication.  A prospective study would be helpful too.

Related blog posts:

EPT for Achalasia

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EPT or esophageal pressure topography (using high-resolution manometry) can help predict outcomes for achalasia (Gastroenterol 2013; 144: 718-25, editorial 681-83).

Background:  Patients with achalasia often present with dysphagia, chest pain, and regurgitation.  These symptoms result from impaired lower esophageal sphincter relaxation and aperistalsis.  While the main treatment has focused on disruption of the sphincter, esophageal body pressures may be important in long-term outcomes.

Three patterns of esophageal body pressures with achalasia:

  • type 1 absence of peristalsis and minimal pressurization
  • type 2 absence of peristalsis with panesophageal pressurization (≥30 mm Hg)
  • type 3 evidence of spasm

According to the cited study which reviewed data from 176 patients in the European achalasia trial (time period: 2003-2008, 18-75 year old), success rates were better with type 2 achalasia (96%, n=114) compared with type 1 (81%, n=44) or type 3 (66%, n=18).

In addition, the EPT findings may influence treatment selection.  Pneumatic dilation (PD) was more successful than Heller myotomy (HM) for type 2 patients (100% vs. 93%, p < 0.05).  However, HM was considered successful more frequently for patients with type 3 achalasia (86% vs. 40% –though not statistically significant due to small numbers).  For type 1, no significant difference was noted between HM and PD at 2 year followup, 81% vs. 85% respectively.

The commentary discusses some of the pertinent issues.   For example, HM may be better than PD among type 1 patients; the exclusion of patients with severe dilatation of esophagus.

Take-home message (from editorial) “The task at hand is to determine whether these distinct categories truly matter in clinical practice…it seems that the subtypes of achalasia do have prognostic value…we …need to determine…whether subtypes can inform treatment options.”

Elevated Celiac Serology Associated with Reduced Infant Birth Weights

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Using a population-based study of 7046 singleton pregnancies (from the Netherlands), the authors of a recent study have shown an inverse relationship between levels of anti-tissue transglutaminase IgA (TTG) antibodies and fetal growth (Gastroenterol 2013; 144: 726-35).

Results:

  • Newborns of positive TTG (>6 U/mL) weighed 159 g less at birth than newborns of mothers who tested negative for TTG.  In addition, newborns with mothers who had intermediate TTG levels ( 0.8 U/mL to 6 U/mL) had growth restriction of 53 g.
  • Among the intermediate TTG group, the results were more pronounced (2-fold greater) in those carrying the HLA risk molecules for celiac disease.
  • These birth weight changes were not associated with maternal nutritional status or deficiencies related to hemoglobin, iron, folate, or vitamin B12 deficiency.
  • Gestational age was not affected by TTG titers.

In the discussion, the authors note that other studies have shown that undiagnosed celiac disease increases the risk for intrauterine growth retardation; this risk can be eliminated by treating celiac disease.  The latter is a risk factor for lower neuropsychological performance.  This study was the first that took into effect the different TTG titers and correlated with additional nutritional parameters.

The authors speculate that celiac disease could have direct effects on the placenta.  In addition, other nutritional parameters could play a role such as vitamin D and calcium which were not included in this study.  Another important consideration is that celiac disease can result in increased miscarriages.  As a result, the “true” effect on newborn growth may be underestimated due to a “survivor bias.”

Related blog posts:

Fecal Transplants -NY Times Opinion Piece

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The following link (thanks to Kayla Lewis) to a recent NY Times article provides a first hand anecdotal account of fecal microbiota transplant for an adult patient with ulcerative colitis and discusses the use of FMT for Clostridium difficile infections.

http://opinionator.blogs.nytimes.com/2013/07/06/why-i-donated-my-stool/?ref=health

Bottom-line: Expect more questions about this emerging treatment.

Also, a quick way to keep up on NY Times -follow the twitter feed: @nytimesHealth

Related blog posts:

Wireless motility capsule -emerging for pediatrics?

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Currently, there are limited options for detecting gastrointestinal motility abnormalities.  The most definitive current evaluation is antroduodenal manometry (ADM) which remains restricted to a few specialized pediatric centers (coming soon to Children’s Center for Digestive Healthcare/Children’s Healthcare of Atlanta –Fall 2013).  And, of course, in many cases of defined motility disorders there are limited available treatments.  This situation has prompted one of my colleagues to state that motility testing is like getting the license plate of the bus that hit you.

A wireless motility capsule has the potential to facilitate motility testing.  A recent study explores it use in 22 patients (8-17 years) referred to a motility center (J Pediatr 2013; 162: 1181-7). The wireless motility capsule, also marketed as the SmartPill, has received FDA approval for use in the diagnosis of gastroparesis and constipation.  It measures intraluminal pressure, temperature, pH, and allows calculation of transit times in different segments of the GI tract.

Methods:

All patients underwent antroduodenal manometry, gastric empyting study (GES), and wireless motility capsule study.  The GES was performed with a 2-hour protocol.  The patient was given a standardized meal of 2 eggs, toast, and jelly with Tc-99m labeled eggs.  A GES was abnormal if >50% of labelled material was in the stomach at 2 hours. Similarly, the wireless motility capsule was ingested immediately prior to a similar standardized meal; this test was performed on a consecutive day with ADM testing.

Results:

  • In the paper, Table II & III lists the values for each test and includes which data was missing.
  • Based on ADM testing: 8 patients had rumination, 10 had normal motility, and 3 had abnormalities (1 with antral hypomotility, 1 with neuropathic dysmotility, 1 with hyperactivity/rumination).
  • Based on wireless capsule, 10 patients had severe gastroparesis.  Of these 10 patients, the ADM was normal in 4 and abnormal in 6.

The authors point out that the wireless motility capsule had excellent sensitivity but only moderate correlation between scintigraphic GES as well as ADM studies.  One possible reason for increased identification of gastric emptying disorders for the capsule include the use of 2-hour rather than 4-hour GES.  In addition, in symptomatic patients, those with normal GES and normal ADM may still have contractility abnormalities  that can be identified with capsule test.

One limitation of the study was the fact that migrating motor complexes (MMCs) was detected in all patients by ADM (as well as by capsule).  As such, there was no opportunity to identify potential false-positive in patients without MMCs.  Similarly, healthy children were not studied and this limits the findings to a highly selected cohort of children referred for motility evaluation.

Related blog posts:

Never quite right

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After esophageal atresia (EA) repair, problems with reflux and dysphagia effect up to 75-100% of patients.  A new study, JPGN 2013; 56: 609-14, helps provide some understanding why the esophagus is never quite right in these patients.

High resolution esophageal manometry (HREM) was performed in 40 patients with a median age of 8 years at three centers. Data was obtained primarily by chart review; in addition, symptomatology at the time of HRE#M was evaluated through a self-assessment questionnaire completed by the child or his primary caregiver.  35 patients had type C EA which typically accounts for 80-85% of all EA cases. Type C EA refers to a proximal esophageal pouch and a distal tracheoesophageal fistula (TEF).  5 patients had type A. Type A EA is an EA without a distal TEF. At the time of the HREM, 7 (18%) were considered asymptomatic.

Findings:

  • Three different motility patterns were identified: aperistalsis in 15 (38%), pressurization in 6 (15%), and distal contractions in 19 (47%).
  • Aperistalsis occurred primarily in patients with long-gap defects and/or following anastomotic leaks. 8 of 15 patients with aperistalsis had undergone fundoplication.
  • Pressurization (as shown in Figure 1) was when contraction of the entire esophageal body  occurred at once rather than in a progressive manner from proximal to distal esophagus. Distal contraction pattern indicated an absence of proximal esophageal contractions. 4 of 6 patients with pressurization pattern had undergone previous fundoplication.
  • Motility patterns were not predictive of symptoms.  Asymptomatic patients were noted with all three patterns.  However, gastroesophageal symptoms predominated in the aperistalsis group.  Dysphagia was frequent in all three groups.

Study limitations included retrospective data, and small numbers of patients. Furthermore, in patients with long-standing esophageal problems, “asymptomatic” may be related to the patient not knowing what “normal” feels like and may be related to compensatory behaviors.

While HREM explains the pathophysiology in EA patients, given the lack of effective medical treatments for motility disturbances, upper endoscopy is likely to be more useful for clinical management by identifying esophagitis and possibly Barrett’s esophagus.

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