Ivacaftor for Cystic Fibrosis

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Recent FDA approval of Ivacaftor (Kalydeco) is a promising step for a subset of patients with cystic fibrosis who have the G551D mutation.  This drug enhances the cystic fibrosis transmembrane regulator (CFTR) gene in these patients; only ~4% of CF patients or about 1200 patients in the US have this genetic defect.

http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm289633.htm

Additional references:

-NEJM 2011; 365: 1663. Effect of VX-770 -a CFTR potentiator -mild improvement in study of 167 pts. (Ivacaftor).
-NEJM 2010; 363: 1991. Effect of VX-770 -a CFTR potentiator -mild improvement in study of 39 adults.

Curing Hepatitis C without interferon

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In the face of increasing morbidity and mortality, better therapies for Hepatitis C have emerged which if applied broadly have an opportunity to change the outcome.  Recently, several articles have highlighted the possibility of treating individuals without interferon.

  • Lok et al. NEJM 2012; 366: 216-224
  • Chayam et al. Hepatology 2012; 55: 742-48
  • Zeuzem et al. Hepatology 2012; 55: 749-58.

In the Lok study, 21 null responders (patients who failed to achieve ≥2log10 decline in HCV RNA after ≥12 weeks of peginterferon and ribavirin) were divided into two groups. In Group A, 36% of patients were able to achieve SVR12 using a combination direct-acting antivirals (DAAs) with non-overlapping resistance profiles — without the use of interferon. Group A patients received BMS-790052 (an oral, first-in-class, NS5A replication complex inhibitor) and BMS-650032 (an oral NS3 protease inhibitor). In Group B which included peginterferon and ribavirin the SVR12 was 100%. There were no serious adverse events, or discontinuations.  The most common side effects were diarrhea, fatigue, headache, and nausea.

In the Chayam study, the combination of BMS-790052 (now called daclatasvir) and BMS-650032 (now called asunaprevir) examined this combination of DAAs in null HCV responders with genotype 1B (in Japan).  Ten patients received both drugs for 24 weeks. All nine who completed treatment had an SVR.  One patient stopped the medication due to elevated bilirubin and lymphopenia which occurred following an apparent infectious gastroenteritis.

In the Zeuzem study, tegobuvir (a nonnucleoside polymerase inhibitor) and GS 9256 (an NS3 serine protease inhibitor) with RBV (n=15), with PEG/RBV (n=15) and without ribavirin (n=16) were administered in three arms for 4 weeks, followed by dual therapy with PEG and RBV.  The primary end point was rapid virologic response (RVR), defined as HCV RNA <25 IU/mL.  Reductions (mean) for HCV RNA were -4.1 log10 IU/mL for dual therapy, -5.1 log10 IU/mL for triple therapy, and -5.7 log10 IU/mL for quadruple therapy.  RVR was noted in 7% of dual Rx, 38% of triple therapy, and 100% of quadruple therapy.

These studies indicate that even for difficult to treat HCV patients that new oral medications are on the horizon that will increase cure rates and may allow effective regimens that do not include interferon.  This is good news because until recently regimens with interferon were more likely to provoke adverse reactions that to guarantee a cure.

Links to relevant blog entries on HCV:

HCV now more deadly than HIV

The cost of progress in treating Hepatitis C

Looking for trouble

Treating reflux does not help asthma

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Studies in adults have looked at the use of PPIs for asthma and have not shown improvement (see references below).  Now a trial of lansoprazole suggests the same is true in children (JAMA 2012; 307: 373-81).  This study was a randomized double-blind placebo-controlled study of 306 children with a mean age of 11; the participants were recruited from 19 academic medical centers in the US.  149 children received lansoprazole and 157 received placebo.  The dose of lansoprazole was 15mg in patients weighing less than 30kg, and 30mg in those weighing more than 30kg.

Those treated with lansoprazole did no better than placebo with regard to symptoms and lung function.  The main outcome was the asthma control questionnaire (ACQ) score. The lansoprazole group had a mean change in this score of 0.2 units which was not a meaningful change. More precise measures of lung function including forced expiratory volume also did not differ.

In a subgroup of 115 patients who had esophageal pH studies, the prevalence of GER was 43%.  Yet, no treatment effect for lansoprazole was observed for any asthma outcome.

Not only did lansoprazole not help, the treatment group experienced more adverse effects, including respiratory infections (relative risk 1.3), sore throats (RR 1.3), and episodes of bronchitis (RR 2.2).  Though not statistically significant, the treatment group had more activity-related fractures, six compared to one in the placebo group.

This study took several years to complete (2007-2010).  I congratulate the authors, especially the third author Benjamin Gold, for this excellent work.

http://www.ccdhc.org/doctors/gold.html

Additional references:

The Medical Pendulum and Gastroesophageal Reflux

GERD and respiratory/ENT issues:

  • –Gastroenterology 2009; 137: 1844. Critical review of below NEJM article. ‘a subset of asthmatics will have objective detection of GERD without typical symptoms…work by Amer Lung Assn suggests that twice daily PPI will not be helpful’..however, ‘perhaps 3-6months of PPI may still be reasonable until we can accurately identify subgroups of pts who may respond.’ –Gary Falk, Cleveland Clinic
  • –NEJM 2009; 360: 1487, 1551. Use of PPIs (nexium 40mg bid) in poorly-controlled asthma with no symptoms of GER –did not help w asthma control & pH studies were not predictive of response. n=412 adults. 40% c abnl pH studies in each group (nexium vs. placebo).
  • –Clin Gastro & Hep 2007; 5: 1379. Review of ENT findings and reflux.
  • –Am J Gastro 2007; 102: 716. Poor specificity of ENT findings for diagnosis of laryngopharyngeal reflux.
  • –Aliment Pharm Ther 2007; 25: 385-92. meta-analysis. Rx c PPIs not more effective than placebo in resolving ENT symptoms presumed to be due to GER. Editorial suggests some patients may benefit, but better tools are needed to identify them.
  • –Gastroenterology 2010; 139: 1887. PPIs decreased postnasal drainage compared to placebo. n=75. (50% vs 5%) age discrepancy in patient populations.
  • –Clin Gastro & Hep 2010; 8: 741 (excellent editorial), 770 (article on rabeprazole improving heartburn Sx in pts with laryngitis), n=82. Editorial suggests 1-2month trial of BID PPI and if not effective, then little to offer. May change when studies looking at surgery (after impedance) outcomes.
  • –Gastroenterology 2010; 139: 754. 716 (editorial). Acoustic cough & reflux. Study recorded cough during pH measurement. n=71. ‘causality cannot be established until effective treatment’ available.

All bleeding stops

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Although the title is technically true, there are preferred ways to stop GI bleeding (Clinical Gastroenterol & Hepatol 2012; 10: 234-39).  This article summarizes the approach for nonvariceal upper GI bleeding.

Recommendations:

  • Endoscopy within 24 hours following ABCs/adequate resuscitation.  Use of a promotility agent prior to endoscopy may be helpful (in pediatric patients: erythromycin ~3 mg/kg)
  • Correct coagulopathy but do not delay endoscopy.
  • Consider nasogastric tube placement.
  • Do not use somatostatin or octreotide.
  • High-risk endoscopic stigmata should receive endoscopic hemostasis.  These lesions include actively spurting, oozing blood, nonbleeding visible vessel, and an adherent clot.
  • Pigmented dots or clean base ulcers do not require endoscopic hemostasis.
  • Endoscopic management includes clips, thermocoagulation, or sclerosant injection alone or in combination with epinephrine injection.  Epinephrine alone is not recommended for high risk lesions.
  • If a clot is found, attempts to remove it should be made to visualize underlying lesion.  If clot is adherent, intensive IV PPI therapy may be sufficient.  A typical dose would be esomeprazole 80mg bolus (for an adult) followed by 8 mg/hour for 72 hours.
  • Stable patients can be fed within 24 hours.
• IV PPI dose: 1mg/kg bolus followed by 0.1mg/kg/hr infusion.

Additional references:

  • -Ann Intern Med 2010; 152: 101-113. Consensus recommendations on UGI bleeding. Early endoscopy (<24hrs), data support attempts to dislodge clots, consider clips or thermocoagulation for Rx. Preendosocpy PPI can be helpful.
  • -Clin Gastro & Hep 2010; 8: 651. Article suggests second look only if difficult visualization on initial endoscopy (eg unable to remove clot).
  • -Ann Intern Med 2010; 152: 101-13. Systematic review of on UGI bleeding. Use IV PPI bolus, then continuous PPI if high risk stigmata after endoscopic Rx. Hospitalize for at least 72hrs.
  • -Gastroenterology 2010; 138: 1252. Review of upper GI bleeding.
  • -Clin Gastro & Hep 2009; 7: 828. Review of recurrent GI bleeding with negative initial evaluation.
  • -Gastroenterology 2008; 134: 1836. Frequent high dose oral PPI also effective with bleeding ulcers: prevacid 120mg x1, then 30mg q3hrs compared favorably with 90mg IV followed by 9mg/hr. n=66. intragastric pH >6 for 68% of study in IV PPI vs. 65% in oral PPI. 1st hour -more rapid onset with IV PPI.
  • -Gastroenterology 2007; 133: 1694. Position statement & review on obscure bleeding.
  • -Ann Intern Med 2003; 139: 843-857. Consensus on nonvariceal bleeding. Rec: lansoprazole 90mg bolus, then 6mg/hr x 72hrs or pantoprazole 80mg then 8mg/hr in high risk lesions
  • -Clin Gastro & Hep 2006; 4: 1459. Trends in non-variceal bleeding between 1993-2003 do NOT show improved outcomes with PPI. Overall mortality fairly steady @3.5%
  • -Clin Gastro & Hep 2005; 3: 959. WCE should be 2nd step in obscure bleed, p egd/col.
  • -NEJM 2004; 351: 488. case review.
  • -Gastroenterology 2002; 123: 17-23. IV erythromycin, 20 minutes before endoscopy, helped clear stomach (82% clear vs. 33% c placebo). Adults in this study received 250 mg. (thus, children probably need 3-4 mg/kg)
  • -Gastro Endosc 2002; 56: 174. erythromycin helpful-3mg/kg IV over 30 min
  • -Gastroenterology 2002; 123: 407-13. Endoscopic Rx of adherent clots c PUDz helpful (epinephrine injection, cold guillotining of clot, then coagulation cautery); Editorial on 632-635 emphasizes vigourous washing BUT NOT to remove adherent clot unless in centers with low rebleeding rates. Additionally, PPIs very helpful in preventing rebleeding in this situation (NEJM 1997; 336: 1054-8).
  • -NEJM 1999; 341: 38. Occult bleeding
  • -Gastroenterology 2000; 118: 197. AGA position statement.
  • -Gastro Endosc 2001; 53: 853 & 859. ASGE guidelines/algorithm for upper & lower GI bleeding

Gluten sensitivity without celiac disease

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Gluten free is big business.  In a range of conditions, eliminating gluten has been advocated to improve symptoms.  The most frequent problem in which a gluten-free diet (GFD) may be beneficial is irritable bowel syndrome (IBS).  A selected summary in Gastroenterology discusses this topic (Gastroenterology 2012; 142: 664-73).

This review highlights an article that showed improvement in a double-blind randomized trial (Am J Gastroenterol 2011; 106: 508-14) & then reviews the topic more broadly.  The study is the first randomized controlled trial that suggests that nonceliac IBS patients may improve with a GFD.  The study looked at 34 patients with IBS who had improved with a GFD & had no evidence of celiac disease (either negative HLA-DQ2/DQ8 or duodenal biopsy).  Then 19 patients had 16g of gluten per day reintroduced; control patients were offered equivalent food that was gluten-free.  The gluten products in the study were free of fermentable oligo-, di-, monosaccharides and polyols to avoid confounders (What to make of FODMAPs).  The patients who continued a GFD had less reported pain, bloating and tiredness.  The GFD group reported good control of symptoms the previous week in 68% vs. 40% in the study group.

The commentary notes that ‘gluten sensitivity’ is big business, accounting for 1.3 billion in 2011 expenditures.  Companies like General Mills, Betty Crocker, PF Chang’s, and Subway are offering gluten-free choices.  Since immune activation and low-grade inflammation may be important for IBS, it is possible that some foods trigger these processes.  At the same time, individuals with reported gluten sensitivity have not been shown to have increased intestinal permeability; this is in contrast to celiac disease (BMC Med 2011; 9; 23).

There may be more patients with IBS who will benefit from a GFD due to gluten sensitivity than patients with celiac disease.

Additional references:

  • -Nutr Clin Pract. 2011;26:294-299.  A gluten-free diet (GFD) is commonly recognized as the treatment for celiac disease. It also has been investigated as a treatment option for other medical conditions, including dermatitis herpetiformis, irritable bowel syndrome, neurologic disorders, rheumatoid arthritis, diabetes mellitus, and HIV-associated enteropathy. The strength of the evidence for the use of a GFD in these nonceliac diseases varies.
  • -Clin Gastro & Hep 2007; 5: 844. GFD in IBS pts (w/o celiac)
  • -Am J Gastro 2009; 104: 1587. Gluten sensitivity in IBS (w celiac)
  • -Gastroenterology 2011; 141: 1187. Prevalence of celiac similar in IBS as general population though higher number (7%) with celiac antibodies (esp gliadin).
  • -Am J Gastro 2008; 103: S472 (abstract P687) Serology for Celiac in IBS patients same as in controls. n=566. n=555 controls.
  • -Clin Gastro & Hep 2007; 5: 844. d-IBS patients may respond to gluten-free diet, especially if positive HLA-DQ2 expression or positive celiac serology.
  • -Lancet 2001; 358: 1504-08. n=300 uninvestigated pts w IBS criteria & 300 controls. 66 w positive serology; 14 w biopsy-proven celiac dz, 43 w normal biopsies. Odds ratio of 7 to have celiac compared to control group (2 w biopsy-proven disease).

Is a biopsy necessary in Celiac disease?

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Yes, at least for now.  That is the conclusion of a recent editorial (JPGN 2012; 54: 310-11) regarding Kurpa et al (JPGN 2012; 54: 387-91).  The article by Kurpa et al discusses the utility of the ESPGHAN criteria for diagnosis of celiac disease.  Among the patients with strongly positive TTG (> 100 units), 94% had a diagnosis of Celiac disease confirmed with biopsy; in addition, this result correlated well with positive endomysial antibody and with positive DQ2/8. In those with TTG (30-99 units), Celiac disease was diagnosed in 69% of children and 86% of adults.

Additional references:

  • -JPGN 2011;52: 554. May not need to biopsy if TTG >100 & responds to GFD
  • -Clin Gastro & Hep 2011; 9: 320. Nat’l hx in children with +serology. n=106. 33% developed villous atrophy c/in 2 yrs.
  • -Gastroenterology 2010; 139: 763. Mortality NOT worsened in undiagnosed celiac dz in Olmstead County, though bone density decreased. n=129 of 16,847. (?milder cases undiagnosed)
  • -J Pediatr 2010; 157: 373, 353. Even pts w/o villous atrophy & +serology, benefited from GFD with regard to GI symptoms and serological markers.
  • -JPGN 2010; 50: 397. n=250. +association
  • -Mohamed BM, et al. The Absence of a Mucosal Lesion on Standard Histological Examination Does Not Exclude Diagnosis of Celiac Disease.  Dig Dis Sci. 2007 May 9;
  • -JPGN 2009; 49: 52. deamidated gliadin -new, accurate biomarker for celiac. n=302.
  • -Gastroenterology 2009; 137: 88. Increased mortality in undiagnosed celiac –4-fold increase. Also, increasing prevalence ~4 fold in last 50 yrs.
  • -Gastroenterology 1967; 52: 893-897. Seminal article ‘gluten as culprit in celiac’
  • -Gastroenterology 2009; 136: 816. Mild enteropathy w Celiac –still needs GFD
  • -JPGN 2008; 47: 618. duodenal bulb always abnl, n=665
  • -Clin Gastro & Hep 2008; 6: 753. Incidence of autoimmune diseases less in those compliant with diet. n=178.
  • -Clinical Gastro & Hep 2008; 6: 426. Usefulness of deamidated gliadin antibodies (about as useful as TTG). In this study with n=216 celiac pts and 124 controls, TTG had sensitivity of 78% and 98% specificity.
  • -JPGN 2007; 45: 497. ~1% of UK kids c celiac; 90% missed. Avon study (ALSPAC). n=5470 screened from cohort of 13,971
  • -NEJM 2007; 357: 1731. Nice review which suggests the introduction of gluten 4-7 months in healthy infants. HLA DQ2 present in 90-95%; HLA DQ8 in remainder. Both also present in gen population, 30-40%. Scalloping of mucosal folds often seen. Can stain bx for CD3, CD8 receptors. More refractory cases stain only for CD3 (neg for CD8).

Stimulants for constipation

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Overall, 12-19% of Americans are affected by chronic constipation (Am J Gastroenterol 2004; 9: 750-59).  Despite the fact that constipation problems are widespread, the amount of useful research available to guide treatment is quite limited.  Two recent articles do offer some information:

  • Clin Gastroenterol Hepatol 2011; 9: 577-83.
  • Gut 2011; 60: 209-18.

The first reference examined the use of bisacodyl in a randomized, double-blind placebo-controlled study in the UK.  During the 4-week treatment period, patients receiving 10mg/day bisacodyl (n=247) had increased stools, from 1.1 per week to 5.2 per week.  Stool frequency also increased to 1.9 per week in the placebo group (n=121).  All secondary endpoints including constipation-associated symptoms (eg. quality of life indices, physical discomfort) improved significantly compared to placebo.  Average age of patients in this study was 55 years.  The main adverse effect was diarrhea –mainly during the 1st week of therapy.

A selected summary in Gastroenterology (Gastroenterology 2012; 142: 402-404) reviews the first study and makes several useful points:

  • Stimulant laxative use has been hindered by myths & misconceptions along with lack of supporting data.  Most recent studies do not support a role of stimulant use in causing enteric neuropathies, a cathartic colon or increasing the risk of colon cancer
  • Osmotic laxatives have been favored in guidelines but this has not been bolstered by supporting data
  • Only recently have two large randomized controlled studies proven the efficacy and safety of stimulant laxatives over the short-term
  • Long-term prospective studies are not available on the use of stimulant laxatives.

The second reference is a systematic review and meta-analysis of randomized controlled trials (RCTs) of pharmacologic therapy for chronic idiopathic constipation.  Twenty one eligible RCTs were identified: eight laxative studies (n=1411), seven prucalopride studies (n=2639), three lubiprostone (n=610), and three linactolide trials (n=1582).  All of these studies showed treatment was superior to placebo. These studies involved subjects who were mainly adults (>90% older than 16 years).

The results showed benefit from both stimulant and osmotic laxatives.  Overall, the osmotic and stimulant laxative studies showed higher response than the pharmacologic agents like prucalopride, lubiprostone, and linaclotide.  Nevertheless, between 50% and 85% of patients did not fulfill criteria for response to therapy.

Additional references:

  • -J Clin Gastro 2003; 36: 386-389.  Safety of stimulants for long-term use.
  • -Am J Gastro 2005; 100: 232-242.  Myths about constipation.  Stimulants have not been proven to cause a “cathartic colon”
  • -J Pediatr 2009; 154: 258.  Constipation associated w 3-fold increase in health utilization/cost.
  • -Clin Gastro  Hep 2009; 7: 20.  Review of complications assoc c constipation in adults.
  • -Pediatrics 2008; 121: e1334.  Behavioral therapy ineffective in treating childhood constipation.
  • -NEJM 2008; 358: 2332, 2344.  Use of methylnatrexone for opioid-induced constipation & trial of n=620 of prucalopride for severe constipation.  Both drugs were helpful.
  • -Gastroenterology 2004; 126: S33. Review of pediatric incontinence.
  • -J Pediatr 2004; 145: 253-4.  Prevalence of encopresis 15% /constipation 23% in obese children  (n=80).  Questionnaire administered to 80 consecutive obese children.
  • -Gastroenterology 2003; 125: 357.  Longterm constipation followup.  one-third with persistent constipation; 60% better at 1 year.  (tertiary referral group)
  • -Pediatrics 2004; 113: 1753 & e520.  When constipation & toileting difficulties both occur, constipation usually precedes toileting problems

Rifaximin for Crohn’s disease?

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Rifaximin (Xifaxan®) shows promise as a new treatment for Crohn’s disease (Gastroenterology 2012; 142: 473-81).  Rifaximin is an oral medication with minimal systemic absorption; it has a good track record in a number of GI indications, including bacterial gastroenteritis (traveler’s diarrhea), bacterial overgrowth in irritable bowel disease, and hepatic encephalopathy.  There are a few reasons why rifaximin would be considered a good candidate treatment for Crohn’s disease:

  • The pathophysiology of Crohn’s disease involves interaction of adherent bacteria to the intestinal mucosa and with the immune system
  • Other antimicrobials have shown benefit for Crohn’s disease
  • Animal models do not manifest Crohn’s disease when in a bacteria-free environment

In this study of 402 patients with moderate-to-severe Crohn’s disease, a multicenter randomized double-blind trial examined efficacy and safety of rifaximin at doses of 400mg, 800mg, and 1200mg twice daily.  The primary end point was remission based on Crohn’s Disease Activity Index (CDAI).

At the end of the 12-week treatment period, 62% of the 800mg group were in remission compared to 43% of the placebo group.  This difference was maintained 12 weeks afterwards with 45% maintaining remission compared with 43% of patients receiving placebo.  When looking at the other dosing regimens, at 12 weeks, 54% of the 400mg group and 47% of the 1200mg group were in remission based on CDAI.

Clinical response, but not remission, occurred in 56% of placebo patients compared with 63% for 400mg patients, 72% for 800mg patients, and 57% of 1200mg patients.  This trial may have been hampered by patient selection in that the placebo response was high.  This may be due to the fact that ~50% of patients had a low CRP value at baseline.

Safety was good in all patient groups.  However, one rifaximin-treated patient developed C difficile infection.

The fact that a clear dose response was not evident suggests the need for more studies.

Additional Rifaximin References:

  • -NEJM 2011; 364: 22 (pg 81-editorial).  About 10% improvement over placebo in pts with IBS-D.  (see abstract below).  Effects lasted up to 3 months.
  • -JPGN 2009; 49: 400-04. helped symptoms in 61% of IBD pts. n=23 (12 w Crohn). dose 10-30mg/kg/day.
  • -Aliment Pharm Ther 2005; 22: 31-35. Use in SBBO. n=90; 1200mg/day x 7 days. NL glucose breath test in 60% (vs 17% in low dose group); no side effects.
  • -Ann Intern Med 2006; 145: 557-563. double-blind, randomized controlled trial, n=87 for IBS. 400mg tid x 10days. Rx resulted in greater IBS improvement, ~40% improvement vs 20% w placebo during 10 week study
  • -IBD 2006; 12: 335. open-label use of rifaximim (400mg BID) for 30 pts c UC flare on ASA products resulted in clinical remission in 23 of 30.
  • -J Infect 2011; 62: 34-38. Rx may lead to resistant staphylococci.
  • -Hepatology 2010; 52: 1484. Review.

Additional Crohn’s Antibiotic/Probiotic References:

  • -IBD 2009; 15; 17. 40% response to Cipro in treatment of peranal fistulas. n=25. No response to metronidazole.
  • -IBD 2008; 14: 1597, 1585. No proven role for probiotics and IBD except pouchitis (after Abx)
  • -Clin Gastro & Hep 2008; 6: 145. Pouch problems reviewed -excellent review.
  • -IBD 2006; 12: 335. open-label use of rifaximim (400mg BID) for 30 pts c UC flare on ASA products resulted in clinical remission in 23 of 30.
  • -Curr Med Res Opinion 2005; 8: 1165-70. Rx for traveler’s diarrhea.  May be useful for Crohn’s as well.
  • -Gastroenterology 2005; 128: 856. Use of ornidazole prophylaxis reduced recurrence p-op from 37.5% to 8%.
  • -IBD 2004; 10: 318-325. antibiotics & IBD review.
  • -Gastroenterology 2004; 127: 412-21. adherent-invasive E. coli associated with ileal mucosa in 22% of Crohn’s (n=63) ileal mucosa vs. 6% of controls (n=16); higher colonization noted in neo-terminal ileums (36%).

Does necrotizing enterocolitis cause neurologic deficits?

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Quite possibly (J Pediatr 2012; 160: 409-14).

There have been recent reports that surgery in preterm and even term infants can affect neurodevelopmental outcomes.  This report, which looked at infants born at <30 weeks or birth weight of <1250 g, adds more information in this area.  The surgery group (n=30) had more white matter injury on MRI and lower developmental scores at 2 years than the nonsurgical group (n=178).  Infants requiring bowel surgery had the worst outcomes.  The exact reasons for these outcomes and the significance are unclear, in part due to the small number of infants with bowel surgery.  Potential factors include inflammatory mediators/cytokines, and anesthesia effects.

The article notes that the FDA has issued warnings regarding anesthetic use in neonates and young children.  These agents may cause abnormalities in the developing brain, particularly in the thalamus.

This study has a number of limitations including the lack of preoperative comparative imaging studies.  Nevertheless, despite unresolved issues regarding causality, it is clear that infants who have necrotizing enterocolitis remain at high risk for poor neurodevelopmental outcomes.

Additional references:

  • -Anesth Analg 2007; 104: 509-20.  Anesthetics in neonates and young children.
  • -J Pediatr 2008; 153: 170-5. Adverse neurodevelopmental outcomes in infants with sepsis or NEC.

Gastroesophageal Reflux: I know it when I see it

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      According to Wikipedia, Justice Potter Stewart, in Jacobellis v. Ohio 378 U.S. 184 (1964) stated the following: I shall not today attempt further to define the kinds of material I understand to be embraced within that shorthand description [“hard-core pornography”]; and perhaps I could never succeed in intelligibly doing so. But I know it when I see it, and the motion picture involved in this case is not that. [Emphasis added.]
     To some extent, ‘I know it when I see it’ has been the mantra about identifying gastroesophageal reflux for advocates for pH-impedance (pH-MII).  Enthusiasts have claimed that pH-MII is vastly superior to pH studies alone for many reasons including the ability to detect more GER episodes than conventional pH studies.  Yet, a major flaw has been a paucity of normative data.  To determine whether there is interobserver and intraobserver agreement in the interpretation of pH-MII, seven expert world groups collaborated on a study to analyze ten pediatric 24-hour tracings (J Pediatr 2012; 160: 441-6).
     Five of these studies were considered easy and five were more challenging due to less obvious features like low baselines, retrograde patterns during swallowing, and moving/crying artifacts.   Among 1242 liquid and mixed GER events, 490 (42%) were scored by the majority of observers.  The authors claim that this is “moderate agreement.”  The automated analysis (AA), not surprisingly, had much better agreement than manual analysis.   With AA there was 94% sensitivity rate and 74% specificity. When looking at AA alone, AA missed 6.5% of events scored by observer consensus and  30% of GER episodes recorded with AA were not detected by majority consensus.
     When looking at each pH-MII recording (Figure 2), there was poor agreement on whether the study was pathologic.  Only five of the studies had uniform agreement that the number of episodes (>73 GER episodes) were either pathologic or not. Those with agreement were all negative studies.  The authors conclude, though, that there was “substantial” agreement based on a mean kappa value of 0.70.
     A comparison to a previous pH-MII publication (Scand J Gastro 2011; 46: 271-6) notes that in this previous study, 83% of pH-MII recordings had a concordant symptom association probability despite underdetection of GER episodes with AA; it was recommended to use ‘AA when the symptom association was positive.  If symptom association was negative, they suggested manual analysis.’
    The conclusions from the current study:
  • ‘In theory, AA is favored over manual analysis due to reproducibility’
  • AA does not seem specific enough to ensure correct marking of GER episodes in infants and children yet
  • Consensus to refine AA needs to be reached …to retain confidence …in impedance

If this is the best that worldwide experts can do with this widespread technology, what does that mean for clinicians in practice?

Additional references:

Recent related posts:

The Medical Pendulum and Gastroesophageal Reflux

Unexplained chest pain

  • -Journal of Gastroenterology and Hepatology 2010;25:817-22. Has some normative pH-MII data.  ‘Can acid (pH) refluxes predict multichannel intraluminal impedance refluxes? A correlation study.’
  • -JPGN 2010; 50: 25. Reflux detected by Impedance does NOT determine fundoplication outcome. n=34.
  • -JPGN 2010; 52: 129. Review. No normative data. Using SAP>95% to correlate symptoms (better than SI or SSI). Main use is to study intractable pts to establish if nonacid reflux is contributing to symptoms.
  • -J Pediatr 2010; 157: 878 (“death of pH probe”), 949. Use of impedance in children. n=225. (70 were discarded). Notes lack of therapeutic possibilities for non-acid reflux.  Symptom index is + if >50%, SAP if >95%. Symptom index is number of symptoms with reflux episode divided by total number of symptom occurrences. SAP, symptom association probability, is a statistical tool that uses 2-minute windows throughout recording to correlate symptom and reflux event.  pH probe 2nd metal for infant -place 2cm above LES.  pH probe 3rd metal for child -place 3cm above LES
  • -Clin Gastro & Hep 2009; 7: 743. n=39 adults. Non-acid reflux events in patients on therapy correlated with acid reflux parameters when patients studied off therapy. Abnormal impedance parameters: total number of reflux events >63 (avg normal was 28). This study relied on # of reflux events more than SAP or SI. SAP or SI is problematic in patients who lack clinical response to PPIs.
  • -Gastroenterology 2009; 136 (suppl 1): S1896. n=143. #of events (not SI or SAP) is then most conservative estimate as well as the one with the highest likelihood of encompassing other symptom assoication parameters.
  • -J Pediatr 2009; 154: 248. n=50. a high # with normal pH had symptom correlation w GER events. (initial cohort was 80 –30 excluded due to problems with study or insufficient symptoms) SAP is superior for correlating symptoms.
  • -Clin Gastro & Hep 2008; 6: 840. Impedance is best tool -D Castell.; -Clin Gastro & Hep 2008; 6: 880.
  • -Clin Gastro & Hep 2008; 6: 482, 521. ‘Impedance/pH is best tool’. Pts who respond to PPIs likely due so due to its effect on chemostimulation; those who continue with symptoms may do so based on mechanostimulation -related to volumes in esophagus not due to acidity.
  • -J Pediatr 2006; 149: 216. Equal frequency of acid and non-acid reflux in 24 pts with asthma. No correlation identified with resp symptoms.
  • -Clin Gastro & Hep 2006; 4: 167. Impedance does not add to pH probe in UNTREATED patients.
  • -JPGN 2002; 34: 511, 519.
  • -Pediatrics 2006; 118: e299, 793. Impedance data in preterm infants. Asymptomatic and affected infants with similar impedance values and both have reflux to upper esophagus.