Probiotics for NEC -More Work is Needed (part 2)

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For very low birth weight (VLBW) premature infants, there is even more evidence that probiotics are effective (The Journal of Pediatrics Volume 165, Issue 2 , Pages 285-289.e1, August 2014 -thanks to Kipp Ellsworth for abstract link).

Abstract ():

Study design

Within the observational period (September 1, 2010, until December 31, 2012, n = 5351 infants) study centers were categorized into 3 groups based on their choice of Lactobacillus acidophilus/Bifidobacterium infantis use: (1) no prophylactic use (12 centers); (2 a/b) change of strategy nonuser to user during observational period (13 centers); and (3) use before start of observation (21 centers). 

Results

The use of probiotics was associated with a reduced risk for necrotizing enterocolitis surgery (group 1 vs group 3: 4.2 vs 2.6%,P = .028; change of strategy: 6.2 vs 4.0%, P < .001), any abdominal surgery, and hospital mortality. Infants treated with probiotics had improved weight gain/day, and probiotics had no effect on the risk of blood-culture confirmed sepsis. In a multivariable logistic regression analysis, probiotics were protective for necrotizing enterocolitis surgery (OR 0.58, 95% CI 0.37-0.91; P = .017), any abdominal surgery (OR 0.7, 95% CI 0.51-0.95; P = .02), and the combined outcome abdominal surgery and/or death (OR 0.43; 95% CI 0.33-0.56; P < .001).

Probiotics For NEC -More Work is Needed (part 1)

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From Kipp Ellsworth’s Twitter Feed:

The Time for a Confirmatory NEC Probiotic Prevention Trial in ELBW Infants is Now. Editorial in J Peds  (The Journal of Pediatrics
Volume 165, Issue 2 , Pages 389-394, August 2014)

This editorial reviews previous studies and recommends implementing a Probiotic Trial in North America. Here’s an excerpt:

“An adequately powered double-blinded placebo-controlled trial replicating a previous effective NEC prevention study in VLBW infants was published (the ProPrem trial)…the study revealed a significant reduction of NEC: from 4.4%-2.0% but no effect on mortality (4.9% vs 5.1%)…A closer look at the results of the ProPrem study, however, reveals that the probiotic supplementation did not have any effect on NEC in the ELBW (<1000 g) infants, which is consistent with two small previous studies reporting data on these infants separately.36, 42 Thus, there is currently no compelling evidence for recommending prophylactic probiotics to prevent NEC in infants with a birth weight <1000 g. Especially important is the lack of safety information in these most immature and highly vulnerable babies…Probiotics appear promising for use as prevention strategy for NEC, but there is still insufficient data for general recommendation of the use of probiotics in the ELBW infant. We argue, therefore, that now is the time to conduct in the North American setting, a high quality confirmative NEC prevention trial using probiotics in at-risk ELBW infants.”

Related blog post:

Use of Gluten-Free Diet with Inflammatory Bowel Diseases

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As noted in a previous blog (The Search for a Dietary Culprit in IBD | gutsandgrowth), alternative diets have been explored both for symptom improvement and in efforts to improve inflammation in individuals with inflammatory bowel diseases (IBD).  A new study from North Carolina indicates that nearly 20% of patients have tried a gluten-free diet (GFD) to help control clinical symptoms in IBD (Inflamm Bowel Dis 2014; 20: 1194-97).

While adoption of a GFD clearly is effective for celiac disease, it has become popular, along with a low FODMAPs diet, as an alternative treatment for irritable bowel syndrome (IBS)/and “non-celiac gluten sensitivity.”  Since IBS is a common comorbidity with IBD (see recent blog: New Biomarker for Crohn’s Disease (Plus Two …), it is not surprising that a GFD would be used by some with IBD.  In this study, the authors performed a cross-sectional study using a GFD questionnaire in 1647 IBD patients though a CCFA longitudinal internet-based cohort.

Results:

  • 19.1% had previously tried a GFD and 8.2% reported current use of GFD.
  • 65.6% described improvement while on a GFD.  Improved symptoms included fatigue, nausea, bloating, abdominal pain, and diarrhea.
  • 0.6% of patients reported a concurrent diagnosis of celiac disease (which is similar to overall celiac prevalence in U.S.)

Given the structure of this study, which is mainly an internet survey, there are many limitations in its interpretation.  Certainly, this study does not prove that a GFD is effective for IBD.  However, it is clear that a GFD is used frequently and may improve IBD/IBS symptoms.

Take-home message: Particularly in patients who have ongoing symptoms despite  mucosal healing, pursuing either a low FODMAPs diet or a GFD may be helpful.

Related blog posts:

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects), implementation of diets and specific medical management interventions should be confirmed by prescribing physician.  Application of the information in a particular situation remains the professional responsibility of the practitioner.

Cognitive Outcomes after Liver Transplantation

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An important measure of liver transplantation (LT) is cognitive/academic outcomes. Previous studies have indicated increased intellectual deficits but were not optimally-designed.  A recent study (J Pediatr 2014; 165: 65-72) overcomes many of the limitations of previous studies.

Study design: Prospective, multicenter longitudinal cohort of neurocognitive functioning after pediatric liver transplantation.  144 participants, ≥2 years after liver transplantation -recruited through Studies of Pediatric Liver Transplantation (SPLIT).  Tested with multiple cognitive test at two separate time points.

Key findings:

  • At the time 2, 29% had full scale IQ (FSIQ) between 71-85 (compared to 14% expected); 7% had FSIQ <71 (compared with 2% expected)
  • 42% received special education.
  • Pretransplant markers of nutritional status and operative complications predicted intellectual outcome
  • Having a primary care provider with a college education was a protective factor.

One limitation of the study was that only 55% of those approached to participate were enrolled; however, the authors noted similar demographics between those who enrolled and those who did not.

Pushback on Probiotics

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I had not paid much attention to a study last year (Lancet 2013; 382: 1249-57) titled, “Lactobacilli and bifidobacteria in the prevention of antibiotic-associated diarrhea and Clostridium difficile diarrhea in older patients (PLACIDE): a randomized, double-blind, placebo-controlled, multcentre trial.”

A useful review (Gastroenterol 2014; 146: 1822-23) of this study provides some useful insight into the use of probiotics.  The authors state that “in the last decade, medical and non medical professionals have endorsed the use of probiotics as a means of preventing AAD through a dogma that adding ‘good bacteria’ will prevent dysbiosis caused by ‘bad bacteria.'”  They note that several meta-analysis have supported a positive benefit for probiotics in this setting; yet, the “results merit cautious interpretation owing to a high risk of bias and notable heterogeneity of included studies.”

The PLACIDE study overcomes many of the previous limitations in this well-designed study design which enrolled a large cohort of 2,981 patients (≥65 years old).  The probiotics used in this trial were lactobacillus acidophilus along with bidodbacterium bifidum and lactis.  Ultimately, “patients receiving probiotics were as likely to develop AAD as patients in the placebo arm (relative risk 1.04).”  The rate of C difficile infection was ~1% and lower than expected.

While this study did not demonstrate any benefit from probiotics, there was no significant harm identified from probiotics; though, patients receiving probiotics were more likely to develop flatus and bloating in comparison to placebo.

Take-home message: “This study now also points away from probiotics being of benefit…probiotics use will not diminish as a result of this trial.  Parties will, argue rightly or wrongly, that the wrong strains were chosen…However, what the PLACIDE trial does point is that there is no clear evidence for use of probiotics in this setting until high-quality RCTs are conducted.”

Another probiotic reference:

JAMA Pediatr 2014; 168: 228-33.  This randomized double-blind, controlled trial conducted in 9 neonatal units in Italy compared L reuteri DSM 17938 to placebo for prevention of colic.  Mean duration of daily crying was 38 min in probiotic group compared with 71 min in placebo-treated patients, though these measures were with a nonvalidated diary.  Conclusions of authors: “prophylactic use of L reuteri DSM 17938 during the first 3 months of life reduced the magnitude of crying and functional gastrointestinal disorders.”

Related blog posts:

Clostridium difficile Epidemiology

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A recent study shows that Clostridium difficile infection (CDI) is identified frequently in young children and that approximately three-fourths had recent preceding antibiotics (Pediatrics 2014; 133: 651-58). Abstract link.

Methods: “Data from an active population- and laboratory-based CDI surveillance in 10 US geographic areas during 2010–2011 were used to identify cases.”

Key findings:

  • Of 944 pediatric CDI cases identified, 71% were community-acquired
  • CDI incidence per 100 000 children was highest among 1-year-olds (66.3)
  • Using a representative sample (n=84) who reported diarrhea on the day of stool collection, 73% received antibiotics during the previous 12 weeks.

Despite the frequency of CDI, understanding a couple of key diagnostic pearls is crucial. According to the American Academy of Pediatrics Committee on Infectious Disease policy guideline: (Link to AAP guideline PDF)

  • Recommends avoid routine testing in pediatric patients less than 1 year of age due to high carriage rates.
  • “Testing for C difficile can be considered in children 1 to 3 years of age with diarrhea, but testing for other causes of diarrhea, particularly viral, is recommended first>
  • “A common mistake is to… test for cure. C difficile, its toxins, and genome are shed for long periods after resolution of diarrheal symptoms.”
  • “An interval greater than 4 weeks since last testing should be used for testing with a recurrence.”

Bottomline: This most recent study reinforces the notion that about 1/4th of pediatric CDI occurs in the absence of recent antibiotics; nevertheless, understanding the limitations of testing for CDI could prevent a fair amount of aggravation.

Related blog posts:

Understanding Cholestatic Pruritus

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A recent review (Hepatology 2014; 60: 399-407) sorts out “facts and fiction” with regard to pruritus in cholestasis.

The authors note that for more than 2000 years there has been a search for the potential pruritogen in cholestasis, “when Aretaeus the Cappadocian (2nd century B.C.) stated that ‘pruritus in jaundiced patients is caused by prickly bilious particles.'”

Key points of review:

Pruritus affects a large number of hepatobiliary diseases

  • Hepatocellular cholestasis: intrahepatic cholestasis of pregnancy (ICP), benign recurrent intrahepatic cholestasis (BRIC), progressive familial intrahepatic cholestasis (PFIC1, PFIC2), Hepatitis C
  • Biliary-liver diseases: primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), PFIC3, Alagille, Drug-induced diseases
  • Obstructive cholestasis: gallstones, IgG4-associated cholangitis, biliary atresia, and other causes

Most recently lysophosphatidic acid LPA) and autotaxin (ATX) have been shown to be important pruritogen candidates in cholestasis

  • “ATX is the main source of circulating LPA levels…In cholestasis, serum ATX activity, but not other putative markers of itch such as serum bile salt levels or serum μ-opiod activity, were correlated with itch intensity.”
  • “Rifampicin was found to reduce ATX expression at the transcriptional level.”  This may explain rifampicin’s efficacy for pruritus in cholestasis.
  • “When the enterohepatic circulation is interrupted by nasobiliary drainage, circulating levels of ATX rapidly dropped concomitant with relief of pruritus.”  So, while ATX is not secreted into bile, other substances in bile, like steroid hormones, like play a role in the induction of ATX.

Current therapeutic recommendations (dosing recommendations provided by authors in Table 3)

  • 1st line: Cholestyramine (except in ICP in which ursodeoxycholic acid is considered 1st line)
  • 2nd line: Rifampicin
  • 3rd line: naltrexone
  • 4th line: sertraline
  • Experimental: ondansetron, phenobarbitol, propranolol, lidocaine, dronabinol, butorphanol, phototherapy, nasobiliary drainage, plasmapharesis (and similar treatments), biliary diversion
  • Liver transplantation

Related blog posts:

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications/diets (along with potential adverse effects) should be confirmed by prescribing physician/nutritionist.  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.

Using Preoperative Aspirin to Prevent Postoperative Problems –Negative Study

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A recent study has looked at whether giving aspirin prior to surgery can help those who take aspirin and also those who do not (NEJM 2014; 1494-503).  This trial called POISE-2 (Perioperative Ischemic Evaluation 2) was undertaken to determine if low-dose aspirin, as compared to placebo, would affect 30-day risk of death or nonfatal myocardial infarction.

The relevance of this study relates to aspirin’s known potential for preventing venous thromboembolism and the fact that “one-third of patients undergoing noncardiac surgery who are at risk for major vascular complications receive perioperative aspirin.”

The study enrolled 10,010 patients and employed a 2-by-2 trial design to account for whether they had been taking aspirin.  The study took place between 2010-2013 at 135 hospitals and 23 countries.  Mean age was 68 years in both groups.

Results:

  • The rate of death was similar in both groups: 7.0% for aspirin and 7.1% for placebo (hazard ratio 0.99)
  • Major bleeding was more common with aspirin than placebo: 4.6% vs. 3.8% (P=0.04).

Bottomline: Perioperative aspirin had no significant beneficial effect.

Related study: NEJM 2014; 370: 1504-13.  Conclusion: “Administration of low-dose clonidien in patients undergoing noncardiac surgery did not reduce the rate of” death or nonfatal myocardial infarction.  Patients who received clonidine had more frequent hypotension and nonfatal cardiac arrest.

Walking with a “Z” or an “X”

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In a number of media outlets, there has been a push for a highly successful (and under appreciated) treatment: walking.

Advantages:

  • No/Low cost
  • Easy
  • Often fun
  • Excellent side effect profile

Here’s a link (Every Body Walk!) and here’s an excerpt:

Researchers have discovered a “wonder drug” for many of today’s most common medical problems, says Dr. Bob Sallis, a family practitioner at a Kaiser Permanente clinic in Fontana, California. It’s been proven to help treat or prevent diabetes, depression, breast and colon cancer, high blood pressure, cardiovascular disease, obesity, anxiety and osteoporosis, Sallis told leaders at the 2013 Walking Summit in Washington, D.C.

“The drug is called walking,” Sallis announced. “Its generic name is physical activity.”

Recommended dosage is 30 minutes a day, five days a week, but children should double that to 60 minutes a day, seven days a week. Side effects may include weight loss, improved mood, improved sleep and bowel habits, stronger muscles and bones as well as looking and feeling better.

Comment: If only “walking” was marketed better.  Physicians know that successful treatments need to have an “x” or a “z” or both to really do well (“X and Z in favor”).

 

 

 

Not Much Data with Allopurinol

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The authors of a recent case report (JPGN 2014; 59: 22-24) note that there has been “only 1 study on the pediatric use of allopurinol in inflammatory bowel disease.”  A previous post on this blog has reviewed the use of allopurinol for IBD and provided several references –mainly from use in adults (Data on Allopurinol | gutsandgrowth).

This current study reports on three cases.  In all three cases the combination of allopurinol with low-dose 6-mercaptopurine resulted in clinical remission, including one patient which was poorly responsive to infliximab.  In all three cases, frequent thiopurine metabolites were obtained to help guide dosing.  Prior to allopurinol, all 3 patients had a 6-MMP/6-TG ratio >20; with use of allopurinol there was a decrease in this ratio.

Among these patients, one developed mild leukopenia which resolved with medication adjustment.

Bottomline: Allopurinol can be effective in optimizing thiopurine treatment, but need to be administered carefully.  More studies on its use are needed.