Category Archives: Uncategorized

Outgrowing the growth charts

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Unfortunately, there is a need for extreme growth charts (Pediatrics 2012; 130: 1136-40).

The authors of this study designed growth charts for morbidly obese children.  The reason for these charts is that there are many pediatric patients who cannot be plotted using the CDC  growth chart which has a maximum BMI of 36 kg per meter-squared.  The CDC charts are based on a preobesity epidemic population data set (1963-94) and has sparse data for those above the 97th percentile.  The manuscript describes how these initial charts were derived.

These new growth charts calculate the BMI as a percentile of the 95th percentile.  For example, multiplying the BMI 95th % by 1.2 would yield a result of 120% of the 95th%.  The authors calculated 1.1 through 1.9 multiples of the 95% for all ages between 2 and 20 years.  On their curve, a BMI as high as 64 kg per meter-squared can be plotted.  This allows easier visual tracking of a patient’s progress.

Drawbacks:

  • Difficult to explain to parents due to confusing phraseology –use of two percentages
  • Many of the patients are now on the growth curve and could appear to be graphically normal despite being morbidly obese

The authors note that their growth charts were incorporated into their electronic medical record (Epic software).

Related blog entry:

Transfusion strategy in acute GI bleeding

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A recent study shows that holding off on blood transfusions can improve survival with severe acute upper gastrointestingal bleeidng (NEJM 2013; 368: 11-21).  This finding is not unexpected as this has been shown in observational studies.  In addition, in critical care patients without acute GI bleeding, a restrictive approach to transfusions has also been beneficial.

This study which enrolled 921 patients (>18 years) assigned 461 to a restrictive transfusion strategy (transfusion if <7 g/dL or at discretion of physician) and 460 to a “liberal” strategy (transfusion if <9 g/dL).

In additon to fewer transfusions, the restrictive group had improved survival:

  • 225 in the restrictive group did not require a blood transfusion compared with 65 in the liberal group
  • Survival at 6 weeks: 95% in the restrictive group compared with 91% in the liberal group.  Hazard ratio 0.55 (confidence interval 0.33 to 0.92) –a 45% reduction in the relative risk of 45-day mortality.
  • Recurrent bleeding occurred in 10% of the restrictive group compared with 16% of the liberal group.
  • The patients with cirrhosis (and Child-Pugh class A or B) were most likely to benefit from a restrictive approach with hazard ratio of 0.30.  Child-Pugh class C did not have a benefit from a restrictive approach with hazard ratio of 1.04.  With the liberal approach, there was a higher portal-pressure gradient within the first five days.

The reasons for bleeding in this study included peptic ulcers in about 50%, and varices in 24%.  The other causes included Mallory-Weiss tears, erosisve gastritis/esophagitis, and neoplasms.

Why does giving less blood result in better outcomes?

  1. Transfusion may impair hemostasis in several ways.  It may result in abnormalities in coagulation properties.  It may counteract splanchnic vasoconstrictive response.  And, in those with cirrhosis, it can increase portal pressure (even in the presence of somatostatin).  All of these mechanims may increase rebleeding.
  2. In addition, systemic effects from transfusion can include circulatory overload and pulmonary edema.

Also (unrelated to this posting), a thoughtful comment to a recent post on FDA regulations was posted by Ben Gold (Can the FDA prohibit free speech? | gutsandgrowth).

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Fecal transplant -now mainstream

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This blog has previously discussed fecal transplants (see below).

Now, in response to an article in the New England Journal of Medicine, this topic is discussed in the NY Times:

Fecal Treatment Gains Favor for Some Illnesses – NYTimes.com

http://www.nejm.org/doi/full/10.1056/NEJMoa1205037?query=featured_home

(method: duodenal infusion)

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HBV: translating advances from adults to pediatrics

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Given the increased difficulties of conducting research in the pediatric population, it can take a long time for pediatric patients to benefit from the research advances demonstrated in adults.  Fortunately, with hepatitis B virus (HBV) the lag time has not been excessive.  A specific example has been a recent study demonstrating the effectiveness of tenofovir in the pediatric population (Hepatology 2012; 56: 2018-26).

In this double-blind, placebo-controlled study,  adolescents with chronic HBV were randomized into tenofovir 300 mg (n=52) or placebo (n=54) once daily for 72 weeks.  101 patients completed the 72 weeks of treatment.  In this population, 85% had received prior HBV therapy and 91% were HBeAg-positive at baseline.  Patients included in the study had to have ALT >2 x ULN or history of this w/in 24 months along with HBV DNA>10 to the 5th copies/mL.  The inclusion criteria required a weight of >35 kg.

Findings:

  • Virologic response (HBV DNA <400 copies/mL): 89% in tenofovir group and 0% in placebo group
  • No resistance noted through 72 weeks.  All cases of virologic breakthrough were associated with non-adherence but no genotypic or phenotypic resistance.
  • Normalization of ALT: among patients with baseline elevation, normalization occurred in 74% of tenofovir group compared with 31% of placebo group
  • Serologic response: 21% of tenofovir group and 15% of placebo group experienced loss of HBeAg by week 72
  • Adverse effects were more frequently noted in placebo group.  No patients met the safety endpoint of a 6% decrease in spine bone mineral density

Since suppression of HBV DNA is a limited surrogate endpoint for the development of long-term sequelae much longer followup is needed to determine the impact of this nucleotide analogue.  In adults, this agent has been associated with reversal of cirrhosis.

Across the globe, 350 million people live with chronic HBV infection and 600,000 die each year due to HBV infection.  About 25% of children with HBV develop cirrhosis or cancer of liver later in life.  Given the magnitude of the problem, the most promising approach remains prevention with vaccination.  Treatment to prevent complications in those already infected is likely to be offered to a tiny fraction of those who might benefit.

Related blog entries:

Kawasaki disease –there’s an app for that!

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With the ubiquitous availability of smart phones, point-of-care technology becomes increasingly sophisticated.  Many are familiar with mobile drug information resources (eg. Lexicomp, Epocrates), but now information is increasingly disease-specific.  An example of this and the data supporting this are available in a recent publication with regards to diagnosing Kawasaki disease(KD) (J Pediatr 2013; 162: 183-88).

After simulating a model with a training cohort of 276 patients with KD and 243 febrile control (FC) patients, the authors validated the model with 136 patients with KD and 121 FCs.  Inclusion criteria for KD were based on the American Heart Association guidelines.

The scoring system which combined clinical findings and laboratory findings resulted in “a sensitive (>95% PPV) and specific (>95% NPV) diagnosis of ~60% of FCs and ~75% of patients with KD.”  In essence, the patients with high or low scores for KD were quite reliable.

To check out the web site:

http://translationalmedicine.stanford.edu/cgi-bin/KD/kd.pl

Potential limitation: The personnel involved in the study were very experienced in KD; thus, the model may be less effective when less skilled personnel obtain the clinical information.

While pediatric gastroenterologists do not frequently see KD patients, the bigger issue is developing point-of care tools. In our electronic health record (EHR), one point-of-care tool I developed was a smart phrase to assess hospitalized patient’s with colitis (see bottom of post in blue).  This smart phrase can be pulled up with three key strokes and helps me assess the severity of the patient’s colitis.

Another useful smartphrase in blue  (that was shared with me from Mike Hart), also retrieved with three key strokes,  is the following:

Here is a weblink on youtube for a video on changing Mic-Key buttons:

http://www.youtube.com/watch?v=Mn4ePSBiCTk

I often share this link with parents at the end of my “after visit summary” note.

These types of tools can improve recognition and treatment in a wide range of areas and are only limited by our imagination.

Pediatric UC Activity Index:

1. Abd pain

No pain —0 points, Pain can be ignored —5 points, Pain cannot be ignored—10 points

2. Rectal bleeding

None —0 points, Small amount & in <50% of stools — 10 points, small with most stools —20 Large amount —30 points

3. Stool consistency

Formed — 0 points, partially formed — 5 points, completely unformed —10 points.

4. #Stools/24hrs

0-2 —0 points, 3-5 —5 points, 6-8 — 10 points, > 8 15 points

5. Nocturnal Stools

No —0 points, Yes —10 points

6. Activity Level

No limitation —0 points, Occasional limitation —5 points, Severe limitations —10 points

 

Total Score: *** @TD@ 

 

Interpretation: 

Remission <10, Mild dz 10-30, Mod dz 31-64, Severe dz >65

 

References: 

1. Gastroenterology 2010; 138: 2282-2291.  PUCAI helps predict IV steroid failure in hospitalized pediatric colitis pts. n=128.  37 failed IV steroids (29%)

Score >45 (on day 3) indicates pts likely to fail IV steroids: Pos PPV 43%, Neg PPV 94%

Score >70 (on day 5) indicates need for alternate rx (+PPV100%) 

25/33 steroid failures responded to IFX.  Colectomy rate 9% initial, & 19% at 1 year.

2. Gastroeterology 2007; 133: 423-32.  Turner et al.

Related blog entry:

Cholestatic Kawasaki Disease | gutsandgrowth

Predicting long-term response with calprotectin levels

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This blog has been a fan of calprotectin levels (see related posts below) as both a screening test for inflammatory bowel disease and as a marker of disease activity.  Now more data is available indicating that calprotectin levels, much like endoscopic mucosal healing, after induction therapy correlates with long-term response (Inflamm Bowel Dis 2012; 18: 2011-17).

This retrospective study (2005-2010) examined 60 patients with IBD with elevated baseline calprotectin levels.  34 patients had Crohn’s disease (CD) and 26 had ulcerative colitis (UC).  42 patients received infliximab therapy and 18 patients received adalimumab.  After induction therapy, therapy was discontinued in primary non responders or continued as scheduled maintenance therapy for at least one year if not relapsing.

The average age at induction for CD patients was 30 and the corresponding age at diagnosis was 21.  For UC patients, the average age at induction was 29 and the corresponding age at diagnosis was 26.

Median calprotectin level at baseline was 810 μg/g (n=60).  After induction, the median value dropped to 97 μg/g (n=60) and at 1 year the value dropped to 27 μg/g (n=25).  The calprotectin level normalized in 31 patients after induction.  At 12 months, the sustained remission was present in 84% (26/31).  In contrast, only 38% (11/29) who had elevated levels after induction were in remission at 12 months.

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Linaclotide –not for kids

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Linaclotide has been approved for adults (≥18 years) with chronic constipation and constipation-predominat irritable bowel syndrome (IBS-C) (Gastroenterol & Hepatol 2012; 8: 653-60).

Linaclotide is a 14-amino acid peptide that stimulates guanylyl cyclase C (GCC) receptors.  It mimics the endogenous peptides guanylin (15 amino acids) and uroguanylin (16 amino acids) which activate GCC through a cascade which activates CFTR to increase luminal levels of bicarbonate, chloride and water.  This in turn improves gastrointestinal transit.

There were several trials undertaken to assess the efficacy of linaclotide in IBS-C:

  • 47 patients (36 women) with IBS-C were treated with linaclotide (100 μg or 1000 μg) or placebo –5 day study. The 1000 μg dose significantly decreased colonic transit time compared with placebo.  No serious adverse events were reported.
  • 420 patients were enrolled in a 12-week, randomized, double-blind, placebo-controlled, dose-ranging study.  The population was 92% female, 80% caucasian with a mean age of 44 years.  337 patients completed the study.  There were improvements in the number of complete spontaneous bowel movements (CSBMs) per week and in abdominal pain.  Additional results:
  1. With 300 μg dose, there were 3.93 CSBMs/week, with150 μg dose 2.79 CSBMs/week compared with 1.47 for placebo.
  2. With 300 μg dose, there was -0.90 in pain score, with 150 μg dose -0.71 compared with -0.49 for placebo.  Overall, abdominal pain improved in 31.1-38.7% of linaclotide-treated patients compared with 22.7% of placebo-treated patients.

For chronic constipation, four trials (n=42, n=310, n=630, and n=642) have shown increased CSBMs/week.  On average, a dose of 290-300 μg dose resulted in 1.8-2.7 CSBMs/week, a dose of 145-150 μg dose resulted in 1.6-2.0 CSBMs/week compared with 0.5-0.6 CSBMs/week for placebo.  Changes in stool frequency were also reflected in quality of life scores.  When linaclotide was stopped, patients reverted to similar stooling rates as placebo-treated patients but no rebound effects were noted.

Prior to approval of linaclotide, lubiprostone (Amitiza) had been the only FDA-approved medication for IBS-C.  For chronic constipation, polyethylene glycol is another approved treatment.

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More frequent pediatric IBD

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Using a national cohort of prospective and retrospective data on pediatric inflammatory bowel diagnosis, (PIBD) a recent report indicates a rising incidence of PIBD in Scotland (Inflamm Bowel Dis 2012; 18: 999-1005).

Key findings:

  • Between 2003-2008, 436 patients were diagnosed with PIBD; this equates to 7.82/100,000; Crohn’s was 4.75 and UC 2.06 per 100,000 respectively
  • Between 1990-1995, 260 patients were diagnosed with PIBD; this equates to 4.45/100,000; Crohn’s was 2.86 and UC 1.59 per 100,000 respectively
  • Mean age of diagnosis in more recent cohort was younger: 12.7 years compared with 11.9 years

Currently, a data-base coordinated in a single center along with collaboration with regional networks enables the capture of all new IBD diagnosis (since 1999).  Prior cohort was determined by “exhaustive examination” of previous IBD records.

Running out of options

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A series of articles on natalizumab were published which give practical advice for this drug which clinicians often turn to when ‘running out of options’ (Gastroenterol Hepatol 2012; 8: 4-17).

Slides from these articles should be available soon (not online on 1/2/13):

http://www.clinicaladvances.com/index.php/our_publications/gastro_hep-issue/gh_november_2012/

According to an algorithm on page 7, in patients with moderate-severe Crohn’s disease who have failed conventional therapies and anti-TNF drugs (or unable to tolerate), the next step is to obtain anti-JCV (John Cunningham Virus) antibody status.  Patients who test negative are ‘Okay to treat with natalizumab’ due to very low risk of progressive multifocal leukoencephalopathy (PML).  Repeated testing at least once a year is then recommended.

For patients who test positive for anti-JCV at any time point, natalizumab can be considered if no other treatment options are available, but the risk of PML is much greater. Previous blog entries (below) have discussed this in greater detail and have provided additional references:

Another article published the experience in 36 Mayo clinic patients between April 2008-September 2010 (Inflamm Bowel Dis 2012; 18: 2203-08).  Consecutive patients who received natalizumab were prospectively followed.  Of the 36 treated with natalizumab, 30 agreed to participate in the study.  23 patients had failed two anti-TNF agents and 7 had failed one anti-TNF agent.  Median age was 35 years.

Results:

  • 14 (46%) had a complete clinical response, 12 had a partial response, and four had no response.  Cumulative probability of a complete response within 1 year was 56%.
  • Time to response: 10% after 1st dose, 50% of patients had complete response after 4th dose
  • Adverse events were common –though this rarely caused drug cessation. Common events included headache and infections (listed in Table 4 of article).  Some infections prompted holding natalizumab for up to 8 weeks.
  • 11 stopped natalizumab due to lack of improvement.

Teduglutide for Short Bowel Syndrome

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More data on teduglutide indicate its potential for short bowel syndrome (SBS) (Gastroenterol 2012; 143: 1473-81, editorial 1416-20).  Treatments for SBS are needed.  One year of parenteral nutrition often costs the health care system in excess of $100,000 per year.  This cost does not account for laboratory studies, health care visits, complications, and hospitalizations.  Treatment of intestinal failure with transplantation “may cost upwards of $1 million.”

In this study of adult patients with an average of 50 years, teduglutide was given in a prospective randomized double-blind study to 42 patients and another 43 patients received placebo. The dose of 0.05 mg/kg/day via subcutaneous injection was chosen based on a previous trial which showed that a higher dose was less effective.  Among these patients, the most common reasons for SBS were vascular disease (34%), Crohn’s disease (21%), volvulus (11%), and injury ((9%).

Bottom line:

  • Teduglutide over a 24-week study was more effective than placebo.  63% of study patients had a drop in parenteral nutrition requirement of more than 20% compared with only 30% of the placebo group.
  • The mean reduction in parenteral nutrition support of teduglutide-treated patients was 4.4 L/week compared with 2.3 L/week for placebo-treated patients.
  • Citrulline, a biomarker of mucosal mass, was increased in the teduglutide group.  In the treatment group, citrulline increased by 20.6 μmol/L compared with 0.7 μmol/L for the placebo group.

How does teduglutide work?  Teduglutide is a much more stable analog of glucagon-like peptide-2 (GLP-2).  The latter is released by the distal small bowel and colon.  GLP-2 promotes intestinal epithelial growth and increases transit time.

What are the adverse effects of teduglutide? First, there is a concern that teduglutide could promote colonic adenomas based on studies in mice.  GLP-2 receptors are present in the lung, and brain (including hypothalamus); its effects in these areas is poorly understood.  In addition, abdominal pain, distention, nausea, peripheral edema, and nasopharyngitis were more common in the treatment group. The long-term consequences of teduglutide therapy are not known.

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