Practice guidelines and 93 OLTx recommendations

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While checklists have a role (Checklists for Crisis and Daily Care | gutsandgrowth), most will not be workable if each has 93 recommendations like the 2012 AASLD Adult Liver Transplant Practice Guidelines (Liver Transplantation 2013; 19: 3-26).

While the guidelines are comprehensive including topics like vascular thrombosis, immunosuppression, late rejection, bone health, kidney diseases, metabolic syndrome, reproductive health, and infectious disease, they are not easily organized.  Some recommendations include the following:

  1. “the frequency of monitoring with liver tests should be individualized by the transplant center (grade 1, level a)”
  2. “depending on the pattern of liver tests, magnetic resonance imaging, computed tomography, ERCP, and ultrasound may be appropriate (grade 1, level a)”
  3. “frequent handwashing reduces the risk of infection…(grade 1, level a)”
  4. “shoes, socks, long-sleeve shirts and long pants should be worn for activities that will involve soil exposure..(grade 1, level a)”
  5. Patients “with PSC and inflammatory bowel disease…should undergo an annual screening colonoscopy ..(grade 1, level b)”
  6. “the ideal immunosuppression for pregnancy is tacrolimus monotherapy”

Thus, the recommendations are sometimes almost worthless like #1-3, sometimes difficult to implement like #4, and sometimes specific like #5-6.

Bottom-line:

While not useful as a practical checklist for routine care, this guideline offers useful information on a broad range of problems for transplant recipients.

Born this way

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“Baby I was born this way” is applicable to more than just Lady Gaga.  It looks like this mantra extends to functional somatic symptoms (FSS) (J Pediatr 2013; 162: 335-42).

This study which was part of a longitudinal birth cohort study, Copenhagen Child Cohort CCC2000, included 6090 children born in a well-defined geographical area around Copenhagen, Denmark in 2000.  At 5-7 year follow-up, a random sample of 3000 members of the cohort were selected; only 2912 were included as 79 were unreachable and 9 had died.  Subsequently, 1327 had complete data and were the final study sample.

FSS were measured by the Soma Assessment Interview.  In the first 10 months of living, regulatory problems which included at least 2 of 3 problems of feeding, sleeping, or tactile reactivity predicted impaired FSS at 5-7 years with aOR 2.9.  Maternal psychiatric illness during the child’s first year of life conveyed an aOR of 7.1.

FSS (ie, headache and recurrent abdominal pain) could develop due to a number of possible mechanisms:

  • hypersensitivity to stimuli
  • autonomic hyper-reactivity
  • regulatory problems may be risk factors for mood and anxiety disorders

While the strengths of this study included prospective data collection by health professionals and a fairly large sample size, there were still numerous limitations.  Measuring regulatory problems in infancy is not fully validated.  In addition, the designation of FSS is problematic as it is difficult to fully exclude organic etiologies which could present with similar complaints.

The association of maternal psychopathology with the development of FSS in their children is of interest.  It is not clear if this risk is due to nurturing effects (i.e., child’s capacity to self-regulate) or due to nature (i.e., inherited susceptibility).

Taking Folic Acid for Autism Prevention

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A large study in JAMA shows an association between taking folic acid and reducing the risk of autism by about 40% (JAMA. 2013;309(6):570-577. doi:10.1001/jama.2012.155925). JAMA Network | JAMA | Association Between Mater

“The study sample of 85,176 children was derived from the population-based, prospective Norwegian Mother and Child Cohort Study.”  The study took place between 2002-2008.  Pregancies in which mothers received folic acid for 4 weeks before the last menstrual period and for at least 8 weeks into the pregnancy were compared with those unexposed to folic acid.

Results:

“At the end of follow-up, 270 children in the study sample had been diagnosed with ASDs: 114 with autistic disorder, 56 with Asperger syndrome, and 100 with PDD-NOS. In children whose mothers took folic acid, 0.10% (64/61,042) had autistic disorder, compared with 0.21% (50/24,134) in those unexposed to folic acid. The adjusted OR for autistic disorder in children of folic acid users was 0.61 (95% CI, 0.41-0.90). No association was found with Asperger syndrome or PDD-NOS, but power was limited. Similar analyses for prenatal fish oil supplements showed no such association with autistic disorder, even though fish oil use was associated with the same maternal characteristics as folic acid use.”

While this study does not prove a causal relationship between maternal folic acid intake and autism, since folic acid is already recommended to prevent neural tube defects, this provides another potential benefit to this intervention.

From ABC news coverage:

Smoking-related mortality

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“The time is always right to do what is right.”  Martin Luther King

When it comes to almost any situation, including smoking cessation, this quote is probably appropriate.  The hazards of smoking are detailed in recent several articles/editorial (NEJM 2013; 368: 341-350, 351-64, 389-90).

In the first article, the authors reviewed smoking-cessation histories from 113,752 women and 88,496 men.  All participants were older than 25 years and interviewed between 1997-2004.  These participants were from a cohort in U.S. National Health Interview Survey (NHIS).  The NHIS is a nationally representative cross-sectional health survey.

The second study involved large populations from the Cancer Prevention Study I (CPS I) which started in 1959 and CPS II which started in 1982.  These were prospective studies followed the mortality associated with smoking.  In all, the populations of these two studies exceeded 1.2 million.

What were the key findings?

1. The benefits of smoking cessation were noted in all age groups.  Those who quit between 25-34 years of age lived 10 years longer.  Those who quit between 35-44 years of age lived 9 years longer. Those who quit between 45-54 years of age lived 6 years longer. Those who quit between 55-64 years of age lived 4 years longer.

2. Smokers mortality worsened compared to the general population over a 50-year period. During the three time periods (1959-65, 1982-88, 2000-10), the mortality dropped by 50% in the overall study population.  However, female smokers mortality remained unchanged and male smokers experienced only a 24% reduction.

Specific hazard ratios (HR) for a large number of conditions are detailed in these studies.  For example, among men, the HR for death due to lung cancer was 24.97 in the contemporary cohort.  Due to the nature of these large cohorts, there are many limitations and it is difficult to draw conclusions about a specific threshold in terms of amount of smoking.  However, the conclusions may actually underestimate the effects of smoking due to undersampling of certain high risk populations, like incarcerated persons and those with mental illness.

The editorial notes that more women die from lung cancer than breast cancer.  Yet, due to smoking’s stigma, there are no ‘race for the cure’ promotions.  In addition, increasingly smoking is a behavior concentrated in persons of lower social status.  As such, it “risks becoming invisible to those who set health policies and research priorities.”

Even Nick Naylor might consider a career change if he read these studies (Thank You for Smoking (film) – Wikipedia, the free encyclopedia).

Shout out for Gluten-Free Camp

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One enjoyable aspect about my work with my colleagues has been their willingness to use their free time to participate and develop programs for children.  For many years, this has included several camps at Camp Twin Lakes, particularly Camp Oasis for children with inflammatory bowel disease. Most of the physicians in our group have given their time to support this camp.  In recent years, Larry Saripkin has spent a week there every summer  and Stan Cohen really established this camp in Atlanta.  In addition, our nurses have volunteered their time as well; they stay busy attending to the medical needs of these kids so they can enjoy a camp experience.

More recently, a camp for kids with celiac disease has been started, Camp WeeKanEatIt.   Under Jeff Lewis’ direction and fundraising, this camp has been started and allows kids  (8-17 yrs) who need to be maintained on a gluten-free diet to experience camp.  Siblings are allowed to attend as well.  Don’t forget this year’s camp dates: June 23-28!

Related links:

New lipid emulsions — lacking data to support usage

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According to a systematic review of the literature regarding ω-3 (n-3FA) fatty acid lipid emulsions, there is a “lack of sufficient high-quality data to support the use of parenteral n-3FA lipid emulsions in children” (JPEN 2013; 37: 44-55). Thanks to Kipp Ellsworth for this reference.

The authors of this study researched 4 databases up to March 2011 and extracted relevant studies.  Five randomized controlled trials and 3 high-quality prospective cohort studies were included.  The strength of evidence was “consistently low or very low across all lipid emulsion comparisons and outcomes.”

Specific criticisms:

  • Few studies examined important outcomes like length of hospital stay or intensive care stay.
  • There was lack of data on growth, cognitive development or potential long-term effects/harms.
  • All of the studies in children varied considerably with regard to the dosing regimens, duration of administration, and duration of followup.
  • The studies were small with sample sizes ranging from 28-91 patients.
  • The 5 RCTs had unclear risk of bias due to inadequate blinding of participants and study personnel.
  • All of the RCTs were funded by the manufacturer.
  • While some biochemical outcomes improved, no difference in mortality has been identified.  A biochemical response is a poor measure of effectiveness.  In fact, several studies have shown deterioration in liver histology and fibrosis despite improved biochemical measures in infants on Omegaven.
  • For Omegaven (fish oil) treatment, all studies used a historical control group.  In these studies, typically the Omegaven dose was half the dose of Intralipid used in the control group.

This article (in its Table 1) identifies the constituents in the commercial available lipid products which include Intralipid, Clinoleic, Liposyn II, Omegaven, SMOFLipid, and Lipoplus.  Intralipid which is widely used is devoid of substantial arachidonic acid (ARA) and docosahexaenoic adic (DHA).  This is particularly important in premature infants as noted in recent blogs:

Omegaven, in particular, and SMOFLipid, to a lesser degree, have much more AA and DHA.  As such, both of these emulsions have the potential improve vision and cognitive outcome in premature infants.

Related blog posts:

Duodenal IELs and the likelihood of celiac disease

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The diagnosis of celiac disease has definitely become more complex due to the interplay of serology, genetic markers, clinical response to gluten-free diets, and histology.  The Mayo clinic pediatric experience with duodenal intraepithelial lymphocytosis (IELs) with normal villous architecture highlights this issue (JPGN 2013; 56: 51-55).

Between 2000-2009, 56 children from the Mayo clinic pathology database of duodenal biopsies (n=1290) were identified.  Among this group, 48 had serological testing for celiac disease (CD).  Ultimately, 9 were labeled with CD, though only 5 met the ‘definite’ criteria.  Other conditions that were associated with increased IELs included the following:

  • Medication exposure
  • Inflammatory bowel disease
  • H pylori infection
  • Autoimmune conditions
  • IgA deficiency

So, which patients with duodenal IELs had CD?

  • “Definite” CD was used to define patients with elevations in two different serologic markers (TTG and EMA) or those with elevation in one serologic marker along with a documented clinical response to a gluten-free diet (GFD).
  • “Possible” CD described patients with normal serology, but serologic titer and clinical response was noted on a GFD.
  • “Unlikely” CD categorized patients with two negative serology markers who had compatible human leukocyte antigen haplotype and had clinical response to GFD.

In addition, if the IELs were predominantly on the villi tips, this increased the likelihood of CD.

Related blog posts:

Three PEG Pediatric Cleanouts

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Several articles highlight the use of polyethylene glycol (Miralax) as a bowel prep for children:

  1. JPGN 2013; 56: 215-19
  2. JPGN 2013; 56: 220-24
  3. JPGN 2013; 56: 225-28

These studies and the accompanying editorial (pg 115) show fairly good results with PEG cleanout regimens.

The first study compared PEG versus senna in a blinded, prospective randomized trial.  After enrolling 30 children (6-21 years of age) at a planned interim analysis, the study showed superiority of PEG (1.5 g/kg/day) when used for 2 days prior to colonoscopy.  In addition to laxatives, patients were instructed to consume full liquid diet for 2 days prior to procedure & clear liquid on day prior (up to 3 hours before procedure).  In the PEG group, good or excellent cleanout scores were noted in 88% compared with only 29% in the senna group. There were no significant adverse effects or electrolyte changes which are well-detailed in this study (Table 2).

The second study evaluated a 1-day regimen with 46 children in a prospective open-label study.  238 g of PEG was mixed with 1.9 L of gatorade and administered over several hours.  Patients (8-18 years) were instructed to take only clears after noon the day prior to procedure Only 37 (82%) were able to take the full preparation.  43 (93%) took at least 75% of the preparation.  Despite issues with tolerance and nausea/vomiting (noted in 60%), 77% were rated as having an effective cleanout.

The third study enrolled 45 children (5-21 years) in a prospective study of a 1-day bowel preparation. Patients <45 kg received 136 g of PEG solution with 32 ounces of Gatorade; patients >45 kg received 255 g in 64 ounces.  44 children completed study.  Patients were told to take PEG over 3 hours the evening prior to procedure and allowed clears until 3 hours prior to procedure.  In this group, nausea was noted in 34% and vomiting in 16%.  However, patients reported that preparation was easy in 61% and tolerable in 39%.  The quality of the preparation was considered excellent in 23%, good in 52%, fair in 23% and poor in 2%.  There were no significant electrolyte changes.

Take Home Message:

Numerous small studies show that PEG solutions can be used as a safe, effective bowel preparation in children.  Shorter duration preparations are more convenient and may result in nausea or vomiting.

In our institution, we frequently use PEG cleanouts.  However, typically our doses of PEG are lower (eg. 136-168 g) and often combined with an enema to complete cleanout process.  Unlike adult preparations, we have not instructed families in split-dose regimens mainly due to concerns about the ability of pediatric patients to adhere to these regimens.

Related blog entry:

Miralax Safety

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Periodically questions about the safety of Miralax arise. Recently, several colleagues have received some questions about the use of Miralax due to information on the internet. You may want to familiarize yourself with this link due to the misinformation which is provided:

http://www.gutsense.org/gutsense/the-role-of-miralax-laxative-in-autism-dementia-alzheimer.html

Some of the misleading statements:

  • Miralax has never been tested for safety in children
  • Miralax makes one cancer-prone by leaving the colon unprotected
  • Miralax may result in severe malnutrition ..leading to Autism
  • Miralax can cause memory loss and neurologic side effects

It is true that there is not enough adequate long-term data on the use of Miralax, though there are studies showing its effectiveness/safety (see below).  However, according to the FDA, there are no neuropsychiatric warnings needed for Miralax:

As with all medications, one has to weigh the risks and the benefits.  Clearly, the risk and consequences of untreated defecation problems can be severe in some children and may have terrible adverse effects on daily living.  The known safety profile of Miralax is very good and its usage has been recommended by the American Gastroenterological Association (AGA) and by the North American Society for Pediatric Gastroenterology Hepatology and Nutrition (NASPGHAN) in position statements on the treatment of constipation:

An article from NY Times on this subject:

Related Blog Posts:

Related references:

-Aliment Pharmacol Ther 2011; 33: 33-40.  Comparison of golytely vs miralax.
-Gastro & Hep 2008; 4: 489.  Safety/effectiveness of PEG3350 as sole agent for cleanout in 245 adults.  Used 204 gram in 32 oz of water.
-Pediatrics 2006; 118: 528.  Data on safety and effectiveness in 79 children (39 c PEG, 40 c MOM).  PEG outperformed MOM.  compliance for PEG was 95%, after 12 months, 62% improved c PEG and 33% recovered (did not need med anymore).
-JPGN 2004; 39: 536. n=75.  good experience with infants & toddlers; 85% short-term/91% long-term success.
-JPGN 2004; 39: 106.  Miralax cleanout: 4 glasses of Miralax, clears , two doses of senna or bisacodyl, & 1 saline enema.
-J Pediatr 2004; 144: 358.  4 day cleanout with Miralax, 1.5g/kg/day; last day with clears.  No enemas given.
-Arch Pediatr Adolesc Med 2003 Pashankar DS et al; n=83. Rx avg 8.7mo. insignificant adverse effects. no loss of efficacy
-Clin Pediatr 2002; Gremse DA. Lactulose & Miralax equivalent , but Miralax preferred
-JPGN 2004; 39: 197.  Published use in infants, n=28
-JPGN 2003; 37: 329 (9A) use of Miralax to 2mo or older, n=23.
-J Pediatr 2002; 141: 410-14.  PEG 3350 at doses of 1-1.5g/kg/d for 3 days relieved an impaction in 95%.
-JPGN 2002; 34: 372-377. n=28 pts + 21 pts c MOM control.  61% vs  67% doing well at 12 month f/u.
-OnlineJournal of Digestive Health 1999; 1.  Miralax results in good long-term success without salt absorption.
-J Pediatr 2001; 139: 428-32.  Mean effective dose was 0.84 g/kg/day (range 0.3-1.4 g/k/d) n=24 (for 8 weeks) 18mo to 11 years.
-JPGN 2001; 32: 514. Safety of miralax & references.

AGA Constipation Guidelines

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Constipation is a ubiquitous problem.  Updated guidelines and a technical review for adults with constipation have been published (Gastroenterol 2013; 144: 211-17, Gastroenterol 2013; 144: 218-38). AGA Institute Policy and Position Statements – Gastroenterology …

For pediatric gastroenterologists, the 2006 NASPGHAN guidelines (Evaluation and Treatment of Constipation – North American Soci) are more useful.  Nevertheless, these AGA guidelines offer some helpful insights.

Definition: “physicians often regard constipation to be synonymous with infrequent bowel movements, typically fewer than 3 per week, patients have a broader set of symptoms” that are considered constipation including hard stools, abdominal discomfort, incomplete evacuation, and excessive straining.  Rome  III criteria: “symptoms for ≥ 6 months and ≥ 2 of the following symptoms for more than one-fourth of defecations during the past 3 months: straining, lumpy or hard stools, sensation of incomplete evacuation, sensation of anorectal obstruction, manual maneuvers to facilitate defecations; ❤ defecations/wk, loose stools are not present and there are insufficient criteria for IBS”

In adults, medical testing:

  • “In the absence of other symptoms and signs, only a complete blood count is necessary.”  Not needed unless other features: TSH, calcium, colonoscopy
  • Anorectal manometry and rectal balloon expulsion should be performed in patients who fail to respond to laxatives.  Defocography should be considered subsequently.  Colonic transit should be evaluated if anorectal test results do not show a defecatory disorder.

Recommended Treatment:

  • Start with increased fiber and laxatives (e.g. PEG, milk of magnesia, bisacodyl).  Newer pharmaceutical agents (e.g. lubiprostone and linaclotide) can be considered if no improvement.
  • Both “normal transit constipation and slow transit constipation can be safely managed with long-term use of laxatives.” (strong recommendation, moderate-quality evidence).  “Contrary to earlier studies, stimulant laxatives (senna, bisacodyl) do not appear to damage the enteric nervous system.  Neurologic damage might just as readily be the cause, not the result.”
  • Pelvic floor retraining by biofeedback rather than laxatives is recommended for defecatory disorders
  • Additional workup in those who do not respond.  Surgical treatment of slow transit constipation (subtotal colectomy or colectomy with ileorectal anastomosis) only when well-documented failure of aggressive prolonged laxatives/prokinetics

The technical review has a table that lists medications associated with constipation, describes pathophysiology in detail, lists the conditions associated with constipation, and explains the testing/medical management in-depth.

Related blog entries:

PEG vs. Fiber for constipation | gutsandgrowth
Stimulants for constipation | gutsandgrowth
It’s worth the cost | gutsandgrowth
ACE report -10 year effectiveness | gutsandgrowth
Linaclotide –not for kids | gutsandgrowth
Clues about constipation and more than 2.5 million … – gutsandgrowth