When death is on the line

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“Never go against a Sicilian when death is on the line“! –from The Princess Bride

With acetaminophen-induced hepatic failure, King’s College Hospital (KCH) Criteria have been helpful for predicting death.  While the Sequential Organ Failure Assessment (SOFA) was not designed by a Sicilian (to the best of my knowledge), it is more sensitive at predicting death than KCH Criteria (Liver Transplantation 2012; 18: 405-412, & editorial 384-86) .

SOFA measures organ dysfunction by evaluating each of the following on a 0-4 scale: respiratory, hepatic, coagulation, cardiovascular, neurologic, and renal.

In the cited study, 125 consecutive adult patients (mean age 38 years) with acetaminophen-induced acute liver failure were evaluated.  KCH criteria had highest specificity (83%) and lowest sensitivity (47%).  The SOFA score had the best discriminative ability.  A SOFA score >7 during the first 96 hours predicted death or transplantation with a 95% sensitivity and 70.5% specificity.  Other specific predictors of poor outcome included higher lactate levels, worsened coagulation parameters, and need for mechanical ventilation.  In this cohort, 67 (54%) survived with medical management, 35 (28%) died and 23 (18%) received a liver transplant.

While sensitivity and specificity will vary based on pretest probability/specific population, what is clear is that relying on KCH criteria alone would be unwise.

Additional references:

  • -J Pediatr 2011; 159: 813.  Study of ALF in young infants.  38% were indeterminate, ~14% NH, 12% herpes.  n=148. 60% survived w/o OLT, 24% died, 16% OLT
  • -Hepatology 2010; 53: 567.  18% of indeterminate ALF may be due to acetaminophen toxicity.
  • The King’s College Criteria identify two groups of patients that have a poor prognosis with acetaminophen induced liver failure (http://en.wikipedia.org/wiki/King’s_College_Criteria)
  • -J Pediatr 2009; 155:801.  Diagnostic evaluation in ALF  –wide variation.  Often not tested for AIH, wilson’s, HAV, HBV
  • -NEJM 2009; 361: 2105.  Changes in FDA labeling of analgesics.  ~30,000 hospitalizations /yr due to acetaminophen overdose in U.S.  –1/2 inadvertent overdose.  Maximum dose -650mg.
  • -Hepatology 2007; 46: 966.  AASLD public policy.  It is leading cause of acute liver failure in U.S –50% of cases with 30% mortality rate.  500 deaths annually.  10% of cases may occur in those receiving the proper doses. In single year, acetaminophen causes more deaths than all the years of statins.
  • -JAMA 2006; 296: 87-93.  Prospective study of daily 4gm acetaminophen in healthy volunteers.  (stayed at research facility).  ALT >3 ULN in 38%.  Resolved over 6 days.
  • -Liver Transplantation 2006; 12: 682.
    -Hepatology 2005; 42: 1364-72.  74 pts died & 23 needed Tx during  6 yr period at 22 tertiary care centers.  48% of cases were unintentional overdoses.
  • -J Pediatr 2002; 140: 522.  Predictors of outcome p acetaminophen ingestion.

More on magnet ingestions

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Magnet ingestion has been a popular topic this past week on the pediatric GI listserv and follows a recent post on this blog as well (Magnet ingestion –urgent removal needed).  Two useful links are listed below:

Infliximab for children with Ulcerative Colitis

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A large multicenter study of patients 6-17 years of age has shown that infliximab (IFX) can be effective for ulcerative colitis (UC) (Clin Gastroenterol Hepatol 2012; 10: 391-99). Our pediatric GI group was part of this multicenter study which enrolled 60 patients. Stanley Cohen was lead CCDHC investigator and is one of the authors.

At week 8, 44 patients (73.3%) had a clinical response to IFX.  This group of ‘responders’ were eligible for the maintenance phase of the study and were divided into a q8 week treatment group (Q8) and a q12 week treatment group (Q12).  During the maintenance phase, patients who had lost response were eligible to have a dose escalation from 5 mg/kg/dose to 10 mg/kg/dose. At week 54,  patients receiving every Q8 had a remission rate of 38% (8 of 21) whereas among the Q12 responder group only 18% (4 of 22) were in remission.  Overall, the authors projected that if the entire cohort had been placed on every 8 week treatment, the response would have been 28% at week 54; in addition, analysis with ‘real-world’ dose adjustments could achieve a 42.8% remission rate.

The main serious adverse events reported during the study was worsening of UC.  Two patients were receiving immunomodulators during the study. Five of 60 patients required a colectomy within the 54-week study period.

The risk/benefit ratio of TNF antagonists for UC has been discussed in related posts (see below).

Previous related posts:

TNF antagonists and UC

Only one chance to make first impression

Additional references:

  • -Am J Gastroenterol (Oussalah A et al) 2010; 105: 2617-25. Multicenter study of IFX for UC.
  • -Gastroenterology 2010; 138: 2282. Severe pediatric UC. 25/33 responded to IFX. colectomy rate 19% at 1 year.

Will NOTES come to pediatrics?

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Natural orifice translumenal endoscopic surgery (NOTES) has been receiving increasing attention and is being considered as a potential alternative to laparascopic surgery; but it will be a long time before NOTES comes to pediatrics.  Initial studies for several indications have been published in the last few years and this experience has recently been reviewed (Gastroenterology 2012; 142: 704-10).

Potential operations include the following:

  • Cholecystectomy.  This has been accomplished transgastric and transvaginally.  One multicenter study published experience with 362 transgastric cases and another with 551 transvaginal cases.
  • Thyroidectomy via a translingual approach.
  • Esophageal myotomy via a transesophageal approach.
  • Appendectomy via a transvaginal approach.
  • Rectal cancer resection via a transrectal approach.

Thus far, complications have been low & no deaths; only infrequently has a laparascopic or open procedure been needed to salvage the operation.  The main limitation to further use of NOTES has been adequate instrumentation and a critical mass of investigators to explore this technique.  As expertise develops in this area, a much larger number of procedures will be undertaken.  In many ways, NOTES is akin to laparascopy in its early days.  Potential advantages of decreased pain and faster recovery are the motivation to continue to work on NOTES.

CLMP–why some children are born with a short gut

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CLMP stands for Coxsackie- and adenovirus receptor-like membrane protein. It is required for intestinal development (Gastroenterology 2012; 142: 453-62).

In this study of seven patients from five families with congenital short-bowel syndrome (SBS), the authors identified a loss-of-function of CLMP in five of the patients.  CLMP is a tight-junction-associated protein that is expressed in the intestine of human embryos throughout development.

To study the effect of CLMP expression, the authors created a zebrafish model with compromised CLMP activity.  This lead to offspring with a foreshortened body and intestine, strengthening the evidence that CLMP dysfunction is responsible for congenital short-bowel syndrome.

Additional references/previous related posts:

MicroRNA signature for eosinophilic esophagitis

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In a previous post discussing MicroRNAs (miRNAs) (MicroRNAs and biliary atresia), I stated that “Despite this intriguing research, it not clear whether or when miRNAs will have an important role in bedside management.”  Well, as more articles emerge on miRNAs, it is becoming clear that miRNAs will have a role in clinical medicine; the questions are when and what cost.

The latest study (J Allergy Clin Immunol 2012; 129: 1064-75) by Lu et al from Cincinnati shows how this technique can identify a specific signature for eosinophilic esophagitis (EoE) and how miRNAs can serve as a biomarker for disease response.  The investigators took plasma and esophageal biopsy specimens from patients with EoE, reflux esophagitis, and healthy controls; they used an array comprising 677 miRNAs.  254 miRNAs were expressed at greater than background levels, but 21 upregulated miRNAs and 11 downregulated miRNAs were markedly different.

To quickly understand how useful this technology could become requires a glance at the “heat maps” showing the expression profile of the 21 upregulated miRNAs and the 11 downregulated miRNAs, comparing EoE with healthy controls (Figures 1 & 3).  In addition, in Figure 3, it is readily apparent that the expression pattern is completely different from reflux esophagitis.  Furthermore, this figure demonstrates visually a normal-appearing pattern in patients who respond to fluticasone.

Other figures in the article and in the appendix demonstrate the complex relationships between these specific miRNAs and target genes.

Key points:

  • miRNAs from tissue or blood could serve as biomarkers for the presence of EoE and response to therapy
  • Of the identified miRNAs, miR-21 and miR-223 strongly correlate with esophageal eosinophilia as well as previously described EoE transcriptome
  • Plasma miRNAs that are most differentiated in EoE include miR-146a, miR-146b, and miR-223.

Related posts:

Guidelines for Eosinophilic Esophagitis

Eosinophilic Esophagitis -Six Food Group Diet

The undiscovered country

Magnet ingestion –urgent removal needed

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This month’s Gastroenterology has an interesting picture of magnet(s) ingestion (Gastroenterology 2012; 142: 701, 1044).  This case report describes an ingestion by a 3-year-old boy who had swallowed 5 ball-shaped magnets.  The authors considered this an emergency even though it appeared that all 5 balls were in the stomach. As it turns out, a gastric mucosa fold was trapped in between the balls.  By taking the child for emergency removal, the authors averted a gastric perforation.

When multiple magnets are ingested, they may attract each other and cause pressure and subsequent damage. Magnet ingestion has become an important ingestion with case reports that have even included a death secondary to sepsis as well as perforations, fistulas, and volvulus.  Due to the potential for severe harm, they should be retrieved when possible ASAP.

Additional references:

Treatment for rumination and belching

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Treatment options for rumination and for belching are limited.  Baclofen improves symptoms and decreases events in both of these disorders (Clin Gastroenterol Hepatol 2012; 10: 379-84).

Rumination is characterized by effortless regurgitation of recently ingested food into the mouth (or beyond). It is easily mistaken for vomiting disorders and motility disturbances.  With rumination, patients have retrograde flow of gastric contents into the esophagus through voluntary, though unintentional, abdominal muscle contractions with increased intragastric pressure increases.

Supragastric belching occurs when air is sucked into the esophagus by decreasing the intrathoracic pressure or by contracting pharyngeal muscles.

Baclofen is an agonist of the γ-aminobutyric acid B (GABA) receptor which results in increased lower esophageal sphincter (LES) pressures and reduced swallowing rates. Baclofen has been shown to improve reflux, mainly by reducing transient LES relaxations (TLESRs) but also by increasing basal LES pressures.

In the majority of patients, the mainstay of treatment has been behavioral which use diaphragmatic breathing to compete/extinguish these behaviors.  There are a shortage of therapists familiar with this approach.  As such, alternative treatments are needed.  In this study, high-resolution manometry-impendance recordings were taken from 16 patients (10 women; mean age 43 years; range 18-89 years); eight of the patients had rumination.  Only 12 patients were included in the final analysis; four patients refused repeat manometry.  Manometry was performed before and after treatment along with recording symptoms.  Both symptoms and manometry recordings improved with Baclofen therapy.  This was a one-week open-label study.  Baclofen was dosed at 10 mg TID.  At baseline the total number of “flow events” was 473; after treatment, this was reduced to 282 events.  In total, rumination events decreased by 68% during treatment.   This improvement correlated with increased LES pressures.

Four of the 12 patients reported mild side effects mainly sleepiness and difficulty concentrating.

Additional references:

  • -Clin Gastroenterol & Hep 2007; 5:772. Review. Supragastric belching usually due to aerophagia and is very frequen (up to 20/hr)t. GERD related belching is less infrequent, has sour taste, usually less loud & after meals. Gum chewing, excessive beverage drinks, rapid eating or drinking,  smoking or using straw for drinking may increase air in the stomach and lead to burping which can be behavioural problem as well.
  • -“Behavioral Treatment of Chronic Belching Due to Aerophagia in a  Normal Adult” Behav Modif 2006; 30; 341
  • -JPGN 2011; 52: 414. Mgt of severe rumination @ Columbus Ohio. n=5. Definitive dx established with AD manometry with typical r-wave pattern (when regurgitates after a meal)
  • -JPGN 2010; 50: 103. Rumination occurring in NL intelligent adolescents. May start with regurgitation and progress to inability to swallow saliva.
  • -Clin Gastro & Hep 2006; 4: 1314. Review of management of rumination/case presentation
  • -Chitkara et al: Teaching diaphragmatic breathing for rumination syndrome. Am J Gastroenterol. 2006 Nov;101(11):2449-52. Review. Can use behavioral interventions such as deep breathing exercises/ diaphragmatic breathing to break the spasms..
  • -Gastroenterology 2006; 130: 1527-28. Review and criteria of rumination.
  • -Pediatrics 2003; 111: 158-62. Review of rumination dx, Rx, & prognosis.
  • -Clin Persp in Gastro 2000; 3 (5): 277.

Additional Baclofen references:

  • -J Pediatr 2006; 149: 436, 468. Baclofen reduces GER. 0.5mg/kg/day
  • -JPGN 2004; 38: 317. Effectiveness of baclofen in neurologically-impaired children w GER. (0.7/kg/day), n=8.
  • -Gastroenterology 2000; 118: 7-13. Use of baclofen to reduce TLESR.
  • -Aliment Pharm Ther 2003; 17: 243-51. Baclofen reduced GER (acid & nonacid). side effects -N, V, dizzy. dose: in adults, start at 5mg tid, increase c 5mg increments every 4th day to 10-20mg tid.

Outcomes of Biliary Atresia

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A retrospective study from the Netherlands showed that timely surgery and postoperative antibiotics were associated with better outcomes in Biliary Atresia (BA) (J Pediatr 2012; 160: 638-44).  While these results are not surprising, due to the length of the study period (1987-2008) and the number of patients (n=214), the study offers insight into a number of unresolved issues with regard to BA.

The type of BA in this series:

  • type I      14  (6.5%)
  • type II      27 (12.6%)
  • type III   172 (80.4%)
  • undetermined  1 (0.9%)

Other notable findings:

  • 10% of their patients had splenic malformations; no significant change in outcome was noted in this subgroup.
  • 18% received high-dose corticosteroids –no benefit was identified in this subgroup.  The authors state that previous studies are inconclusive; a large US trial of prednisolone (4 mg/kg/day initially) is pending.
  • 31% received ursodeoxycholic acid –no benefit was identified in this subgroup.
  • Overall survival improved a little during the study period, mostly due to increased availability of liver transplantation. 4-year transplant-free survival was 46% and 4-year overall survival was 73%.   Table II (pg 641) in their study lists six other international studies.  Recent studies in some countries have reported 4-year survivals of 82-91%.
  • Antibiotic usage (most commonly co-trimoxazole) was associated with improved outcomes, presumably due to less frequent bouts of cholangitis.  Yet, in this study the reported incidence of cholangitis was not lower.  The authors do not have an explanation for this finding.

Age at time of Kasai:

  • ≤45 days 19%
  • 46-60 days 37%
  • 61-89 days 36%
  • ≥90 days 8%
  • Median was 59 days.  Authors note that Netherland guidelines call for all infants with jaundice at 3 weeks to have a fractionated bilirubin.

Related blog entries:

Minimizing malnutrition in Biliary Atresia

The heart connection

MicroRNAs and biliary atresia

Additional references:

  • -JPGN 2010; 51: 631.  n=91.  Operation w/in 100 days.  Data suggesting that 60 day cutoff is not valid. (Hong Kong)
  • -J Pediatr Surg 2003; 38: 997-1000. n=735.  90 day cutoff was key with 5-yr & 10-yr survival. (Japan)
  • -JPGN 2010; 51:61.  Canadian experience. n=230.  Center size did not affect outcome.  Overall 39% at 4yrs had survival with native liver.
  • -Liver transplantation 2009; 15: 829, 876.  With combo of Kasai & Tx, >95% exteneded survival (previously 100% fatal).  >80% will need a liver Tx at some point –~50% before age 2.  Increased fibrosis & genes for fibrosis may increase risk for poor outcome.
  • -JPGN 2009; 48: 72.  Review of 13 year experience. n=91.
  • -Pediatrics 2008; 121: e1438.  Single center (Australia?) noted longer delay in dx of BA over 15-year period from 48.5 days (1990-94) to 59.5 (95-99) to 69 days (2000-2004).
  • -JPGN 2008; 46: 238, 299.  More data on age of dx of BA and outcomes from Sweden.
  • -J Pediatr 2006; 149: 393.  Long term outcome of BA -28yrs in England.  7/56 survived long term with native liver; 5-yr native liver survival was 46%, 10-yr was 32%.
  • -J Pediatr 2006; 148: 467, 432..  Outcome of BA in US.  Avg age of referral was 53 days and HPE avg at 61 days.  one-third will survive to age 10 with native liver; overall 90% survival with kasai/hpe & Tx; 50-60% clear jaundice p Kasai.  yellow alert campaign: www.childliverdisease.org/jaundice
  • -Clin Gastro & Hep 2006; 1411.  BA with choledochal cyst. Nice pics of types of BA. Japanese pathologic classification:  Type 1 with atresia after gallbladder (CBD), type II atresia of common hepatic duct/CBD/GB  c normal intrahepatic ducts, Type III atresia of entire ductal system.
  • -Pediartics 2006; 117: 1147.  Usefulness of stool color cards for screening program.
  • -J Pediatr 2005; 147: 142 & 180-5.  23% c BA survive c native liver for more than 20 yrs; 88% survival for 3 yrs p-OLT; risk factors for poor outcome discussed including poor nutrition & age <5 months.
  • -J Pediatr 2004; 144: 123-5.  severity of fibrosis at time of Kasai inversely correlated with survival
  • -JPGN 2003; 37: 430-33.  Residual fibrosis/cirrhosis noted in 54%/40% respectively of pts with normal labs, median age 13 yrs.
  • -JPGN 2003; 37: 4-21. Review of BA

Cardiovascular disease for the entire family

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This month’s Journal of Pediatrics features an article for the entire family (J Pediatr 2012; 160: 590-7 [editorial pg 539]).  The authors demonstrate that children screened for cholesterol can serve as an index case for the entire family.  During a 26-year prospective followup of 852 pediatric patients (5-19 years old at enrollment) from Cincinnati, the authors assessed relationships of childhood risk factors with parental cardiovascular disease (CVD), type 2 diabetes (T2DM), and high blood pressure (HBP).

  • Pediatric HBP and low HDL cholesterol were predictive of parental CVD ≤age 50
  • Pediatric HBP and high triglycerides were predictive of parental CVD ≤age 60
  • Pediatric high triglycerides and high LDL cholesterol were predictive of parental CVD ≤age 66

The related editorial reviews large studies regarding lipid assessments, including the Bogalusa study with more than 3000 children and the Muscatine study with more than 14,000 children.  In addition, the editorial reviews the recommendations from an expert pediatric panel which suggested screening all children for dyslipidemia between 9 and 11 years. Interestingly, the editorial reviews the fact that screening for cholesterol has not been shown to harm children.  “The evidence is not sufficient to demonstrate any adverse affects.”

Although no harm has been proven, the expert recommendations do not have prospective data demonstrating benefit either.  While it is known that atherosclerotic lesions, including fatty streaks and calcifications, can develop in childhood, it is not known that current treatment strategies will improve long-term outcomes.  This study, however, provides an additional rationale for screening; namely, by identifying children with dyslipidemia, primary care providers can identify parents with cardiovascular disease who are more likely to benefit from urgent intervention.

Additional references:

  • http://hin.nhlbi.nih.gov/atpiii/calculator.asp?usertype=prof (cholesterol risk calculator)
  • Pediatrics 2011; 128 (suppl 5): S213-56.  Expert panel guidelines for cardiovascular health and risk reduction in children and adolescents.
  • -NEJM 2011; 365: 2078.  Use of statins to lower LDL to 60-70 range halted progression of coronary artery disease.
  • -Pediatrics 2007; 120: e189, e215.  US Preventive Services Task Force:  “the evidence is insufficient to recommend for or against routine screening for lipid disorders” up to age 20.  Consider pediatric drug Rx:
    1. After dietary failure
    2. LDL >190
    3. LDL >160 & FHx of CVD before age 55
    4. triglycerides >250-500 persistently
  • Pediatric Nutrition Handbook AAP Lipid types:type I -increased trig  (rare)
    type IIa -increased chol & LDL
    (most common)
       Homozygous: chol >500
         xanthomas before 10 yrs, vascular dz before age 20
       Heterozygotes with lower chol
    type IIb -elevated trig & chol/LDL
    (3rd most common)
    type III -abnormal LDL density (rare)
    type IV -elevated trig (2nd most common)
         may be increased with diabetes, obesity, inadequate fasting; may need to study parents to establish dx
    type V -increased trig/VLDL (rare)
         exclude nephrotic synd, hypothyroid, diabetes