Does necrotizing enterocolitis cause neurologic deficits?

Posted on March 13, 2012 by gutsandgrowth

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

Posted on March 12, 2012 by gutsandgrowth

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.

A drug that makes a difference: ondansetron

Posted on March 11, 2012 by gutsandgrowth

Ondansetron (Zofran ®) use has become more common and is making a difference (JPGN 2012; 54: 381-86). This drug has been a terrific advance for so many individuals with disorders that provoke vomiting and nausea. Not only does it have a high degree of effectiveness, but side effects are also quite uncommon.

The cited study documents ondansetron’s increasing use in Toronto. This retrospective cohort study of children younger than 18 years with gastroenteritis examined emergency room visits between 2003 and 2008. 20% of 22,125 charts were selected randomly for review (n=3508 patients in final analysis). During the study period, intravenous rehydration decreased from 27% to 13% and ondansetron use increased from 1% to 18%. Associated with ondansetron use, mean length of stay decreased from 8.6 to 5.9 hours. Also, the week following the index visit, there was a reduction in return visits from 18% to 13% as well as decreased need for intravenous rehydration (7% to 4%).

The authors state that analysis elsewhere has indicated that appropriate usage of ondansetron for this indication could result in savings of more than $65 million each year in the U.S. The main limitation of this study is that other factors could have changed during the study period and resulted in some of these improvements; though, this institution did not have any major changes which could be identified.

Of course, ondansetron is used in many other clinical settings besides the emergency room. Though the drug is expensive, it is worth the cost.

Additional references:

-Arch Pediatr Adolesc Med 2008; 162: 858-65. Use of antiemetic agents in AGE.
-Ann Emerg Med 2008; 52: 22e6-9e6. Use of oral ondansetron in children with AGE who failed oral rehydration.
-NEJM 2006; 354: 1698. Use of zofran did not decrease hospitalization but did decrease need for IV fluids and decreased vomiting.

Pediatric capsule endoscopy experience

Posted on March 10, 2012 by gutsandgrowth

Capsule endoscopy (CE) in pediatric gastroenterology has become a routine procedure. The experience of our group is noted in a recent study (JPGN 2012; 54: 409-13). In this study, our single pediatric center reviewed 284 CE procedures (277 patients) over a five-year period. The youngest patient to swallow a capsule was 4.6 years old. Twenty capsules were placed endoscopically, with the youngest & smallest patient being 3 years old (13.5kg). A patency capsule was used in 23 patients.

Overall, the yield with CE was high. 205 (72%) had positive findings; 154 (54%) had small bowel findings. The study also compared its data to pediatric and adult meta-analysis. Similar to other pediatric studies, Crohn disease was the most common indication; in adult studies, CE is used mostly for occult GI bleeding and anemia. CE procedures did not reach the colon in 65 (21%); 36 of these incomplete procedures had positive findings.

Capsule retention occurred in seven patients (2.4%) which is similar to the meta-analysis studies as well. Six of the seven had surgery due to capsule retention, though one surgical procedure had been planned and capsule helped identify stricture site. In addition, one of the seven was retrieved through a tight ileostomy.

Additional references:

-Gastroenteology 2010; 139: 1468. Predictions for upcoming advances.
-Gastroenterology 2009; 137: 1197. Strongest indication -obscure bleeding.
-JPGN 2009; 49: 196. Capsule retention in 5.2% in known IBD. overall 3 of 207 studies (1.4%) To date, >170,000 capsule studies worldwide.
-Gastrointest Endosc 2008; 68: 255-66. Authors recommend using CT/colonoscopy as primary investigations & reserving capsule only if negative initial evaluation. 17% of pts had asymptomatic partial small bowel obstruction -contraindicating use of capsule.
-Endoscopy 2008; 40: 30-35 & -IBD 2008; 14: 1287. Consider wireless capsule before IPAA in UC.
-IBD 2008; 14: 1219. Correlation of capsule & MRI enterolysis. Capsule detected more mucosal lesions.
-JPGN 2008; 47: 31. Capsule endoscopy may reclassify pediatric IBD
–Speed matters. Additional references listed on this previous blog entry.

Staggering cost of obesity

Posted on March 9, 2012 by gutsandgrowth

For a single individual, the burden of obesity can be enormous; for a society, the projected costs for health and economics are hard to fathom (Lancet 2011; 378: 815-25).

By 2030, this report projects that there will be 65 million more obese adults in the US and 11 million more in the UK. This is expected to cause an additional 6-8.5 million cases of diabetes, 5.7-7.3 million cases of heart disease/stroke, about 500,000 cases of cancer, and loss of 26-55 milion life years. The medical costs are estimated to increase $48-66 billion/year in the US.

These projections are based on expected increases in the percentage of individuals who are obese. In 2008, approximately 32% of US adult men were obese based on BMI; in 2030, the projected number is 50-51% for men. Among US women: 35% in 2008 –> 45-52% in 2030.

To flatten the curve on spending, we will need to look at flattening other curves.

Additional references:

A liver disease tsunami
-NEJM 2011; 365: 1597. Persistence of hormonal adaptations with weight loss. Due to persistent changes in hormones like leptin & peptide YY, hard to keep wt off -result is increased appetite.
-NEJM 2009; 360: 859. Composition of diet does not seem to be important. Total calories important.
-Pediatrics 2007; 120: suppl 4: S164-S287.
-NEJM 2007; 357: 370. obestiy spreads in social network. Your friends may be more influential than your genetics.
-Gastroenterology 2007; 132: 2085-2276. Special issue on obesity issues.
-NEJM 2006; 355: 1593. Case review on obesity c DDx and mgt.
-Pediatrics 2003; 112: 424. Position paper on prevention in childhood.
-Gastroenterology 2001; 120: 669-681. (review)
-J Pediatr 2005; 147: 429. TV viewing predicts adult BMI.
-Lancet 2001; 357: 505-8. One extra soda/day incr risk of obesity by 60%
-NEJM 1999; 341: 1097. BMI & mortality.

VTE with IBD

Posted on March 8, 2012 by gutsandgrowth

In our children’s hospital, work is underway to systematically screen children for risk factors for venous thromboembolism (VTE) and to establish an algorithm to lower the risk of a VTE with either mechanical or pharmacologic treatments. One of the risk factors has been the presence of inflammatory bowel disease (IBD). The absolute risk of IBD for VTE is not clear. However, a recent study relates the risk among a large Danish population of adults and children (Gut 2011; 60: 937-43).

The study included 49,799 patients with IBD (14,211 Crohn’s, 35,229 UC) and compared with 477,504 members of the general population. VTE risk for IBD was increased with HR of 2.0. The incidence of VTE increased with age; however, the RR was higher in younger patients. Among those less than 20 years, HR was 6.6 for VTE; HR 6.0 for DVT and 6.4 for PE. In this age group, “unprovoked” VTE had HR of 4.5. Unprovoked VTE was defined as event occurring without malignancy, recent surgery, pregnancy or fracture.

Although the relative risk is increased, the authors caution that the absolute risk in younger patients is low. In those IBD patients less than 20 years, the incidence rate was 8.9 per 10,000 person years. In contrast, in those IBD patients older than 60, the incidence rate was 54.6 per 10,000 person years. There did not seem to be a significant difference between Crohn’s disease and ulcerative colitis in absolute or relative risk. The authors conclude that in those IBD patients younger than 20 years without ‘other VTE risk factors or limited mobility, the benefits of prophylaxis may no longer outweigh the risks.” In older patients (>60 years), even outpatients experiencing flares might benefit from VTE prophylaxis.

Additional references:

-NEJM 2012; 366: 860 (letter to editor). Authors emphasize importance of VTE with UC, especially during flares.
-Lancet 2010; 375: 657-63. VTE with active IBD and in remission.
-Clin Gastroenterol Hepatol 2008; 6: 41-5. Thrombosis with IBD.
-Gut 2004; 53: 542-8. IBD -risk factor for VTE?
-Gut 2004; 53 (suppl 5): v1-16. IBD guidelines for management.

More on PNAC

Posted on March 7, 2012 by gutsandgrowth

In a previous blog entry (PNAC, PNALD, and IFAC), reduction in intralipids was shown to improve parenteral nutrition associated cholestasis (PNAC). This change in the use of parenteral nutrition (PN) and others are emphasized in a review article by the American Pediatric Surgical Association (J Ped Surg 2012; 47: 225-40).

This review tries to provide evidence-based guidelines for PNAC with ratings of the evidence for each of their recommendations.

A summary of their findings is given in Figure 1 of the article. Key points:

PN duration is a significant predictor for cholestasis
NEC & sepsis both play a role in the development of PNAC
Insufficient data to determine if antibiotics used to decrease bacterial translocation/hepatocyte damage may be beneficial
Fat emulsion restriction may reduce PNAC without detriment to growth
Fish-oil based lipid emulsions are safe and effective for PNAC. “Despite the promise of Omegaven…the literature is insufficient to provide a recommendation higher than grade C.” (Grade C= “possibly effective, ineffective, or harmful;” requires at least 2 convincing class III studies [class III studies generally are non-randomized non-blinded studies]). Information to obtain Omegaven:

http://www.oley.org/documents/How_Physicians_Can_Obtain_Omegaven.pdf
http://www.oley.org/lifeline/PN_Liver_Disease.html

Strong evidence that higher initial protein load does not increase the risk of PNAC
Strong evidence that trophic feeds are beneficial to reduce PNAC
Weak/conflicting evidence that there is any benefit of Aminosyn over Trophamine
Weak evidence to support the routine removal of copper or manganese from PN as a prophylactic strategy to prevent PNAC
Weak evidence to support prophylactic cycling of PN to reduce PNAC. There are also concerns about the development of hypoglycemia in preterm infants off of PN
Use of CCK is not recommended
Oral bile acids may result in improvement
Erythromycin may promote motility and facilitate enteral feeds, thereby reducing PNAC

HEROES trial

Posted on March 6, 2012 by gutsandgrowth

HEROES is definitely a catchy acronym (Arch Intern Med 2011; 171: 1929-36); HEROES is short for Helicobacter eradication relief of dyspeptic symptoms.

In pediatric practice, when Helicobacter pylori infection is identified, efforts are made to eradicate it. However, studies have not been conclusive about whether this is beneficial for individuals with ‘functional dyspepsia.’ A 2006 Cochrane review of 21 trials found only 6 were positive for eradication. Previous trials had not focused on primary care patients who may be more prone to respond. As such, the investigators randomly assigned 404 patients (adults with average age of 46 years) into a group (n=201) treated with antibiotics and a control group (n=203); this was a randomized double-blind placebo-controlled clinical trial at a single center. All eligible patients had to meet the Rome III criteria for functional dyspepsia and have H pylori infection. Individuals with heartburn and irritable bowel were excluded. The antibiotic group received omeprazole, amoxicillin, and clarithromycin whereas the control group received omeprazole and placebo –both groups received treatment for 10 days.

In the antibiotic group, 49% achieved at least a 50% reduction in symptoms at 12 months; the control group had a 36.5% response. Overall, 78.1% of the antibiotic cohort improved compared with 67.5% in the control cohort.

Although the findings of the study indicate improvement with a course of antibiotics, what to do with these results is not clear. Worldwide, at least 50% of the population is infected by H pylori. In addition, dyspeptic symptoms afflict up to 40% of the adult population in Western countries. Due to the enormity of these problems, translating the results of this study into practical treatment strategies is difficult.

Additional references:

-JPGN 2011; 52: 387. Impact of Rome III criteria on yield. Still 2.8% w/o alarm symptoms that had significant endoscopic findings.
-Clin Gastro & Hep 2008; 6: 746. Antidepressant venlafaxine not effective in functional dyspepsia in double-blind, randomized, placebo-controlled study. n=160.
-Cochrane Database Syst Rev 2006; (2): CD002096. Rx of H pylori in functional dyspepsia.
-Gastroenterology 2007; 133: 799. Natural hx of functional disorders: 20% persist w same Sx, 40% develop other Sx, 40% get better. Large study from Olmstead county (n=1365)
-Gastroenterology 2007; 132: 1684. Changes in cerebral blood flow during gastric balloon distention in dyspepsia.
-Gastroenterology 2006; 130: 1466-79. Functional gastroduodenal d/o. Acid suppression is 1st line Rx.
-Gastroenterology 2005; 129:1753-55, 1756-80, 1711. Mgt & guidelines for dyspepsia. In pts < 55 w/o alarm sx, test for H pylori and rx c PPI. In pts who don’t respond, consider EGD. Other Rx unclear: prokinetics, anticholinergics, antidepressants.
-Gastroenterology 2004; 127; 1239. Review of functional dyspepsia. Rx initial c acid-blocker/prokinetic reasonable, if not helpful, consider tricyclic, or clonidine. Eliminate H pylori. Sumatriptan may help
-J Pediatr 2005; 146: 448, 500. Dyspepsia in children often associated with delayed GE and reduced gastric volumes
-Gastroenterology 2003; 125: 1219-26. Algorithm suggested:1. chech H pylori 2. Rx c PPI/H2RA. 3. If persists, EGD. If EGD neg, consider elavil
-Clinical Gastro & Hepatology 2003; 1: 356. Increased Mast cells noted.
-Gastroenterology 2002; 123: 1778, 2132. Use of hypnosis for NUD.
-Ann Intern Med 2001; 134: 361-369. Meta-analysis of H pylori & NUD. Non-significant/minor improvement c eradication.

PNAC, PNALD, and IFAC

Posted on March 5, 2012 by gutsandgrowth

Intravenous lipids may cause parenteral nutrition associated cholestasis (PNAC), parenteral nutrition associated liver disease (PNALD), or intestinal failure associated cholestasis (IFAC) (J Pediatr 2012; 160: 421-7 & editorial 361-2). PNAC refers to cholestasis due to parenteral nutrition and PNALD refers to PNAC that has progressed to liver dysfunction or permanent liver injury.

In a previous blog (Four advances for intestinal failure), one of the advances for intestinal failure that was noted was the reduction of lipid infusions with parenteral nutrition which reduces IFAC. This study adds additional information to this area. In this prospective study, 31 patients were enrolled in a reduced IV fat emulsion group and compared with a matched historical control group. The reduced fat group received 1gm/kg of a standard soybean-based lipid emulsion (liposyn 20%) twice weekly. Patients were eligible if they received PN for >2 weeks and had a direct bilirubin >2.5 mg/dL.

Outcomes:

Total bilirubins dropped 0.73 mg/dL each week in the reduced fat group; in the control group, the bilirubin increased 0.29 mg/dL each week
Growth was similar in both groups
Essential fatty acid deficiency (biochemical not clinical features) was identified in 13 of 31 infants among the restricted IV fat emulsion group.

Essential fatty acid deficiency was defined as having a triene: tetraene ratio >0.05 (mild), >0.2 (moderate) or >0.4 (severe).

Limitations:

Historical control group & small study population
Fat-restricted group received enteral antibiotics which may have helped reduce cholestasis
Majority of patients with relatively short duration of TPN: 18 of 31 for less than one month

The reasons why lipids may contribute to PNAC/PNALD/IFAC include the presence of phytosterols. This in turn may damage hepatocytes via the farnesoid X receptor. One other aspect of the study was that the fat-restricted cohort had a higher mortality. This was thought to be related to the cohort being sicker rather than to any nutritional effect. Specific causes of death included respiratory failure in a patient with an abdominal wall defect, chylothorax/sepsis in a patient with a congenital diaphragmatic hernia, and cardiopulmonary failure in a patient with pulmonary hypoplasia.

The article does throw into question whether the use of a fish oil lipid preparation is needed to improve cholestasis. In studies supporting fish oil preparations, a confounder was that the total lipid administered was reduced to 1 gm/kg/day in comparison to soybean lipids which were administered at 2-3 gm/kg/day. This study suggests that reducing the total amount of lipid infusion is the more important factor.

The accompanying editorial makes a couple of useful points:

Increasing enteral feeds (>50%) is as effective as using less intravenous lipids
Use of standard lipids at 1gm/kg/day decreased IFAC from 15% to 4% in their intestinal failure patient population
Drastic reductions in lipids lead to essential fatty acid deficiency and should be avoided.
Use of Omegaven has not been shown to prevent liver fibrosis even with resolution of cholestasis; similarly, these studies do not inform fully on the long-term liver effects of reducing standard lipids
Neurologic followup will be important
Explains “Morton’s fork.” John Morton was a 16th century Archbishop who wanted to increase taxes on people who were living lavishly. In addition, he wanted to increase taxes on those living modestly (must be hiding wealth).

Additional references:

-NEJM 2010; 362: 181. Letter to editor describes use of fish oil in (n=125) Boston pediatric patients.
-JPGN 2009; 48: 209. n=12. SBS. 9/12 improved with Omegaven. 3 had transplant (L-ITx). No controls.
-Pediatrics 2008; 121: e678-86. n=18. Use of fish oil improved cholestasis compared to historical controls.
-Pediatrics 2006; 118: e197-e201. Reversal of TPN-AC c IV omega-3 fatty acids (fish oil-derived) instead of intralipids

Another life-threatening complication of HCV

Posted on March 3, 2012 by gutsandgrowth

Epidemiological studies have shown a causal relationship between B-cell non-Hodgkin lymphoma (B-NHL) and hepatitis C virus (HCV) (Hepatology 2012; 55: 634-641). This is not simply an association but a cause and effect.

The cited reference reviews several aspects of this relationship including the mechanisms of lymphoproliferation, the epidemiology, the clinical manifestations, the treatment, the prognosis, and preventive measures.

With regard to epidemiology, the odds ratios are between 2.4 and 5.2. This is a small risk compared to hepatocellular carcinoma.
Management: Lymphoma may regress with HCV treatment, indicating a role for HCV in pathogenesis. HCV treatment may prevent the occurrence of B-NHLs as well. For aggressive lymphomas, patients require systemic treatment with rituximab-based regimens (1st line treatment).

B-NHLs are not nearly as important as cirrhosis and hepatocellular carcinoma in terms of mortality and morbidity in patients with HCV. It is nevertheless quite significant considering the number of infected persons worldwide.