Helicobacter pylori –useful advice

Helicobacter pylori (H pylori) infections remain an important cause of gastritis, ulcers, and adenocarcinoma of the stomach.  One new approach in treatment has been the use of sequential therapy.  More data is now available on the effectiveness of this approach and choice of antibiotics (Gastroenterology 2012; 143: 55-61 & editorial 10-12).

In the study, a 10-day sequential regimen (SR) was compared with a 5-day concomitant regimen (CR).

  • CR group (n=90): esomeprazole 40 mg BID, amoxicillin 1 g BID, levofloxacin 500 mg BID, tinidazole 500 mg BID.  Eradication rate (intention-to-treat): 92%
  • SR group (n-90): esomeprazole 40 mg BID, amoxicillin 1 g BID for 5 days, then esomeprazole 40 mg BID, levofloxacin 500 mg BID, tinidazole 500 mg BID for 5 days. Eradication rate (intention-to-treat): 93%
  • Both groups had good results in part due to low resistance rates

Useful advice on this study from the editorial:

  • ‘We prefer concomitant therapy because it is not complex and it may retain its effectiveness at a slightly higher level of resistance compared with sequential therapy.”  Authors prefer 4-drug non-bismuth-containing concomitant treatment.
  • With bismuth therapy (eg. bismuth-metronidazole-tetracycline-PPI), authors prefer a 14 day course.  10-day treatment may be effective when metronidazole resistance is considered unlikely.
  • “Clarithromycin should be abandoned as an empiric regimen” due to resistance in U.S.
  • Fluoroquinolone resistance is increasing rapidly and “prior use virtually ensures resistance.”  Suggested use of fluoroquinolone therapy among adults would be as a rescue therapy (failed 2 different therapies), using dosing regimen as noted in cited study, and in patient without history of prior fluoroquinolone use (&/or proof on susceptibility testing)
What about treatment in kids?
In pediatrics, guidelines for treatment have been recently updated (JPGN 2011; 53: 230-43). (Benjamin Gold, MD -one of my partners is one of the authors and was the lead author of the first guidelines published in 2000.)  NASPGHAN guidelines. PDF of powerpoint slides: H. pylori infection in children: ESPGHAN/ NASPGHAN guidelines … & pdf of text: Evidence-based guidelines from ESPGHAN and NASPGHAN for …
Recommendations for first line treatment are a triple-based therapy with PPI and two antibiotics (eg. amoxicillin and metronidazole).  Alternatives, include bismuth plus two antibiotics, or sequential therapy.  Use of clarithromycin is recommended only after susceptibility testing.

Additional references:

  • -Gut 2010; 59: 1143-53.  Changing treatment recommendations for Helicobacter pylori in the face of resistance.
  • -Am J Gastroenterol 2007;  102: 1808-1825. American College of Gastroenterology Guideline on the Management of Helicobacter pylori Infection.  Doxycycline can be used in place of tetracycline
  • -Gastroenterol 2007; 133: 985. Review. Good article for resistant infections.
  • -Gastroenterol 2005; 129:1414-19.  Sequential Rx (amox + PPI x 5 days, then biaxin, tinidazole, PPI for 5 days) had 97% success.

Clues about constipation and more than 2.5 million views

A recent article identifies some important factors contributing to constipation in Hong Kong children (JPGN 2012; 55: 56-61).

Using a territory-wide questionnaire in 2318, Hong Kong Chinese elementary school students, the authors identified several factors associated with constipation which was present in 12.2% of this cohort:

  • Refusal to pass bowel movements at school (OR 1.97).  In Hong Kong, students spend >8 hours per day at school.
  • Having dinner with one/both parents <50% of time (OR 1.52).  May indicate less time with parents and less parental prompting.
  • Nighttime sleep <7 hours (OR 1.87).  This is postulated to be related to increased homework and more stress which may affect gut motility.
  • Frequent fast food consumption (OR 1.14).  This may be associated with less fiber intake.

On a tangential note, one of my sons informed me of “bad lip reading” on YouTube; some of these clips are really funny.  Since there was one relevant to the subject at hand, with over 2.5 million views, I’ve provided a link:

“Everybody Poops” – a bad lip reading of the Black Eyed Peas …

Additional blog entries related to constipation:

Stimulants for constipation

Diagnostic tests hardly ever help patients poop

It’s worth the cost

Think twice about checking thyroid

Looking better or feeling better in EoE?

When seeing a new diagnosis of eosinophilic esophagitis (EoE), I often try to explain that there are two potential goals of treatment: clinical remission (improvement in symptoms) and histologic remission (improvement in appearance of esophagus with microscope).  Unfortunately, these two outcomes are not always synchronous; more proof of this comes from a recent study (Clin Gastroenterol Hepatol 2012; 10: 742-49, 750-52 [editorial]).

In this double-blind, randomized, placebo-controlled study of fluticasone in adult patients with a new diagnosis of EoE, 19 patients were treated with fluticasone (880 μg BID) and 15 patients were treated with placebo inhaler –for six weeks.  Initially, 21 patients were assigned to each group; 2 dropped out of treatment group and 6 dropped out of placebo group before completion of followup EGD.   The average age in the treatment group was 37 years versus 38 years in the placebo group.  A complete histologic response was defined as >90% reduction in mean eosinophil count; this occurred in 62% of fluticasone patients and in none of the placebo group, based on an intention-to-treat analysis.  Another measure of eosinophil activity, eosinophil-derived neurotoxin (EDN), was reduced by 81% on intracellular staining in the treatment group compared with 8% in the placebo group.  Figures 1 through 3 show this staining –it’s pretty cool!

Yet, the clinical response was not statistically different.  Dysphagia was reduced by 57% in the treated subjects compared to 33% in the placebo subjects in an intention-to-treat analysis.  Results were improved modestly in those who actually were treated: 63% (12 of 19) compared to 47% of placebo patients.  A complete response for dysphagia was noted in 42.9% of fluticasone group compared with 28.6% of control group based on an intention-to-treat analysis.  A fairly high rate of candidiasis was noted in treated patients 26%;  no placebo patients developed candida.

Another interesting finding was that among those who continued PPIs for heartburn symptoms the response to fluticasone was not improved.  40% of PPI users had a complete histologic response compared with 79% of non-PPI users.

So what are the reasons for the discrepancy between clinical and histologic response?

  • Established strictures and small-caliber esophagus may require dilation rather than medicines to relieve dysphagia
  • Esophageal fibrosis and subsequent esophageal compliance may not respond to topical therapy or take a lot longer to improve
  • Secondary candidiasis may reduce clinical response –though in this study, 5 of 6 patients with candida did in fact have symptom resolution
  • Compensatory behaviors may improve clinical symptoms –chewing food, cutting up food better, drinking more fluids, and avoiding some foods.  This may make it harder to detect important differences.

Patient information link: (Eosinophilic esophagitis – CCDHC Home)

Related posts:

Look of improvement on an EoE diet

Guidelines for Eosinophilic Esophagitis

Eosinophilic Esophagitis -Six Food Group Diet

The undiscovered country

MicroRNA signature for eosinophilic esophagitis

Regurgitation harder to treat than heartburn, especially for NERDs

While all pediatric gastroenterologists know that the title of this blog entry is right, it is helpful to have data.

A recent study (Clin Gastroenterol Hepatol 2012; 10: 612-19) used a reflux questionnaire to evaluate responsiveness of regurgitation from 2 randomized controlled trials.  The trials compared a newer acid blocker (AZD0865 dosed at 25-75 mg/day)) to esomeprazole (20-40 mg/day).  Patients had either non-erosive reflux disease (NERD , n=1460),  or reflux esophagitis, (RE, n=1314).  Inclusion criteria included the presence of substernal burning for ≥4 days/week.

Regurgitation-taste (RT), defined as an “acid taste in the mouth,” or regurgitation-movement (RM), defined as an “unpleasant movement of material upwards from the stomach” were analyzed.  Among NERD patients, either or both symptoms were present in 53% at baseline compared with 54% among the RE group.  In both NERD and RE patients, the presence of these regurgitation symptoms was associated with a poorer response to therapy.

  • Complete response of NERD patients with regurgitation symptoms:  RT 34%, RM 26%; in comparison to heartburn response of NERD patients which was 49%
  • Complete response of RE patients with regurgitation symptoms:  RT 44%, RM 33%; in comparison to heartburn response of NERD patients which was 55%

Additional references/blog entries:

Diet or drugs for cyclic vomiting syndrome

Dietary modifications are frequently recommended for migraines.  Given the overlapping features between migraines and cyclic vomiting syndrome (CVS), dietary treatments for CVS have aimed at eliminating trigger foods.  Investigators from the UK describe a single center cohort of 21 children (2-16 years) were placed on a low-amine diet with instruction from a dietician (JPGN 2012; 54: 698-99).  16 (76%) of the children had a strong family history of migraines.  The diet was implemented for a ‘minimum of 6 to 8 weeks.’ 13 had a complete resolution of vomiting and 18 (86%) had at least a partial response.

Specific foods that were avoided included cheese, chocolate, citrus fruits, pork, peas, broad beans, shellfish, yeast extract, beef extract, gravies, caffeine, and alcohol.

This small study does not prove that a low-amine diet is effective.  In fact, most of the information on a low-amine diet is derived from alternative medicine sources (eg .  Low Amine Diet | www.integrative-medicine.com.au).  Nevertheless, it is likely that a subset of patients will benefit from avoidance of trigger foods.  How to identify potential culprits is unclear.

NASPGHAN Guidelines for CVS (JPGN 2008; 47: 379):

  • Diagnostic criteria: (90% will have idiopathic CVS)

1. at least 5 attacks or 3 over 6-month interval
2. episodic, last 1 hour to 10 days & at least a week apart
3. stereotypical pattern for individual patient
4. vomiting >4 times/hr for at least 1 hour
5. healthy in between & no other attributable problem

  • PROPHYLACTIC Measures:

Avoid triggers:
fasting, excessive excitement (eg. downplay big events), sleep deprivation
foods that trigger symptoms (?chocolate, cheese, caffeine, MSG)
excessive fatigue

Assure adequate carbohydrates
-provide sugar-containing drinks & extra snacks before exertion & bedtime

  • PROPHYLACTIC TREATMENT:

Less than 5 years:
1. cyproheptadine (0.25-0.5mg/kg/day divided bid)
2. propranolol 0.25-1/kg/day –often 10mg bid or tid
contraindications: asthma, diabetes, heart disease, depression
keep resting heart rate >60

5 years & older
1. amitriptyline (or nortriptyline -liquid formulation) start at 0.25mg/kg qhs and increase ’til 1mg/kg/dose
check EKG before and 10 days after peak dose
2. propranolol 0.25-1/kg/day –often 10 mg bid or tid
contraindications: asthma, diabetes, heart disease, depression
keep resting heart rate >60

Alternative prophylactic treatments:
1. phenobarbital 2mg/kg qhs
2. anticonvulsants: topiramate, valproid acid, gabapentin, levetiracetam -?consult neurology

Supplements:
L-carnitne 50-100mg/kg/day divided bid (max 1gm tid)
Co-enzyme Q10 10mg/kg/day divided bid (max 100mg tid)

  • SUPPORTIVE/ABORTIVE CARE

Fluids: D10NS w KCL @ 1.5 maintenance (or possibly D10 0.45NS -some children prone to hyponatremia); add TPN if no enteral intake for 3-5 days
Antiemetics:
1. ondansetron 0.3-0.4mg/kg/dose q4hours (max 20mg); alternative granisetron
Sedatives:
Benadryl 1mg/kg/dose q6hours
Ativan 0.05-0.1mg/kg/dose q6hours
Thorazine (chlorpromazine) 0.5-1mg/kg/dose q6hrs (with benadryl)
Analgesics:
Toradol 0.4-1mg/kg/dose q6hrs (max 30mg)
Narcotics (morphine)

May need to treat hyponatremia, hypertension, hematemesis (H2RAs & PPIs)

Also, can try Sumatriptan 20mg intranasally at onset of episode as potential abortive measure or other triptan

  • TYPICAL EVALUATION:

1. CMP, Amylase/lipase, UGI on all patients
2. If pain/hematemesis, check U/S of abd/pelvis, and EGD
3. If abnormal neuro features: (motor asymmetry, gait abnormality, severe altered mental status)
ammonia
lactate, serum amino acids, urine organic acids, plasma carnitine/acylcarnitine profiles, urine ketones
MRI brain
4. If precipitated by fasting/high protein meals, or intercurrent illness= neuro w/u w/o brain MRI.

  • ALARM symptoms:

1. pain & bilious emesis
2. attacks precipitated by intercurrent illness, fasting or high protein meals
3. progressive/worsening/chronic pattern
4. abnormalities on neuro exam

**Note to blog readers –I recommend that all drug dosing be reviewed for individual patients.  The recommended doses are based on my reading of the referenced material & transcription errors are possible.

Additional references:

  • -Clin Gastro & Hep 2007; 5: 44. Use of zonisamide or levetiracetam (used at Sz dosing in 20 adults); 75% response & 20% remission.
  • -J Pediatr 2002; 141: 724. Suggests initial treatment along with UGI as most cost-effective strategy. Extensive w/u in those with persistent sx.
  • -Am J Gastro 1999; 94: 2855. response to TCAs.
  • -J Pediatr 1999; 134: 567. 82% migraine-assoc or FHx. Better response to Rx
  • NASPGHAN 2003:  postgraduate course (B Li):80% response to elavil if fhx migraines.
    “There are no controlled randomized, double-blinded trials, only open label ones. In these studies, beta-blockade (Pfau Pediatrics 97:364,1996), cyproheptadine (Anderson Pediatrics 100:977, 1997), amitriptyline (Anderson), phenobarbital (Gokhale JPGN 25:64, 1997) and erythromycin (Vanderhoof JPGN 17:387, 1993) all have approximately 70% efficacy as prophylactic agents. In Dave Fleisher’s work, he has demonstrated a 70% effect of consultation alone without pharmacologic therapy. In other words, there appears to be a striking placebo effect in this disorder that should temper any interpretation of results. In addition, I believe CVS is a heterogeneous disorder that has multiple etiologies that could allow it to respond to multiple classes of agents.”

DDx:
Infection, IBD, addison’s, diabetes, renal dysfxn, metabolic errors/urea cycle d/o, FAO d/o, porphyria, CDG (glycosylation), pregnancy, ipecac/munchausen, PUDz, Giardia, pancreatitis, UPJ, malrotation/duplication, increased ICP/CNS Dz, Migraine-equivalent

Workup:

1. CBC, ESR, amylase, ammonia,UA, stool heme, chem 20, HCG
2. UGI
3. giardia ag, abd U/S & DPTA, EGD, urine organic acids, plasma amino acids, carnitine, lactate, pyruvate, sinus films, head CT/MRI, toxicology, delta-aminolevulic acid/ porphobilinogen (urine), beta-HCG, serum transferrin isoelectric focusing

Best gastrostomy tube

A recent report touts the feasibility of a one-step percutaneous gastrojejunostomy (GJ) as the latest advance in enteral access (JPGN 2012; 54: 820-21).  This reference describes a new variation in technical placement: gastropexy using t-fasteners to secure gastrostomy tube site and then advancing neonatal scope via gastrostomy site to advance guidewire for  GJ placement.  This technique was used in three infants.

Most centers have developed their own protocols for enteral access and it is likely that the familiar approach to that center will be safest for their patient population.  Recently, the subject of gastrostomy tube placement was extensively reviewed in our institution (see below) due to variation in care at two children’s hospitals.  In one hospital, the surgical group primarily placed laparascopic button gastrostomies and argued that better visualization led to lower complications like colonic interposition.  Furthermore, this approach was considered similar in cost effectiveness as the group would place a primary Mic-Key® (http://www.mic-key.com/home.aspx) thereby eliminating the need for anesthesia for a button placement.

The alternative approach utilized a Corflo® gastrostomy tube (http://www.corpakmedsystems.com/product_main/enteral_main.html#FeedingTubes).  The advantages of this approach were 1) less anesthetic time/a smaller operation, and 2) lower likelihood of tube dislodgment.  This group approach argued that dislodgment was the greatest risk and that there was no urgency for a button tube.

Despite a joint meeting of these groups weighing the pros and cons, there was not a single best gastrostomy tube.

My experience is that tube dislodgment is quite common with button tubes.  In addition, primary button tubes can be difficult to size when the patient is under anesthesia.  As such, it is my practice to discourage primary gastrostomy button placement.  In addition, most patients who need gastrostomy tubes can wait until they are good surgical candidates both in terms of cardiorespiratory status and size.

Resources:

Gtube Products:
• AMT clamp –helps eliminate tubing pullouts
www.amtinnovation.com

• Gtube washable pads
www.oley.org  (specific web address: http://oley.org/lifeline/TubetalkJF11.html)

Additional references:

  • -J Pediatr 2011; 159: 602. Preemptive gtube assoc with improved survival post Norwood. High number needed fundoplication.
  • -JPGN 2011; 53: 293. 95% success with PEG in infants 2.1-5.6kg
  • -JPEN 2011; 35: 50-55. Predictive factors of mortality after PEG.
  • -JPGN 2009; 49: 237. Gtube improves height & weight in Rett syndrome.
  • -Clin Gastro & Hep 2007; 5: 1372. PEG placement does NOT prolong life in dementia patients.
  • -Arch Dis Child 2006; 91: 478-82. PEG reduced hospitalizations for respiratory dz in 57 severely impaired children
  • -J Pediatr 2006; 149: 837. inreased risk of PEG in SMA type 1 -42% w aspiration; 17% death (2/12)
  • -Pediatrics 2004; 114: 458-61. Moratlity rate of 0.4% -one death related to sepsis/peritonitis & 5% complication rate.
  • -Teitelbaum JE, Gorcey SA, Fox VL. Combined endoscopic cautery and clip closure of chronic gastrocutaneous fistulas. Gastrointest Endosc. 2005;62(3):432-435
  • -JPGN 2006; 43: 624. Satisfaction with PEGs: 94% of parents viewed PEG as positive influence on child’s situation & 98% would have chosen PEG insertion again (n=121).
  • -Sullivan PB, Dev Med Child Neurol 2005; 47: 77-83. 57 CP pts -almost all had improved health/nutrition p gtube
  • -Gastroenterology 2001; 121: 970-1001 & JPEN 2004; 28: S16. Provision of nutrition does not, for the most part, favorably alter clinical outcome.
  • -Lancet 2005; 365: 755-763. Pts c stroke/PEG did not do better than those c stroke/NGT.
  • -Sullivan PB, Dev Med Child Neurol 2004; 46: 796-800. gtube improves QOL.

Gastrostomy Tube Review with annotated references: Laparoscopic gtube versus conventional PEG placement

 Zamakhshary et al.  JPS 2005; 40: 859-62.   i.  Retrospective review, n=119 (only 26 with laparoscopy =21%). (2002-2003)  ii.  States same operative time of ~53 min by combining 2nd procedure w PEG (in 77% w PEG).  It takes these authors a long time to perform PEG and gtube change procedures.  Also, it is not noted how many of these 2nd procedures were coordinated with other needed anesthesias.  (Many times a PEG is replaced at the time of another procedure.)   iii.   3 PEG with transcolonic tube, 2 failed PEG –one with peritonitis, 4 with tract disruption when PEG pulled.  Similar rate of local problems (eg granulation tissue).  ARTICLE does not detail when PEG tubes are pulled –VERY high rate of tract disruptions.   iv. Article missing key details regarding size of PEGs & gtube buttons which may impact complications.  v. Cited advantages according to authors:

  1. “eliminates” risk of hollow viscus injury (JH: this is NOT  accurate)
  2. Useful for small infants (<2kg) (JH: usually gtube NOT needed in <2kg)
  3. Enables “ideal” location (JH: this is NOT  accurate)
  4. Primary button ‘advantage’ (JH: DOES NOT cite potential pitfalls like button too tight, possibility of balloon breakdown, possibly higher rate of dislodgment)

 Vervloessem et al. JPS 2009; 18: 93-97.     i. Retrospective review: 1992-2008.  N=467.  ONLY 19 Lap PEG –thus limited ability to provide comparison.  ii. Cites 59 “major complications” due to PEG –Table 2, including “13” new cases of GERD after PEG (or worsened GERD).  Of the major complications, important complications included 1 sepsis death, 7 peritonitis, 5 gastrocolic fistulas, 4 major granulation tissue, and 11 buried bumpers.  iii.  States that VPS is risk factor for infection but does not state whether any Lap gtubes were done in these patients.  iv. Complication rate decreased over the years—p=0.003; thus PEG procedure became safer with time and experience.   Could not demonstrate a decrease in complications with lap gtube versus PEG.  Authors recommend lap PEG in specific situations such as previous abdominal surgery or if not a good puncture site.

 Segal et al. JPGN 2001; 33: 495-500.    i. Retrospective study, n=110 (1990-97). N=110 –ALL PEG (no LAP). Thus, limited utility in comparing two methods. ii. “44%” developed late complications with PEG.  Most common: 24 extruded tubes/buried tubes (would NOT be better with lap button); other important: cologastric fistula n=2, peritonitis.  Table 1 indicates that 75% of dislodgment were due to buttons not PEG.  12 of the complications were granulation tissue and proliferative gastric mucosa.  Buried tubes occurred 14 & 19 months after placement with button tube!!   iii.  Thus this article adds little to the discussion of PEG vs lap gtube.

Akay et al. JPS 2010; 45: 1147-52  i.  Retrospective review (2004-2008) n=238 (134 PEG, 104 LAP)  ii. PEG with higher complications;  authors were changing PEG after 6-8 weeks. iii.  6 patients had early PEG dislodgment –this is higher than expected.  iv. 1 patient with gastrocolic-cutaneous fistula with both PEG & with LAP.  v. Table 4 lists complications: similar stomal issues, 2 patients with leak after PEG exchange (too early! –see page 1152) vi. Cited advantages: “eliminating” risk of hollow viscus injury, allows for sutures, small infants (<2kg) & possible primary buttons.**These authors did not place primary buttons –this makes it difficult to draw any conclusions about PEG vs primary LAP button.  Many feel PEG tube is a better tube and less prone to dislodgment than button and guarantees appropriate size.

Lantz et al. Int J Pediatr 2010; ID# 507616, 1-4.   i. Literature review, included 54 studies that qualified (1995-2009).  N=4331 (1027 LAP, 3304 PEG).  Very few details given in this review.  ii.Fistulas in 1.27% of PEG vs 0% for LAP.  iii.  Lists significant limitations: different studies, not blinded, nonpublication bias.  iv.  “This study highlights the need …for trials, comparing PEG to” LAP. v.  Does not include the limitation that LAP technique developed later and with more experience less complications.  Except for gastrocolic-cutaneous fistulas –no specific information is given about complications.

Avitsland et al.  JPGN 2006; 43: 624-28.  i. Restrospective review. N=121 –all PEGs  ii.     PEG “safe technique…major complications rare.”  “Most children experience minor stoma-related complications.”  iii. 29 died due to other factors.  Of 85 with f/u, 21 able to remove gastrostomy.  iv. No early mortality (<30 days).  1 of 85 had tube dislodgment.  3 had tube migration into esophagus (in cases where tube was not endoscopically removed).  v.     Frequent tube site problems ~75% -most easily treated. vi. Parents with high satisfaction: 83/85 (98%) would choose PEG again, 80/85 (94%) stated PEG improved child’s situation

Gauderer M. JPS 2001; 36: 217-19.   i.  Focused literature search and personal 20 year experience. ii. >216,000 PEGs performed annually in U.S. according to article (~5000 children).  PEG procedure developed 1st for children. iii.  Suggested approach to PEG with or w/o fundoplication: “Because PEG is such a simple procedure, a well-accepted approach is to place gastrostomy initially in children who can tolerate nasogastric tube feedings and add an antireflux procedure later, if needed.”

Srinivasan et al. JPGN 2009; 49: 584-88.   i.Prospectively collected data from observational study, n=601 (384 PEG insertions, 165 button conversions).  ALL pediatric. ii.  Complications:  PEG site erythema 15%, buried bumper migration (1 patient), 3 PEG dislodgments, one patient had laparotomy due to severe pain (no findings identified).   No procedure-related mortality.   iii.  49 of 384 removed –no longer needed.  iv. “The role of PEG is well established…our experience..PEG has been generally safe, with low procedure-related morbidity in children.”

Nutr Clin Pract 2005; 20 (6): 607-12.  Bankhead RR et al. i. Comparison of 91 patients.  23 PEG, 39 LAP, 29 open.  ii.   PEG had lowest complication rate

Surg Endosc 2006; 20: (8): 1248-51.  Ljungdahl M.                                         i.     Prospective, randomized study. N=70.  ii.  PEG with lower complication rate than surgical (open) gastrostomy –lower mortality & morbidity in adult patients.

UK Review Online: http://www.patient.co.uk/doctor/PEG-Feeding-Tubes-Indications-and-Management.htm   2009  i. Review of alternatives to PEG for gastrostomy insertion. There are alternative methods of gastrostomy tube insertion to PEG. They are: a) Laparoscopic insertion b) Open surgical technique c)Percutaneous radiologically guided gastrostomy (PRG) insertion. ii.  “There are reports over the years since introduction of PEG in the 1980s with often inconclusive results.21▪    A small study from Ireland and one from London favour PRG in patients with amyotrophic lateral sclerosis as it avoids the need for sedation or endoscopy.22,23▪  One meta-analysis suggested a higher success rate with PRG than with PEG, and less morbidity than either PEG or surgery.24 However a more recent comparison of a relatively small number of endoscopic, surgical and laparoscopic placement favoured PEG25 and another favoured PEG over PRG.26▪     A literature review suggested PEG as the procedure of choice for placement of gastrostomy tubes.27▪    A recent prospective randomized trial favoured PEG over surgical gastrostomy insertion.28▪     There is some evidence that polyurethane PEGs are less troublesome than silicone PEGs (less tube deterioration, less blockage).29▪    PEG is preferred in trauma patients.30▪                Antibiotic prophylaxis for PEG insertion appears to reduce the incidence of wound infection.19,20▪      Laparoscopic insertion was considered preferable to PEG by one study in children with PEG insertion having higher complication rate in children and often requiring repeat anaesthetics.31   An earlier study in children showed similar results for surgical, PRG and PEG insertion but did not look at the laparoscopic technique.32    A recent study from Norway found PEG insertion safe and very well tolerated by children and parents but made no comparison with other techniques.

Conclusions of review: PEG likely increases risk of gastrocolic fistulas (1-2%) but this has been reported with LAP as well.  The incidence is low.  No well-designed  studies have demonstrated superiority of LAP over PEG in terms of safety.  Potential drawbacks of LAP are likely underreported.  There have been cases of severe peritonitis at local hospitals following lap with primary gtube balloon misplacement.  Many feel PEG tube is a better tube and less prone to dislodgment than button (dislodgment is most frequent serious adverse event) and can be easily adjusted to  appropriate size.  To minimize complications, tube should not  be changed early.

Natural laws not patentable: the case with Prometheus

While most individuals might think of greek mythology or the recent movie when hearing the word “Prometheus,” pediatric gastroenterologists might think of the company that performs a number of useful diagnostic tests.  Recently, Prometheus has had a legal setback (NEJM 2012; 365: 2338-40). 

Since the 1990s, Prometheus has tested for azathioprine (& 6-mercaptopurine) metabolites.  A therapeutic level of 6-thioguanine (6-TG), a metabolite for these drugs, is recognized as generally between 230-400 pmol per 8×10(to the 8th) red cells.  Levels outside this range often require drug adjustments.

When the Mayo clinic started to offer a slightly different assay, priced 25% below Prometheus’s test, Prometheus sued for patent infringement.  The court held that “if a law of nature is not patentable, then neither is a process reciting a law of nature;”  hence, Prometheus’s patent was rejected.

There are implications of this lawsuit on the use of a large number of biomarkers.  For example, patents for BRCA DNA sequences that increase the risk for cancer will probably be overturned.  Industry groups argue that denying patents will halt progress as companies will not be able to recoup investments in biomarker development.  Congress could consider passing laws allowing exclusive marketing of these innovations.  Alternatively, adequate funding through the NIH (National Institutes of Health) could allow development of biomarkers without the need for patents; in fact, 100 projects are in progress at this time.

Assessing and discussing risk of lymphoma in IBD

A recent article has shown that the absolute lymphoma risk from medications in children and young adults with IBD is quite low (Inflamm Bowel Dis 2012; 18: 838-43).

In this single center study from 1979-2008, 1374 pediatric IBD patients had charts reviewed to determine whether lymphoma developed.  In total, two male patients who had received thiopurines developed lymphoma (one Hodgkin, one anaplastic large cell) in 6624 patient-years of follow-up.  Both patients are alive after chemotherapy.  Mean follow-up was 4.8 years per patient.  The absolute lymphoma incidence rate was 3 per 10,000 patient-years; after thiopurine exposure, the rate was 4.5 per 10,000 patient-years compared to an expected 0.58 per 10,000 patient-years.

In this study, 22% of the patients had received TNF inhibitors.  None developed lymphoma.  The risk of biologics could not be fully assessed due to a limited study period: 713 person-years taking the medication.

The risk of thiopurine-associated lymphoma was similar to previous studies but did not reach statistical significance.  As related in other studies, the risk of biologic agents, like Remicade, Humira, and Cimzia, is heavily influenced by whether patients had also received immunomodulators.

One useful way to try to convey this risk has been with diagrams.  One useful diagram is a palette of one thousand people or of 10,000 people showing the absolute risk and one showing the risk for other complications like infection.  You can make your own by going to the following link:

Download Communication Tools

RiskComm

Additional references/blog entries:

Only one chance to make first impression

Biologics | Living Longer | Arthritis Today Magazine -From Arthritis magazine: biologics improve survival in Rheumatoid arthritis

Why “therapeutic dose” of codeine can kill

While this blog has described some of the huge problems with the overuse of narcotics (Deadly consequences of pain management), another danger with narcotics occurs especially with codeine due to its metabolism via the CYP2D6 pathway; codeine is particularly risky in young children.  A reminder of this is a recent case report (Pediatrics 2012; 129: e1343-1347).

During my training, I was told by an ENT doctor that he never prescribed codeine in children less than 6 years of age due to safety concerns.  While he could not explain the mechanism, this case report does.  This case report describes three children with severe cases (two were fatal) from North America.  In the two fatal cases, gene duplications encoding Cytochrome P450 2D6 (CYP2D6) caused a significantly greater production of morphine from its parent drug, codeine.  This risk of respiratory depression may be enhanced in ENT cases especially in children with obstructive sleep apnea.

The risk from codeine involves individuals who are ‘ultra-metabolizers’ of CYP2D6; this is because the metabolized drug in this case, morphine, is more potent than the parent drug, codeine.  Other opioids that are similar to codeine, like hydrocodone and oxycodone, may have additional risk as well.  Ultra-metabolizers include up to 7% of all caucasians.  In addition, 5-10% of caucasians are poor-metabolizers which would result in a lack of therapeutic effect with codeine.

While ultra-metabolizers of CYP2D6 function are prone to codeine toxicity, poor-metabolizer individuals will have an exaggerated response when the parent drug is more potent than its metabolites.  In addition, there are numerous drugs (not metabolized by CYP2D6) which interact to inhibit the function of CYP2D6 (eg. diphenhydramine).  Thus, these drugs can potentiate the effect of CYP2D6 on its substrates.

Other drugs commonly used by gastroenterologists and metabolized by CYP2D6 include tricyclic antidepressants, most SSRIs, metoclopropramide, ondansetron, and promethazine.  In ultra-metabolizer individuals, many of these drugs will not work because the quickly-produced metabolites, unlike the parent substrate, do not have therapeutic effects.

Additional references:

  • N Engl J Med 2004; 351: 2827-31.  Codeine Intoxication Associated with Ultrarapid CYP2D6 Metabolism. 62 year old: “12 hours after the last dose of codeine, the blood level of morphine was 20 to 80 times as high as the blood level that would have been expected on the basis of measurements in healthy persons ” due to ultrametabolism of CYP2D6 in combination with inhibition of CYP3A4 activity by other medications
  • CYP2D6 – Wikipedia, the free encyclopedia
  • Drug and Alcohol Dependence 89 (2007) 190–194. Association of CYP2D6 ultrarapid metabolizer genotype with deficient patient satisfaction regarding methadone maintenance treatment
  • What happens when codeine is used with drugs – WorstPills.org –

What do you know about the “exposome”?

I had not heard of the term “exposome” until last week (Gastroenterology 2012; 142: 1403-4).  However, this term was coined in 2005 (Cancer Epidemiol Biomarkers Prev 2005; 14: 1847-50).    This term is meant to describe the environmental analog of the genome.

Particularly with the gastrointestinal tract, environmental exposures are often considered a cofactor in disease development.  While there has been an increased understanding of the role of genes in the development of disease, it is abundantly clear that environment exposures can independently cause disease or act as a ‘second hit.’  The gastrointestinal tract is exposed to fluids which contain a multitude of elements and microorganisms, and to foods with their variability in nutrients, microbes and pollutants.  Other environmental factors include smoking, ionizing radiation, noise, breastfeeding, medications, and antimicrobials.

This cited commentary explains how environmental scientists are trying to unravel the ‘exposome.’

  • Bottom-up strategy:  measure external sources of the individual exposome at multiple time points.  This strategy may benefit from improvement in informatics, remote & personal sensing devices.
  • Top-down strategy: examines internal milieu including blood, biologic specimens, and transcriptomics/proteonomics.  Early examples include distinct signatures associated with specific environmental exposures.

Both strategies require validation to understand how external exposures trigger internal changes and disease expression.  Promising fields in gastroenterology for the study of the exposome include IBD, gastrointestinal cancers, functional disorders, and even obesity.  It is likely that studies of the exposome will answer questions about why the frequency of so many diseases are changing much more readily than studies of the genome.

Related blog posts:

Eat your veggies…if you don’t want to get sick

Why are we seeing so many more cases

Additional references:

  • -PLoS One 2010; 5 e10746.  Novel associations between type 2 diabetes and specific chemical exposures.
  • -Nature 2006; 444: 1027-31.  Obesity-associated gut microbiome.
  • -BMC Med Genomics 2010; 3: 17.  Chemical factors associated with disease-related gene expression data.