Most Popular 2020 Posts

I want to thank all of you who take an interest in my blog, particularly those who give suggestions, references, and encouragement. The following posts were the most popular from the past year.

Related post: Favorite Posts of 2020

Sandy Springs at Sunrise

FDA ‘Safety Initiative’ Now Means an Ounce of Ethanol Costs $30,000

Ethanol locks are now going to be ridiculously expensive (possibly $30,000 per month -for 1 oz) due to an FDA initiative which aims to improve drug safety. Paradoxically, this could endanger the health of many vulnerable children.

Modern Healthcare: Unapproved Drug Initiative adds up to $30 billion in healthcare costs Thanks to Jennifer Sterner-Allison for this reference.

An excerpt:

A regulatory pathway that aims to ensure drug safety is inflating healthcare spending by billions of dollars, according to a new report.

Four widely used drugs funneled through the Unapproved Drug Initiative will increase spending by more than $20.25 billion over a five-year span as manufacturers hiked prices between 525% to 1,644%…

“Hospitals are absorbing additional cost for drugs that are not innovative, not curing new diseases, do not have overwhelming R&D investment, and are often the preferred drug of choice.”…

The 2006 Unapproved Drug Initiative requires manufacturers to pull these drugs and prove to the FDA that they are safe. Typically, fewer manufacturers remain in the market after the FDA intervenes, which allows price manipulation.

Drugs that go through the UDI pathway can earn the manufacturer up to seven years of patent protection, which can prevent competition. At minimum, other suppliers of the drug targeted by the UDI also have to leave the market and receive approval, which can reduce competition.

The situation with ethanol is particularly egregious, said Erin Fox, a drug shortage expert and senior director of drug information and support services at University of Utah Health.

Belcher Pharmaceuticals is charging $1,000 per milliliter, which equates to $30,000 for one shot of ethanol, since it received an orphan drug designation through the UDI, granting Belcher’s drug exclusivity through 2025, she said. Belcher won the orphan drug classification, a status for drugs that treat rare diseases, for its treatment of hypertrophic obstructive cardiomyopathy.

“It is the perfect example of how this FDA approval process is broken,” Fox said. “Pediatric hospitals are going to be particularly impacted because ethanol is sometimes used to ‘lock’ IV ports to prevent infections in high-risk patients.”..

“FDA’s Unapproved Drug Initiative continues to have serious unintended consequences and in my opinion should be halted,” she said

My take: I have contacted the American Academy of Pediatrics and asked them to try to work on this problem.  The high cost of ethanol may prevent its routine use and result in central line infections, hospitalizations and even death in vulnerable children.

Related blog posts (on utility of Ethanol Locks):

Blogs related to Pharmaceutical Practices:

Ethanol locks can minimize infections among patients who receive intravenous nutrition (“TPN”) which was popularized by Dr. Dudrick.  Due to the exorbitant costs of ethanol, this may lead to increased infections, hospitalizations and even death.


Enteral Autonomy in Pediatric Intestinal Failure

A recent study (FA Khan et al. J Pediatr 2015; 167: 29-34 -thanks to Mike Hart for forwarding this reference) provides data from a multicenter retrospective cohort of 272 infants.  These infants had of IF were defined by requiring >60 days of PN; they were enrolled in the Pediatric Intestinal Failure Consortium.  The median followup was 33.5 months.  The most common etiologies of IF were necrotizing enterocolitis (NEC), gastroschisis, small bowel atresia, and volvulus. Key findings:

  • 43% achieved enteral autonomy (EA), defined as freedom from PN for >3 months, 13% remained dependent on PN, and 43% had died, undergone intestinal transplantation, or both.
  • Infants with EA were more likely to have had NEC, preserved ileocecal valve, longer preserved small bowel length, and care at a non-transplant center (with retrospective study, high likelihood of a selection bias).

The associated editorial by Valeria Cohran (pages 6-8) notes that pediatric intestinal transplants peaked in frequency in 2007, but in 2014 there only 56 performed.  She also notes that the care of these children with short bowel syndrome in the first year of life is approximately $500,000 ± $250,000!  The improved survival is attributed to minimizing cholestasis with new lipid strategies, minimizing blood stream infections with better care and ethanol locks, and the use of autologous bowel reconstruction surgery. Bottomline: This study and several others show that meticulous care and advances in the treatment of intestinal failure improve the likelihood of survival without the need for intestinal transplantation. FULL CITATION: Khan FA et al. Predictors of enteral autonomy in children with intestinal failure: A multicenter cohort study. J Pediatr 2015 Jul; 167:29-34. [Free full-text J Pediatr article PDF | PubMed® abstract] Related blog posts:

These windows were huge -Grand Tetons in background

These windows were huge -Grand Tetons in background



Stick with the (intestinal) rehab program?

More data on the progress of treatment of short bowel syndrome (SBS) programs:

  • Avitzur J, et al. JPGN 2015; 61: 18-23

In this study, the researchers from Toronto and the Group for Improvement of Intestinal Function and Treatment (GIFT) retrospectively examine 84 patients over 3 time periods: 1999-2002, 2003-2005, and 2006-2009.

Key points:

  • Across those time periods, the authors find fewer SBS patients that needed to be listed for transplantation despite similar baseline characteristics.  In addition, many more patients in the late period were removed from the transplant waiting list due to clinical improvement.
  • Another important finding was a drop in mortality (15% vs >60%) and a shift from previous causes like liver failure and sepsis to death from other comorbid conditions.
  • “Since 2009, we have performed only 1 IT [intestinal transplant].”  They note this is a worldwide trend with ~50% reduction in pediatric IT since 2008.
  • Even with ultrashort bowel (small bowel length <30 cm), there are reports that “50% of these patients achieved PN independence within 2 years.”  As such, this is a declining indication for IT listing. In this study, ultrashort bowel was the reason for listing in 11% in the last period compared 21% in the first time period.

Why is this happening?

The authors credit the intestinal rehab program (IRP) for this impact along with specific management changes including new lipid emulsions/lipid minimization to reduce IFALD, use of ethanol locks to reduce bloodstream infections, and bowel reconstructive procedures (e.g. STEP).

Briefly noted: Merras-Salmio L, Pakarinen MP. JPGN 2015; 61: 24-9. This second retrospective study (n=48) from Finland reinforces the view of improvements in cholestasis  and prognosis from 1988-2014.  Similar strategies, as noted above, were implemented in SBS management protocols.

Bottomline: The outlook has improved for SBS.  While this is good news, at the same time, there will be less pediatric gastroenterologists with extensive intestinal transplantation experience.

In Wyoming often there are stretches of nearly deserted highways

In Wyoming often there are stretches of nearly deserted highways

Related blog posts:

More Evidence to Support Ethanol Locks

For many years, ethanol locks have been promoted as a way to reduce central catheter-associated bloodstream infections (CCABSI).  A recent study (Ardura M I, et al. JAMA Pediatr.doi.10.1001/jamapediatrics.2014.3291 -published online Feb 2, 2015, thanks to Ben Gold for this reference) showed a dramatic reduction in CCABSI among 24 children with intestinal failure.

This study examined outcomes from January 2011-Jan 2012 with the outcomes from February 2012-December 2013.  In the latter period, ethanol lock prophylaxis was added to the CCABSI “prevention bundle” both in inpatient and outpatient settings.

Key finding: Rates of CCABSI decreased from 6.99 per 1000 catheter days to 0.42 per 1000 catheter days.

One aspect of this study that is very important is that the QI team included a specialized CVC nurse who evaluated and performed all CVC care and teaching.

Their protocol is detailed in their methods section.  Some of the details:

  • Their ethanol lock utilized a 70% solution on a daily basis.
  • The CVC nurse verified that the catheter was silicone prior to initial lock.
  • CVC nurse used Alteplase prior to initial dwell.
  • Dwell volume was determined by CVC nurse by withdrawing flush until blood return and then adding 0.1 mL for children <15 kg and adding 0.2 mL for children >15 kg (max volume 3 mL).
  • Dwell times were minimum of 2 hours and maximum of 24 hours.
  • At the end of the dwell time, twice the amount of the predetermined ethanol volume was withdrawn and then 5 to 10 mL of normal saline was used as a flush.

Bottomline: Ethanol locks have the potential to reduce CCABSI by 90%; this can reduce hospitalizations, prevent complications, and possibly improve survival.

Related blog posts:

Heart-Shaped Polyp (from ACG twitter feed -recommends screening colonoscopy)

Heart-Shaped Polyp (from ACG twitter feed -recommends screening colonoscopy)

Ethanol locks -jump on the bandwagon

From Nutrition in Clinical Practice, published online before print, December 11, 2012, doi:10.1177/0884533612468009 (Thanks to Kipp Ellsworth for this link from his twitter feed):

“Our group of patients (n=14) showed a 73% reduction in CABSIs and a 77% reduction in catheter removal due to infection after ethanol lock therapy. In our patient population, weekly ethanol lock therapy for 2 hours is an effective technique to reduce CABSIs and catheter removal in long-term home PN patients.”

CABSIs =catheter-associated bloodstream infections

Four advances for intestinal failure

Several advances in the management of intestinal failure have the potential to improve the outlook for our intestinal failure (IF) (aka Short Bowel Syndrome) patients (JPEN 2012; 36: 36S-42S).

Although IF patients already have improving survival with rates of 80-95% over followup ranging from 1-5 years, many still do not survive, primarily due to bacterial infections or chronic liver disease.  Ongoing research has made some promising steps in the management of these pediatric patients.  This article focuses on four of these steps.

1. Citrulline monitoring

  • Major source of citrulline is enterocyte production.  Citrulline is an amino acid not encoded in human genetic code; it is present in some proteins as a product of posttranslational modification.
  • Watermelon is one of few dietary sources.
  • Useful biomarker for bowel length/absorption –independent of inflammatory markers
  • Levels >15-20 μmol/L indicate good likelihood of achieving enteral autonomy
  • Levels <12μmol/L indicate a very low likelihood of achieving enteral autonomy

2. Teduglutide therapy

  • Analog of glucagon-like peptide 2 (GLP-2) but harder to degrade (longer half-life)
  • Preliminary studies in adults indicate improvement in absorption and villous histology after subcutaneous administration for three weeks.  Improvements reverse when drug is discontinued.
  • Since GLP-2 is produced by colon & increased in IF (if colon present), unclear whether exogenous administration will be as beneficial in patients with residual colon

3. Lipid minimization &/or fish oil lipids

  • Cholestasis increases in patients receiving more than 1 g/kg/day of intralipids (soy based).
  • Fish oil (Omegaven) has shown benefit in lowering cholestasis in numerous case reports.  This may be due the high content of anti-inflammatory ω-3 fatty acids.
  • Another preparation SMOFLipid is a mixed formulation and may be safer than pure fish oil; randomized controlled studies of both of these lipid formulations are underway.
  • Fish oil has not been shown to improve histology
  • Parenteral nutrition associated liver disease (PNALD) may improve with lowering lipids & may not need omegaven

4. Ethanol locks

  • May be beneficial in treating and preventing central line infections.  In both situations, in small studies, ethanol locks lowered incidence of recurrent infections.
  • Six studies involving 75 patients (66 pediatric patients) lowered infection rates from approximately 10 per 1000 catheter days to 2 per 1000 catheter days.
  • Ethanol concentrations were mostly 70% in these studies, though 25% has been used.
  • Dwell times ranged from 2-14 hours.
  • Randomized studies are in progress.
  • Fewer infections should reduce the likelihood of death from sepsis and death due to loss of venous access.

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.
  • -NEJM 2009; 361: 998. Intestinal Rx.  Review claims ~90% 1yr survival. 47% 5yr, 61% 3yr (expecting to go higher)
  • -JPGN 2009; 48: 334. Isolated liver w SBS feasible IF 50cm small bowel remaining or 30cm w ICV, 50% enteral nutrition >4 weeks with good growth, no dysmotility.
  • -Pediatrics 2008; 121: e678. n=18. use of fish oil improved cholestasis compared to historical controls.
  • -Gastroenterology 2008; 135: 61, 303. Survival of ITx (vs. HAL).  In many conditions, better off from survival standpoint without Tx. Tx if failure of TPN (severe liver dz/thrombosis of >/= 2 central veins, multiple bouts of sepsis/frequent dehydration), high risk of death, severe short bowel (<10cm in infants and <20cm in adults), pseudoobstruction, unwillingness to accept long-term tpn. 93% of TPN patients who did not have TPN-complications had 93% survival rate.  Thus, TPN is first line Rx as survival and quality of life often better.
  • -Pediatrics 2006; 118: e197-e201.  Reversal of TPN-AC c IV omega-3 fatty acids (fish oil-derived) instead of intralipids
  • -Liver Transplantation 2006; 12: 1062, 1040. Liver transplant alone reasonable to consider in some SBS patients who tolerate >50% enteral therapy and are less than 2 years old.
  • -Gastroenterology 2006; 130. Supp 1. Summary of NIH workshop on intestinal failure. TX Indications: Liver disease, thrombosis of major veins, recurrent catheter-related sepsis, frequent severe dehydration/electrolyte imbalance.
  • -JPGN 2005; 41: 47A (pg507). Poor prognosis: <40cm, needing >40kcal/kg PN, increased bili (>150 μmol/L)
  • -J Pediatr 2005; 146: 542. Serum citrulline > 19 μ/L associated with bowel adaptation/weaning off HAL.
  • -J Pediatr 2004; 145: 157-163. Survival of SBS with as little as 15
  • -Arch Pediatr Adolesc Med 2006; 160: 104953.  Use of ethanol lock (70%, 08-1.4mL for 12-24hrs, then withdraw). n=51.  High success rate in salvaging line
  • -J Pediatr 2001; 139: 27-33. Review of 30 pts. 3 of 30 pts with bowel length 40cm or less able to wean PN.
  • -Gastroenterology 2001; 120: 806-815. Glucagon-like peptide 2 improves nutrient absorption marginally.