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.

 

“Weekend Effect” and Pediatric IBD

The “weekend effect” is a term used to indicate that outcomes for many medical conditions are worse when patients are admitted to the hospital on the weekend.

A recent study (MD Egberg et al. Inflamm Bowel Dis 2020; 26: 254-60; editorial by C Ballengee Menchini 261-2) documents the degree of this effect on the risk of complications for pediatric patients with inflammatory bowel disease (IBD).

This study used a cross-sectional analysis with the Kids’ Inpatient Database (KID), a nationally representative database.  The study included 3255 urgent surgical hospitalizations and included patients 18 years old and younger.

Key findings:

  • The risk difference for weekend Crohn’s disease (CD) surgical hospitalizations involving a complication vs weekday hospitalizations was 4%
  • The risk difference for weekend ulcerative colitis (UC) surgical hospitalizations involving a complication vs weekday hospitalizations was 7%
  • The relative risk of surgical complications was 30% and 70% higher for weekend admissions for CD and UC respectively
  • For both weekend and weekday admissions, the most common complications were ‘postoperative intestinal/hepatic complications,’ ileus and sepsis
  • Hospital teaching status and population-density did not affect outcomes

Possible Reasons for Weekend Effect:

  • Reduced hospital staffing
  • Delayed seeking care by patients which increases illness severity
  • Reduced access to diagnostic resources
  • Lack (or reduced) of access to specialist care

Limitations include reliance on administrative data and potential for misclassification and unidentified confounding variables.

Related blog post:

From Weekend Hike on Mount Yonah:

 

 

IBD Shorts February 2020

Cost of IBD Care is Increasing. From Healio Gastro: Chronic inflammatory disease expenditures nearly double over last 2 decades Reference: Click B, et al. Poster 22. Presented at: Crohn’s and Colitis Congress; Jan. 23-25, 2020; Austin, Texas

An excerpt from Healio Gastro summary: [Using] the Medical Expenditure Panel Survey (MEPS), a nationally representative database of health care use and expenditure data collected since 1998The researchers assessed total annual, outpatient, inpatient, emergency and pharmacy expenditures in both patients with IBD (n = 641) and RA (n = 641). They used three separate time periods – 1998-2001, 2006-2009 and 2012-2015 –to compare expenditures over time…

Median per-patient annual health care expenditure in patients with IBD was $6,570 compared with $4,010 in patients with RA across all years of the study. Total annual spending increased approximately 2.2 times (95% CI, 1.6-3; P < .01) over the study period and was 36% higher in IBD than RA (P = 0.01).

Pharmaceutical spending increased more than fourfold (95% CI, 3.2-6.1; P < .01) and became the largest cost category (44% total). However, inpatient expenses in IBD decreased 40% over the study period.

My take: While the cost has increased, these new treatments are improving outcomes.  With the emergence of biosimilars, there may be improvement in pharmaceutical spending.

More on Proactive Therapeutic Drug Monitoring (pTDM) Being Helpful: SR Fernandes et al. Inflamm Bowel Dis 2020; 26: 263-70, editorial 271-2.  In this study, a prospective group of patients (n=56) undergoing pTDM were compared with a historical control group (n=149). pTDM had less frequent surgery (9% vs. 21%) and higher rates of mucosal healing (73% vs. 39%).  Treatment escalation was 3 times more common with pTDM than in the control group.

Increased risk of VTE in IBD patientsJD McCurdy et al. Inflamm Bowel Dis 2020; https://doi.org/10.1093/ibd/izaa002

Abstract Link: Risk of Venous Thromboembolism After Hospital Discharge in Patients With Inflammatory Bowel Disease: A Population-based Study

In a population-based study from Ontario, the authors analyzed a total of 81,900 IBD discharges (62,848 nonsurgical and 19,052 surgical) which were matched to non-IBD controls… The cumulative incidence of VTE at 12 months after discharge was 2.3% for nonsurgical IBD patients and 1.6% for surgical IBD patients…Nonsurgical IBD patients and surgical patients with ulcerative colitis are 1.7-fold more likely to develop postdischarge VTE than non-IBD patients.

Liver Shorts -February 2020

Caution with hemoglobin A1c interpretation: MM Kelsey et al. J Pediatr 2020; 216: 232-5. In the HEALTHY Study (n=8814), the authors note that a hemoglobin A1c was ≥5.7% in 2% of normal weight youth.  “This suggests need for cautious interpretation of prediabetes hemoglobin A1cs in youth”

Daily aspirin for NAFLD: TG Simon et al. Clin Gastroenterol Hepatol 2019; 17: 2776-84.  In this prospective cohort of 361 adults with biopsy-proven NAFLD, the use of daily aspirin (in 151) was associated with lower odds of NASH (aOR.68) and reduced risk of  fibrosis (aOR 0.54).  “The greatest benefit found with at least 4 years or more of aspirin use” (aHR =0.50).  The associated editorial (pages 2651-3) recommends controlled studies to determine if potential benefits outweigh the known risks (eg. bleeding).

Glecaprevir/pibrentasvir for HCV Treatment Failure:  AS Lok et al. Gastroenterol 2019; 157: 1506-17.  This randomized study with 177 patients showed that 16 weeks of glecaprevir and pibrentasvir was effective in retreatment of patients with genotype 1 hepatitis C viral infection (after prior failure with sofosbuvir plus an NS5A inhibitor).  The sustained virologic response 12 weeks after treatment was >90%.

Liver transplantation for Niemann-Pick Disease, type B:  YLY Luo et al. Liver Transplantation 2019; 25: 1233-40. This report analyzed 7 children receiving liver transplantation for Niemann-Pick disease, type B.  The authors report survival in the entire cohort and with normalized liver function within 3 weeks.  In addition, they noted improvement in psychomotor ability ( 10 months after transplantation) and resolution of insterstitial lung disease.  They state that developmental delay still existed in 4 patients during follow-up.  The editorial (1140-1) notes that these findings need to be confirmed but open a new window in improving the phenotype.  “A similar experience occurred with LT in maple syrup urine disease (MSUD), in which the liver is considered to host only 12-15% of the defective  enzyme responsible for the disease…in MSUD, liver replacement is able to counteract 85% of extrahepatic expression of the disease and to completely correct the phenotype.”

Increased Abdominal-Surgery Risk in Patients with Idiopathic Noncirrhotic Portal Hypertension: L Elkrief et al. Hepatology 2019; 70: 911-24. Among 44 patients (median age 44 years) with noncirrhoitic portal hypertension, 16 (33%) had one or more portal hypertension-related complication within 3 months after surgery.  4 (9%) died within 6 months.  “An unfavorable outcome (i.e. either liver or surgical complication or death) occurred in 22 (50%) patients” and was more likely in those with ascites, creatinine >100 micromol/L, or other extrahepatic complications related to portal hypertension.

One of my blog readers shared this image of “Liver Shorts” that can be purchased online

Clinical Practice Advice: Pancreatic Necrosis

Recently the AGA published expert practice advice for pancreatic necrosis: TH Baron et al. Gastroenterol 2020; 158: 67-75.

Link to full-text PDF:  American Gastroenterological Association Clinical Practice Update: Management of Pancreatic Necrosis.  The link includes 5 figures which provide algorithms based on their recommendations.

I’ve copied their 15 best practice advice below and highlighted the most useful.  Early in the course of pancreatic necrosis, it can be difficult to discern if an infection is present due to a robust inflammatory response; some findings suggestive of infection include gas in the collection, bacteremia, sepsis, or clinical deterioration.  Generally, surgical, endoscopic or radiologic intervention is more optimal when there is a walled-off pancreatic necrosis (WON) which typically takes 4 weeks or more.

Best Practice Advice 1

Pancreatic necrosis is associated with substantial morbidity and mortality and optimal management requires a multidisciplinary approach, including gastroenterologists, surgeons, interventional radiologists, and specialists in critical care medicine, infectious disease, and nutrition. In situations where clinical expertise may be limited, consideration should be given to transferring patients with significant pancreatic necrosis to an appropriate tertiary-care center.

Best Practice Advice 2

Antimicrobial therapy is best indicated for culture-proven infection in pancreatic necrosis or when infection is strongly suspected (ie, gas in the collection, bacteremia, sepsis, or clinical deterioration). Routine use of prophylactic antibiotics to prevent infection of sterile necrosis is not recommended.

Best Practice Advice 3

When infected necrosis is suspected, broad-spectrum intravenous antibiotics with ability to penetrate pancreatic necrosis should be favored (eg, carbapenems, quinolones, and metronidazole). Routine use of antifungal agents is not recommended. Computed tomography–guided fine-needle aspiration for Gram stain and cultures is unnecessary in the majority of cases.

Best Practice Advice 4

In patients with pancreatic necrosis, enteral feeding should be initiated early to decrease the risk of infected necrosis. A trial of oral nutrition is recommended immediately in patients in whom there is absence of nausea and vomiting and no signs of severe ileus or gastrointestinal luminal obstruction. When oral nutrition is not feasible, enteral nutrition by either nasogastric/duodenal or nasojejunal tube should be initiated as soon as possible. Total parenteral nutrition should be considered only in cases where oral or enteral feeds are not feasible or tolerated.

Best Practice Advice 5

Drainage and/or debridement of pancreatic necrosis is indicated in patients with infected necrosis. Drainage and/or debridement may be required in patients with sterile pancreatic necrosis and persistent unwellness marked by abdominal pain, nausea, vomiting, and nutritional failure or with associated complications, including gastrointestinal luminal obstruction; biliary obstruction; recurrent acute pancreatitis; fistulas; or persistent systemic inflammatory response syndrome.

Best Practice Advice 6

Pancreatic debridement should be avoided in the early, acute period (first 2 weeks), as it has been associated with increased morbidity and mortality. Debridement should be optimally delayed for 4 weeks and performed earlier only when there is an organized collection and a strong indication.

Best Practice Advice 7

Percutaneous drainage and transmural endoscopic drainage are both appropriate first-line, nonsurgical approaches in managing patients with walled-off pancreatic necrosis (WON). Endoscopic therapy through transmural drainage of WON may be preferred, as it avoids the risk of forming a pancreatocutaneous fistula.

Best Practice Advice 8

Percutaneous drainage of pancreatic necrosis should be considered in patients with infected or symptomatic necrotic collections in the early, acute period (<2 weeks), and in those with WON who are too ill to undergo endoscopic or surgical intervention. Percutaneous drainage should be strongly considered as an adjunct to endoscopic drainage for WON with deep extension into the paracolic gutters and pelvis or for salvage therapy after endoscopic or surgical debridement with residual necrosis burden.

Best Practice Advice 9

Self-expanding metal stents in the form of lumen-apposing metal stents appear to be superior to plastic stents for endoscopic transmural drainage of necrosis.

Best Practice Advice 10

The use of direct endoscopic necrosectomy should be reserved for those patients with limited necrosis who do not adequately respond to endoscopic transmural drainage using large-bore, self-expanding metal stents/lumen-apposing metal stents alone or plastic stents combined with irrigation. Direct endoscopic necrosectomy is a therapeutic option in patients with large amounts of infected necrosis, but should be performed at referral centers with the necessary endoscopic expertise and interventional radiology and surgical backup.

Best Practice Advice 11

Minimally invasive operative approaches to the debridement of acute necrotizing pancreatitis are preferred to open surgical necrosectomy when possible, given lower morbidity.

Best Practice Advice 12

Multiple minimally invasive surgical techniques are feasible and effective, including videoscopic-assisted retroperitoneal debridement, laparoscopic transgastric debridement, and open transgastric debridement. Selection of approach is best determined by pattern of disease, physiology of the patient, experience and expertise of the multidisciplinary team, and available resources.

Best Practice Advice 13

Open operative debridement maintains a role in the modern management of acute necrotizing pancreatitis in cases not amenable to less invasive endoscopic and/or surgical procedures.

Best Practice Advice 14

For patients with disconnected left pancreatic remnant after acute necrotizing mid-body necrosis, definitive surgical management with distal pancreatectomy should be undertaken in patients with reasonable operative candidacy. Insufficient evidence exists to support the management of the disconnected left pancreatic remnant with long-term transenteric endoscopic stenting.

Best Practice Advice 15

A step-up approach consisting of percutaneous drainage or endoscopic transmural drainage using either plastic stents and irrigation or self-expanding metal stents/lumen-apposing metal stents alone, followed by direct endoscopic necrosectomy, and then surgical debridement is reasonable, although approaches may vary based on the available clinical expertise.

Related blog post: NASPGHAN 2017 Postgraduate Course Part 1 -includes slides on pancreatic fluid collection management

 

Neurocognitive Function with Pediatric Intestinal Failure

Lately, there have been a lot of articles on neurocognitive function.  The latest (A Gold et al. JPGN 2020; 70: 225-31) describes the myriad of problems facing children with intestinal failure (IF). The authors literally used 12 different measures of neurocognitive and academic measures –though not all 28 subjects had each of these measures (Table 2).

Caveats:

  • The authors specifically excluded 5 children with severe neurodevelopmental problems that precluded participation in standardized assessment and 10 children who were transplant recipients.
  • Also, when judging the results, it is important to keep in mind that their cohort had a good maternal education level; 68% were college graduates.

Key findings:

  • 13 of 28 (46%) received a diagnosis of cognitive/learning DSM diagnosis
  • 29% met diagnostic criteria for a learning disability, 7% for ADHD, and 11% for intellectual disability; comparison Canadian prevalence rates are 4%, 5%, and 1% respectively
  • The number of first-year septic episodes was associated with poorer outcomes; ≥2 or more episodes increased the likelihood.
  • Sustained cholestasis was associated with poor outcomes
  • The average level of intellectual functioning in their sample of 28 children was within 1 standard deviation of the population mean

There are a lot of risk factors for neurodevelopment impairment in these children with IF: prematurity, nutritional status/specific nutrient deficiencies, cholestasis, need for anesthesia/surgeries

My take: More than half of children with IF had neurodevelopemental impairment.  In this cohort, recurrent sepsis in the first year of life and sustained cholestasis were associated risk factors.

Related blog posts:

Sunrise in Sandy Springs

 

Antibiotic Selection for Suspected Central Line Infections

A recent study (BP Raphael et al. JPGN 2019; 70: 59-63) describes 309 central line-associated bloodstream infections (CLABSI) in 90 children were dependent on parenteral nutrition (median age 3.8 years).

Key findings:

  • 60% of isolated organisms were gram-positive, 34% were gram-negative, and 6% fungi.
  • For gram-positive organisms, 51% were sensitive to methicillin
  • For gram-negative organisms, 71% were sensitive to piperacillin-tazobactam, 97% to cefepime, and 99% to meropenem

Based on these findings, the authors advocate the following:

  • “Vancomycin and cefepime provide improve coverage over vancomcyin piperacillin-tazobactam for” CLABSI
  • Empiric use of vancomycin and meropenem “may be justified” in septic shock “where maximal probability of cure outweighs risks of long-term drug resistance”
  • If there is an increased fungemia risk, such as prior fungal infections, shock, or immunodeficiency, the authors recommend adding fluconazole

Another advantage of cefepime over piperacillin-tazobactam is a reduced risk of acute kidney injury which has been associated with the latter.

My take: Individual institutions may have variable organism sensitivity.  In the absence of institutional data, this recommendations are a good starting point.

Related blog post: #NASPGHAN19 Intestinal Failure Session Part 1

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