Aspen Webinar 2021 Part 4 – IFALD Update

More from Aspen Webinar 2021. This blog entry has abbreviated/summarized several presentations. Though not intentional, some important material is likely to have been omitted; in addition, transcription errors are possible as well. An excellent review from Dr. Sokol.

What’s New with IFALD Ronald Sokol

Key points:

  • Biliary cirrhosis related to parenteral nutrition has been the major indication for small bowel  transplantation/multi-visceral transplantation. IFALD presentations: Steatosis, biliary tract disease and cholestasis
  • Conjugated bilirubin >2.5 had RR 22.5 for mortality (prior to availability of intestinal transplantation)
  • Even after weaning off PN, studies have shown long-lasting fibrosis and steatosis in more than 40% of patients (>8 yrs off PN)
  • Intestinal microbiome is altered in patients with IFALD
  • Puder M et al. (Ann Surg 2009; 250: 395) showed that fish oil (at lower doses) was associated with improvement/resolution of parenteral nutrition associated cholestasis (PNAC)
  • Lipid reduction also is associated with cholestasis resolution
  • Treatments: Advance enteral feeds, lipid modulation, prevent CLABSI, treat bacterial overgrowth, GLP-2, and STEP procedure/tapering
  • SMOF lipid allows full dosing of lipids (3 gm/kg)
  • Caution with Fish oil (omegaven): 1. Does not prevent hepatic fibrosis progression 2. Reduction of lipid doses can have negative effects on brain growth
  • Lipid management has been crucial in reducing the number of children needing intestinal transplantation

Some of the slides:

IBAT Inhibitors Frederick Suchy

Key  points:

  • IBAT inhibitors block intestinal absorption of bile acids/disrupt enterohepatic circulation; this leads to augmented bile acid excretion in stools
  • IBAT inhibitors may reduce liver damage in the setting of cholestasis/accumulation of toxic bile acids
  • Potential diseases for IBAT inhibitors include Alagille syndrome and PFIC
  • Van Wessel et al (J Hepatol 2020; 73: 84-93) correlated survival with PFIC1/PFIC2 with bile acid levels and showed improvement in survival in those with surgical biliary diversion
  • Goals for IBAT inhibitor trials: improvement in pruritus, bile acids, reduced ALT, hepatic fibrosis, HCC and need for liver transplantation
  • Marixibat is available for use as an FDA approved breakthrough medication for Alagille and PFIC2 in pediatric patients older than 1 year
  • Odexibat is designated as an orphan drug for Alagille, PFIC, PBC, and biliary atresia
  • Safety appears good with IBAT inhibitors. Fat soluble vitamin monitoring is needed

Case report: Alejandro Velez Lopez

3 yo presented with fatigue and jaundice, 3 weeks after COVID-19 infection. She was not taking any medications.  Labs:  ALT 939, AST 1321, T bili 5.5, D bili 0.9, INR 2, Plts 174, Hgb 12.8, LDH 1297. remained positive for SARS-CoV2 by PCR. Acetaminophen -no exposure.  Evaluation: LKM 1:1280. Neg ANA, NL Ferritin, NL sIL2r, Other viral studies negative, NL IgG. Developed encephalopathy with NH4 317, INR peaked at 2.8.  Treated with steroids, rifaximin and lactulose.  Liver biopsy showed sub-massive necrosis and fibrosis (indicative of  autoimmune hepatitis, likely triggered or exacerbated by COVID-19).  Patient responded to medical therapy and did not require liver transplantation.

How Important is Heparin for Preventing Occlusion of Catheters in Pediatrics?

According to a recent Cochrane review, heparin use is NOT more effective than saline flushes. Thanks to Ben Gold for providing this reference.

Bradford NK, Edwards RM, Chan RJ. Link: Normal saline (0.9% sodium chloride) versus heparin intermittent flushing for the prevention of occlusion in long-term central venous catheters in infants and children. Cochrane Database Syst Rev. 2020;4(4):CD010996. doi: 10.1002/14651858.CD010996.pub3.

Key findings:

  • The four trials (n=255) directly compared the use of normal saline and heparin; the studies all used different protocols for the intervention and control arms, however, and all used different concentrations of heparin.
  • The estimated RR for CVC occlusion per 1000 catheter days between the normal saline and heparin groups was 0.75 (95% CI 0.10 to 5.51; 2 studies, 229 participants; very low certainty evidence).
  • The estimated RR for CVC‐associated blood stream infection was 1.48 (95% CI 0.24 to 9.37; 2 studies, 231 participants; low‐certainty evidence).
  • The duration of catheter placement was reported to be similar for the two study arms in one study (203 participants; moderate‐certainty evidence), and not reported in the remaining studies.
  • This is in agreement with another updated Cochrane review assessing the effectiveness and safety of intermittent locking of CVCs with heparin vs. normal saline to prevent occlusion in adults (11 studies; N=2,392). The pooled analysis did show fewer occlusions with heparin than with normal saline (RR 0.70, 95% CI 0.51 to 0.95; P = 0.02; 1672 participants; 1025 catheters from 10 studies; I² = 14%), but it is based on a very low-quality of evidence given the differences in methodology, unclear allocation concealment, imprecision, and suspicion of publication bias. (López-Briz E, Ruiz Garcia V, Cabello JB, et al. Heparin versus 0.9% sodium chloride locking for prevention of occlusion in central venous catheters in adults. Cochrane Database Syst Rev. 2018;7(7):CD008462. doi: 10.1002/14651858.CD008462.pub3)

My take: This review found there was not enough evidence to determine which solution, saline or heparin, is more effective for reducing complications.

Related blog posts:

Is It OK To Swim With A Central Line?

D Wendel et al. JPGN 2021; 72: 474-486. Free full text: Management of Central Venous Access in Children With Intestinal Failure: A Position Paper From the NASPGHAN Intestinal Rehabilitation Special Interest Group

This is a very useful article with recommendations for central venous access in children. The main recommendations are summarized in Table 3 & listed below; however, there is a lot of detailed information in the article on frequent issues like schools, travel (including dealing with TSA), sports, and even swimming. In addition, the article delineates recommendations for management and prevention of line complications.

1. Recommendations for venous access:

  • Tunneled, single lumen, cuffed silicone catheters should be used for children with IF.
  • Upper extremity access is the preferred location when available.

2. Recommendations pertaining to routine CVC care:

  • Proper technique and hygiene surrounding CVC care are of paramount importance in preventing CVC-associated complications. Caregivers should receive directed education regarding CVC care before initial discharge, with subsequent reinforcement education as needed.
  • CHG impregnated supplies (disk, sponge, or dressing) should be considered for central line dressing in pediatric IF patients.
  • Routine surveillance of central venous access should be performed by US. MR, CT, or traditional venography should be reserved for when further delineation of access is required.

3. Recommendations regarding general considerations—sports, travel, and emergencies:

  • All children with IF should be provided with an emergency letter that details the specific needs of the individual child in case of an emergency. (See at bottom for example -Figure 1)
  • Discuss with families the risks of swimming and sports participation with strategies to protect the dressing and central line.
  • All travel plans should be discussed with the intestinal rehabilitation team well in advance of travel to facilitate discussion of a plan of care in case of emergency.

4. Recommendations regarding central line-associated bloodstream infections:

  • All children with IF and CVC who develop a fever (≥38.0°C) should be admitted to the hospital and assessed for bacteremia with central and peripheral blood cultures while receiving broad-spectrum empiric antibiotics through the CVC for at least 48 h, awaiting culture results regardless of other infectious sources.
  • If clinically stable, discuss with the patient’s IRP before line removal for CLABSI.
  • Prophylactic lock therapy with ethanol or other nonantibiotic locks should be strongly considered in all children with IF who have had at least one central line-associated bloodstream infection or are at high risk for infection.

5. Recommendations pertaining to central line mechanical complications:

  • In children with IF, CVC should be repaired whenever possible to preserve central venous access.
  • Children with IF and a newly identified CRT should be treated with low molecular weight heparin for at least 6 weeks with guidance from a hematologist.
  • Children with IF who have persistence of at least one chronic thrombus should be maintained on prophylactic anticoagulation with low molecular weight heparin.
  • Children who have lost multiple sites of central venous access should be considered for referral to an intestinal transplant center for evaluation and management

6. Recommendations for central venous access program management:

  • All centers following children with IF should, at a minimum, track the number of outpatient CLABSI per 1000 catheter days.

With regard to swimming: “Swimming introduces an incompletely defined but potentially severe risk to those requiring chronic central venous access. Contamination of various chlorine-treated (swimming pools), stagnant (lakes and ponds), and flowing (oceans and rivers) bodies of water with human pathogens has been well documented, though proper maintenance may minimize outbreaks. The potentially fatal risk of such contaminants gaining access to central circulation via the CVC is unclear…Parents seeking guidance are confronted by mixed messaging from support programs, online resources and blogs, and even IRP. These conflicting recommendations and practices reflect the paucity of data to guide a safe and clear approach for swimming with a central line…[in one study of 16 home PN programs] swimming in low-risk situations [was permitted but] recommended immediate site cleaning and dressing change following water exposure and avoidance of submersion for 4–6 weeks after CVC placement. Ultimately, the decision to permit children with IF to swim lies with the parent or guardian.”

For pets (like Charlie), this article notes that “steps should be taken to promote line integrity in the presence of pets. Particularly in the setting of pets that may attempt to chew or play with tubing, adequate physical protection of the insertion site and catheter itself is recommended. Any line or tubing puncture by an animal should prompt immediate evaluation. Family awareness of zoonotic disease risk and advocacy of handwashing before and after animal care should be made clear.”
Figure 1 -Emergency Letter Template

Related blog posts:

Disclaimer: This blog, gutsandgrowth, assumes no responsibility for any use or operation of any method, product, instruction, concept or idea contained in the material herein or for any injury or damage to persons or property (whether products liability, negligence or otherwise) resulting from such use or operation. These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  Because of rapid advances in the medical sciences, the gutsandgrowth blog cautions that independent verification should be made of diagnosis and drug dosages. The reader is solely responsible for the conduct of any suggested test or procedure.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

Short Bowel Syndrome and Long Duration of Feeding Problems

VJ Christian et al. JPGN 2021; 72: 442-445. Pediatric Feeding Disorder in Children With Short Bowel Syndrome

This small (n=28) retrospective study provides useful information on the persistence of feeding problems in children with short bowel syndrome (SBS). The authors defined a pediatric feeding disorder (PFD) as “reliance on enteral feeds to sustain nutrition, reliance on high-calorie oral supplements to sustain nutrition, or feeding skill dysfunction resulting in not consuming an age-appropriate diet.” Patients who remained on PN were considered to have a PFD as well.

Key findings:

  • Of the 21 patients (75% of total cohort) who were weaned off parenteral nutrition, 57.1%, 81.0%, 90.5%, and 100.0% achieved this by 12, 24, 36, and 48 months of age, respectively. Median age at time of weaning PN was 10.8 months.
  • Of the 13 patients who were weaned off enteral nutrition (EN), 30.8%, 69.2%, 76.9%, and 100.0% achieved this by 12, 24, 36, and 48 months, respectively. Median age of weaning EN was 15.7 months. Overall, about a third of patients required EN beyond 2 years of life.
  • The prevalence of PFD (of entire cohort) was 100.0%, 76.5%, 68.8%, and 70.0% at 1, 2, 3, and 4 years of age, respectively

My take: When parents ask how long it will be before my child is off PN and eating by mouth, this study’s results could be useful.

Chicago at Sunrise

Related blog posts for Short Bowel Syndrome:

Parenteral Nutrition: “The Scar Remains”

A recent study (KM Gura et al. J Pediatr 2021; 230: 46-54. Fish Oil Emulsion Reduces Liver Injury and Liver Transplantation in Children with Intestinal Failure-Associated Liver Disease: A Multicenter Integrated Study) provides multicenter data comparing fish oil emulsion (FOLE) (Omegaven) with a historical control of soybean emulsion (SOLE) (Intralipid). The FOLE group was enrolled between 2004-2018; the SOLE group had data from 1999-2012.

Key points:

  • Among FOLE recipients (n=189), 65% experienced cholestasis resolution vs 16% of SOLE recipients (n=73) (P < .0001).
  • The aspartate aminotransferase to platelet ratio index scores improved in FOLE recipients (1.235 vs 0.810 and 0.758, P < .02) but worsened in SOLE recipients (0.540 vs 2.564 and 2.098; P ≤ .0003) 
  • Liver transplantation was reduced in FOLE vs SOLE (4% vs 12%; P = .0245).

My main criticisms of the study:

  1. While the methods explain that FOLE received 1 gm/kg/d, compared with 3 gm/kg/d for SOLE, this was NOT reviewed in the discussion. This is quite important in terms of proving that one product is preferred over the other. With lipid toxicity, it would be expected that delivering 3 times as much would be more damaging on the liver.
  2. The discussion does not discuss the potential neurological consequences of lipid minimization/lower doses of lipids. In the same Journal of Pediatrics issue, Bell et al report that 77% of SBS in their cohort of extremely premature infants with short bowel syndrome had moderate-to-severe neurodevelopmental impairment (related blog post: Neurodevelopmental Impairment in the Majority of Extremely Premature Infants with Short Bowel Syndrome)
  3. The discussion has only a single sentence regarding the change in care between the eras of SOLE and FOLE: “Additional limitations include a relatively small sample size and changes in surgical, medical, and nutritional practice between the 2 eras that could not be controlled for this study.”
  4. Also, the discussion omits the development of other FOLE alternatives (eg. SMOFlipid) which has been a very important advance in the management of patients with SBS.

The commentary by Samuel Kocoshis (J Pediatr 2021; 230: 11-12) provides a good deal of insight. The title and first paragraph provides some interesting historical context: (full text) “Even When the Would Is Healed, the Scar Remains” “The above maxim was coined by the Roman author Publilius Syrus when referring to wounds of most tissues or body parts.1 Because hepatic regeneration was recognized (as evidenced by the story of Prometheus’s liver being eaten daily by an eagle only to regenerate the next day) in Syrus’s time, his dictum was too far too simplistic when applied to the liver. One must delve more deeply into the mechanism of liver injury to ascertain just when hepatic scaring persists or when it disappears.”

My take: This study illustrates harm reduction with the change in lipid administration. The development of new lipid products has made a huge difference in the outcomes of children with short bowel syndrome.

Related blog posts:

Advice on Parenteral Vitamin Shortages

ASPEN website: 2021 Parenteral Nutrition Multivitamin Product Shortage Considerations

Related Blog Posts:

Neurodevelopment Impairment in the Majority of Extremely Preterm Infants with Short Bowel Syndrome

Link to article (paywall)/abstract: Neurodevelopmental and Growth Outcomes of Extremely Preterm Infants with Short Bowel Syndrome

Key finding from study:

  • Moderate-severe neurodevelopmental impairment was present in 77% of children with extreme prematurity and with short bowel syndrome compared to 44% with extreme prematurity without necrotizing enterocolitis, spontaneous intestinal perforation or short bowel syndrome. 

One of the authors, Ira Adams-Chapman, recently passed away (link to obituary: Ira Adams-Chapman, 1965-2020). She and I were residents together in Cincinnati. She was a terrific person.

Is GLP2 Worth $300K per Year?

E Ramos Boluda et al. JPGN 2020; 71: 734-739. Experience With Teduglutide in Pediatric Short Bowel Syndrome: First Real-life Data

S Hill. JPGN 2020; 71: 697-698 (editorial) Use of GLP-2 May Herald a New Era of Improved Outcome of Short Bowel Syndrome-associated Intestinal Failure

The study and associated editorial highlight the effectiveness of GLP-2 in a prospective cohort of 17 patients with short bowel syndrome. It is noted that Dr. Hill has received funding from the pharmaceutical manufacturer of the product.

Key findings:

  •  A total of 12 of 17 patients achieved parenteral independence: 3 patients after 3 months of treatment, 4 patients at 6 months, and 5 after 12 months.
  • The percentage able to wean off parenteral nutrition was 17%, 44%, and 60% at 3, 6, and 12 months respectively. Only 1 patient did not exhibit improvement
  • Plasma citrulline levels, a marker for enteral autonomy, increased from a baseline average of 20 micromol/l to 37.5, 46.75, and37.9at 3, 6, and 12 months respectively.
  • Adverse reactions included abdominal pain 30%, nauseas 18%, injection-site reactions 22%, and headache 16%.

Both the editorial and the study comment briefly on the cost of the therapy. The editorial also notes the current recommendation for surveillance endoscopy in view of a hypothetical risk of malignancy.

My take: Is GLP2 Worth the Cost? It probably depends on who is paying and long-term safety data. Perhaps, we will develop tools to improve prediction of which patients will achieve enteral autonomy with GLP2 who would otherwise require ongoing parenteral nutrition.

Related blog posts:

Nutrition Pearls -Fiber in Short Bowel and Good Growth with Cystic Fibrosis

One useful resource for NASPGHAN members (NASPGHAN Nutrition Pearls) has been the short monthly nutrition pearl videos (about 10 of them so far). Here are some pointers from the most recent of these.

In October: Fiber for Short Bowel Syndrome –Beneficial for those with a colon in continuity:

Commercial products with limited data supporting use in short bowel syndrome
All of the fiber products are fermented in colon and may be beneficial. Highlighted products are more likely to help with stool consistency (thickening).

In September: Growth in Cystic Fibrosis

Related blog posts for Short Bowel Syndrome:

Related blog posts for Cystic Fibrosis:

Short Gut Diet -CHOA Approach

Recently Kipp Ellsworth, with input from members of the nutritional team, developed our first institutional Short Gut Diet.

Per Kipp, this diet is “designed to facilitate digestion while minimizing abdominal pain and ostomy/stool output in our inpatients with truncated intestinal anatomy.  Previously, clinicians ordered a regular diet for our short gut patients, with parents and nurses providing oversight of the ordering process based on their knowledge of short gut diet precepts.  Obviously this non-standardized approach resulted in significant noncompliance, another onerous daily task for nursing, and a failure of inpatient short gut diet principles reinforcement.  I anticipate the new diet serving as an omnipresent education tool, reinforcing short gut diet precepts for patients and parents during their inpatient stays.”

Related blog posts: