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
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
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
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.
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.
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.”
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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.
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.
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:
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.
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.”
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.
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.
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.
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.