Methods: This was a retrospective secondary outcome analysis of a randomized controlled trial performed between June 2012 and June 2015. Infants with extremely low birth weight received either a mixed (soybean oil, medium chain triglycerides, olive oil, fish oil) or a soybean oil-based lipid emulsion for parenteral nutrition (up to 3 gm/kd/day). At 5 years 6 months of age, data of 153 of 206 infants (74%) were available for analysis.
My take: The discussion highlights the lack of a positive benefit from the mixed emulsion. However, one of the biggest concerns with lipid emulsions occurs in the setting of lipid emulsion restriction due to parenteral nutrition associated liver disease. Because mixed emulsions are better tolerated, this helps minimize lipid restriction which could result in worsened neurocognitive outcomes.
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.
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.
This study evaluated neurodevelopmental outcomes using Bayley Scales. the authors provided a secondary outcome analysis of a double-blind randomized trial of 206 extremely low birth weight infants. Participants received either SMOFlipid or soybean oil-based lipid. Lipids were dosed at </+ 3 g/kg/day.
Parenteral nutrition using a mixed lipid emulsion (SMOF) containing fish oil did not improve neurodevelopment of extremely low birth weight infants at 12 and 24 months corrected age
At 24 months of age, specifically, there was again no significant differences in any of the following areas (median values):
cognitive: SMOF: 95 & soybean oil: 95
language: SMOF: 89 & soybean oil 89
motor scores: SMO 94 & soybean oil: 94
Limitations: One of the reasons why this study did not find any difference is that it was not powered for assessment of neurodevelopmental outcomes. The authors provide other potential reasons:
DHA in SMOFlipid provided 43 mg/kg/d, while more than the soybean-lipid, is at the lower end of published fetal accretion rates (40-67 mg/kg/day)
DHA deficits may not have been pronounced enough in this study to see an effect of SMOFlipid on neurodevelopement
Full feeds were reached after 23 days (IQR, 17-37 days); thus, it is possible that infants with longer term dependency on parenteral nutrition would benefit more
My take: SMOFlipid has not been proven to have more favorable long-term neurocognitive effects than intralipid. However, for children with prolonged need for parenteral nutrition, SMOFlipid is more likely to allow full dosing which in itself may be an important contributor to better outcomes. That is, soybean-lipid emulsions are more likely to be reduced due to cholestasis and this could lead to nutritional deprivation.
“We pooled data from 8 phase 2 or phase 3 trials of treatment-naïve patients with HCV genotype 1 to 6 infections, without cirrhosis or with compensated cirrhosis, who received 8 weeks of glecaprevir/pibrentasvir.” (n=1248) Key finding: Overall rates of sustained virologic response at post-treatment week 12 were 97.6% (1218 of 1248) in the intention to treat (ITT) and 99.3% (1218 of 1226) in the modified ITT populations.
This review discussed the use of SMOFlipid that includes soybean, medium-chain triglycerides, olive and fish oils. Key points:
“Lipid minimization strategies have also been shown to reverse IFALD [intestinal failure associated liver disease]. There are, however, considerable concerns regarding adequate weight gain, compromise to neurodevelopment, and EFAD [essential fatty acid deficiency]”
“Thee is actually considerable safety data for CLE [composite lipid emulsion] in neonates, albeit over the short term.”
“In Canada, CLE is currently the lipid emulsion of choice for all infants at risk of IFLAD.”
Methods: “We collected information on weight-adjusted, submaximal physical work capacity (PWC), ultrasound-determined hepatic steatosis, iron indices, and hematologic and metabolic parameters from 390 female and 458 male participants of the Raine Study—a longitudinal study of disease development … in Western Australia”
Key finding: “Fourteen percent of the cohort had NAFLD. PWC was significantly reduced in adolescents with NAFLD compared to adolescents without NAFLD (reduction of 0.17 W/kg, P = .0003, adjusted for sex and body mass index [BMI])… we found NAFLD to be associated with decreased cardiorespiratory fitness, independent of BMI. The relationship between transferrin saturation and PWC in adolescents with NAFLD indicates that functional iron deficiency might contribute to reductions in cardiorespiratory fitness.”
“Thousands of Georgia’s poor and uninsured adults who meet a work or activity requirement will soon be eligible for Medicaid, with perhaps 50,000 added to the rolls within two years…And more than 350,000 very poor, uninsured Georgia adults still won’t meet Georgia’s requirements for Medicaid”
“At the same time, the 400,000 Georgians who bought individual health insurance plans on the federal healthcare.gov Affordable Care Act shopping website will find they can’t do that anymore. Instead they will be directed to contact information for private brokers or insurance companies”
Both SMOFlipid and Omegaven help prevent and/or treat parenteral nutrition associated cholestasis.
SMOFlipid is much less expensive (see slide below) -50 gm of SMOFlipid ~$5 compared to 10 gm of Omegaven at $35, thus omegaven costs more than 30 times SMOFlipid.
Though SMOFlipid is not FDA approved in children, it is being used widely and allows for increased calories compared to lipid minimization with intralipid and could improve neurocognitive outcomes.
SMOF dosing (listed below) with goal of 3 g/kg in preterm infants.
Resolution of cholestasis does not mean reversal of cirrhosis. Thus, lipid emulsion intervention at earlier stage may be important.
Bram Raphael Getting In Line: Towards a Clinical Practice Guideline For CVC Salvage
Several infections are very difficult to clear, especially yeast, enterococcus, and pseudomonas
Salvaging central lines may obviate the need for multi-visceral transplant which carries a 5-year ~50% mortality rate
Cefepime provides good gram-negative coverage; consider meropenem in those with septic shock
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A recent study (C Belza et al. JPEN 2019; https://doi.org/10.1002/jpen.1692) showed that SMOFlipid reduced the frequency of cholestasis in intestinal failure patients. Thanks to Kipp Ellsworth for reference.
This was a retrospective cohort study of infants with IF with a minimum follow‐up of 12 months in 2008–2016. Patients were stratified into 2 groups: group 1 received SMOFlipid; group 2 was a historical cohort who received Intralipid. The primary outcome was liver function evaluated using conjugated bilirubin (CB) levels…
Thirty‐seven patients were evaluated (17 = SMOFlipid, 20 = Intralipid). SMOFlipid patients were less likely to reach CB of 34 (24% vs 55%, P = 0.05), 50 µmol/L (11.8% vs 45%; P = 0.028), and did not require Omegaven (0% vs 30%; P = 0.014). CB level at 3 months after initiation of parenteral nutrition (PN) was lower in patients receiving SMOFlipid (0 vs 36 µmol/L; P = 0.01). Weight z‐scores were improved for patients receiving SMOFlipid at 3 months (−0.932 vs −2.092; P = 0.028) and 6 months (−0.633 vs −1.614; P = 0.018).
A recent study (C Binder et al. J Pediatr 2019; 211: 46-53) examined electrophysiological brain maturation in a randomized double-blinded controlled trial of SMOF lipid compared to soybean lipid emulsion for extremely low birth weight (ELBW) premature infants. This was a prespecified secondary outcome analysis of a randomized trial of 230 infants (2012-2015).
It is recognized that the ELBW infants have very little nutritional reserve. In addition, DHA which is transferred to the fetus in high amounts in the last trimester is absent from parenteral soybean lipid emulsions. Thus, the authors explored whether SMOF lipid which is a mixture of lipids (30% soybean oil, 30% medium-chain triglycerides, 25% olive oil, and 15% fish oil) and contains DHA would have a favorable effect on neurocognitive outcomes.
In this study, the authors examined amplitude-integrated electroencephalography measurements (aEEG) to assess neurodevelopment. Both groups received similar lipid dosing, SMOF 2.2 g/day and Soybean 2.1 g/day.
Among the available 121 infants in the subgroup with aEEG (n=63 SMOF, n=58 soybean), maximum maturational scores on aEEG were achieved 2 weeks earlier in the SMOF group (36.4 weeks vs 38.4 weeks, P<.001).
aEEG is a marker of neurocognitive development; however, more adequate outcomes of neurodevelopmental progress are needed. The authors plan to follow these infants up to 5 years of age.
My take: This study is very favorable for the use of SMOF lipids in premature infants. — SMOF lipid emulsion by itself may improve neurocognitive outcomes. In addition, clinicians are more likely to provide adequate amounts of lipid calories with SMOF as compared to soybean emulsion which is often restricted to minimize liver injury. Giving adequate lipid calories is also likely to enhance neurological outcomes.
Related blog posts:
Downside of Lipid Reduction (Nutrition Week Day 1) This study showed that higher lipid intake in a cohort of neonates born at <30 weeks during the first 2 weeks after birth was associated with a lower incidence of brain lesions and dysmaturation when examined by MRI at term equivalent age (TEA).
A recent double-blind randomized study (A Repa et al. J Pediatr 2018; 194: 87-93) compared a mixed lipid emulsion (SMOFlipid) to a soybean-oil lipid in 223 extremely low birth weight infants. Median time on parenteral nutrition was ~23 days.
The primary outcome of parenteral nutrition associated cholestasis (PNAC) was NOT significantly different in the two groups: 10.1% for SMOF and 15.9% for control group (P=.20).
No other outcome measures were affected, including ROP, BPD and growth.
The authors note that even the control group had less cholestasis than previous cohorts and indicated that the use of probiotics and possibly more aggressive enteral feeds were at work.
My take (borrowed in part from authors): These results “cannot be generalized to infants with substantially longer time on PN.” However, this study shows that SMOFlipid alone will not prevent cholestasis, which is well-known to be multifactorial.