Neonatal Intensive Care Unit Mixed Lipid Emulsion Use Associated With Reduced Cholestasis at Discharge in Surgical Patients.

INTRODUCTION: Parenteral nutrition associated cholestasis (PNAC) is a common morbidity in neonates requiring total parenteral nutrition (TPN). Previous studies in infants with intestinal failure have shown a benefit of mixed lipid emulsion (MLE) in reducing PNAC. It is not known whether this benefit extends to a general neonatal intensive care unit (NICU) population, where MLE is used on a selective basis. The objective of this study is to examine associations between MLE use and PNAC rate in the general NICU setting. METHODS: This is a retrospective review of NICU patients who received TPN for 7 or more days. We compared patients born between 1/1/2014 and 12/31/2015 (pre-MLE) to patients born between 7/1/2017 and 12/31/2018 (post-MLE). Fisher's exact test and two-sample t-test were used to compare the two groups. RESULTS: There were 353 patients in 2014-2015 and 271 patients in 2017-2018. Demographics were similar between the two groups, but there were more patients with congenital heart disease in the MLE era (P < 0.001). Mortality was similar (6.2% pre-MLE versus 6.3% post-MLE). There was no significant difference in PNAC rate between the pre-MLE (11.5%) and post-MLE (14.1%) patient cohorts (P = 0.342). Among patients receiving MLE (n = 38), 58% developed PNAC, while only 6.4% of the post-MLE cohort not receiving MLE developed PNAC. Of the patients coded with a surgical diagnosis, there was no significant difference in PNAC rates between pre-MLE and post-MLE groups. Discharge rates of PNAC did differ between pre-MLE surgical patients (13.0%) and post-MLE surgical patients (8.2%). In the subgroup of post-MLE surgical patients, PNAC rate differed significantly between those receiving MLE (43.5%) and not receiving MLE (15.4%). However, this difference was resolved by discharge (8.7% versus 7.7%). CONCLUSIONS: There were no significant differences in PNAC rates between the pre-MLE and post-MLE cohorts. However, in surgical patients, MLE was associated with reduced PNAC at discharge, with levels equivalent to those seen in neonates receiving TPN for 7 or more days, despite having a higher starting rate of PNAC. Further studies are needed to determine whether the general NICU population may benefit from MLE or certain selective subpopulations like surgical patients.

Analysis of risk factors for parenteral nutrition-associated cholestasis in preterm infants: a multicenter observational study.

BACKGROUND: It is proposed that the development of parenteral nutrition-associated cholestasis (PNAC) was significantly associated with preterm birth, low birth weight, infection, etc.; however, the etiology and pathogenesis of PNAC are not fully understood. Most of the studies examining PNAC-associated risk factors were single-center studies with relatively small sample sizes. OBJECTIVE: To analyze the risk factors associated with PNAC in preterm infants in China. METHODS: This is a retrospective multicenter observational study. Clinical data on the effect of multiple oil-fat emulsions (soybean oil-medium chain triglycerides-olive oil-fish oil, SMOF) in preterm infants were collected from a prospective multicenter randomized controlled study. A secondary analysis was performed in which preterm infants were divided into the PNAC group and the non-PNAC group based on the PNAC status. RESULTS: A total of 465 cases very preterm infants or very low birth weight infants were included in the study in which 81 cases were assigned to the PNAC group and 384 cases were assigned to the non-PNAC group. The PNAC group had a lower mean gestational age, lower mean birth weight, longer duration of invasive and non-invasive mechanical ventilation, a longer duration oxygen support, and longer hospital stay (P < 0.001 for all). The PNAC group had higher respiratory distress syndrome, hemodynamically significant patent ductus arteriosus, necrotizing enterocolitis (NEC) with stage II or higher, surgically treated NEC, late-onset sepsis, metabolic bone disease, and extrauterine growth retardation (EUGR) compared to the non-PNAC group (P < 0.05 for all). In contrast with the non-PNAC group, the PNAC group received a higher maximum dose of amino acids and fat emulsion, more medium/long-chain fatty emulsion, less SMOF, had a longer duration of parenteral nutrition, lower rates of breastfeeding, higher incidence of feeding intolerance (FI), more accumulated days to achieve total enteral nutrition, less accumulated days of total calories up to standard 110 kcal/kg/day and slower velocity of weight growth (P < 0.05 for all). Logistic regression analysis indicated that the maximum dose of amino acids (OR, 5.352; 95% CI, 2.355 to 12.161), EUGR (OR, 2.396; 95% CI, 1.255 to 4.572), FI (OR, 2.581; 95% CI, 1.395 to 4.775), surgically treated NEC (OR, 11.300; 95% CI, 2.127 ~ 60.035), and longer total hospital stay (OR, 1.030; 95% CI, 1.014 to 1.046) were independent risk factors for the development of PNAC. SMOF (OR, 0.358; 95% CI, 0.193 to 0.663) and breastfeeding (OR, 0.297; 95% CI, 0.157 to 0.559) were protective factors for PNAC. CONCLUSIONS: PNAC can be reduced by optimizing the management of enteral and parenteral nutrition and reducing gastrointestinal comorbidities in preterm infants.

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OBJECTIVES: To compare the impact of two types of fat emulsion on clinical outcomes in preterm infants with varying duration of parenteral nutrition (PN). METHODS: Preterm infants meeting the inclusion criteria were randomly assigned to two groups: medium/long-chain triglyceride fat emulsion (referred to as MCT/LCT) group or multi-oil fat emulsion (containing soybean oil, medium-chain triglycerides, olive oil, and fish oil; referred to as SMOF) group. The infants were stratified into groups based on the duration of PN (15-21 days, 22-28 days, and ≥29 days). Clinical characteristics, nutritional status, biochemical indicators, and clinical outcomes were compared between the two groups. RESULTS: Compared with the MCT/LCT group, the SMOF group had lower peak levels of triglyceride during the hospital stay in preterm infants with PN of 15-21 days, 22-28 days, and ≥29 days, respectively (P<0.05). Logistic regression trend analysis showed that with a longer duration of PN, the risk of parenteral nutrition-associated cholestasis (PNAC) and bronchopulmonary dysplasia (BPD) significantly increased in the MCT/LCT group (P<0.05), while the risk of brain injury did not significantly change (P>0.05). In the SMOF group, the risks of PNAC and BPD did not significantly change with a longer duration of PN (P>0.05), but the risk of brain injury significantly decreased (P=0.006). CONCLUSIONS: Compared to MCT/LCT, SMOF have better lipid tolerance. With a longer duration of PN, SMOF does not increase the risks of PNAC and BPD and had a protective effect against brain injury. This suggests that in preterm infants requiring long-term PN, the use of SMOF is superior to MCT/LCT.

[Value of the combined use of aminotransferase-to-platelet ratio index and total bile acid for predicting parenteral nutrition-associated cholestasis in preterm infants with gestational age <34 weeks]. / è°·è‰è½¬æ°¨é ¶ä¸Žè¡€å°æ¿æ¯”å€¼æŒ‡æ•°è”åˆæ€»èƒ†æ±é ¸å¯¹èƒŽé¾„<34å‘¨æ—©äº§å„¿è‚ å¤–è¥å »ç›¸å ³æ€§èƒ†æ±æ·¤ç§¯ç—‡çš„é¢„æµ‹ä»·å€¼.

OBJECTIVES: To explore the value of the combined use of aspartate aminotransferase-to-platelet ratio index (APRI) and total bile acid (TBA) for predicting parenteral nutrition-associated cholestasis (PNAC) in preterm infants with gestational age <34 weeks. METHODS: A retrospective analysis was performed on medical data of 270 preterm infants born at <34 weeks of gestation who received parenteral nutrition (PN) during hospitalization in the First Affiliated Hospital of Wannan Medical College from January 2019 to September 2022, including 128 infants with PNAC and 142 infants without PNAC. The medical data between the two groups were compared, and predictive factors for the development of PNAC were explored through multivariate logistic regression analysis. The receiver operating characteristic (ROC) curve was used to evaluate the value of APRI alone, TBA alone, and the combination of both for predicting PNAC. RESULTS: TBA levels in the PNAC group after 1, 2, and 3 weeks of PN were higher than those in the non-PNAC group (P<0.05). APRI in the PNAC group after 2 and 3 weeks of PN was higher than that in the non-PNAC group (P<0.05). Multivariate logistic regression analysis showed that elevated APRI and TBA after 2 weeks of PN were predictive factors for PNAC in preterm infants (P<0.05). ROC curve analysis showed that the sensitivity, specificity, and area under the curve (AUC) for predicting PNAC by combining APRI and TBA after 2 weeks of PN were 0.703, 0.803, and 0.806, respectively. The AUC for predicting PNAC by combining APRI and TBA was higher than that of APRI or TBA alone (P<0.05). CONCLUSIONS: After 2 weeks of PN, the value of combining APRI and TBA for predicting PNAC is high in preterm infants with gestational age <34 weeks.

Prediction, identification and progression of histopathological liver disease activity in children with intestinal failure.

BACKGROUND & AIMS: Diagnostic criteria, progression risk and optimal monitoring for intestinal failure (IF)-associated liver disease (IFALD) remain undefined. We assessed predictors, non-invasive markers and progression of histopathological liver disease in patients with IF. METHODS: In total, 77 children with IF and median age of 1.7 years underwent diagnostic liver biopsy, which was repeated in 48 patients after 2.9 years with simultaneous evaluation of liver biochemistry, liver stiffness, serum citrulline (a surrogate for viable enterocyte mass), spleen size, esophageal varices and clinical data. Patients were staged according to histopathological liver disease activity: active IFALD (cholestasis and/or inflammation), chronic IFALD (significant fibrosis and/or steatosis), or no IFALD (none of these features). RESULTS: Diagnostic liver biopsy revealed active, chronic or no IFALD in 48%, 21% and 31% of patients. Active IFALD was segregated by low serum citrulline, parenteral nutrition (PN) dependency and young age, while weaning off PN and older age predicted chronic IFALD. Although the liver histopathology in most patients either normalized (52%) or transformed to a less reactive (chronic) disease stage (23%), 19% of patients retained and 6.3% progressed to an active cholestatic/inflammatory IFALD phenotype. Decreased serum citrulline and PN-dependency also predicted active IFALD in follow-up biopsies. Increased median liver biochemistry values and liver stiffness only associated with active IFALD, which was accurately identified by gamma-glutamyltransferase (GGT), citrulline and liver stiffness, their combinations reaching diagnostic and follow-up AUROC values above 0.90. CONCLUSIONS: Active IFALD, essentially predicted by intestinal disruption and PN-dependency, was accurately detected by GGT, liver stiffness and citrulline, which together with recent advances in clinical management options, provides new avenues for monitoring and targeted liver protection in patients with IF. LAY SUMMARY: Liver disease is a common and critical complication in patients with intestinal failure, who require intravenous nutrition for survival due to severe intestinal dysfunction. We showed that both intravenous nutrition dependency and intestinal disruption essentially predicted development of active histopathological liver disease, which persisted in 25% of patients during long-term follow-up and could be accurately detected without the need for liver biopsy. Identification of the active and potentially progressive histopathology offers new possibilities for monitoring and targeted liver protection in patients with intestinal failure.

Risk factors of parenteral nutrition-associated cholestasis in very-low-birthweight infants.

AIM: We aimed to explore risk factors associated with parenteral nutrition-associated cholestasis (PNAC) in very-low-birthweight (VLBW) infants. METHODS: VLBW infants receiving parenteral nutrition (PN) for at least 14 days were enrolled in a retrospective dual-centre study and divided into two groups chronologically: group A (2000-2007) and group B (2008-2015). The incidence of PNAC and related factors were investigated. We compared the differences between PNAC and non-PNAC groups. A multivariate binary logistic regression analysis was carried out to identify the potential risk factors of PNAC. RESULTS: A total of 387 VLBW infants (53 in group A and 334 in group B) were enrolled in the study. The total incidence of PNAC was 6.7%, 9.4% in group A and 6.3% in group B. The dosage of amino acid (P = 0.009), glucose (P = 0.006), PN calories (P = 0.021) and the ratio of glucose/fat (P = 0.014) were significantly higher in group B than in group A. Non-protein energy to nitrogen ratio (P = 0.017) was lower in group B. Birthweight was significantly lower in the PNAC group than in the non-PNAC group (P = 0.021). Subgroup analysis showed that gestational age and duration of PN were significantly different between the PNAC and non-PNAC groups (P < 0.05). Logistic regression showed that prolonged duration of PN (≥43 days) (odds ratio 3.155, 95% confidence interval 1.009-9.861, P = 0.048) was an independent risk factor of PNAC. CONCLUSIONS: For VLBW infants, prolonged duration of PN is a risk factor for the development of PNAC. PNAC may be prevented by weaning off PN as early as possible in VLBW infants.

Predictive value of the aspartate aminotransferase to platelet ratio index for parenteral nutrition associated cholestasis in extremely low birth weight infants.

BACKGROUND: Parenteral nutrition (PN) improves the survival of premature infants. However, prolonged PN increases the risk of PN-associated cholestasis (PNAC). OBJECTIVE: We aimed to evaluate the predictive value of aspartate aminotransferase (AST)-to-platelet ratio index (APRI) for PNAC in infants with extremely low birth weight (ELBW, birth weight < 1000 g) infants. METHODS: We retrospectively reviewed the medical records of ELBW infants from March 2010 to February 2017. Clinical data and the serial APRI, AST, alanine aminotransferase (ALT), AST-to-ALT ratio, and direct bilirubin (DB) were analyzed. PNAC was diagnosed in infants with a history of PN for at least 2 weeks and direct bilirubin concentrations > 2 mg/dL after other causes of neonatal cholestasis were excluded. RESULTS: Among the 179 eligible ELBW infants, 56 (31.3%) were diagnosed with PNAC. APRI significantly differed between infants with PNAC and those without PNAC. The best APRI cut-off point was 0.410 at 2 weeks after the start of PN (area under the receiver operating characteristic curve = 0.752, p < 0.05; positive predictive value, 50.6%; negative predictive value, 84.1%). CONCLUSION: APRI at 2 weeks after PN could be a reliable predictor of PNAC development in ELBW infants on PN.

Intravenous Lipid Emulsions in Infants: Is Balanced Better?

Parenteral nutrition (PN) is frequently required by extremely preterm infants due to gastrointestinal immaturity and complications of prematurity. Parenteral nutrition-associated cholestasis (PNAC) and intestinal failure-associated liver disease (IFALD) are common complications of prolonged PN. Plant-based intravenous lipid emulsions, containing proinflammatory omega-6 fatty acids and phytosterols, may contribute to these conditions as well as other comorbidities such as bronchopulmonary dysplasia and retinopathy of prematurity. Intravenous lipid emulsions containing animal-based fats, such as fish oil, contain fewer proinflammatory omega-6 fatty acids and more anti-inflammatory omega-3 fatty acids and antioxidants. SMOFlipid, recently Food and Drug Administration (FDA)-approved for adult use, is a blend of plant- and animal-based lipid emulsions with a favorable omega-6:omega-3 ratio that may prevent the development and progression of PNAC/IFALD in infants. Careful review of data supporting this alternative intravenous lipid emulsion is required prior to widespread use in neonatal intensive care.

Risk factor analysis of parenteral nutrition-associated cholestasis in extremely low birth weight infants.

AIM: Parenteral nutrition (PN) provides an alternative nutrition source for preterm infants who are intolerant of enteral nutrition. However, prolonged PN increases the risk of PN-associated cholestasis (PNAC). We conducted this study to determine the incidence and risk factors of PNAC in extremely low birth weight (ELBW) infants. METHODS: We retrospectively reviewed the medical records of ELBW infants from March 2010 to April 2015. PNAC was diagnosed in infants with a history of PN for at least two weeks and direct bilirubin concentrations >2 mg/dL after other causes of neonatal cholestasis were excluded. RESULTS: Of the 114 eligible ELBW infants, 41 (36%) were diagnosed with PNAC. The multivariate analysis showed that birth weight, sepsis, necrotising enterocolitis, fluconazole prophylaxis and the duration of PN and hospitalisation were independent risk factors for the development of PNAC (p < 0.05). However, parenteral fish oil-based lipid preparation (FOLP) did not reduce the risk of PNAC. Although PNAC was not a direct cause of death, it was associated with an increased risk of mortality. CONCLUSION: PNAC was common in ELBW infants, was associated with various clinical factors and increased the risk of mortality. However, we did not observe the protective effect of FOLP against PNAC.

Parenteral fish oil-containing lipid emulsions may reverse parenteral nutrition-associated cholestasis in neonates: a systematic review and meta-analysis.

BACKGROUND: Growing evidence indicates that fish oil-containing lipid emulsions have a beneficial effect on parenteral nutrition-associated cholestasis (PNAC) in adults; however, data are limited in neonates regarding the effect of fish oil on PNAC. OBJECTIVE: We conducted a meta-analysis of studies that addressed the effect of fish oil-containing lipid emulsions on reversing and preventing PNAC. METHODS: We searched PubMed, the EMBASE database, and the Cochrane Library for this systematic review and meta-analysis. The methodologic assessment of studies was performed with the Jadad scale and the Newcastle-Ottawa Scale. Comprehensive Met-Analysis version 2.0 was used for the statistical analysis. We performed a meta-analysis with the primary outcomes of reversal of PNAC and the occurrence of PNAC in newborn infants, including preterm infants, after parenteral administration of fish oil-containing lipid emulsions. RESULTS: Of the 36 studies identified, 7 fulfilled the inclusion criteria and were used in this meta-analysis, including 3 studies with 93 participants in which reversal of PNAC was an outcome and 4 studies with 1012 participants on preventing PNAC. The use of fish oil-containing lipid emulsions was more likely to reverse PNAC (OR: 6.14; 95% CI: 2.27, 16.6; P < 0.01), but the use of fish oil-containing lipid emulsions did not have a significant effect on the development of PNAC (OR: 0.56; 95% CI: 0.28, 1.10; P = 0.09) compared with soybean-based or olive oil-based lipid emulsions. CONCLUSIONS: The pooled data suggest that the use of fish oil-containing lipid emulsions is effective for reversing PNAC but cannot prevent PNAC in neonates who require prolonged parenteral nutritional support.

Home Parenteral Nutrition for Children: What Are the Factors Indicating Dependence and Mortality?

Parenteral nutrition (PN) in children with short bowel syndrome is crucial and lifesaving. Taking care of such patients requires interprofessional practice and multiple team resource management. Home PN (HPN) usage allows patients and families to live regular lives outside hospitals. We share our experiences for the last two decades and identify the risk factors for complications and mortality. A retrospective study of HPN patients was conducted between January 2000 and February 2022. Medical records of age, body weight, diagnosis, length of residual intestines, HPN period, central line attempts, complications, weaning, and survival were collected and analyzed. The patients were classified as HPN free, HPN dependent, and mortality groups. A total of 25 patients received HPN at our outpatient clinic, and one was excluded for the adult age of disease onset. There were 13 patients (54.1%) who were successfully weaned from HPN until the record-enroled date. The overall mortality rate was 20.8% (five patients). All mortality cases had prolonged cholestasis, Child Class B or C, and a positive Pediatric End-Stage Liver Disease (PELD) score. For HPN dependence, extended resection and multiple central line placement were two significant independent factors. Cholestasis, Child Class B or C, and positive PELD score were the most important risk factors for mortality. The central line-related complication rate was not different in all patient groups. The overall central line infection rate was 1.58 per 1000 catheter days. Caution should be addressed to prevent cholestasis and intestinal failure-associated liver disease during the HPN period, to prevent mortality. By understanding the risks of HPN dependence and mortality, preventive procedures could be addressed earlier.

Neurodevelopmental Outcome of Extremely Low Birth Weight Infants with Cholestasis at 12 and 24 Months.

INTRODUCTION: The aims of the study were to describe the neurodevelopmental outcome of extremely low birth weight (ELBW) infants with parenteral nutrition-associated cholestasis (PNAC) and to assess whether PNAC is associated with adverse neurodevelopmental outcome. METHODS: The study is a secondary analysis of controlled trial (June 2012-October 2017) on PNAC incidence in ELBW infants receiving two different parenteral lipid emulsions (mixed lipid emulsion containing fish oil vs. soybean oil-based). Neurodevelopmental follow-up at 12- and 24-month corrected age was compared in infants with and without PNAC. A machine learning-based regression analysis was used to assess whether PNAC was associated with adverse neurodevelopmental outcome. RESULTS: For assessment of neurodevelopmental outcome (Bayley-III), 174 infants were available at 12-month (PNAC: n = 21; no PNAC: n = 153) and 164 infants at 24-month (PNAC: n = 20; no PNAC: n = 144) corrected age. The neurodevelopment of ELBW infants with PNAC was globally delayed, with significantly lower cognitive, language, and motor scores at both 12- and 24-month corrected age. Regression analyses revealed that PNAC was associated with an adverse motor outcome. CONCLUSION: ELBW infants with PNAC are at increased risk for adverse neurodevelopmental outcome.

Mdr3 gene mutation in preterm infants with parenteral nutrition-associated cholestasis.

To investigate the relationship of multidrug resistance 3 (Mdr3) gene mutation and parenteral nutrition-associated cholestasis (PNAC) in preterm infants. Preterm infants who had received total parenteral nutrition for at least 14 days were enrolled: 76 preterm infants in the PNAC group and 80 preterm infants in the non-PNAC group. Genomic DNA was extracted from white blood cells. Twenty-eight exons of the Mdr3 gene were amplified by polymerase chain reaction. PNAC infants of 1 month corrected age with the Mdr3 gene mutation and abnormal liver biochemistry were selected for the experimental liver biopsy group. Five normal adult living liver transplantation donors were enrolled in a normal donor group. The Mdr3 missense mutations c.1031G>A, c.3347G>A, and c.485T>A, and the Mdr3 frameshift mutation c.2793_2794insA were found in the PNAC group. The allele frequency and genotype frequency of c.1031G>A, c.3347G>A, and c.485T>A in the Mdr3 gene in the PNAC group were significantly higher than those in non-PNAC group (p < 0.05). The rate of Mdr3 gene mutations c.1031G>A, c.485T>A, c.3347G>A, and c.2793_2794insA in the PNAC group was higher than in the non-PNAC group (21.05% vs. 1.25%, respectively, χ2  = 15.747, p < 0.05). Mdr3 gene mutations c.2793_2794insA, c.1031G>A, c.3347G>A, and c.485T>A may be the genetic cause of PNAC.

Dexamethasone may affect the occurrence of parenteral nutrition-associated cholestasis in preterm neonates.

Introduction: Glucocorticoids are currently used for the co-therapeutic management of autoimmune hepatitis and some cholestatic diseases. Thus far, we do not know the efficacy of glucocorticoids in the treatment of parenteral nutrition-associated cholestasis. We aimed to analyze whether the administration of late postnatal dexamethasone for treating bronchopulmonary dysplasia influence the occurrence of parenteral nutrition-associated cholestasis in preterm neonates. Methods: A retrospective study was conducted for 78 preterm neonates without major anomalies (gestational age was <30 weeks, and birthweight was ≤1000 g) hospitalized in a neonatal unit. Total and direct serum bilirubin levels were measured about every two weeks for all neonates. Data including the administration of dexamethasone, intravenous nutrition, and enteral feeding were collected by at least three audits. Results: A total of 15 preterm neonates were diagnosed with parenteral nutrition-associated cholestasis, and after stopping parenteral nutrition, the direct bilirubin value decreased to the normal level for no longer than 150 days. The prolonged duration of parenteral nutrition was a risk factor, and late postnatal dexamethasone treatment was a protective factor in reducing the incidence of parenteral nutrition-associated cholestasis. Conclusion: Dexamethasone treatment may reduce the occurrence of parenteral nutrition-associated cholestasis in preterm neonates.

Depletion and enrichment of phytosterols in soybean oil lipid emulsions directly associate with serum markers of cholestasis in preterm parenteral nutrition-fed pigs.

BACKGROUND: Clinical reports show a positive correlation between phytosterol concentrations and severity of cholestatic liver disease markers in infants during long-term administration of parenteral lipid emulsions. Establishing a causal link between phytosterols and cholestasis has been complicated by confounding factors of lipid emulsion load, fatty acid composition, and vitamin E in many of these studies. The goal of this study is to determine whether altering the phytosterol concentration within a common soybean oil-based emulsion will alter the onset and severity of cholestasis in parenterally fed preterm piglets. METHODS: Preterm piglets were administered, for 21 days, either enteral nutrition (ENT) or parenteral nutrition (PN) prepared from a soybean oil-based emulsion containing either 24.0% (depleted [DEP]), 100% (Intralipid; normal phytosterol [NP] concentration), or 144% (enriched [ENR]) total phytosterol concentration. RESULTS: At the end of the study, plasma and liver phytosterol concentrations were highest in the ENR group, followed by NP and then DEP and ENT. Serum direct bilirubin, serum bile acids, and γ-glutamyltransferase were higher in the ENR and NP groups compared with either DEP or ENT groups. All PN lipid groups showed evidence of mild hepatic steatosis but no change in hepatic expression of proinflammatory cytokines or Farnesoid X receptor target genes. CONCLUSION: The increase in serum direct bilirubin was lower in the DEP group vs the lipid emulsions with normal or ENR phytosterols. Our results provide additional evidence that phytosterols are linked to an increase in serum markers of cholestasis in preterm PN-fed pigs.

Fecal sphingolipids predict parenteral nutrition-associated cholestasis in the neonatal intensive care unit.

BACKGROUND: Parenteral nutrition-associated cholestasis (PNAC) in the neonatal intensive care unit (NICU) causes significant morbidity and associated healthcare costs. Laboratory detection of PNAC currently relies on elevated serum conjugated bilirubin levels in the aftermath of impaired bile flow. Here, we sought to identify fecal biomarkers, which when integrated with clinical data, would better predict risk for developing PNAC. METHODS: Using untargeted metabolomics in 200 serial stool samples from 60 infants, we applied statistical and machine learning approaches to identify clinical features and metabolic biomarkers with the greatest associative potential for risk of developing PNAC. Stools were collected prospectively from infants receiving PN with soybean oil-based lipid emulsion at a level IV NICU. RESULTS: Low birth weight, extreme prematurity, longer duration of PN, and greater number of antibiotic courses were all risk factors for PNAC (P < 0.05). We identified 78 stool biomarkers with early predictive potential (P < 0.05). From these 78 biomarkers, we further identified 12 sphingomyelin lipids with high association for the development of PNAC in precholestasis stool samples when combined with birth anthropometry. CONCLUSION: We demonstrate the potential for stool metabolomics to enhance early identification of PNAC risk. Earlier detection of high-risk infants would empower proactive mitigation with alterations to PN for at-risk infants and optimization of energy nutrition with PN for infants at lower risk.

Fish oil-containing lipid emulsions prevention on parenteral nutrition-associated cholestasis in very low birth weight infants: a meta-analysis.

BACKGROUND: The effect of fish oil-containing lipid emulsions on preventing parenteral nutrition-associated cholestasis (PNAC) in very low birth weight (VLBW) infants is not known. Thus, we conducted a meta-analysis to identify any prevention effect. METHODS: PubMed, EMBASE, and CENTRAL were searched up to 26 January 2021 for studies related to the preventive effect of fish oil-containing lipid emulsions and fish oil-free lipid emulsions on cholestasis in VLBW infants. Revman 5.3 was used to synthesize the results. A fixed-effect model was used to summarize the data when the heterogeneity was non-significant (I2 < 50%), and a random-effects model was used when the heterogeneity was significant (I2 > 50%). RESULTS: Of 728 articles, 11 randomized controlled trials met the inclusion criteria. The meta-analysis indicated that fish oil-containing lipid emulsion reduced the occurrence of PNAC significantly with risk ratio (RR) = 0.53, 95% confidence interval (CI) 0.36-0.80, P = 0.002. The heterogeneity was non-significant with I2 = 23%. Subgroup analysis based on parenteral nutrition duration and median birth weight was performed. The synthesis results for patients with parenteral nutrition duration exceeding 14 days revealed I2 = 35% (P = 0.15) and pooled RR = 0.47, 95% CI 0.30-0.73, P = 0.0008; and for patients with duration less than 14 days revealed I2 = 0% (P = 0.72) and pooled RR = 1.14, 95% CI 0.39-3.35, P = 0.81. The synthesis for patients with birth weight more than 1000 g revealed I2 = 0% (P = 0.41) and pooled RR = 0.55, 95% CI 0.26-1.18, P = 0.12; and for patients with birth weight below 1000 g revealed I2 = 44% (P = 0.11) and pooled RR = 0.53, 95% CI 0.33-0.85, P = 0.009. CONCLUSIONS: The fish oil-containing lipid emulsion can reduce the occurrence of PNAC in VLBW infants based on the available original randomized controlled trial studies, especially for patients with parenteral nutrition duration exceeding 14 days and extremely low birth weight infants. Future studies should be performed before a definitive conclusion can be established.

Growth of Head Circumference and Body Length in Preterm Infants Receiving a Multicomponent vs a Soybean-Based Lipid Emulsion: A Randomized Controlled Trial.

BACKGROUND: The growth of very low-birth-weight (VLBW) infants relies, to a large extent, on parenteral nutrition (PN) during the early weeks of life. Despite the parenteral nutrients supply, extrauterine growth restriction remains the main concern for these infants. A parenteral multicomponent lipid emulsion (MLE) might improve growth and neurological outcomes, delivering fats for brain growth that the traditional soybean-based lipid emulsion (SLE) fails to provide. We hypothesize that the use of an MLE in PN may reduce the loss of head circumference (HC) z-score from birth to 36 weeks' postmenstrual age (PMA) or at discharge compared with the use of an SLE in VLBW infants. METHODS: Infants with BW ≤1250 g, without malformations or chromosomal abnormalities, were randomly assigned to receive an MLE or an SLE. The primary outcome was the change in HC z-score (HC Δ z-score) from birth to 36 weeks' PMA or at discharge. Secondary outcomes included the change in weight and length z-score (W Δ z-score and L Δ z-score) as well as incidence of late-onset sepsis and PN-associated cholestasis (PNAC). RESULTS: Of the 128 infants randomized, 51 infants in the MLE group and 50 infants in the SLE group were analyzed. The MLE was significantly associated with a decreased loss in HC and length z-scores from birth to 36 weeks' PMA or at discharge. CONCLUSIONS: This is the first randomized controlled trial providing the evidence that an MLE is associated with improved HC growth in comparison with a pure SLE.

Intravenous Lipid Emulsions in the Prevention and Treatment of Liver Disease in Intestinal Failure.

The development of intestinal failure-associated liver disease (IFALD) in pediatric and adult patients on parenteral nutrition is usually multifactorial in nature due to nutritional and non-nutritional causes. The role of lipid therapy as a contributing cause is well-established with the pathophysiological pathways now better understood. The review focuses on risk factors for IFALD development, biological effects of lipids, lipid emulsions and the mechanisms of lipid toxicity observed in laboratory animals followed by a synopsis of clinical studies in pediatric and adult patients. The introduction of fish oil-based lipid emulsions that provide partial or complete lipid replacement therapy has resulted in resolution of IFALD that had been associated with soybean oil-based therapy. Based on case reports and cohort studies in pediatric and adult patients who were at risk or developed overt liver disease, we now have more evidence that an early switch to partial or complete fish oil-based lipid therapy should be implemented in order to successfully halt and reverse IFALD.

Intestinal failure-associated liver disease (IFALD): insights into pathogenesis and advances in management.

Premature infants and children with intestinal failure (IF) or short bowel syndrome are susceptible to intestinal failure-associated liver disease (IFALD, previously referred to as parenteral nutrition-associated liver disease, or PNALD). IFALD in children is characterized by progressive cholestasis and biliary fibrosis, and steatohepatitis in adults, and is seen in individuals dependent upon prolonged administration of PN. Many factors have been proposed as contributing to the pathogenesis of IFALD. In recent years, the focus has been on the potential synergistic roles of the intestinal microbiome, increased intestinal permeability, activation of hepatic innate immune pathways, and the use of intravenous soybean-oil-based intravenous lipid emulsions (SO-ILE). In vitro and in vivo studies have identified stigmasterol, a component of the plant sterols present in SO-ILE, as playing an important role. Although various strategies have been adopted to prevent or reverse IFALD, most suffer from a lack of strong evidence supported by well-designed, prospective clinical trials with clearly defined endpoints. Reduction in the amount of SO-ILEs or replacement with non-SO-ILEs has been shown to reverse IFALD although safety and long-term effectiveness have not been studied. Medical and surgical modalities to increase intestinal adaptation, advance enteral feedings, and prevent central line bloodstream infections are also important preventative strategies. There is a continued need to conduct high-quality, prospective trials with clearly define outcome measures to ascertain the potential benefits of these strategies.