Kara L. Calkins

Fetal Origins of Adult Disease

Dr. David Barker first popularized the concept of fetal origins of adult disease (FOAD). Since its inception, FOAD has received considerable attention. The FOAD hypothesis holds that events during early development have a profound impact on ones risk for development of future adult disease. Low birth weight, a surrogate marker of poor fetal growth and nutrition, is linked to coronary artery disease, hypertension, obesity, and insulin resistance. Clues originally arose from large 20th century, European birth registries. Today, large, diverse human cohorts and various animal models have extensively replicated these original observations. This review focuses on the pathogenesis related to FOAD and examines Dr. David Barkers landmark studies, along with additional human and animal model data. Implications of the FOAD extend beyond the low birth weight population and include babies exposed to stress, both nutritional and nonnutritional, during different critical periods of development, which ultimately result in a disease state. By understanding FOAD, health care professionals and policy makers will make this issue a high health care priority and implement preventive measures and treatment for those at higher risk for chronic diseases.

Pediatric Intestinal Failure–Associated Liver Disease Is Reversed With 6 Months of Intravenous Fish Oil

BACKGROUND Studies have suggested that when intravenous (IV) soybean oil (SO) is replaced with fish oil (FO), direct hyperbilirubinemia is more likely to resolve. The necessary duration of FO has not been established. This study seeks to determine if 24 weeks of FO is an effective and safe therapy for intestinal failure-associated liver disease (IFALD). MATERIALS AND METHODS This is a clinical trial using patients with IFALD between the ages of 2 weeks and 18 years. SO was replaced with FO (1 g/kg/d) in 10 patients who were receiving most of their calories from parenteral nutrition (PN). Patients were compared with 20 historic controls receiving SO. SO for both groups was prescribed by the primary medical team at variable doses. The primary outcome was time to reversal of cholestasis. Secondary outcomes were death, transplant, and full enteral feeds. Safety measurements included growth, essential fatty acid deficiency, and laboratory markers to assess bleeding risk. RESULTS The Kaplan-Meier method estimated that 75% in the FO group would experience resolution of cholestasis by 17 weeks vs 6% in the SO group (P < .0001). When compared with the SO group, the FO group had decreased serum direct bilirubin concentrations at weeks 8 (P = .03) and 12, 16, 20, and 24 weeks (P < .0001). Although length z score at the end of the study increased in the FO group compared with baseline (P = .03), there were no significant differences in other outcomes. CONCLUSIONS A limited duration of FO appears to be safe and effective in reversing IFALD.

Complications Associated with Parenteral Nutrition in the Neonate

Although parenteral nutrition (PN) is life-sustaining, it is associated with many complications including parenteral nutrition-associated liver disease (PNALD) and central line-associated bloodstream infections (CLASBIs), which carry a high morbidity and mortality and impose a burden on the health care system. Evidence has emerged that the dose and composition of intravenous lipid products may alter the incidence of PNALD. However, other patient and PN-related factors, such as prematurity, birth weight, and gastrointestinal anatomy and function, are important. To improve neonatal care, future research on optimizing the content of PN and decreasing the incidence IFALD and CLASBIs is required.

The impact of intravenous fish oil emulsions on pediatric intestinal failure-associated liver disease.

Purpose of reviewTo provide an overview of how intravenous omega-3 fatty acids (O3FAs) have been used to prevent and treat pediatric intestinal failure-associated liver disease (IFALD). This review will introduce the most recent and relevant human and basic science data on the topic, and comment on how alterative lipid emulsions may alter the future course of children with IFALD. Recent findingsAnimal and cohort studies along with case reports have reported that Omegaven (Fresenius Kabi, Bad Homburg vdh, Germany), which contains high concentrations of O3FAs, can reverse IFALD and prevent the need for combined liver-intestinal transplantation and death. Laboratory work and human data support that O3FAs increase antioxidant activity and biliary flow and decrease inflammation and de-novo lipogenesis. Many postulate that intravenous O3FAs may positively affect cognitive function, immune status, nutrition, and intestinal adaptation and decrease the risk of adult-onset chronic diseases. Although evidence continues to mount to support the use of parenteral O3FA products, questions remain. SummaryO3FAs have altered the way in which basic scientists and clinicians approach IFALD. Knowledge gaps, however, still exist before this therapy can be considered standard of care.

Low-Dose Intravenous Soybean Oil Emulsion for Prevention of Cholestasis in Preterm Neonates

BACKGROUND Premature infants depend on intravenous fat emulsions to supply essential fatty acids and calories. The dose of soybean-based intravenous fat emulsions (S-IFE) has been associated with parenteral nutrition (PN)-associated liver disease. This studys purpose was to determine if low-dose S-IFE is a safe and effective preventive strategy for cholestasis in preterm neonates. MATERIALS AND METHODS This is a multicenter randomized controlled trial in infants with a gestational age (GA) ≤29 weeks. Patients <48 hours of life were randomized to receive a low (1 g/kg/d) or control dose (approximately 3 g/kg/d) of S-IFE. The primary outcome was cholestasis, defined as a direct bilirubin ≥15% of the total bilirubin at 28 days of life (DOL) or full enteral feeds, whichever was later, after 14 days of PN. Secondary outcomes included growth, length of hospital stay, death, and major neonatal morbidities. RESULTS In total, 136 neonates (67 and 69 in the low and control groups, respectively) were enrolled. Baseline characteristics were similar for the 2 groups. When the low group was compared with the control group, there was no difference in the primary outcome (69% vs 63%; 95% confidence interval, -0.1 to 0.22; P = .45). While the low group received less S-IFE and total calories over time compared with the control group (P < .001 and P = .03, respectively), weight, length, and head circumference at 28 DOL, discharge, and over time were not different (P > .2 for all). CONCLUSION Compared with the control dose, low-dose S-IFE was not associated with a reduction in cholestasis or growth.

Does hospital transfer predict mortality in very low birth weight infants requiring surgery for necrotizing enterocolitis

BACKGROUND Necrotizing enterocolitis (NEC) is a leading cause of infant mortality, and the most common reason for emergent surgery in very low birth weight (VLBW, < 1,500 g) infants. We investigated whether transfer for higher level of surgical care affects mortality in this population. METHODS VLBW infants who underwent NEC surgery were reviewed retrospectively from the California Patient Discharge Linked Birth Cohort Database (1999-2007). Transfer for emergent operation was defined as surgery ≤2 days after transfer. Mortality was analyzed with multivariate logistic regression. RESULTS Overall, 1,272 VLBW infants with surgical NEC were identified, with a 39% mortality. Transfer for operative care occurred in 406 (32%) infants. Unadjusted mortality was not increased for infants who were transferred compared with not transferred (37% vs. 40%; P = .25). Adjusted mortality for infants transferred for operative care did not differ from those who received operative care at their primary neonatal intensive care unit (odds ratio 0.75, 95% confidence interval 0.42-1.32). Lower birth weight, lack of prenatal care, peritoneal drainage as sole surgical intervention, and pulmonary interstitial emphysema/pulmonary hemorrhage were associated with increased odds of mortality (P < .05). CONCLUSION VLBW infants with surgical NEC do not demonstrate increased risk of mortality when transferred emergently for operative care. Future efforts must engage health professionals caring for this vulnerable population to maximize resource allocation and safety.

Low-Dose Parenteral Soybean Oil for the Prevention of Parenteral Nutrition–Associated Liver Disease in Neonates With Gastrointestinal Disorders A Multicenter Randomized Controlled Pilot Study

Background: Neonates with gastrointestinal disorders (GDs) are at high risk for parenteral nutrition–associated liver disease (PNALD). Soybean-based intravenous lipid emulsions (S-ILE) have been associated with PNALD. This study’s objective was to determine if a lower dose compared with a higher dose of S-ILE prevents cholestasis without compromising growth. Materials and Methods: This multicenter randomized controlled pilot study enrolled patients with GDs who were ⩽5 days of age to a low dose (~1 g/kg/d) (LOW) or control dose of S-ILE (~3 g/kg/d) (CON). The primary outcome was cholestasis (direct bilirubin [DB] >2 mg/dL) after the first 7 days of age. Secondary outcomes included growth, PN duration, and late-onset sepsis. Results: Baseline characteristics were similar between the LOW (n = 20) and CON groups (n = 16). When the LOW group was compared with the CON group, there was no difference in cholestasis (30% vs 38%, P = .7) or secondary outcomes. However, mean ± SE DB rate of change over the first 8 weeks (0.07 ± 0.04 vs 0.3 ± 0.09 mg/dL/wk, P = .01) and entire study (0.008 ± 0.03 vs 0.2 ± 0.07 mg/dL/wk, P = .02) was lower in the LOW group compared with the CON group. Conclusion: In neonates with GDs who received a lower dose of S-ILE, DB increased at a slower rate in comparison to neonates who received a higher dose of S-ILE. Growth was comparable between the groups. This study demonstrates a need for a larger, randomized controlled trial comparing 2 different S-ILE doses for cholestasis prevention in neonates at risk for PNALD.

Effect of High-Dose Cysteine Supplementation on Erythrocyte Glutathione A Double-Blinded, Randomized Placebo-Controlled Pilot Study in Critically Ill Neonates

BACKGROUND This studys objective was to determine if parenteral cysteine when compared with isonitrogenous noncysteine supplementation increases erythrocyte reduced glutathione (GSH) in neonates at high risk for inflammatory injury. MATERIAL AND METHODS Neonates with a score for neonatal acute physiology >10 requiring mechanical ventilation and parenteral nutrition (PN) were randomized in a double-blinded, placebo-controlled study to receive parenteral cysteine-HCl (CYS group) or additional PN amino acids (ISO group) at 121 mg/kg/d for ≥7 days. A 6-hour [(13)C2] glycine IV infusion was administered at study week 1 to determine the fractional synthetic rate of GSH (FSR-GSH). RESULTS Baseline characteristics were similar between the CYS (n = 17) and ISO groups (n = 21). Erythrocyte GSH and total glutathione concentrations, GSH:oxidized GSH (GSSG), and FSR-GSH after treatment were not different between groups. However, the CYS group had a larger individual positive change in GSH and total glutathione (infusion day - baseline) compared with the ISO group (P = .02 for each). After adjusting for treatment, a lower enrollment weight and rate of red blood cell transfusion were associated with a decreased change in total glutathione and GSH (P < .05 for each). CONCLUSION When compared with isonitrogenous noncysteine supplementation, high-dose cysteine supplementation for at least 1 week in critically ill neonates resulted in a larger and more positive individual change in GSH. Smaller infants and those who received transfused blood demonstrated less effective change in GSH with cysteine supplementation. The benefit of cysteine remains promising and deserves further investigation.

Short-term intravenous fish oil and pediatric intestinal failure associated liver disease: 3-year follow-up on liver function and nutrition

Intravenous fish oil (FO) has changed the management of intestinal failure associated liver disease (IFALD). This report describes two IFALD patients who received FO for 5 and 10 months, respectively and reports on their 3-year follow-up.

Intravenous Fish Oil and Pediatric Intestinal Failure–Associated Liver Disease: Changes in Plasma Phytosterols, Cytokines, and Bile Acids and Erythrocyte Fatty Acids:

BACKGROUND Soybean oil (SO) emulsions are associated with intestinal failure-associated liver disease (IFALD); fish oil (FO) emulsions are used to treat IFALD. SO and FO differ with respect to their fatty acid and phytosterol content. In children with IFALD whose SO was replaced with FO, we aimed to (1) quantify changes in erythrocyte fatty acids and plasma phytosterols, cytokines, and bile acids and (2) correlate these changes with direct bilirubin (DB). DESIGN This study enrolled IFALD children who received 6 months of FO. Blood samples were collected prior to FO, and after 2 weeks and 3 and 6 months of FO. The primary outcome was 3-month vs baseline biomarker concentrations. RESULTS At study initiation, the median patient age was 3 months (interquartile range, 3-17 months), and mean ± standard deviation DB was 5.6 ± 0.7 mg/dL (n = 14). Cholestasis reversed in 79% of subjects. Eicosapentaenoic and docosahexaenoic acid was greater than baseline (P < .001, all time points). Linoleic and arachidonic acid and sitosterol and stigmasterol were less than baseline (P < .05, all time points). Three- and 6-month interleukin-8 (IL-8) and total and conjugated bile acids were less than baseline (P < .05). Baseline IL-8 was correlated with baseline DB (r = 0.71, P < .01). Early changes in stigmasterol and IL-8 were correlated with later DB changes (r = 0.68 and 0.75, P < .05). CONCLUSION Specific fat emulsion components may play a role in IFALD. Stigmasterol and IL-8 may predict FO treatment response.