Circadian Sinusoidal Infusions of Total Parenteral Nutrition Are Well Tolerated and Alter Macronutrient Utilization in Mice: Pilot Data

Objectives: Total Parenteral Nutrition (TPN) is a lifesaving therapy providing intravenous nutrition when enteral use is contraindicated. Prolonged TPN can induce hepatic complications (i.e., PN associated liver dysfunction [PNALD]) affecting 40% of patients. TPN is often infused at a steady rate which contributes to PNALD. Restricting TPN infusion to the evening can delay the condition, raising the possibility that specific infusion patterns may prevent PNALD. We hypothesized that, compared to steady-rate infusions, a sinusoidal infusion schedule matched to diurnal consumption patterns in mice, would attenuate PNALD. Methods: 17 male C57B/6 mice aged 9-11 weeks were randomly assigned to 3 groups: chow (n=5), steady rate (n=6), and sinusoidal (n=6). The jugular vein was cannulated with 0.12 mm diameter silicon catheter attached to TPN syringe on a programmable pump. Mice were housed in a metabolic chamber (Promethion Core, Sable Systems International, Las Vegas NV) at 30°C and infused with 5.5 mL/d of TPN formula (21.5% dextrose, 5.6% amino acids, 2% Intralipid-20) at a steady or sinusoidal rate for 5 days. Mice were euthanized and tissues were weighed, processed, and snap frozen. Average daily respiratory exchange rate (RER) was extracted for analysis and qPCR was conducted on hepatic metabolic targets. Results: Two-way ANOVA revealed significant group and time effects on RER (F = 1.19, r2 = 0.14, p = 0.004) with a mean difference of 0.063 (95% CI = 0.058 – 0.068, p < 0.001) between steady (mean = 0.96, min = 0.88, max = 1.11) and sinusoidal groups (mean = 0.90, min = 0.78, max = 0.96). PCR revealed trending differential expression of Srebp1 (F = 2.053, p = 0.18) and Acaca (F = 2.041, p = 0.18) driven by relatively higher expression under steady rate infusion. There were no significant differences in metabolic tissue weights or intestine length between groups. Conclusions: Sinusoidal infusions, matched to ad-libitum consumption patterns, are tolerated and do not induce complications in murine TPN. This novel approach may improve lipid utilization and match with circadian rhythm of metabolism. Further investigations are underway to establish this mouse model of human PNALD. Funding Sources: Metabolism and Nutrition Training Program T32 (DK 007665)Wisconsin Dairy Innovation Hub Start-up Funding.