Background & aims: The United States Pharmacopeia (USP) has adopted Chapter <729> that set two globule size limits for all lipid emulsions with the mean droplet size at no >500 nm, while large-diameter fat globules as the percent fat>5 microm or PFAT(5) must be <0.05%. A quantitative risk assessment of toxicity from the intravenous infusion of all-in-one (AIO) admixtures made from a lipid emulsion that meets USP standards (fine) vs. one that does not (coarse), was conducted.
Methods: Two separate 96-h infusion studies in rats receiving nutritionally complete AIOs made from a fine (F) vs. a coarse (C) 20% starting lipid emulsion (SLE) with either 18 or 36% as fat calories were performed. The animals were equally divided in each (18% fat, n=18; 36% fat, n=22) to receive AIOs made from F or C lipids. PFAT(5) levels were measured at the outset and every 24h at the change of infusions and blood levels of liver enzymes AST and GST, and serum triglycerides (TG) were measured at the end of study.
Results: On average, the starting PFAT(5) values for infusions of F-AIOs were 0.018+/-0.007 (n=48) vs. C-AIOs at 0.183+/-0.026% (n=48), whereas the 24-h average was 0.234+/-0.211% (n=168) vs. 1.033+/-0.224% (n=180), respectively. No significant differences in the blood-based parameters were noted in rats between F-AIOs and C-AIOs in the studies comparing 18 or 36% of fat calories, respectively. When the data were combined into all F- vs. all C-AIOs, AST was significantly higher in C-AIOs (157+/-41) vs. F-AIOs (130+/-37), p=0.036. TG was lower in C (69+/-37) vs. F (106+/-70), nearly reaching statistical significance (p=0.056) with no differences in GST levels for C (21+/-9) vs. F (17+/-9), p=0.199. When stratified according to a PFAT(5) of <or>0.4%, C-AIOs were significantly higher than F-AIOs for AST (157+/-41 vs. 130+/-37, p=0.004), and TG was significantly lower in C- vs. F-AIOs (67+/-36 vs. 117+/-71, p=0.022), respectively.
Conclusions: Coarse lipid emulsions that fail pharmacopeial limits produce less stable AIOs and are associated with evidence of worsened hepatic injury.