Intravenous Lipid Emulsion Attenuates Hepatic, Renal, Cerebral and Testicular Histopathological Injury but Not Renal...

Background: Butyrophenone neuroleptics are used in veterinary practice-haloperidol in the capture and translocation of wild ungulates, azaperone in swine-and antipsychotics prescribed to owners are a recognised cause of accidental toxicosis in dogs and cats. Organ-level toxicity data for this drug class are nonetheless almost absent in any species. Intravenous lipid emulsion (ILE) is an established antidote in small-animal emergency medicine for lipophilic intoxications, but the veterinary evidence base consists of case reports with clinical endpoints, and no controlled study has examined what ILE does to the tissues themselves. This study used an acute rodent overdose model to provide that organ-level assessment. Methods: Forty male Wistar albino rats were randomised to four groups of ten: control (saline 2 mL/kg oral gavage), HP (17.5 mg/kg oral gavage), HP + ILE (17.5 mg/kg HP plus 20% ILE 7.5 mL/kg intravenously at 0.5 h and 8 h, an empirical regimen) and ILE alone. Endpoints were assessed at 24 h. Seventeen histopathological parameters across seven organs were scored semi-quantitatively by a blinded pathologist (n = 10 per group), with independent re-scoring of a stratified random 30% subsample by a second blinded pathologist. Serum total oxidant status (TOS), total antioxidant status (TAS), oxidative stress index (OSI) and routine biochemistry were measured in animals with adequate serum (n = 34 and n = 35). Comparisons used Kruskal-Wallis and Mann-Whitney U tests with Benjamini-Hochberg false discovery rate (FDR) control. Results: Haloperidol produced significant injury in the liver, kidney, brain and testis (all p < 0.001 vs. control) and mild histological cardiac changes (degeneration p = 0.014; congestion p = 0.034); lung and eye were unaffected. Serum urea was markedly elevated in HP (67.4 ± 13.2 vs. 46.5 ± 8.8 mg/dL; p = 0.001, d = 1.82) and HP + ILE (61.5 ± 8.7 mg/dL; p = 0.003), with unchanged creatinine, and correlated strongly with renal histopathology (renal inflammation vs. urea ρ = 0.74, p < 0.001). ILE significantly attenuated histopathological injury in 8 of the 12 haloperidol-associated parameters after FDR correction (renal congestion q = 0.032, r = 0.70; testicular Johnsen score q = 0.032, r = 0.66); the testicular score improved significantly relative to HP (q = 0.032) but remained statistically indistinguishable from control (p = 0.072), which does not establish equivalence. ILE did not reduce serum urea (HP + ILE vs. HP, p = 0.26) and did not modify the mild histological cardiac changes (p ≥ 0.40); no functional or electrophysiological cardiac endpoint was assessed. No group difference was detected in serum TOS or OSI (p = 0.43 and p = 0.51), whereas TAS was significantly reduced in the ILE-alone group (p = 0.011); the biological interpretation of this TAS finding remains uncertain, because interference of residual lipaemia with the spectrophotometric assay could not be excluded and would also propagate to the derived OSI. No tissue oxidative marker was measured. Transaminases were not elevated by haloperidol and showed no correlation with hepatic histopathology (|ρ| ≤ 0.17, all p > 0.34). ILE alone caused no histopathological abnormality at this dose and time point. Inter-observer agreement was high (95.6% exact agreement; median weighted κ = 0.893). Conclusions: In this acute overdose model, ILE is associated with a differential and structurally incomplete histopathological response: microscopic injury improves in four organs while renal function does not, and the mild histological cardiac changes are unaltered. Serum transaminases did not reflect concurrent organ-level injury at 24 h. Serum TOS and OSI showed no detectable group differences, while TAS was reduced in the ILE-alone group with an uncertain biological interpretation. Given the analytical uncertainty and the limited sample size, these indices provided no usable surrogate information about organ-level injury in this model. These findings define which organ systems respond and require confirmation in target veterinary species before informing clinical practice.