Propofol versus Propofol/Remifentanil for Deep Sedation in Prolonged Mechanically Ventilated Rabbits; Blood Biochemical Profile and Histopathological Findings Preliminary Results
The aim of this study was to compare the biochemical profile as well as the histopathological findings of vital organs of rabbits deeply sedated with either propofol or propofol plus remifentanil for prolonged mechanical ventilation.
Eight male, clinically healthy New Zealand White rabbits were intubated under xylazine-ketamine-isoflurane anesthesia. After isoflurane discontinuation, the animals received either propofol (group P, n=4) or propofol plus remifentanil (group P/R, n=4) by continuous intravenous infusion for a maximum period of 38 hours. Propofol was infused at an initial dose (ID) of 0.33±0.03 mg/kg/min (group P) or 0.36±0.05 mg/kg/min (group P/R) which was increased up to 1.15±0.12 mg/kg/min (group P) or 0.63±0.05 mg/kg/min (group P/R). Remifentanil was infused at an ID of 0.19±0.03 μg/kg/min which was increased up to 0.41±0.02 μg/kg/min. The initial doses were adjusted in order to achieve adequate sedative and analgesic effect based on reflexes, HR, arterial pressure and attempt for spontaneous breathing. Blood samples were collected every 12 hours for aspartate aminotransferase (AST), alanine aminotransferase (ALT), γ-glutamine transferase (γ-GT), lactate dehydrogenase (LDH), creatine phosphokinase (CK), alkaline phosphatase (ALP), C-reactive protein (CRP), urea, creatinine, total protein, albumin, globulin, potassium, sodium, calcium, magnesium, phosphorus, cholesterol, triglycerides, glucose, total bilirubin and direct bilirubin levels determination. At the end of the experiment, the heart, the lungs, the liver (with the gallbladder) and the kidneys were excised and fixed in formalin 10% in order to be processed for histopathological examination. Statistics; data were expressed as means ± SD and were subjected to repeated measures ANOVA. The means were tested using the Student t-test. Statistical significance if P<0.05.
The mortality rate was 100%. The animals survived for 36.3±2.0 h (group P) or 36.8±0.9 h (group P/R). Biochemical profile: By the 12th hour, LDH, CK, urea, total proteins, globulin, cholesterol, triglyceride and total bilirubin levels were increased beyond normal range in both groups, while AST and ALT only in group P/R. LDH, CK and urea were significantly higher (P<0.05) in group P/R. It was remarkable that triglycerides reached extreme values in both groups. Total protein, globulin, cholesterol and total bilirubin were higher (P<0.05) in group P, while direct bilirubin increased only in this group. Histopathological findings: lungs; interstitial pneumonia and pulmonary edema (both groups), heart; inflammatory infiltration present between the myocardial fibers (both groups), liver; active hepatitis (both groups) and necrosis of hepatocytes (group P/R), gallbladder; total necrosis of the wall (group P), small foci with necrosis of the mucosa (group P/R), kidneys; acute tubular necrosis (both groups).
In conclusion, propofol alone or in combination with remifentanyl causes multi-organic damage when administered by continuous intravenous infusion in PMV rabbits as suggested by blood biochemistry and histopathological findings of vital organs. Liver damage is more detrimental when propofol is combined with remifentanyl. However, the degree of gallbladder damage seems to be related with propofol dose. The extreme blood triglyceride levels could be explained, in part, to the lipid content of propofol's solvent. The damage of the heart, the lungs and the kidneys are irrelevant to propofol dose or remifentanyl co-administration. Subsequently, these adverse multi-organic effects lead to death.