Abstract

In humans, prolonged sedations with propofol or using high doses have been associated with propofol infusion syndrome. The main objective of this study was to evaluate the effects of prolonged high-dose administration of a specific propofol emulsion (Propofol Lipuro) and an improved lipid formulation (SMOFlipid) in liver mitochondrial bioenergetics and oxidative stress of rabbits, comparatively to a saline control. Twenty-one male New Zealand white rabbits were randomly allocated in three groups that were continuously treated for 20 h. Each group of seven animals received separately: NaCl 0.9 % (saline), SMOFlipid (lipid-based emulsion without propofol) and Lipuro 2 % (propofol lipid emulsion). An intravenous propofol bolus of 20 mg kg−1 was given to the propofol Lipuro group to allow blind orotracheal intubation and mechanical ventilation. Anesthesia was maintained using infusion rates of: 20, 30, 40, 50 and 60 mg kg−1 h−1, according to the clinical scale of anesthetic depth and the index of consciousness values. The SMOFlipid and saline groups received the same infusion rate as the propofol Lipuro group, which were infused during 20 consecutive hours. At the end, the animals were euthanized, livers collected and mitochondria isolated by standard differential centrifugation. Mitochondrial respiration, membrane potential, swelling and oxidative stress were evaluated. Data were processed using one-way ANOVA (p < 0.05). The animals revealed a significant decrease in cardiovascular parameters showing bradycardia and severe hypotension. No statistical differences were observed when using pyruvate as substrate, however, when using succinate as respiratory substrate, significant decrease in ADP-stimulated respiration rate was observed for SMOFlipid group (p = 0.002). Lipid peroxides (p < 0.01) and protein carbonyls (p = 0.01) showed a statistically significant difference between propofol Lipuro and the SMOFlipid groups. These results suggest that lipid-based emulsions can be involved in the regulation of different pathways that ultimately lead to a decrease of state 3 mitochondrial respiration rate. The infusion of propofol Lipuro during prolonged periods, in addition to marked hypotension and hypoperfusion, also showed to have higher anti-oxidant activity and lower impairment of the mitochondrial function comparatively to the improved lipid formulation, SMOFlipid, using the rabbit as animal model.Electronic supplementary materialThe online version of this article (doi:10.1186/s40064-016-2970-2) contains supplementary material, which is available to authorized users.

Highlights

  • Propofol is a hypnotic drug largely used through the last decades for both human and animal anesthesia and sedation of healthy and critical patients (Li et al 2012)

  • In vivo studies were conducted by Yspilantis et al (2007), where New Zealand rabbits were continuously sedated for 32.3 ± 5.4 h with propofol and after 20 h of anesthesia they showed blood biochemical and histological changes in the main organs resembling propofol infusion syndrome (PRIS) (Ypsilantis et al 2007)

  • The doses used in our study were high comparatively to that used in humans, the doses used were just to maintain the animals in a sedated level of anesthesia, as it was showed by the IoC values, that were never lower than 60, indicating that no overdoses were reached

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Summary

Introduction

Propofol is a hypnotic drug largely used through the last decades for both human and animal anesthesia and sedation of healthy and critical patients (Li et al 2012) This small lipophilic molecule holds favorable pharmacokinetic and pharmacodynamic properties as rapid onset, short clinical effect and fast recovery that turn it the choice intravenous (IV) drug for continuous infusion for the most diverse procedures (Fodale and La Monaca 2008). Adverse side effects were observed when propofol was administered in high doses or for long uninterrupted periods to humans, especially, children (>4 mg kg−1 h−1; >48 h) (Kam and Cardone 2007; Ahlen et al 2006; Agrawal et al 2013) and rabbits (>20 mg kg−1 h−1; >20 h) (Ypsilantis et al 2007), indicating the presence of a complex set of signs and symptoms that owned the name of propofol infusion syndrome (PRIS). The present study aims to evaluate the in vivo effects on hepatic mitochondrial bioenergetics and oxidative stress parameters after a long-term high-dose administration of a specific propofol formulation (Propofol Lipuro) and an improved lipid emulsion (SMOFlipid) on rabbits

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