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CRITICAL CARE AND TRAUMA

Oxidative Stress Status During Exposure to Propofol, Sevoflurane and Desflurane

Bernard Allaouchiche, MD PhD^*, Richard Debon, MD^*, Joëlle Goudable, PhD, Dominique Chassard, MD PhD^*, and Frédéric Duflo, MD^*

*Department of Anesthesiology and Intensive Care, EA 18/96, Hotel-Dieu Hospital, Lyon, France, and Department of Biochemistry, Edouard Herriot Hospital, Lyon, France

Address correspondence and reprint requests to Bernard Allaouchiche, MD, PhD, Department of Anesthesiology and Intensive Care, Hôtel Dieu Hospital, 1, place de l’Hôpital, 69288 Lyon Cedex 02, France. Address e-mail to allaouch{at}univ-lyon1.fr

	Abstract

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We evaluated the circulating and lung oxidative status during general anesthesia established with propofol, sevoflurane, or desflurane in mechanically ventilated swines. Blood samples and bronchoalveolar lavage fluid (BAL) specimens were respectively performed via an internal jugular vein catheter and a nonbronchoscopic BAL for baseline oxidative activity measurements: malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GPX). A 4-h general anesthesia was then performed in the three groups of 10 swine: the Propofol group received 8 mg · kg^-1 · h^-1 of IV propofol as the sole anesthetic; the Desflurane group received 1.0 minimum alveolar concentration of desflurane; and the Sevoflurane group received 1.0 minimum alveolar concentration of sevoflurane. We observed significantly larger levels of MDA in plasma and BAL during desflurane exposure than with the other anesthetics. We also observed smaller concentrations of circulating GPX and alveolar GPX. We found a significant decrease for MDA measurements in the plasma and the pulmonary lavage during propofol anesthesia. We also found larger values of GPX measurements in the serum and the pulmonary lavage. No significant changes were observed when animals were exposed to sevoflurane. No significant changes were found for circulating concentrations of SOD during exposure to all anesthetics. In this mechanically ventilated swine model, desflurane seemed to induce a local and systemic oxidative stress, whereas propofol and sevoflurane were more likely to have antioxidant properties.

IMPLICATIONS: Superoxide is an unavoidable byproduct of oxygen metabolism that occurs in various inflammatory reactions. Inhalation of volatile anesthetics under mechanical ventilation induces an inflammatory response. We evaluated the bronchoalveolar and systemic oxidative stress in swine during exposure to propofol and newer volatile anesthetics. Desflurane induces more lipid peroxidation than do the other anesthetics.

	Introduction

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Pulmonary infections are a major factor of postoperative morbidity and mortality (1). Although various factors are implicated, the type and the duration of anesthesia can alter the alveolar macrophages that are considered as the first line of pulmonary defense (2). Previous studies in animals suggest that exposure to volatile anesthetics can suppress the cytotoxic or phagocytosis response of alveolar macrophages (3). Moreover, inhalation of volatile anesthetics during mechanical ventilation can augment gene expression of proinflammatory cytokines in the pulmonary lavage (2). Thus, general anesthesia (i.e., volatile anesthetics) can impair immunologic defense mechanisms while inducing an inflammatory reaction in alveolar macrophages.

The release of inflammatory mediators and free radicals has been clearly demonstrated in generalized inflammatory reactions involving the production of leukocytes (4). In addition, airway inflammation appears to play a central pathophysiological role in patients with asthma, adult respiratory distress syndrome, and chronic obstructive pulmonary disease wherein an increased oxidative stress has been shown in the bronchoalveolar lavage (BAL) fluid and in the blood (1,5–8).

The aim of our study was to assess evidence of oxidative stress in the porcine BAL fluid and blood occurring 2 h and 4 h after exposure to desflurane, sevoflurane, or propofol.

	Methods

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After approval by the Claude Bernard University Committee on Animal Research, we studied 30 healthy young pigs (3–4 mo old; 23 ± 2 kg, mean ± SD). They were obtained from a seller and housed in the university vivarium for 3–5 days.

After 10 mg/kg of intramuscular (IM) ketamine as premedication, general anesthesia was induced with propofol 2 mg/kg infused in an auricular vein. The trachea was intubated with a 6.0-mm cuffed tube and mechanical ventilation was started (Sa 2; Dräger, Lübeck, Germany) at a FIO₂ of 0.21. A 5F double-lumen central venous catheter was introduced in the internal jugular vein for blood sampling and hydration. A common carotid artery catheter was inserted for continuous systemic arterial pressure monitoring and for immediate gas analysis. A nonbronchoscopic BAL was performed using the blinded protected bronchoalveolar lavage (PBAL) catheter technique for pulmonary specimens (Combicath^TM; Plastimed, St. Leu La Foret, France). Cardiovascular and oxygen saturation monitoring was performed during the entire procedure. The PBAL was inserted using a previously described technique (9). After the blinded introduction in the bronchial system, the inner catheter was advanced until resistance was encountered and 20 mL of sterile saline was administered. The fluid was then withdrawn by hand suction into the infusion syringe. When at least 5 mL of fluid had been sterilely retrieved, the entire catheter was removed. The entire sampling procedure lasted <2 min. Heparinized blood and alveolar samples were centrifuged (1500 rpm, 10 min) and supernatants were immediately stored at -80°C until measurements. Malondialdehyde (MDA), glutathione peroxidase activity (GPX) and superoxide dismutase (SOD) concentrations were measured as previously described. Briefly, MDA is currently estimated by measurement of thiobarbituric acid reactant substances. Thiobarbituric acid reactant substances were evaluated in plasma by fluorescence measurement (10). GPX catalyzes the oxidation of glutathione (GSH) by cumene hydroperoxide. In the presence of GSH reductase and reduced nicotinamide adenine dinucleotide phosphate, the oxidized GSH is converted to the reduced form with a concomitant oxidation of reduced nicotinamide adenine dinucleotide phosphate to nicotinamide adenine dinucleotide phosphate. GPX activity was measured by the decrease of reduced nicotinamide adenine dinucleotide phosphate absorbance at 340 nm (11). SOD activity was measured by monitoring the autooxidation of pyrogallol according to Marklund and Marklund (12). One unit of SOD activity is defined as the amount of the enzyme required to inhibit the rate of pyrogallol autooxidation by 50%. GPX and SOD activity results are expressed as unit per gram of hemoglobin in blood (U/g Hb) and as unit per liter in BAL (U/L). The swine were equally and randomly allocated to three different anesthesia groups; the Propofol group received 8 mg · kg^-1 · h^-1 of IV propofol as the sole anesthetic, the Desflurane group was exposed to 1.0 minimum alveolar concentration (10%) of desflurane and the Sevoflurane group was exposed to 1.0 minimum alveolar concentration of sevoflurane (2.5%). Blood and alveolar samples were collected within 2 h and 4 h of anesthesia. Inspired and expired gases, including end-tidal anesthetic concentrations and carbon dioxide levels, were measured using a calibrated gas analyzer (PM 8050; Dräger). Ventilation was adjusted to maintain an end-tidal normocapnia at baseline values (35–45 mm Hg). During the entire procedure, hydration was ensured by saline 5 mL^-1 · kg^-1 · h^-1 as the sole perfusion. During the entire experiment, data were recorded as follows: heart rate, systemic arterial pressures, central venous pressure, end-tidal carbon dioxide, and central core temperature.

All data are expressed as mean with 95% confidence interval. Demographic and clinical data were compared using the Kruskal-Wallis statistic or the Friedman statistic when appropriate. The blood and the BAL oxidative stress status were evaluated in all groups before and within 2 h and 4 h of general anesthesia using two-way repeated-measures analysis of variance. When statistical significance was established (P < 0.05), the Bonferroni test was performed to isolate the source of significance.

	Results

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There were no significant between-group differences over time in heart rate, arterial mean pressure, central venous pressure, respiratory rates, core temperature, and oxygen and carbon dioxide tension (data not shown). The recovery rate of PBAL was approximately 30%.

Circulating Lipid Peroxidation
MDA excretion increased significantly during exposure to desflurane (29% within 2 h and 48% within 4 h), whereas significantly smaller concentrations of MDA were found during exposure to propofol (-23% within 2 h and -31% within 4 h). There were no significant differences during exposure to sevoflurane over time (Fig. 1A).

View larger version (29K): [in this window] [in a new window]   Figure 1. A, plasma malondialdehyde (MDA) before (initial) and during exposure to different anesthetics (2 h and 4 h). B, alveolar malondialdehyde (MDA) before (initial) and during exposure to different anesthetics (2 h and 4 h). Data are expressed as mean with 95% confidence interval. *P < 0.02 versus initial time; &P < 0.02 versus 2 h; #P < 0.02 versus sevoflurane; P < 0.02 versus propofol.

Circulating Activity of Antioxidant Enzymes
Concentrations of GPX were significantly reduced during exposure to desflurane (-45% within 2 h and -80% within 4 h) whereas measurements of GPX levels were significantly higher during expo sure to propofol (70% within 2 h and 104% within 4 h). There were no significant differences during exposure to sevoflurane over time (Fig. 2A and 3). Concentrations of SOD were not statistically altered over time and between different exposures to anesthetics.

View larger version (33K): [in this window] [in a new window]   Figure 2. A, blood cells glutathione peroxidase (GPX) before (initial) and during exposure to different anesthetics (2 h and 4 h). B, alveolar glutathione peroxidase (GPX) before (initial) and during exposure to different anesthetics (2 h and 4 h). Data are expressed as mean with 95% confidence interval. *P < 0.02 versus initial time; &P < 0.02 versus 2 h; #P < 0.02 versus sevoflurane; P < 0.02 versus propofol.

View larger version (42K): [in this window] [in a new window]   Figure 3. Serum superoxide dismutase (SOD) before (initial) and during exposure to different anesthetics (2 h and 4 h). Data are expressed as mean with 95% confidence interval.

	Discussion

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Our results show that animals exposed to desflurane have increased MDA concentrations and enhanced GPX consumption both in serum and in lavage. Conversely, animals exposed to propofol have lower circulating and local measurements of MDA levels and reduced GPX consumption. Sevoflurane did not induce a chemical reaction sequence leading to the generation of oxygen free radicals.

Free radicals such as superoxide radical or hydroxyl radical are constantly produced as a normal consequence of aerobic metabolism (13). Oxidative stress results from an imbalance between radical-generating and radical-scavenging systems leading to cell membrane impairment or DNA damage (13). MDA is a reflection of lipid peroxidation, whereas SOD and GPX are important antioxidant defenses. These enzymes are involved in the clearance of superoxide and H₂O₂ to maintain the structure and function of biological membranes (13). SOD dismutases superoxide H₂O₂ and this compound is catabolized by catalase and GPX. In higher organisms, GPX appears to have largely supplanted the need for catalase membranes (13). Thus, our findings support the existence of a local and systemic oxidative stress from mechanically ventilated animals during exposure to desflurane. Moreover, anesthesia conducted with propofol reduced oxidative stress and enhanced antioxidant defense mechanisms expressed by larger concentrations of free radical scavengers.

One of the factors that might be responsible for oxidative stress associated with desflurane anesthesia is the increased expression of proinflammatory cytokines in alveolar macrophages. This event occurs after inhalation of volatile anesthetics under mechanical ventilation (2,14). Increased alveolar fluid gene expression for tumor necrosis factor-, interferon-, interleukin-1ß, and macrophage inflammatory protein-2 have been found in anesthetized rats after inhalation of volatile anesthetics (2). However, the authors did not study anesthesia conducted with desflurane. Moreover, in this latter work, sevoflurane appeared to induce an inflammatory response, whereas the smallest changes in expression of proinflammatory cytokines occurred during exposure to sevoflurane.

Propofol has chemical similarities with the phenol-based antioxidant, mimicking free radicals scavenging properties. It resembles the endogenous antioxidant -tocopherol (15,16). De La Cruz et al. (17,18) found that propofol increased glutathione activity in male rats and in platelets from surgical patients. The authors have found an increased antioxidant GSH activity, expressed by reduced concentrations of GPX, and larger concentrations of GSH reductase and transferase. These discrepancies could come from the duration of the exposure to the anesthetic. We studied oxidative stress within two and four hours of anesthesia. Propofol first inhibits GPX activity to augment the pool of antioxidant defenses that protect the tissue against possible oxidative stress and then enhances GPX activity when oxidative stress situations do not occur.

Systemic SOD activity was not altered in our work during the exposure to various anesthetics. However, the adaptive antioxidant response of SOD is not accompanied by GPX enzymatic activity upregulation. Boya et al. (19) studied the antioxidant status and the oxidative stress in peripheral blood mononuclear cells from 49 patients with chronic hepatitis C. They found larger concentrations of SOD with reduced GSH activity despite oxidative stress. Alveolar concentrations of SOD were not detectable. In our laboratory, SOD activity is routinely measured in erythrocyte by the method described above. Therefore, this procedure could not be applied to the BAL samples.

In conclusion, excessive generation of reactive oxygen species is one of the mechanisms incriminated in the pathogenesis of generalized (i.e., sepsis, transplantation, ischemic-reperfusion injury, burns) or local (i.e., asthma, chronic obstructive pulmonary disease, chronic hepatitis, nephrotic syndrome) inflammatory reactions. There is evidence for the implication of oxidative damage by reactive oxygen species. A major advantage of desflurane over currently available anesthetics is that the blood-gas partition coefficient is lower than all available anesthetics. This property predicts rapid recovery from general anesthesia. However, our results show that inhalation of desflurane produces a systemic and a local oxidative stress in comparison with the inhalation of sevoflurane. The potential effect of desflurane on oxidative stress might lead to the preferred use of sevoflurane or propofol. Finally, our data indicate that exposure to propofol reduces lipid peroxidation and enhances antioxidant defenses.

	References

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Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999