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Anesth Analg 2002;94:1617-1620
© 2002 International Anesthesia Research Society

REGIONAL ANESTHESIA

Small-Dose Propofol Sedation Attenuates the Formation of Reactive Oxygen Species in Tourniquet-Induced Ischemia-Reperfusion Injury Under Spinal Anesthesia

Ya-Jung Cheng, MD*, Yong-Ping Wang, MD*, Chiang-Ting Chien, PhD{dagger}, and Chau-Fong Chen, PhD{ddagger}

*Department of Anesthesiology and {dagger}Office for Medical Research Administration, National Taiwan University Hospital, and {ddagger}Department of Physiology, College of Medicine, National Taiwan University, Taipei, Taiwan

Address correspondence and reprint request to Chau-Fong Chen, PhD, Department of Physiology, College of Medicine, National Taiwan University, No. 7, Chung-Shan South Road, Taipei, Taiwan 10016, Republic of China. Address e-mail to chfochen{at}ha.mc ntu.edu.tw.


   Abstract
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 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
The release of a tourniquet produces reactive oxygen species (ROS), which can cause ischemia-reperfusion injury. We investigated the effects on ROS production in 22 adult ASA physical status I–II patients sedated with small-dose propofol infusion and IV midazolam undergoing elective total knee replacement under intrathecal anesthesia, allocated randomly to one of two groups. In the Propofol group, sedation was performed with propofol 0.2 mg/kg followed by infusion at a rate of 2 mg · kg-1 · h-1. In the Control group, IV midazolam 5 mg was given. ROS production was measured by lucigenin chemiluminescence analysis. Blood samples were obtained from the radial artery after spinal anesthesia, 1 min before release of the tourniquet and 5 and 20 min after reperfusion. The ischemic time was approximately 70 min. ROS production decreased nonsignificantly before reperfusion in both groups but increased significantly 5 and 20 min after reperfusion in the Midazolam group. In the Propofol group, no significant increase of ROS production was found. We conclude that small-dose propofol infusion attenuates ROS production in tourniquet-induced ischemia-reperfusion injury.

IMPLICATIONS: Small-dose propofol sedation, compared with IV midazolam, attenuates free radical production after release of the tourniquet during total knee replacement under spinal anesthesia.


   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
The application of a tourniquet for limb surgery is often used to limit distal dissection and to improve exposure of the operative field. However, the release of a tourniquet causes an ischemia-reperfusion injury. Massive and abrupt release of oxygen free radicals after reperfusion, followed by endothelial dysfunction or neutrophil infiltration (1), triggers the oxidative damage. Pulmonary complications and arrhythmias were reported on limb ischemia-reperfusion injury (2). Such complications are a concern, especially in the age group receiving total knee replacement (TKR) with tourniquet application.

The release of oxygen free radicals disturbs the prooxident-antioxident balance and plays a central role in the pathophysiological sequelae of reperfusion injury (3). The cytotoxic effects of reactive oxygen species (ROS) are the initiation of peroxidation of polyunsaturated fatty acids in membrane or plasma lipoproteins and the direct inhibition of mitochondrial respiratory chain enzymes (4). Oxidative stress also results in cell injury involving DNA, protein, and lipid. Base damage products (such as 8-hydroxydeoxyguanosine), carbonyls, and other amino acid modifications (such as methionine sulfoxide and malondialdehyde [MDA]) were used to evaluate the oxidative damage on DNA, protein, and lipid (5). However, we measured the initial ROS production by chemiluminescence (CL) in this study. This method can monitor the initial reactive oxygen metabolites formed, including superoxide (O2·-), H2O2, OH· and HOCl.

Propofol (2,6-diisopropylphenol) is chemically similar to phenol-based free radical scavengers (6), producing a concentration-dependent reduction in CL from stimulated leukocytes (7). However, the concentration for propofol having a preventive effect on free radical formation varies on the basis of different experimental methods. Large concentrations (much larger than the anesthetic level) of propofol were shown to prevent free radical production (8). In clinical practice, Kahraman et al. (9) showed that propofol infusion in general anesthesia (IV propofol 2–2.5 mg/kg, followed by a continuous infusion of propofol at a rate of 10 mg · kg-1 · h-1, reducing to 8 and 6 mg · kg-1 · h-1, respectively, at 10-min intervals), compared with isoflurane, attenuates formation of lipid peroxides in tourniquet-induced reperfusion injuries by measuring MDA. The goal of this study was to evaluate the effects on ROS production under sedation by IV midazolam or small-dose propofol infusion before and after release of the tourniquet in TKR under spinal anesthesia.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
After obtaining our ethics committee’s approval and informed patient consent, we studied 22 adults—ASA physical status I–II patients undergoing unilateral TKR with use of a tourniquet. A 22-gauge arterial catheter with heparin lock was inserted on the contralateral arm from the extremity with an IV line for blood sampling. Intrathecal anesthesia by 0.5% heavy bupivacaine 10–12 mg was performed first. After spinal anesthesia was ensured by pinprick to be adequate, sedation was started after a baseline blood sample was obtained. These patients were randomly separated into two groups. Small-dose propofol infusion 2 mg · kg-1 · h-1 after a 0.2 mg/kg bolus was given in one group, and IV midazolam 5 mg was given in the other group. On the basis of the previous study, the arterial serum propofol levels were approximately 0.6–0.9 µg/mL after a 20-min infusion (10).

A tourniquet was applied at a pressure approximately twice the systolic arterial blood pressure. Blood samples for free radicals were also obtained 1 min before tourniquet release and 5 and 20 min after tourniquet release (reperfusion). The blood samples were immediately wrapped in aluminum foil and kept on ice until CL measurement, which was usually performed within 2 h (11). Immediately before CL mea-surement, 0.1 mL of phosphate-buffered saline buffer (pH 7.4) was added to 0.2 mL of blood sample. The CL was measured in a completely dark chamber of the CL analyzing system. After 100 s of background level determination, 1.0 mL of 0.1 mM lucigenin in phosphate-buffered saline (pH 7.4) was injected into the sample. The CL was continuously monitored for an additional 600 s; integrating the area under the curve and subtracting it from the background level calculated the total amount of CL. The assay was performed in duplicate for each sample and was expressed as CL counts per 10 s for whole blood CL. The mean ± SE of the CL level of each sample was calculated. Significant differences between groups were analyzed with the Mann-Whitney U-test. Intragroup comparisons were performed by one-way repeated-measures analysis of variance, and P < 0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
As shown in Table 1, there were no significant differences between the groups in demographic data. The duration of tourniquet application was approximately 70 min. The ROS production in both groups is shown in Figure 1. Basal ROS production was comparable in the groups. In the Midazolam group, the CL count decreased nonsignificantly 1 min before reperfusion but increased in a statistically significant pattern at 5 and 20 min after release of the tourniquets. In the Propofol sedation group, the CL count decreased nonsignificantly before tourniquet release, and then it slightly increased and decreased nonsignificantly at 5 and 20 min after reperfusion. There was significantly higher ROS production in the Midazolam group than in the Propofol group at 5 and 20 min after reperfusion. (Fig. 1)


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  		Table 1. Patient Characteristics
 


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  		Figure 1. Whole blood reactive oxygen species (ROS) production (chemiluminescence [CL] counts) in small-dose Propofol infusion and IV Midazolam groups. *Significantly different from baseline data. #Significantly different between groups. T1 = baseline data after spinal anesthesia; T2 = 1 min before reperfusion; T3 = 5 min after reperfusion; T4 = 20 min after spinal anesthesia.

 

   Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
The main finding in our study is that small-dose propofol infusion prevents abrupt ROS formation after reperfusion by tourniquet release on TKR patients under spinal anesthesia. It is the lowest serum level reported to prevent ROS production. On the basis of our previous study, the serum level of propofol should be less than 1 µg/mL with such an infusion rate (12). The concentration of propofol required to ameliorate free radical formation varied in previous studies. Green et al. (6) showed that it should be larger than 10 µg/mL—much larger than the anesthetic concentration. Propofol in the anesthetic concentration, used for the induction and maintenance of general anesthesia, was proved to have beneficial effects on surgical stress (13) and reperfusion injury (9). The pattern of ROS formation from surgical stress is different from that of reperfusion injury. The release of a tourniquet causes an abruptly massive production of ROS and starts oxidative damage. In our study, ROS production decreased nonsignificantly in both groups before reperfusion, which may have resulted from the effects of sedation from releasing the stress in the operating room. Propofol reduces the stress-inducing hormones, such as adrenaline, noradrenaline, and cortisol (14). In our study, the midazolam used for sedation may have decreased the free radical production under surgical stress, but propofol prevented the abrupt ROS formation after reperfusion. Although IV midazolam seems to be an advantageous sedative with an amnesic effect, it has been reported as having no effect on ROS production on a cell-free ROS-generating system (15). However, propofol has been reported to increase antioxidant capacity (16) or to protect erythrocytes against oxidative stress (17). This may be the reason why small-dose propofol infusion can prevent reperfusion-induced ROS production.

CL is used widely as a sensitive assay for monitoring free radicals and reactive oxygen metabolites from enzyme, cell, or organ systems (18). Considering total ROS production, CL may be more beneficial than measuring MDA. MDA is one of the toxic metabolites after lipid peroxidation after ROS production. Other methods measuring the antioxidizing enzyme activities (major glutathione system) were also used to evaluate the oxidizing-antioxidizing balance. However, measuring ROS production is directly measuring the substances starting reperfusion injury. Prevention of ROS production blocks the starting signals for lipid peroxidation, which brings reperfusion injury.

The highest CL counts happened at 20 minutes after reperfusion in our study, and we did not follow the data after the end of surgery. In previous reports, the postischemic DNA damage in human leukocytes was most pronounced 5–30 minutes after tourniquet release and then decreased over a 2-hour period, but it did not return to baseline level with flow cytometry (19). In our study, ROS production increased significantly 5 and 20 minutes after reperfusion. We assumed that our 20-minute postreperfusion data were near the highest ROS production during the operation.

Postischemic reperfusion injury represents a source of substantial morbidity and mortality in various fields of medicine, i.e., myocardial infarction, stroke, trauma, septic or hemorrhagic shock, multiple organ failure, coronary thrombolysis, bypass surgery, and organ transplantation. ROS production after ischemia-reperfusion injury may bring more severe pulmonary complications and induce a cardiovascular reflex (20) that may be more dangerous in the age groups that receive TKR. It will be valuable to give these patients a small-dose propofol infusion for sedation during spinal anesthesia.


   Acknowledgments
 
Supported by National Taiwan University Hospital Research Grant NTUH89S2003.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication February 5, 2002.




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Lippincott, Williams & Wilkins 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 HighWire Press