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Anesth Analg 2003;97:13-18
© 2003 International Anesthesia Research Society

CARDIOVASCULAR ANESTHESIA

The Effect of Clomethiazole on Plasma Concentrations of Interleukin-6, -8, -1ß, Tumor Necrosis Factor-{alpha}, and Neutrophil Adhesion Molecule Expression During Experimental Extracorporeal Circulation

D. Harmon, MMedsci FCARCSI*, E. Coleman, Dip Lab Med, FCCP{dagger}, C. Marshall, BSc ACP{dagger}, W. Lan, MB*, and G. Shorten, MD PhD*

*Department of Anaesthesia & Intensive Care Medicine, Cork University Hospital, University College Cork; and {dagger}Department of Clinical Perfusion, Cork University Hospital, Cork, Ireland

Address correspondence and reprint requests to George Shorten, MD, PhD, Department of Anesthesia & Intensive Care Medicine, Cork University Hospital, Wilton Rd., Cork, Ireland. Address e-mail to shorteng{at}shb.ie


   Abstract
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 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Clomethiazole (CMZ), a neuroprotective drug, has antiinflammatory actions. We investigated the effects of CMZ administration on plasma concentrations of interleukin (IL)-6, IL-8, IL-1ß, tumor necrosis factor-{alpha}, and neutrophil adhesion molecule expression during experimental extracorporeal circulation. Five healthy volunteers each donated 500 mL of blood, which was subsequently divided into equal portions. Identical extracorporeal circuits were simultaneously primed with donated blood (250 mL) and circulated for 2 h at 37°C. CMZ was added to 1 of the circuits of each pair to achieve a total plasma concentration of 40 µmol/L. Blood samples were withdrawn at (i) donation, (ii) immediately after addition of CMZ, and at (iii) 30, 60, 90, and 120 min after commencing circulation. Plasma concentrations of IL-6, IL-8, and tumor necrosis factor-{alpha} were less in the CMZ group compared with control after 60 min of circulation (2.2 [0.3] versus 3.2 [0.4], 14.9 [4.8] versus 21.9 [18.4], 63.3 [43.5] versus 132.2 [118.9] pg/mL, respectively, P < 0.05). After 120 min of circulation, neutrophils from CMZ-treated circuits showed significantly less CD18 expression compared with control (237.5 [97.4] versus 280.5 [111.5], P = 0.03). The addition of CMZ to experimental extracorporeal circuits decreases the inflammatory response. This effect may be of clinical benefit by decreasing inflammatory-mediated neurological injury during cardiopulmonary bypass.

IMPLICATIONS: Enhancement of {gamma}-aminobutyric acidA-mediated effects by clomethiazole (CMZ) and associated neuroprotection has been established in animal models of cerebral ischemia. In an ex vivo study, we demonstrated antiinflammatory activity of CMZ in experimental extracorporeal circulation. This represents a potential neuroprotective mechanism of CMZ in patients undergoing coronary artery bypass surgery.


   Introduction
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 Introduction
Methods
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 Discussion
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Adverse neurological and neuropsychological effects are major determinants of overall clinical outcome after coronary artery bypass graft (CABG) surgery. Such dysfunction is attributed to cerebral embolization, the inflammatory response induced by cardiopulmonary bypass (CPB) and cerebral ischemia reperfusion injury (1).

Patients undergoing cardiac surgery demonstrate a marked generalized inflammatory response (2). Although surgical trauma and ischemia contribute to this response, extracorporeal CPB also has an important proinflammatory role. Based on animal investigations (3), it is likely that nonspecific inflammation exacerbates the injury associated with focal cerebral ischemia after microgaseous or macroatheromatous cerebral embolization, which occurs during CABG. Therapies aimed at preventing this inflammatory response have demonstrated neuroprotective efficacy in experimental models of cerebral ischemia (4). The use of heparin-coated circuits, which decrease the CPB-induced inflammatory response, also produce a better neurological outcome after cardiac surgery (5).

Clomethiazole (CMZ) (INN: clomethiazole; BAN: chlormethiazole) is derived from the thiazole moiety of thiamine. It possesses sedative, hypnotic, and anticonvulsant properties (6), and has been administered for a variety of clinical indications over the last 30 yr. CMZ acts at the {gamma}-aminobutyric acid (GABA) receptor to potentiate the effects of GABA and modulate Cl-1 channel opening directly (7). CMZ decreases hippocampal CA1 damage when infused 1 and 4 hr after a 5-min ischemic insult (bilateral carotid occlusion) in gerbils (8). In a transient middle cerebral artery occlusion model in rats, CMZ when administered subcutaneously, decreased the volume of cerebral ischemic damage (9). Its neuroprotective action is mediated by GABA potentiation. CMZ has recently been shown to possess antiinflammatory properties. It potently and selectively inhibits p38 mitogen-activated protein kinase in primary cortical glial cultures (10). This offers an alternative (antiinflammatory) mechanism by which the neuroprotective effects of CMZ may be mediated.

The coexistence of several proinflammatory stimuli during cardiac surgery, poses a problem when attempting to identify the mechanism by which a specific therapy exerts its effect. To overcome this problem, it is necessary to isolate the different inflammatory components of the procedure. Because CPB is responsible for some of the inflammatory effects that occur during CABG, we used an experimental extracorporeal circulation model to determine whether CMZ modified this important component of the overall inflammatory response, which occurs in clinical practice. To this end, we serially measured plasma concentrations of interleukin (IL)-6, IL-8, IL-1ß, tumor necrosis factor (TNF)-{alpha}, and expression of the neutrophil adhesion molecules L selectin and CD18 in blood circulating in an isolated CPB circuit.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
With institutional ethical committee approval, and written informed consent from each, 5 healthy volunteers (receiving no medications and not having undergone surgery within the previous 3 mo) donated 500 mL of blood, which was collected in 2 blood transfer bags (250 mL each) containing no anticoagulant. The following additions were made to these bags: 1) CMZ: CMZ 6.7 mg dissolved in 30 mL of normal saline and heparin 1000 IU, and 2) control: normal saline 30 mL and heparin 1000 IU.

The mass of CMZ was calculated to produce a plasma concentration of 40 µM when the bag’s contents were added to the primed CPB circuits. This concentration of CMZ (40 µM) was selected because it has previously been shown to produce antiinflammatory effects with 25–75 fold greater potency for inhibition of c-fos mRNA expression than for enhancement of GABAA chloride currents (10). Infusions of CMZ in the gerbil model of cerebral ischemia, with an end infusion total plasma concentration of 13 µM, have been demonstrated to be neuroprotective (11). The bags were allowed to equilibrate at room temperature for 30 min at which time each aliquot of blood was added simultaneously, through the prime port, to 1 of 2 identical CPB circuits, each primed with 270 mL of Hartman solution and 1600 IU of heparin. The circuits comprised 3/8-in. polyvinylchloride tubing, a roller pump (Jostra AB, Lund, Sweden), and a Terumo Capiox SX 18 hollow fiber membrane oxygenator and reservoir (Terumo UK, Knowsley, Merseyside, UK). Each circuit was used only once and discarded. Simultaneously, two perfusionists (unaware of circuit allocation) commenced circulation in the two circuits according to the following protocol. Flow was maintained at 2.5 L/min, pH 7.20–7.40, PO2 25–35 kPA, and PCO2 3.2–4.5 kPA. The circuit was maintained at 37°C throughout.

Serial blood samples (5 mL) were withdrawn at the following times: At blood donation (time 0), 10 min after the addition of saline, heparin ± CMZ to the transfer packs (time 1), at start of CPB within 3 min of commencing circulation in the CPB circuit (time 2), and at 30 (time 3), 60 (time 4), 90 (time 5), and 120 (time 6) min after starting CPB.

Each sample was analyzed for adhesion molecule expression and determination of plasma cytokine concentrations. For measurement of adhesion molecule expression, 4 0.1-mL aliquots of whole blood were stained immediately using monoclonal antibodies for L selectin, CD18, and mouse immunoglobulin G (control) (Serotec, Kidlington, UK). The whole blood was then lysed to remove red cells, thus permitting the expression of surface markers on white cell populations to be determined using flow cytometry (FACScan cytofluorometer; Becton Dickinson, Mountain View, CA). Neutrophils were gated by their characteristic light scatter profile. The mean channel fluorescence intensity of stained neutrophils was detected on the basis of a minimal number of 5000 cells collected, analyzed using the FACScan Research Software version B (Becton Dickinson). At the same time, the second portion of blood from each sample was centrifuged to separate the plasma, which was then stored in polypropylene tubes at -70°C for subsequent analysis of cytokine concentrations. IL-6, IL-8, IL-1ß, and TNF-{alpha} plasma concentrations were determined using enzyme-linked immunosorbent assays (Quantikine R&D Systems Europe Ltd., Abingdon, Oxon, UK) according to manufacturer instructions. The sensitivity for IL-6, IL-8, IL-1ß, and TNF-{alpha} were: 0.7, 10, 1, and 4.4 pg/mL, respectively. The inter- and intra-assay precisions for IL-6, IL-8, IL-1ß, and TNF-{alpha} for the range of values obtained in this study are: 1.6%–4.2% and 3.3%–6.4%, 6.1%–9.7% and 5.4%–6.5%, 4.1%–8.4% and 2.8%–5.4%, 5.4%–7.4% and 4.2%–5.2%, respectively. Data were expressed as mean (SD). Blood-gas, acid-base, electrolyte values, adhesion molecule expression, and cytokine concentrations conformed to a normal distribution. Analysis of variance with post hoc testing with Student-Newman-Keuls where appropriate was used to analyze data. P < 0.05 was considered significant.


   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
During experimental extracorporeal circulation, there were no significant differences in blood-gas tension, acid-base and electrolyte values between control and CMZ groups (Table 1).


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  		Table 1. Blood-Gas and Acid-Base Variables, and Electrolyte Concentrations After 30 and 120 Min of Experimental Extracorporeal Circulation
 
Compared with baseline (time 0), the concentrations (pg/mL) of IL-6, IL-8, and TNF-{alpha} increased by the end of extracorporeal circulation (time 6—120 min) in control and CMZ groups (Tables 2 and 3). For each of these cytokines (IL-6, IL-8, and TNF-{alpha}), plasma concentrations were larger in the control than the CMZ groups at 60, 90, and 120 min (Tables 2 and 3). The concentrations of IL-1ß did not increase by the end of extracorporeal circulation compared with baseline in either group (Table 3).


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  		Table 2. IL-6 and IL-8 Plasma Concentrations
 

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  		Table 3. IL-1ß and TNF-{alpha} Plasma Concentrations
 
In both control and CMZ circuits, no significant increase in neutrophil CD18 expression was observed in either group throughout the experimental period. At 120 min after commencing circulation, but not before, neutrophil CD18 expression was less in the CMZ compared with the control group (237.5 [97.4] versus 280.5 [111.5], respectively, P = 0.03) (Fig. 1).



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  		Figure 1. Neutrophil CD18 expression in control and treated circuits. Values are expressed as mean channel fluorescence (MCF): control n = 5, clomethiazole n = 5. *P < 0.05 compared with corresponding control value. t0 = blood donation, t1 = 10 min after addition of drugs, t2 = 3 min after start of isolated bypass, t3 = 30 min after start of isolated bypass, t4 = 60 min of isolated bypass, t5 = 90 min after start of isolated bypass, and t6 = 120 min after start of isolated bypass.

 
Compared with baseline (time 0), neutrophil L selectin expression did not increase at any time, in either group (Fig. 2).



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  		Figure 2. Neutrophil L selectin expression in control and treated circuits. Values are expressed as mean channel fluorescence (MCF): control n = 5, clomethiazole n = 5. t0 = blood donation, t1 = 10 min after addition of drugs, t2 = 3 min after start of isolated bypass, t3 = 30 min after start of isolated bypass, t4 = 60 min of isolated bypass, t5 = 90 min after start of isolated bypass, and t6 = 120 min after start of isolated bypass.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
A marked inflammatory response to experimental isolated CPB was demonstrated by serial measurement of plasma concentrations of IL6, IL8, and TNF-{alpha} and of neutrophil CD18 expression. This response was less in blood to which CMZ (final concentration 40 µM) was added. In this experiment, any observed differences in the inflammatory response were unlikely to be attributed to differences in flow characteristics or acid-base status, because these variables were similar in the two groups.

TNF-{alpha} shares a central role with IL-1ß in initiating the inflammatory cascade. In the clinical setting, plasma concentrations of TNF-{alpha} increase during and after CPB (12). A significant increase in plasma TNF-{alpha} concentration with experimental extracorporeal circulation as in our model, is inconsistent with the findings of McBride et al. (12) in a similar model. In their study, large dose fentanyl was added to the isolated CPB circuits, CPB temperature was maintained at 28°C, and sampling performed for only 90 minutes. These factors may help explain differences in results. Similar to McBride et al. (12), in our study, plasma concentration of IL-1ß did not increase. This cytokine is increased at end of clinical CPB (13).

IL-6 is one of the mediators of the acute phase response. Of the proinflammatory cytokines, plasma concentration of IL-6 seems to be the most sensitive and increases correlate most closely with the magnitude of the inflammatory stimulus. Its plasma concentration is increased at end of clinical CPB (14). Using our model, a significantly increased plasma concentration of IL-6 was demonstrated, with less increase in the CMZ-treated circuits.

The proinflammatory cytokine, IL-8, promotes neutrophil integrin expression and facilitates transmigration of these cells along a concentration gradient (chemotaxis its primary role). Large concentrations of IL-8 are found in both plasma and bronchoalveolar lavage samples in cardiac surgery (15). In the current study, IL-8 concentrations increased in both groups during CPB, but to a markedly lesser degree in circuits to which CMZ had been added. The increase in plasma IL-8 concentration observed after 120 minutes was similar to that which occurs during clinical bypass (15) and after a similar period of experimental circulation (16).

In this study, there was no change in L selectin expression in the control group over time. This contrasts with several previous studies, which demonstrated marked shedding of L selectin in isolated CPB circuits (17). The lack of significant effect in our study may be attributed to the use of a staining technique, which minimized the effect caused by ex vivo cell manipulation (18). In the current study, whole blood was stained, and the excess stain then removed before cell separation. This ensured that adhesion molecules upregulated by the separation technique itself were not exposed to the fluorescent dyes. Our results are consistent with those of Gilliland et al. (19) who used a similar technique. It is interesting to note that the result of this study mimicked the clinical situation, which is not characterized by marked shedding of L selectin (20).

In contrast to its apparent lack of effect on L selectin, neutrophil CD18 expression was less in CMZ-treated circuits compared with controls at 120 min of circulation. Clinical significance of this result is uncertain because of large standard deviations. ß2 integrins are of fundamental importance in the interaction between neutrophils and endothelium. All members of this family share the ß subunit CD18, noncovalently bound to one of the {alpha} subunits, namely, CD11a, b, or c. The expression of CD18, therefore, reflects the expression of the whole family of ß2 integrins. Overall, however, our model did not demonstrate CD18 upregulation during circulation. These results differ from those observed during clinical bypass (21). In an experimental circulation model, McBride et al. (12) failed to demonstrate upregulation of neutrophil CD18. Because the groups in this study were relatively small (n = 5) and intersample variability was great, the lack of significance could represent a type II error. Indeed, post hoc power analysis revealed a >70% difference in CD18 expression would have been required to be detected with 80% power. The selection of five subjects per group was based on previously published research (12) in which the variability in neutrophil CD18 expression was considerably less than observed in the current study.

CMZ interacts with the p38 mitogen-activated protein kinase (MAPK) pathway by inhibiting phosphorylation of substrates hsp27 and ATF-2 (10). The MAPKs have a central role in mediating signal transduction in neutrophils in response to external stimuli (22). They are also important in integrin expression (23), IL-8 release (24), and priming of neutrophil respiratory burst (25). This offers an alternative (antiinflammatory) mechanism, a direct MAPK inhibitory action, by which the neuroprotective effects of CMZ may be mediated. The effects of CMZ on p38 activity in neutrophils have not been examined.

CMZ (68 mg/kg IV over 24 hours) administered within 12 hours of symptom onset has not improved outcome in patients with major ischemic stroke (26). A recent study (27) failed to demonstrate neuroprotectant efficacy of CMZ in CABG surgery. There was a trend toward a better outcome in the CMZ group but because of an unexpected small incidence of cognitive decline in the control group, the study may not have been adequately powered. A further study limitation was that change in cognitive test scores were compared without considering measurement error, practice, and level of education effects (28). CMZ infusion was discontinued at the end of surgery whereas the CPB inflammatory response persisted for 48 hrs postoperatively. This negative result is thus not definitive.

Our conclusions are limited because the experiments were performed with simulated CPB and not human CPB. The immune response in simulated CPB differs principally from in vivo CPB, because of a complete absence of a protective antiinflammatory response (15). A further difference is exposure to an endothelial surface. It is also pertinent to remember that these effects are induced by the repeated passage of diluted blood through an oxygenator at normothermia. The potential effects of hypothermia, rewarming, and exposure of this blood to the pulmonary and systemic vasculature are not assessed in this model. Proportionate relevance of contact activation may also be different. Study results must be interpreted against a background of a small sample size and large standard deviations.

In conclusion, this study confirms that CMZ has antiinflammatory properties. During experimental extracorporeal circulation, and in clinically relevant concentrations, CMZ decreased the magnitude of neutrophil adhesion molecule upregulation during experimental CPB. CMZ administration was associated with inhibition of the proinflammatory cytokines (IL-6, IL-8, and TNF-{alpha}). If such findings were duplicated in vivo, CMZ might be expected to attenuate some of the inflammatory response during cardiac surgery. This may be a further possible neuroprotective mechanism for this drug during CPB.


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication February 11, 2003.




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W. T. McBride, N. Khalil, P. Elliott, and M. Armstrong
Clomethiazole Alters Immune Function Within an Isolated Cardiopulmonary Bypass Circuit
Anesth. Analg., April 1, 2004; 98(4): 1191 - 1191.
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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