Anesth Analg 2006;103:809-814
© 2006 International Anesthesia Research Society
doi: 10.1213/01.ane.0000237308.28739.d8
CARDIOVASCULAR ANESTHESIA
Clonidine Attenuated Early Proinflammatory Response in T-Cell Subsets After Cardiac Surgery
Vera von Dossow, MD*,
Nadine Baehr, Cand Med*,
Maryam Moshirzadeh, MD*,
Christian von Heymann, MD*,
Jan P. Braun, MD*,
Ortrud V. Hein, MD*,
Michael Sander, MD*,
Klaus-D Wernecke, PhD
,
Wolfgang Konertz, MD
, and
Claudia D. Spies, MD*
From the *Department of Anesthesiology and Intensive Care Medicine, Campus Virchow-Klinikum and Campus Charité Mitte, Charité; Institute of Medical Biometry, Campus Charité Mitte, Charité; Department of Cardiovascular Surgery, Campus Charité Mitte, Charité, Universitaetsmedizin Berlin, Berlin, Germany.
Address correspondence and reprint requests to Claudia Spies, MD, Professor of Anesthesiology, Department of Anesthesiology and Intensive Care Medicine, Campus Virchow-Klinikum and Campus Charité Mitte, Charité, Universitaetsmedizin Berlin, Schumannstr. 20/21, 10117 Berlin, Germany. Address e-mail to claudia.spies{at}charite.de.
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Abstract
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T-cells play a central role in the immune response to injury. Cardiac surgery is associated with significant risk of systemic inflammatory response syndrome and subsequent unbalanced induction of proinflammatory cytokines. As clonidine has immunomodulating properties via reducing sympathetic activity, this study involved the analysis of T-cell function in the early postoperative period in patients undergoing coronary artery bypass graft surgery. Forty patients undergoing cardiac surgery were randomly allocated to one of the following groups: clonidine group (n = 20) [clonidine 1 µg kg–1 h–1] and placebo group (n = 20). Study medication was started after induction of anesthesia and maintained until 6 h after surgery. Blood samples to determine Th1 and Th2 cells and cytotoxic lymphocytes (Tc1 and Tc2 cells) were drawn preoperatively, on admission to the intensive care unit, 6 and 12 h postoperatively as well as on the morning of days 1 and 2 after surgery. In the clonidine group significantly lower levels of Th1/Th2 ratios as well as Tc1/Tc2 ratios were found 6 h postoperatively compared to the placebo group (P < 0.05). Clonidine changed the ratio of T-lymphocyte subpopulations in peripheral blood in favor of a proinflammatory response, which might be favorable for maintaining immune balance after surgery.
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Introduction
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Cardiac surgery with cardiopulmonary bypass (CPB) may induce a systemic inflammatory response syndrome characterized by hemodynamic, respiratory, and biological disturbances resulting from a combination of several factors, including surgical trauma, myocardial ischemia/reperfusion, and endotoxin release (1,2). A prolonged activation of the immune system can lead to an increased risk of postoperative complications, especially postoperative infections, and ultimately, multiple organ failure (3,4). Furthermore, increased levels of proinflammatory cytokines have generally been associated with negative outcome after cardiac surgery (1).
Systemic inflammatory response syndrome after cardiac surgery and its influence on host immunity remains a significant problem, as it is associated with a massive, unbalanced induction of cytokines (5). Previous studies revealed that cardiac surgery resulted in alterations within the specific, adaptive immune system which primarily affects T helper cells (5,6). The so-called "proinflammatory Th1-mediated pathway" has been shown to be temporarily depressed while the so-called "antiinflammatory Th2-mediated pathway" remains unaffected or is even upregulated, which has been associated with an increased susceptibility for postoperative infections (6,7). However, T-cells can augment immune responses locally and systemically (8,9). An early Th1 response after surgery has been hypothesized to support the inflammatory response by producing the cytokines interleukin (IL)2, IL-12 and interferon (IFN)-
(5), which might reflect the magnitude of the initial inflammation.
The 
-2 agonist, clonidine, reduces anesthetic requirements attenuating sympathoadrenal responses during surgery and reducing plasma concentrations of norepinephrine (NE) through stimulation of presynaptic 2 adrenoceptors (AR) (10,11). While the use of clonidine during coronary artery bypass graft surgery (CABG) did not appear to influence the perioperative stress response (12), its immunomodulatory effects in the context of CPB remain to be characterized. Since ß-AR are expressed on CD4+ helper and CD8+ cytotoxic cells (13), only these cell types would be expected to be sensitive to inhibition of NE (14). Swanson et al. (15) found that exposure of naive CD4+ T cells to NE during the process of differentiation into Th1 cells caused these cells to produce higher levels of IFN- than cells that had not been exposed to NE. In addition, patients with chronic heart failure receiving ß-adrenergic-blocker therapy exhibited significantly lower Th1/Th2 ratios, lower NE plasma levels, and decreased proinflammatory cytokine production. Furthermore, Liebmann et al. (16) suggested that ß-adrenergic-blocker therapy might enhance the immunosuppressive property of 2-adrenergic drugs.
We investigated the influence of perioperative clonidine infusion on the early T-cell immune response, i.e., on Th1/Th2 ratios as well as Tc1/Tc2 ratios in patients undergoing elective CABG surgery.
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METHODS
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Forty patients undergoing elective CABG surgery were included in this prospective, randomized, double-blind, controlled study after we received the approval of our institutional human investigation committee and written informed consent from the patients. Entry criteria included patients older than 18 yr with three-vessel-disease, stable angina pectoris, left ventricular ejection fraction over 40%, left ventricular end-diastolic pressure less than 17 mm Hg, absence of significant preexisting pulmonary disease (determined by clinical examination, chest radiography, lung function tests, and blood gas analysis). Exclusion criteria were patients < 18 yr, any history of impairment of the immune system, immunosuppressive therapy, and signs of preexisting infection (white cell blood count >12,000/µL, body temperature >38°C, C-reactive protein >5 mg/dL) as well as liver insufficiency (>Child B). Patients undergoing off-pump cardiac surgery or hypothermic bypass were also excluded. Patients with increased catecholamine therapy (NE >0.15 µg kg–1 min–1, dopamine >10 µg kg–1 min–1) before, during, and after surgery, massive transfusion (>4 allogenic transfusions), as well as patients with rethoracotomy were excluded from the study.
Oral premedication was with 1–2 mg flunitrazepam the evening before surgery and 0.07–0.1 mg kg–1 of oral midazolam half an hour before transfer to the operating room. Before induction of anesthesia, all patients received 7–10 mL kg–1 of balanced crystalloid solution. Anesthesia was induced in all patients with etomidate (0.2 mg kg–1), fentanyl (5–7 µg kg–1), and pancuronium bromide (0.1 mg kg–1). Anesthesia was maintained with isoflurane 1.0 MAC and fentanyl IV (5–10 µg kg–1 h–1) (17).
Group Assignment
Patients were randomized to one of the following groups: the clonidine group and the placebo group. After induction of anesthesia, continuous infusion of the study medication was started with 1.0 µg kg–1 h–1 intraoperatively and was maintained until 6 h postoperatively. According to the study protocol, postoperatively, patients in the clonidine group received clonidine 1–3 µg kg–1 h–1 whereas patients in the placebo group received saline infusion. The degree of sedation was measured guided by the Bispectral index (BIS) and using the Ramsay Sedation Score (18). Clonidine infusion was adjusted according to adverse hemodynamic responses and BIS measurements: if study dosage achieved maximum rate (3 µg kg–1 h–1) and BIS > 75, propofol was additionally administered (0.5–3 mg kg–1 h–1) in both groups. In addition, all patients received boli of morphine (2–5 mg IV) postoperatively on demand.
Intraoperatively patients' lungs were ventilated with a tidal volume of 6 mL kg–1, adjusting the respiratory rate to an end-tidal carbon dioxide of 32–34 mm Hg. Normoventilation was confirmed by hourly blood gas tension measurements and continuous measurement of the end-expiratory carbon dioxide concentration. Perioperative antibiotic prophylaxis was provided with three doses of 1.5 g of cefuroxime after induction of anesthesia, after weaning from CPB and 6 h after admission to the intensive care unit (ICU).
All patients received 400 IU kg–1 heparin before commencement of CPB so as to achieve an activating clotting time more than 400 s. Membrane oxygenators (Quadrox®; Jostra, Hirlingen, Germany) were used for normothermic, nonpulsatile CPB. The pump flow rate was set to more than 2.5 L min–1 m–2, and the mean arterial blood pressure was kept to more than 50 mm Hg. The pump was primed with 800 mL of balanced crystalloid solution and 500 mL of hydroxyethyl starch solution (10%). During commencement of extracorporal circuit, all patients received a total of 50,000 KIU kg–1 of aprotinin. Cardiac arrest was induced and maintained by intermittent anterograde administration of warm-blood cardioplegia solution enriched with potassium (19). Hemodynamic variables (mean arterial blood pressure) and oxygen-related variables were measured via arterial radial catheter as well as via a central venous catheter (central venous pressure) continuously and via blood gas analysis. The total amount of intraoperative vasoactive drugs and cardiac pacing requirements were recorded. The patients' intraoperative urine volume was documented. Body temperature was measured using a Foley catheter with a thermistor tip (Tyco Healthcare, Neustadt, Germany). According to our institutional standard (17), dopamine and glycerol trinitrate were used as required during weaning from CPB. Red blood cell transfusions were given to maintain hematocrit levels more than 23%–24% during CPB. Continuous five-lead automated ST segment analysis was used to detect intraoperative myocardial ischemia. Ischemia was defined as ST segment depression > 1 mm or elevation > 2 mm at 60 ms after the J point, persisting for at least 2 min. Transesophageal echocardiography was used according to our clinical standard (17).
All patients remained endotracheally intubated and mechanically ventilated for transfer to the ICU and remained sedated 2 h postoperatively according to our standard to assure no postoperative bleeding. Patients were weaned from mechanical ventilation as soon as they were normothermic, hemodynamic stability had been established, and blood loss was satisfactory (<100 mL h–1) (17). Tracheal extubation was performed when the patient was awake, cooperative, and successfully weaned from the respirator (20). Heart rate, mean arterial blood pressure, central venous pressure, oxygen saturation as well as blood temperature were monitored continuously. Venous blood samples to determine immune variables as well as C-reactive protein, leukocytes, and lactate were taken preoperatively, on admission to the ICU, 6 h, 12 h postoperatively as well as on the first and second postoperative day. Cardiovascular and respiratory adverse events were defined as a change in arterial blood pressure of more than 20% from baseline, bradycardia <50 bpm, tachyarrhythmia, and a respiratory rate less than 8 or more than 25 breaths per minute after tracheal extubation. In the postoperative course the Acute and Chronic Health Evaluation Score (APACHE II) as well as the duration of ICU stay and hospital stay were documented. The study was blinded intraoperatively and postoperatively.
Th1/Th2 and Tc1/Tc2 cytokine ratios from peripheral blood T-cells were analyzed by flowcytometric measurement of intracellular cytokine production after in vitro whole blood stimulation with phobol-12-myristate-13-acetate and ionomycin. The working procedure was based on the protocol for flowcytometric measurement of intracellular cytokine production (Becton Dickinson, Heidelberg, Germany). Cell preparation, cell culture as well as the staining and stimulation procedure are described in a previous publication (21).
Multiparameter Flow Cytometric Analysis
A FACScan Cytometer (Becton Dickinson) fitted with a 15 mW air-cooled 488-nm argon ion laser and filter settings for FITC (530 nm), PE (585 nm), and PE-Cy5 emitting in the deep red (>650 nm) was used. Data acquisition on the flow cytometer was done with FACScan Research Software (Becton Dickinson). After appropriate instrument settings and spectral compensations, the settings were not changed and stability was regularly checked with fluorescent beads (CalibriteTM 3, Fa. Becton Dickinson). A minimum of 15,000 events was computed using log-amplified fluorescence signals and linearly amplified side scatter and forward scatter signals. The data were analyzed using Cell QuestTM Software (Becton Dickinson) and results were shown as percentage of positive cells. A gate was set around the lymphocyte cluster on forward scatter versus side scatter dot plots to exclude monocytes, neutrophils, and debris from data analysis. Negative control reagents were used to verify the staining specificity of experimental antibodies and as a guide for setting markers to delineate positive and negative populations. According to the literature, the ratios were given as percentages of: Th1/Th2 ratio: % IFN CD3+ CD4+/%IL-4 CD3+ CD8–; Tc1/Tc2 ratio: % IFN CD3+ CD8++/%IL-4 CD3+ CD8++.
To exclude natural killer cells, monocytes, dendritic cells, it was a prerequisite that CD3+CD8– and CD3+CD4+ were 5% or less and CD3+CD8+ and CD3+CD4– were 5% or less.
The cytokines tumor necrosis factor (TNF)-, IL-6, IL-8, and IL-10 were analyzed by a sandwich enzyme-linked immunosorbent assay (Enzyme Immunoassay Kit, Immunotech, Beckman Coulter Company, Marseille, France). Blood samples were collected in iced sterile tubes (EDTA/serum) and after centrifugation the supernatants were stored in liquid nitrogen at –70°C. Detection limits (EDTA-plasma) were as follows: IL-6: 3 pg mL–1 (4.6% and 12.1% intra- and interassay variation coefficient, respectively); IL-8: 8 pg mL–1 (5.0%–11.1%), IL-10: 5 pg mL–1 (3.0% and 7.0%).
Blood samples to determine cytokines of lipopolysaccharide (LPS)-stimulated whole blood cells were drawn preoperatively, on admission to ICU, 6 h postoperatively, and on the morning of day 1 and 2 after surgery. Heparinized whole blood, 50 µL, was incubated at 37°C for 4 h with the stimulation solution containing culture medium with 500 pg/mL lyophilized LPS. Whole blood cells were stimulated to produce cytokines, in particular, TNF-, IL-12, and IL-10 which were measured in the supernatant after centrifugation for 5 min at 1,000g using commercially available kits (Quantikine® Immunoassay Kit; R&D Systems, Minneapolis, MN): TNF-: 4.4 pg mL–1 (4.6% and 5.8%); (Enyzme Immunoassay Kit; Immunotech, Beckman Coulter Company): IL-12: 5 pg mL–1 (2.8%–6.7%) and IL-10: 5 pg mL–1 (3.0%–7.0%).
Plasma adrenocorticotrophic hormone (ACTH) concentrations were determined by commercially available immunoassay kits (Immulite® ACTH; Diagnostic Products Cooperation, Los Angeles, CA). The assay sensitivity was 9 pg mL–1 (3.1% and 5.9%). Plasma cortisol concentrations were analyzed using a commercially available kit (Calibrator kit, Bayer Corporation, BGD, Tarrytown, NY). The assay sensitivity was 5.5 pg mL–1 (3.1% and 9.1%).
All data were expressed as median and quartiles. All parameters with respect to time were analyzed using nonparametric multivariate analysis of variance (MANOVA) for repeated measurements in a two-factorial design [first factor (group): placebo group versus clonidine group, second factor (time)] (22), the Mann–Whitney U-test, and Fisher's exact test, respectively. A P-value <0.05 was considered significant. The numerical calculations were performed with SAS for WINDOWS, Release 8.02; Copyright 1999–2001, SAS Institute, Cary, NC.
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RESULTS
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Thirty-five patients were included in the data analysis (Fig. 1). Basic patient characteristics as well as surgery and comorbidities did not differ between groups (Table 1). None of the patients received acetylsalicylic acid before surgery. All patients received autotransfusion of shed blood from the thoracic cavities during and after CPB, whereas only 9 patients (clonidine Group 6 patients versus placebo Group 3 patients) received allogenic transfusion to maintain hematocrit more than 23%–24% during CPB.
Hemodynamic variables, including mean arterial blood pressure, heart rate as well as central venous pressure, did not differ between groups (Table 2). However, dopamine dosage was significantly increased in the clonidine group (P < 0.05) (Table 2). Clinical signs of ischemia, ST-elevations, myocardial isoenzyme activity, and creatine kinase-MB (CK-MB) > 10% of CK if CK exceeded 80 U/L, or troponin T > 0.2 µg/L plus clinical or electrocardiogram signs of acute myocardial ischemia at any time after surgery did not differ between groups. Ramsay Sedation Score and BIS did not differ between groups. Propofol consumption was significantly less in the clonidine group compared to the placebo group, whereas morphine consumption did not differ between groups (Table 3).
In the clonidine-group Th1/Th2 ratio (Fig. 2, P < 0.05) as well as Tc1/Tc2 ratio (Fig. 3, P < 0.05) were significantly lower 6 h postoperatively compared to the placebo group. In addition, plasma IL-10 levels were not significantly lower in the clonidine Group 6 h postoperatively [162.6 pg mL–1 (47.0–273.0)] compared to the placebo group [217.4 pg mL–1 (116.6–314.6)]. No differences were found between the groups with respect to plasma cytokines TNF-, IL-6, IL-8, and LPS-stimulated cytokines in whole blood cells (TNF-, IL-12, and IL-10). Conventional laboratory variables, such as leukocytes and C-reactive protein, did not differ between groups in the perioperative course. Plasma lactate levels were significantly lower 12 h after operation in the clonidine group compared to the placebo group (Fig. 2, P 
0.05). ACTH and cortisol plasma levels did not differ between groups. APACHE III score on admission to ICU as well as the ICU stay did not differ between groups (Table 3).
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Figure 2. Perioperative Th1/Th2 ratio. Th1/Th2 = T-helper-cell ratio; gray plots: placebo-group; white plots: clonidine-group; preop: preoperative; ICU: admission to intensive care unit; postop 6 h: 6 h after surgery; postopd1: day 1 after surgery; postopd2: day 2 after surgery; *P = 0.021 (intergroup).
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Figure 3. Perioperative Tc1/Tc2 ratio. Tc1/Tc2 = cytotoxic T-lymphocyte ratio; gray plots: placebo-group; white plots: clonidine-group; preop: preoperative; ICU: admission to intensive care unit; postop 6 h: 6 h after surgery; postopd1: day 1 after surgery; postopd2: day 2 after surgery; *P = 0.034 (intergroup).
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DISCUSSION
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In this randomized, double-blind controlled study, we demonstrated significantly lower Th1/Th2 ratios and Tc1/Tc2 ratios in the clonidine group 6 h after cardiac surgery. No differences were found with respect to plasma cytokine levels or LPS-stimulated cytokines in whole blood cells.
This is the first study to investigate the influence of perioperative clonidine infusion on the early T-cell response (i.e., on Th1/Th2 as well as on Tc1/Tc2 ratios) in patients undergoing elective CABG surgery with the use of CPB.
In our study, Th1/Th2 ratios and Tc1/Tc2 ratios were significantly lower 6 h postoperatively in the clonidine group compared to the placebo group. As previous studies demonstrated a surgery-induced enhanced early phase of lymphocyte activation, we used the flow cytometry method for quantifying early T-cell activation (5,23). A greater augmentation of lymphocyte activation in CD4+ (Th) cells compared to CD8+ (Tc) cells during the postoperative period was demonstrated by Shimaoka et al. (23). In addition, Th1 cells may support an inflammatory response by producing the cytokines IL-2, IL-12, and IFN- (5). It was hypothesized that this early T-cell response might reflect the magnitude and nature of the initial immunoinflammation (5). In contrast to our findings, Ellis and Pedlow (24) reported no influence of clonidine on lymphocyte subsets, but a significant decrease of NE plasma levels in patients undergoing major noncardiac surgery. Decreased NE plasma levels after clonidine administration have been reported previously (10), especially in patients undergoing cardiac surgery (25). Dorman et al. (10) hypothesized that the major effect of 2-adrenergic receptor agonists is on tonic activity while sympathetic nervous system responsivity to stressful stimuli appears to be unaffected. The above-mentioned studies are difficult to be compared with our study because of the different study designs (premedication with clonidine versus continuous infusion, IV, or orally administered, measurement of circulating T-cell populations versus measurement of their functional activity) and patient collective (noncardiac versus cardiac surgery).
However, the influence of the sympathetic nerve system on the immune system, in particular the cell-mediated immune system, is not fully understood (26). A previous study (27) presented evidence that catecholamines may be pivotal in the immunomodulation of Th1 and Th2 cell interactions. Interestingly, ß-ARs have been documented on CD4+ and CD8+ T cells (28). In particular, they are expressed solely on naive CD4+ helper T cells but not on Th2 cells (27). ß-AR activation caused cytokine production by T cells (28). Swanson et al. (15) found that exposure of naive CD4+ T cells to NE during the process of differentiation into Th1 cells caused these cells to produce higher levels of IFN- after antigen stimulation than cells that had not been exposed to NE. In addition, ß-adrenergic-blocker therapy caused significantly lower Th1/Th2 ratios and decreased NE levels as well as lower IFN- levels in patients with chronic heart failure (14). This means, considering the above-mentioned studies, that clonidine might have caused the observed changes limited on the T-cell subset response by reducing sympathetic tone whereas the systemic inflammatory response was not affected. Therefore, future studies are needed to clarify the role of clonidine in the context of the systemic inflammatory response.
In our study, we noted no effect of clonidine on ACTH, cortisol concentrations, or on plasma cytokines and LPS-stimulated whole blood cells, which is in accordance with previous studies (29,30).
Our study has several limitations due to the fact that multiple modifying factors might have biased the immune response after cardiac surgery. All patients in our study received aprotinin according to our clinical standard (17), which is known to have antiinflammatory effects. In addition, allogenic blood transfusion and autolog transfusion of shed blood from the thoracic cavities, given during and after CPB, support the proinflammatory response. Furthermore, middle-sternotomy, surgery, per se, as well as the type of extracorporal circuit and temperature during CBP might influence the inflammatory response. However, there were no differences between groups. As this was a pilot study, we cannot conclude that timing of sample intervals was adequate, reflecting the influence of clonidine on postoperative Th1/Th2 ratio as well as Tc1/Tc2 ratio. However, in this study we focused on the immunomodulatory effect of clonidine on T-cell subsets in the early postoperative period.
In conclusion, Th1/Th2 as well as Tc1/Tc2 ratios were significantly lower 6 h after cardiac surgery with clonidine compared to placebo. A possible explanation might be that clonidine, by reducing sympathetic tone via 2-AR, changed the early T-cell subset response in favor of the proinflammatory response after cardiac surgery. This might be important for maintaining immune balance perioperatively. However, the systemic inflammatory response was not affected by clonidine in this study. Therefore, additional investigations are needed to better define the role of 2 adrenergic drugs in cardiac surgery.
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Footnotes
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Accepted for publication June 6, 2006.
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REFERENCES
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|---|
- Paparella D, Yau TM, Young E. Cardiopulmonary bypass induced inflammation: pathophysiology and treatment. An update. Eur J Cardiothorac Surg 2002;21:232–44.[Abstract/Free Full Text]
- Doerge H, Schöndube FA, Doerge P, et al. Procalcitonin is a valuable prognostic marker in cardiac surgery but not specific for infection. Thorac Cardiovasc 2003;51:322–6.
- Sablotzki A, Friedrich I, Mühling J, et al. The systemic inflammatory response syndrome following cardiac surgery: different expression of proinflammatory cytokines and procalcitonin in patients with and without multiorgan dysfunctions. Perfusion 2002;17:103–9.[Abstract/Free Full Text]
- Angele MK, Faist E. Clinical review: immunodepression in the surgical patients and increased susceptibility to infection. Crit Care 2002;6:298–305.[ISI][Medline]
- Hirai S. Systemic inflammatory response syndrome after cardiac surgery under cardiopulmonary bypass. Ann Thorac Cardiovasc Surg 2003;9:365–70.[Medline]
- Franke A, Lante W, Feckeldey V, et al. Pro-inflammatory cytokines after different kinds of cardio-thoracic surgical procedures: is what we see what we know? Eur J Cardiothorac Surg 2005;28:569–75.[Abstract/Free Full Text]
- Markewitz A, Lante W, Franke A, et al. Alterations of cell-mediated immunity following cardiac operations: clinical implications and open questions. Shock 2001;16:10–15.[Medline]
- Sweeney KJ, Kell MR, Coates C, et al. Serum antigen(s) drive the proinflammatory T cell response in acute pancreatitis. Br J Surg 2003;90:313–9.[ISI][Medline]
- Kell MR, Kavanaugh EG, Goebel A, et al. Injury primes the immune system for an enhanced lethal T-cell response against bacterial superantigen. Shock 1999;12:139–44.[ISI][Medline]
- Dorman T, Clarkson K, Rosenfeld B, et al. Effects of clonidine on prolonged sympathetic response. Crit Care Med 1997;25:1147–52.[ISI][Medline]
- Tank J, Jordan J, Diedrich A, et al. Clonidine improves spontaneous baroreflex sensitivity in conscious mice through parasympathetic activation. Hypertension 2004;43:1042–7.[Abstract/Free Full Text]
- Loick HM, Schmidt C, Van Aken H, et al. High thoracic epidural anesthesia, but not clonidine, attenuates the perioperative stress response via sympatholysis and reduces the release of troponin T in patients undergoing coronary artery bypass grafting. Anesth Analg 1999;88:701–9.[Abstract/Free Full Text]
- Khan MM, Sansoni P, Silverman ED, et al. ß-Adrenergic receptors on human suppressor, helper and cytolytic lymphocytes. Biochem Pharmacol 1986;35:1137–42.[ISI][Medline]
- Gage JR, Fonarow G, Hamilton M, et al. ß-Blocker and angiotensin-converting enzyme inhibitor therapy is associated with decreased Th1/Th2 cytokine ratios and inflammatory production in patients with chronic heart failure. Neuroimmunomodulation 2004;11:173–80.[ISI][Medline]
- Swanson MA, Lee WT, Sanders, VM. IFN- production by Th1 cells generated from naive CD4 (+) T cells exposed to norepinephrine. J Immunol 2001;166:232–40.[Abstract/Free Full Text]
- Liebmann PM, Hofer D, Felsner P, et al. ß-blockade enhances adrenergic immunosuppression in rats via inhibition of melatonin release. J Neuroimmunol 1996;67:137–42.[ISI][Medline]
- Kox W, Spies C. Cardiac anesthesia. In: Kox WJ, Spies C, eds. Check-up anesthesiology. Berlin: Springer, 2003:446–8.
- Ramsay MAE, Savege TM. Controlled sedation with alphaloxone/alphadalone. BMJ 1974;2:656–9.[ISI][Medline]
- Braun JP, Schroeder T, Buehner S, et al. Splanchnic oxygen transport, hepatic function and gastrointestinal barrier after normothermic cardiopulmonary bypass. Acta Anesthesiol Scand 2004;48:697–703.[ISI][Medline]
- Ely EW, Patricia A. Large scale implementation of a respiratory therapist-driven protocol for ventilator weaning. Am J Respir Crit Care Med 1999;159:439–46.[Abstract/Free Full Text]
- Spies CD, von Dossow V, Eggers V, et al. Altered cell-mediated immunity and increased postoperative infection rate in chronic alcoholic patients. Anesthesiology 2004;100:1088–100.[ISI][Medline]
- Brunner E, Domhof S, Langer F. Non-parametric analysis of longitudinal data in factorial experiments. New York: Wiley, 2002.
- Shimaoka M, Hosotsubo K, Sugimoto M, et al. The influence of surgical stress on T cells: enhancement of early phase lymphocyte activation. Anesth Analg 1998;87:1431–5.[Abstract/Free Full Text]
- Ellis JE, Pedlow S. Premedication with clonidine does not attenuate suppression of certain lymphocyte subsets after surgery. Anesth Analg 1998;87:1426–30.[Abstract/Free Full Text]
- Kulka P, Tryba M, Zenz M. Dose-response effects of Intravenous clonidine on stress response during induction of anesthesia in coronary artery bypass grafting. Anesth Analg 1995;80:263–8.[Abstract]
- Elenkow I, Wilder R, Chrousos GP, Vizi SE. The sympathetic nerve – an integrative interface between two supersystems: the brain and the immune system. Pharmacol Rev 2000;52:595–638.[Abstract/Free Full Text]
- Sanders VM, Baker RA, Ramer-Quinn DS, et al. Differential expression of the ß-2-adrenergic resceptor by Th1 and Th2 clones: implications for cytokine production and B cell help. J Immunol 1997;158:4200–10.[Abstract]
- Kohm AP, Sanders VM. Norepinephrine and ß2-adrenergic receptor stimulation regulate CD4+ T and B lymphocyte function in vitro and in vivo. Pharmacol Rev 2001;53:487–525.[Abstract/Free Full Text]
- Kim MH, Hahn TH. The effect of pre-treatment on the perioperative proinflammatory cytokines, Cortisol and ACTH responses in patients undergoing total abdominal hysterectomy. Anesth Analg 2000;90:1441–4.[Abstract/Free Full Text]
- Venn RM, Bryant A, Hall GM, Grounds RM. Effects of dexmedetomidine on adrenocortical function, and the cardiovascular, endocrine and inflammatory responses in postoperative patients needing sedation in the intensive care unit. Br J Anaesth 2001;86:650–6.[Abstract/Free Full Text]
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Abstract
Introduction
