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Anesth Analg 2002;95:531-536 © 2002 International Anesthesia Research Society
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Clinical Biochemistry and  |
Abstract |
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Surgery is associated with activation of neutrophils and their influx into affected tissue. The pathogenic role of superoxide production generated by activated neutrophils has been documented repeatedly. Ketamine suppresses neutrophil oxygen radical production in vitro. In the present study, we compared the effect of adding small-dose ketamine to opioids during the induction of general anesthesia on superoxide production by neutrophils after coronary artery bypass grafting (CABG). Thirty-five patients undergoing elective CABG were randomized to one of two groups and prospectively studied in a double-blinded manner. The patients received either ketamine 0.25 mg/kg or a similar volume of saline in addition to large-dose fentanyl anesthesia. Blood samples were drawn before the operation, immediately after cardiopulmonary bypass, 24 and 48 postoperative h, and on postoperative Days 3–6. Functional capacity of neutrophils was assessed by superoxide generation after stimulation with phorbol 12-myristate 13-acetate, opsonized zymosan, or formyl-methionyl-leucyl-phenylalanine. The addition of small-dose ketamine to general anesthesia attenuates increased production of the superoxide anion (O2-) by neutrophils without chemical stimulation and after stimulation with phorbol 12-myristate 13-acetate, formyl-methionyl-leucyl-phenylalanine, and opsonized zymosan for 4–6 days after CABG. In addition, ketamine attenuated the percentage of neutrophils on postoperative Days 2–6. In the Control group, superoxide production significantly increased compared with the baseline value. By contrast, in the Ketamine group, this difference was not significant.
IMPLICATIONS: In a randomized, double-blinded, prospective clinical study, we compared the effect of adding small-dose ketamine to opioids during general anesthesia on superoxide production and showed that ketamine suppressed the increase of superoxide anion production by neutrophils after coronary artery bypass grafting.
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Introduction |
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Several studies have suggested that neutrophils and inflammatory mediators play an important role in the pathogenesis of postoperative complications (1). The inflammatory response to cardiac surgery has received considerable attention (2), and it is considered that blood contact with the surface of extracorporeal circuit apparatus, surgical trauma, and reperfusion injury may contribute to morbidity and mortality after cardiac surgery. Therefore, cardiopulmonary bypass (CPB) has been proposed as a model for studying the inflammatory pathways involved in the systemic inflammatory response syndrome (3). Modulation of neutrophil responses by anesthetics may have an important role in limiting tissue injury after CPB. Interleukin-6 (IL-6) delays neutrophil apoptosis, resulting in larger populations of surviving neutrophils with greater collective capacity for superoxide production, and this may be the mechanism whereby IL-6 contributes to organ dysfunction (4). In a previous study, our group demonstrated that a single dose of ketamine 0.25 mg/kg administered before CPB as an addition to general anesthesia suppressed the increase in serum IL-6 levels during coronary artery bypass grafting (CABG) and for 7 days after surgery (5). In addition, ketamine inhibits tumor necrosis factor alpha (TNF-
) production in a dose-dependent manner, inhibits leukocyte adherence in the rat (6,7), and suppresses neutrophil oxygen radical production in vitro (8). However, there are no reports on the effects of small-dose ketamine on superoxide production by neutrophils clinically. In the present study, we compared the effect of adding small-dose ketamine to opioids during general anesthesia on superoxide production by neutrophils after CPB for CABG. |
Methods |
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Thirty-five patients undergoing elective CABG were randomized from hospital registration numbers to one of two groups and prospectively studied in a double-blinded manner. The institutional ethics committee approved the protocol for the study, and written informed consent was obtained from all participating patients. Patients were assigned to one of two experimental groups: a control group that was managed according to a standardized anesthetic regimen of large-dose fentanyl and a ketamine group that received in addition a bolus of small-dose ketamine during the induction of anesthesia. Patients excluded from the study included those with a left ventricular ejection fraction of <0.4, those requiring preoperative inotropic or intraaortic balloon pump support, and those with uncontrolled systemic disease (diabetes, hypertension, or renal failure). All patients received antianginal and antihypertensive medications until and including the day of surgery. Patients receiving aspirin or nonsteroidal antiinflammatory drugs had these discontinued 10 days before surgery. At the time of operation and after surgery, no patients were receiving corticosteroid therapy. All patients were premedicated with intramuscular injections of morphine 0.1 mg/kg and scopolamine 0.3–0.4 mg 60 min before the induction in addition to their usual cardiac medication. On arrival in the operating room, patients received 1–2 mg of midazolam IV, and oxygen was administered via a face mask. Thereafter, radial artery and right internal jugular catheters were inserted under local anesthesia. Continuous monitoring of two electrocardiograph leads (II and modified V5), radial artery pressure, central venous pressure, oxygen saturation, end-tidal carbon dioxide, and esophageal, rectal, and myocardial temperatures was performed. After CPB, left atrial pressures were continuously monitored via a catheter inserted through the left superior pulmonary vein. In all patients, anesthesia was induced by IV fentanyl 15 µg/kg, midazolam 10 mg, and pancuronium 0.1 mg/kg.
Patients were randomized to receive an IV bolus of either ketamine 0.25 mg/kg (Ketamine group) or an equal amount of isotonic sodium chloride solution (Control group). Maintenance of anesthesia was provided by fentanyl and midazolam, and blood pressure was controlled by isoflurane and nitroglycerine. All patients were ventilated to achieve normocapnia using a pressure-controlled ventilator with an inspired oxygen fraction of 1.0. All operations were performed by the same two surgeons using similar techniques. Before CPB, all patients received 300 U/kg of heparin for anticoagulation, with reversal by protamine to normal activated coagulation time after CPB. Aprotinin was not administered to any patient in the study. CPB was performed using a membrane oxygenator (Polystan Safe II; Polystan A/S, Vaerlose, Denmark) with nonheparin-coated tubing from the same manufacturer. The aorta was cross-clamped immediately after achieving satisfactory CPB, and cardioplegia was administered consisting of a mixture of four parts autologous blood to one part St Thomas Hospital II cardioplegia. Mild hypothermia (32°C rectal temperature) was maintained, and pump flows were adjusted to maintain a nonpulsatile perfusion pressure of 70–90 mm Hg.
After CABG, patients were transferred to the intensive care unit where postoperative care was standardized for all patients with ventilation to maintain PaO2 >70 mm Hg and normocapnia; weaning and extubation were performed in all patients 6–8 h after surgery when deemed clinically appropriate. To ensure postoperative hemodynamic stability, patients were initially treated with adequate fluid replacement and an infusion of dopamine (3–5 µg · kg-1 · min-1). Patients who required more aggressive inotropic support (epinephrine or norepinephrine) were removed from the study. All patients received cefuroxime 750 mg every 8 h for a further 48 h.
Allogeneic packed red blood cells were transfused whenever the hematocrit decreased to less than 20%. Patients and personnel involved in patient management and data collection were unaware of the assigned group. All side effects and patient complications were recorded by a physician who was unaware of the study groups. Blood samples for the analysis of neutrophils were drawn from the antecubital vein before the operation, immediately after CPB, at 24 and 48 postoperative h, and on postoperative Days 3–6. After collection of blood samples, 95% purity of neutrophils was obtained by Ficoll/Hypaque centrifugation, dextran sedimentation, and hypotonic lysis of erythrocytes, as previously described (9). Cells were counted, and viability was determined by trypan blue exclusion.
Superoxide Generation
The production of the superoxide anion (O2-) by intact granulocytes was measured as the superoxide dismutase inhibitable reduction of acetyl-ferricytochrome C by the microtiter plate technique, as previously described (9). Superoxide production by the cells was stimulated by the addition of phorbol 12-myristate 13-acetate (PMA)(50 ng/mL), opsonized zymosan (OZ) (1 mg/mL), or formyl-methionyl-leucyl-phenylalanine (FMLP) (0.1 µg/M). The reduction of acetyl ferricytochrome C was followed by the change of absorbance at 550 nm at 2- to 5-min intervals on a Thermomax Microplate Reader (Molecular Devices, Melno Park, CA). The maximal rates of superoxide generation were determined and expressed as nanomoles O2-/103 cells/10 min using the extinction coefficient E550 = 21 mM - 1 cm2. Statistical analysis was performed using Stata 7.0 (StataCorp, College Station, TX). Unpaired two-sample t-test was used to test the difference between the mean in the two groups. The paired t-test was used to test the relationship between initial values and values of different observation time points. Results are expressed as mean ± SD. P < 0.05 was considered significant.
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Results |
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Thirty-five patients were enrolled in the study and randomized into two groups. Sixteen patients were entered into the Ketamine group, and 19 patients were entered into the Control group, with no significant differences in patient characteristics. The method and amounts of anesthesia were similar. Both groups had nearly identical CPB, cross-clamping, and operation times (Table 1). There was no mortality in either group. In the Control group, there were four patients with either hemodynamic instability or low output syndrome after surgery. In the Ketamine group, one patient had a CPB time more than 160 min. These patients were excluded from the study. All patients in both groups required an allogeneic packed red blood cell transfusion (two units) either during surgery or in the immediate postoperative period. In the Ketamine group, the total dosage requirement of fentanyl during the operation was smaller (22 µg/kg) than that in the Control group (32 µg/kg), but the difference was not significant. Heart rate, mean arterial blood pressure, and central venous pressure were recorded for all patients. At no time was there any significant difference in these variables between the two groups.
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Superoxide generation of neutrophils was assessed after stimulation with PMA, FMLP, OZ, and without stimulation. The production of the superoxide anion (O2-) by neutrophils after stimulation with PMA is shown in Figure 1. Both groups had similar superoxide anion (O2-) levels before surgery, immediately after separation from CPB, 24 h, 48 h, 72 h, and on the fourth day after surgery. On postoperative Days 5 and 6, superoxide generation in the Ketamine group was significantly smaller (P < 0.001 and P < 0.0001). In addition, in the Control group superoxide production significantly increased compared with the baseline value (P < 0.015). By contrast, in the Ketamine group, this difference was not significant.
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The production of O2- by neutrophils after stimulation with FMLP is shown in Figure 2. In both groups, the preoperative, post-CPB, 24-h, and 48-h postoperative levels of O2- were similar. Seventy-two hours after CPB, levels of O2- increased in the Control group. On postoperative Days 4, 5, and 6, there were significant differences between the two groups. In the Control group, superoxide generation significantly increased compared with the baseline value (P < 0.01). In the Ketamine group, there was no significant difference.
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The production of the O2- by neutrophils after stimulation with OZ is shown in Figure 3. In both groups, the preoperative, post-CPB, 24-h, 48-h, and 72-h postoperative levels of O2- were similar. On postoperative Days 4, 5, and 6, the levels of O2- significantly increased in the Control group (P < 0.04, P < 0.02, and P < 0.0005, respectively). Superoxide anion levels were significantly higher in the Control group compared with the baseline value (P < 0.007). In the Ketamine group, there was no statistically significant difference.
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The production of the O2- by neutrophils without stimulation is shown in Figure 4. In both groups, the preoperative, post-CPB, 24-h, and 48-h levels of O2- were similar. On postoperative Days 4, 5, and 6, the levels of O2- were significantly higher in the Control group (P < 0.05, P < 0.04, and P < 0.0006, respectively). In the Control group, superoxide production significantly increased compared with the baseline value (P < 0.015 and P < 0.001), but there was no significant difference in the Ketamine group.
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Total blood neutrophil count (Fig. 5) was significantly lower in the Ketamine group on the second, third, fourth, fifth, and sixth days after the CPB (24 h, 48 h, and 72 h, P < 0.03; fourth, fifth, and sixth days, P < 0.05).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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This study suggests that the addition of small-dose ketamine (0.25 mg/kg) to general anesthesia attenuates increased production of the superoxide anion (O2-) by neutrophils after stimulation with PMA, FMLP, and OZ, and in the absence of chemical stimulation for four to six days after CPB. In the Control group, superoxide generation significantly increased compared with the baseline value. By contrast, in the Ketamine group, there was no significant difference. In addition, in our study, small-dose ketamine attenuated increased percentages of neutrophils on postoperative Days 2, 3, 4, and 6.
Once an inflammatory response is initiated, neutrophils are the first cells to be recruited to sites of infection or injury (1). Under normal conditions, neutrophils can migrate to sites of injury without damage to host tissues. This damage may occur through activation during migration, adherence to endothelium or epithelium, extracellular release of substances from damaged cells, or as a consequence of superoxide generation through xanthine oxidase. The initial rolling step is initiated by an injury-mediated increase in endothelial P-selectin expression, which interacts with its neutrophil counterreceptor, P-selectin glycoprotein 1. Interaction of leukocyte ß2 integrins, CD 11a/CD 18 and CD 11b/CD 18, with endothelial intercellular adhesion molecule 1 results in firm neutrophil adherence (10). Neutrophil transmigration into the interstitial compartment is facilitated by platelet-endothelial cell adhesion molecule 1 (11,12). Neutrophils are responsive to many chemotaxins, including activated complement fragments (C5a), TNF-, IL-1, and IL-6. Macrophages may produce cytokines that increase neutrophil activation, and at the inflammatory site, mainly activated neutrophils are present (11). Under the conditions of CPB and aortic cross-clamping, the heart and the lungs are excluded from the circulation. After release of the aortic cross-clamp, reperfusion of the heart leads to a cardiac inflammatory response, as evidenced by the transcardiac release of proinflammatory cytokines (TNF- and IL-6), and activated neutrophil adhesion (12). Tonz et al. (1) suggested that acute lung injury, as a result of oxidative injury during CPB, is related to the activation of neutrophils; these may be inappropriately recruited to the pulmonary bed producing systemic edema, ventilation/perfusion mismatch, hypoxemia, and atelectasis. Neutrophil adhesions to microvascular endothelium, extravasation, and tissue damage are the final steps of inflammatory response to injury. The systemic response to inflammation induces the production of IL-1 and TNF-, which induce synthesis of IL-6. The key cytokine in routine surgery is IL-6; this cytokine reflects activation of the inflammatory cascade, and there is general agreement that the magnitude and duration of the IL-6 response reflects the inflammatory changes after surgical trauma (13,14). Neutrophil apoptosis may be one of the mechanisms of limiting tissue injury at sites of inflammation. Phagocytosis of apoptotic neutrophils inhibits the release of proinflammatory cytokines. IL-6 delays neutrophil apoptosis, resulting in larger populations of surviving neutrophils with a greater collective capacity for superoxide production. The IL-6 treated populations produce more superoxide after 24 hours than controls (4). Anesthesia has little effect on the inflammatory response to surgery because it cannot influence tissue trauma directly (15–17). Remifentanil, fentanyl, and alfentanil do not influence neutrophil function, even in concentrations larger than those encountered during in vivo conditions (18). However, our group demonstrated that small-dose ketamine (0.25 mg/kg), added to opioid-based anesthesia, suppressed the increase of serum IL-6 during and after cardiac surgery (5).
Immunomodulatory influences of ketamine deserve special interest and may be important when ketamine is used for the induction of anesthesia in patients with sepsis, reducing the need for inotropic support in septic patients (19). Van der Linden et al. (20) studied the effects of four often used anesthetics, halothane, isoflurane, alfentanil, and ketamine, on cardiovascular function and oxygen balance in a dog model of septic shock. Ketamine preserved cardiovascular function best and seemed to have the least deleterious effects on hypoxic tissues. Kawasaki et al. (21) suggested that the protective effects of ketamine in septic patients are because of suppression of the excessive production of proinflammatory cytokines. Ketamine suppresses neutrophil oxygen radical production in vitro (7) and modulates the stimulated adhesion molecule expression on human neutrophils (22). Schmidt et al. (7) suggested that ketamine inhibits endotoxin-induced leukocyte adherence in postcapillary venules as a result of inhibitory production of TNF-. When ketamine was given after endotoxin-induced injury in chronically instrumented sheep, lung injury was significantly attenuated in this group (23). Ketamine, as an acute modulator of neutrophil activation, may be helpful in states of acute inflammation, such as postischemic reperfusion (24).
We do not know the mechanism of ketamine suppression of superoxide anion (O2-) production in patients after CPB. Ketamine had no effect on superoxide anion production by neutrophils in blood samples obtained from healthy adult volunteers at clinically relevant concentrations but inhibited it at larger concentrations in vitro (25).The use of neutrophils from patients with acute respiratory distress syndrome or after cardiac surgery may elicit different results. During CPB, our patients were maintained mildly hypothermic (32°C rectal temperature). The cellular response to the extracorporeal circulation is significantly delayed, but not attenuated, in hypothermic patients (1).In normothermia, neutrophil activation reached a peak at two days after ischemia but shifted to three days in hypothermia (26).Neutrophil functions are clinically influenced by multiple factors, which are present in patients during CPB. Our experimental protocol standardized these factors, such as method and amounts of anesthetic, with nearly identical CPB, cross-clamping, and operation times. Regarding outcome, all patients were discharged from the hospital on the seventh postoperative day, whereas five patients with perioperative and postoperative complications were removed from the study. In our patients, the inflammatory response as represented by superoxide levels after cardiac surgery often remained at subclinical levels within the limitation of the standardization of our study.
The results of this study indicate that ketamine decreases superoxide anion (O2-) production by neutrophils after cardiac surgery, which is an intriguing observation that requires further clinical evaluation. This attenuation may be caused by the inhibition of proinflammatory cytokine production.
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References |
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- Tonz M, Mihaljevic T, von Segesser LK, et al. Acute lung injury during cardiopulmonary bypass: are the neutrophils responsible? Chest 1995; 108: 1551–6.
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[Abstract/Free Full Text] - Roytblat L, Talmor D, Rachinsky M, et al. Ketamine attenuated the interleukin-6 response after cardiopulmonary bypass. Anesth Analg 1998; 87: 266–71.
[Abstract/Free Full Text] - Takenaka I, Ogata M, Koga K, et al. Ketamine suppresses endotoxin-induced tumor necrosis factor- production in mice. Anesthesiology 1994; 80: 402–8.[Web of Science][Medline]
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- Brix-Christensen V, Tónnesen E, Sorensen IJ, et al. Effects of anaesthesia based on high versus low doses of opioids on the cytokine acute-phase protein responses in patients undergoing cardiac surgery. Acta Anaesthesiol Scand 1998; 42: 63–70.[Web of Science][Medline]
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[Abstract/Free Full Text] - Kawasaki T, Ogata M, Kawasaki C, et al. Ketamine suppresses proinflammatory cytokine production in human whole blood in vitro. Anesth Analg 1999; 89: 665–9.
[Abstract/Free Full Text] - Weigand MA, Schmidt H, Zhao Q, et al. Ketamine modulates the stimulated adhesion molecule expression on human neutrophils in vitro. Anesth Analg 2000; 90: 206–16.
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