Ann Thorac Surg 2001;72:1945-1949
© 2001 The Society of Thoracic Surgeons
Original article: cardiovascular
High-dose cimetidine reduces proinflammatory reaction after cardiac surgery with cardiopulmonary bypass
Eiki Tayama, MD*a,
Nobuhiko Hayashida, MDa,
Shuji Fukunaga, MDa,
Keiichiro Tayama, MDa,
Toru Takaseya, MDa,
Ryouichi Hiratsuka, MDa,
Shigeaki Aoyagi, MDa
a Department of Surgery, Kurume University School of Medicine, Kurume-city, Japan
Accepted for publication August 8, 2001.
* Address reprint requests to Dr Tayama, Department of Surgery, Kurume University School of Medicine, 67 Asahi-machi, Kurume-city, 830-0011 Japan
e-mail: eiki{at}med.kurume-u.ac.jp
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Abstract
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Background. Cimetidine, which is usually used for gastric ulcer, enhances cellular immunity. The effect of cimetidine on perioperative proinflammatory response after cardiac surgery with cardiopulmonary bypass was investigated.
Methods. Elective coronary artery bypass graft cases in which CPB was performed were placed randomly in a cimetidine (C) group (n = 20) or a no-treatment (N) group (n = 20). The time course of plasma levels of neutrophil elastase, interleukin (IL)-6 and IL-8, leukocyte counts, lymphocyte recovery ratio, C-reactive protein, creatine-kinase-MB, and oxygenation index were analyzed.
Results. The plasma levels of neutrophil elastase and IL-8 were inhibited in the C groups at 2 hours after CPB termination. In a comparison of the two groups, the C group demonstrated higher lymphocyte recovery ratio and lower C-reactive protein on postoperative day 5 and shorter intubation time. No intergroup differences were observed in IL-6, leukocyte counts, creatine-kinase-MB levels, or oxygenation index.
Conclusions. Cimetidine may reduce surgical stress and augment the immune system after cardiac surgery with cardiopulmonary bypass.
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Introduction
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To reduce the inflammatory response and its subsequent damaging effects after open heart surgery various therapeutic modalities have been attempted, such as pharmacologic strategies (including corticosteroids, aprotinin, antioxidants, and others), modification of a mechanical device (heparin-coated circuit), and modification of surgical techniques (off-pump surgery). Cimetidine, a histamine type 2 (H2) receptor antagonist, is widely used for prophylaxis against the aspiration of gastric content syndrome and prevention of perioperative stress ulceration. In addition to this primary effect cimetidine increases immunoreactivity by activating interleukin (IL)-2 production [1, 2], inhibiting suppressor T lymphocyte activity [1, 3], and enhancing natural killer cell activity [4]. Subsequently those enhanced immunoresponses lead to improved long-term outcome of malignant disease treatment and intensive care unit management [5]. However, little is known about the immunoreactive effects of perioperative administration of cimetidine in cardiac surgery [6], particularly with regard to proinflammatory mediators. The objective of this study was to clarify how cimetidine affects proinflammatory mediators and to determine whether it is useful as a therapeutic agent for cardiac surgery with cardiopulmonary bypass (CPB).
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Patients and methods
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A total of 40 scheduled coronary artery bypass surgery cases (no combined surgery, valve operation, left ventricle aneurysmectomy, or carotid endarterectomy) were placed randomly into the cimetidine (C) group (n = 20) or the no-treatment (N) group (n = 20). Patients with severe diabetes or chronic obstructive pulmonary disease were excluded. All patients signed a consent form approved by the Human Experimental Committee of Kurume University. The C-group patients orally received 200 mg of cimetidine (SmithKline Beecham, Tokyo, Japan) on the preoperative night and on the morning of the operative day. Soon after induction of anesthesia, 400 mg of cimetidine was intravenously infused for more than 20 minutes. In addition, 200 mg of this drug was administered intravenously every 6 hours after surgery until postoperative day (POD) 2. The N-group patients were administered no H2 blocker perioperatively. To avoid any of various immunoreactive effects of the steroid neither group used it perioperatively.
The extracorporeal circulation circuit consisted of a QUADROX Bioline oxygenator/reservoir (JOSTRA, Hirrlingen, Germany) and a Carmeda BioMedicus BP-80 centrifugal pump, tubing, and an arterial filter (Medtronic, Minneapolis, MN). The entire blood contact surface was heparin bonded. Before initiating the CPB, 300 IU/kg of heparin was administrated intravenously in both groups. Additional heparin was given if needed to maintain an activated clotting time of greater than 480 seconds. Cold antegrade blood cardioplegia and moderate general hypothermia (30°C to 32°C) were employed. After termination of CPB, 1.5 mg of protamin was administrated for each 100 IU of heparin. Additional protamin was given if necessary.
Peripheral blood samples were taken to measure plasma levels of neutrophil elastase (enzyme immunoassays), interleukin (IL)-6 and IL-8 (enzyme-linked immunosorbent assay) at the following time points: before systemic heparinization (pre-CPB), 60 minutes into CPB initiation (CPB-60 minutes), at termination of CPB (end-CPB), 2 hours after CPB termination (post-CPB-2 hours), and at POD1. All tubes containing anticoagulants were kept on ice until centrifugation, which was performed within 3 hours.
The lymphocyte recovery ratio, which represented the actual circulating lymphocyte count divided by the preoperative lymphocyte count, was derived preoperatively and on POD1, 3, and 5. On the same timing leukocyte count and C-reactive protein (CRP) were also measured. The value of creatine kinase-MB isoenzyme (CK-MB) was monitored preoperatively (preop), immediately postoperation (end-op), 3 hours after return to the intensive care unit (ICU-3 hours), and POD1.
To evaluate the clinical impacts, time course of oxygenation index and intubation time were also analyzed. Oxygenation index, which represented PaO2 divided by FiO2, was measured at preop, end-op, ICU-3 hours, ICU-6 hours, ICU-9 hours, and ICU-12 hours.
Statistical analyses
The data were expressed as the mean ±SD. A two-way repeated-measures analysis of variance was used to analyze effects of group or time of neutrophil elastase, IL-6, IL-8, leukocyte count, lymphocyte recovery ratio, CRP, CK-MB, and oxygenation index. When analysis of variance indicated significant effects of group or time, the differences were specified with unpaired Student’s t test. Unpaired Student’s t test was also used for other various factors to analyze differences between the two groups. A p value less than 0.05 was considered statistically significant.
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Results
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Patient characteristics and variables pertaining to the operations were comparable (Table 1). The postoperative course was uneventful in all patients.
Table 2 shows time differences for all measurements and significant group differences were seen in neutrophil elastase, IL-8, lymphocyte recovery ratio, and CRP. The plasma neutrophil elastase levels in the C group were significantly lower at the end of CPB (1298.3 ± 811.2 µg/L versus 1920.8 ± 984.7 µg/L, p = 0.0354) and 2 hours after CPB termination (1328.4 ± 698.7 µg/L versus 2228.4 ± 1150.2 µg/L, p = 0.0049; Fig 1). The levels of IL-8 (45.8 ± 39.6 pg/mL versus 234.7 ± 158.5 pg/mL, p < 0.0001) was inhibited at 2 hours after CPB termination by treatment (Fig 2). The lymphocyte recovery ratio decreased initially (POD1), then gradually increased in both groups (Fig 3). The postoperative lymphocyte recovery ratio level in the C group showed a relatively higher tendency (although it was not statistically significant except on POD5). On POD5, the C group demonstrated apparently higher lymphocyte recovery ratio levels (120.8% ± 45.9% versus 83.6% ± 22.3%, p = 0.014) with lower CRP (4.8 ± 2.9 versus 7.3 ± 3.2, p = 0.026) than in the N group (Fig 4). Additionally, intubation time of the C group was shorter than that of the N group (8.63 ± 3.29 hours versus 12.0 ± 4.14 hours, p = 0.007).
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Fig 1. The time course of plasma concentration of neutrophil elastase is shown (mean ± SD). The plasma neutrophil elastase levels in the C group were significantly lower at the end of cardiopulmonary bypass (CPB) and 2 hours after CPB. (Squares = cimetidine-treated group; circles = no-treatment group; POD = postoperative day. *p < 0.05; ** p < 0.01.)
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Fig 2. The time course of the plasma concentration of interleukin-8 is shown (mean ± SD). At post-cardiopulmonary bypass (CPB) 2 hours, the plasma concentration of interleukin-8 in the cimetidine-treated group was significantly lower than that in the no-treatment group. (Squares = cimetidine-treated group; circles = no-treatment group; POD = postoperative day. *p < 0.001.)
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Fig 3. The time course of the lymphocyte recovery ratio, which represented the actual circulating lymphocyte count divided by the preoperative lymphocyte count (mean ± SD). At postoperative day (POD) 5, the cimetidine-treated group demonstrated significantly higher lymphocyte recovery ratio than did the no-treatment group. (Squares = cimetidine-treated group; circles = no-treatment group. *p < 0.01.)
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Fig 4. The plasma level of C-reactive protein. At postoperative day (POD) 5, the cimetidine-treated group demonstrated significantly lower C-reactive protein levels than did the no-treatment group. (Squares = cimetidine-treated group; circles = no-treatment group. *p < 0.05.)
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In contrast, no statistical group differences were observed in the levels of IL-6, leukocyte count, CK-MB, or oxygenation index. Postoperative blood loss and amount of blood products requirement were comparable in two groups.
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Comment
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It has been well documented that CPB produces a systemic inflammatory response syndrome attributable to the release of proinflammatory mediators such as complements, cytokines, and neutrophil elastase [7, 8]. The degree of release of these mediators is thought to be associated with the incidence of postoperative organ failure and mortality. If proinflammatory cytokines or neutrophil elastase production could be reduced during and after CPB, some postoperative organ failure such as cardiac dysfunction and respiratory distress syndrome might be avoided. To date a number of therapeutic interventions to minimize the cytokine response including pharmacologic agents, heparin coating circuits, and hemofiltration have been investigated.
Cimetidine, an H2 blocker, is widely known as a gastric ulcer medicine. However, this medicine is uniquely effective on the immunoresponse system. Cimetidine has been shown to increase immunoreactivity by activating interleukin-2 production [1, 2], inhibiting suppressor T lymphocyte activity [1, 3], and enhancing natural killer cell activity [4]. Improved immunoreactivity by cimetidine has been considered to be associated with prolonged survival time in patients with malignant disease [5] and with improvement in resistance to infection [9]. In the field of cardiovascular surgery, Katoh and associates [6] reported that perioperative administration of cimetidine inhibited reduction of natural killer cell activity on postoperative day 1 in cardiac operations with CPB. They concluded that cimetidine may preserve cell-mediated immune response and decrease susceptibility to infection. In contrast, there is a concern that excessive enhanced cellular function may lead to auto-injury. Our study attempted to clarify whether cimetidine has the potential to reduce proinflammatory response in patients undergoing CPB.
This study demonstrated that a perioperative high dose of cimetidine reduces postoperative production of neutrophil elastase and IL-8. Although there were no statistical differences, IL-6 also demonstrated similar tendencies. Those proinflammatory factors are known to be increased in response to CPB and to reflect the degree of inflammatory injury [8]. Neutrophil elastase has been implicated in neutrophil-mediated endothelial injury in vitro in vital tissues [9] and impairs respiratory function due to pulmonary leukosequestration, increased pulmonary permeability, and compartmental fluid changes [7]. Raised IL-6 level has been linked to cardiac dysfunction after CPB (8) and IL-8 can activate neutrophils and increase endothelial cell permeability associated with CPB [10] and can also stimulate histamine release [11, 12]. Thus, reduced production of these proinflammatory factors should contribute to reduce the postoperative distant organ failure associated with CPB. Additionally, the recovery from lymphocytopenia showed a stronger tendency in the C group than in the N group although a statistical difference was seen only on POD5. The lymphocyte recovery ratio level represents the degree of surgical stress and has consequently been proposed as a simple postoperative prognosis indicator [13]. Higher lymphocyte recovery ratio in the C-group indicated surgical stress was lessened therefore, possibly by preserved cellular immunity.
Another advantageous aspect for postoperative management by cimetidine may be reflected in respiratory function: the C group showed shorter intubation time although oxygenation index was not clearly improved.
There were no intergroup differences in postoperative CK-MB value. This finding may suggest that cimetidine does not have a protective effect on the myocardium during or after ischemia. The myocardium has been considered to be a major source of IL-6 and IL-8 after myocardial ischemia or infarction [12]. However, reduced proinflammatory cytokine production by cimetidine was not considered to be a result of reduced myocardial ischemic damage.
No adverse or advantageous effects were observed on circulation in this series. However, bolus administration of cimetide may lead to hypotension [14], slow drip infusion was recommended [15]. Additionally, administrated dose should be reduced for patients with renal dysfunction and for elderly patients [15].
The mechanisms of reduced production of proinflammatory cytokines and improved lymphocyte recovery ratio are still unclear. Histamine inhibits several lymphocyte functions and reduces the production of lymphokines such as macrophage migration-inhibitory factor, leukocyte migration-inhibitory factor [16], IL-2, interferon-
[17], and tumor necrosis factor-
[18]. Further, histamine also inhibits the production of IL-1–like activity by lipopolysaccharide-stimulated human manocytes [19]. Because cimetidine blocks these effects by histamine it may improve immunologic reaction. In fact, one previous report indicated that cimetidine completely reversed the histamine-mediated increase in IL-1--induced IL-6 synthesis [20]. As previously described, cimetidine inhibits suppressor T-lymphocyte activity, increases IL-2 production, and enhances natural killer cell activity [3, 4]. In addition cimetidine has the most potent antioxidative activity of well-known OH scavengers including mannitol and dimethyl sulfoxide [21]. Because reactive oxygen species contribute to the production of proinflammatory cytokines [22], reduced proinflammatory cytokines might be associated with inhibition of reactive oxygen.
Interestingly cimetidine, ranitidine, and famotidine show different immunomodulating effects. Cimetidine seems to have the strongest effect on immunomodulation, followed by ranitidine then famotidine [4]. These differences may be associated with structural differences. The high lipid-solubility of cimetidine may lead to alteration of the physical properties of membranes. At this juncture, it is unclear whether cimetidine’s immunologically beneficial effects can be expected from other type H2 blockers.
High-dose administration of cimetidine reduced production of perioerative neutrophil elastase and IL-8, improved recovery from postoperative lymphocytepenia, and inhibited CRP response. No adverse effects were observed. Our findings indicate that cimetidine is useful as a therapeutic agent to reduce inflammatory reaction and augment the immune system after cardiac surgery with CPB.
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Abstract
Introduction
