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Ann Thorac Surg 1997;63:129-137
© 1997 The Society of Thoracic Surgeons
Division of Cardiovascular Surgery, Research Institute of Angiocardiology, Faculty of Medicine, Kyushu University, Fukuoka, Japan
Accepted for publication July 19, 1996.
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Abstract |
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 TopFootnotes Abstract IntroductionPatients and MethodsResultsCommentAcknowledgmentsReferences |
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Methods. Twenty-four patients undergoing valve replacement were studied in a randomized, double-blind trial. Twelve of these patients (S group) received bolus methylprednisolone, 20 mg/kg body weight, and the remaining 12 patients (C group) received a placebo intravenously before and after bypass. Blood cell count, C-reactive protein, lymphocyte surface markers (CD3, CD4, CD8, CD16, and CD20), phytohemagglutinin response, interleukin-2 production, and natural killer cell activity were examined on admission through day 7. Cardiac output, blood gas, electrolyte, lactate, and serum glucose levels were examined perioperatively.
Results. The peak white blood cell count in the S group was higher than that in the C group (analysis of variance: p [group] = 0.0436). The peak C-reactive protein level was higher in the C group than in the S group (p [group] < 0.0001). From the analysis of the surface markers, the steroid increased the natural killer cells before and soon after bypass (p [group] = 0.0117), and later tended to increase the CD4+ T and B cells during the postoperative recovery period. The phytohemagglutinin response in both groups decreased after bypass (p [time] < 0.0001), but the steroid caused exaggerated decreases before (p < 0.01 by Student's t test) and soon after (p < 0.001) bypass in the S group (analysis of variance: p [group] = 0.0127). The interleukin-2 production was suppressed by bypass alone after the bypass in the C group, but was further suppressed by the steroid before and after bypass in the S group (p [group] = 0.0446). The cardiac index, water balance, electrolytes, arterial oxygen tension, and timing of extubation were not different between the groups. In contrast, the glucose (p [group] = 0.0486) and lactate (p [group] = 0.0525) levels were higher in the S group than those in the C group.
Conclusions. T-cell functions are synergistically suppressed by cardiopulmonary bypass and high-dose methylprednisolone in heart operations. The hemodynamic benefits of the steroid are negligible, whereas glucose tolerance is worsened by the steroid during bypass.
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Introduction |
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TopFootnotesAbstractIntroductionPatients and MethodsResultsCommentAcknowledgmentsReferences |
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Massive administration of a corticosteroid before and after CPB has been a part of the pump technique for more than 20 years at our institution. However, we have previously reported that both posttransfusion graft-versus-host disease and postoperative wound infection were significant problems at our institution [16, 17]. Although the cause of the extremely wide prevalence of graft-versus-host disease after heart operations only in Japan is still enigmatic [18], the steroids commonly (>80% by our own survey) used in Japan for CPB may contribute to the pathogenesis of posttransfusion graft-versus-host disease after heart operations.
In the present study, therefore, we examined the effects of CPB and methylprednisolone on patients' immunologic activities during and after heart operations. To detect subtle differences, we examined not only the lymphocyte surface markers but also lymphocyte functions. Those included T-cell proliferation, interleukin-2 productivity, and natural killer (NK) cell activity. Metabolisms, hemodynamics, and infection markers including C-reactive protein were also examined to follow the diverse actions of the steroid.
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Patients and Methods |
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TopFootnotesAbstractIntroductionPatients and MethodsResultsCommentAcknowledgmentsReferences |
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There was no mortality during the study, but patients who underwent intraaortic balloon pumping (n = 1) or allogeneic blood transfusion (n = 2) were excluded from this study at the halfway point. The opened envelope was passed onto the next patient. Of the remaining 24 patients, 12 (S group) received methylprednisolone (Solu-Medrol; Upjohn Co, Kalamazoo, MI), 20 mg/kg body weight, and the other 12 (C group) received a placebo (saline solution) intravenously 5 to 10 minutes before and after CPB. This experimental dose of methylprednisolone (total dose, 40 mg/kg) has been used at our institution for the past 10 years in all the pump cases.
Technique of Cardiopulmonary Bypass
The extracorporeal circuit consisted of a hollow-fiber membrane oxygenator (Univox IC; Baxter Healthcare Corp, Irvine, CA) with an arterial line filter (AF-1025D; Baxter). Polyvinylchloride tube (Baxter) and silicone rubber pump tube (Bakelite; Sumitomo Co, Ltd, Tokyo, Japan) were used. The circuit was primed with 1,800 mL of Ringer's lactate solution, 150 mL of 25% human albumin, 60 mEq of sodium bicarbonate, 1,000 mg of vitamin C, and 2,000 mg of cefmetazole. A nonpulsatile flow of 2.5 L • min-1 • m-2 and moderate hypothermia (28°C of rectal temperature) were used. Meticulous check of the venous cannulas for appropriate venous drainage was performed throughout the CPB period to prevent positive water balance of CPB. To correct excess of water balance caused by crystalloid cardioplegia (approximately 2 L) infusion [19] and ice slush (approximately 1 L) for topical cooling, the extracorporeal ultrafiltration method with a hemoconcentrator (HC-100N; Senko Medical Instruments Co, Ltd, Tokyo, Japan) was used.
Heparin (300 IU/kg body weight) was given intravenously before cannulation of the aorta, and was neutralized by an intravenous drip-infusion of 300 IU/kg of protamine sulfate within 5 minutes after the end of CPB. The water balance of CPB (in milliliters) was recorded at the end of CPB.
Technique of Anesthesia and Operation
Anesthesia was started with a bolus of fentanyl (20 µg/kg) followed by pancuronium (0.1 mg/kg). A total of 100 µg/kg of fentanyl was usually used by the end of operation. Nitroglycerin administration (1 µg • kg-1 • min-1) was started at the beginning of CPB. In all patients, prosthetic valve replacement with a CarboMedics valve (CarboMedics Co, Ltd, Austin, TX) was performed. Inotropic drugs were given on demand at the time of weaning from CPB. Blood salvaged with a cell-saving device (Haemonetics, Braintree, MA) and thawed autologous blood were used to maintain left atrial pressure at 5 to 12 mm Hg in the operating room. The water balance of anesthesia including the pump balance was recorded at the end of anesthesia. Intraoperative insulin was not used for any of the patients throughout this study.
Hematology
Blood samples to examine the immunologic parameters were taken from the patients on admission, 5 minutes after bolus injection of heparin and methylprednisolone (or placebo) but soon before the start of CPB (Pre-CPB), 5 minutes after the end of drip infusion of protamine and bolus injection of methylprednisolone (or placebo) (Post-CPB), and on days 1, 3, 5, and 7. Radial arterial lines were used to draw blood when available.
All blood samples were kept at an appropriate temperature, and were sent to and examined by SRL Hachioji Laboratory (SRL Co, Ltd, Tokyo, Japan) within 24 hours. All the tubes that contained anticoagulant (and medium) for each assay were prepared by the SRL. The samples were not processed at our institution before transfer to the laboratory. Tests on the samples included complete blood cell count, C-reactive protein, lymphocyte surface markers (CD3 [Leu4] for pan T cells, CD4 [Leu3a] for helper/inducer T cells, CD8 [Leu2a] for killer/suppressor T cells, CD16 [Leu11] for NK cells, and CD20 [B1] for B cells) examined by flow cytometry, phytohemagglutinin blastoid response examined by 3H-thymidine uptake of T lymphocytes, interleukin-2 production of concanavalin A-stimulated lymphocytes examined by the radioimmunoassay, and NK cell activity examined by cytotoxicity against 51Cr-labeled K-562 cells. These assay methods used by the SRL, Japan's largest laboratory test company, were similar to the methods that we have previously described in the murine systems [20, 21].
For analysis of the kinetics of lymphocyte subsets, the absolute number (
= total lymphocyte count given by the complete blood count x composition of each subset given by the flow cytometry) was demonstrated at each time point.
Hemodynamics, Metabolism, and Blood Gas
In all patients, a Swan-Ganz catheter (744H-7.5; Baxter) was inserted in the operating room, and the cardiac output was examined before initiating CPB, after terminating CPB, and 3, 6, and 12 hours after the operation. Blood gas, electrolyte (Na+, K+, Cl-, and Ca++), lactate, and serum glucose levels were examined every 30 to 60 minutes in the operating room.
Postoperative Care
In the intensive care unit, all patients' lungs were ventilated until an air/oxygen mixture of 0.3 and a positive end-expiratory pressure of 5 cm H2O could sufficiently keep the arterial oxygen tension greater than 100 mm Hg. Ten percent glucose solution (800 mL • m-2 • 24 h-1) was used as a standard infusion. The blood from the cell-saving device, thawed autologous blood, and 4.4% human albumin solution were given to keep the left atrial filling pressure at 5 to 12 mm Hg. Dopamine and dobutamine were administered to keep the mean arterial pressure above 70 mm Hg. All patients received nitroglycerin, 0.5 to 1.0 µg • kg-1 • min-1, as a vasodilator. Patients were sedated with haloperidol on demand. After the extremities were sufficiently warmed, bolus furosemide (5 to 20 mg) was intravenously given when the patients' arterial oxygen tension was lower than the predetermined level. Furosemide was also used to control higher potassium levels and higher filling pressures.
The patients were extubated usually on day 1 or 2 postoperatively. The patient's body weight was measured every day. Digoxin (0.125 to 0.25 mg/day), furosemide (20 to 80 mg/day), and spironolactone (25 to 50 mg/day) were orally started on the day of extubation in all patients.
Statistical Analysis
The data were usually expressed as mean ± standard deviation. The kinetic data in the two groups were first analyzed by the two-way repeated measure analysis of variance (ANOVA). Student's t test was performed to compare the values between the two groups. The 
2 test with Yates' correction was used to compare the incidence in the two groups. A p value was calculated by means of the SAS system at the Kyushu University Hospital. A p-value of less than 0.05 was taken to be significant.
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Results |
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TopFootnotesAbstractIntroductionPatients and MethodsResultsCommentAcknowledgmentsReferences |
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. No significant differences in sex, age, operation, number of reoperation, body size, and number of diabetic patients were observed between the two groups. Also, no differences between the two groups were seen in operative time, CPB time, and aortic cross-clamp time. The water balance during CPB and anesthesia was similar in both groups. In all patients, cryopreserved autologous concentrated blood and plasma were transfused. The amount of the transfusion was similar in both groups. The maximal levels of creatine kinase and creatine kinase-MB fraction among those patients examined 3, 6, 12, 24, and 72 hours after aortic declamping were not significantly different in the two groups. The maximal doses of dopamine plus dobutamine that were used in the operating room and intensive care unit were also similar in both groups. The patients were extubated in 1.42 ± 0.64 days (range, 1 to 3 days) in the S group and 1.30 ± 0.46 days (range, 1 to 2 days) in the C group (not significantly different). Postoperative wound infection was not observed in either of the two groups.
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). The peak white blood cell count that appeared on days 1 to 3 in the S group was higher than that in the C group (p < 0.01 by Student's t test on day 1; ANOVA: p [group] = 0.0436, p [time] < 0.0001, p [interaction] = 0.0023). The lymphocyte count tended to be higher in the S group throughout the test period than that in the C group (p < 0.01 by Student's t test on day 7; ANOVA: p [group] = 0.0615, p [time] < 0.0001, p [interaction] = 0.5923) (Fig 1b). The hemoglobin levels and platelet counts were not different between the groups (data not shown).
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). The body weight increased on day 1 by the operation from 56.8 ± 11.0 kg (admission) to 57.9 ± 11.6 kg (day 1) in the C group, whereas it increased from 59.1 ± 9.3 kg to 59.8 ± 9.6 kg in the S group (Fig 1d). However, there was no significant difference between the groups (ANOVA: p [group] = 0.7273, p [time] < 0.0001, p [interaction] = 0.0049).
Changes in T, B, and Natural Killer Cells
The CD3+ pan T cells significantly decreased after CPB and reached the minimal values on day 1 in both groups (Fig 2a). No difference in this value was evident between the groups (ANOVA: p [group] = 0.1717, p [time] < 0.0001, p [interaction] = 0.0900), but the CD3+ cell number tended to increase more (p < 0.05 by Student's t test on day 7) in the S group by day 7 (Fig 2b).
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The CD16+ NK cells increased at the Post-CPB point and decreased by day 3 in the C group. In the S group, however, the CD16+ cells significantly increased by the steroid treatment alone at the Pre-CPB point (p < 0.01 by t test), and further increased at the Post-CPB point (p < 0.05), followed by gradual decrease by day 3 (ANOVA: p [group] = 0.0117, p [time] < 0.0001, p [interaction] = 0.0002) (Fig 2c).
Changes in T-Cell Subsets
The changes in CD4+ T cells were generally similar to the changes in the CD3+ pan T cells (Fig 3a). The CD4+ T cells decreased to the minimal value at the Post-CPB point, then gradually recovered in both groups (Fig 3a). The calculated CD4+ T-cell numbers were similar in both groups at the Pre-CPB and Post-CPB points, but the recovery of the cell number in the S group tended to be faster than that in the C group (p < 0.01 by Student's t test on day 7; ANOVA: p [group] = 0.0785, p [time] < 0.0001, p [interaction] = 0.0069) (Fig 3a).
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The CD4/CD8 ratio, which represents the host's immunocompetence, decreased at the Post-CPB point and then returned to normal on day 1 in both groups (Fig 3c). The ratio further increased by day 7 in both groups, but there was no difference between the two groups [ANOVA; p (group) = 0.1925, p (time) < 0.0001, p (interaction) = 0.0391].
Changes in T- and Natural Killer Cell Activities
The phytohemagglutinin response, which represents the pan T-cell functions, was suppressed at the Post-CPB point and returned to normal by day 3 in the C group (Fig 4a). This response was strongly suppressed by the pre-CPB administration of methylprednisolone at the Pre-CPB point (p < 0.01 by Student's t test), and was further suppressed after CPB (p < 0.001). The recovery of the phytohemagglutinin response was significantly delayed in the S group (p < 0.01 by t test on day 3; ANOVA: p [group] = 0.0127, p [time] < 0.0001, p [interaction] < 0.0001) (Fig 4a).
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). That is, the interleukin-2 production was deeply suppressed by CPB alone at the Post-CPB point and day 1 in the C group, but was further suppressed by the steroid treatment at Pre-CPB (p < 0.01 by Student's t test), Post-CPB (p < 0.05), and day 3 (p < 0.01) in the S group (ANOVA; p [group] = 0.0446, p [time] < 0.0001, p [interaction] = 0.0052).
The NK cell activity did not differ between the two groups (ANOVA; p [group] = 0.7784, p [time] < 0.0001, p [interaction] = 0.2157) (Fig 4c), and tended to increase during CPB in both groups. However, it was subjected to strong suppression by day 1, followed by gradual recovery by day 5 in both groups.
Hemodynamics and Pulmonary Function
The cardiac index showed no significant difference between the S group and the C group (ANOVA: p [group] = 0.6400, p [time] < 0.0001, p [interaction] = 0.0604) (Fig 5a). The arterial oxygen tension at 100% O2 decreased after CPB in the C group. This change was not ameliorated by the methylprednisolone treatment in the S group (ANOVA: p [group] = 0.2325, p [time] < 0.0001, p [interaction] = 0.4956) (Fig 5b).
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). There was no difference in the base excess between the groups throughout the operation (data not shown).
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). The glucose levels increased by CPB, and this increase was marginally higher in the S group than that in the C group (p < 0.01 by Student's t test at the end of operation; ANOVA: p [group] = 0.0525, p [time] < 0.0001, p [interaction] = 0.1768]. No statistical differences between the groups were observed in all the electrolyte (sodium, potassium, and calcium) levels and their correction doses (data not shown). |
Comment |
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TopFootnotesAbstractIntroductionPatients and MethodsResultsCommentAcknowledgmentsReferences |
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As for NK cells, some studies have shown that the number and activity of NK cells increases during CPB [13, 22]. In fact, the number and maybe their activities increased during CPB in the C group in the present study. This temporary increase in the NK cell count and activity during CPB in the C group, however, was followed by their strong suppression from day 1 through day 7. Although steroids are known to suppress NK cells in vitro [23], the methylprednisolone treatment increased the NK cell count at the Pre-CPB and Post-CPB points in the present study. This increase in the NK cell count and activity in the S group was also followed by their strong suppression from day 1 through day 7. The prolonged suppression of the NK cell count and activity for up to 7 days after CPB with or without the steroid may be partially explained by the surgical stress [24] or catecholamine levels [25]. Recently, however, interleukin-12 has been shown to control the NK cell number and activity [26], although it was not examined in the present study.
Although the T-cell functions were more severely impaired in the S group than in the C group during and after the heart operations, the immunosuppression may be compensated by the higher number of total white blood cells in the S group (see Fig 1). However, steroids are reported to be suppressive also of polymorphonuclear cells [7] and macrophages [10]. Thus, we have preliminarily examined the neutrophil superoxide generation by using the flow cytometry method [27]. At admission, Pre-CPB, and Post-CPB points, the superoxide generation was 74.3% ± 1.3%, 85.7% ± 4.4%, and 99.2% ± 0.1% in the C group (n = 3), whereas it was 71.7% ± 2.2%, 92.8% ± 4.1%, and 99.5% ± 0.1% in the S group (n = 3), respectively. This result suggests that the neutrophils are increased by CPB not only in their absolute number but also in their activity, and that this change is not impaired by methylprednisolone treatment.
Taking all these immunologic considerations together, the synergistic immunosuppression caused by methylprednisolone and CPB was remarkable on T-cell functions in the present study. However, the contribution of these immunologic changes to the actual prevalence of graft-versus-host disease, neoplasm, or bacterial or viral infection is not clear from the present study. To test this hypothesis, a nationwide survey will certainly be required, because the number of heart operations in a single institution is relatively small in Japan.
The increase in the C-reactive protein levels after cardiac operations was dramatically suppressed by the steroid treatment. In concordance with the previous studies [5, 7], a prolonged high fever (>38°C rectal) was almost always (11 of 12 patients) observed in the intensive care unit by the next morning in the patients without methylprednisolone, whereas it was rare (2 of 12 patients) and of short duration in the patients with the steroid in the present study (p = 0.001). A decrease in the systemic and filling pressures was observed during elevated fevers in most of the C-group patients, but was readily corrected by the infusion of the autologous blood and human albumin solution. Moreover, the cardiac index in both the S and C groups was similar during the test period, suggesting an insignificant hemodynamic difference between the groups.
Although some reports described a significant decrease in the water balance after cardiac operations with CPB involving steroid use [5, 7], our pump technique did not produce any significant difference in the water balance during CPB between the S and C groups. Furthermore, the arterial oxygen tension, which is reported to be ameliorated by steroids [7], was not different between the groups after CPB. The patients were similarly extubated and discharged from the intensive care unit. Therefore, cardiac operations without steroids may not produce an excess water balance when the use of CPB is restricted to 2 to 3 hours or less and a careful pump technique is performed. Moreover, placebo-controlled trials on the use of high-dose steroids for septic shock [28] concluded that steroids provide no benefit in the treatment of severe sepsis and septic shock. In the present study glucose tolerance was a definite disadvantage of methylprednisolone use. The blood glucose and lactate levels were higher in the S group than that in the C group.
In conclusion, T-cell functions were synergistically suppressed by CPB and high-dose methylprednisolone in patients undergoing heart operations. The hemodynamic benefits of steroid use were negligible in the patients undergoing heart operations using CPB for approximately 2 to 3 hours, and glucose tolerance was worsened during the CPB period. Hence, the use of high-dose steroids during CPB should be restudied and restricted to the patients in whom the hemodynamic advantages of steroids are believed to outweigh the risk of the immunosuppression.
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Acknowledgments |
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TopFootnotesAbstractIntroductionPatients and MethodsResultsCommentAcknowledgmentsReferences |
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Footnotes |
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TopFootnotesAbstractIntroductionPatients and MethodsResultsCommentAcknowledgmentsReferences |
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TopFootnotesAbstractIntroductionPatients and MethodsResultsCommentAcknowledgmentsReferences |
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after elective cardiopulmonary bypass. Perfusion 1993;8:233–8.
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