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J Thorac Cardiovasc Surg 1994;108:620-625
© 1994 Mosby, Inc.
CARDIOPULMONARY BYPASS, |
Shiga, Japan
From The Second Department of Surgery, Shiga University of Medical Science, Otsu, Japan.
Received for publication Sept. 24, 1993. Accepted for publication March 16, 1994. Address for reprints: Shoji Watarida, MD, The Second Department of Surgery, Shiga University of Medical Science, Seta Tsukinowa, Otsu, Shiga, 520-21, Japan.
Abstract
Levels of endogenous endotoxins have been reported to increase after cardiopulmonary bypass. Endotoxin levels have also been implicated in multiple organ failure and may contribute to the immunocompromised state seen after bypass. We evaluated the effects of pulsatile cardiopulmonary bypass circulation on endogenous endotoxin levels. The study population consisted of 15 consecutive adult patients who underwent cardiac operations with cardiopulmonary bypass. Pulsatile flow was used during aortic crossclamping in eight patients (group I) and nonpulsatile flow was used in the remaining seven patients (group II). Changes in blood endotoxin levels were monitored during aortic crossclamping, after release of the clamp, and after weaning from bypass. The blood endotoxin level at each stage was expressed as a percentage of the level at the beginning of bypass. Group I patients a significantly lower blood endotoxin percentage than group II (from 20 to 120 minutes after the initiation of aortic crossclamping). In group I, the blood endotoxin percentage was nearly constant during aortic crossclamping. After release of aortic crossclamping, group I also had a lower blood endotoxin percentage than group II. Endogenous endotoxin levels appear to increase in the presence of intestinal congestion and ischemia. Improvement in intestinal circulation by pulsatile cardiopulmonary bypass may prevent increases in endogenous endotoxin levels by reducing these factors. (J THORACCARDIOVASCSURG1994;108:620-5)
The term endotoxin was coined in 1892 by Pfeiffer after toxins found in a heat-resistant strain of cholera bacilli. In the 1950s, Westphal demonstrated that endotoxins were primarily lipopolysaccharides. Clinically, endotoxins were first measured by Levin, Tomasulo, and Oser 
1 in 1968. They described a method of detecting endotoxins based on the aggregation and gel formation of minute amounts of endotoxins by Limulus lysate (a component of Limulus blood cells). Various methods have since been developed to analyze endotoxins qualitatively and quantitatively. By means of these methods, the diverse biologic activities of endotoxins have been discovered. Numerous reports have indicated that endotoxemia is involved in postoperative multiple organ failure 2,3 and that levels may increase during cardiopulmonary bypass (CPB). 4 Inasmuch as immune function appears to decrease after CPB, 5-7 we hypothesized that reduction of blood endotoxin levels may help prevent postoperative multiple organ failure and achieve better surgical results. We 8-10 have previously reported clinical and experimental studies on the usefulness of pulsatile CPB. In this study, we hypothesized that pulsatile CPB might decrease endogenous endotoxemia by improving splanchnic blood flow, and we examined the association between pulsatile CPB on the blood endotoxin levels. The aim of this study was to examine the usefulness of pulsatile CPB for reducing the endogeneous endotoxin levels in the blood.
PATIENTS AND METHODS
Our study population consisted of 15 consecutive adult patients who underwent cardiac operations with CPB, and informed consent was obtained from each patient. Patients were enrolled between April 1988 and March 1989 (Table I). No study patient had any preoperative sign of clinical infection. The study was approved by the institutional review board and informed consent was obtained from each patient. There were eight men and seven women in the study. Patients' ages at the time of operation ranged from 29 to 68 years, with an average of 53.8 ± 12.1 years (mean ± standard deviation). The preoperative diagnosis was angina pectoris in nine patients, mitral stenosis in four patients, incomplete-type endocardial cushion defect in two patients, and a combination of atrial septal defect and mitral regurgitation in one patient. The surgical procedure was coronary artery bypass grafting in nine patients, mitral valve replacement in five, and total correction in three patients, Intraoperative anesthetic management was uniform for all patients. Pulsatile and nonpulsatile CPB flow was used during aortic crossclamping. Pulsatile flow was generated with a Sarns 7400 roller pump (Sarns Inc./3M Health Care, Ann Arbor, Mich.) at a pump flow rate of 2.4 L/min per square meter body surface area, a pulse pressure of 30 mm Hg, a mean blood pressure of 50 mm Hg, and a pulse rate of 70 beats/min. Pulsatile flow was used only during aortic crossclamping. Nonpulsatile flow was generated with a Sarns 7400 roller pump at a flow rate of 2.4 L/min per square meter body surface area and a mean blood pressure of 50 mm Hg. Oxygenation was provided by a membrane oxygenator in all cases (Capiox E, Terumo Corp., Tokyo, Japan). A cold blood cardioplegic solution was administered intermittently via the aortic root and ice cold Ringer's solution was applied topically to the heart. The patients were divided into two groups on the basis of the use of pulsatile or nonpulsatile flow during CPB: the pulsatile flow group consisted of eight patients (group I) and the nonpulsatile flow group consisted of seven patients (group II). Blood endotoxin levels during aortic crossclamping, during rewarming after unclamping, and after weaning from the artificial heart-lung system were measured and expressed as a percentage of the level at the beginning of CPB (Et%).
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Measurement of endotoxins
Endotoxin levels were measured with an endotoxin-specific chromogenic test (Endospecy test; Seikagaku Kogyo, Tokyo, Japan). This test consists of factor G–free Limulus amebocyte lysate and a chromogenic substrate. 9 The sample was pretreated with perchloric acid and sodium hydroxide before endotoxin levels were determined. The endotoxin level at the beginning of CPB was designated as 100% (baseline level). Endotoxin levels on subsequent occasions were expressed as a percentage relative to the baseline level (Et%) after correction for hematocrit levels. This allowed for comparisons of endotoxin levels at a hematocrit value of 25%.
Statistical analysis
Values were expressed as mean ± standard deviation. The significance of differences was tested by means of a Mann-Whitney U test. Differences were considered to be significant at a p value of less than 0.05. Statview II (Abacus Concepts, Inc.) statistical software for the Macintosh computer was used for statistical analyses.
RESULTS
The total CPB time did not differ significantly between group I (158 to 425 minutes, 253.3 ± 84.0 minutes) and group II (152 to 345 minutes, 270.1 ± 70.9 minutes). Aortic crossclamping time also did not differ significantly between group I (50 to 175 minutes, 117.3 ± 43.9 minutes) and group II (93 to 168 minutes, 131.6 ± 31.8 minutes). Finally, the minimum rectal temperature also did not differ significantly between group I (21.9° to 28.0° C, 24.1° ± 2.3° C) and group II (23.9° to 26.3° C, 25.2° ± 0.3° C) (Table II). One patient with mitral stenosis (case 4, group I) died on postoperative day 16 after mitral valve replacement because of multiple organ failure caused by a low cardiac output syndrome. The other 14 patients had no significant postoperative complications. Endotoxins were not found in any of the priming fluids (0 pg/ml). Additionally, after the priming fluid was mixed in the extracorporeal circuit and circulated for 10 minutes, endotoxins were still not found in any of our patients (0 pg/ml). No great variation was observed among the patients. The hematocrit value during CPB was 23% to 28%. No patients required any blood transfusions.
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Table III, Fig 1). Twenty minutes after the initiation of aortic crossclamping, the Et% in group I (83% ± 39%) was significantly lower than in group II (172% ± 84%) (p < 0.05). This parameter then remained significantly higher in group II than in group I until 120 minutes after the initiation of aortic crossclamping (p < 0.05). In group II, the Et% increased slightly during the course of aortic crossclamping. In group I, however, the Et% did not change during the course of aortic crossclamping.
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Table IV, Fig 2). At two points during the rewarming processes (30 and 60 minutes after release of the aortic clamp), the Et% was significantly lower in group I (88 ± 33% at 30 minutes and 74% ± 45% at 60 minutes) (p < 0.05) than in group II (171% ± 61% at 30 minutes and 143% ± 68% at 60 minutes). In group II, the Et% at 60 minutes after release of the aortic crossclamp (that is, the point when rewarming was nearly complete) was lower than the Et% recorded 30 minutes after release of the aortic crossclamp. This difference, however, was not statistically significant.
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Table IV Fig. 2). The Et% was significantly higher in group II than in group I immediately and 2 hours after weaning from CPB (group I. 57% ± 24% and 102% ± 62%; group II, 143% ± 116% and 175% ± 158%, respectively). The Et% remained higher in group II (362% ± 215%) than in group I (172% ± 106%) even 12 hours after cessation of CPB. DISCUSSION
Endotoxins, that is, lipopolysaccharides, constitute the adventitia of the cell wall of gram-negative bacilli and have diverse biologic activities and may contributute to the development of multiple organ failure. 12,13 Elevated blood levels of endotoxins (i.e., endotoxemia) have been noted in patients with multiple organ failure. An impairment of reticuloendothelial or immune function may lead to endogenous endotoxemia by intestinal gram-negative bacilli, such as Escherichia coli. It has been noted that immune function appears to be depressed in patients immediately after CPB 5-7 and that the risk for multiple organ failure caused by endogeneous endotoxemia is high during this period. Only a few reports examining endotoxin levels during CPB have been published, and no reports assessing endotoxin levels during pulsatile CPB have appeared. Rocke and associates 4 have reported that blood endotoxin levels increase during aortic crossclamping. Jansen and colleagues 14 have reported that the release of endotoxin, associated with the formation of tumor necrosis factor, plays an additional role in the development of the whole-body inflammatory reaction, independent of the material activation. Andersen and colleagues 15 have also reported that patients "free of endotoxins" before the operation had rising concentrations to 64 ng/L by the end of CPB, with a peak median level of 95 ng/L at 90 minutes after CPB. Nilsson and coworkers have reported that endotoxin levels increase during CPB. They suggested that this endotoxin release may be from the extracorporeal equipment. In our study, however, endotoxins were not found in any of the priming fluids. The increase in endotoxin after release of the aortic crossclamp might be explained by the preceding hypoperfusion of the splanchnic bed by reduced peak arterial pressure associated with the nonpulsatile flow of the pump during CPB. 4 In the present study, patients in the nonpulsatile CPB group had a significant increase in blood endotoxin levels with aortic crossclamping. In the pulsatile CPB group, however, no significant elevation was noted in endogenous endotoxin levels during aortic crossclamping. Thus our study demonstrates the clinical utility of pulsatile CPB in preventing increases in endogenous endotoxin levels.
Totsuka and associates, 3,17 have reported three possible routes for the transfer of endogenous endotoxins into the blood: (1) transfer from the intestine into the portal vein; (2) transfer from the intestine into the systemic circulation via the intestinal lymphatics, thoracic duct, and venous angle; and (3) adsorption into the portal vein and intestinal lymphatics from the peritoneal cavity. An important relationship was noted between the lymphatic system and the intestine in endogenous endotoxemia. This relationship is based on observations that demonstrate that thoracic duct drainage significantly reduces blood endotoxin levels. Previous studies have shown that CPB can lead to ischemic damage of organs perfused by the splanchnic circulation. 18,19 During CPB, the intestine tends to become edematous and congested because of perfusion of blood with low osmotic pressure. Thus endogenous endotoxin levels in intestinal blood are likely to increase during CPB. The liver also tends to become congested during CPB, and Kupffer cell function is believed to be disturbed during this period, 20 leading to further elevations in hepatic blood endotoxin levels. A possible mechanism to explain the decrease in endotoxin levels noted with pulsatile CPB is that pulsatile CPB increases intestinal 21 and hepatic blood flow 22 and improves splanchnic circulation, thereby leading to a decrease in the transfer of endogenous endotoxins into the blood and an improvement in the endotoxin-disposing capability of the liver. Fortunately, in our study, endotoxin-induced multiple organ failure was not recognized. However, we consider that pulsatile CPB should be used during aortic crossclamping in cardiac operations for patients whose status is poor before the operation.
References
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