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Ann Thorac Surg 1997;64:1381-1388
© 1997 The Society of Thoracic Surgeons
Division of Cardiothoracic Surgery, The University of Illinois, Chicago, Illinois
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Abstract |
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Methods. Seven acyanotic infants had CPB initiated at an FiO2 of 1.0. Of 21 cyanotic infants, 7 (group 1) had CPB initiated at an FiO2 of 1.0, 6 (group 2) at an FiO2 of 0.21, and 8 (group 3) underwent CPB using leukocyte filtration. Biopsy of right atrial tissue was performed before and 10 to 20 minutes after the initiation of CPB. The tissue was incubated in 4-mmol/L t-butylhydroperoxide (a strong oxidant), and the malondialdehyde (MDA) level was measured to determine the antioxidant reserve capacity. The more MDA produced, the greater was the depletion of tissue antioxidants secondary to oxygen free radical formation during reoxygenation.
Results. There was no difference in the prebypass antioxidant reserve capacity between cyanotic and acyanotic hearts (492 ± 72 versus 439 ± 44 nmol MDA/g protein). However, after the initiation of CPB without leukocyte filtration, MDA production rose markedly in the cyanotic (groups 1 and 2) as compared with the acyanotic hearts (322% versus 40%; p < 0.05), indicating a depletion of antioxidants. In cyanotic hearts, initiating CPB at an FiO2 of 1.0 (group 1) resulted in increased MDA production (407% versus 227%) as compared with hearts in which CPB was initiated at an FiO2 of 0.21 (group 2), indicating a greater generation of oxygen free radicals in group 1. Conversely, there was only a minimal increase in MDA production in 8 of the 21 infants (group 3) in whom white blood cells were effectively filtered (19% versus 322%; p < 0.05).
Conclusions. First, increased amounts of oxygen free radicals are generated in cyanotic infants with the initiation of CPB. Second, this production is reduced by initiating CPB at an FiO2 of 0.21 or by effectively filtering white blood cells. Third, these changes parallel those seen in the acute experimental model, validating its use for future study.
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Introduction |
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Recent experimental studies have documented that 1 to 2 hours of acute hypoxia followed by abrupt reoxygenation results in an injury characterized by a decrease in systolic contractility, an increase in diastolic stiffness, and elevated pulmonary vascular resistance [1–4]. This injury, which has been referred to as the reoxygenation injury, is mediated by oxygen free radicals and can be modified by leukocyte depletion or by reoxygenating at a lower oxygen concentration [4, 5]. However, the relevance of these experimental findings has been questioned, because chronic hypoxia secondary to congenital heart disease may allow compensatory changes to develop that can prevent or modify the reoxygenation injury. We therefore used the same biochemical tests as used in our experimental studies to examine the effects of abrupt reoxygenation using cardiopulmonary bypass in cyanotic and acyanotic infants undergoing operative repair (1) to determine whether a similar reoxygenation injury occurs clinically and (2) to determine whether it can be modified by leukocyte depletion or a lower fraction of inspired oxygen.
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Material and Methods |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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). After systemic heparinization, cannulas were placed in the ascending aorta and right atrium for single or bicaval cannulation. The bypass circuit was heparinized, primed with packed red blood cells, which were first washed (Dideco Shiley auto transfusion system; Shiley Corp, Irvine, CA), one unit of fresh frozen plasma, and 200 mg of calcium gluconate; the pH was adjusted with NaHCO3. After cardiopulmonary bypass was instituted, the aortic pressure was maintained at 30 to 50 mm Hg by adjusting flow from 2.0 to 2.5 L • min-1 • m-2.
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CYANOTIC INFANTS.
In 7 cyanotic infants (group 1) the cardiopulmonary bypass prime was circulated using 100% oxygen (PO2, 400 to 550 mm Hg), and after initiating bypass this was decreased slowly to keep the arterial PO2 between 200 and 300 mm Hg. In 6 infants (group 2) the cardiopulmonary bypass prime was circulated using 21% oxygen, resulting in a PO2 of 140 to 155 mm Hg. Bypass was then initiated, and 5 to 10 minutes later the oxygen level was increased slowly to maintain an arterial PO2 of 200 to 300 mm Hg.
Eight other cyanotic patients (group 3) had blood for the bypass prime passed through a Pall RC-400 leukocyte filter (Pall Biomedical, Glencoe, NY) before it was added to the bypass circuit. A continuous leukocyte-depleting BC-1 filter (Pall Biomedical) was placed in the arterial line circuit. All these patients were newborns (5 to 21 days old) weighing between 2.5 and 4.0 kg and therefore required bypass flows of less than 700 mL/min. The white blood cell (WBC) filters (BC-1) were used for the first 30 to 60 minutes of bypass and then removed by redirecting the arterial line (using a Y connector) across a standard Pall 40-µm (LPE-1440) arterial filter for the remainder of the operation. Pressure across the BC-1 and standard arterial filters was measured at 5, 10, and 30 minutes. The protocol described for group 1 was followed in 3 of these infants, initially circulating the prime using 100% oxygen, and the protocol for group 2 was followed in the other 5 infants, circulating the prime using 21% oxygen.
Tissue and Serum Measurements
A small piece of right atrial tissue was removed in all patients during venous cannulation, and another piece was removed 10 to 20 minutes after initiating cardiopulmonary bypass and before aortic cross-clamping. The tissue was immediately frozen in liquid nitrogen, and the antioxidant reserve capacity in the tissue was analyzed. Blood was obtained from the patient before bypass, 5 and 30 minutes after initiating cardiopulmonary bypass, and on arrival in the intensive care unit. This was analyzed for the total WBC count (Cell-dyne 3000; Abbott Laboratories, Deerfield, IL), neutrophil count (manual differential), and platelet count (expressed per milliliter times 1,000).
Biochemical Measurements
The myocardial antioxidant reserve capacity was assessed according to the method of Godin and Garnett [6] by determining in vitro lipid peroxidation in cardiac tissue that was homogenized and incubated with t-butylhydroperoxide at a concentration of 4 mmol/L for 15 minutes at 37°C. Lipid peroxidation was determined by measuring thiobarbituric acid–reactive substances spectrophotometrically at 532 nm. A standard curve is run simultaneously and lipid peroxidation is expressed as nanomoles malondialdehyde (MDA) per gram protein of heart tissue. Ten to 15 mg of dry tissue was homogenized at 4°C in 1.75 mL of 0.5-mol/L Tris buffer and 0.1-mmol/L EDTA (pH, 7.6). Aliquots of the particle-free homogenate were incubated with 4-mmol/L t-butylhydroperoxide for 30 minutes at 37°C. The mixture was then deproteinized with an equal volume of 28% trichloroacetic acid containing 0.1-mmol/L sodium arsenite. The concentration of MDA in the protein-free supernatant was determined by heating it in boiling water for 15 minutes with 0.5% thiobarbituric acid in 0.025-mmol/L sodium hydroxide and reading the color at 532 nm. The antioxidant reserve capacity is expressed as the percentage increase in MDA production as compared with prebypass levels. This allows each child to act as its own control, because it is the change in tissue antioxidants that quantitates exposure to oxygen free radicals.
Statistics
Data were analyzed using JMP V2.0 (SAS Institute, Carey, NC) on a Macintosh IIVX computer (Apple Inc, Cupertino, CA). Paired Student's t test was used for comparing variables among experimental groups at a probability level of less than 0.05. Group data are expressed as the mean ± standard error of the mean.
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Results |
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. The pressure across the BC-1 filter ranged between 14 and 45 mm Hg (28 ± 4 mm Hg) at flows of 200 to 600 mL/min (341 ± 45 mL/min) and did not increase during the 30 to 60 minutes the filter was in place. The blood was then redirected across a standard arterial filter, and the pressure ranged from 5 to 10 mm Hg at flows of 150 to 300 mL/min. The flow at this time was usually lower because systemic hypothermia had already been instituted. The prebypass total WBC (10.2 ± 0.9), neutrophil (5.3 ± 0.4), and platelet (309 ± 12) counts were within normal limits and not significantly different between acyanotic and cyanotic patients. In the non–WBC-filtered infants, the total WBC (3.6 ± 0.6) and neutrophil (2.0 ± 0.6) counts were moderately decreased 5 minutes after initiating bypass. However, they were already increasing after 30 minutes of bypass (WBC, 5.4 ± 0.8; neutrophil, 3.7 ± 0.7) and were increased above prebypass levels on arrival of the infants in the intensive care unit (WBC, 15.5 ± 2.0; neutrophil, 12.9 ± 1.3; Fig 1). Conversely, if leukocyte depletion was used, the total WBC and neutrophil counts fell abruptly 5 minutes after starting bypass (WBC, 1.3 ± 0.3; neutrophil, 0.4 ± 0.06; p < 0.05 versus nonfiltered patients) and remained low 30 minutes later (WBC, 0.6 ± 0.1; neutrophil, 0.4 ± 0.07). Although on arrival of these infants in the intensive care unit these levels were not as in high as those in the nonfiltered patients, they had returned to normal levels (WBC, 7.9 ± 0.7; neutrophil, 5.4 ± 0.4; see Fig 1). Platelet counts followed similar trends, with a greater reduction in the WBC filter patients at 5 minutes (46 ± 13 versus 116 ± 12; p < 0.05) and 30 minutes (48 ± 12 versus 98 ± 12; p < 0.05) after initiating bypass and a lower level on their arrival in the intensive care unit (93 ± 14 versus 148 ± 16; p < 0.05).
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. There was no difference in the prebypass antioxidant reserve capacity between cyanotic and acyanotic hearts (492 ± 72 versus 439 ± 44 nmol MDA/g protein). However, after cardiopulmonary bypass was initiated, MDA production rose markedly in cyanotic infants without a WBC filter (groups 1 and 2) as compared with the production in acyanotic infants (322% ± 140% versus 40% ± 29%; p < 0.05) (see Fig 2). In cyanotic infants initiating bypass using 100% oxygen (group 1) resulted in a greater MDA production than that in infants in whom bypass was initiated using 21% oxygen (group 2), indicating greater exposure to oxygen free radicals during reoxygenation (see Fig 3), but this did not reach statistical significance (407% ± 170% versus 227% ± 78%). Conversely, there was only a minimal increase in MDA production in the 8 of 21 cyanotic infants (group 3) in whom WBCs were filtered (19% ± 11% versus 322% ± 140%; p < 0.05), indicating a marked reduction in the loss of tissue antioxidants when a leukocyte depletion filter was used. Indeed the antioxidant reserve capacity did not differ from that in the acyanotic infants (19% ± 11% versus 40% ± 29%). Although all patients undergoing leukocyte depletion had relatively small changes in their antioxidant reserve capacity, the smallest increase occurred in the 5 infants who also had bypass initiated using 21% oxygen (6% ± 6% versus 39% ± 24%; p < 0.05) (see Fig 4).
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Comment |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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Myocardial tissue was biopsied before and after bypass was initiated to determine the antioxidant reserve capacity, thus allowing the quantification oxygen free radical formation during reoxygenation. The antioxidant reserve capacity is determined by adding a strong oxidant (t-butylhydroperoxide) to myocardial tissue and measures the tissue's ability to scavenge the resulting oxygen radicals and prevent MDA formation (a by-product of lipid peroxidation) [1, 2, 4, 6]. Therefore it tests the endogenous tissue stores of oxygen radical scavengers (eg, glutathione, vitamin E, superoxide dismutase, catalase). The more MDA produced, the lower the levels of these endogenous stores. Tissue antioxidants are lost when oxygen free radicals are produced and need to be scavenged, such as when the hypoxemic heart is abruptly reoxygenated using cardiopulmonary bypass [1, 2, 4]. We chose this test because it has been used in numerous experimental studies of acute hypoxia and therefore allowed us to compare our clinical results with the results of previous experimental studies to determine the validity of our experimental model [1–4]. In addition, there appears to be a close link between antioxidant depletion, oxidant damage, and cardiac and pulmonary dysfunction [1–4]. The antioxidant reserve capacity also predicts the ability of the heart to withstand a subsequent ischemic challenge. Only a minor functional impairment develops after aortic clamping in normal hearts with abundant antioxidants, whereas hearts with a limited antioxidant reserve capacity exhibit marked contractile depression after cardioplegic arrest [1, 5, 7, 8].
There was no difference in the prebypass antioxidant reserve capacity between cyanotic and acyanotic hearts. This parallels experimental findings observed after acute hypoxia [1, 4]. However, abrupt reoxygenation of cyanotic infants without a WBC filter (groups 1 and 2) resulted in a significant depletion of endogenous tissue antioxidants (see Fig 2). Because the prebypass endogenous tissue stores of antioxidants were not different between acyanotic and cyanotic hearts, this suggests that the abrupt reoxygenation of chronically hypoxemic infants causes the generation of abundant oxygen free radicals. Conversely, the initiation of bypass in acyanotic infants caused a minimal change in the antioxidant reserve capacity, implying that, in the absence of hypoxia, only a small quantity of oxygen free radicals is generated. This small increase in the antioxidant reserve capacity of acyanotic hearts may reflect the high levels of oxygen (100%) used in the bypass circuit, as there is recent evidence that even a PO2 of 185 mm Hg may be detrimental [9]. Alternatively, cardiopulmonary bypass has been shown to produce an inflammatory reaction characterized by the activation of numerous pathways, some of which may result in the generation of oxygen radicals [10].
Cyanotic infants reoxygenated using a PO2 of 400 to 550 mm Hg (group 1, 100% oxygen) showed the greatest loss of the myocardial antioxidant reserve capacity (highest MDA formation), indicating the greatest exposure to oxygen free radicals (see Fig 3). This phenomenon of oxidant damage in response to reoxygenation has previously been demonstrated in cyanotic patients [8, 11, 12]. However, the same test (antioxidant reserve capacity) was used in the present investigation as that used in experimental studies of acute hypoxia to allow comparisons [1, 2, 4]. Although both cyanotic infants and acute hypoxic animals exposed to 100% oxygen show a reoxygenation injury, the quantity of MDA generated is four to six times greater in cyanotic infants [1, 4]. This suggests a greater production of oxygen free radicals in response to reoxygenation after chronic cyanosis. One reason for this may be that cyanotic infants can become ischemic during exercise or stress, subjecting them to not only a hypoxic, but also an ischemic, injury [13, 14]. In contrast, our acute hypoxic experimental model does not result in ischemia [4, 15, 16]. Alternatively, compensatory changes that occur in the cyanotic infant may predispose to the generation of larger amounts of oxygen radicals with the reintroduction of high levels of oxygen. This oxidant injury may explain why ventricular function is often depressed in cyanotic infants undergoing extracorporeal membrane oxygenation or surgical repair [7, 12, 17, 18].
Compared with cyanotic infants reoxygenated using 100% oxygen (group 1), the initiation of bypass using 21% oxygen (group 2) reduced the change in the antioxidant reserve capacity, but this did not reach statistical significance because of the large variability in the patients and the small number of patients (see Fig 3). The improvement in the antioxidant reserve capacity that occurs with lower levels of oxygen also parallels experimental results, but the change was still substantially greater than that seen after acute experimental hypoxia, suggesting once again that the cyanotic patient is more susceptible to an oxygen-mediated injury [5]. However, the use of 21% oxygen to prime the bypass circuit resulted in a PO2 of 140 to 155 mm Hg, which was substantially higher than the PO2 of 80 to 100 mm Hg used in the experimental study [5]. This may have at least partially accounted for the lack of improvement seen in response to 21% oxygen, as several investigators have shown that the oxygen free radical production and myocardial injury that occur after the reoxygenation of isolated heart preparations are proportional to the oxygen tension [19, 20]. Because the current membrane oxygenators are so efficient, however, it will take oxygen concentrations of less than 21% to obtain a PO2 of 80 to 100 mm Hg in the bypass prime. These levels (PO2, 80 to 100 mm Hg) have also been shown to improve tissue perfusion during cardiopulmonary bypass, and therefore higher oxygen levels are probably never needed, because a PO2 of greater than 100 to 150 mm Hg confers only a negligible increase in the oxygen content [5, 9].
Activated WBCs have been shown to play a major role in the generation of oxygen free radicals after ischemia [4, 21–23]. It therefore seems likely they are also active in the reoxygenation injury, because both ischemia and hypoxia subject myocardial tissue to low levels of oxygen [1, 3, 11, 21]. Our data support this hypothesis. When the number of neutrophils was reduced in cyanotic infants by a leukocyte-depleting filter (group 3), the detrimental effects of sudden reoxygenation were eliminated, resulting in preservation of the antioxidant reserve capacity (see Fig 3). This is once again precisely what was demonstrated in the experimental setting after acute hypoxia, in which it correlated with an improvement in myocardial and pulmonary function [4]. In addition, other clinical investigators have shown that even partially removing WBCs during cardiopulmonary bypass can cause both oxygen radical formation and postoperative pulmonary vascular resistance to be reduced [24]. It is therefore likely that an improvement in the antioxidant reserve capacity translates into an improvement in myocardial and pulmonary function. Furthermore, although no patient reoxygenated with leukocyte-depleted blood showed a substantial change in the antioxidant reserve capacity, the generation of oxygen free radicals was further suppressed by using 21% oxygen (see Fig 4). Indeed the antioxidant reserve capacity in these infants was unchanged from baseline values and even lower than that in acyanotic patients, suggesting the effects of oxygen and WBC filtration are additive.
In the present study, WBC filtration substantially reduced the number of leukocytes, both initially and after 30 minutes of cardiopulmonary bypass (see Fig 1). Besides the injury caused by activated WBCs, they also bind to activated platelets, and platelet counts were substantially lower in the leukocyte-depleted infants. By removing the activated platelets, a WBC filter may also help prevent other adverse effects, such as thromboxane release and vasoconstriction [21, 25–27]. In addition, because activated WBC-platelet complexes are larger, they are more likely to be trapped by a filter. Therefore, even though the neutrophil count was not reduced to 0, it is probable that very few activated WBCs escaped filtration. Unfortunately, no WBC filter currently on the market is ideal. We chose the Pall BC-1 filter because it is the most efficient leukocyte filter available and it worked well in our experimental study [4]. At flows of 500 to 600 mL/min the BC-1 removes almost all WBCs in one pass, and these flows are adequate for 3 to 4-kg newborns. We kept the filter in the bypass circuit for up to 60 minutes without any complications, and the pressure across the filter remained low with no significant change over time. However, because WBC filters are flow dependent, if higher flows are utilized, these filters are less efficient. In addition, the BC-1 can only be used up to flows of approximately 600 to 700 mL/min. Therefore it would not be applicable in larger infants. Instead, a Pall LG-6 filter would be required, because this filter can be used at flows of up to 6 L/min. However, it is less efficient at removing WBCs during the first pass, and instead removes neutrophils slowly over time. However, because this filter is also flow dependent, it may remove a large number of WBCs at lower flow rates. Therefore it may still be effective in infants or small children. In contrast, there is no good arterial leukocyte-depleting filter for larger children. Because the reoxygenation injury probably occurs early, the complete removal of WBCs is important during the initial reintroduction of oxygen. Because of this, we prefiltered all blood added to the cardiopulmonary circuit using a Pall RC-400 leukocyte filter. This resulted in extremely low WBC counts in the prime and has been shown by Komai and associates [24] to reduce oxygen radical formation and improve postoperative pulmonary vascular resistance even in acyanotic infants. Therefore, even if an in-line arterial filter is not used, we strongly believe blood for the bypass prime should always be leukocyte depleted. Although there is some concern that leukocyte depletion may cause postoperative infection rates to increase, this has not been noted in more than 21,000 patients; indeed, there is evidence that it may even lower the risk of infection (Ortolano, personal communication, 1997 [28, 29]). In fact, the WBC count had been restored to prebypass levels by the time the patient arrived in the intensive care unit, making an increased risk of infection unlikely.
There are potential limitations to this study. The ages and preoperative myocardial state of the acyanotic and cyanotic infants were different. The acyanotic patients were older, hemodynamically more stable, and undergoing elective operations. In contrast, the cyanotic infants were predominantly newborns requiring urgent operations for the management of much more complex cardiac problems. Despite these differences, however, the preoperative antioxidant reserve capacity did not differ between the cyanotic and acyanotic infants nor did it correlate with the age of the patient. Similarly, the postoperative antioxidant reserve capacity seemed to correlate only with the method of reoxygenation, and not with the patient's age. This is evident from the fact that, although the type of congenital anomaly and the age of the patients were similar in the cyanotic infants in groups 1 (100% oxygen) and 2 (21% oxygen), the change in the postoperative antioxidant reserve capacity was markedly different. The specific mechanism responsible for the increase in oxygen free radical formation is unknown and was not addressed. However, it appears that it is at least partially related to the oxygen concentration and the WBC count, as indicated by the finding that modifying either of these factors reduced oxygen radical formation during reoxygenation. Although the effect of chronic cyanosis on neutrophil function is unknown, hypoxia is known to alter the vascular endothelial cell, thereby increasing its ability to bind to activated WBCs. This may partially explain why neutrophils cause adverse effects in cyanotic infants.
In summary, our study findings support those of previous investigations and show that cyanotic infants are predisposed to the generation of large quantities of oxygen free radicals in response to the initiation of cardiopulmonary bypass [8, 11]. However, oxygen free radical production can be limited by decreasing the oxygen concentration of the bypass circuit or, more effectively, by leukocyte filtration. Because myocardial necrosis and decreased ventricular function can occur in cyanotic infants after apparently successful surgical procedures, reducing the oxygen level and leukocyte filtration may improve operative results, as experimentally myocardial function has been found to correlate with the antioxidant reserve capacity [1, 4, 5, 7]. Furthermore, and possibly most importantly, these results closely parallel the experimental findings observed after acute hypoxia, suggesting that this model is clinically applicable to the cyanotic infant and can be used for further study of this phenomenon.
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Footnotes |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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Address reprint requests to Dr Allen, Division of Cardiothoracic Surgery, University of Illinois at Chicago, 840 S. Wood St, 417 CSB (M/C 958), Chicago, IL 60612.
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I. Schulze-Neick, D. J. Penny, M. L. Rigby, C. Morgan, A. Kelleher, P. Collins, J. Li, A. Bush, E. A. Shinebourne, and A. N. Redington L-Arginine and Substance P Reverse the Pulmonary Endothelial Dysfunction Caused by Congenital Heart Surgery Circulation, August 17, 1999; 100(7): 749 - 755. [Abstract] [Full Text] [PDF]
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G. Nollert, M. Nagashima, J. Bucerius, T. Shin'oka, and R. A. Jonas OXYGENATION STRATEGY AND NEUROLOGIC DAMAGE AFTER DEEP HYPOTHERMIC CIRCULATORY ARREST. I. GASEOUS MICROEMBOLI J. Thorac. Cardiovasc. Surg., June 1, 1999; 117(6): 1166 - 1171. [Abstract] [Full Text] [PDF]
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G. Nollert, M. Nagashima, J. Bucerius, T. Shin'oka, H. G. W. Lidov, A. d. Plessis, and R. A. Jonas OXYGENATION STRATEGY AND NEUROLOGIC DAMAGE AFTER DEEP HYPOTHERMIC CIRCULATORY ARREST. II. HYPOXIC VERSUS FREE RADICAL INJURY J. Thorac. Cardiovasc. Surg., June 1, 1999; 117(6): 1172 - 1179. [Abstract] [Full Text] [PDF]
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Y. J. Gu, A.J. de Vries, P. Vos, P. W. Boonstra, and W. van Oeveren Leukocyte depletion during cardiac operation: a new approach through the venous bypass circuit Ann. Thorac. Surg., March 1, 1999; 67(3): 604 - 609. [Abstract] [Full Text] [PDF]
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G. Trittenwein, A. T Rotta, B. Gunnarsson, and D. M Steinhorn Lipid peroxidation during initiation of extracorporeal membrane oxygenation after hypoxia in endotoxemic rabbits Perfusion, January 1, 1999; 14(1): 49 - 57. [Abstract] [PDF]
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M. Kronon, K. S. Bolling, B. S. Allen, A. O. Halldorsson, T. Wang, and S. Rahman The importance of cardioplegic infusion pressure in neonatal myocardial protection Ann. Thorac. Surg., October 1, 1998; 66(4): 1358 - 1364. [Abstract] [Full Text] [PDF]
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A. Halldorsson, M. Kronon, B. S. Allen, K. S. Bolling, T. Wang, S. Rahman, H. Feinberg, and R. S. Hartz Controlled Reperfusion After Lung Ischemia: Implications For Improved Function After Lung Transplantation J. Thorac. Cardiovasc. Surg., February 1, 1998; 115(2): 415 - 425. [Abstract] [Full Text] [PDF]
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