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J Thorac Cardiovasc Surg 1995;110:165-171
© 1995 Mosby, Inc.

SURGERY FOR CONGENITAL HEART DISEASE

Plasma antioxidant depletion after cardipulmonary bypass in operations for congenital heart disease

Morgantown, W.Va.

Supported by a grant from the West Virginia Affiliate, American Heart Association.

Presented in part at the Mid-Atlantic Pediatric Cardiology Meeting, Charlottesville, Va., May 1993, and at the American College of Cardiology (1993;21:323A).

Received for publication Feb. 25, 1994. Accepted for publication Nov. 14, 1994. Address for reprints: Lee A. Pyles, MD, 2306 Robert C. Byrd Health Science Center of West Virginia University, Morgantown, WV 26506-9214.

Abstract

We describe the use of two in vitro tests to characterize plasma antioxidant capacity at the time of cardiac bypass in operations for congenital heart disease in 30 patients aged 3 days to 16 years (average 4.4 ± 0.9 years [standard error]). Bypass and crossclamp time, circuit volume, and type of operation were recorded for each patient. First, a test of plasma radical antioxidant power measured chain breaking (secondary) antioxidant capacity of plasma to prevent oxidation of linoleic acid in vitro. Second, overall ability of plasma to prevent lipid peroxidation was assessed by a classic test of plasma inhibition of malondialdehyde formation in a beef brain homogenate. Plasma total radical antioxidant power level at baseline was 0.74 ± 0.03µmol/ml plasma, which decreased to 0.15 ± 0.05µmol/ml plasma after bypass (p< 0.001) and 0.26 ± 0.08µmol/ml plasma with recovery (n= 18, p< 0.001). Analysis of variance of postbypass total radical antioxidant power value showed age (p= 0.0002, r= 0.63) and bypass time (p= 0.009, r= 0.4677) to be significant factors. Pump prime volume in milliliters per kilogram and preoperative hemoglobin value were not significant factors. Beef brain malondialdehyde formation in vitro was limited 92% ± 3% by normal plasma before operation versus 53% ± 5% after operation (p< 0.001) and 51% ± 5% at recovery after arrival in the pediatric intensive care unit (p< 0.001). Analysis of variance of the changes from before to after operation showed age (p= 0.0015, r= 0.55) and bypass time (p= 0.033, r= 0.39) to be significant factors. Thus antioxidant capacity of plasma is significantly diminished after cardiopulmonary bypass in children. Young patient age and long duration of cardiopulmonary bypass are identified as factors that correlate positively with depletion of antioxidant capacity with bypass. (J THORACCARDIOVASCSURG1995;110:165-71)

Infants are clinically known to tolerate cardiopulmonary bypass less well than adults. Studies by Kirklin and associates ¹ and Bull, Cooper, and Stark ² have provided important data in this regard. Because these latter investigators noted preservation of myocardial adenosine triphosphate during bypass to be a crucial factor, we have investigated cardiopulmonary bypass from the perspective of identifying factors that could come into play if a reperfusion injury were a significant effect.

A number of investigators, beginning with Hearse and associates, ³ have suggested that reactive oxygen-containing species or "oxygen radicals" play a significant pathophysiologic role in reperfusion injury. Previous studies have shown evidence of conjugated diene and lipid peroxide production with bypass, but the clinical significance of these observations is not known. ^4-6 A cascade of complement activation, neutrophil activation, and interleukin production has been documented. ^7,8 Hydrogen peroxide elevation and vitamin E depletion have been noted after bypass. ^9,10 During repair of tetralogy of Fallot, derangements of plasma antioxidant enzymes and elevated myocardial conjugated dienes have been demonstrated. ^11,12 These studies of tetralogy repair have suggested that an oxygen radical-mediated process could occur during bypass that is independent of myocardial ischemia and reperfusion.

Plasma antioxidants were investigated in this study with two tests that assess evidence of efforts to combat oxygen radical damage during bypass. The plasma total radical antioxidant test (TRAP assay) is a relatively new method but a modified version has now been used to investigate extracorporeal circulation in adults. ^13,14 TRAP capacity was found to be increased in the adults after cardiopulmonary bypass, with use of a modification of the initially published method. ¹⁴ The beef brain malondialdehyde inhibition test (MDA inhibition) has not been previously used to investigate bypass. The TRAP and MDA inhibition tests complement each other because the TRAP assay measures secondary (or chain breaking) antioxidant capacity and the MDA inhibition test measures overall antioxidant capacity including primary enzymatic detoxification of reactive oxygen species in plasma. Rather than investigate change in an isolated substance of unknown significance to the clinical setting of cardiac bypass such as vitamin E, urea, or bilirubin, we have studied two tests of global antioxidant capacity. ¹⁵ These studies should provide new information regarding the importance of oxygen radicals in cardiopulmonary bypass and the extent of overall antioxidant depletion.

METHODS

Samples.
Antioxidant levels were measured in 30 infants and children, aged 3 days to 16 years. Mean values (plus or minus the standard error) were as follows: age 4.4 ± 0.9 years, weight 17.5 ± 3.6 kg, body surface area 0.64 ± 0.08 m² , hemoglobin 12.7 ± 0.4 gm/dl, cardiopulmonary bypass time 106 ± 8 minutes, and aortic crossclamp time 54 ± 5 minutes. Operations performed included atrial septal defect repair (9), ventricular septal defect repair (6), aortic commissurotomy (2), subaortic membrane resection (2), Rastelli conduit revision (2), arterial switch operation for transposition of the great arteries (3), and one each of Senning procedure for transposition of the great arteries, ventricular septal defect repair with subaortic resection, Fontan procedure, bidirectional Glenn shunt, tetralogy repair, and mitral valve replacement.

The only additive to the bypass circuit was mannitol 0.5 gm/kg, which was added before institution of cardiopulmonary bypass. Plasma samples were obtained before and immediately after cardiopulmonary bypass and on patient arrival in the intensive care unit. No subjects were taken to a recovery room. Blood was drawn into clean plastic syringes and immediately transferred to tubes containing sodium heparin (3 ml) (Becton Dickinson, Inc., Oxnard, Calif.) and placed on ice. The tubes were then centrifuged at 3500 rpm (1000 g^-1 ) at 4º C and the supernatant plasma fraction separated. The plasma fraction was stored for up to 4 weeks at -70º C pending analysis. The amount of blood required was 3 to 5 ml to provide 1.2 to 1.5 ml of plasma for the two tests. The thiobarbituric acid reactive substances (TBARS) assay requires 0.3 ml of plasma for determination and was done in duplicate. The plasma antioxidant assay requires 100 µl of plasma and was done in duplicate for this study. Informed consent was obtained from parents of patients included in the study using a protocol approved by the Institutional Review Board of West Virginia University.

TRAP assay.
The antioxidant test was done as described by Lindeman and associates ¹⁶ after Wayner and associates. ¹³ Oxidation of linoleic acid was initiated and then quenched, first with the unknown plasma sample and then with a known amount of a control antioxidant, the water-soluble vitamin E analog, TROLOX (6-hydroxy-9,5,7,8-tetramethylchroman-2-carboxylic acid; Hoffmann-La Roche Inc., Nutley, N.J.). A ratio of the antioxidant capability of plasma to that of the TROLOX control was determined. Oxygen consumption was measured in a YSI model 5300/5301/5331 oxygen electrode and bath system (Yellow Springs Instrument Corp., Yellow Springs, Ohio) to quantify the reaction. For this determination 100 µl of plasma and 4 µl linoleic acid (Sigma Chemical Co., St. Louis, Mo.) were vortex-mixed together. Fifty µl of this mixture was added to 3.0 ml of phosphate-buffered saline solution (PBS; Sigma) containing 4.0 mmol/L 2,2'-azo-bis-(2-amidinopropane hydrochloride) (ABAP; Polysciences, Warrington, Pa.), the oxygen radical generator, at 37º C in the oxygen electrode cell. After the induction period in which the antioxidant activity of the plasma was consumed, 25 µl of 0.4 mmol/L TROLOX was added to the cell. The antioxidant capacity of the plasma was calculated as follows: Antioxidant capacity = N(TROLOX) (T_plasma /T_TROLOX ) (f), where N = 2 (stoichiometric factor for TROLOX) and f = dilution factor (Fig. 1).

View larger version (22K): [in this window] [in a new window]   Fig. 1. Peroxidation of linoleic acid is measured as decrease in dissolved oxygen from 100% to 0% in an oxygen electrode cell. TRAP is calculated by comparing reaction inhibition time (T) for plasma versus known amount of vitamin E analog, TROLOX (6-hydroxy-2,5,7,8- tetramethylchroman-2-carboxylic acid). ABAP is added to reaction cell to induce oxygen radical formation and lipid peroxidation of linoleic acid.

Fresh brain was obtained from slaughterhouse cows. The tissue was sliced into small pieces. Ice-cold phosphate-saline buffer (10 mmol/L KH₂PO₄/K₂HPO₄, pH 7.4, in 0.142 mol/L NaCl; Sigma) was added in an amount to equal four times the brain weight. The brain was homogenized for 3 minutes and then spun at 1000 g^-1 (3500 rpm) for 15 minutes. Supernatant fluid was decanted into 20 ml disposable containers and stored at -20º C for up to 8 weeks. To perform assays, the brain stock was diluted with three additional volumes of PBS. Assays were done in duplicate. Samples were prepared by adding 40 µl of plasma to 4 ml of dilute brain homogenate, and blanks were prepared by adding 40 µl of PBS to the dilute brain homogenate. Glass tubes were used. Homogenate was always added to plasma to wash the small amount of plasma down the tube and facilitate mixing. A standard curve was constructed as part of each assay by measuring the MDA chromagen formed from 1,1,4,4-tetramethoxy propane (Sigma) in 4 ml PBS. Tubes were incubated at 37º C for 1 hour or held at 0º C to allow minimal oxidation for time zero controls. Two milliliters of 25% trichloroacetic acid (Fisher Scientific Company, Pittsburgh, Pa.) were added to all tubes, which were then spun at 1000 g^-1 (3500 rpm) for 15 minutes. Four milliliters of supernatant were removed and transferred to a new tube. One milliliter of 1% 2-thiobarbituric acid (Sigma, 10 gm/L wt/vol) was added to all tubes. Each tube was covered with a glass bead to exclude additional air during heating. All tubes were incubated at 95º C for 15 minutes. After incubation, test tubes were cooled in an ice water slurry. TBARS were extracted to an n-butanol-pyridine mixture (Fisher). Spectrophotometric absorbances at 510, 532, and 560 nm were simultaneously determined. One-milliliter aliquots of the extract were aspirated into the flow cell by a sipper apparatus on a Beckman model DR-6 spectrophotometer (Beckman Instruments, Inc. Fullerton, Calif.). Antioxidant activity (AOA) was calculated by the following formula (MDA = TBARS level from the beef brain homogenate):

Statistical analysis.
Data analysis was done with paired and unpaired t tests as appropriate using Microsoft Excel spreadsheets. Single variable and multivariate analysis of variance was done with the Jmp statistical program for Macintosh and a Macintosh Ilci computer (Apple Computer, Cupertino, Calif.) after data were imported from Microsoft Excel (Microsoft Corporation, Redmond, Wash.).p Values of 0.05 or less were considered to be significant with actual values listed, unless p < 0.001. Results are expressed as mean plus or minus the standard error.

RESULTS

Thirty subjects underwent cardiopulmonary bypass for cardiac operation. Plasma from all subjects was evaluated with the TRAP assay and the beef brain MDA antioxidant activity assay. Before bypass, the mean TRAP value for all 30 patients was 0.74 ± 0.03 µmol antioxidant activity per milliliter of plasma. Baseline TRAP value varied directly with age of the child (r = 0.50, p = 0.0045). TRAP capacity decreased to 0.15 ± 0.05 µmol per milliliter plasma after bypass (p < 0.001) and 0.26 ± 0.08 µmol per milliliter plasma with recovery (n = 18, p < 0.001). Univariate analysis of variance showed age (r = 0.63, p = 0.0002) and bypass time (r = 0.47, p = 0.009) to be significantly correlated with TRAP values after bypass. Fig. 2 shows the 30 patients grouped by ages 0 to 1 month, 1 to 12 months, and 1 to 16 years. Multivariate analysis of variance of postbypass TRAP value for the 20 patients older than 1 year of age showed age (p = 0.007) and bypass time (p = 0.05) to be significant factors in a model with a correlation coefficient (r) of 0.73 (TRAP2 = 0.213 + 0.0374 years – 0.0025 cardiopulmonary bypass time; p = 0.004 for the model). Hemoglobin value and presence or absence of cyanosis were not predictive factors for the entire group or any of the subgroups of ages 0 to 1 month, 1 to 12 months, or older than 1 year.

View larger version (50K): [in this window] [in a new window]   Fig. 2. Plasma antioxidant capacity is shown at baseline (shaded columns), after bypass (black columns), and at recovery (hatched columns) for three age groups: less than 1 month, 1 to 12 months, and older than 12 months. Column graph shows increased baseline levels in older age groups. Asterisks show significant p values versus baseline as follows: younger than 1 month: postbypass, p = 0.003 and recovery, p = 0.03; 1 to 12 months: postbypass, p < 0.001; older than 1 year: postbypass, p < 0.001 and recovery, p < 0.001. The amount of changes was not significantly different for three groups.

View larger version (77K): [in this window] [in a new window]   Fig. 3. MDA beef brain values shown at baseline (shaded columns), after bypass (black columns), and at recovery (hatched columns) for three age groups: less than 1 month, 1 to 12 months, and older than 12 months. Column graph shows variable baseline levels in older age groups. Asterisks show significant p values versus baseline as follows: younger than 1 month: postbypass, p = 0.006; 1 to 12 months: postbypass, p < 0.001 and recovery, p < 0.01; older than 1 year: postbypass, p < 0.001 and recovery, p < 0.001. Amount of changes was not significantly different for three groups.

View larger version (137K): [in this window] [in a new window]   Fig. 4. Plasma antioxidant capacity (TRAP) after cardiopulmonary bypass is totally depleted in 21 of 30 subjects. Prebypass tracings, obtained after induction of anesthesia, are identical to those generated from normal plasma. Postbypass plasma of these subjects shows rapid oxygen consumption rate without addition of ABAP reaction initiator. Oxygen consumption rate for postbypass plasma averages 3.87% ± 0.48% oxygen per minute compared with 0.59% ± 0.03% oxygen per minute at baseline before bypass.

This study demonstrates, with two separate methods, depletion of the antioxidant capacity of plasma that has been exposed to an extracorporeal circuit. The observations add to the theory that cardiac bypass represents a total body inflammatory process. The oxygen radical generation suggested by this study and those of Roysten, ⁵ Fleming, ⁴ Davies, ⁶ Cavarocchi, ⁹ Del Nido, ¹¹ and Teoh ¹² and their associates is presumably a result of an interaction between the host and the bypass circuit rather than a reaction to hypoxia and reperfusion. Our data suggest that this systemic reaction is largely completed after the patient is weaned from bypass because antioxidant capacity changes little from after bypass in the operating room to recovery in the pediatric intensive care unit. By measurement of antioxidant capacity of the sample rather than lipid peroxide levels or some other marker of oxygen radical activity, issues of the suitability of these tests for this patient population are avoided. ^15,18

Our study was designed to investigate the effect of cardiopulmonary bypass on plasma antioxidant capacity. After cardiopulmonary bypass, plasma antioxidant capacity was markedly diminished by both methods. Depletion of TRAP capacity correlated with young age and long bypass time. Antioxidant activity measured by beef brain MDA inhibition assay is also markedly diminished after cardiopulmonary bypass. Again, age correlates with antioxidant depletion. Length of cardiopulmonary bypass does not correlate well with extent of depletion of beef brain MDA inhibition. Although the TRAP test is designed to assess only secondary or chain-breaking antioxidant capacity and the beef MDA test measures total antioxidant capacity, the two tests show the same general trends. Beef MDA capacity is clearly more diminished for the subjects with complete depletion of secondary (chain breaking) capacity as measured with the TRAP test. Antioxidant depletion after cardiopulmonary bypass correlates with well-known clinical indicators of increased morbidity in operations for congenital cardiac disease, namely age and length of bypass. ¹⁹

Our finding that postbypass plasma-induced oxidation of linoleic acid, without addition of the radical generator ABAP, is of great interest. The reason for this spontaneous oxidation of postbypass plasma is unknown. Several mechanisms are possible and include preservation of a relatively stable (possibly carbon centered) radical such as ascorbate in the plasma or formation through red blood cell hemolysis of a powerful Fenton reagent able to greatly accelerate the rate of spontaneous radical production in vitro. ^20,21 A large body of evidence suggests that oxygen radicals mediate the pathophysiologic changes observed after ischemia and reperfusion. ^22-24 Recent studies have suggested that the immature heart may be more susceptible to reperfusion injury and support the idea that neither neutrophils nor endothelial cells are absolute prerequisites for reoxygenation-induced myocardial injury. ^25,26 Compatible with a reoxygenation/reperfusion injury, Corno and associates ²⁷ have shown markedly improved preservation of ventricular function after 12 hours of ischemic arrest in piglets when the oxygen radical scavenging agents superoxide dismutase and catalase are administered at the time of arrest. ²⁷ Del Nido and co-workers ¹¹ demonstrated the presence of linoleate- and arachidonate-derived conjugated dienes in myocardial samples from patients undergoing elective repair of tetralogy of Fallot as the patients were placed on cardiopulmonary bypass, suggesting that free radical generation and injury to myocardium could occur with initiation of bypass and not necessarily after cardioplegia or circulatory arrest. In a later study, Teoh and colleagues ¹² reported that patients with tetralogy of Fallot had decreased levels of myocardial antioxidant enzymes and suggested that this predisposed the cyanotic patients to reperfusion injury after cardiac operation. It is possible that these patients are at risk for greater oxidative damage related to the bypass circuit, although we did not have a large enough population of children with cyanosis to investigate this.

Elucidation of the time frame and necessary components that produce the humoral cascade, neutrophil activation, and oxygen radical generation will require further study but may determine future improvements to the cardiopulmonary bypass process. Efficacy of oxygen radical scavengers can be tested without exposing patients or animals to antioxidant agents with use of the assay systems described in this study. Further investigation to determine the etiologic process of the accelerated postbypass oxygen consumption in the TRAP cell will be of interest because this may provide a clue to an optimal antioxidant regimen for cardiopulmonary bypass.

We gratefully acknowledge the assistance of Gerrald Hobbs, PhD, who provided statistical consultation, and Cathy Guthrie, who prepared the manuscript.

References

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This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Robert A. Gustafson Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Pyles, L. A. Articles by Einzig, S. Search for Related Content PubMed PubMed Citation Articles by Pyles, L. A. Articles by Einzig, S.