Markers Of Ischemia-reperfusion Injury Research Articles

Prolonged hypothermic machine perfusion enables daytime liver transplantation – an IDEAL stage 2 prospective clinical trial

Liver transplantation is traditionally performed around the clock to minimize organ ischemic time. However, the prospect of prolonging preservation times holds the potential to streamline logistics and transform liver transplantation into a semi-elective procedure, reducing the need for nighttime surgeries. Dual hypothermic oxygenated machine perfusion (DHOPE) of donor livers for 1-2h mitigates ischemia-reperfusion injury and improves transplant outcomes. Preclinical studies have shown that DHOPE can safely extend the preservation of donor livers for up to 24h. We conducted an IDEAL stage 2 prospective clinical trial comparing prolonged (≥4h) DHOPE to conventional (1-2h) DHOPE for brain-dead donor livers, enabling transplantation the following morning. Liver allocation to each group was based on donor hepatectomy end times. The primary safety endpoint was a composite of all serious adverse events (SAE) within 30 days after transplantation. The primary feasibility endpoint was defined as the number of patients assigned and successfully receiving a prolonged DHOPE-perfused liver graft. Trial registration at: WHO International Clinical Trial Registry Platform, number NL8740. Between November 1, 2020 and July 16, 2022, 24 patients were enrolled. The median preservation time was 14.5h (interquartile range [IQR], 13.9-15.5) for the prolonged group (n=12) and 7.9h (IQR, 7.6-8.6) for the control group (n=12; p=0.01). In each group, three patients (25%; 95% CI 3.9-46%, p=1) experienced a SAE. Markers of ischemia-reperfusion injury and oxidative stress in both perfusate and recipients were consistently low and showed no notable discrepancies between the two groups. All patients assigned to either the prolonged group or control group successfully received a liver graft perfused with either prolonged DHOPE or control DHOPE, respectively. This first-in-human clinical trial demonstrates the safety and feasibility of DHOPE in prolonging the preservation time of donor livers to enable daytime transplantation. The ability to extend the preservation window to up to 20h using hypothermic oxygenated machine preservation at a 10°C temperature has the potential to reshape the landscape of liver transplantation. University Medical Center Groningen, the Netherlands.

End-ischemic hypothermic oxygenated machine perfusion does not improve renal outcome following liver transplantation from aged donors: A single-center retrospective report.

Organ transplantation using grafts from elderly donors entails a higher risk for severe ischemia-reperfusion injury (IRI). Advanced IRI after liver transplantation (LT) seems to be associated with the development of acute kidney injury (AKI). We studied if end-ischemic hypothermic oxygenated machine perfusion (HOPE) of liver grafts, aimed at mitigating liver IRI, impacts on the frequency and severity of AKI after LT. LTs performed at our center between January 2017 and December 2022 using organs from deceased brain-dead donors aged 70 or older were reviewed. From November 2020 on, HOPE was performed routinely in this donor category. The frequency and severity of AKI (KDIGO criteria) within 48 hours of graft reperfusion and the model of early allograft function (MEAF) were compared between HOPE-LTs (n = 30) and control LTs (n = 71). AKI developed in 23/30 (77%) HOPE-LTs and in 40/71 (56%) control LTs (p = n.s.), with no difference in severity and timing between groups. Renal replacement therapy was required in 3/30 (10%) HOPE-LTs and 6/71 (8%) control LTs. In addition, transaminase leak during the first week (marker of IRI) and MEAF were similar between groups. These findings persisted after propensity matching. Histology showed more hepatocyte vacuolization and higher Suzuki score in HOPE-LTs. Although this analysis could have been underpowered, no trends supporting the benefit of HOPE on liver and renal injury after LT were ever identified. In conclusion, HOPE in this group of older donors does not seem to improve either graft IRI, or the incidence of early AKI after LT.

Strategies in Organ Preservation-A New Golden Age.

Strategies in Organ Preservation-A New Golden Age.

Abstract 177: A Multimodal Neuroprotection Strategy Using Ketamine, Melatonin, and Limited Initial Reoxygenation Following Cardiac Arrest Does Not Improve MRI Cytotoxic Injury in a Swine Model: A Pilot Study

Introduction: Reperfusion/ischemic brain injury following arrest is a major cause of death/disability among patients surviving to admission. Aside from targeted temperature management, no proven neuroprotective strategies exist. Melatonin (anti-epileptic/antioxidant) and ketamine (glutamate inhibitor), along with controlled reintroduction of oxygenated blood have been proposed to reduce secondary injury. Hypothesis: We hypothesized that a combination of above therapies would reduce the ischemic burden measured on MRI following cardiac arrest if administered upon initial reperfusion. Methods: 6 swine underwent isoflurane anesthesia and control MRI (DTI b2000/20 directions, DSC). Swine were randomized to fixed periods of cardiac arrest (2 swine to 20 min and 1 to 30 min in both control and treated groups), and ECMO catheters placed in the distal aorta and right atrium, then ventricular fibrillation induced by a bipolar pacing catheter. Following ischemia, swine were reperfused at 2.8-3.5 L/min with either unblended oxygenated blood in the control group, or 21% oxygenated blood increased to 30% after 4 minutes and then titrated to maintain PaO2 of 80-100 mm Hg, melatonin 5 mg/kg bolus then 5 mg/kg/hr and ketamine 4 mg/kg/hr for 2 hours in the treated group. After 4 min swine were defibrillated until return of heartbeat. Animals were weaned from pump, decannulated, and epinephrine and fluid boluses administered for hemodynamic support, then re-imaged within 2 hours post-resuscitation using same protocol. Whole brain ADC measurements were performed on gray and white matter. Frontal lobe regions of interest drawn for DSC perfusion parameters. Results: Baseline hemodynamic parameters: BP, Heart Rate, End-Tidal CO2, and SpO2 were similar between animals. There was no difference in percent change ADC in gray or white matter between treated and untreated swine (p=0.9), or difference in CBV (p=0.67). CBF showed an upward trend in treated animals (p=0.17). Conclusions: A multimodal neuroprotective strategy of melatonin, ketamine, and controlled reoxygenation failed to demonstrate measurable impact on MRI markers of ischemia-reperfusion injury in this pilot study. The translation of promising neuroprotectants might be triaged using the employed model.

Thiol/disulfide homeostasis in pregnant women with obstructive sleep apnea syndrome

Background Repetitive episodes of hypoxia and reoxygenation during sleep in patients with obstructive sleep apnea syndrome (OSAS) resemble an ischemia-reperfusion injury. We aimed to test the hypothesis that oxidative stress occurs in pregnant women with OSAS. We also aimed to compare thiol/disulfide homeostasis with ischemia-modified albumin (IMA) and total antioxidant capacity (TAC) as markers of ischemia-reperfusion injury in pregnant women with and without OSAS and healthy control. Methods This study included 29 pregnant women with OSAS, 30 women without OSAS in the third trimester applying for periodic examinations, and 30 healthy women. Serum IMA and TAC (using the ferric reducing power of plasma method) were measured. Serum thiol/disulfide homeostasis was determined by a novel automated method. Results The mean age of the pregnant women with OSAS was 31.0 ± 4.7 years with a mean gestational age of 36.5 ± 3.0 weeks. The mean age of pregnant women without OSAS was 29.8 ± 4.9 years with a mean gestational age of 36.9 ± 2.7 weeks. The mean age of the nonpregnant control group was 29.7 ± 6.4 years. Both native thiol (291 ± 29 μmol/L versus 314 ± 30 μmol/L; p = .018) and total thiol (325 ± 32 versus 350 ± 32, p = .025) levels were lower in pregnant women with OSAS compared to pregnant women without OSAS, respectively (p < .01). Conclusions This is the first study demonstrating the thiol/disulfide homeostasis in pregnant women with OSAS. Native thiol and total thiol levels were lower in pregnant women with OSAS compared to those without OSAS. However, dynamic thiol/disulfide homeostasis parameters cannot provide valuable information to discriminate OSAS in pregnant women.

The Effect and Safety of Prostaglandin Administration in Pediatric Liver Transplantation.

BackgroundProstaglandins are often administered after liver transplantation (LT) to diminish ischemia-reperfusion injury (IRI), to favor liver recovery and to prevent vascular thrombosis. Possible beneficial effects in adult liver recipients are controversial, but the single existing pediatric small case series shows no significant impact of prostaglandin administration after LT. The purpose of this study was to analyze the effect of the prostaglandin dinoprostone in pediatric liver recipients.MethodsA retrospective analysis of 41 children (<16 years) who underwent LT between March 2008 and December 2013 was performed. Dinoprostone was administered at a rate from 0.1 to a maximum of 0.6 μg/kg per hour immediately after LT and for a maximum of 5 days. Effect of dinoprostone on post-LT IRI and hepatic function up to 60 postoperative days and number of hypotensive episodes were analyzed.ResultsThe median cumulative dose of dinoprostone was 28 μg/kg (interquartile range, 23.2). Dinoprostone had no significant effect on post-LT liver function tests and factor V levels at any of the administered dosages. There was no significant association between the total quantity of vasopressor given and the number of hypotensive episodes observed in 8 patients. One patient showed a short-lasting hypotension, possibly related to the administration of dinoprostone.ConclusionsThis study did not show, at any dosage between 0.1 and 0.6 μg/kg per hour, any differences in beneficial or harmful effects of high- or low-dose dinoprostone administered immediately after pediatric LT on markers of IRI, hepatic function, or hypotension.

High preoperative bilirubin values protect against reperfusion injury after live donor liver transplantation.

Heme Oxygenase-1 and its product biliverdin/bilirubin have been demonstrated to protect against ischemia/reperfusion injury (IRI). We investigated whether increased preoperative bilirubin values of transplant recipients decrease IRI. Preoperative bilirubin levels of live donor liver recipients were correlated to postoperative liver transaminase as a marker of IRI. Additionally, two recipient groups with pretransplant bilirubin levels >24μmol/l (n=348) and ≤24μmol/l (n=118) were compared. Post-transplant liver function, complications, length of hospital stay, and patient and graft survival were assessed. Preoperative bilirubin levels were negatively correlated to the postoperative increase in transaminases suggesting a protective effect against IRI. The maximal rise of ALT after transplantation in high versus low bilirubin patients was 288 (-210-2457) U/l vs. 375 (-11-2102) U/l, P=0.006. Bilirubin remained a significant determining factor in a multivariate linear regression analysis. The MELD score and its individual components as a marker of severity of chronic liver disease were significantly higher in the high versus low bilirubin group (P<0.001). Despite this, overall complication rate (21.0% vs. 21.2%, P=0.88), hospital stay [13 (4-260) vs. 14 (6-313) days, P=0.93), and 1-year graft survival (90.8% vs. 89.0%, P=0.62) were similar in both groups. High bilirubin levels of liver recipients before live donor transplantation is associated with decreased postoperative IRI.

Comparative study of ischemia modified albumin and nitric oxide in hyperthyroidism

Objective: Ischemia modified albumin (IMA) is an altered type of serum albumin that forms under conditions of oxidative stress. Increased IMA has been described as a marker of ischemia reperfusion injury and dysfunction of the endothelial L-arginine/nitric oxide (NO) pathway (affecting NO levels) is a common mechanism by which several cardiovascular risk factors mediate their deleterious effects on the vascular wall. No reports are available in literature to comment on the simultaneous measurement of IMA and NO in hyperthyroidism. Therefore, this study was planned to evaluate these levels in newly diagnosed patients of hyperthyroidism. Materials and Methods: This study was conducted on 50 newly diagnosed hyperthyroid patients and the results were compared with 50 age and sex matched healthy controls. IMA levels and NO were estimated by standard colorimetric methods. Results: NO concentration was found to be significantly low in hyperthyroid patients (6.4 ± 3.8 μmol/L) as compared with control subjects (36.24 ± 7.61 μmol/L) (P < 0.05), while IMA levels were found to be higher in hyperthyroid group (0.662 ± 0.17 ABU) than healthy controls (0.290 ± 0.09 ABU) (P < 0.05). IMA levels were negatively correlated with NO (r = −0.761, P < 0.001) and correlation was highly significant. Conclusion: Increased ischemia modified albumin levels may be a consequence of and cause for decreased nitric oxide levels in hyperthyroidism and this study may help to establish the role of oxidative stress and ischemia reperfusion in the pathogenesis of hyperthyroidism.

Does preoperative administration of allopurinol protect the lungs from ischemia–reperfusion injury occuring during cardiopulmonary bypass?

It is investigated whether preoperative allopurinol administration protects lung injury induced by cardiopulmonary bypass (CPB). Sixty patients with coronary artery disease who need elective coronary artery bypass grafting operations by using CPB were taken into this study. They were divided into two groups; control and allopurinol. Allopurinol (300 mg/day) was administered to the latter group during the preoperative period of 5 days. Standard CPB procedures were used in all cases. Blood was sampled for TNF-alpha, IL-6, IL-8, IL-10 before anesthesia (T0), after anesthesia and before skin incision (T1), before CPB (T2), after aortic declamping (T3), at the end of CPB (T4), 6 hours after operation (T5), 12 hours after operation (T6), and 24 hours after operation (T7). Pulmonary function test (PFT) was performed before and following the 6th day of operation. TNF-alpha, IL-6, IL-8 increased in both groups at T3, T4, T5 and T6 compared to control (p<0.05). TNF-alpha, IL-6, and IL-8 levels were lower in group A at T3, T4, T5 and T6 (p<0.05). Creatinin phosphokinase (CK) levels were lower in group A at T6 (p<0.05). CK-MB levels were lower in group A than in group C (p<0.05). Pulmonary function test (PFT) did not yield any differences between the groups. Preoperative allopurinol administration decreases the inflammation and myocardial injury according to biochemical markers of ischemia reperfusion injury. However, this biochemical success does not rebound to PFT (Tab. 5, Ref. 15).

Microvascular porcine model for the optimization of vascularized composite tissue transplantation

BackgroundDevastating extremity injuries are prevalent but most often survivable on the modern battlefield. The complexity of these injuries requires advanced methods of reconstruction. This study is designed to validate the feasibility of gracilis myocutaneous flap transplantation via microvascular free tissue transfer in a porcine model. This model will facilitate study of autotransplant physiology as well as vascularized composite allotransplantation as an evolving method for reconstructing previously nonreconstructable injuries. Material and methodsA donor gracilis myocutaneous flap is procured from Yorkshire swine. The right external carotid artery and internal jugular vein are prepared as the recipient axis for microvascular anastomoses. Group 1 undergoes immediate microvascular anastomosis with resultant 1-h ischemic period. Group 2 undergoes delayed anastomosis with 3-h ischemic period. Markers of ischemia-reperfusion injury are evaluated after anastomosis and on postoperative days 1, 2, 7, and 14. ResultsA novel porcine model for microvascular composite tissue transplantation is demonstrated. Ischemia period-dependent elevations in circulating biomarkers (lactate dehydrogenase [LDH], creatine kinase [CK], and aspartate transaminase [AST]) demonstrate the effects of prolonged ischemia. Both groups showed marked LDH elevation without significant statistical intergroup difference (P=0.250). The difference in CK and AST levels at 24h showed strong significance (P<0.0001). ConclusionsA novel method of vascularized gracilis myocutaneous flap transplantation was validated in the Yorkshire swine. Assays for skeletal muscle tissue injury (LDH, CK, and AST) showed ischemia period-dependent response providing assessment of ischemia-reperfusion injury at the cellular level. Subsequent studies will evaluate agents that mitigate ischemia-reperfusion injury and transition these findings to potentiate vascularized composite allotransplantation.

The effects of dexmedetomidine on ischemia reperfusion injury in patients undergoing arthroscopy under spinal anesthesia.

Ischemia and reperfusion injury due to tourniquet application during arthroscopy is a well known problem. This study aimed to compare the effects of dexmedetomidine and ketamine on hemodynamic and respiratory variables and on total anti-oxidant status (TAS), total oxidant status (TOS) and malondialdehyde (MDA) as markers of ischemia-reperfusion injury. This study was approved by a local ethics committee. The study was performed on patients undergoing arthroscopic operation under spinal anesthesia. Thirty patients were randomized into two groups: Group D (dexmedetomidine; n=15) and Group K (Ketamine; n=15). Spinal anesthesia at the L2-4 level was achieved using a 25G spinal needle with hyperbaric bupivacaine at a dose of 12-15 mg in all patients. In Group D, patients were sedated with dexmedetomidine at a dose of 0.3-0.5 μg/kg/h, while Group K received ketamine at a dose of 1-1.5 mg/kg/h. Hemodynamic parameters, oxygen saturation, Ramsey sedation scale (RSS), and TAS, TOS, and MDA levels were recorded. Demographic parameters, TAS, TOS and MDA levels were similar between groups. In Group K, the TOS levels after tourniquet removal were significantly lower than at baseline and during the use of the tourniquet. Preoperative hemodynamic and respiratory variables were similar in both groups. Blood pressure values were decreased compared to baseline but these decreases were not statistically significant. In patients undergoing arthroscopy under spinal anesthesia, dexmedetomidine had effects similar to ketamine, led to insignificant alterations in hemodynamic and respiratory variables during surgery and had comparable effects on ischemia-reperfusion injury. Thus, we think that dexmedetomidine can be a safe alternative to ketamine as an intraoperative sedative.

Polyol pathway and modulation of ischemia-reperfusion injury in Type 2 diabetic BBZ rat hearts.

We investigated the role of polyol pathway enzymes aldose reductase (AR) and sorbitol dehydrogenase (SDH) in mediating injury due to ischemia-reperfusion (IR) in Type 2 diabetic BBZ rat hearts. Specifically, we investigated, (a) changes in glucose flux via cardiac AR and SDH as a function of diabetes duration, (b) ischemic injury and function after IR, (c) the effect of inhibition of AR or SDH on ischemic injury and function. Hearts isolated from BBZ rats, after 12 weeks or 48 weeks diabetes duration, and their non-diabetic littermates, were subjected to IR protocol. Myocardial function, substrate flux via AR and SDH, and tissue lactate:pyruvate (L/P) ratio (a measure of cytosolic NADH/NAD+), and lactate dehydrogenase (LDH) release (a marker of IR injury) were measured. Zopolrestat, and CP-470,711 were used to inhibit AR and SDH, respectively. Myocardial sorbitol and fructose content, and associated changes in L/P ratios were significantly higher in BBZ rats compared to non-diabetics, and increased with disease duration. Induction of IR resulted in increased ischemic injury, reduced ATP levels, increases in L/P ratio, and poor cardiac function in BBZ rat hearts, while inhibition of AR or SDH attenuated these changes and protected hearts from IR injury. These data indicate that AR and SDH are key modulators of myocardial IR injury in BBZ rat hearts and that inhibition of polyol pathway could in principle be used as a therapeutic adjunct for protection of ischemic myocardium in Type 2 diabetic patients.

041 Aged Rats Display Increased Ischemia‐Reperfusion Skin Injury in the in vivo Magnet Model

Introduction: Ischemia‐reperfusion (IR) injury is commonly associated with numerous pathologies including pressure sores, venous stasis ulcers, and lower extremity diabetic ulcers. The purpose of this study is to further investigate the relationship between age and ischemia‐reperfusion skin injury in a rat model utilizing magnets for the purpose of injury creation. Methods: Magnets were designed for subcutaneous placement and calibrated such that a second magnet placed externally over them would cause compression that exceeds capillary perfusion pressure (ischemia). Removing the external magnet results in reperfusion of the skin. After placing subcutaneous magnets in aged and young Fisher 344 rats, repeated cycles of external magnet placement and removal were performed. Results: Visual analysis of the skin revealed statistically significant greater areas of injury in the aged rats relative to their younger counterparts (37.4 ± 13.3% vs. 24.1 ± 14.8%, P &lt; .02) Conclusions: Aged rats demonstrate an increased degree of injury relative to their younger counterparts in response to ischemia‐reperfusion injury. Future studies will attempt to delineate differences in the markers of IR injury (such as myeloperoxidase and vitamin E levels) in aged versus young rats, giving insight to the mechanisms responsible for the impaired wound healing seen in the elderly.

Beta-galactosidase as a marker of ischemic injury and a mechanism for viability assessment in porcine liver transplantation.

Glycohydrolases are a group of enzymes contained predominantly within lysosomes, which are released during Kupffer cell activation or death. One of these, beta-galactosidase, has been proposed as a marker of ischemia-reperfusion injury in the liver because Kupffer cell activation represents a primary event in the injurious reperfusion cascade. In this study, we compared B-galactosidase with more traditional indicators of liver injury and function in a porcine model of liver preservation. Porcine livers were allocated into two groups: group C (n = 5), preserved in University of Wisconsin solution by standard cold storage for 24 hours, and group W (n = 5), perfused with oxygenated autologous blood on an extracorporeal circuit for 24 hours. Both groups were subsequently tested on the circuit during a 24-hour reperfusion phase. The perfusate was sampled for levels of beta-galactosidase, as well as traditional markers of liver injury and function. A sharp increase in beta-galactosidase levels was seen on reperfusion of cold preserved livers to a level of 1,900 IU/mL. This contrasted dramatically with normothermically preserved livers, in which the level never exceeded 208 IU/mL (P =.002). beta-Galactosidase levels showed much earlier and greater increases compared with transaminase levels in livers injured by ischemia. A rapid elevation in beta-galactosidase levels corresponded well with poor liver function and more liver injury. Measurement of beta-galactosidase is a simple test that quantifies ischemia-reperfusion injury of preserved livers. It is more sensitive than transaminases, with faster and larger increases in levels after ischemic injury. It can be useful in assessing the viability of a liver during machine preservation.

Evaluation of Ischemic Injury during Liver Procurement from Non-Heart-Beating Donors

The aim of this study was to assess liver viability after different periods of cardiac arrest and the predictive value of two markers of ischemia-reperfusion injury. Methods: A pig liver transplantation model of non-heart-beating donors was studied. Four donor groups were designed; three groups were submitted to different periods of cardiac arrest (20, 30 and 40 min), and the fourth group served as the control group (without cardiac arrest). In the non-heart-beating donor groups, normothermic recirculation was established 30 min prior to total body cooling. Aminotransferase, α-glutathione-S-transferase, and hyaluronic acid determinations as well as liver biopsies, were serially performed. Results: Although hepatocellular function could be preserved after 40 min of cardiac arrest, histological lesions at 5 days were considered irreversible due to the presence of a necrotic biliary tract. An overall significant relationship was found between the time period of cardiac arrest (20, 30 or 40 min) and the levels of hyaluronic acid (p = 0.004) or α-glutathione-S-transferase (p = 0.01) obtained during liver procurement and transplantation. Conclusions: The period of cardiac arrest is the determinant factor of liver viability after liver transplantation from non-heart-beating donors. As early markers of endothelial or hepatocellular damage, hyaluronic acid or α-glutathione-S-transferase levels may help to evaluate the ischemic injury of a potential donor.

Manganese Superoxide Dismutase

Recent evidence has suggested that ischemia-reperfusion injury is fundamental to the pathogenesis of acute pancreatitis. This study was designed to determine whether acute pancreatitis is associated with elevated serum manganese superoxide dismutase (MnSOD), a key antioxidant enzyme, considered a marker of ischemia-reperfusion injury in myocardial infarction. Thirty-four patients with acute pancreatitis had measurements of MnSOD on days 0, 2, and 5 after recruitment. The patients were recruited within 12 h of admission to hospital and had measurements of MnSOD on days 0, 2, and 5. Patients with severe acute pancreatitis had significantly elevated serum MnSOD concentrations on days 2 and 5 compared with patients with mild acute pancreatitis, but not on the day of recruitment. Elevated serum MnSOD correlated with peripheral plasma markers of lipid peroxidation (malondialdehyde) and neutrophil activation (myeloperoxidase) and was associated with decreased plasma ascorbic acid concentrations. The serial measurement of serum MnSOD may prove useful as a marker of the effectiveness of treatment designed to limit ischemia-reperfusion injury in patients with severe acute pancreatitis.

Deferoxamine cardioplegia reduces superoxide radical production in human myocardium

Recent studies have demonstrated enhanced myocardial protection during ischemia using the oxygen free radical scavenger, deferoxamine. This effect of deferoxamine may be related either to its iron-chelating property or to intervention in an iron-independent mechanism. We tested the latter by determining the rate of superoxide anion production and the degree of lipid peroxidation in human myocardial tissue after including deferoxamine in cardioplegic solution. Fourteen patients who underwent aortic, mitral, or double valve replacement were included in the study. The mean value for superoxide radical production was 59.8 +/- 17.0 nmol.min-1.g-1 for the control group (group C; n = 7) and 21.3 +/- 8.1 (p < 0.001) for the deferoxamine-treated group (group D; n = 7). The mean value for thiobarbituric reactive substances was 80.00 +/- 23.4 in group C and 38.7 +/- 23.8 nmol.min-1.g-1 in group D (p < 0.01). In conclusion, deferoxamine appears to have a moderating effect on the biochemical markers of ischemia reperfusion injury. Its scavenging effect on superoxide anion could play a role in the cellular defense against oxygen radicals during cardiac operations.