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Corticosteroids and Cardiopulmonary Bypass^*

A Review of Clinical Investigations

^* From the Department of Anesthesia and Critical Care, University of Chicago, Chicago, IL.

Correspondence to: Mark A. Chaney, MD, Department of Anesthesia and Critical Care, University of Chicago 5841 South Maryland Ave, MC-4028, Chicago, IL 60637; e-mail: mchaney{at}airway.uchicago.edu

	Abstract

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Traditionally, corticosteroids have been administered to patients undergoing cardiac surgery with cardiopulmonary bypass (CPB) to ward off detrimental physiologic alterations associated with activation of the systemic inflammatory response, yet few well-controlled investigations exist, and use of these drugs in this setting remains controversial. This review article critically examines the results of clinical investigations in this area, and certain conclusions are suggested. The constellation of findings indicate that corticosteroids offer no clinical benefits to patients undergoing cardiac surgery with CPB and in fact may be detrimental. Further directions for clinical research in this area are also suggested.

Key Words: cardiopulmonary bypass • corticosteroids • systemic inflammatory response syndrome

	Introduction

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Cardiopulmonary bypass (CPB) exposes blood to large areas of synthetic materials that trigger the production and release of numerous chemotactic and vasoactive substances.^{1 2} This ensuing abnormal whole-body inflammatory response can complicate the postoperative period by causing major organ dysfunction. Traditionally, corticosteroids have been administered to patients undergoing cardiac surgery to ward off these detrimental physiologic alterations, yet few well-controlled investigations exist, and use of these drugs in this setting remains controversial.^{3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48} This review article critically examines the results of clinical investigations in this area. Well-controlled clinical investigations^{3 5 10} (prospective, randomized, double-blind, placebo-controlled) indicate that use of corticosteroids in this setting causes detrimental postoperative hemodynamic, pulmonary, and metabolic alterations and prolongs postoperative tracheal extubation time. Thus, new evidence indicates that routine administration of corticosteroids not only offers no clinical benefits to patients undergoing cardiac surgery with CPB, their use in this setting may in fact be contraindicated.^{3 5 10}

	Detrimental Physiologic Effects of CPB

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It has been known for many years that CPB induces a systemic inflammatory response syndrome (SIRS) in patients following cardiac surgery that can lead to major organ injury and postoperative morbidity.^{1 2} Initiation of CPB sets in motion an extremely complex and multifaceted response involving complement activation (both classic and alternative pathways) along with activation of platelets, neutrophils, monocytes, and macrophages, thus initiating the coagulation, fibrinolytic, and kallikrein cascades, increasing blood levels of various endotoxins and cytokines (interleukins [ILs]), tumor necrosis factor, etc.), and increasing endothelial cell permeability. Transvascular migration of activated leukocytes occurs into tissues; various proteases and neutrophil elastase are released, which causes additional vascular and parenchymal damage. The ensuing SIRS is further amplified by release of additional mediators (endotoxins, cytokines, etc.).

The basic physiologic insults caused by CPB have been associated with major postoperative morbidity, including neurologic dysfunction, pulmonary dysfunction, renal dysfunction, and/or hematologic abnormalities. Additional clinical manifestations associated with the SIRS include increased metabolism (fever), fluid retention, myocardial edema, and detrimental hemodynamic alterations.

Over the years, a wide variety of anti-inflammatory treatment options have been used in patients subjected to CPB in hopes of attenuating the SIRS, including leukocyte depletion techniques, neutrophil adhesion molecule blockade, heparin coating of CPB circuitry, and, most recently, use of monoclonal antibodies directed specifically against various inflammatory mediators. Although results from animal work appear promising, definite clinical benefit in humans has yet to be demonstrated. Corticosteroids, potent anti-inflammatory agents that possess multi-inhibitory effects on numerous components of the inflammatory response, represent an appealing treatment option in this scenario.

	Pharmacokinetics and Pharmacodynamics of Corticosteroids

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Two types of corticosteroids exist: mineralocorticoids (primarily regulate electrolyte homeostasis) and glucocorticoids (primarily regulate carbohydrate metabolism).⁴⁹ The prototype mineralocorticoid is desoxycorticosterone, and the prototype glucocorticoid is cortisol. It is must be emphasized that the biological characteristics of corticosteroids range over a spectrum from that of a strictly mineralocorticoid type to that of a strictly glucocorticoid type. Cortisone was the first corticosteroid used (around 1950) for its anti-inflammatory effect. Subsequent modification and manipulation of structure has yielded a wide variety of synthetic analogs with an increased ratio of anti-inflammatory effects to electrolyte and metabolic effects. Organic chemists have synthesized a bewildering number of such modified corticosteroids that exhibit substantial anti-inflammatory properties yet do not initiate serious electrolyte disturbances even at large doses. Of these synthetic corticosteroid analogs, methylprednisolone and (to a much lesser extent) dexamethasone represent the two most commonly utilized agents in patients subjected to CPB in hopes of attenuating the SIRS.

Changes in corticosteroid molecular structure may bring about changes in biological potency as a result of alterations in absorption, protein binding, rate of metabolic transformation, rate of excretion, ability to traverse membranes, and/or intrinsic effectiveness of the molecule at its site of action. In plasma, a large percentage of corticosteroid is reversibly bound to two proteins under normal circumstances (corticosteroid-binding globulin and albumin). Globulin has high affinity yet low total binding capacity, while albumin has low affinity yet relatively large binding capacity. Consequently, at low or normal concentrations of corticosteroids, most of the hormone is bound to globulin. When the amount of corticosteroid is increased, concentrations of both free and albumin-bound steroid increase with little change in the concentration of that bound to globulin. The free conticosteroid, as opposed to the protein-bound corticosteroid, is biologically active and available for hepatic metabolism and renal excretion. Corticosteroids, like other steroid hormones, are thought to exert their influence by controlling the rate of synthesis of proteins by stimulating transcription of RNA.

The physiologic effects of corticosteroids are numerous and widespread (Table 1 ). They influence carbohydrate metabolism, protein metabolism, lipid metabolism, electrolyte and water balance, the cardiovascular system, skeletal muscle, the CNS, the formed elements of blood, and they possess anti-inflammatory properties and affect other organs and tissues in a wide variety of ways. In essence, corticosteriods endow the organism with the capacity to resist many types of noxious stimuli and environmental change. The actions of corticosteroids are often complexly related to functions of other hormones, and a given dose of corticosteroid may by physiologic or pharmacologic depending on the environment and activities of the organism.

The cardiovascular effects of corticosteroids are primarily secondary to consequences of regulation of renal sodium ion excretion and volume shifts. Corticosteroid-induced hypertension may be the result of prolonged, excessive sodium retention and/or edema within the walls of arterioles (reducing their lumina and increasing peripheral vascular resistance). Another possibility is that salt retention, or mineralocorticoids themselves, sensitize blood vessels to pressor agents, in particular angiotensin and catecholamines. Corticosteroids also exert important actions on the various elements of the circulatory system, including capillaries, arterioles, and myocardium. In the absence of corticosteroids, there is increased capillary permeability, inadequate vasomotor response of small vessels, and reduction in cardiac size and output.

When glucocorticoids are administered for prolonged periods of time in high doses (or endogenously secreted in large amounts), wasting of skeletal muscle occurs (the mechanism of which is unknown). Corticosteroids can also affect the CNS in a number of indirect ways, in particular via glucose homeostasis, maintaining adequate circulation, and electrolyte homeostasis. They may also have direct effects, but these are as yet, poorly defined. An array of reactions, varying in degree and kind, is observed in patients administered glucocorticoids for therapeutic purposes. Most patients respond with an elevated mood, yet others exhibit euphoria, insomnia, restlessness, and increased motor activity. Some patients may become anxious, depressed, or even psychotic. Also, corticosteroids have been shown to affect brain excitability and alter the EEG.

Glucocorticoids increase the hemoglobin and red-cell content of blood, an effect that may be secondary to the capacity of these corticosteroids to retard erythrophagocytosis. Glucocorticoids also increase the number of polymorphonuclear leukocytes in the blood as a result of an increased rate of entrance into the blood from the marrow and a diminished rate of removal from the circulation. In contrast, lymphocytes, eosinophils, monocytes, and basophils in blood decrease in number following administration of glucocorticoids (secondary to redistribution, not destruction).

Cortisol and synthetic analogs of cortisol prevent/suppress development of local heat, redness, swelling, and tenderness by which inflammation is recognized. At the microscopic level, inhibition of the early phenomenon of the inflammatory process occurs (edema, fibrin deposition, capillary dilatation, migration of leukocytes into the inflamed area, and phagocytic activity), as well as inhibition of late phenomenon (capillary proliferation, fibroblast proliferation, collagen deposition). Corticosteroids inhibit the inflammatory response whether the inciting agent is radiant, mechanical, chemical, infectious, or immunologic. It is this suppression of inflammation and its consequences that have made corticosteroids such valuable therapeutic agents (at times, lifesaving). The anti-inflammatory effects depend on the direct local action of the corticosteroids. The most important factor in the anti-inflammatory effect of glucocorticoids may be their ability to inhibit recruitment of neutrophils and monocytes-macrophages into the affected area. Neutrophils also have a diminished tendency to adhere to capillary endothelial cells in areas of inflammation. Glucocorticoids also block the effects of migration inhibitory factor (produced by activated lymphocytes) on macrophages. Thus, the movement of macrophages is no longer impeded and they do not accumulate locally. Low concentrations of glucocorticoids also inhibit the formation of plasminogen activator by neutrophils. This enzyme converts plasminogen to plasmin, which is thought to facilitate entrance of leukocytes into areas of inflammation by hydrolysis of fibrin and other proteins. Glucocorticoids may also inhibit phospholipose A₂ and thereby diminish the release of arachidonic acid from phospholipids. This decreases formation of prostaglandins, leukotrienes, and related compounds such as prostaglandin endoperoxides and thromboxane, which play important roles in chemotaxis and inflammation.

Corticosteroid toxicity can be caused by either withdrawal of the drug or continued use of large doses. Withdrawal of the drug may initiate signs and symptoms of acute adrenal insufficiency. Continued use of large doses of drug may lead to suppression of the pituitary-adrenal axis, fluid and electrolyte disturbances, hyperglycemia/glycosuria, increased susceptibility to infections, peptic ulcers, osteoporosis, myopathy, behavioral disturbances, posterior subcapsular cataracts, arrest of growth, and Cushing’s habitus, among others. However, a single dose of corticosteroid, even a large one, is virtually without harmful effects; and a few days of therapy, in the absence of specific contraindications, is unlikely to produce harmful effects except at the most extreme doses.

	Historical Overview of Corticosteroid Use During CPB

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In the early 1960s, animal and human studies^{50 51} revealed the beneficial physiologic effects of corticosteroid administration in shock and sepsis models. Soon thereafter, investigators studied the effects of corticosteroid treatment during CPB, which at that time was thought to induce detrimental physiologic alterations similar to shock and sepsis.^{52 53} In dogs, Moses et al⁵² reported that hydrocortisone (or its equivalent in methylprednisolone) attenuated detrimental physiologic effects (acidosis, elevated lactate levels, etc.) associated with extracorporeal perfusion and foreshadowed application to humans: "... it is conceivable that such administration before prolonged cardiopulmonary bypass in humans would be of value." Subsequently, in humans, Replogle et al⁵³ reported that dexamethasone ("massive doses") attenuated lysosomal enzyme release (ß-glucuronidase) associated with CPB. In these early investigations, the specific corticosteroid chosen was empirical and the dose administered often massive. In the late 1960s, methylprednisolone became the drug of choice because of its anti-inflammatory potency and minimal tendency to induce sodium and water retention.⁵⁴ An IV dose of 30 mg/kg was at this time deemed "optimal" because this amount was shown to be beneficial in clinical shock studies⁵⁴ yet possess no detrimental systemic effects when administered to a small group (n = 12) of healthy volunteers (no larger doses were studied, however).⁵⁵

A pivotal study was published in 1970 by Dietzman et al,⁴⁸ who reported that methylprednisolone, 30 mg/kg, was effective in treating "low output syndrome" in dogs and humans following cardiac surgery. Specifically, in 98 dogs, methylprednisolone administration decreased systemic vascular resistance (SVR), increased cardiac index (CI), improved tissue perfusion, and increased survival from 22 to 65%.⁴⁸ In 19 humans, following cardiac valve replacement, the same beneficial hemodynamic effects were observed.⁴⁸ The authors justifiably conclude that on "the basis of this experimental and preliminary clinical evidence this treatment plan merits further investigation."⁴⁸

The initial clinical investigation describing beneficial effects of methylprednisolone pretreatment prior to CPB appeared the following year, in 1971.⁴⁷ Wilson et al⁴⁷ studied 50 patients undergoing CPB procedures and found that administration of methylprednisolone, 15 mg/kg, to patients prior to CPB prevented detrimental pulmonary vascular and alveolar architectural changes as assessed via perioperative lung biopsies (light microscopy, electron microscopy, enzyme studies) when compared to patients not receiving the drug. This encouraging initial investigation, along with others that followed in the 1970s,^{39 40 41 42 43 44 45 46} prompted many clinicians to routinely administer methylprednisolone, 30 mg/kg, to patients who were to undergo CPB. In the early 1980s, Thompson et al^{34 36} assayed blood samples in patients receiving methylprednisolone, 30 mg, prior to CPB and found that plasma concentrations of the drug declined substantially (approximately 50%) with initiation of CPB (secondary to pump prime dilution), yet plasma concentrations were well maintained into the postoperative period if a repeat dose of 30 mg/kg was administered during initiation of CPB. Obviously, the plasma concentration of methylprednisolone that is "effective" is not known. Thus, by 1982, the dose of methylprednisolone was empirically set at 30 mg/kg twice and remains the standard to this day.

	Clinical Investigations in the 1970S

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Following the provocative studies published in 1970 by Dietzman et al⁴⁸ and in 1971 by Wilson et al⁴⁷ indicating that methylprednisolone administration may benefit patients undergoing CPB, many investigators began to focus on this area. Initial clinical results however, were not encouraging. Coffin et al⁴⁶ in 1975 prospectively administered methylprednisolone, 30 mg/kg, to 50 patients prior to CPB and compared perioperative data with 50 historical control subjects not receiving the drug. These investigators found that patients receiving methylprednisolone experienced longer periods of postoperative respiratory support (mean ± SD, 85 ± 181 h vs 27 ± 16 h, p = 0.05), a higher incidence of low cardiac output syndrome (24% vs 12%, p = 0.01), and higher operative mortality (22% vs 16%, not statistically significant) when compared to historical control subjects.⁴⁶ However, the design of this study (prospective administration of drug, historical control subjects) does not eliminate the possibility that patients receiving methylprednisolone were at higher risk to begin with. In a small (31 patients) prospective study, Enderby et al⁴⁰ found no beneficial effects on perioperative pulmonary function (PaO₂, PaCO₂, alveolar-arterial oxygen gradient [P(A-a)O₂], shunt) in patients receiving methylprednisolone, 30 mg/kg, when compared to patients not receiving the drug.

In contrast to these discouraging studies, other clinical investigations revealed potential benefits of methylprednisolone. A large (427 patients) observational study published in 1975 by Dietzman et al⁴⁵ revealed that, when compared to control patients, patients receiving methylprednisolone, 30 mg/kg, prior to CPB exhibited significantly less (p < 0.01) vasoconstriction (assessed via total peripheral resistance index, skin color, urine output) and significantly improved (p < 0.0005) perfusion flows (assessed via calibration curve of CPB arterial pump). Clinically, patients receiving methylprednisolone "were mentally alert earlier, required less pulmonary support, and left the ICUs earlier than the control group" yet no definitive data were presented.⁴⁵ Two years later, in 1977, another large (150 patients) observational study by Rao et al⁴³ suggested that, when compared to control patients, patients receiving methylprednisolone, 1 g, prior to CPB exhibited a lesser incidence of myocardial infarction, cardiac arrhythmia, cerebral vascular accident, and pulmonary embolism perioperatively and had significantly better (p = 0.05) heart function at the end of CPB (rated as "good," "fair," or "poor" by the investigators) and significantly fewer (p = 0.05) total incidents of postoperative complications.

Stimulated by emerging data revealing an anti-ischemic effect of steroids on the infarcted area of myocardium in both animal and human investigations,^{56 57 58 59} Morton et al⁴⁴ published the first well-designed (prospective, randomized, double-blind, placebo-controlled) investigation involving methylprednisolone and CPB. They studied 95 patients undergoing coronary artery bypass grafting (CABG), with half receiving methylprednisolone (2 g or 30 mg/kg) immediately prior to induction of anesthesia and half receiving placebo at the same time.⁴⁴ However, there was no difference between the two groups regarding ease of separation from CPB, postoperative blood levels of cardiac enzymes and isoenzymes, postoperative ECG evidence of myocardial infarction, or postoperative respiratory insufficiency.⁴⁴ In contrast to this study, another clinical investigation published 2 years later, in 1978, revealed that methylprednisolone may possess cardioprotective properties.⁴¹ Fecht et al⁴¹ studied 50 patients undergoing CABG, half receiving methylprednisolone (1 g early during CPB, 1 g late during CPB) and half receiving mannitol (600 mg twice, at the same two times). Perioperative myocardial biopsies with subsequent electron microscopy revealed that methylprednisolone helped preserve cardiac cellular integrity (less mitochondrial damage).⁴¹ Furthermore, patients receiving methylprednisolone exhibited improved bypass graft flow rates (56% higher), improved postoperative urine output (67% higher), and fewer postoperative chest radiographic abnormalities.⁴¹

The decade of the 1970s closed with publication by Niazi et al³⁹ of the second well-designed investigation involving methylprednisolone and CPB. Ninety patients undergoing elective cardiac surgery were randomized to receive an injection prior to CPB: 30 patients received methylprednisolone, 30 mg/kg; 30 patients received dexamethasone, 6 mg/kg; and 30 patients received placebo therapy.³⁹ Patients receiving methylprednisolone exhibited a higher mean CI before (p < 0.01) and after (p < 0.05) CPB as well as a lower mean total peripheral vascular resistance before (p < 0.10) and after (p < 0.20) CPB when compared to the other two groups.³⁹ While there was no difference between the three groups regarding perioperative oxygen consumption (O₂), postoperative blood levels of lactic acid were higher in patients receiving methylprednisolone (p < 0.005), a finding the authors attributed to improved microcirculatory flow ("washout" phenomenon).³⁹ Patients receiving dexamethasone behaved no differently than patients receiving placebo regarding all important perioperative physiologic variables.³⁹

	Clinical Investigations in the 1980S

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The decade of the 1980s began with publication by Toledo-Pereyra et al³⁷ of a relatively large (95 patients), well-designed investigation involving adult and pediatric patients undergoing a wide variety of cardiac surgeries. Forty-seven patients randomly received methylprednisolone, 30 mg/kg, seven times perioperatively: 1 h preoperatively, 5 min prior to CPB, immediately after CPB, and then every 6 h for the next 24 h.³⁷ Forty-eight patients randomly received placebo in an identical, blinded manner.³⁷ There was no difference between the two groups regarding perioperative laboratory data (arterial blood gases, serum sodium, serum potassium), perioperative complications (urinary tract infection, fever, pneumonia, stress ulcer, sepsis), or discharge day (methylprednisolone group, 15.5 ± 8.6 days [mean ± SD]; placebo group, 16.7 ± 13.1 days).³⁷ However, the methylprednisolone group had significantly less deaths than the placebo group (two deaths vs eight deaths, respectively; p < 0.05), a finding the authors were unable to explain.³⁷

Two investigations by the same group from London in the early 1980s revealed the importance of administering a supplemental dose of methylprednisolone with initiation of CPB to compensate for hemodilution (and thus maintain blood levels of the drug).^{34 36} In the first observational investigation, Thompson and Broadbent³⁶ found that, when compared to patients receiving saline solution, patients receiving methylprednisolone, 30 mg/kg, prior to CPB exhibited significantly increased (p < 0.001) O₂ immediately following CPB and significantly increased (p < 0.05) serum phosphate levels in the immediate postoperative period. The authors attributed the increased O₂ associated with methylprednisolone to improved tissue perfusion because at this time there was no difference between groups regarding CI.³⁶ Additionally, there was no difference between groups regarding perioperative hemoglobin 2,3-diphosphoglycerate levels, standard partial oxygen pressure values, or oxygen availability.³⁶ In a subset of four patients receiving methylprednisolone, plasma radioimmunoassays revealed a rapid decline in drug levels (1 to 2 h after administration) that was further exacerbated with initiation of CPB.³⁶ The second observational study by the same group revealed that plasma levels of methylprednisolone were well maintained throughout CPB if two doses were administered (30 mg/kg after anesthesia induction and 30 mg/kg at CPB initiation).³⁴ However, marked differences in plasma levels of methylprednisolone were observed between individual patients 5 min after administration of the initial injection, despite a standardized, weight-related dose (range, 140 to 330 µg/mL).³⁴ As with their previous study, there was no difference between the methylprednisolone and placebo groups regarding perioperative hemoglobin 2,3-diphosphoglycerate levels, standard partial oxygen pressure values, or CI.³⁴

In the early 1980s, important research performed at the University of Alabama in Birmingham revealed the pivotal role that complement activation plays in the basic physiologic insults caused by CPB.^{60 61} These investigators discovered that initiation of CPB was associated with complement activation, neutrophilia, transpulmonary neutropenia, and pulmonary-vascular sequestration of complement-activated granulocytes, and theorized that the major postoperative morbidity associated with CPB (neurologic dysfunction, pulmonary dysfunction, renal dysfunction, and/or hematologic abnormalities) was related in part to complement activation.^{60 61} Subsequently, a majority of the investigations involving methylprednisolone and CPB in the 1980s focused on complement activation. Many small observational studies^{29 30 35 38} involving adult and pediatric patients during this time indicated that a single dose of methylprednisolone, 30 mg/kg, prior to CPB was unable to prevent complement activation associated with CPB. Another small observational study also revealed that higher doses suggested by studies by Boscoe et al³³ (30 mg/kg after anesthesia induction and 30 mg/kg at CPB initiation) were unable to prevent complement activation associated with CPB. One investigation actually hinted that methylprednisolone, 30 mg/kg, may actually increase complement activation.³² However, two studies did suggest that methylprednisolone may confer benefits despite inability to inhibit complement activation.^{29 30} One revealed that methylprednisolone may be able to attenuate complement-mediated neutrophil activation (assessed in vivo and in vitro) associated with CPB.³⁰ The other study revealed that, when compared to control patients, patients receiving methylprednisolone exhibited significantly increased (p < 0.01) postoperative blood granulocyte levels (indicating less complement-mediated aggregation and/or adherence) and significantly decreased (p < 0.01) postoperative bronchial lavage fluid granulocyte levels (indicating less alveolar influx of granulocytes).²⁹

However, two investigations in the late 1980s revealed that methylprednisolone may inhibit complement activation associated with CPB and bubble oxygenators.^{28 31} Cavarocchi et al³¹ in 1986 randomly divided 91 patients undergoing a wide variety of cardiac surgeries into three groups: 30 patients received bubble oxygenators, 31 patients received bubble oxygenators and methylprednisolone (30 mg/kg prior to CPB), and 30 patients received membrane oxygenators. The two groups receiving methylprednisolone or membrane oxygenators behaved similarly; both groups, when compared to the bubble oxygenator group, exhibited significantly decreased (p < 0.0001) complement activation and significantly decreased (p < 0.0001) transpulmonary leukocyte sequestration associated with CPB.³¹ Another small observational study using bubble oxygenators revealed that, when compared to control subjects, patients receiving methylprednisolone, 30 mg/kg, prior to CPB exhibited significantly decreased (p < 0.01) complement activation and significantly increased (p < 0.01) blood levels of circulating endotoxins during CPB.²⁸ The issue regarding bubble oxygenators vs membrane oxygenators should be emphasized. Many of the older studies involving corticosteroids and CPB utilized bubble oxygenators, whereas the current standard of practice is to utilize membrane oxygenators. There is no doubt that bubble oxygenators possess greater capability of inducing the SIRS associated with CPB,^{1 2} and this fact should be accounted for when analyzing and interpreting studies involving corticosteroids and CPB.

	Clinical Investigations From 1990 TO THE PRESENT

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Numerous investigations^{3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27} during the last 11 years have explored the potential clinical benefits of routine administration of methylprednisolone to patients undergoing cardiac surgery with CPB. A fair proportion of these investigations have been prospective, randomized, double-blind, placebo-controlled clinical trials.^{3 5 7 10 13 25 27} Most of the clinical investigations in the early 1990s continued to focus on the potential ability of methylprednisolone to attenuate the SIRS associated with CPB. Most recent clinical investigations continue to assess the effects of the drug on the SIRS, yet also have begun to assess clinical outcomes.

One can assess the SIRS that is associated with CPB in a wide variety of ways. Most commonly, this is performed by assaying blood levels of numerous proinflammatory and/or anti-inflammatory mediators. While a few investigations have shown no effect,^{16 26} the vast majority of investigations performed have revealed the ability of methylprednisolone to beneficially alter the balance of these mediators in the blood of patients following exposure to CPB (by attenuating increases in proinflammatory mediators and/or augmenting increases in anti-inflammatory mediators). Numerous observational studies have shown that methylprednisolone (in a wide variety of dosing schedules) can attenuate increases in the proinflammatory mediators IL-1,¹⁹ IL-6,^{9 12 20 21 23} IL-8,^{9 17 18 19 21 23} tumor necrosis factor,^{17 18 20 21 22} and plasma endotoxin,⁶ yet augment increases in the anti-inflammatory mediators IL-4¹⁴ and IL-10^{14 17 18} associated with CPB. Additional observational studies have revealed that the drug attenuates complement activation,^{15 19} attenuates increases in bronchial epithelial nitric oxide concentration,²⁰ and decreases neutrophil CD11b surface glycoprotein upregulation^{22 24} associated with CPB, all of which should be beneficial. Clinical benefits suggested by these observational studies include an increased CI,²³ a decreased pulmonary capillary wedge pressure,²³ and a decreased incidence of postoperative hyperthermia,¹⁶ yet postoperative hyperglycemia may ensue.⁴ Lastly, these studies^{8 18} suggest that preoperative administration (as much as 8 h) may be important when optimizing beneficial effects.

Several well-designed (prospective, randomized, double-blind, placebo-controlled) clinical trials^{3 5 7 10 13 25 27} have supported and extended the results of these observational studies. In 1991, Jansen et al²⁷ revealed that, when compared to control subjects receiving placebo treatment, patients receiving methylprednisolone (30 mg/kg following anesthesia induction) had significantly lower blood levels of leukotriene B₄ (p < 0.05) and tissue plasminogen activator (p < 0.01) yet similar blood levels of complement C3a and elastase following exposure to CPB. Two years later, in 1993, Jorens et al²⁵ reported that patients receiving methylprednisolone (30 mg/kg following anesthesia induction) had significantly lower blood levels of IL-8 (p < 0.05) and significantly less neutropenia (p < 0.05) yet similar blood levels of complement C3a on exposure to CPB, when compared to control subjects receiving placebo. Furthermore, they also discovered that harvested alveolar macrophages from patients administered methylprednisolone released significantly less IL-8 (p < 0.05) than did macrophages from control subjects receiving placebo.²⁵

Most recent clinical investigations continue to assess the effects of methylprednisolone on the SIRS yet also have begun to assess clinical outcomes. In 1997, Mayumi et al¹³ revealed that, when compared to control subjects receiving placebo, patients receiving methylprednisolone (20 mg/kg twice) had significantly increased blood levels of WBCs (p = 0.04) and natural killer cells (p = 0.01) yet significantly decreased blood levels of IL-2 (p = 0.04), C-reactive protein (p < 0.0001), and phytohemagglutinin response (p < 0.01) following exposure to CPB. Because their constellation of findings suggested that T-cell functions were synergistically suppressed by methylprednisolone and CPB, the authors conclude that the drug may promote an immunocompromised state (yet no postoperative wound infections were observed).¹³ Postoperatively, patients receiving methylprednisolone had significantly higher blood glucose (p < 0.01) and lactate (p < 0.05) levels and a significantly decreased incidence of postoperative hyperthermia (p = 0.001) when compared to control subjects receiving placebo.¹³ There was no difference between the methylprednisolone and placebo groups regarding perioperative CI, water balance, arterial blood gas levels, electrolytes, nor extubation time (1.42 ± 0.64 days vs 1.30 ± 0.46 days, respectively).¹³ In 1999, Tassani et al⁷ revealed that, when compared to control subjects receiving placebo, patients receiving methylprednisolone (1 g prior to CPB) had significantly decreased blood levels of IL-6 (p < 0.05) and IL-8 (p < 0.05) and significantly increased blood levels of IL-10 (p < 0.05) on exposure to CPB. Clinically, patients receiving methylprednisolone exhibited decreased P(A-a)O₂ (376 mm Hg vs 428 mm Hg, respectively; p < 0.05), increased pulmonary compliance (44 mL/mm Hg vs 39 mL/mm Hg, respectively; p < 0.05), and increased CI (4.1 vs 3.6 L/min/m², respectively; p < 0.05) following exposure to CPB, when compared to control subjects receiving placebo.⁷ Postoperatively, patients receiving methylprednisolone exhibited increased blood glucose concentrations (203 mg/dL vs 146 mg/dL, respectively; p < 0.001) and similar extubation times (8.1 h vs 9.2 h, respectively) when compared to control subjects receiving placebo.⁷ While the investigation of Tassani et al⁷ revealed potential clinical benefits of methylprednisolone (improved oxygenation, improved pulmonary compliance, increased CI, etc.), the study can be criticized because of lack of standardization in key areas (mechanical ventilation parameters) and the routine use of aprotinin (known to attenuate the SIRS associated with CPB⁶² ) in all patients.

Most recent clinical investigations by Chaney et al^{3 5 10} indicate that routine administration of methylprednisolone to patients undergoing cardiac surgery with CPB not only offers no clinical benefits, its use in the era of early tracheal extubation may in fact be contraindicated. In their first studies, these investigators in prospective, randomized, blinded fashion administered methylprednisolone (30 mg/kg twice) to 30 patients undergoing elective CABG while 30 similar patients received placebo.^{5 10} Perioperative care was standardized, including intraoperative baseline anesthetic and mechanical ventilation parameters.^{5 10} They found that patients receiving methylprednisolone had significantly larger increases in postoperative P(A-a)O₂ (199 to 420 mm Hg vs 237 to 360 mm Hg, respectively; p = 0.001), shunt (12 to 27% vs 14 to 21%, respectively; p = 0.001), and CI (2.1 to 3.0 L/min/m² vs 2.1 to 2.5 L/min/m², respectively; p = 0.04), yet significantly smaller increases in postoperative SVR (1,199 to 1,045 dyne·s·cm^-5 vs 1,247 to 1,312 dyne·s·cm^-5, respectively; p = 0.05) when compared to control subjects receiving placebo.^{5 10} Furthermore, the drug was unable to prevent significant perioperative increases in blood C3a levels (p < 0.01) and significant postoperative decreases in dynamic lung compliance (p < 0.000001).^{5 10} Lastly, when compared to control subjects receiving placebo, patients receiving methylprednisolone required significantly more dobutamine (24 patients vs 15 patients, respectively; p = 0.02), significantly less nitroglycerin (4 patients vs 12 patients, respectively; p = 0.02), and had prolonged extubation times (12.8 h vs 10.1 h, respectively; p = 0.05) during the postoperative period.^{5 10} Thus, this constellation of findings unexpectedly revealed that methylprednisolone may initiate detrimental pulmonary and hemodynamic effects that may hinder early tracheal extubation following cardiac surgery.^{5 10}

These unexpected results stimulated the same group to perform another investigation in this area.³ In this study, 90 patients were prospectively randomized into three groups: one group received methylprednisolone (30 mg/kg twice), one group received the drug at half that dose (15 mg/kg twice), and the last group received placebo in a blinded fashion.³ Once again, the perioperative care was standardized including intraoperative baseline anesthetic and mechanical ventilation parameters.³ The results on this investigation were similar.³ Patients receiving methylprednisolone (either dose) exhibited significantly increased CI (p = 0.0006), significantly decreased SVR (p = 0.0005), and significantly increased shunt (p = 0.002) during the immediate postoperative period.³ All three groups exhibited significant increases in P(A-a)O₂ (p < 0.0001), significant decreases in dynamic lung compliance (p < 0.0001), and significant decreases in static lung compliance (p < 0.0001) during the immediate postoperative period, with no differences between groups.³ Perioperative fluid balance and weights were similar between groups.³ A statistically significant difference in peak postoperative blood glucose level existed (p = 0.016) among the group receiving 30 mg/kg twice (mean ± SD, 311 ± 90 mg/dL), the group receiving 15 mg/kg twice (292 ± 93 mg/dL), and the group receiving placebo (234 ± 96 mg/dL).³ Lastly, in patients extubated within 12 h of ICUs arrival, a statistically significant difference in extubation times existed (p = 0.025) between the group receiving 30 mg/kg twice (7.5 ± 2.7 h), the group receiving 15 mg/kg twice (5.9 ± 2.2 h), and the group receiving placebo (5.7 ± 2.3 h).³ Thus, the findings of this investigation³ support and extend the previous studies by the same group,^{5 10} and indicate that methylprednisolone offers no clinical benefits to patients undergoing cardiac surgery with CPB, and may in fact be detrimental by initiating postoperative hyperglycemia and possibly hindering early postoperative tracheal extubation for undetermined reasons.

	Summary

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Prospective, randomized, double-blind, placebo-controlled clinical investigations involving methylprednisolone and patients undergoing cardiac surgery with CPB are summarized in Table 2 . As can be seen, all involved small numbers of patients and most did not tightly control perioperative management (intraoperative baseline anesthetic technique, mechanical ventilation parameters, technique of CPB, etc.). Despite these facts, the results of these clinical investigations, along with the results of less well-controlled clinical investigations, suggest certain conclusions. It appears that methylprednisolone is able to reliably (and beneficially) alter the balance of proinflammatory and anti-inflammatory mediators in the blood of patients subjected to CPB, indicating that the drug decreases the SIRS associated with CPB. However, whether or not suppression of the SIRS is clinically beneficial remains to be determined. Specific hemodynamic benefits (increased CI, decreased SVR) seem to be associated with use of the drug in this setting yet these alterations may increase the need for postoperative IV hemodynamic agents (vasoconstrictors, etc.). From a pulmonary perspective, the use of methylprednisolone in this setting does not appear to offer any clinical benefits and may be detrimental. The drug is unable to reliably prevent postoperative decreases in pulmonary compliance and increases in P(A-a)O₂ (perhaps by increasing pulmonary shunt) and may hinder early postoperative tracheal extubation for undetermined reasons. Lastly, while methylprednisolone is unable to beneficially affect perioperative fluid balance (and weight), it is clear that the drug will increase perioperative blood glucose levels (possible increasing morbidity). Thus, this constellation of findings indicate that methylprednisolone offers no clinical benefits to patients undergoing cardiac surgery with CPB and in fact may be detrimental by initiating postoperative hyperglycemia and possibly hindering early postoperative tracheal extubation for undetermined reasons.

	Future Directions

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	Footnotes

 
Abbreviations: CABG = coronary artery bypass grafting; CI = cardiac index; CPB = cardiopulmonary bypass; IL = interleukin; P(A-a)O₂ = alveolar-arterial oxygen gradient; SIRS = systemic inflammatory response syndrome; SVR = systemic vascular resistance; O₂ = oxygen consumption

Received for publication April 20, 2001. Accepted for publication September 4, 2001.

	References

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1. Asimakopoulos, G, Smith, PLC, Ratnatunga, CP, et al (1999) Lung injury and acute respiratory distress syndrome after cardiopulmonary bypass. Ann Thorac Surg 68,1107-1115[Abstract/Free Full Text]
2. Boyle, EM, Pohlman, TH, Johnson, MC, et al (1997) The systemic inflammatory response. Ann Thorac Surg 64,S31-S37[CrossRef]
3. Chaney, MA, Durazo-Arvizu, RA, Nikolov, MP, et al (2001) Methylprednisolone does not benefit patients undergoing coronary artery bypass grafting and early tracheal extubation. Thorac Cardiovasc Surg 121,561-569[Abstract/Free Full Text]
4. London, MJ, Grunwald, GK, Shroyer, LW, et al (2000) Association of fast-track cardiac management and low-dose to moderate-dose glucocorticoid administration with perioperative hyperglycemia. J Cardiothorac Vasc Anesth 14,631-638[CrossRef][ISI][Medline]
5. Chaney, MA, Nikolov, MP, Blakeman, BP, et al (1999) Hemodynamic effects of methylprednisolone in patients undergoing cardiac operation and early extubation. Ann Thorac Surg 67,1006-1011[Abstract/Free Full Text]
6. Wan, S, LeClerc, JL, Huynh, CH, et al (1999) Does steroid pretreatment increase endotoxin release during clinical cardiopulmonary bypass? Thorac Cardiovasc Surg 117,1004-1008
7. Tassani, P, Richter, JA, Barankay, A, et al (1999) Does high-dose methylprednisolone in aprotinin-treated patients attenuate the systemic inflammatory response during coronary artery bypass grafting procedures? J Cardiothorac Vasc Anesth 13,165-172[CrossRef][ISI][Medline]
8. Lodge, AJ, Chai, PJ, Daggett, CW, et al (1999) Methylprednisolone reduces the inflammatory response to cardiopulmonary bypass in neonatal piglets: timing of dose is important. Thorac Cardiovasc Surg 117,515-522
9. Kawamura, T, Inada, K, Nara, N, et al (1999) Influence of methylprednisolone on cytokine balance during cardiac surgery. Crit Care Med 27,545-548[CrossRef][ISI][Medline]
10. Chaney, MA, Nikolov, MP, Blakeman, B, et al (1998) Pulmonary effects of methylprednisolone in patients undergoing coronary artery bypass grafting and early tracheal extubation. Anesth Analg 87,27-33[Abstract/Free Full Text]
11. Gott, JP, Cooper, WA, Schmidt, FE, et al (1998) Modifying risk for extracorporeal circulation: trial of four anti-inflammatory strategies. Ann Thorac Surg 66,747-754[Abstract/Free Full Text]
12. Diego, RP, Mihalakakos, PJ, Hexum, TD, et al (1997) Methylprednisolone and full-dose aprotinin reduce reperfusion injury after cardiopulmonary bypass. J Cardiothorac Vasc Anesth 11,29-31[CrossRef][ISI][Medline]
13. Mayumi, H, Zhang, QW, Nakashima, A, et al (1997) Synergistic immunosuppression caused by high-dose methylprednisolone and cardiopulmonary bypass. Ann Thorac Surg 63,129-137[Abstract/Free Full Text]
14. Wan, S, LeClerc, JL, Schmartz, D, et al (1997) Hepatic release of interleukin-10 during cardiopulmonary bypass in steroid-pretreated patients. Am Heart J 133,335-339[CrossRef][ISI][Medline]
15. Loubser, PG (1997) Effect of methylprednisolone on complement activation during heparin neutralization. J Cardiovasc Pharmacol 29,23-27[CrossRef][ISI][Medline]
16. Toft, P, Christiansen, K, Tonnesen, E, et al (1997) Effect of methylprednisolone on the oxidative burst activity, adhesion molecules and clinical outcome following open heart surgery. Scand Cardiovasc J 31,283-288[ISI][Medline]
17. Tabardel, Y, Duchateau, J, Schmartz, D, et al (1996) Corticosteroids increase blood interleukin-10 levels during cardiopulmonary bypass in men. Surgery 119,76-80[CrossRef][ISI][Medline]
18. Wan, S, DeSmet, JM, Antoine, M, et al (1996) Steroid administration in heart and heart-lung transplantation: is the timing adequate? Ann Thorac Surg 61,674-678[Abstract/Free Full Text]
19. Engelman, RM, Rousou, JA, Flack, JE, et al (1995) Influence of steroids on complement and cytokine generation after cardiopulmonary bypass. Ann Thorac Surg 60,801-804[Abstract/Free Full Text]
20. Hill, GE, Snider, S, Galbraith, TA, et al (1995) Glucocorticoid reduction of bronchial epithelial inflammation during cardiopulmonary bypass. Am J Respir Crit Care Med 152,1791-1795[Abstract]
21. Teoh, KHT, Bradley, CA, Gauldie, J, et al (1995) Steroid inhibition of cytokine-mediated vasodilation after warm heart surgery. Circulation 92[suppl],II347-II353
22. Hill, GE, Alonso, A, Spurzem, JR, et al (1995) Aprotinin and methylprednisolone equally blunt cardiopulmonary bypass-induced inflammation in humans. Thorac Cardiovasc Surg 110,1658-1662
23. Kawamura, T, Inada, K, Okada, H, et al (1995) Methylprednisolone inhibits increase of interleukin 8 and 6 during open heart surgery. Can J Anaesth 42,399-403[Abstract/Free Full Text]
24. Hill, GE, Alonso, A, Thiele, GM, et al (1994) Glucocorticoids blunt neutrophil CD11b surface glycoprotein upregulation during cardiopulmonary bypass in humans. Anesth Analg 79,23-27[Abstract/Free Full Text]
25. Jorens, PG, De Jongh, R, De Backer, W, et al (1993) Interleukin-8 production in patients undergoing cardiopulmonary bypass: the influence of pretreatment with methylprednisolone. Am Rev Respir Dis 148,890-895[ISI][Medline]
26. Karlstad, MD, Patterson, SK, Guszcza, JA, et al (1993) Methylprednisolone does not influence endotoxin translocation during cardiopulmonary bypass. J Cardiothorac Vasc Anesth 7,23-27[CrossRef][Medline]
27. Jansen, NJG, van Oeveren, W, van Vliet, M, et al (1991) The role of different types of corticosteroids on the inflammatory mediators in cardiopulmonary bypass. Eur J Cardiothorac Surg 5,211-217[Abstract]
28. Andersen, LW, Baek, L, Thomsen, BS, et al (1989) Effect of methylprednisolone on endotoxemia and complement activation during cardiac surgery. J Cardiothorac Anesth 3,544-549[CrossRef][Medline]
29. Fosse, E, Mollnes, TE, Osterud, A, et al (1987) Effects of methylprednisolone on complement activation and leukocyte counts during cardiopulmonary bypass. Scand Thorac Cardiovasc Surg 21,255-261[ISI][Medline]
30. Tennenberg, SD, Bailey, WW, Cotta, LA, et al (1986) The effects of methylprednisolone on complement-mediated neutrophil activation during cardiopulmonary bypass. Surgery 100,134-142[ISI][Medline]
31. Cavarocchi, NC, Pluth, JR, Schaff, HV, et al (1986) Complement activation during cardiopulmonary bypass: comparison of bubble and membrane oxygenators. Thorac Cardiovasc Surg 91,252-258
32. Ferries, LH, Marx, JJ, Ray, JF (1984) The effect of methylprednisolone on complement activation during cardiopulmonary bypass. J Extracorp Technol 16,83-88
33. Boscoe, MJ, Yewdall, VMA, Thompson, MA, et al (1983) Complement activation during cardiopulmonary bypass: quantitative study of effects of methylprednisolone and pulsatile flow. BMJ 287,1747-1750
34. Thompson, MA, Broadbent, MP, English, J (1982) Plasma levels of methylprednisolone following administration during cardiac surgery. Anaesthesia 37,405-407[ISI][Medline]
35. Hammerschmidt, DE, Stroncek, DF, Bowers, TK, et al (1981) Complement activation and neutropenia occurring during cardiopulmonary bypass. Thorac Cardiovasc Surg 81,370-377
36. Thompson, MA, Broadbent, MP (1980) Methylprednisolone prior to cardiopulmonary bypass. Anaesthesia 35,345-353[ISI][Medline]
37. Toledo-Pereyra, LH, Lin, CY, Kundler, H, et al (1980) Steroids in heart surgery: a clinical double-blind and randomized study. Am Surg 46,155-160[ISI][Medline]
38. Haslam, PL, Townsend, PJ, Branthwaite, MA (1980) Complement activation during cardiopulmonary bypass. Anaesthesia 35,22-26[ISI][Medline]
39. Niazi, Z, Flodin, P, Joyce, L, et al (1979) Effects of glucocorticosteroids in patients undergoing coronary artery bypass surgery. Chest 76,262-268[Abstract/Free Full Text]
40. Enderby, DH, Boylett, A, Parker, DJ (1979) Methylprednisolone and lung function after cardiopulmonary bypass. Thorax 34,720-725[Abstract]
41. Fecht, DC, Magovern, GJ, Park, SB, et al (1978) Beneficial effects of methylprednisolone in patients on cardiopulmonary bypass. Circ Shock 5,415-422[ISI][Medline]
42. Gnanadurai, TV, Branthwaite, MA, Colbeck, JF, et al (1978) Lysosomal enzyme release from the lungs after cardiopulmonary bypass. Anaesthesia 33,227-231[ISI][Medline]
43. Rao, G, King, J, Ford, W, et al (1977) The effects of methylprednisolone on the complications of coronary artery surgery. Vasc Surg 11,1-7[ISI][Medline]
44. Morton, JR, Hiebert, CA, Lutes, CA, et al (1976) Effect of methylprednisolone on myocardial preservation during coronary artery surgery. Am J Surg 131,419-422[CrossRef][ISI][Medline]
45. Dietzman, RH, Lunseth, JB, Goott, B, et al (1975) The use of methylprednisolone during cardiopulmonary bypass: a review of 427 cases. Thorac Cardiovasc Surg 69,870-873
46. Coffin, LH, Shinozaki, T, De Meules, JE, et al (1975) Ineffectiveness of methylprednisolone in the treatment of pulmonary dysfunction after cardiopulmonary bypass. Am J Surg 130,555-559[CrossRef][ISI][Medline]
47. Wilson, JW, Young, WG, Miller, BJ (1971) Pulmonary cellular changes prevented or altered by methyl prednisolone sodium succinate [abstract]. Fed Proc 30,686
48. Dietzman, RH, Castaneda, AR, Lillehei, CW, et al (1970) Corticosteroids as effective vasodilators in the treatment of low output syndrome. Chest 57,440-453[Abstract]
49. Haynes, RC, Murad, F (1985) Adrenocorticotropic hormone, adrenocortical steroids and their synthetic analogs: inhibitors of adrenocortical steroid biosynthesis. Gilman, AG Goodman, LS Rall, TWet al eds. The pharmacologic basis of therapeutics 7th ed ,1459-1489 Macmillan Publishing Company New York, NY.
50. Weil, MH, Whigham, H (1965) Corticosteroids for reversal of hemorrhagic shock in rats. Am J Physiol 209,815-819[Abstract/Free Full Text]
51. Sambhi, MP, Weil, MH, Vdhoji, VN (1965) Acute pharmacodynamic effects of glucocorticoids; cardiac output and related hemodynamic changes in normal subjects and patients in shock. Circulation 31,523-530[Abstract/Free Full Text]
52. Moses, ML, Camishion, RC, Tokunaga, K, et al (1966) Effect of corticosteroid on the acidosis of prolonged cardiopulmonary bypass. J Surg Res 6,354-360[CrossRef][ISI][Medline]
53. Replogle, RL, Gazzaniga, AB, Gross, RE (1966) Use of corticosteroids during cardiopulmonary bypass: possible lysosome stabilization. Circulation (Suppl I),I86-I91
54. Motsay, GJ, Alho, A, Jaeger, T, et al (1970) Effects of corticosteroids on the circulation in shock: experimental and clinical results. Fed Proc 29,1861-1873[Medline]
55. Novak, E, Stubbs, SS, Seckman, CE, et al (1970) Effects of a single large intravenous dose of methylprednisolone sodium succinate. Clin Pharmacol Ther 11,711-717[ISI][Medline]
56. Morrison, J, Maley, T, Reduto, L, et al (1975) Effect of methylprednisolone on predicted myocardial infarction size in man. Crit Care Med 3,94-102[CrossRef][Medline]
57. Busuttil, RW, George, WJ, Hewitt, RL (1975) Protective effect of methylprednisolone on the heart during ischemic arrest. Thorac Cardiovasc Surg 70,955-965
58. Spath, JA, Lane, DL, Lefer, AM (1974) Protective action of methylprednisolone on the myocardium during experimental myocardial ischemia in the cat. Circ Res 35,44-51[Abstract/Free Full Text]
59. Libby, P, Maroko, PR, Bloor, CM, et al (1973) Reduction of experimental myocardial infarct size by corticosteroid administration. J Clin Invest 52,599-607
60. Kirklin, JK, Westaby, S, Blackstone, EH, et al (1983) Complement and the damaging effects of cardiopulmonary bypass. Thorac Cardiovasc Surg 86,845-857
61. Chenoweth, DE, Cooper, SW, Hugli, TE, et al (1981) Complement activation during cardiopulmonary bypass; evidence for generation of C3a and C5a anaphylatoxins. N Engl J Med 304,497-503[Abstrac