David C. Warltier

The systemic inflammatory response to cardiac surgery: Implications for the anesthesiologist

THE purpose of this review is to evaluate recent developments in our understanding of the inflammatory response to cardiac surgery. Scientific knowledge in this field is continually expanding, potentially significant advances are regularly reported, and this area constitutes a major interface of clinical and basic scientific research. The review is divided into four major sections. The first section describes the pathophysiology of the inflammatory response to cardiac surgery. Factors that influence the extent of the inflammatory response, including the immunomodulatory effects of drugs commonly administered perioperatively, are discussed in the second section. The third section examines the evidence that the inflammatory response contributes to adverse perioperative events, in particular organ dysfunction, while the final section evaluates potential therapeutic strategies to control this response. The review concludes with a summary of potential future research directions and key deficiencies in our knowledge regarding the inflammatory response to cardiac surgery.

isoflurane Mimics Ischemic Preconditioning via Activation of Katp Channels : reduction of Myocardial Infarct Size with An Acute Memory Phase

Background: The authors tested the hypothesis that isoflurane directly preconditions myocardium against infarction via activation of K sub ATP channels and that the protection afforded by isoflurane is associated with an acute memory phase similar to that of ischemic preconditioning. Methods: Barbiturate‐anesthetized dogs (n = 71) were instrumented for measurement of systemic hemodynamics. Myocardial infarct size was assessed by triphenyltetrazolium chloride staining. All dogs were subjected to a single prolonged (60 min) left anterior descending coronary artery (LAD) occlusion followed by 3 h of reperfusion. Ischemic preconditioning was produced by four 5‐min LAD occlusions interspersed with 5‐min periods of reperfusion before the prolonged LAD occlusion and reperfusion. The actions of isoflurane to decrease infarct size were examined in dogs receiving 1 minimum alveolar concentration (MAC) isoflurane that was discontinued 5 min before prolonged LAD occlusion. The interaction between isoflurane and ischemic preconditioning on infarct size was evaluated in dogs receiving isoflurane before and during preconditioning LAD occlusions and reperfusions. To test whether the cardioprotection produced by isoflurane can mimic the acute memory of ischemic preconditioning, isoflurane was discontinued 30 min before prolonged LAD occlusion and reperfusion. The mechanism of isoflurane‐induced cardioprotection was evaluated in two final groups of dogs pretreated with glyburide in the presence or absence of isoflurane. Results: Myocardial infarct size was 25.3 +/‐ 2.9% of the area at risk during control conditions. Isoflurane and ischemic preconditioning produced significant (P < 0.05) and equivalent reductions in infarct size (ischemic preconditioning alone, 9.6 +/‐ 2.0; isoflurane alone, 11.8 +/‐ 2.7; isoflurane and ischemic preconditioning, 5.1 +/‐ 1.9%). Isoflurane‐induced reduction of infarct size also persisted 30 min after discontinuation of the anesthetic (13.9 +/‐ 1.5%), independent of hemodynamic effects during LAD occlusion. Glyburide alone had no effect on infarct size (28.3 +/‐ 3.9%), but it abolished the protective effects of isoflurane (27.1 +/‐ 4.6%). Conclusions: Isoflurane directly preconditions myocardium against infarction via activation of KATP channels in the absence of hemodynamic effects and exhibits acute memory of preconditioning in vivo.

Isoflurane protects against myocardial infarction during early reperfusion by activation of phosphatidylinositol-3-kinase signal transduction: evidence for anesthetic-induced postconditioning in rabbits.

Background: Brief episodes of ischemia during early reperfusion after coronary occlusion reduce the extent of myocardial infarction. Phosphatidylinositol-3-kinase (PI3K) signaling has been implicated in this “postconditioning” phenomenon. The authors tested the hypothesis that isoflurane produces cardioprotection during early reperfusion after myocardial ischemia by a PI3K-dependent mechanism. Methods: Pentobarbital-anesthetized rabbits (n = 80) subjected to a 30-min coronary occlusion followed by 3 h reperfusion were assigned to receive saline (control), three cycles of postconditioning ischemia (10 or 20 s each), isoflurane (0.5 or 1.0 minimum alveolar concentration), or the PI3K inhibitor wortmannin (0.6 mg/kg, intravenously) or its vehicle dimethyl sulfoxide. Additional groups of rabbits were exposed to combined postconditioning ischemia (10 s) and 0.5 minimum alveolar concentration isoflurane in the presence and absence of wortmannin. Phosphorylation of Akt, a downstream target of PI3K, was assessed by Western blotting. Results: Postconditioning ischemia for 20 s, but not 10 s, reduced infarct size (P < 0.05) (triphenyltetrazolium staining; 20 ± 3% and 34 ± 3% of the left ventricular area at risk, respectively) as compared with control (41 ± 2%). Exposure to 1.0, but not 0.5, minimum alveolar concentration isoflurane decreased infarct size (21 ± 2% and 43 ± 3%, respectively). Wortmannin abolished the protective effects of postconditioning (20 s) and 1.0 minimum alveolar concentration isoflurane. Combined postconditioning (10 s) and 0.5 minimum alveolar concentration isoflurane markedly reduced infarct size (17 ± 5%). This action was also abolished by wortmannin (44 ± 2%). Isoflurane (1.0 minimum alveolar concentration) increased Akt phosphorylation after ischemia (32 ± 6%), and this action was blocked by wortmannin. Conclusions: Isoflurane acts during early reperfusion after prolonged ischemia to salvage myocardium from infarction and reduces the threshold of ischemic postconditioning by activating PI3K.

Mechanisms of Cardioprotection by Volatile Anesthetics

A RAPIDLY growing body of evidence indicates that volatile anesthetics protect myocardium against reversible and irreversible ischemic injury. Identifying the mechanisms by which volatile agents mediate these antiischemic actions is the subject of intense research. This objective has been difficult to accomplish because volatile anesthetics also profoundly affect cardiovascular function. Volatile agents reduce arterial and coronary perfusion pressure, cause dose-related depression of myocardial contractility, produce coronary vasodilation, affect electrophysiologic function, and modify autonomic nervous system activity to varying degrees. Therefore, the antiischemic effects of volatile anesthetics may be mediated, at least in part, by favorable alterations in myocardial oxygen supply–demand relations, preservation of energy-dependent cellular functions, and increased coronary blood flow. However, it seems unlikely that changes in myocardial metabolism and coronary perfusion caused by volatile anesthetics are solely responsible for protection against ischemic damage. Instead, several endogenous signal transduction pathways, acting through the adenosine triphosphate (ATP)–sensitive potassium (KATP) channel and involving the generation of reactive oxygen species (ROS), have been implicated in mediating the antiischemic actions of volatile anesthetics. The experimental and clinical findings documenting the phenomenon of volatile anesthetic preconditioning against ischemic injury of myocardium are evaluated. Recent findings in vitro and in vivo that seek to define the intracellular mechanisms responsible for these beneficial actions are also summarized.

Recovery of contractile function of stunned myocardium in chronically instrumented dogs is enhanced by halothane or isoflurane

Following brief periods (5–15 min) of total coronary artery occlusion and subsequent reperfusion, despite an absence of tissue necrosis, a decrement in contractile function of the postischemic myocardium may nevertheless be present for prolonged periods. This has been termed “stunned” myocardium to differentiate the condition from ischemia or infarction. Because the influence of volatile anesthetics on the recovery of postischemic, reperfused myocardium has yet to be studied, the purpose of this investigation was to compare the effects of halothane and isoflurane on systemic and regional hemodynamics following a brief coronary artery occlusion and reperfusion. Nine groups comprising 79 experiments were completed in 42 chronically instrumented dogs. In awake, unsedated dogs a 15-min coronary artery occlusion resulted in paradoxical systolic lengthening in the ischemic zone. Following reperfusion active systolic shortening slowly returned toward control levels but remained approximately 50% depressed from control at 5 h. In contrast, dogs anesthetized with halothane or isoflurane (2% inspired concentration) demonstrated complete recovery of function 3–5 h following reperfusion. Because the anesthetics directly depressed contractile function, additional experiments were conducted in which a 15-minute coronary artery occlusion was produced during volatile anesthesia; however, each animal was allowed to emerge from the anesthetized state at the onset of reperfusion. Similar results were obtained in these experiments, demonstrating total recovery of contractile function within 3–5 h following reperfusion. Thus, despite comparable degrees of contractile dysfunction during coronary artery occlusion in awake and anesthetized dogs, the present results demonstrate that halothane and isoflurane produce marked improvement in the recovery of segment function following a transient ischemic episode. Therefore, volatile anesthetics may attenuate postischemic left ventricular dysfunction occurring intraoperatively and enhance recovery of regional wall motion abnormalities during reperfusion.

Levosimendan, a New Positive Inotropic Drug, Decreases Myocardial Infarct Size via Activation of KATP Channels

We tested the hypothesis that levosimendan, a new positive inotropic drug that activates adenosine triphosphate-regulated potassium (KATP) channels in vitro, decreases myocardial infarct size in vivo. Myocardial infarct size was measured after a 60-min left anterior descending coronary artery occlusion and 3 h of reperfusion in dogs receiving either IV vehicle (0.9% saline) or levosimendan (24 &mgr;g/kg bolus followed by an infusion of 0.4 &mgr;g · kg−1 · min−1) in the presence or absence of glyburide (a KATP channel antagonist) pretreatment (100 &mgr;g/kg). Levosimendan increased (P < 0.05) the maximal rate of increase of left ventricular pressure and decreased myocardial infarct size from 24% ± 2% (control experiments) to 11% ± 2% of the left ventricular area at risk for infarction. Glyburide did not alter the hemodynamic effects of levosimendan but blocked levosimendan-induced reductions of infarct size. Subendocardial collateral blood flow was similar among groups. However, levosimendan increased subepicardial and midmyocardial collateral perfusion in the absence, but not in the presence, of glyburide. Levosimendan exerts cardioprotective effects via activation of KATP channels at a dose that simultaneously enhances myocardial contractility. Implications Levosimendan may be advantageous in patients requiring inotropic support who are also at risk of myocardial ischemia. Activation of adenosine triphosphate-regulated potassium channels during infusion of levosimendan may produce cardioprotective effects while simultaneously enhancing ventricular contractile function.

Ischemia-Induced Coronary Collateral Growth Is Dependent on Vascular Endothelial Growth Factor and Nitric Oxide

Background—We hypothesized that ischemia-induced expression of vascular endothelial growth factor (VEGF) and the production of NO stimulate coronary collateral growth. Methods and Results—To test this hypothesis, we measured coronary collateral blood flow and VEGF expression in myocardial interstitial fluid in a canine model of repetitive myocardial ischemia under control conditions and during antagonism of NO synthase. Collateralization was induced by multiple (1/h; 8/d), brief (2 minutes) occlusions of the left anterior descending coronary artery for 21 days. In controls, collateral blood flow (microspheres) progressively increased to 89±9 mL · min−1 · 100 g−1 on day 21, which was equivalent to perfusion in the normal zone. Reactive hyperemic responses (a measure of the severity of ischemia) decreased as collateral blood flow increased. In NG-nitro-l-arginine methyl ester (L-NAME)– and L-NAME+nifedipine–treated dogs, to block the production of NO and control hypertension, respectively, collateral blood flow did not increase and reactive hyperemia was robust throughout the occlusion protocol (P <0.01 versus control). VEGF expression (Western analyses of VEGF164 in myocardial interstitial fluid) in controls peaked at day 3 of the repetitive occlusions but waned thereafter. In sham-operated dogs (instrumentation but no occlusions), expression of VEGF was low during the entire protocol. In contrast, VEGF expression was elevated throughout the 21 days of repetitive occlusions after L-NAME. Reverse transcriptase–polymerase chain reaction analyses revealed that the predominant splice variant expressed was VEGF164. Conclusions—NO is an important regulator of coronary collateral growth, and the expression of VEGF is induced by ischemia. Furthermore, the induction of coronary collateralization by VEGF appears to require the production of NO.

Sevoflurane Reduces Myocardial Infarct Size and Decreases the Time Threshold for Ischemic Preconditioning in Dogs

BACKGROUND Recent evidence indicates that volatile anesthetics exert protective effects during myocardial ischemia and reperfusion. The authors tested the hypothesis that sevoflurane decreases myocardial infarct size by activating adenosine triphosphate-sensitive potassium (K(ATP)) channels and reduces the time threshold of ischemic preconditioning necessary to protect against infarction. METHODS Barbiturate-anesthetized dogs (n = 75) were instrumented for measurement of aortic and left ventricular pressures and maximum rate of increase of left ventricular pressure and were subjected to a 60-min left anterior descending (LAD) coronary artery occlusion followed by 3-h reperfusion. In four separate groups, dogs received vehicle or the K(ATP) channel antagonist glyburide (0.1 mg/kg intravenously), and 1 minimum alveolar concentration sevoflurane (administered until immediately before coronary artery occlusion) in the presence or absence of glyburide. In three additional experimental groups, sevoflurane was discontinued 30 min (memory) before the 60-min LAD occlusion or a 2-min LAD occlusion as an ischemic preconditioning stimulus was used with or without subsequent sevoflurane (with memory) pretreatment. Regional myocardial perfusion and infarct size were measured with radioactive microspheres and triphenyltetrazolium staining, respectively. RESULTS Vehicle (23 +/- 1% of the area at risk; mean +/- SEM) and glyburide (23 +/- 2%) alone produced equivalent effects on myocardial infarct size. Sevoflurane significantly (P < 0.05) decreased infarct size (13 +/- 2%). This beneficial effect was abolished by glyburide (21 +/- 3%). Neither the 2-min LAD occlusion nor sevoflurane followed by 30 min of memory were protective alone, but together, sevoflurane enhanced the effects of the brief ischemic stimulus and profoundly reduced infarct size (9 +/- 2%). CONCLUSION Sevoflurane reduces myocardial infarct size by activating K(ATP) channels and reduces the time threshold for ischemic preconditioning independent of hemodynamic effects in vivo.

Mechanism of Preconditioning by Isoflurane in Rabbits: A Direct Role for Reactive Oxygen Species

Background Reactive oxygen species (ROS) contribute to myocardial protection during ischemic preconditioning, but the role of the ROS in protection against ischemic injury produced by volatile anesthetics has only recently been explored. We tested the hypothesis that ROS mediate isoflurane-induced preconditioning in vivo. Methods Pentobarbital-anesthetized rabbits were instrumented for measurement of hemodynamics and were subjected to a 30 min coronary artery occlusion followed by 3 h reperfusion. Rabbits were randomly assigned to receive vehicle (0.9% saline), or the ROS scavengers N-acetylcysteine (NAC; 150 mg/kg) or N-2-mercaptopropionyl glycine (2-MPG; 1 mg · kg−1· min−1), in the presence or absence of 1.0 minimum alveolar concentration (MAC) isoflurane. Isoflurane was administered for 30 min and then discontinued 15 min before coronary artery occlusion. A fluorescent probe for superoxide anion production (dihydroethidium, 2 mg) was administered in the absence of the volatile anesthetic or 5 min before exposure to isoflurane in 2 additional groups (n = 8). Myocardial infarct size and superoxide anion production were assessed using triphenyltetrazolium staining and confocal fluorescence microscopy, respectively. Results Isoflurane (P < 0.05) decreased infarct size to 24 ± 4% (mean ± SEM; n = 10) of the left ventricular area at risk compared with control experiments (43 ± 3%; n = 8). NAC (43 ± 3%; n = 7) and 2-MPG (42 ± 5%; n = 8) abolished this beneficial effect, but had no effect on myocardial infarct size (47 ± 3%; n = 8 and 46 ± 3; n = 7, respectively) when administered alone. Isoflurane increased superoxide anion production as compared with control experiments (28 ± 12 vs. −6 ± 9 fluorescence units;P < 0.05). Conclusions The results indicate that ROS produced following administration of isoflurane contribute to protection against myocardial infarction in vivo.

Mechanism of myocardial protection by isoflurane : Role of adenosine triphosphate-regulated potassium (KATP) channels

Background The mechanism of the protective actions of volatile anesthetics in ischemic myocardium has not been clearly elucidated. The role of myocardial adenosine triphosphate‐regulated potassium (KATP) channels in isoflurane‐induced enhancement of recovery of regional contractile function after multiple brief occlusions and reperfusion of the left anterior descending coronary artery (LAD) was studied in dogs anesthetized with barbiturates. Methods Dogs (n = 32) were instrumented to measure left ventricular and aortic blood pressure, cardiac output, LAD coronary blood flow velocity, and subendocardial segment length. Regional myocardial perfusion was measured using radioactive microspheres. Hemodynamics and percentage segment shortening (%SS) in the LAD perfusion territory were evaluated after instrumentation was complete; after pretreatment with the KATP channel antagonist, glyburide (0.05 mg/kg sup ‐1) or drug vehicle (polyethylene glycol in ethyl alcohol; control experiments); and in the presence or absence of 1 MAC isoflurane administered for 30 min before and during five 5‐min occlusions and reperfusion of the LAD in four experimental groups. Isoflurane was discontinued at the onset of the final reperfusion period. Measurements of hemodynamics, %SS, and myocardial perfusion were repeated at several intervals during 180 min after reperfusion of the LAD. Results Left anterior descending coronary artery occlusion caused regional dyskinesia during each 5‐min occlusion in each dog. Control and glyburide‐pretreated dogs demonstrated poor recovery of %SS by 180 min after reperfusion (2 +/‐ 10 and 7 +/‐ 6% of baseline, respectively). In contrast, dogs anesthetized with isoflurane exhibited complete recovery of function (%SS) by 180 min after reperfusion (82 +/‐ 8% of baseline). Enhanced recovery of regional contractile function by isoflurane was abolished by pretreatment with glyburide 180 min after reperfusion (16 +/‐ 10% of baseline). Improvement of functional recovery of stunned myocardium by isoflurane, and the blockade of this action by glyburide, was not associated with changes in hemodynamics or regional myocardial perfusion. Conclusions The results indicate that isoflurane prevents decreased systolic shortening caused by multiple episodes of ischemia and reperfusion. These actions result in improved recovery of contractile function of postischemic, reperfused myocardium and are mediated by isoflurane‐induced activation of KATP channels.