Michael Zaugg

Preconditioning by Sevoflurane Decreases Biochemical Markers for Myocardial and Renal Dysfunction in Coronary Artery Bypass Graft Surgery: A Double-blinded, Placebo-controlled, Multicenter Study

Background Preconditioning by volatile anesthetics is a promising therapeutic strategy to render myocardial tissue resistant to perioperative ischemia. It was hypothesized that sevoflurane preconditioning would decrease postoperative release of brain natriuretic peptide, a biochemical marker for myocardial dysfunction. In addition, several variables associated with the protective effects of preconditioning were evaluated. Methods Seventy-two patients scheduled for coronary artery bypass graft surgery under cardioplegic arrest were randomly assigned to preconditioning during the first 10 min of complete cardiopulmonary bypass with either placebo (oxygen–air mixture only) or sevoflurane 4 vol% (2 minimum alveolar concentration). No other volatile anesthetics were administered at any time during the study. Treatment was strictly blinded to anesthesiologists, perfusionists, and surgeons. Biochemical markers of myocardial dysfunction and injury (brain natriuretic peptide, creatine kinase–MB activity, and cardiac troponin T), and renal dysfunction (cystatin C) were determined. Results of Holter electrocardiography were recorded perioperatively. Translocation of protein kinase C was assessed by immunohistochemical analysis of atrial samples. Results Sevoflurane preconditioning significantly decreased postoperative release of brain natriuretic peptide, a sensitive biochemical marker of myocardial contractile dysfunction. Pronounced protein kinase C &dgr; and &egr; translocation was observed in sevoflurane-preconditioned myocardium. In addition, postoperative plasma cystatin C concentrations increased significantly less in sevoflurane-preconditioned patients. No differences between groups were found for perioperative ST-segment changes, arrhythmias, or creatine kinase–MB and cardiac troponin T release. Conclusions Sevoflurane preconditioning preserves myocardial and renal function as assessed by biochemical markers in patients undergoing coronary artery bypass graft surgery under cardioplegic arrest. This study demonstrated for the first time translocation of protein kinase C isoforms &dgr; and &egr; in human myocardium in response to sevoflurane.

Volatile anesthetics mimic cardiac preconditioning by priming the activation of mitochondrial KATP channels via multiple signaling pathways

Background Volatile anesthetics induce pharmacological preconditioning in cardiac tissue. The purpose of this study was to test whether volatile anesthetics mediate this effect by activation of the mitochondrial adenosine triphosphate–sensitive potassium (mitoKATP) or sarcolemmal KATP (sarcKATP) channel in rat ventricular myocytes and to evaluate the signaling pathways involved. Methods A cellular model of ischemia with subsequent hypoosmolar trypan blue staining served to determine the effects of 5-hydroxydecanoate, a selective mitoKATP channel blocker, HMR-1098, a selective sarcKATP channel blocker, diazoxide, a preconditioning mimicking agent, and various modulators of putative signaling pathways on cardioprotection elicited by sevoflurane and isoflurane. Microscopy was used to visualize and measure autofluorescence of flavoproteins, a direct index of mitoKATP channel activity. Results Volatile anesthetics significantly enhanced diazoxide-mediated activation of mitoKATP channels as assessed by autofluorescence of myocytes. Conversely, volatile anesthetics alone did not alter mitoKATP channel activity, implying a priming effect of volatile anesthetics on mitoKATP channels. Administration of the protein kinase C inhibitor chelerythrine completely blocked this effect. Also, pretreatment with volatile anesthetics potentiated diazoxide-mediated protection against ischemia, as indicated by a reduction in trypan blue–positive myocytes. Importantly, cardioprotection afforded by volatile anesthetics was unaffected by the sarcKATP channel blocker HMR-1098 but sensitive to modulations of nitric oxide and adenosine–Gi signaling pathways. Conclusions Using autofluorescence in live cell imaging microscopy and a simulated model of ischemia, the authors present evidence that volatile anesthetics mediate their protection in cardiomyocytes by selectively priming mitoKATP channels through multiple triggering protein kinase C–coupled signaling pathways. These observations provide important new insight into the mechanisms of anesthetic-induced preconditioning.

Beneficial effects from β-adrenergic blockade in elderly patients undergoing noncardiac surgery

BackgroundPerioperative β-blockade has been shown to improve long-term cardiac outcome in noncardiac surgical patients. A possible mechanism for the reduced risk of perioperative myocardial infarction is the attenuation of the excitotoxic effects of catecholamine surges by β-blockade. It was hypothe

Isoflurane postconditioning prevents opening of the mitochondrial permeability transition pore through inhibition of glycogen synthase kinase 3β

Background:Postischemic administration of volatile anesthetics activates reperfusion injury salvage kinases and decreases myocardial damage. However, the mechanisms underlying anesthetic postconditioning are unclear. Methods:Isolated perfused rat hearts were exposed to 40 min of ischemia followed by 1 h of reperfusion. Anesthetic postconditioning was induced by 15 min of 2.1 vol% isoflurane (1.5 minimum alveolar concentration) administered at the onset of reperfusion. In some experiments, atractyloside (10 &mgr;m), a mitochondrial permeability transition pore (mPTP) opener, and LY294002 (15 &mgr;m), a phosphatidylinositol 3-kinase inhibitor, were coadministered with isoflurane. Western blot analysis was used to determine phosphorylation of protein kinase B/Akt and its downstream target glycogen synthase kinase 3β after 15 min of reperfusion. Myocardial tissue content of nicotinamide adenine dinucleotide served as a marker for mPTP opening. Accumulation of MitoTracker Red 580 (Molecular Probes, Invitrogen, Basel, Switzerland) was used to visualize mitochondrial function. Results:Anesthetic postconditioning significantly improved functional recovery and decreased infarct size (36 ± 1% in unprotected hearts vs. 3 ± 2% in anesthetic postconditioning; P < 0.05). Isoflurane-mediated protection was abolished by atractyloside and LY294002. LY294002 inhibited isoflurane-induced phosphorylation of protein kinase B/Akt and glycogen synthase kinase 3β and opened mPTP as determined by nicotinamide adenine dinucleotide measurements. Atractyloside, a direct opener of the mPTP, did not inhibit phosphorylation of protein kinase B/Akt and glycogen synthase kinase 3β by isoflurane but reversed isoflurane-mediated cytoprotection. Microscopy showed accumulation of the mitochondrial tracker in isoflurane-protected functional mitochondria but no staining in mitochondria of unprotected hearts. Conclusions:Anesthetic postconditioning by isoflurane effectively protects against reperfusion damage by preventing opening of the mPTP through inhibition of glycogen synthase kinase 3β.

Translocation of Protein Kinase C Isoforms to Subcellular Targets in Ischemic and Anesthetic Preconditioning

Background Translocation of protein kinase C (PKC) to subcellular targets is a pivotal signaling step in ischemic preconditioning (IPC). However, to date, it is unknown whether PKC isoforms translocate in anesthetic preconditioning (APC). Methods The PKC blockers chelerythrine and rottlerin and the adenosine triphosphate–dependent potassium (KATP) channel blockers HMR-1098 and 5-hydroxydecanoate were used to assess the role of PKC and KATP channels in isolated perfused rat hearts subjected to IPC or APC (1.5 minimum alveolar concentration isoflurane) followed by 40 min of ischemia and 30 min of reperfusion. Immunohistochemical techniques were used to visualize PKC translocation after preconditioning. In addition, the phosphorylation status of PKC isoforms was assessed. Results Chelerythrine, rottlerin, and 5-hydroxydecanoate blocked IPC and APC with respect to functional recovery, albeit IPC at higher concentrations. HMR-1098 did not affect IPC or APC. PKC&dgr; and PKC&egr; translocated to nuclei in both IPC and APC, which was inhibited by chelerythrine and rottlerin. PKC&dgr; translocated to mitochondria but not to the sarcolemma, and PKC&egr; translocated to the sarcolemma and intercalated disks but not to mitochondria. Interestingly, PKC&egr; was accumulated at the intercalated disks in control and preconditioned hearts. Phosphorylation of PKC&dgr; on serine643 was increased in IPC and APC and blocked by chelerythrine and rottlerin, whereas phosphorylation of PKC&dgr; on threonine505 was increased only in IPC and not blocked by chelerythrine or rottlerin. PKC&egr; on serine729 did not change its phosphorylation status. Conclusions This study indicates that translocation of PKC&dgr; plays a pivotal role in IPC and APC and suggests that phosphorylation of PKC&dgr; on serine643 may be of particular relevance in transferring the APC stimulus to mitochondrial KATP channels.

Perioperative beta-adrenergic receptor blockade: physiologic foundations and clinical controversies.

THE recent focus on perioperative -adrenergic receptor blockade (PBB) to reduce cardiac morbidity or mortality follows nearly 40 yr of research documenting the cardioprotective effects of -adrenergic receptors (BARs). On the basis of two influential randomized controlled trials demonstrating improvement in perioperative (30day) or long-term (1to 2-yr) outcome in high-risk patients, this practice is now routinely recommended by consultants and has recently been highlighted as a “toptier” patient safety practice by the Institute of Medicine. As such, it may serve as a performance measure for quality improvement. However, many aspects remain controversial. This commentary examines physiologic concepts and potential uses of PBB in patients undergoing noncardiac surgery. Given well-documented difficulties with guideline compliance for blockade after acute myocardial infarction (MI) (secondary prevention), it is to be expected that similar attempts in the large pool of eligible perioperative patients will require substantial ongoing efforts.

Adrenergic receptor genotype but not perioperative bisoprolol therapy may determine cardiovascular outcome in at-risk patients undergoing surgery with spinal block: the Swiss Beta Blocker in Spinal Anesthesia (BBSA) study: a double-blinded, placebo-controlled, multicenter trial with 1-year follow-up

Background:Neuraxial blockade is used as primary anesthetic technique in one third of surgical procedures. The authors tested whether bisoprolol would protect patients at risk for cardiovascular complications undergoing surgery with spinal block. Methods:The authors performed a double-blinded, placebo-controlled, multicenter trial to compare the effect of bisoprolol with that of placebo on 1-yr composite outcome including cardiovascular mortality, nonfatal myocardial infarction, unstable angina, congestive heart failure, and cerebrovascular insult. Bisoprolol was given orally before and after surgery for a maximum of 10 days. Adrenergic receptor polymorphisms and safety outcome measures of bisoprolol therapy were also determined. Results:A total of 224 patients were enrolled. Spinal block could not be established in 5 patients. One hundred ten patients were assigned to the bisoprolol group, and 109 patients were assigned to the placebo group. The mean duration of treatment was 4.9 days in the bisoprolol group and 5.1 days in the placebo group. Bisoprolol therapy reduced mean heart rate by 10 beats/min. The primary outcome was identical between treatment groups and occurred in 25 patients (22.7%) in the bisoprolol group and 24 patients (22.0%) in the placebo group during the 1-yr follow-up (hazard ratio, 0.97; 95% confidence interval, 0.55–1.69; P = 0.90). However, carriers of at least one Gly allele of the β1-adrenergic receptor polymorphism Arg389Gly showed a higher number of adverse events than Arg homozygous (32.4% vs. 18.7%; hazard ratio, 1.87; 95% confidence interval, 1.04–3.35; P = 0.04). Conclusions:Perioperative bisoprolol therapy did not affect cardiovascular outcome in these elderly at-risk patients undergoing surgery with spinal block.

Remote ischemic preconditioning applied during isoflurane inhalation provides no benefit to the myocardium of patients undergoing on-pump coronary artery bypass graft surgery: lack of synergy or evidence of antagonism in cardioprotection?

Background: Two preconditioning stimuli should induce a more consistent overall cell protection. We hypothesized that remote ischemic preconditioning (RIPC, second preconditioning stimulus) applied during isoflurane inhalation (first preconditioning stimulus) would provide more protection to the myocardium of patients undergoing on-pump coronary artery bypass grafting. Methods: In this placebo-controlled randomized controlled study, patients in the RIPC group received four 5-min cycles of 300 mmHg cuff inflation/deflation of the leg before aortic cross-clamping. Anesthesia consisted of opioids and propofol for induction and isoflurane for maintenance. The primary outcome was high-sensitivity cardiac troponin T release. Secondary endpoints were plasma levels of N-terminal pro-brain natriuretic peptide, high-sensitivity C-reactive protein, S100 protein, and short- and long-term clinical outcomes. Gene expression profiles were obtained from atrial tissue using microarrays. Results: RIPC (n = 27) did not reduce high-sensitivity cardiac troponin T release when compared with placebo (n = 28). Likewise, N-terminal pro-brain natriuretic peptide, a marker of myocardial dysfunction; high-sensitivity C-reactive protein, a marker of perioperative inflammatory response; and S100, a marker of cerebral injury, were not different between the groups. The incidence for the perioperative composite endpoint combining new arrhythmias and myocardial infarctions was higher in the RIPC group than the placebo group (14/27 vs. 6/28, P = 0.036). However, there was no difference in the 6-month cardiovascular outcome. N-terminal pro-brain natriuretic peptide release correlated with isoflurane-induced transcriptional changes in fatty-acid metabolism (P = 0.001) and DNA-damage signaling (P < 0.001), but not with RIPC-induced changes in gene expression. Conclusions: RIPC applied during isoflurane inhalation provides no benefit to the myocardium of patients undergoing on-pump coronary artery bypass grafting.

Sevoflurane Inhalation at Sedative Concentrations Provides Endothelial Protection against Ischemia–reperfusion Injury in Humans

Background:Endothelial cells can be protected against cytokine-induced toxicity by volatile anesthetics. The authors tested whether inhalation of sevoflurane at subanesthetic concentrations provides protection against postocclusive endothelial dysfunction induced by ischemia–reperfusion injury of the forearm in humans. Methods:Five healthy male volunteers were enrolled in this study with crossover design. Each subject was randomly exposed to 15 min of forearm ischemia in the presence or absence of sevoflurane. Sevoflurane was inhaled at 0.5–1 vol% end-tidal concentrations from 15 min before ischemia until 5 min after the onset of reperfusion. Hyperemic reaction, an indicator of ischemic injury and endothelial function, was determined at 15 and 30 min of reperfusion using venous occlusion plethysmography. Also, markers of leukocyte activation (CD11b, CD42b) were measured by flow cytometry during reperfusion. Results:Fifteen minutes of forearm ischemia followed by reperfusion diminished postocclusive endothelium-dependent hyperemic reaction at 15 and 30 min of reperfusion. Peri-ischemic inhalation of sevoflurane, targeted at 0.5–1 vol% end-tidal concentrations, markedly improved postocclusive hyperemic reaction. In addition, inhalation of sevoflurane attenuated activation of leukocytes, as measured by CD11b expression, after ischemia–reperfusion injury. No changes in CD42b expression were observed after ischemia–reperfusion of the forearm. Conclusions:These data suggest that human endothelium, a key component of all vital organs, is receptive to protection by sevoflurane in vivo. Peri-ischemic administration of sevoflurane mimics a combination of pharmacologic preconditioning and postconditioning and protects at even low sedative concentrations (< 1 vol%). Inhibition of leukocyte adhesion is likely to be involved in the protection.

RESPIRATORY FUNCTION IN THE ELDERLY

Aging reduces the reserve capacity of virtually all pulmonary functions. Age-related alterations in the respiratory system are based on structural changes that lead to functional impairment of gas exchange. Pulmonary complications during anesthesia and the postoperative period are significantly increased in elderly patients with pre-existing diseases. The physiologic changes in the aged respiratory system and their anesthetic implications are reviewed in this article.