Sevoflurane and organ protection Chatchai Prechawai Department of Anesthesiology Faculty of Medicine Prince of songkla University

 Perioperative myocardial infarction (PMI) is associated with mortality rates of up to 40% Lee Th. Circulation 1999; 100: Poldermans D. N Engl J Med 1999;341:  Non fatal PMI increases the risk of both cardiovascular death and a further non-fatal myocardial infarction in the first 6 months after major non-cardiac surgery Mangano DT. JAMA 1992; 268:

Therapeutic strategies  Coronary revascularization  Beta-blockers  Alpha2-adrenoceptor agonists  Aspirin  Statins  etc…… Priebe HJ. Br J Anaesth 2005; 95: 3-19.

Myocardial Infraction Ischaemic Preconditi oning Hibernatin g Myocardiu m Stunned Myocardiu m ISCHA EMIA Acute occlusion and cell death Chronic ischaemia Shot, controlled ischaemic episodes with intervening reperfusion Prolonged, acute ischaemic event followed by reperfusion Spectrum of myocardial ischemia myocardial ischemia

Ischemic preconditioning  Brief episodes of ischemia in the heart, occurring before a subsequent longer interruption of blood flow, provides protection against dysfunction and necrosis  4 cycles of 5-min left circumflex coronary artery occlusions, before a 40-min occlusion, reduced myocardial infarction by 75% Murray CE, Circulation 1986; 74:

Sommerschild HT, Kirkeboen KA. Acta Anaesthesiol Scand 2002; 46:

Preconditi oning Stimulus Preconditi oning Stimulus Signal Amplification Immed iate Protect ion Immed iate Protect ion Delayed Protection “2 nd window effect” Delayed Protection “2 nd window effect” Minu tes Hour s Days Hawaleshka A, Can J Anaesth 1998; 45: De Hert SG. Curr Opin Anaesthesiol 2004; 17: Sommerschild HT, Acta Anaesthesiol Scand 2002; 46:

PKC= protein kinase C HSP= heat stress proteins AOE= antioxidant enzymes K ATP channels= ATP-dependent K channels Signals Signal Amplific ation Signal Amplific ation Effecto rs Adenosine Bradykinin Norepinep hrine Nitric oxide K ATP channels HSP AOE G- proteins PKC

Ade= adenosine Br= Bradykinin Ne= norepinephrine PLC= phospholipase C DAG= diacetylglycerol ITP= inositol triphosphate AOE HSP Nucl eus PKCPKC PKCPKC DAG+ ITP A1A1 G Protei n PLC B2B2 Ad e BrNeNe K+K+ Hyperpolari zation α1α1 Ca 2+ lnflux AP duration Myocardial Energy Consumptio n PKC= protein kinase C HSP= heat stress proteins AOE= antioxidant enzymes A1= Adenosine receptor type 1 a1= alpha adrenergic receptor type 1 B2= bradykinin receptor type 2 K+= potassium

Ischemic preconditioning Ischemic preconditioning in other organs  Brain  Lung  Liver  Kidney  Small intestine Dirnagl U, Trends Neurosci 2003; 26: Koti RS, Dig Surg 2003; 20: Mc Laren AJ, Transpl Int 2003: 16: Kosieradzki M, Surgery 2003; 133: Head BP, Curr Opin Anaesthesiol 2007; 20: Clarkson AN. Life Sci 2007; 80: Kitano H, J Cereb Blood Flow Me tab 2007; 27: Lee TH, Anesthesiology 2004; 101: Bedirli N, Anesth Analg 2008; 106:

Sevoflurane and cardioprotection Volatile and IV anesthetics that effect K ATP channels  Isoflurane  Sevoflurane  Desflurane  Morphine  Fentanyl Zaugg M, et al. Br J Anaesth 2003; 91: Zaugg M, et al. Br J Anaesth 2003; 91: Zaugg M, et al. Br J Anaesth 2003; 91:

Sevoflurane and cardioprotection  Sevoflurane but not propofol preserved LV function after CPB with less evidence of myocardial damage in the first 36 hr postoperatively.  Suggest a cardioprotective effect of sevoflurane during coronary artery surgery De Hert SG. Anesthesiology 2002; 97: 42-9  Also in high-risk coronary patients De Hert SG. Anesthesiology 2003; 99:

De Hert SG. Anesthesiology 2002; 97: 42-9

De Hert SG. Anesthesiology 2003; 99:

Sevoflurane and cardioprotection  In patients undergoing CABG surgery with CPB, the cardioprotective effects of sevoflurane were clinically most apparent when it was administered throughout the operation De Hert SG, et al. Anesthesiology 2004; 101:

De Hert SG, et al. Anesthesiology 2004; 101:

Sevoflurane and cardioprotection  Patients receiving sevoflurane for off- pump coronary artery surgery had less myocardial injury during the first 24 postoperative hours then patient receiving propofol. Conzen PF. Anesthesiology 2003;99:

Sevoflurane group Propofol group Conzen PF. Anesthesiology 2003;99:

Sevoflurane and cardioprotection  Sevoflurane suppressed the production of IL-6 and IL-8, but not IL-10 and IL-1ra.  Changes in the balance between pro- and anti-inflammatory cytokines may be one of the most important mechanisms of myocardial protection caused by sevoflurane Kawamura T. J Cardiothorac Vasc Anesth 2006; 20:

Sevoflurane and cardioprotection  Sevoflurane decreases the inflammatory response after CPB, as measured by the release of IL-6, CD11b/CD18, and TNF-α.  Myocardial function after CPB, as assessed by RWMA and LVSWI, was also improved with sevoflurane. Nader DN. J Cardiothorac Vasc Anesth 2004; 18: RWMA = regional wall motion abnormality LVSWI=left ventricular stroke work index

 Period A IV anesthetics  Period B volatile anesthetics (sevoflurane 0.5-2%) Van der Linden PJ, Anesthesiology 2003; 99:

 Period A IV anesthetics  Period B volatile anesthetics (sevoflurane 0.5-2%) Van der Linden PJ, Anesthesiology 2003; 99:

Anesthetic preconditioning  22 studies, involving 1,922 patients  Volatiles anesthetics were associated with significant reductions of MI (2.4% vs 5.1%) and mortality (0.4% vs 1.6%) Landoni G. J Cardiothorac Vasc Anesth 2007; 21:

Julier K, et al. Anesthesiology 2003; 98: Translocation of PKC to cardiomyocytes in CABG patients’ right atrial tissues samples Percentages of PKC Nucleus of PKC Lipofuscin pigment

Julier K, et al. Anesthesiology 2003; 98: brain natriuretic peptide: a sensitive biochemical marker of myocardial contractile dysfunction Troponin T Creatinine kinase

Pooled estimates risk for MI Landoni G. J Cardiothorac Vasc Anesth 2007; 21:

Pooled estimates of 30-day postoperative mortality Landoni G. J Cardiothorac Vasc Anesth 2007; 21:

Anesthetic preconditioning  Sevoflurane has cardioprotective effects that result in decreased morbidity and mortality.  Choice of anesthetic regimen based on administration of haloganated anesthetics is associated with a better outcome after cardiac surgery

 Kaplan-Meier curves for adverse cardiac events during 1 yr of follow up after sevoflurane and placebo preconditioning in 72 pts undergo CABG surgery Garcia C. Br J Anaesth 2005; 94:

Sevoflurane and neuroprotection  Transient ischemic attack can induce ischemic preconditioning within the brain Wegener S, et al. Stroke 2004; 35:  CNS has been highlighted as being the most vulnerable organ system in the body to an ischemic insult.  A brief disruption (5 min) to CBF has been shown to cause neuronal injury, while cardiomyocytes and kidney cells require min of ischemia to induce cellular damage. Lee JM, et al. J Clin Invest 2000; 106:

Sevoflurane and neuroprotection  Clear evidence exists that demonstrates exposing adult rats to volatile anesthetics can trigger both acute and late phases of ischemic tolerance within the brain Kapinya K, et al. brain Res 2002; 872: Zheng S, Zuo Z. Neuroscience 2003;118: Zheng S, Zuo Z. Mol Pharm 2004; 65:

Control No cardiac arrest Cardiac arrest Early sevoflurane (15 min) before cardiac arrest Late sevoflurane (24 hr) before cardiac arrest Sevoflurane- induced preconditioning protects against cerebral ischemic neuronal damage in rats Payne RS. Brain Res 2005; 1034:

Pape, M. et al. Anesth Analg 2006;103: Neuronal cell damage

Pape, M. et al. Anesth Analg 2006;103: Double immunostaining of activated caspase-3 and NeuN (key proteins of apoptosis)

A high, but clinically usable, concentration of sevoflurane increases the time during hypoxia until the postsynaptic evoked response is blocked and improves recovery of the response after 5 min of hypoxia Matei G. J Neurosurg Anesth 2002; 14:

Sevoflurane and kidney protection  Sevoflurane has direct anti- inflammatory and antinecrotic effects in vitro in a renal cell type particularly sensitive to injury following IR injury Lee TH, Am J Physiol Renal Physiol 2006; 291: F67-F78.

Julier K, et al. Anesthesiology 2003; 98: Biomarkers for perioperative renal function at various time pointsin CABG surgery Biomarkers for perioperative renal function at various time points in CABG surgery Postoperative plasma cystatin C conc. Increased significantly less in sevoflurane-preconditioned patients

Sevoflurane and liver protection  Significant decrease in serum alanine and aspartate aminotransferase (ALT, AST) levels  Hepatic tissue blood flow (HTBF) was remarkably better in sevoflurane group  Tumor necrosis factor-α (TNF-α) and IL-1β values were lowest in sevoflurane group Bedirli N, et al. Anesth Analg 2008; 106:830-7.

Liver sections of rat after 4 hr reperfusion Control group Isoflurane group Sevoflurane group

Easy titration anesthetic depthEasy titration anesthetic depth Low incidence adverse airway eventsLow incidence adverse airway events Exellent bronchodilationExellent bronchodilation Safe use above 1 MACSafe use above 1 MAC Hemodynamic stabilityHemodynamic stability Proven beneficial cardiac profileProven beneficial cardiac profile Rapid and predictable recoveryRapid and predictable recovery