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

Sevoflurane and Sevoflurane and organ protectionorgan protection

Chatchai Prechawai Chatchai Prechawai Department of AnesthesiologyDepartment of Anesthesiology

Faculty of MedicineFaculty of MedicinePrince of songkla UniversityPrince of songkla University

Perioperative myocardial infarction (PMI) Perioperative myocardial infarction (PMI) is associated with mortality rates of up to 40%is associated with mortality rates of up to 40%

Lee Th. Circulation 1999; 100: 1043-9.Lee Th. Circulation 1999; 100: 1043-9.Poldermans D. N Engl J Med 1999;341: 1789-94.Poldermans D. N Engl J Med 1999;341: 1789-94.

Non fatal PMI increases the risk of both Non fatal PMI increases the risk of both cardiovascular death and cardiovascular death and a further non-fatal myocardial infarction a further non-fatal myocardial infarction in the first 6 months after major non-cardiac in the first 6 months after major non-cardiac surgerysurgery

Mangano DT. JAMA 1992; 268: 233-9.Mangano DT. JAMA 1992; 268: 233-9.

Therapeutic strategiesTherapeutic strategies Coronary revascularizationCoronary revascularization Beta-blockersBeta-blockers Alpha2-adrenoceptor agonistsAlpha2-adrenoceptor agonists AspirinAspirin StatinsStatins etc……etc……

Priebe HJ. Br J Anaesth 2005; 95: 3-19Priebe HJ. Br J Anaesth 2005; 95: 3-19..

Myocardial

Infraction

IschaemicPrecondit

ioning

Hibernating

Myocardium

StunnedMyocardiu

m

ISCHAISCHAEMIAEMIA

ISCHAISCHAEMIAEMIA

Acute occlusionand cell death

Chronic ischaemia

Shot, controlledischaemic episodes

with intervenin

greperfusio

nProlonged, acute

ischaemic event

followed by

reperfusionSpectrum ofSpectrum of

myocardial ischemiamyocardial ischemia

Ischemic preconditioningIschemic preconditioning

Brief episodes of ischemia in the heart, Brief episodes of ischemia in the heart, occurring before a subsequent longer occurring before a subsequent longer interruption of blood flow, provides interruption of blood flow, provides protection against dysfunction and protection against dysfunction and necrosisnecrosis

4 cycles of 5-min left circumflex coronary 4 cycles of 5-min left circumflex coronary artery occlusions, before a 40-min artery occlusions, before a 40-min occlusion, reduced myocardial infarction occlusion, reduced myocardial infarction by 75%by 75%

Murray CE, Circulation 1986; 74: 1124-36.Murray CE, Circulation 1986; 74: 1124-36.

Sommerschild HT, Kirkeboen KA. Acta Anaesthesiol Scand 2002; 46: 123-37.Sommerschild HT, Kirkeboen KA. Acta Anaesthesiol Scand 2002; 46: 123-37.

Preconditioning

Stimulus

Preconditioning

Stimulus

Signal Amplification

Immediate

Protection

Immediate

Protection

DelayedProtection

“2nd window

effect”

DelayedProtection

“2nd window

effect”

Minutes

Hours

DaysHawaleshka A, Can J Anaesth 1998; 45: 670-82.

De Hert SG. Curr Opin Anaesthesiol 2004; 17: 57-62.

Sommerschild HT, Acta Anaesthesiol Scand 2002; 46: 123-37.

PKC= protein kinase C HSP= heat stress proteins AOE= antioxidant enzymes KATP channels= ATP-dependent K channels

Signals

Signals

SignalAmplification

SignalAmplification

Effectors

Effectors

AdenosineBradykininNorepinephrineNitric oxideKATP channelsHSPAOE

G-proteinsPKC

Ade= adenosine Br= Bradykinin Ne= norepinephrine

PLC= phospholipase CDAG= diacetylglycerolITP= inositol triphosphate

AOE

HSPNucleus

PKC

PKC

DAG+ITP

A1G

Protein

PLC

B2

Ade

Br Ne

K+

Hyperpolarization

α1

Ca2+ lnflux

AP duration

MyocardialEnergy

Consumption

PKC= protein kinase CHSP= heat stress proteinsAOE= antioxidant enzymesA 1 = Adenosine receptor type 1a1 = alpha adrenergic receptor type 1B2 = bradykinin receptor type 2K+= potassium

Ischemic preconditioningIschemic preconditioning

Ischemic preconditioning in other organsIschemic preconditioning in other organs Brain Brain LungLung LiverLiver KidneyKidney Small intestineSmall intestine

Dirnagl U, Trends Neurosci 2003; 26: 248-54.Dirnagl U, Trends Neurosci 2003; 26: 248-54.Koti RS, Dig Surg 2003; 20: 383-96.Koti RS, Dig Surg 2003; 20: 383-96.

Mc Laren AJ, Transpl Int 2003: 16: 701-8.Mc Laren AJ, Transpl Int 2003: 16: 701-8.Kosieradzki M, Surgery 2003; 133: 81-90.Kosieradzki M, Surgery 2003; 133: 81-90.

Head BP, Curr Opin Anaesthesiol 2007; 20: 395-99.Head BP, Curr Opin Anaesthesiol 2007; 20: 395-99.Clarkson AN. Life Sci 2007; 80: 1157-75.Clarkson AN. Life Sci 2007; 80: 1157-75.

Kitano H, J Cereb Blood Flow Me tab 2007; 27: 1108-28.Kitano H, J Cereb Blood Flow Me tab 2007; 27: 1108-28.Lee TH, Anesthesiology 2004; 101: 1313-24.Lee TH, Anesthesiology 2004; 101: 1313-24.

Bedirli N, Anesth Analg 2008; 106: 830-7.Bedirli N, Anesth Analg 2008; 106: 830-7.

Sevoflurane and Sevoflurane and cardioprotectioncardioprotection

Volatile and IV anesthetics that effect Volatile and IV anesthetics that effect K K ATPATP channels channels

Isoflurane Isoflurane Sevoflurane Sevoflurane Desflurane Desflurane Morphine Morphine FentanylFentanyl

Zaugg M, et al. Br J Anaesth 2003; 91: 551-65.Zaugg M, et al. Br J Anaesth 2003; 91: 551-65.

Zaugg M, et al. Br J Anaesth 2003;Zaugg M, et al. Br J Anaesth 2003; 91: 566-76. 91: 566-76.


Sevoflurane but not propofol preserved Sevoflurane but not propofol preserved LV function after CPB with less evidence of LV function after CPB with less evidence of myocardial damage in the first 36 hr myocardial damage in the first 36 hr postoperatively.postoperatively.

Suggest a cardioprotective effect of Suggest a cardioprotective effect of sevoflurane during coronary artery surgerysevoflurane during coronary artery surgery

De Hert De Hert SSG. Anesthesiology 2002; 97: 42-9G. Anesthesiology 2002; 97: 42-9

Also in high-risk coronary patients Also in high-risk coronary patients

De Hert SG. Anesthesiology 2003; 99: 314-23.De Hert SG. Anesthesiology 2003; 99: 314-23.

De Hert De Hert SSG. Anesthesiology 2002; 97: 42-9G. Anesthesiology 2002; 97: 42-9

De Hert SG. Anesthesiology 2003; 99: 314-23.De Hert SG. Anesthesiology 2003; 99: 314-23.


In patients undergoing CABG surgery In patients undergoing CABG surgery with CPB, the cardioprotective effects with CPB, the cardioprotective effects of sevoflurane were clinically most of sevoflurane were clinically most apparent when it was administered apparent when it was administered throughout the operationthroughout the operation

De Hert SG, et al. Anesthesiology 2004; 101: 299-310.De Hert SG, et al. Anesthesiology 2004; 101: 299-310.

De Hert SG, et al. Anesthesiology 2004; 101: 299-310.De Hert SG, et al. Anesthesiology 2004; 101: 299-310.

De Hert SG, et al. De Hert SG, et al.

Anesthesiology 2004; 101: 299-310.Anesthesiology 2004; 101: 299-310.


Patients receiving sevoflurane for off-Patients receiving sevoflurane for off-pump coronary artery surgery had pump coronary artery surgery had less myocardial injury during the first less myocardial injury during the first 24 postoperative hours then patient 24 postoperative hours then patient receiving propofol.receiving propofol.

Conzen PF. Anesthesiology 2003;99: 826-33.Conzen PF. Anesthesiology 2003;99: 826-33.

Sevoflurane groupSevoflurane group Propofol groupPropofol group

Conzen PF. Anesthesiology 2003;99: 826-33.Conzen PF. Anesthesiology 2003;99: 826-33.


Sevoflurane suppressed the production of Sevoflurane suppressed the production of IL-6 and IL-8, but not IL-10 and IL-1ra.IL-6 and IL-8, but not IL-10 and IL-1ra.

Changes in the balance between pro- and Changes in the balance between pro- and anti-inflammatory cytokines may be one of anti-inflammatory cytokines may be one of the most important mechanisms of the most important mechanisms of myocardial protection caused by myocardial protection caused by sevofluranesevoflurane

Kawamura T. J Cardiothorac Vasc Anesth 2006; 20: 503-8.Kawamura T. J Cardiothorac Vasc Anesth 2006; 20: 503-8.


Sevoflurane decreases the inflammatory response Sevoflurane decreases the inflammatory response after CPB, as measured by the release of IL-6, after CPB, as measured by the release of IL-6, CD11b/CD18, and TNF-CD11b/CD18, and TNF-αα..

Myocardial function after CPB, as assessed by Myocardial function after CPB, as assessed by RWMA and LVSWI, was also improved with RWMA and LVSWI, was also improved with sevoflurane.sevoflurane.

Nader DN. J Cardiothorac Vasc Anesth 2004; 18: 269-7. Nader DN. J Cardiothorac Vasc Anesth 2004; 18: 269-7.

RWMA = regional wall motion abnormalityRWMA = regional wall motion abnormality

LVSWI=left ventricular stroke work indexLVSWI=left ventricular stroke work index

Period A IV anestheticsPeriod A IV anesthetics Period B volatile anesthetics (sevoflurane 0.5-2%) Period B volatile anesthetics (sevoflurane 0.5-2%)

Van der Linden PJ, Anesthesiology 2003; 99: 516-7.Van der Linden PJ, Anesthesiology 2003; 99: 516-7.

Period A IV anestheticsPeriod A IV anesthetics Period B volatile anesthetics (sevoflurane 0.5-2%) Period B volatile anesthetics (sevoflurane 0.5-2%)

Van der Linden PJ, Anesthesiology 2003; 99: 516-7.Van der Linden PJ, Anesthesiology 2003; 99: 516-7.

Anesthetic Anesthetic preconditioningpreconditioning

22 studies, involving 1,922 patients22 studies, involving 1,922 patients Volatiles anesthetics were associated with Volatiles anesthetics were associated with

significant reductions of MI significant reductions of MI (2.4% vs 5.1%) and mortality (0.4% vs 1.6%(2.4% vs 5.1%) and mortality (0.4% vs 1.6%))

Landoni G. J Cardiothorac Vasc Anesth 2007; 21: 502-11.

Julier K, et al. Anesthesiology 2003; 98: 1315-27.Julier K, et al. Anesthesiology 2003; 98: 1315-27.

Translocation of PKC to cardiomyocytes in Translocation of PKC to cardiomyocytes in CABG patients’ right atrial tissues samplesCABG patients’ right atrial tissues samples

Percentages of PKCPercentages of PKC

Nucleus of PKCNucleus of PKC

Lipofuscin Lipofuscin pigmentpigment


brain natriuretic peptide: a sensitive biochemical marker of myocardial contractile dysfunction

Troponin T

Creatinine kinase

Pooled estimates risk for MIPooled estimates risk for MI


Pooled estimates of 30-day postoperative mortalityPooled estimates of 30-day postoperative mortality


Anesthetic Anesthetic preconditioningpreconditioning

Sevoflurane has cardioprotective Sevoflurane has cardioprotective effects that result in decreased effects that result in decreased morbidity and mortality.morbidity and mortality.

Choice of anesthetic regimen based Choice of anesthetic regimen based on administration of haloganated on administration of haloganated anesthetics is associated with a better anesthetics is associated with a better outcome after cardiac surgeryoutcome after cardiac surgery

Kaplan-Meier curves for adverse cardiac events Kaplan-Meier curves for adverse cardiac events during 1 yr of follow up after sevoflurane and during 1 yr of follow up after sevoflurane and placebo preconditioning in 72 pts undergo CABG placebo preconditioning in 72 pts undergo CABG surgerysurgery

Garcia C. Br J Anaesth 2005; 94: 159-65.Garcia C. Br J Anaesth 2005; 94: 159-65.

Sevoflurane and Sevoflurane and neuroprotectionneuroprotection

Transient ischemic attack can induce ischemic Transient ischemic attack can induce ischemic preconditioning within the brainpreconditioning within the brain

Wegener S, et al. Stroke 2004; 35: 616-21.Wegener S, et al. Stroke 2004; 35: 616-21.

CNS has been highlighted as being the most CNS has been highlighted as being the most vulnerable organ system in the body to an vulnerable organ system in the body to an ischemic insult.ischemic insult.

A brief disruption (5 min) to CBF has been shown A brief disruption (5 min) to CBF has been shown to cause neuronal injury, while cardiomyocytes to cause neuronal injury, while cardiomyocytes and kidney cells require 20-40 min of ischemia to and kidney cells require 20-40 min of ischemia to induce cellular damage.induce cellular damage.

Lee JM, et al. J Clin Invest 2000; 106: 723-31.Lee JM, et al. J Clin Invest 2000; 106: 723-31.

Sevoflurane and Sevoflurane and neuroprotectionneuroprotection

Clear evidence exists that Clear evidence exists that demonstrates exposing adult rats to demonstrates exposing adult rats to volatile anesthetics can trigger both volatile anesthetics can trigger both acute and late phases of ischemic acute and late phases of ischemic tolerance within the braintolerance within the brain

Kapinya K, et al. brain Res 2002; 872: 282-93.Kapinya K, et al. brain Res 2002; 872: 282-93.Zheng S, Zuo Z. Neuroscience 2003;118: 99-106.Zheng S, Zuo Z. Neuroscience 2003;118: 99-106.

Zheng S , Zuo Z. Mol Pharm 2004; 65: 1172-80.Zheng S , Zuo Z. Mol Pharm 2004; 65: 1172-80.

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 Sevoflurane- induced preconditioning protects against cerebral ischemic neuronal damage in ratscerebral ischemic neuronal damage in rats

Payne RS. Brain Res 2005; 1034: 147-52Payne RS. Brain Res 2005; 1034: 147-52..

Pape, M. et al. Anesth Analg 2006;103:173-179

Neuronal cell damage

Pape, M. et al. Anesth Analg 2006;103:173-179

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: 293-8.

Sevoflurane and Sevoflurane and kidney protectionkidney protection

Sevoflurane has direct anti-Sevoflurane has direct anti-inflammatory and antinecrotic inflammatory and antinecrotic effects in vitro in a renal cell type effects in vitro in a renal cell type particularly sensitive to injury particularly sensitive to injury following IR injuryfollowing IR injury

Lee TH, Am J Physiol Renal Physiol 2006; 291: F67-F78.Lee TH, Am J Physiol Renal Physiol 2006; 291: F67-F78.


Biomarkers for perioperative renal function at various time Biomarkers for perioperative renal function at various time pointspoints in CABG surgeryin CABG surgery

Postoperative plasma cystatin C conc. Increased Postoperative plasma cystatin C conc. Increased significantly less in sevoflurane-preconditioned significantly less in sevoflurane-preconditioned patientspatients

Sevoflurane and Sevoflurane and liver protectionliver protection

Significant decrease in serum alanine and Significant decrease in serum alanine and aspartate aminotransferase (ALT, AST) aspartate aminotransferase (ALT, AST) levelslevels

Hepatic tissue blood flow (HTBF) was Hepatic tissue blood flow (HTBF) was remarkably better in sevoflurane groupremarkably better in sevoflurane group

Tumor necrosis factor-Tumor necrosis factor-αα (TNF- (TNF-αα) and IL-1) and IL-1ββ values were lowest in sevoflurane groupvalues were lowest in sevoflurane group

Bedirli N, et al. Anesth Analg 2008; 106:830-7.Bedirli N, et al. Anesth Analg 2008; 106:830-7.



Liver sections of rat after 4 hr reperfusionLiver sections of rat after 4 hr reperfusion

Control groupControl group

Isoflurane groupIsoflurane group

Sevoflurane groupSevoflurane 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

Documents

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