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8/8/2019 Improving Neuroprotection During Dhca, By Vicki Mahan, Md, Instructor in Surgery (Ppt Slide Show)(2)
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IMPROVING NEUROPROTECTION
DURING DEEP HYPOTHERMIC
CIRCULATORY ARREST
Vicki Mahan, MDClinical Session
June 14, 2007
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About 10,000 babies born in the United StatesAbout 10,000 babies born in the United States
every year with congenital heart disease thatevery year with congenital heart disease thatrequires surgical intervention early in liferequires surgical intervention early in life
Estimatedb
rain injury in these patients is 10%Estimatedb
rain injury in these patients is 10%to 30%to 30%
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MAJOR NEUROLOGICALMAJOR NEUROLOGICAL
DEFICITSDEFICITS Cognitive deficitsCognitive deficits
Seizures (acute > chronic)Seizures (acute > chronic)
ChoreoathetosisChoreoathetosis
Spastic quadriparesisSpastic quadriparesis
Bilateral motor deficits (spastic diplegia and spasticBilateral motor deficits (spastic diplegia and spasticquadriparesis)quadriparesis)
HemiparesisHemiparesis
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NEUROPATHOLOGYNEUROPATHOLOGY
focalfocal focal cerebral infarctionfocal cerebral infarction--strokestroke
ischemiaischemia
periventricular leukomalaciaperiventricular leukomalacia
generalizedgeneralized parasagittal cerebral injuryparasagittal cerebral injuryselective neuronal necrosisselective neuronal necrosis
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WHAT IS DHCA?WHAT IS DHCA?
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DEEP HYPOTHERMICDEEP HYPOTHERMIC
CIRCULATORY ARREST (DHCA)CIRCULATORY ARREST (DHCA)
Mild hypothermiaMild hypothermia 30 C to 34 C30 C to 34 C
Moderate hypothermiaModerate hypothermia 25 C to 30 C25 C to 30 C
Deep hypothermiaDeep hypothermia 15 C to 22 C15 C to 22 C
Circulatory arrestCirculatory arrest no flow in the blood vesselsno flow in the blood vessels
DHCADHCA no blood flow during deepno blood flow during deephypothermiahypothermia
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HOW DO WE DOHOW DO WE DO
DHCA?DHCA?
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TECHNIQUE OF DHCA TECHNIQUE OF DHCA
Usually plannedUsually planned
With initiation of cardiopulmonarybypass, theWith initiation of cardiopulmonarybypass, the
heat exchanger water is reduced to 5 Cheat exchanger water is reduced to 5 C
Patient is cooled until esophageal, rectal, andPatient is cooled until esophageal, rectal, andtympanic temperature is 15tympanic temperature is 15--18 C18 C
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Arterial pump head is stopped and arterial line isArterial pump head is stopped and arterial line isclampedclamped
Venous line is unclamped to drain the volumeVenous line is unclamped to drain the volume
from the patient until the level in the venousfrom the patient until the level in the venous
reservoir stops risingreservoir stops rising
Venous line is clampedVenous line is clamped
Drugs and anesthetic agents being given byDrugs and anesthetic agents being given by
perfusion are turned offperfusion are turned off Recirculation line is unclamped and recirculationRecirculation line is unclamped and recirculation
is begun through the oxygenatoris begun through the oxygenator
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Once the arrest period is over, the arterial pumpOnce the arrest period is over, the arterial pump
head is stopped and recirculation line is clampedhead is stopped and recirculation line is clamped
Arterial line is unclamped and arterial pump isArterial line is unclamped and arterial pump is
startedstarted
Perfusate (blood) is transfused back into thePerfusate (blood) is transfused back into thepatient to reestablish circulating volumepatient to reestablish circulating volume
Venous line is unclamped and cardiopulmonaryVenous line is unclamped and cardiopulmonarybypass is reinstituedbypass is reinstitued
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ADVANTAGES OF DHCA ADVANTAGES OF DHCA
Bloodless operating field with improved exposureBloodless operating field with improved exposure
Decreased exposure to cardiopulmonarybypass with its sequelae (such as activation of white cellsDecreased exposure to cardiopulmonarybypass with its sequelae (such as activation of white cellsand endothelium, activation of cascades, consumption of coagulation factors and platelets,and endothelium, activation of cascades, consumption of coagulation factors and platelets,hemolysis, etc.)hemolysis, etc.)
Diminished risk of embolism (solids and gases)Diminished risk of embolism (solids and gases)
No cannulas in the operating fieldNo cannulas in the operating field
Less distortion of heartLess distortion of heart -- cannulas are not in placecannulas are not in place
Reduced metabolismReduced metabolism
Lower C3a, interleukin 8, interleukin 6 (when compared with lowLower C3a, interleukin 8, interleukin 6 (when compared with low--flow CPB)flow CPB)
? less fluid accumulation? less fluid accumulation
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A Comparison of the Perioperative Neurologic Effects ofA Comparison of the Perioperative Neurologic Effects ofHypothermic CirculatoryArrest versus LowHypothermic CirculatoryArrest versus Low--FlowFlow
Cardiopulmonary Bypass in Infant Heart SurgeryCardiopulmonary Bypass in Infant Heart Surgery
NEJM Volume 329:1057NEJM Volume 329:1057--1064 October 7, 19931064 October 7, 1993
Criteria for eligibilityCriteria for eligibility DD--transposition of the great arteriestransposition of the great arterieswith/without VSD, repair scheduled before 3 months of age,with/without VSD, repair scheduled before 3 months of age,coronary artery anatomy considered suitable for ASOcoronary artery anatomy considered suitable for ASO
Criteria for exclusionCriteria for exclusion birth weight less than 2.5 kg, abirth weight less than 2.5 kg, arecognizable syndrome of congenital anomalies, associatedrecognizable syndrome of congenital anomalies, associatedextracardiac anomalies of more than minor severity, previousextracardiac anomalies of more than minor severity, previouscardiac surgery, associated cardiovascular anomalies requiringcardiac surgery, associated cardiovascular anomalies requiring
aorticaortic--arch reconstruction or other open surgical proceduresarch reconstruction or other open surgical procedures
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Patients enrolled between April 1988 and FebruaryPatients enrolled between April 1988 and February
19921992
191 eligible191 eligible 180 enrolled180 enrolled
ASO performed in 171 (remaining 9 found at operationASO performed in 171 (remaining 9 found at operationto have coronary artery anatomy unsuitable forto have coronary artery anatomy unsuitable forarterialarterial--switch operation)switch operation) 129 had IVS, 42 had VSD129 had IVS, 42 had VSD
Randomly assigned to either total circulatory arrest orRandomly assigned to either total circulatory arrest orlowlow--flowbypass (50 cc/minute/kgbody weight)flowbypass (50 cc/minute/kgbody weight)
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Used alphaUsed alpha--stat pH strategystat pH strategy
Crystalloid hemodilution to hematocrit of 20%Crystalloid hemodilution to hematocrit of 20%
Mean circulatory arrest time was 55 minutesMean circulatory arrest time was 55 minutes
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Surgical mortality, hospital course, incidence of nonSurgical mortality, hospital course, incidence of non--
neurologic events similar in the 2 groupsneurologic events similar in the 2 groups
Neurologic Effects:Neurologic Effects:
Strategy of circulatory arrest associated with higherStrategy of circulatory arrest associated with higherlikelihood of clinical and EEG seizures, longer time tolikelihood of clinical and EEG seizures, longer time torecovery of normal brain activities (as assessed byrecovery of normal brain activities (as assessed by
EEG), greater release of CPKEEG), greater release of CPK--BB over the first 6BB over the first 6hours after surgeryhours after surgery
Duration of circulatory arrest time importantDuration of circulatory arrest time important
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IMPROVINGIMPROVING
NEUROLOGICNEUROLOGICOUTCOMESOUTCOMES
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PERIOPERATIVE MANAGEMENTPERIOPERATIVE MANAGEMENT
POSTCONDITIONING WITH CO2POSTCONDITIONING WITH CO2
PRECONDITIONING WITH COAND CO2PRECONDITIONING WITH COAND CO2
TOPIRAMATETOPIRAMATE
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PERIOPERATIVEPERIOPERATIVE
MANAGEMENTMANAGEMENT
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PERIOPERATIVEPERIOPERATIVE
MANAGEMENT OF DHCAMANAGEMENT OF DHCA AnesthesiaAnesthesia
Duration ofTotal CirculatoryArrestDuration ofTotal CirculatoryArrest
Cooling/WarmingCooling/Warming
Depth of HypothermiaDepth of Hypothermia pH ManagementpH Management
HematocritHematocrit
CPB AdditivesCPB Additives
HemoconcentrationHemoconcentration
SteroidsSteroids
Oxygenator UsedOxygenator Used
Cerebral Perfusion (Antegrade, Retrograde)Cerebral Perfusion (Antegrade, Retrograde)
Pulsatile versus NonPulsatile versus Non--pulsatilepulsatile
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pH MANAGEMENTpH MANAGEMENT
When blood is cooled during cardiopulmonaryWhen blood is cooled during cardiopulmonary
bypass, pH becomes more alkalinebypass, pH becomes more alkaline
pHpH--stat strategystat strategy adding carbon dioxideadding carbon dioxide --compensates for this shiftcompensates for this shift
Carbon dioxide is a potent cerebral vasodilatorCarbon dioxide is a potent cerebral vasodilator
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pH STRATEGY DURINGpH STRATEGY DURING
CARDIOPULMONARY BYPASSCARDIOPULMONARY BYPASS
--stat strategystat strategy arterial blood measured at 37 Carterial blood measured at 37 C
with pH of 7.40 and arterial pCO2 of 40 mm Hgwith pH of 7.40 and arterial pCO2 of 40 mm Hg
(the hypothermic blood is alkalemic and(the hypothermic blood is alkalemic andhypocapneic)hypocapneic)
pHpH--stat strategystat strategy hypothermic arterial blood athypothermic arterial blood atpH of 7.40 and arterial pCO2 of 40 mm HgpH of 7.40 and arterial pCO2 of 40 mm Hg
(blood at 37 C is acidemic and hypercapneic)(blood at 37 C is acidemic and hypercapneic)
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ADVANTAGES/DISADVANTAGESADVANTAGES/DISADVANTAGES
--stat strategy: preserves autoregulation,stat strategy: preserves autoregulation,optimizes cellular enzyme activity, but lessoptimizes cellular enzyme activity, but lessmetabolic suppressionmetabolic suppression
pHpH--stat strategy: improves cerebral blood flow,stat strategy: improves cerebral blood flow,cerebral oxygenation, and brain coolingcerebral oxygenation, and brain cooling
efficiency during CPB,b
ut greater risk ofefficiency during CPB,b
ut greater risk ofmicroembolism and free radicalmicroembolism and free radical--mediatedmediateddamagedamage
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Four groups (according to cooling/rewarmingFour groups (according to cooling/rewarming
strategy)strategy) alpha/alpha, alpha/pH, pH/alpha,alpha/alpha, alpha/pH, pH/alpha,pH/pHpH/pH
49 449 4--weekweek--old pigletsold piglets
24 piglets24 piglets cerebral highcerebral high--energy phosphate levelsenergy phosphate levelsand intracellular pH measured by magneticand intracellular pH measured by magneticresonance spectroscopyresonance spectroscopy
25 piglets25 piglets cerebral blood flow measured bycerebral blood flow measured by
labeled microspheres, cerebral metabolic rate bylabeled microspheres, cerebral metabolic rate byoxygen and glucose extraction, and redox state ofoxygen and glucose extraction, and redox state ofcytochrome aacytochrome aa33, and hemoglobin oxygenation by, and hemoglobin oxygenation bynear infrared spectroscopynear infrared spectroscopy
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CONCLUSIONSCONCLUSIONS
Cerebral blood flow greater with pHCerebral blood flow greater with pH--stat than with alphastat than with alpha--statstatduring coolingduring cooling
Cytochrome aaCytochrome aa33values became more reduced during coolingvalues became more reduced during coolingwith alphawith alpha--stat than with pHstat than with pH--statstat
Recovery of cerebral intracellular pH faster in group pH/pHRecovery of cerebral intracellular pH faster in group pH/pHcompared with that in group alpha/alphacompared with that in group alpha/alpha
Intracellular pH became more acidic during early reperfusionIntracellular pH became more acidic during early reperfusiononly in group alpha/alphaonly in group alpha/alpha continuous recovery in othercontinuous recovery in other
groupsgroups ConclusionConclusion mechanisms in effect duringboth cooling andmechanisms in effect duringboth cooling and
rewarming phases before and after DHCA that couldrewarming phases before and after DHCA that couldcontribute to improved cerebral outcomes with phcontribute to improved cerebral outcomes with ph--statstat
relative to more alkaline strategiesrelative to more alkaline strategies
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pH STRATEGY AT CHILDRENSpH STRATEGY AT CHILDRENS
HOSPITAL BOSTONHOSPITAL BOSTON
CoolingCooling pHpH--stat management below 30stat management below 30
degrees centrigradedegrees centrigrade
RewarmingRewarming pHpH--stat management below 30stat management below 30
degrees centrigradedegrees centrigrade
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HEMATOCRITHEMATOCRIT
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Higher Hematocrit ImprovesHigher Hematocrit Improves
Cerebral Outcome After DeepCerebral Outcome After Deep
Hypothermic CirculatoryHypothermic Circulatory
ArrestArrest
Shinoka T, ShumShinoka T, Shum--Tim D, Jonas RA, Lidov HGW, Laussen PC, Miura T and duTim D, Jonas RA, Lidov HGW, Laussen PC, Miura T and duPlessis APlessis A
Childrens Hospital Boston/Harvard Medical SchoolChildrens Hospital Boston/Harvard Medical SchoolJ Thorac Cardiovasc Surg 1996;112:1610J Thorac Cardiovasc Surg 1996;112:1610--2121
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17 piglets17 piglets 3 groups (Group I received colloid and crystalloid3 groups (Group I received colloid and crystalloidprime with resulting hematocrit
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RESULTS
Group I significant loss of phosphocreatineand intracellular acidosis during early cooling
Final recovery same for all groups
Group I cytochrome aa3 more reduced duringDHCA than in Groups II and III
Neurologic deficit score best preserved in
Group III on first postoperative day Histologic assessment worst in Group I in
neocortex
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CONCLUSIONS
Extreme hemodilution results in evidence of
inadequate oxygen delivery during initial cooling
phase and during DHCA
Whole blood priming associated with optimal
preservation of high-energy phosphates andbetter early neurologic and histologic scores
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POSTCONDITIONING WITHPOSTCONDITIONING WITH
CARBON DIOXIDECARBON DIOXIDE
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HYPERCARBIA ANDHYPERCARBIA AND
BRAIN INJURYBRAIN INJURY
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TRADITIONAL MANAGEMENT TRADITIONAL MANAGEMENT
OF BRAIN INJURYOF BRAIN INJURY
Hyperventilate to improve cerebral perfusionHyperventilate to improve cerebral perfusion
pressurepressure
Hypocarbia leads to cerebral arteriolarHypocarbia leads to cerebral arteriolar
constriction and decreased cerebral blood flowconstriction and decreased cerebral blood flow
Possibly reduces intracranial pressurePossibly reduces intracranial pressure
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NORMAL RESPONSE TONORMAL RESPONSE TO
BRAIN TRAUMABRAIN TRAUMA Patients hypoventilate after severe head injuryPatients hypoventilate after severe head injury
Hypercarbia resultsHypercarbia results
Carbon dioxide vasodilates cerebrovasculatureCarbon dioxide vasodilates cerebrovasculature
Possible defense mechanism to reduce ischemicPossible defense mechanism to reduce ischemicinjury of the braininjury of the brain
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CPP = MAPCPP = MAP ICPICP
CPPCPP cerebral perfusion pressurecerebral perfusion pressure
MAPMAP mean arterial pressuremean arterial pressure
ICPICP intracranial pressureintracranial pressure
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CVR = 8CVR = 8l/l/rr44
CVRCVR cerebral vascular resistancecerebral vascular resistance viscosityviscosity
ll lengthlength
pipirr -- radiusradius
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CBF = CPP/CVRCBF = CPP/CVR
CBF = CPP/ 8CBF = CPP/ 8l/l/rr44
CBF = CPP xCBF = CPP x rr44/ 8/ 8ll
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ARTERIOLARARTERIOLARDIAMETERDIAMETER
DETERMINANT OFDETERMINANT OFCEREBRAL BLOODCEREBRAL BLOOD
FLOWFLOW
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CBF not modulated by changes in MAP or ICPCBF not modulated by changes in MAP or ICP
CBF varies to maintain a constant relationship of CBFCBF varies to maintain a constant relationship of CBFto metabolic demand (increase in metabolic activityto metabolic demand (increase in metabolic activityresults in increase of cerebral blood flow)results in increase of cerebral blood flow)
? Manipulations that increase CBF? Manipulations that increase CBF improve clinicalimprove clinicaloutcomesoutcomes
Carbon dioxide potent modulator of cerebral vascularCarbon dioxide potent modulator of cerebral vascularresistanceresistance
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POSTCONDITIONING WITH
CARBON DIOXIDE
12 piglets CPB DHCA for 100 minutes
rewarm to baseline and wean from CPB
sacrificed 6 hours after weaning from CPB
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PO
ST
CO
NDIT
IO
NING ST
UDY GRO
UPS
GROUP CARBON DIOXIDE # PIGLETS
I 35 TO 50 6
II 50 TO 65 6
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Flow 5 radioisotopes (immediatelybeforeCPB, immediately after weaning from CPB, 1
hour after weaning from CPB, 3 hours afterweaning from CPB, 6 hours after weaning from
CPB)
H & E
Caspase-3
TUNEL
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PRECONDITIONINGPRECONDITIONING
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Preconditioning occursPreconditioning occurswhen a subinjuriouswhen a subinjurious
exposure renders theexposure renders thebrain less vulnerable to abrain less vulnerable to a
subsequent damagingsubsequent damagingexposureexposure
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1. Murry CE, Jennings RB, and Reimer KA.1. Murry CE, Jennings RB, and Reimer KA.Preconditioning with Ischemia: a Delay ofPreconditioning with Ischemia: a Delay ofLethal Cell Injury in Ischemic Myocardium.Lethal Cell Injury in Ischemic Myocardium.
Circulation. 1986;74(5):1124Circulation. 1986;74(5):1124--36.36.
2. Wegener S, Gottschalk B, Jovanovic V, Knab R,2. Wegener S, Gottschalk B, Jovanovic V, Knab R,
Fiebach JB, et al. Transient Ischemic AttacksFiebach JB, et al. Transient Ischemic AttacksBefore Ischemic Stroke: Preconditioning theBefore Ischemic Stroke: Preconditioning the
Human Brain?: A Multicenter MagneticHuman Brain?: A Multicenter MagneticResonance Imaging Study. Stroke.Resonance Imaging Study. Stroke.
2004;35:6162004;35:616--21.21.
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CARBON MONOXIDECARBON MONOXIDE
ANDAND
PRECONDITIONINGPRECONDITIONING
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MODELS OF PRECONDITIONINGMODELS OF PRECONDITIONING
WITH CARBON MONOXIDEWITH CARBON MONOXIDE
CO was considered a metabolic waste productCO was considered a metabolic waste product
MoritaMorita cell culture model of hypoxiacell culture model of hypoxiaCOCOinhibited vascular smooth muscle cell growth ininhibited vascular smooth muscle cell growth in
response to hypoxic stress (activated sGC andresponse to hypoxic stress (activated sGC andcGMP system)cGMP system)
OtterbeinOtterbein inhaled COinhaled COcytoprotective effectcytoprotective effect
in an animal model of oxidantin an animal model of oxidant--induced tissueinduced tissueinjury (hyperoxic lung injury)injury (hyperoxic lung injury)
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Mouse lung I/R modelMouse lung I/R model CO given before andCO given before andthroughout experimentthroughout experiment decreased number ofdecreased number ofapoptotic cells in the lungs of COapoptotic cells in the lungs of CO--treated animalstreated animals
Mouse hemorrhagic shock and resuscitation modelMouse hemorrhagic shock and resuscitation model
(Zuckerbraun)(Zuckerbraun) CO given before and duringCO given before and duringhemorrhagic shockhemorrhagic shock decreases the systemicdecreases the systemicinflammatory response and hepatic injury (serum ILinflammatory response and hepatic injury (serum IL--66less, serum ILless, serum IL--10 higher, lung myeloperoxidase levels10 higher, lung myeloperoxidase levels
lower, serum ALT lower, decreased relative EF5lower, serum ALT lower, decreased relative EF5staining of liver, decreased liver and intestinal damagestaining of liver, decreased liver and intestinal damageby histology, incrased liver ATP and viability)by histology, incrased liver ATP and viability)
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Rat liver transplantation model (Kaizu) - CO given 1
hour before transplant and for 24 hours after
transplant decreased serum AST and ALT,suppressed hepatic necrosis and neurophil
accumulation at 6 to 48 hours after transplantation,inhibited TNF-, intercellular adhesion molecule 1
and iNOS messenger RNA (conclusion CO
treatment suppresses early proinflammatory geneexpression and neutrophil infiltration and ameliorateshepatic I/R injury)
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GASOTRANSMITTERS
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CLASSIFICATION OF
GASOTRANSMITTERS (1) They are small molecules of gas, like nitric oxide (NO) and carbon monoxide (CO).
(2) They are freely permeable to membrane. As such, their effects will not rely on cognatemembrane receptors.
(3) They are endogenously and enzymatically generated and their generation is regulated.
(4) They have well-defined specific functions at physiologically relevant concentrations. Forinstance, NO and COboth participate in vasorelaxation and synaptic transmission in the centralnervous system.
(5) Their cellular effects may or may not be mediated by second messengers, but should havespecific cellular and molecular targets. For instance, NO and CO activate KCa channels in plasmamembrane either directly or mediated by the cGMP pathway.
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H2S CO NOMain substrates L-cysteine Heme L-arginineGenerating enzymes CBS, CSE HO NOSInducer NO Free radicals Acetylcholine
Endotoxin
Scavenger Hemoglobin Hemoglobin HemoglobinInhibitor D,L-propargylglycerine Zinc-PPIX L-NAME
Protein targets KATPchannel, cAMP (?) cGMP, KCachannel cGMP
KCachannel
Amino acid targets ? Histidine CysteineHalf-life in solution Minutes Minutes Seconds
Production tissue source SMC, not in EC ECSMC
METABOLISM AND FUNCTION
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GASOTRANSMITTERS--NEUROPROTECTION
PERICONDITIONING
NO
? CO2
CO H2S
PRECONDITIONING POSTCONDITIONING