Chapter 7. Inhalation Anesthetics

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Chapter 7. Inhalation Anesthetics

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• R1 ???

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Inhalation anesthetics

• Nitrous oxide, Chloroform and Ether.
• Ethyl chloride, ethylene, cyclopropane
• Methoxyflurane and Enflurane
• Nitrous oxide, Halothane, Isoflurane, Desflurane,
  and Sevoflurane.

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Inhalation anesthetics

• The course of general anesthesia
• 1) Induction
• 2) Maintenance
• 3) Emergence
• Useful in the induction of pediatric patients
• Adults prefer rapid induction with intravenous
  agents.

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Inhalation anesthetics

• Pharmacokinetics (how a body affects a drug)
• Relationship between a drugs dose, tissue
  concentration, and elapsed time
• Pharmacodynamics (how a drug affects a body)
• The study of drug action, including toxic
  responses
• MAC (Minimum alveolar concentration)
• Clinical pharmacology of individual agents
• Nitrous oxide, Halothane, Isoflurane,
  Desflurane, Sevoflurane

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Pharmacokinetics

• Mechanism of action of inhalation anesthetics
  remains unknown
• Depends on attainment of a therapeutic tissue
  concentration in the central nervous system
• There many steps, between the administration of
  an anesthetic from a vaporizer and its deposition
  in the brain

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Pharmacokinetics Factors affecting inspiratory
concentration(FI )

• Fresh gas flow rate (FGF rate)
• Volume of the breathing system
• (breathing circuit volume)
• Any absorption by the machine or breathing
  circuit (circuit
  absorption)

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Pharmacokinetics Factors affecting alveolar
concentration(FA )

• Uptake
• Ventilation
• Concentration

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Pharmacokinetics Factors affecting alveolar
concentration(FA )

• Uptake
• 1) FA/FI lt1.0
• 2) Uptake ? ? Alveolar concentration ? ? FA/FI
  ?
• 3) Gas concentration ? Partial pressure
• Alveolar partial pressure
• ? Anesthetic partial pressure in blood
• ? Brain tissue concentration
• 4) Uptake of Anesthetic agent ? ? Induction ?

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Pharmacokinetics Factors affecting alveolar
concentration(FA )

• Anesthetic uptake factors
• 1) Solubility in the blood
• 2) Alveolar blood flow
• 3) Difference in partial pressure between
  alveolar gas
  
• and venous blood

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Pharmacokinetics Factors affecting alveolar
concentration(FA )

• Solubility in the blood
• 1) Solubility Insoluble agents(N2O) lt
  soluble agents(halothane)
• FA Insoluble agents(N2O) gt soluble
  agents(halothane)
• Induction speed Insoluble gt soluble
  agents
• 2) Partition coefficients(?)
• Relative solubility of an anesthetic
  in air, blood, and tissues
• 3) Blood/gas partition coefficient? ?
  Solubility in Blood ? ?
• Uptake ? ? Alveolar partial pr??
  induction speed ?

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Pharmacokinetics Factors affecting alveolar
concentration(FA )

• Alveolar blood flow
• 1) In the absence of pulmonary shunting ABF
  CO
• CO? ? Uptake ? ? Alveolar partial pr??
  induction speed ?
• 2) Insoluble agent
• Alveolar blood flow ?? ??
• 3) Soluble agent
• Low CO ? Alveolar concentration ??
  overdosage

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Pharmacokinetics Factors affecting alveolar
concentration(FA )

• Difference in partial pressure between alveolar
  gas and venous blood
• 1) No tissue uptake ? Alveolar to venous
  partial pr difference 0
• 2) Factors affecting tissue uptake
• Tissue solubility of the agent(
  tissue/blood partition coefficient)
• Tissue blood flow
• Difference in partial pressure between
  arterial blood and the tissue

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Pharmacokinetics Factors affecting alveolar
concentration(FA )
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Pharmacokinetics Factors affecting alveolar
concentration(FA )

• 4 group of tissue by solubility and blood flow
• 1) Vessel-rich group
• ex) brain, heart, liver, kidney,
  endocrine organ
• 2) Muscle group
• ex) skin, muscle
• 3) Fat group
• 4) Vessel-poor group
• ex) bone, ligament, teeth, hair,
  cartilage

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Pharmacokinetics Factors affecting alveolar
concentration(FA )
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Pharmacokinetics Factors affecting alveolar
concentration(FA )
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Pharmacokinetics Factors affecting alveolar
concentration(FA )

• Ventilation
• Constantly replacing anesthetics taken up by
  
• pul bloodstream ? FA/FI ? for soluble agent

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Pharmacokinetics Factors affecting alveolar
concentration(FA )

• Concentration
• 1) Concentration effect
• Concentrating effect
• Augmented inflow effect
• 2) Second gas effect

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Pharmacokinetics Factors affecting alveolar
concentration(FA )

• (Anesthetic gas 50 uptake)
• 10/9011
  40/6066
• ? Concentrating effect

Gas 40
O2 20
Anesthetic gas 20
O2 80
Gas 10
O2 80
Anesthetic gas 80
O2 20
?
?
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Pharmacokinetics Factors affecting alveolar
concentration(FA )

• 1 of
  second gas 1 of
  second gas (1.7)
  
• 
  
  
  1 of second gas
• 
  
  
• 
  
  
  
• 
  
  
  
  0.4 of second gas
• 
  
  
  
  -

O2 19
N2O 80
O2 19(31.7)
N2O 40(66.7)
O2 19
N20 40
O2 7.6
N2O 32
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Pharmacokinetics Factors affecting alveolar
concentration(FA )

• Alveolar partial pr gt Arterial partial pr
• ?
  Alveolar-arterial difference
• 1) Venous admixture
• 2) Alveolar dead space
•  
• 3) Nonuniform alveolar gas distribution
•  
• 4) Ventilation/perfusion mismatch
• (ex atelectasis,
  emphysema, neumonia)

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Pharmacokinetics Factors affecting alveolar
concentration(FA )

• Recovery from anesthesia
• - Anesthetic concentration in brain
  tissue ?
• Anesthetics can be eliminated by
• 1) biotransformation
• 2) transcutaneous
• 3) exhalation

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Pharmacokinetics Factors affecting elimination

• Induction? ????? ???? Recovery? ??
• Rebreathing
• High Fresh gas flows
• Low Anesthetic-circuit volume
• Low absorption by the Anesthetic-circuit
• Decreased Solubility
• High CBF(Cerebral Blood Flow)
• - Increased Ventilation

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Pharmacokinetics Factors affecting elimination

• Diffusion hypoxia
• 1) Directly affect oxygenation by
  displacing O2
• 2) diluting alveolar CO2 ? respiratory
  drive ?
• ? prevent 100 O2 510min

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PharmacodynamicsTheories of anesthetic action

• Pharmacodynamics
• the study of drug action, including toxic
  responses
• how a drug affects a body
• General anesthesia
• reversible loss of consciousness
• analgesia of the entire body
• amnesia
• muscle relaxation
• General anesthesia agent
• inert elements ( ex xenon )
• simple inorganic compounds ( ex nitrous
  oxide)
• halogenated hydrocarbons ( ex halothane )
• complex organic structures (ex
  barbiturate )

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PharmacodynamicsTheories of anesthetic action

• Agent-specific theory  
• Unitary hypothesis
• Critical volume hypothesis
• Fluidization theory of anesthesia
• Lat phase separation theory

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PharmacodynamicsMAC(Minimum alveolar
concentration)

• Alveolar concentration that prevents movement in
  50 of patients in response to a standardized
  stimulation
• MAC is useful measure
• brain partial pressure ??
• agents ??potency ??
• experimental evaluation? ?? ??
• The MAC value for different anesthetics are
  roughly additive
• The same MAC ? CNS depression
• ? Myocardial
  depression

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PharmacodynamicsMAC(Minimum alveolar
concentration)

• Point on dose-response curve
• ? ED50,( median
  effective dose)
• 1.3 MAC of any of the volatile anesthetics
  prevent movement in about 95 patients surgical
  incision
• ? ED95
• MAC Awake 0.3 0.4 MAC
• One of the most striking is the 6 decrease in
  MAC per decade of age, regardless of volatile
  anesthetic
• Unaffected by species, sex, or duration of
  anesthesia

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PharmacodynamicsMAC(Minimum alveolar
concentration)
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Nitrous oxidePhysical properties

• ???? ??? ??? inorganic anesthetic gas
• ??, ??
• ??? ?, ??? ? ?? O2 ??? ??? ?? ??
• ??, ????? gas??? ??, ?? ????? ????? ??? ??
• ??? ??

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Nitrous oxideEffect on organ system-
Cardiovascular

• In vitro- stimulate the sympathetic nervous
  system in vitro, direct depression of
  myocardial contractility
• In vivo- Stimulation of catecholamine
• ? ABP, CO, HR Unchanged or
  slightly?
• N2O? Myocardial depression? unmasked ?? ??
• Coronary artery diseases
• Severe hypovolemia
• ? BP ? ? myocardial ischemia
• Constriction pulmonary vascular smooth muscle
• ? pulmonary
  vascular resistance ?
• ? Rt.
  Ventricular end-diastolic pr. ?
• Endogenous catecholamine level ?
• ? epinephrine
  induced arrhythmia ?

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Nitrous oxideEffect on organ system- Respiratory

• CNS stimulation, pulmonary stretch receptor
  activation ? respiratory rate?(tachypnea) tidal
  volume?
• net effect -gt minimal change in minute
  ventilation
• and resting
  arterial CO2 level
• Hypoxic drive?

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Nitrous oxideEffect on organ system- Cerebral

• Cerebral blood flow Cerebral blood volume?
• ? Intracranial
  pressure mild?
• CMOR2(Cerebral oxygen consumption)?
• Levels of nitrous oxide below MAC provide
  analgesia in dental surgery and other minor
  procedures

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Nitrous oxideEffect on organ system- Etc.

• Neuromuscular
• not provide significant muscle relaxation
• not a triggering agent of malignant
  hyperthermia
• Renal
• Renal vascular resistance ? ? renal blood
  flow ?
• glomerular filtration rate(GFR)
  urinary output ?
• Hepatic
• Hepatic blood flow ?
• Gastrointestinal
• Activation of the chemoreceptor trigger
  zone and the vomiting center in the medulla
• ?Postoperative
  nausea vomiting

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Nitrous oxide Biotransformation toxicity

• Eliminated by exhalation almost
• diffuses out
  through skin small amount
• biotransformation
  than less 0.01
• Vit B12??? cobalt ??? ???? ??
• ? Vit B12 dependent enzyme ?
• ?? Myelin??? ??? methionine synthetase
  ?
• ? DNA??? ??? thymidylate
  synthetase ?
• ? Prolonged exposure of anesthetic level
• ?? Bone marrow depression(ex megaloblastic
  anemia )
• ? Neurological deficiencies
• (experipheral neuropathies and
  pernicious anemia)
• Teratogenic effect
• Polymorphonuclear leukocytes ?chemotaxis?
  motility? ?? ? immunological response change

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Nitrous oxide Contraindication

• Air embolism
• Pneumothorax
• Acute intestinal obstruction
• Intracranial air ( ex dural closure or
  pneumoencephalus? ?? tension pneumocephalus)
• Pul. air cyst
• Intraocular air bubble
• Tympanic membrane grafting
• Pulmonary HTN patient

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Nitrous oxide Drug interaction

• MAC 105 vol
• ? combination with the more potent
  volatile agent
• Neuromuscular blockade?
• (but effect N2Olt volatile agents)
• Requirements of other agents?
• Second gas effect

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HalothanePhysical properties

• Halogenated alkane
• Nonexplosive
• Nonflammable
• Least expensive volatile anesthetics

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HalothaneEffect on organ system- Cardiovascular

• Dose-dependent reduction of arterial blood
  pressure
• ? Myocardial
  depression (2.0MAC BP 50?)
• Coronary artery vasodilator
• But Systemic arterial pressure ? ?
  coronary blood flow ?
• Hypotension ? Vagal stimulation ?, HR?
  
• But this reflex?, sinoatrial node
  conduction slowing
• 
  ?Junctional rhythm and bradycardia
• In infant HR? myocardial contratility?? CO?
• Sensitize the heart to the arrhythmogenic effects
  to epinephrine
• epinephrine 1.5µg/kg ?? ????

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HalothaneEffect on organ system- Respiratory

• Rapid, shallow breathing Not enough to counter
  TV?
• ? alveolar ventilation?, resting PaCO2?
• Cause of ventilatory effect
• central mechanism (medullary depression)
• peripheral mechanism (intercostal muscle
  dysfunction)
• ? pre-existing lung disease
• ? surgical stimulation
• Hypoxic drive?
• A potent bronchodilators
• (? Airway reflex ?, bronchial smooth
  muscle ?? )
• Mucociliary function ?
• ? postoperative
  hypoxia atelectasis??

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HalothaneEffect on organ system- Cerebral

• Cerebral vessels dilating
• ? cerebral vascular resistance? ,
  CBF ?
• Autoregulation (Arterial blood pressure? ????
  CBF? ???? ??) ? Intracranial pressure?
• Prevent Hyperventilation

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HalothaneEffect on organ system- Etc.

• Neuromuscular
• Skeletal muscle relaxation
• Non-depolarizing neuromuscular-blocking
  agents (NMBA) effect?
• Malignant hyperthermia
• Renal
• Renal blood flow, GFR(glomelular filtration
  rate), urinary output ?
• (? Arterial blood pressure cardiac
  output ?)
• GFR? lt Renal blood flow? ? Filtration
  fraction?
• Prevent Preoperative hydration
• Hepatic
• CO? ? hepatic blood flow?
• Hepatic artery vasospasm
• The metabolism and clearance of Fentanyl,
  phenytoin, verapamil?

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Halothane Biotransformation toxicity

• Be oxidized in the liver by a cytochrome P450
  (2EI)
• 
  ?
  trifluoroacetic acid
• 
  
• Inhibited by pretreatment with
  disulfiram
• viral hepatitis, impaired hepatic perfusion,
  hepatocyte hypoxia, sepsis, hemolysis, benign
  postoperative intrahepatic cholestasis, drug
  induced hepatitis ? postoperative hepatic
  dysfunction
• Halothane hepatitis is extremely rare (1/35000 )
• - Hepatitis is increased risk at
• halothane ??? ??
  ???? ?? ?? ??
• ??? ??? ??
• Halothane ???
  ??? ???? ?? ??
• ????? halothane
  ??? ?? Hx()? ??

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Halothane Contraindication

• Halothane? ??? ???? ?? ?? ? ??? ???? ? ?? ??? ??
  ?
• Intracranial mass lesion ? Intracranial
  hypertension
• Hypovolemic pt.
• Severe cardiac disease ( ex aortic stenosis )
• Epinephrine? ???? ??? ??
• Pheochromocytoma

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Halothane Drug interaction

• ß- adrenergic blocking agent (propranolol),
• Ca channel blocking agent (verapamil)
• 
  ? Myocardial depression?
• Tricyclic antidepressants, MAO inhibitor
• ? fluctuations in blood
  pressure arrhythmias
• ( but not
  absolute contraindication)
• Aminophylline ? Severe ventricular arrhythmias

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Isoflurane Physical properties

• Nonflammable volatile anesthetic
• Pungent ethereal oder
• Chemical isomer of enflurane
• but different physiochemical property

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Isoflurane Effects on organ system-
Cardiovascular

• Minimal cardiac depression
• but carotid baroreflex ? HR??
  CO??
• ß-adrenergic stimulation
• ? skeletal muscle blood flow?
• systemic vascular
  resistance?
• arterial blood pressure ?
• Isoflurane??? ??? ??
• ? HR ?, arterial blood
  pressure?,
• norepinephrine? plasma
  level?
• Dilates coronary arteries

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Isoflurane Effects on organ system- Respiratory

• Respiratory depression, Tachypnea ( less
  pronounced)
  
• ? minute ventilation?(
  more pronounced)
• 0.1MAC?? ??? Isoflurane? hypoxia?
• hypercapnia? ?? ???? ?? ??? ????
• Good bronchodilator

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Isoflurane Effects on organ system- Cerebral

• gt1.0 MAC CBF intracranial pressure?
• but Isoflurane lt Halothane
• Reversed by hyperventilation
• Cerebral metabolic oxygen requirement?
• 2.0 MAC
• ? electrically silent
  electroencephalogram(EEG)
• EEG suppression
• ? cerebral ischemia?
  brain protection

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Isoflurane Effects on organ system- Etc.

• Neuromuscular
• Relax skeletal muscles
• Renal
• Renal blood flow ?, glomerular filtration rate
  ? ,
• urinary output ?
• Hepatic
• Total hepatic flow ?
• Hepatic oxygen supply better maintained than
  with Halothane

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Isoflurane Biotransformation toxicity

• Trifluoroacetic acid? ??
• Serum fluoride fluid levels may rise
• But no nephrotoxicity

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Isoflurane Contraindication

• No unique contraindication

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Isoflurane Drug interaction

• Safe dose of Epinephrine up to 4.5 µg/kg
• NMBAs effect?

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Desflurane Physical properties

• Isoflurane? ?? ??? ??
• High vapor pressure ? special vapor
• Low solubility in blood and body tissues
• ? Ultrashort duration
• ? Very rapid wash in and wash out
  of anesthetic
• Moderate potency

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Desflurane Effects on organ system-
Cardiovascular

• Similar to isoflurane
• Dose?? systemic vascular resistance? ? arterial
  blood pressure ?
• CO unchanged or mild?(12 MAC)
• Heart rate, central venous pressure, pulmonary
  artery pressure moderate?
• Cardiovascular disease ? desflurane concentration
  rapid?? heart rate, BP, catecholamine level
  worrisome?
• Attenuated by fentanyl, esmolol, clonidine
• coronary blood flow unchanged

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Desflurane Effects on organ system- Respiratory

• TV ? RR ?
• Alveolar ventilation ? ? resting PaCO 2 ?
• Ventilatory response ?
• Pungency and airway irritation during induction
• ? salivation, breath-holding, coughing,
  laryngospasm

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Desflurane Effects on organ system- Cerebral

• Similar to Isoflurane
• Directly vasodilates the cerebral vasculature
• 
  ? CBF ?, ICP?
• Cerebral metabolic rate of oxygen(CMRO2) ?
• ? cerebral
  vasoconstriction CBF?
• Cerebral oxygen consumption ?
• ?During periods of desflurane-induced
  hypotension,
• CBF is adequate to maintain
  aerobic metabolism

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Desflurane Effects on organ system- Etc.

• Neuromuscular
• dose-dependent of TOF ?? ???????
• Renal
• No evidence of any nephrotoxic effects
• Hepatic
• No evidence of hepatic injury

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Desflurane Biotransformation toxicity

• Minimal metabolism
• Insignificant percutaneous loss
• CO poisoning(by carbon dioxide absorbent)
• disposing of dried out
  absorbent or use of calcium hydroxide ? minimize
  the risk

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Desflurane Contraindication

• Severe hypovolemia
• Malignant hyperthermia
• Intracranial hypertension

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Desflurane Drug interaction

• Potentiates nondepolarizing neuromuscular
  blocking agents
• Safe dose of Epinephrine Up to 45 µg/kg
• Associated with delirium in some pediatric
  patients

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Sevoflurane Physical properties

• Nonpungency rapid increase in alveolar
  anesthetic concentration
• ? Smooth rapid
  inhalation induction
• Rapid emergence than Isoflurane
• Faster emergence
• ? Greater incidence of delirium in some
  pediatric patients
• treated with 1.02.0 µg/kg
  of fentanyl

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Sevoflurane Effects on organ system-
Cardiovascular respiratory

• Cardiovascular
• Depresses myocardial contractility.
• Systemic vascular resistance arterial
  blood pr. ?
• Prolong the QT interval
• Respiratory
• Depresses respiration
• Reverse bronchospasm

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Sevoflurane Effects on organ system- Cerebral

• CBF, ICP slight?
• gt1.5 MAC ? impair autoregulation of CBF
• ? CBF ? during hemorrhagic
  hypotension
• Cerebral metabolic oxygen requirement?

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Sevoflurane Effects on organ system- Etc.

• Neuromuscular
• Produce adequate muscle relaxation
  intubation of children
• Renal
• RBF slight?
• Hepatic
• Portal vein blood flow? but hepatic artery
  blood flow? ? Maintain total hepatic blood flow
  oxygen delivery

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Sevoflurane Biotransformation toxicity

• Liver microsomal enzyme P-450(2E1)? ?? ??
• ? Inorganic fluoride nephrotoxicity
• but clinically
  associated with significant renal dysfunction
• By Alkali ( Barium hydroxide lime or soda lime )
• Sevoflurane ? Nephrotoxic end product
• ( Compound A,
  fluorometal-2, 2-difluoro-1-vinylether )
• Compound A? ?? ??? ????? ??
• Respiratory gas temperature?
• Low-flow anesthesia
• Dry barium hydroxide absorbent (Baralyme)
• Sevoflurane concentration?
• Anesthetic of long duration
• Hydrogen fluoride ? acid burn on respiratory
  mucosa

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Sevoflurane Contraindication

• Severe hypovolemia
• Malignant hyperthermia
• Intracranial hypertension

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Sevoflurane Drug interaction

• Potentiates NMBAs
• Catecholamine-induced arrhythmia???? ??