INHALED ANESTHETICS AND GASES

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INHALED ANESTHETICS AND GASES

• HARRY SINGH, MD
• DEPT. OF ANESTHESIOLOGY
• UTMB

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HISTORY

• Horace Wells administered N2O for dental
  extraction in 1844
• William Green Morton demonstrated use of ether
  for surgical anesthesia on October 16, 1846 at
  MGH
• Inventor and revealer of anesthetic inhalation
• Before whom in all time, surgery was agony.
• By whom pain in surgery was averted and annulled.
• Since whom science has control of pain

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KEY TOPICS

• Potency or MAC
• Factors affecting uptake and distribution
• Effects on various organ systems
• Metabolism and toxic effects
• N2O and Xenon
• Mechanisms of action

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STRUCTURE OF DIETHYL ETHER
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ANESTHETIC POTENCY

• MAC
• MAC awake 0.3 MAC
• MAC BAR 1.5XMAC
• MAC intubation 2XMAC
• Alveolar concentration represents brain
  concentration after a short period of
  equilibration

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FACTORS AFFECTING MAC

• Temperature ? 2-5 for 1 0C ? temp.
• Age Maximum at 6 months?6/decade
• CNS catecholamine stimulation? MAC
• Benzodiazepine, opiates,alpha-2 agonists?MAC
• Inhaled anesthetics additive effect
• 1 N2O decreases MAC by 1
• Pregnancy ? MAC
• Ethanol acute ?MAC, chronic ? MAC
• Metabolic acidosis, hypoxia, hypotension? MAC
• Hypernatremia?MAC
• Hyponatremia, hypermagnesemia ?MAC

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MAC, BP, VAPOR PRESSURE

• MAC BP(0C) VP
  (200C)
• Halothane 0.77 50.2 241 mmHg
• Enflurane 1.7 56.2 175 mmHg
• Isoflurane 1.15 48.5 238 mmHg
• Sevoflurane 2.0 58.5 160 mmHg
• Desflurane 6.0 23 664 mmHg
• N2O 104
• Xenon 71

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UPTAKE AND DISTRIBUTION

• Goal To develop and maintain a satisfactory
  partial pressure or tension of anesthetic at the
  site of anesthetic action in brain
• DeliveredgtInspiredgtAlveolargtArterialgtBrain
• Concentration Partial pressure/barometric
  pressurex100
• Brain with its high perfusion per gram rapidly
  equilibrates with anesthetic partial pressure in
  blood

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Nitrous oxide
1.0
Desflurane
Sevoflurane
Isoflurane
FA/F1
Halothane
0.5
0
10
20
30
0
Anesthesia administration (min)
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Human Blood/Gas and Tissue/Blood Partition
Coefficients (MeanSD)1-4
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UPTAKE AND DISTRIBUTION

• Balance between the delivery of anesthetic and
  its removal by uptake or metabolism determines
  FA/FI ratio at any given time after
  administration of inhaled anesthetic
• The rate of rise of alveolar concentration (FA)
  toward inspired concentration (FI) or FA/FI ratio
  determines speed of induction of anesthesia
• 1. Alveolar ventilation
• 2. The inspired concentration (concentration
  effect)
• 3. Second gas effect

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Ventilation lit/min
8
1.0
4
2
Nitrous oxide
8
Halothane
4
8
0.5
FA/F1
2
4
Diethyl ether
2
0
0
0
20
40
60
Anesthesia administration (min)
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UPTAKE AND DISTRIBUTION

• Concentration Effect The inspired anesthetic
  concentration also determines the rate of rise of
  alveolar concentration toward inspired
  concentration (FA/FI) ratio. The greater the
  inspired concentration, the more rapid is the
  rate of rise in FA/FI ratio. It results from two
  factors
• 1. A concentrating of the residual gases
• 2. Increase in inspired ventilation

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UPTAKE AND DISTRIBUTION

• Second Gas Effect Factors governing
  concentration effect also influence concentration
  of any gas given concomitantly with N2O (Second
  gas effect). It results from two factors
• 1. The loss of volume associated with N2O uptake
  concentrates the second gas
• 2. Replacement of the gas taken up by an increase
  in inspired ventilation augments the amount of
  second gas in the lung.

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C 1 of second gas
B 1.7 of second gas
A 1 of second gas
19 O2
31.7 O2
19 O2
Absorbed gases replaced by added ventilation
Uptake of half of the N2O
40 N2O
66.7 N2O
80 N2O
7.6 O2
0.4 of second gas
32 N2O
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Anesthesia administration (min)
1.0
65 N2O
Desflurane in 65 N2O
0.9
5 N2O
FA/F1
0.8
Desflurane in
5 N2O
0
0
20
10
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UPTAKE AND DISTRIBUTION

• Anesthetic Uptake Factors Solubility x Cardiac
  output x Alveolar to venous partial pressure
  difference.
• Solubility Primary factor that determines FA/FI
  ratio
• Blood/gas partition coefficient Relative
  affinity or partitioning of an anesthetic between
  two phases at equilibrium.
• Larger blood/gas partition coefficient? more
  solubility?greater uptake?? FA/FI ratio
• Cardiac output ? Cardiac output? ?FA/FI ratio

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PARTITION COEFFICIENT OF NITROUS OXIDE
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UPTAKE AND DISTRIBUTION

• Alveolar to venous anesthetic gradient depends on
  tissue uptake.
• Tissue uptake
• 1. Tissue solubility (tissue/blood partition
  coefficient)
• 2. Tissue blood flow
• 3. Arterial to tissue anesthetic partial pressure
  difference

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Tissue group characteristics
Tissue Group
Characteristic
Vessel-Rich
Muscle
Fat
Vessel-Poor
Percentage of body mass
10 50 20
20
Perfusion as percentage of cardiac output
75 19 6
0
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UPTAKE AND DISTRIBUTION

• Tissue Groups Three tissue groups form depots
  for anesthetic within the body.
• Vessel rich group (VRG) Brain, heart,
  splanchnic bed, liver, kidney and endocrine
• Equilibrates with blood in 4-8 minutes
• Muscle group (MG) Muscle and skin
• Equilibrates with blood in 2-4 hours
• Fat group (FG) Equilibration 70-80 min for N2O
• 30 hours for
  sevoflurane
• Vessel poor group (VPG)) Bone , cartilage,
  ligaments, tendons-no uptake

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RECOVERY FROM ANESTHESIA

• Recovery correlates with fall in alveolar
  concentration
• Solubility Low solubility?Rapid recovery
• DesfluranegtSevofluranegtIsoflurane
• Duration of anesthesia
• MAC awake Varies with different anesthetics
• MAC awake of N2Ogt Inhlaled anesthetics
• Lower MAC awake More amnestic the agent
• Metabolism Alveolar washout of halothane more
  rapid than enflurane
• Residual gases in the anesthetic circuit.

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CARDIOVASCULAR EFFECTS

• Systolic and Diastolic Function
• Dose related negative inotropic effect
• HalothaneEnfluranegtIsofluraneDesfluraneSevoflur
  ane
• Dose related prolongation of isovolemic
  relaxation, early LV filling and filling
  associated with atrial systole

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CARDIOVASCULAR EFFECTS

• Systemic Hemodynamics
• Depress baroreceptors.
• No change in CI except halothane (?CI)
• Desflurane 1 MAC?1.5 - 2 MAC ? HR and BP
• Sevoflurane 1 MAC?1.5 - 2 MAC ? HR or no change
• Isoflurane Intermediate effect
• All cause concentration related decreases in BP
• Sevoflurane, desflurane, isoflurane?? SVR
• Halothane, enflurane? Myocardial depression

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CARDIOVASCULAR EFFECTS

• Epinephrine induced arrhythmias
• Halothane arrythmogenic
• Other agents safer
• Coronary Steal
• Coronary vasodilataion with isoflurane may cause
  detrimental redistribution of coronary blood flow
  away from ischemic myocardium with hypotension
  leading to coronary steal
• No coronary steal if hypotension avoided

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CARDIOVASCULAR EFFECTS

• Myocardial Protection
• Protect against reversible and irreversible
  ischemia
• Reduce the infarct size
• Decrease myocardial reperfusion injury and
  improve functional recovery after global ischemia
• Activation of intracellular transduction pathways
  involving A1 receptors, PKC, G proteins and
  mitochondrial or sarcolemmal KATP Channels

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PULMONARY EFFECTS

• Respiratory depression leading to ? MV and ?pCO2
  DesfluranegtIsofluranegtSevoflurane
• Depress ventilatory responses to hypercarbia and
  hypoxia in a dose dependent manner
• Respiratory Irritation
• 2 MAC Desflurane 75
• 2 MAC Isoflurane 50
• 2 MAC Sevoflurane 0
• 1 MAC No respiratory irritation
• Sevoflurane agent of choice for inhalation
  induction

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PULMONARY EFFECTS

• Potent bronchodilators in animals and human
• Halothane probably the most potent bronchodilator
• Preferential dilatation of distal airways as
  compared to proximal airways
• Action mediated through several complex
  mechanisms leading to ? intracellular Ca

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PULMONARY EFEFCTS

• Depress mucociliary clearance and function of
  type II alveolar cells
• Attenuate hypoxic pulmonary vasoconstriction
  (HPV) in vitro
• Modest inhibitory effects on HPV in vivo leading
  to shunting and decreased oxygenation.

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CENTRAL NERVOUS SYSTEM

• ? EEG wave frequency and ? amplitude
• Higher conc. (2 MAC) Isoelectric EEG and burst
  suppression
• Protect against ischemia by ? CMRO2
• Cerebral vasodilation leading to ? ICP
• Enflurane and sevoflurane to a lesser extent can
  cause convulsions
• Dose related ? amplitude and ? latency of evoked
  potentials

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UTERINE AND FETAL EFFECTS

• Dose dependent relaxation of uterus
• Increased blood loss during CD
• Lower concentrations (0.5MAC safer)
• Inhaled anesthetics cross placenta
• Higher concentration Fetal cardiovascular
  depression
• Reduction of CBF and O2 delivery to brain

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NEUROMUSCULAR SYSTEM

• Dose dependent muscle relaxation
• Can cause sufficient relaxation to permit
  endotracheal intubation and facilitate intra
  abdominal procedures
• Potentiate the action of muscle relaxants
• Non depolarizers gt Depolarizers
• All trigger MH Halothane worse

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NITROUS OXIDE

• Clear, colorless and odorless gas
• Supplied in pressurized cylinders
• Elimination through exhalation
• No biotransformation
• Uptake and elimination rapid due to low blood/gas
  partition coefficient (0.47)

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NITROUS OXIDE

• Analgesia in a dose dependent manner
• gt60 produce amnesia
• Cant be used as sole anesthetic (MAC 104)
• Direct negative inotropic effect
• Mild sympathetic nervous system agonist
• Modest increases in PAP and PVR
• Mild respiratory depression
• Cerebral vasodilation leading to ? ICP
• ? CMRO2

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NITROUS OXIDE

• Expansion of closed gas spaces
• N2O 31 times more soluble than nitrogen (nitrogen
  blood gas partition coefficient0.015)
• Moves faster into spaces than nitrogen can move
  out
• Contraindicated in pneumothorax, air embolism,
  posterior fossa surgery, laparoscopy and
  tympanoplasty
• Diffusion hypoxia or Fink effect
• Significant for 5-10 min after discontinuation of
  anesthesia during recovery
• 1. Large amounts of released N2O displace O2
• 2. Reduced alveolar ventilation due to fall in
  CO2

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METABOLISM

• Halothane 20
• Enflurane 2.5
• Isoflurane 0.2
• Desflurane 0.01-0.02
• Sevoflurane5

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HEPATOTOXICITY

• Correlates with extent of oxidative metabolism
• HalothanegtEnfluranegtIsofluranegtDesflurane
• 50 case reports with enflurane
• Fewer case reports with isoflurane
• One case report with desflurane

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HALOTHANE HEPATITIS

• Trifluoroacetic acid, chlorine and bromine
• Major metabolite Trifluoracetic acid
• Intermediate reactive metabolite TFA-Cl
• Trifluoracetylated proteins?formation of
  anti-trifluoracetylated protein antibodies
• Subsequent exposures lead to massive hepatic
  necrosis
• Sevoflurane metabolism different from other
  inhaled anesthetics
• Sevoflurane Inorganic fluoride and
  hexafluoroisopropanol

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CLINICAL FEATURES

• MILD FORM
• Incidence 15
• Repeat exposure not necessary
• Mild elevation of ALT, AST
• Focal necrosis
• Self limited

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CLINICAL FEATURES

• FULMINANT FORM
• Incidence 110,000
• Multiple exposures
• Marked elevation of ALT, AST, bilirubin and
  alkaline phosphatase
• Massive hepatic necrosis
• Mortality 50
• Antibodies to halothane altered protein antigen

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NEPHROTOXICITY

• Methoxyflurane Vasopressin resistant high output
  renal failure
• Related to inorganic fluoride
• Subclinical nephrotoxicity 50-80 uM/lit
• Overt nephrotoxicity 80-175 uM/lit
• 2-4 MAC-hr enflurane 20-30 uM/lit
• 2-4 MAC-hr isoflurane 3-8 uM/lit
• Desflurane Unchanged

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NEPHROTOXICITY

• 1-2 MAC-hr sevoflurane 10-20 uM/lit
• 2-7 MAC-hr sevoflurane 20-40 uM/lit
• 15 sevoflurane anesthetics?gt50 uM/lit
• Absence of sevoflurane nephrotoxicity contradicts
  classical fluoride hypothesis of 50 uM toxic
  threshold

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COMPOUND A

• Sevoflurane decomposes to compound A in presence
  of CO2 absorbents (alkali)
• Higher compound A formation
• Low FGF
• Higher absorbent temperature
• ? CO2 production
• Greater sevoflurane concentrations
• Baralyme gt soda lime
• Compound A renal injury
• Dose and time dependent, transient, 150 ppm-hr

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CO2 Flow vs COMPOUND A and Temperature
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FGF vs COMPOUND A
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COMPOUND A

• Toxic threshold reached after prolonged
  sevoflurane anesthesia
• Compound A nephrotoxicity more of theoretical
  concern
• Patients with preexisting renal disease should
  not be exposed to sevoflurane
• Sevoflurane should not be used with FGF lt 1
  lit/min
• For exposure greater than 2 MAC hr, FGF should be
  increased to 2 lit/min or above

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CARBON MONOXIDE

• CO formation occurs in presence of desiccated CO2
  absorbents
• DesfluranegtIsofluranegtEnflurane
• Common scenario-First case Monday morning
• Intraoperative detection difficult
• Pulse oxymeters cant distinguish between
  carboxyhemoglobin and oxyhemoglobin

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CARBON MONOXIDE

• Factors influencing CO production
• Choice of anesthetic agent
• Inspired anesthetic concentration
• Temperature and degree of dryness of CO2
  absorbent
• Type of absorbent Baralyme gt Soda lime
• Precautions Use of fresh absorbent, use of soda
  lime instead of baralyme and avoiding techniques
  drying CO2 absorber
• CO toxicity Undetected in great proportion of
  cases

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HEMATOPOIETIC AND NEUROLOGIC EFFECTS OF N2O

• N2O by oxidation of vit B12 inhibits methionine
  synthetase preventing conversion of
  methyltetrahydrofolate to tetrahydrofolate
• Reduced synthesis of thymidine
• 50 N2O for 12 hrs-mild megaloblastic changes
• Marked changes after exposure for 24 hrs
• Complete bone marrow failure after exposure for
  several days
• Subacute combined degeneration of spinal cord
  after exposure for several months
• Should not be used in vit B12 deficient patients

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XENON

• Not approved for clinical use in humans yet
• Inert gas with anesthetic properties
• Obtained by fractional distillation of air
• Expensive to manufacture
• Minimal hemodynamic side effects
• ? Pulmonary airway resistance (high density)
• Not metabolized
• Doesnt trigger MH in animals
• Positive environmental effects

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MECHANISMS OF ACTION

• KEY POINTS
• The structural diversity of inhaled anesthetics
  suggests that they all do not interact with
  single receptor site (multisite theory).
• Physical or biochemical changes important to
  mechanism occur within seconds and are rapidly
  reversible
• Inhaled anesthetics have inhibitory synaptic
  gtaxonal effects in the brain and spinal cord.
• Immobility occurs by action on the spinal cord
• Amnesia is achieved by action on the brain.

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MECHANISMS OF ACTION

• Many excitatory (e.g. glutamate) and inhibitory
  (GABA, glycine) neurotransmitters alter the
  anesthetic requirement.
• Gaseous agents ( N2O and xenon) exert their
  effect by inhibition of excitatory glutamate
  (NMDA) receptors
• Volatile agents exert their greater effect by
  enhancing inhibitory GABA or glycine transmission

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MECHANISMS OF ACTION

• Meyer Overton Hypothesis describes the
  correlation between lipid solubility and
  anesthetic potency (unitary theory of narcosis)
• MAC X Oil/gas partition coefficient1.84 atm for
  conventional anesthetics
• Additive effect of inhaled anesthetics
• However some volatile halogenated compounds like
  non-immobilizers, transitional compounds and
  alcohols dont obey Meyer Overton hypothesis

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Neurotransmitter release
(GABA, glycine)
Postsynaptic membrane
Ca2 entry
Action potential
Inhibitory postsynaptic potential
CI-
Voltage
CI-
Anesthetic
CI-
Time
B
A
Extracellular
a
B
a
B
B
Critical amino acids
4
2
3
1
Intracellular
Channel pore
Putative anesthetic site
D
C
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SUGGESTED READINGS

• Inhaled Anesthetics in Millers Anesthesia (Vol
  1), Editor Ronald D Miller, Churchill
  Livingstone.
• The Pharmacology of Inhaled Anesthetics by Edmond
  I Eger II, James B Eisenkraft, Richard B
  Weiskopf.
• Basic Physics and Measurement in Anaesthesia,
  Editor Paul D Davis and Gavin NC Kenny.

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