1. Anesthesia Agents IV
Wayne E. Ellis, Ph.D., CRNA

2. Effects On Renal System
Decreased renal blood flow
Decreased Glomerular Filtration Rate
Decreased urine output

3. Effects on Cardiac System
SVR mostly decreased by Isoflurane/Desflurane
Most Myocardial depression occurs with Halothane/Enflurane
Halothane/sevoflurane mostly depress baroreceptor reflex (no HR increases despite decreased BP)
Isoflurane/Desflurane least depress baroreceptor reflex (HR increases with decreased BP)  

4. Halothane / Epinephrine
Maximum adult dose of Epinephrine with Halothane is 1mcg/kg
-2 to 3mcg/kg with any other agent
Children less sensitive to Epinephrine/Halothane
max epinephrine 1.5mcg/kg
3mcg/kg with other agents
Avoid using Aminophylline with Halothane.
-Aminophylline triggers the release of norepinephrine.
Halothane sensitizes myocardium to catecholamines.
Limit Epinephrine, norepinephrine, Isoproterenol, and dopamine use.

5. Halothane / Epinephrine
Dysrhythmias are easily induced.
Avoid Halothane in patients with acute cocaine intoxication.
Cocaine blocks reuptake of norepinephrine.

6. Effects On Brain
Isoflurane causes hypothermia by depressing hypothalamus temp regulator
Volatile agents dilate cerebral vasculature
Increased cerebral blood flow
(mostly with Halothane)
Decreased cerebral metabolism
Increased ICP (least with Isoflurane)
Depressed neuronal function

7. Respiratory Effects
Dose dependent decrease in ventilatory response to CO2
0.1 MAC completely block ventilatory response to hypoxemia
Enflurane / Desflurane causes the highest symptoms of ventilatory depression
Halothane causes the least symptoms of ventilatory depression
Agents are effective bronchodilators
Halothane / Sevo are least pungent and airway irritant
1-1.5 MAC or more inhibits Hypoxic Pulmonary Vasoconstriction

8. Metabolism Agents metabolized in liver by cytochrome P-450
N2O metabolized to N2 in intestine by anaerobic bacteria

9. Blood Gas Solubility
Blood solubility determines the speed of build-up / elimination from blood / brain
Blood:Gas coefficient provides a measure of blood solubility
Shows volatile agents in liquid(blood) compared to gas phase
Isoflurane blood:gas ratio is 14/10 =1.4

10. Uptake Speed of uptake determined by blood/gas ratio
More blood solubility = > blood/gas ratio = slower uptake
Speed of uptake/elimination from brain is inversely R/T solubility.
Lower blood solubility means faster induction/recovery
Higher blood solubility means slower induction/recovery
Slower uptake leads to smaller FA/FI ratio
FA = Fraction of inhalation agent in alveolar gas
FI = Fraction of inhalation agent in inspired gas
FA/FI in 30mins is inversely related to blood solubility
Halothane with high solubility diffuses more from alveoli to blood
With high solubility alveolar partial pressure (FA/FI) builds up slowly    

11. Uptake Desflurane is poorly blood soluble:
Small quantities diffuse from alveoli to blood
FA/FI increases rapidly
Uptake is slow
Speed of onset is fast
Induction is fast

12. Uptake Isoflurane, Halothane, & Enflurane are highly blood soluble:
Alveolar uptake with high solubility agents is slow
Agents with high blood/gas ratio are highly blood soluble
Uptake by blood is fast/large
Speed of onset and FA/FI is slow
Great pulmonary circulation uptake
Prolonged induction

13. Uptake Agents with highest oil/gas ratio are: More lipid soluble
More potent
Have smaller MAC
The lower the MAC the greater the potency

14. Factors That Affect Brain Uptake
High blood solubility leads to slower brain uptake
Decreased cardiac output increases agents carried to brain
Increased alveolar ventilation speeds brain uptake
Increased inspired concentration speeds brain uptake
Blood flow controls tissue uptake

15. N2O N2 is 34X less soluble in blood than N2O
N2 is carried very poorly in blood
Gas diffusion is proportional to it's blood solubility (Fick's law)

16. Concentration Effect More N2O diffuse into blood than N2 diffuse out
N2O is 34X more soluble than N2
More N2O leaves the alveoli
Alveoli shrink in size
Alveolar concentration of N2O remains high
Fick's law of diffusion explains the concentration effect

17. Second Gas Effect
Increased uptake of volatile agent when given together with N2O
Fick's law also explains second gas effect

18. Dilutional Effect When N2O is turned off:
More N2O diffuse from blood to alveoli
Less N2 diffuse from alveoli to blood
Blood has limited capacity to hold N2(poor solubility)

19. Dilutional Effect Alveoli Expands CO2/O2 are diluted
Diffusional hypoxia occurs in patients on room air O2 during emergence

20. Cardiovascular & Respiratory Effect
N2O increases both SVR/PVR
N2O has a mild sympathomimetic effect

21. Contraindications To N2O Use
Malignant Hyperthermia
Venous Air Embolism
Middle Ear Surgery
Closed Pneumothorax
Bowel Obstruction

22. Disadvantages Very rare risk of renal toxicity
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Disadvantages
Very rare risk of renal toxicity
Risk of seizures in patient with seizure history
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23. Isoflurane Halogenated methyl ethyl ether Pungent, ethereal ordor
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Isoflurane
Halogenated methyl ethyl ether
Pungent, ethereal ordor
Coughing
Breath holding
Synthesized
Clinical Practice 1981
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24. Properties Clear, nonflammable liquid Volatile at room temperature
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Properties
Clear, nonflammable liquid
Volatile at room temperature
Vapor pressure C
Molecular weight
Solubility
Blood/gas = 1.4
Oil/gas = 90.8
MAC
70% Nitrous Oxide = 0.5
100% Oxygen = 1.15
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25. Advantage < blunting of the baroreceptor reflex Maintenance of CO
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Advantage
< blunting of the baroreceptor reflex
Maintenance of CO
Increase in heart rate
Epinephrine
> halothane
< enflurane
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26. Disadvantage Tachycardia Hypotension Extremely potent vasodilator
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Disadvantage
Tachycardia
Hypotension
Extremely potent vasodilator
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27. Inhalation Agents 27

28. Anesthetic Agents Classes of inhaled anesthetics
Hydrocarbons
Chloroform - highly toxic
Ethers
Cyclopropane, ethylene and ether - explosive
Non- carbon-base gases
Nitrous oxide, xenon
Halogenation reduces flammability
Flurination reduces solubility
Triflurocarbon groups add stability
Campagna, JC N Eng J Med 2003;348(21): 28

29. Terminology Partition coefficients
Represent the relative affinity of a gas for two different substances (solubility)
Measured at equilibrium so -----
PARTIAL PRESSURES ARE EQUAL BUT
The amounts of gas dissolved in each substance (concentration) are not equal
Most commonly refer to blood:gas partition coefficient
The larger the number, the more soluble the gas in blood 29

30. Blood:Gas Partition Coefficients
Anesthetic
Blood:Gas PC
Desflurane
0.42
Nitrous Oxide
0.46
Sevoflurane
0.65
Isoflurane
1.46
Enflurane
1.91
Halothane
2.50
Barash 4th Edition p378 30

31. Induction of Anesthesia
Rate of increase in alveolar anesthetic concentration (FA) toward the concentration inspired (FI) during induction relates inversely to the solubility of the potent agent in the blood 31

32. DESFLURANE (Suprane) Fluorinated methyl-ethyl ether
At room temperature
Vapor pressure (20o C) – 669 mmHg
Clear, nonflammable liquid
Pungent odor
Least soluble potent anesthetic
Blood-gas coefficient 0.42 32

33. DESFLURANE (Suprane) Boiling point is 22.8o C
Vapor pressure of desflurane changes greatly with small fluctuations in temperature
Accurate gas delivery with normal plenum vaporizer is impossible
Requires a special vaporizer
That is heated and pressurized
Ensures that desflurane 100% vaporized
Injects small amount of pure desflurane vapor into fresh gas flow utilizing a transducer
Requires electrical power
Requires a warm-up period 33

34. Desflurane Pharmacodynamics almost identical to isoflurane
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Desflurane
Pharmacodynamics
almost identical to isoflurane
Dose related decreases in BP and CO
Greater than seen with isoflurane
Factor of rapidity of increasing dose
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35. Properties Volatile at room temperature Stored under pressure
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Properties
Volatile at room temperature
Stored under pressure
Boiling Point C
Vapor Pressure C
Solubility
Blood/gas = 0.42
Oil/gas = 18.7
MAC
70% Nitrous Oxide = 2.83
100% Oxygen = 6
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36. Desflurane Similar to Nitrous Oxide < isoflurane Pharmacokinetics
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Desflurane
Pharmacokinetics
Low blood/gas partition coefficient
“Very fast-on, fast-off”
Similar to Nitrous Oxide
Metabolism
< isoflurane
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37. DESFLURANE – Clinical Aspects
MAC in 20-60y olds is 6.0  0.09%
Decreases with:
Advancing age
Decreased body temperature
Administration of other CNS depressants
Cardiovascular effects
Direct effects similar to isoflurane
Sympathetic nervous system activation
Mechanism unclear
? due to rapid stimulation of airway receptors
Can result in significant  HR and BP
Related to rate of rise of desflurane concentration 37

38. DESFLURANE – Clinical Aspects
Respiratory effects
Depressant
Pungent odor prevents mask inductions
Recovery
Emergence rapid
May be associated with emergence delirium
Discharge to home similar to other agents 38

39. Soda Lime Cycle Absorbents Initially calcium hydroxide used alone
abundant, inexpensive and easily handled
Slaked lime
Not efficient by itself
NaOH added to increase efficiency
Mixtures of sodium and calcium hydroxide developed and referred to as SODA LIME
Soda lime
Ineffective unless moisture added to granules
Neutralization increases as moisture content increases 39

40. DESFLURANE – Complications
Biodegradation is minimal
CO production from absorbents
1st report by Middleton 1965
Scattered reports in literature
Fang et al 1994
Demonstrated CO production with desiccated absorbents
Increases with increase in temperature
Highest production with Desflurane
Recommendations
Turn off gas flow when machine not in use
Change soda lime if dormant > 24 hrs
Change absorbent when color change occurs
Change all absorbent
Change compact canisters more frequently
Moon RE, APSF Newsletter 1994;9:13-16
Fang ZX, APSF Newsletter 1994:9:25-36
Berry PD, Anesth 1999;90(2):
Olympia MA, APSF Newsletter 2005;20(2):25-29 40

41. Carbon Monoxide (CO) Toxicity
Occurs when Desflurane, Ethrane, Forane degraded by dry soda lime or Baralyme
> 600 ppm
Does not occur with fully hydrated absorbents
Common scenario:
* Monday morning case and gas has been left on over the weekend, drying the absorbent
Absorber temperature rapidly rises

42. Avoiding the problem of CO Toxicity
Use fresh absorbent
Use soda lime rather than barium hydroxide
Use the new CO2 absorbent called “Amsorb”
Prevents anesthetic breakdown that would lead to CO formation
Absorbs less CO2 than other absorber compounds
Turn off gas when case complete

43. SEVOFLURANE (Ultane) A methyl-isopropyl ether At room temperature
Vapor pressure (20o C) – 170 mmHg
Clear, nonflammable liquid
Little or no odor
Blood-gas coefficient 0.65 43

44. Sevoflurane Clear, volatile liquid Vapor pressure 160 torr @ 20C
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3/25/2017
Sevoflurane
Clear, volatile liquid
Vapor pressure C
Solubility
Blood/gas = 0.59
Oil/gas = 55
MAC
70% Nitrous Oxide = 0.66
100% Oxygen = 1.71
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45. Sevoflurane Pleasant smelling Well tolerated for inhalation induction
As temperature increases, degradation occurs
Compound (Substance) A
Unstable in soda lime
High degree of metabolism
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46. SEVOFLURANE – Clinical Aspects
MAC varies with age
3.3% -- Neonates
2.03% -- Age 1-9y
2.93% -- Teenagers
1.3% -- Mid-age adults
1.2% -- > 80y
Potent cardiorespiratory depressant
Profile is similar to isoflurane and desflurane
Recovery rapid 46

47. Sevoflurane Pleasant smelling Well tolerated for inhalation induction
Clear, volatile liquid
Pleasant smelling
Well tolerated for inhalation induction
As temperature increases, degradation occurs
Compound (Substance) A
Unstable in soda lime
High degree of metabolism
Tachycardia seen with > 1.5 MAC
No increase in CVP

48. Sevoflurane Molecular Weight 200 Boiling Point 58.5 o C
Vapor pressure C
Odor Ethereal, Pleasant
Solubility
Blood/gas – 0.69
Brain/Gas 1.7
Oil/gas – 55
MAC
Nitrous Oxide
Oxygen

49. Pulmonary Effects of Sevoflurane
Can be used safely for inhalation induction
Quick induction
Does not initiate coughing, secretions, breath -holding, laryngospasm
Can be used for difficult airway & intubation:
Fiberoptic with spontaneous ventilations
Can maintain spontaneous respirations + anesthesia

50. Sevoflurane Breakdown in Sodalime
Compound A is of most concern
Up to 60 ppm in normally operating anesthesia circuit
Average concentrations ppm
1% = 10,000 ppm
Renal ppm

51. Factors affecting Compound A Production
Dilutent gas flow
Temperature
Sodalime moisture content
Sevoflurane concentration
Time

52. From Sevoflurane

53. Neurologic Effects
Isoflurane, Desflurane & Sevoflurane decrease CMRO2 in a dose-related fashion
Increases CBF in dose-related fashion (Hoffman)
4% ET: Minimal vasodilation
9% ET: Greater vasodilation
No seizure activity noted with Desflurane
Epileptiform EEG pattern with Sevoflurane during mask induction
Increased HR with either spontaneous respirations or controlled hyperventilation

57. Methoxyflurane Methyl Ethyl ether Sweet, pungent smell
CHCl2CF2OCH3
CH3 metabolically unstable
Sweet, pungent smell
Tolerated for inhalation induction
Very slow
Not easily managed in adults
Metabolism – high
Polyuric dysfunction - High output renal failure
Caused by release of Fluoride ion during metabolism, Plasma fluoride > 50 micromols puts patient at risk

58. Methoxyflurane Extremely high lipid solubility
Vapor Pressure C
Boiling Point o
Solubility
Blood/gas
MAC
100% Oxygen – 0.23
Extremely high lipid solubility
High output renal failure

59. SEVOFLURANE – Degradation
In Vivo
Biotransformation results in organic and inorganic fluoride metabolites
Occurs via cytochrome P-450 catalyzed oxidation producing a transient intermediate that decomposes into
Inorganic fluoride
Organic fluoride metabolite hexafluoroisopropanol (HFIP)
Conjugated with glucuronide and excreted in the urine
Renal toxicity correlates with peak serum F-
< 40 M -- no clinical effects
50-80 M -- subclinical toxicity
M -- mild toxicity
M -- overt toxicity
Duration of exposure may be more important than peak serum levels
Hobbhahn J, ESA Refresher Courses 2000;3 RC 1 59

60. SEVOFLURANE – Degradation
In Vitro
Reacts with CO2 absorbers
Baralyme > soda lime
Low flows
Dry absorbent
High absorbent temperatures
High sevoflurane concentrations
Forms compounds A, B, C, D
Only compound A clinically significant
Compound A is a haloalkene (vinyl halide)
Formed when sevoflurane reacts with strong bases in absorbents
Animal models demonstrate renal toxicity
In rats nephrotoxicity characterized by necrosis of proximal tubular cells
Clinically presents with diuresis, proteinuria, glucosuria and enzymuria
Threshold for damage in rats approximately ppm for 3 hrs
Related to bioactivation of this compound by renal β-lyase pathway
No evidence this is dangerous to humans 60

61. SEVOFLURANE – Sleeping with uncertainty
2004 reports of
Exothermic reactions
Spontaneous ignition
Explosions
Fires
Fatheree RS, Anesth 2004;101:
Wu J, Anesth 2004;101:
Castro BA, Anesth 2004;101: 61

62. Recovery after Desflurane and Sevoflurane Anesthesia Clinical Implications
Duration
2 hours
10.9
17.8
12.7
21.2
4 hours
11.3
20.8
14.8
25.3
8 hours 14 28 19 33
Response to Command (min)
Orientation (min)
P<0.015 vs. sevoflurane
Eger EI, Anesth Analg 1998;86(2):
Joshi D. Anesth Analg 1998;86(2): 62

63. Enflurane Halogenated methyl ethyl ether Pungent, ethereal odor
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3/25/2017
Enflurane
Halogenated methyl ethyl ether
Pungent, ethereal odor
Less potent than other volatile agents
Synthesized
Clinical Use
Isomer of isoflurane
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64. Properties Clear, nonflammable liquid Volatile at room temperature
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Properties
Clear, nonflammable liquid
Volatile at room temperature
Vapor pressure C
Molecular weight 184
Solubility
Blood/gas = 224
Oil/gas = 98.5
MAC
70% Nitrous Oxide = 0.6
100% Oxygen = 1.7
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65. Advantages Extremely rare risk of postop liver dysfunction
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Advantages
Extremely rare risk of postop liver dysfunction
Increased doses of epinephrine
> halothane or isoflurane
< dysrhythmias
Muscle relaxant
Caution in patients with Myasthenia Gravis
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66. Disadvantages Very rare risk of renal toxicity
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Disadvantages
Very rare risk of renal toxicity
Risk of seizures in patient with seizure history
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67. Methoxyflurane Methyl Ethyl ether Sweet, pungent smell
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Methoxyflurane
Methyl Ethyl ether
Sweet, pungent smell
Tolerated for inhalation induction
Very slow
Not easily managed in adults
Metabolism - high
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68. Methoxyflurane Extremely high lipid solubility
Advanced Pharmacology
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Methoxyflurane
Vapor Pressure C
Solubility
Blood/gas = 12
MAC
100% Oxygen = 0.16
Extremely high lipid solubility
High output renal failure
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69. United States Eagle mourns . . .