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

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

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)  

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.

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

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

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

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

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

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    

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

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

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

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

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)

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

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

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)

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

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

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

Disadvantages Very rare risk of renal toxicity Advanced Pharmacology 3/25/2017 Disadvantages Very rare risk of renal toxicity Risk of seizures in patient with seizure history WEllis 3/25/2017 22 18 22

Isoflurane Halogenated methyl ethyl ether Pungent, ethereal ordor Advanced Pharmacology 3/25/2017 Isoflurane Halogenated methyl ethyl ether Pungent, ethereal ordor Coughing Breath holding Synthesized 1965 Clinical Practice 1981 WEllis 3/25/2017 23 19 23

Properties Clear, nonflammable liquid Volatile at room temperature Advanced Pharmacology 3/25/2017 Properties Clear, nonflammable liquid Volatile at room temperature Vapor pressure 240 torr @ 20 C Molecular weight 184 Solubility Blood/gas = 1.4 Oil/gas = 90.8 MAC 70% Nitrous Oxide = 0.5 100% Oxygen = 1.15 WEllis 3/25/2017 24 24

Advantage < blunting of the baroreceptor reflex Maintenance of CO Advanced Pharmacology 3/25/2017 Advantage < blunting of the baroreceptor reflex Maintenance of CO Increase in heart rate Epinephrine > halothane < enflurane WEllis 3/25/2017 25 20 25

Disadvantage Tachycardia Hypotension Extremely potent vasodilator Advanced Pharmacology 3/25/2017 Disadvantage Tachycardia Hypotension Extremely potent vasodilator WEllis 3/25/2017 26 21 26

Inhalation Agents 27

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):2110-2124 28

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

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

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

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

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

Desflurane Pharmacodynamics almost identical to isoflurane Advanced Pharmacology 3/25/2017 Desflurane Pharmacodynamics almost identical to isoflurane Dose related decreases in BP and CO Greater than seen with isoflurane Factor of rapidity of increasing dose WEllis 3/25/2017 34 22 34

Properties Volatile at room temperature Stored under pressure Advanced Pharmacology 3/25/2017 Properties Volatile at room temperature Stored under pressure Boiling Point 23.5 C Vapor Pressure 664 torr @ 20 C Solubility Blood/gas = 0.42 Oil/gas = 18.7 MAC 70% Nitrous Oxide = 2.83 100% Oxygen = 6 WEllis 3/25/2017 35 35

Desflurane Similar to Nitrous Oxide < isoflurane Pharmacokinetics Advanced Pharmacology 3/25/2017 Desflurane Pharmacokinetics Low blood/gas partition coefficient “Very fast-on, fast-off” Similar to Nitrous Oxide Metabolism < isoflurane WEllis 3/25/2017 36 36

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

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

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

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):613-616 Olympia MA, APSF Newsletter 2005;20(2):25-29 40

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

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

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

Sevoflurane Clear, volatile liquid Vapor pressure 160 torr @ 20C Advanced Pharmacology 3/25/2017 Sevoflurane Clear, volatile liquid Vapor pressure 160 torr @ 20C Solubility Blood/gas = 0.59 Oil/gas = 55 MAC 70% Nitrous Oxide = 0.66 100% Oxygen = 1.71 WEllis 3/25/2017 44 44

Sevoflurane Pleasant smelling Well tolerated for inhalation induction As temperature increases, degradation occurs Compound (Substance) A Unstable in soda lime High degree of metabolism WEllis 3/25/2017 45

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

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

Sevoflurane Molecular Weight 200 Boiling Point 58.5 o C Vapor pressure 160 torr @ 20C Odor Ethereal, Pleasant Solubility Blood/gas 0.59 – 0.69 Brain/Gas 1.7 Oil/gas 53.4 – 55 MAC Nitrous Oxide 0.66 Oxygen 1.71

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

Sevoflurane Breakdown in Sodalime Compound A is of most concern Up to 60 ppm in normally operating anesthesia circuit Average concentrations 20-25 ppm 1% = 10,000 ppm Renal toxicity @ 25-60 ppm

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

From Sevoflurane

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

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

Methoxyflurane Extremely high lipid solubility Vapor Pressure 22.5 torr @ 20C Boiling Point 105 o Solubility Blood/gas 12 MAC 100% Oxygen 0.16 – 0.23 Extremely high lipid solubility High output renal failure

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 90-120 M -- mild toxicity 80-175 M -- overt toxicity Duration of exposure may be more important than peak serum levels Hobbhahn J, ESA Refresher Courses 2000;3 RC 1 59

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 96-114 ppm for 3 hrs Related to bioactivation of this compound by renal β-lyase pathway No evidence this is dangerous to humans 60

SEVOFLURANE – Sleeping with uncertainty 2004 reports of Exothermic reactions Spontaneous ignition Explosions Fires Fatheree RS, Anesth 2004;101:531-533 Wu J, Anesth 2004;101:534-537 Castro BA, Anesth 2004;101:537-539 61

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):414-421 Joshi D. Anesth Analg 1998;86(2):267-273 62

Enflurane Halogenated methyl ethyl ether Pungent, ethereal odor Advanced Pharmacology 3/25/2017 Enflurane Halogenated methyl ethyl ether Pungent, ethereal odor Less potent than other volatile agents Synthesized - 1963 Clinical Use - 1972 Isomer of isoflurane WEllis 3/25/2017 63 16 63

Properties Clear, nonflammable liquid Volatile at room temperature Advanced Pharmacology 3/25/2017 Properties Clear, nonflammable liquid Volatile at room temperature Vapor pressure 172 torr @ 20 C Molecular weight 184 Solubility Blood/gas = 224 Oil/gas = 98.5 MAC 70% Nitrous Oxide = 0.6 100% Oxygen = 1.7 WEllis 3/25/2017 64 64

Advantages Extremely rare risk of postop liver dysfunction Advanced Pharmacology 3/25/2017 Advantages Extremely rare risk of postop liver dysfunction Increased doses of epinephrine > halothane or isoflurane < dysrhythmias Muscle relaxant Caution in patients with Myasthenia Gravis WEllis 3/25/2017 65 17 65

Disadvantages Very rare risk of renal toxicity Advanced Pharmacology 3/25/2017 Disadvantages Very rare risk of renal toxicity Risk of seizures in patient with seizure history WEllis 3/25/2017 66 18 66

Methoxyflurane Methyl Ethyl ether Sweet, pungent smell Advanced Pharmacology 3/25/2017 Methoxyflurane Methyl Ethyl ether Sweet, pungent smell Tolerated for inhalation induction Very slow Not easily managed in adults Metabolism - high WEllis 3/25/2017 67 67

Methoxyflurane Extremely high lipid solubility Advanced Pharmacology 3/25/2017 Methoxyflurane Vapor Pressure 22.5 torr @ 20C Solubility Blood/gas = 12 MAC 100% Oxygen = 0.16 Extremely high lipid solubility High output renal failure WEllis 3/25/2017 68 68

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