wayne e. ellis, ph.d., crna. effects on renal system decreased renal blood flow decreased glomerular...

Wayne E. Ellis, Ph.D., CRNA

Decreased renal blood flow

Decreased Glomerular Filtration Rate

Decreased urine output

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)  

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.

Dysrhythmias are easily induced.

Avoid Halothane in patients with acute cocaine intoxication.

Cocaine blocks reuptake of norepinephrine.

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

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

Agents metabolized in liver by cytochrome P-450

N2O metabolized to N2 in intestine by anaerobic bacteria

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

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    

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

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

Agents with highest oil/gas ratio are:

More lipid soluble More potent Have smaller MAC The lower the MAC the greater the

potency

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

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)

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

Increased uptake of volatile agent when given together with N2O

Fick's law also explains second gas 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)

Alveoli Expands

CO2/O2 are diluted

Diffusional hypoxia occurs in patients on room air O2 during emergence

N2O increases both SVR/PVR

N2O has a mild sympathomimetic effect

Malignant Hyperthermia

Venous Air Embolism

Middle Ear Surgery

Closed Pneumothorax

Bowel Obstruction

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Very rare risk of renal toxicityRisk of seizures in patient with

seizure history

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Halogenated methyl ethyl etherPungent, ethereal ordor

CoughingBreath holding

Synthesized 1965Clinical Practice 1981

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Clear, nonflammable liquidVolatile at room temperatureVapor pressure 240 torr @ 20

CMolecular weight 184Solubility

Blood/gas = 1.4Oil/gas = 90.8

MAC70% Nitrous Oxide = 0.5100% Oxygen = 1.15

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< blunting of the baroreceptor reflexMaintenance of CO

Increase in heart rate

Epinephrine> halothane< enflurane

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TachycardiaHypotensionExtremely potent vasodilator

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

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

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

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

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

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

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Pharmacodynamicsalmost identical to isofluraneDose related decreases in BP and COGreater than seen with isoflurane

Factor of rapidity of increasing dose

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Volatile at room temperatureStored under pressureBoiling Point 23.5 CVapor Pressure 664 torr @ 20

CSolubility

Blood/gas = 0.42Oil/gas = 18.7

MAC70% Nitrous Oxide = 2.83100% Oxygen = 6

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PharmacokineticsLow blood/gas partition coefficient“Very fast-on, fast-off”

Similar to Nitrous OxideMetabolism

< isoflurane

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

Respiratory effects◦ Depressant◦ Pungent odor prevents mask inductions

Recovery◦ Emergence rapid◦ May be associated with emergence delirium◦ Discharge to home similar to other agents

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

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

Occurs when Desflurane, Ethrane, Forane degraded by dry soda lime or Baralyme > 600 ppm

Does not occur with fully hydrated absorbentsCommon scenario: * Monday morning case and gas has been left

on over the weekend, drying the absorbentAbsorber temperature rapidly rises

Use fresh absorbentUse soda lime rather than barium

hydroxideUse the new CO2 absorbent called

“Amsorb” Prevents anesthetic breakdown that would lead

to CO formationAbsorbs less CO2 than other absorber

compounds

Turn off gas when case complete

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

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Clear, volatile liquidVapor pressure 160 torr @ 20CSolubility

Blood/gas = 0.59Oil/gas = 55

MAC70% Nitrous Oxide = 0.66100% Oxygen = 1.71

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Pleasant smellingWell tolerated for inhalation inductionAs temperature increases, degradation

occursCompound (Substance) A

Unstable in soda limeHigh degree of metabolism

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

Clear, volatile liquid

Pleasant smellingWell tolerated for inhalation inductionAs temperature increases, degradation occurs

Compound (Substance) A

Unstable in soda limeHigh degree of metabolismTachycardia seen with > 1.5 MACNo increase in CVP

Molecular Weight 200Boiling Point 58.5 o CVapor pressure 160 torr @ 20COdor Ethereal, PleasantSolubility

Blood/gas 0.59 – 0.69Brain/Gas 1.7Oil/gas 53.4 – 55

MACNitrous Oxide 0.66Oxygen 1.71

Can be used safely for inhalation induction

Quick inductionDoes not initiate coughing, secretions, breath

-holding, laryngospasmCan be used for difficult airway & intubation:

Fiberoptic with spontaneous ventilations

Can maintain spontaneous respirations + anesthesia

Compound A is of most concernUp to 60 ppm in normally operating anesthesia

circuitAverage concentrations 20-25 ppm

1% = 10,000 ppm

Renal toxicity @ 25-60 ppm

Dilutent gas flowTemperatureSodalime moisture contentSevoflurane concentrationTime

From Sevoflurane

Isoflurane, Desflurane & Sevoflurane decrease CMRO2 in a dose-related fashion

Increases CBF in dose-related fashion (Hoffman)4% ET: Minimal vasodilation9% ET: Greater vasodilation

No seizure activity noted with DesfluraneEpileptiform EEG pattern with Sevoflurane during

mask inductionIncreased HR with either spontaneous respirations or

controlled hyperventilation

Methyl Ethyl etherCHCl2CF2OCH3

CH3 metabolically unstableSweet, pungent smellTolerated for inhalation induction

Very slowNot easily managed in adults

Metabolism – highPolyuric dysfunction - High output renal failure

Caused by release of Fluoride ion during metabolism, Plasma fluoride > 50 micromols puts patient at risk

Vapor Pressure 22.5 torr @ 20CBoiling Point 105 o

SolubilityBlood/gas 12

MAC100% Oxygen 0.16 – 0.23

Extremely high lipid solubilityHigh output renal failure

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

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

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

Desflurane Sevoflurane Desflurane Sevoflurane

Anesthesia

Duration2 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)

Eger EI, Anesth Analg 1998;86(2):414-421

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

P<0.015 vs. sevoflurane

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Halogenated methyl ethyl etherPungent, ethereal odorLess potent than other volatile agentsSynthesized - 1963Clinical Use - 1972Isomer of isoflurane

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Clear, nonflammable liquidVolatile at room temperatureVapor pressure 172 torr @ 20 CMolecular weight 184Solubility

Blood/gas = 224Oil/gas = 98.5

MAC70% Nitrous Oxide = 0.6100% Oxygen = 1.7

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Extremely rare risk of postop liver dysfunction

Increased doses of epinephrine> halothane or isoflurane < dysrhythmias

Muscle relaxantCaution in patients with Myasthenia Gravis

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Very rare risk of renal toxicityRisk of seizures in patient with seizure

history

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Methyl Ethyl etherSweet, pungent smellTolerated for inhalation

inductionVery slowNot easily managed in adults

Metabolism - high

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Vapor Pressure 22.5 torr @ 20CSolubility

Blood/gas = 12

MAC100% Oxygen = 0.16

Extremely high lipid solubilityHigh output renal failure

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