Volatile anesthetics

Question 1

Modern inhaled anesthetics

Answer 1

Volatile anesthetics

• isoflurane
• desflurane
• sevoflurane
• –> all have ether moiety
• –> liquid at room temp
• –> desflurane has unique vapor pressure, uses own vaporizer

N2O is a gas at room temp

Question 2

Why use inhalend anesthetics?

Answer 2

• Reliable effects
• Hallmark of general anesthesia –> cause unconsciousness, amnesia, immobility
• Level and effect of anesthesia can be safely monitored
• Inexpensive
• Ease of administration

Question 3

Monitoring effects of anesthesia

Answer 3

Vital signs

• EKG rhythm, heart rate
• BP
• O2 sat
• with spontaneous respiration –> resp rate, tidal vol, pattern of respiration

Movement in response to surgery

Levels of exhaled gases –> O2, N2, CO2, N2O, volatile anesthetics

Question 4

Goal of inhaled anesthetics

Answer 4

• To produce the anesthetic state by establishing a specific concentration of anesthetic molecules in the CNS
• Achieved by establishing the specific partial pressure of the agent in the lungs, which ultimately equilibrates with the brain

Question 5

Mechanism of action

Answer 5

• poorly understood
• immobility –> acts on spinal cord
• amnestic effects –> acts on brain (hippocampus, amygdala, cerebral cortex)
• CNS depression
• –> enhance inhibitory neurotransmitters (GABA + glycine)
• –> block excitatory neurotransmitters (NMDA)

Question 6

Definition

• partial pressure
• solubility

Answer 6

Partial pressure –> for any mixture of gases in a closed container, each gas exerts a pressure proportional to its fractional mass

Solubility –> used to describe tendency of a gas to equilibriate with a solution, hence determining its concentration in solution
- implications –> anesthetic gases administered via the lungs diffuse into blood until the partial pressures in alveoli and blood are equal

Question 7

Minimum alveolar concentration (MAC)

Answer 7

Effects of inhaled anesthetics must be based on a dose –> this dose is the MAC

• MAC is the alveolar concentration of an anestetic at one atmosphere that prevents movement in response to a surgical stimulus in 50% of patients
• it is analogous to the ED50 expressed for IV drugs
• MAC>0.5 = amnesia
• MAC =1 = surgical anesthesia
• MACs are additive
• MAC declines 6% per decade of life –> highest at 6 months

Question 8

Blood:gas partition coefficient or solubility
Blood brain partition coefficient
Blood:fat partition coefficient or solubility
oil-gas partition coefficient

Answer 8

Blood:gas partition coefficient or solubility –> solubility of a gas in blood

Blood brain partition coefficient –> mirrors blood-gas solubility

Blood:fat partition coefficient or solubility –> solubility of gas in tissue/fat

Oil-gas partition coefficient –> correlates lipid solubility with potency

• potency is roughly equivalent to MAC
• N2O <iso

Question 9

MACs and solubilities

Answer 9

N20

• MAC = 104
• blood-gas partition coefficient = 0.46
• oil-gas partition coefficient = 1.4
• fat-blood solubility = 2.3

Isoflurane

• MAC = 1.17
• blood-gas partition coefficient = 1.46
• oil-gas partition coefficient = 91
• fat-blood solubility = 45

Sevoflurane

• MAC = 1.8
• blood-gas partition coefficient = 0.69
• oil-gas partition coefficient = 147
• fat-blood solubility = 48

Desflurane

• MAC = 6.6
• blood-gas partition coefficient = 0.42
• oil-gas partition coefficient = 19
• fat-blood solubility = 27

Question 10

Factors that increase and decrease MAC

Answer 10

Factors that increase MAC

• increased central neurotransmitter levels –> MAO inhibitors, cocaine, levodopa, ephedrine, acute detroamphetamine administration
• chronic alcohol abuse
• hyperthermia
• hypernatremia

Factors that decrease MAC

• increased age
• metabolic acidosis
• hypoxia
• decreased CNS NT levels –> a-methyldopa, reserpine, chronic detroamphetamine administration, levodopa
• hypothermia
• hyponatremia
• pregnancy
• acute alcohol intoxication
• drugs –> lithium, lidocaine, opioids, barbiturates, alpha 2 agonists, ketamine

Question 11

Pharmacokinetics of inhaled anesthetics

Answer 11

At equilibrium = PA = Pa = Pbr

Based on concentration gradient

• uptake from alveoli into systemic circulation
• uptake from circulation into brain
• redistribution of anesthetic throughout the body

Induction –> Pbr equilibrates with PA (and Pa) within 6-12 minutes
- highly perfused tissues equlibrate faster

The vascular system delivers blood to 3 physiologic tissue groups –> the vessel rich group, the muscle group and the fat group

• VRG = brain, heart, kidney, liver, digestive tract and glandular tissues
• anesthetic is delivered most rapidly to the VRG because of high blood flow –> here it diffuses according to partial pressure gradients
• CNS tissue takes in the anesthetic according to the tissue solubility, and at a high enough tissue concentration, unconsciousness and anesthesia are achieved
• increasing CNS tissue conc cause progressively deeper stages of anesthesia

PA mirrors the Pbr

• index of anesthetic depth
• reflection of rate of induction and recovery from anesthesia
• measure of potency

Thus, monitoring MAC of inhaled anesthetics provides an index of their effects in the brain –> anesthesia machine measures level of inspired and exhaled anesthetic gas

Question 12

Factors determining PA

Answer 12

Inspired anesthetic partial pressure (PI)

• higher PI accelerates induction, offsets uptake into blood
• as uptake into the blood decreases, PI can be decreased to maintain a constant Pbr

Alveolar ventilation

• increased ventilation accelerates induction by more rapidly increasing PA
• offsets uptake into blood

Cardiac output

• influences uptake into the blood by controlling how much anesthetic is carried from the alveoli
• low CO speeds induction

Question 13

Uptake and distribution

Answer 13

Uptake - follows ratio of fractional concentration of alveolar anesthetic to inspired anesthetic (FA/FI) over time
- the faster FA rises relative to FI, the faster the speed of induction since FA is proportional to PA

Solubility = main factor controlling rate of induction and emergence
- N2O<iso

Question 14

Recovery from anesthesia

Answer 14

Inhaled anesthetic turned off

• PA = 0
• Patient breathes 100% oxygen

Partial pressure gradient reversed
- stored anesthetic in tissues diffuses down its concentration gradient into the blood and is exhaled

Similar to induction

• solubility of agent –> less soluble agents will allow faster emergence
• depends on alveolar ventilation –> more ventilation allows faster emergence
• depends on CO –> lower CO allows faster emergence

Different than induction

• tissue concentration –> tissues serve as a reservoir of inhaled anesthetics
• –> concentration depends on solubility and duration of anesthesia
• –> can have variable concentrations in different tissue
• metabolism –> minimal with modern anesthetics

Diffusion hypoxia

• occurs with N2O administration
• high initial outpouring of N2O from blood to alveoli can dilute and decrease PaO2
• hypoxia if patient breathes room air and not given enough high concentrations of O2

Question 15

Desirable properties of an inhaled anesthetic

Answer 15

Anesthesia machine and breathing circuit

• lack of flammability
• ease of vaporization at room temp
• chemical stability

Lungs and breathing

• rapid induction and emergence
• lack of airway irritation
• bronchodilation
• lack of resp depression

Other requirements

• maintenance of MAP + HR
• low solubility in skeletal muscle and fat
• potency

Question 16

Effects of inhaled anesthetics on circulatory system

Answer 16

MAP - decrease in MAP due to decrease in systemic vascular resistance
- N2O little change in MAP and SVR

HR –> small increase, iso>des
- no effect with N2O and sevo

Desflurane - transient circulatory stimulation with abrupt increase >1 MAC –> increase in HR + MAP

Little effect on CO
Few cardiac arrhythmias
Sevo may prolong QT interval
N2O - increases pulm vascular resistance

Cardioprotection –> ischemic preconditioning

• a preconditioning stimulus such as brief coronary occlusion and ischemia initiates a signaling cascade of intracellular events that reduces ischemia and reperfusion myocardial injury
• ischemic preconditioning seen with volatile anesthetics in patients with compromised regional perfusion

Question 17

Effects of inhaled anesthetics on ventilation

Answer 17

• increase RR and decrease tidal vol –> minute ventilation preserved (RRxTV)
• decrease in FRC
• increase in dead space
• less efficient gas exchange with deeper anesthesia, PaCO2 increases
• less responsive to CO2 at higher MAC –> apnea
• inhalation induction –> best with seco and N20 (they are non-pungent)
• bronchodilation
• depression of pharyngeal and laryngeal reflexes

second gas effect of N2O

• ability of high volume uptake of one gas, N2O, to accelerate rate of increase of PA of concurrently administered “companion gas”
• “concentrating effect” - conc of second gas in smaller lung vol due to high vol uptake of the first gas

Question 18

Effects of inhaled anesthetics on CNS

Answer 18

All cause cerebral vasodilation

• increased cerebral blood flow
• increased intracranial pressure

Uncoupling of CBF and CMRO2 –> decrease in CMRO2

Dose dependent EEG depression

N2) –> some mild analgesic properties

Question 19

Other effects of inhaled anesthetics

Answer 19

Neuromuscular effects

• dose related skeletal muscle relaxation
• enhance activity of all paralytics

Decreased renal blood flow –> decreased GFR, decreased urine output

Decreased hepatic blood flow

Question 20

Adverse effects - Compound A formation

Answer 20

Sevoflurane undergoes degradation in CO2 absorbents to form a vinyl ether called compound A

• production enhanced in low flow or closed circuit breathing systems, also warm or very dry CO2 absorbents
• well-defined species differences in the threshold for compound A induced nephrotoxicity

Question 21

Adverse effects - CO and heat

Answer 21

Inhaled anesthetics degraded by CO2 absorbents to CO when normal water content of the absorbent (13-15%) is markedly decreased ( significant heat production, fires and patient injuries

Question 22

Adverse effects - hepatic

Answer 22

Postop liver dysfunction associated with volatile anesthetics, commonly halothane

2 mechanisms

• more common form –> hepatocyte toxicity, relatively mild
• with repeat exposure, probably immune reaction to metabolites –> severe liver damage and fulminant hepatic failure

Unlike halothane, current volatile anesthetics have minimal adverse effects on the liver and might afford some protection for hepatocytes from ischemic and/or hypoxic injury

Question 23

N2O toxicity

Answer 23

N2O decreases activity of vit B12 dependent enzymes = methionine synthetase and thymidylate synthetase
- Use > 24 hours –> megaloblastic anemia, pernicious anemia, neuropathy

Ability of N2O to expand air filled spaces –> most clinically relevant concern

• due to its greater solubility in blood compared to nitrogen
• N2O diffuses from blood into closed gas spaces (bowel, middle ear) easily
• 75% N2O can expand a pneumothorax to double or triple its size in 10 and 30 min, respectively

Question 24

Malignant hyperthermia

Answer 24

Hypermetabolic reaction due to exposure to VA or succinylcholine

• 1/15,000 children, 1/50,000 adults
• 80% mortality without treatment, 5% with
• can occur during or a few hours after surgery

Mechanism

• autosomal dominant inheritance
• aberrant RYR1 receptor in skeletal muscle voltage gated Ca channel in T tubule
• uncontrolled CA release from SR
• sustained contractility and rigidity
• myocyte ischemia and cell death
• very increased CO2 production, anaerobic metabolism, severe acidosis
• hyperkalemia, myoglobinuria, renal failure

Question 25

Signs of malignant hyperthermia

Answer 25

``` Exhaled CO2>55mmHg Metabolic and respiratory acidosis pH<7.25 Hyperthermia up to 43 °C +/- muscle rigidity Hyper-/hypotension Tachycardia, dysrhythmias Renal failure Disseminated intravascular coagulation (DIC) Death: Cardiac arrest, pulmonary/cerebral edema ```

Question 26

Treatment of malignant hyperthermia

Answer 26

Discontinue triggering agents Dantrolene 2.5 mg/kg, followed by infusion Hyperventilate pt with 100% O2 Cool pt Treat hyperK+, dysrhythmias, metabolic acidosis Maintain good UO Call for help