Cardiac Lecture Series
Mohamed Ismaeil, MD
Inhaled anesthetics and gases
History
History
Physical properties of inhaled anaesthetics and gases
PHYSICAL PROPERTIES
What are Inhaled Anesthetics
Structure of Diethyl Ether
N=N=O
Nitrous Oxide
Halothane
Enflurane
F H
F – C – C* – Br
F Cl
F F F
Cl – C* – C – O – C – H
H F F
F H F
F– C – C* – O – C – H
F Cl F
Isoflurane
F F H H
C
F C O C F
F C H
F F
Sevoflurane
F H F
F – C – C* – O – C – H
F F F
Desflurane
Effect of Chemical Structure on Physical Properties
Vapor Pressure and Boiling Point
Vapor Pressure dependent on temperature and physical characteristics of liquid, independent of atmospheric pressure
BP and VP of Inhaled Anesthetics
Agent | BP (0C) | VP (20 0C) |
Halothane | 50 | 243 |
Enflurane | 56 | 175 |
Isoflurane | 48 | 238 |
Sevoflurane | 58 | 160 |
Desflurane | 23 | 664 |
Nitrous Oxide | -89 | |
Xenon | -107 | |
Significance of Boiling Point
Diffusion of Gases Through Liquids
When a gas comes into contact with a liquid such as water, there is a tendency for the gas to dissolve in the liquid.
At equilibrium the concentration of a gas in the liquid is determined by its partial pressure in the gas and by its solubility in the liquid.
This relationship is described by Henry’s law.
Concentration of dissolved gas = Partial pressure of gas x Solubility coefficient
Diffusion of Gases Through Liquids
The solubility coefficient is a measure of how easily the gas dissolves in the liquid. In water the solubility coefficient for oxygen is 0.024, and for carbon dioxide it is 0.57.
Thus carbon dioxide is approximately 24 times as soluble in water as oxygen. Gases do not actually produce partial pressure in a liquid as they do when in the gaseous state.
Diffusion of Gases Through Liquids
However, knowing the concentration of the gas in liquid, it is possible to determine mathematically (general gas law) its partial pressure as if it were in a gaseous state.
Because the partial pressure thus calculated is a measure of concentration, it can be used to determine the direction of diffusion of gas through a liquid: gases move from areas of higher to areas of lower partial pressure.
Solubility of Inhaled Anesthetics
Solubility of Inhaled Anesthetics
Partition Coefficients of Inhaled Anesthetics
| Halothane | Enflurane | Isoflurane | Sevoflurane | Desflurane | N2O |
Blood/ Gas | 2.54 | 1.8 | 1.4 | 0.69 | 0.42 | 0.47 |
Brain/ Blood | 1.9 | - | 1.6 | 1.7 | 1.3 | 0.5 |
Fat/ Blood | 51 | - | 45 | 48 | 27 | 2.3 |
The blood: gas pc is useful, really.
FA/FI Ratio of Inhaled Anesthetics
Effect of Rubber and Plastic Components
Odor
Respiratory Irritation
2 MAC Desflurane: 75%
2 MAC Isoflurane : 50%
2 MAC Sevoflurane: 0%
1MAC: No irritation with any of three
Sevofluane: Agent of choice for induction
Products of Anesthetic Degradation
Anesthetic | Moist Absorbent | Dry Absorbent |
Desflurane | None | CO |
Isoflurane | None | CO |
Sevoflurane | Compound A | Compound A |
Compound A / BCDFE
Pentafluoroisopropenyl fluoromethyl ether (PIFE, C4H2F6O)
Extraction of acidic proton in presence of strong base (KOH, NaOH)
Baralyme > Soda lime
Production inversely related to FGF
Production directly related to absorbent temperature
Deprotonation of halothane by soda lime-BCDFE (2-bromo-2-chloro-1,1-difluoro ethylene)
Xenon
Inert gas with anesthetic properties
Normal constituent of atmospheric air at a concentration of <0.086 ppm
Removed by fractional distillation of liquefied air
Highly insoluble
Blood/gas Partition Coefficient 0.14
Oil/gas Partition Coefficient 1.9
Environment friendly
Density 5.8 gm/L (N2O 1.53 ; Air 1).
Greater density→ ↑ Airway resistance
FGF vs Compound A
Temperature vs CompoundA
Nitrous Oxide
Clear, colorless, odorless gas
Molecular weight: 44
Supplied through pipeline or pressurized cylinders
BP: -890C
Critical temperature: 36.5 0C
Critical Pressure: 73 bars
Specific gravity: 1.53 at 0C
Filling ratio: 0.65
Effect of Nitrous Oxide on �Closed Gas Spaces
Nitrogen: Blood/gas partition coefficient 0.015
Nitrous Oxide: 0.47
N2O leaves blood 34 times faster than N2 is absorbed
Theoretical limit to increase in volume is a function of alveolar nitrous oxide concentration.
At equilibrium, concentration of N2O in closed gas space equal alveolar concentration.
Alveolar concentration of 50% N2O may double volume of gas space
Pharmacokinetics and pharmacodynamics
Pharmacokinetics
UPTAKE AND DISTRIBUTION
Factors Affecting Inspiratory Concentration (FI)
1. Fresh gas flow rate
2. The volume of the breathing circuit
3. Any absorption by the machine or breathing circuit
Uptake and distribution
To induce anesthesia the bucket (PA) must be full. Unfortunately the bucket has a leak (uptake). To fill the bucket you must either (a) pour it in faster (increase delivery) or (b) slow down the leak (decrease uptake).
a
b
Factors Affecting Alveolar Concentration (FA)
1. Uptake
2. Ventilation
3. Concentration
Uptake
The slower of the rate of induction
The slower the rate of rise of the alveolar concentration
The greater the difference between FA and FI (the lower the FA/FI ratio)
The greater the uptake
Anesthetic agents are taken up by pulmonary circulation during induction 🡪 FA/FI < 1
Factors Affecting Anesthetic Uptake
1. Solubility in the blood
2. Alveolar blood flow
3. The difference in partial pressure between alveolar gas and venous blood
Solubility in Blood
Partition coefficients: the ratio of the concentration of anesthetic gas in each of two phases at equilibrium (equal partial pressures)
The higher the blood/gas coefficient
Alveolar Blood Flow
Equal to cardiac output (in the absence of pulmonary shunting)
Cardiac output increases
Anesthetic uptake increases
The rise in alveolar partial pressure slows
Induction is delayed
Low-output states 🡪 will affect the less soluble agents more
Myocardial depressant (halothane) 🡪 lowering cardiac output 🡪 positive feedback loop
The Partial Pressure Difference between Alveolar Gas and Venous Blood
Depends on tissue uptake
Factors affecting transfer of anesthetic from blood to tissue:
1. Tissue solubility (tissue/blood partition coefficient)
2. Tissue blood flow
3. The difference in partial pressure between arterial blood and tissue
Ventilation
Increasing alveolar ventilation 🡪 constantly replacing anesthetic taken up by bloodstream 🡪 better maintenance of alveolar concentration
Ventilation depressant (halothane) 🡪 decrease the rate of rise in alveolar concentration 🡪 negative feedback loop
Concentration
1. Concentrating effect
2. Augmented inflow effect
20
100
80
100
50% uptake
50% uptake
10
40
60
90
20%
80%
67%
11%
X 4
X 6
2
10
32
40
20%
80%
72
100
12
100
12%
72%
Factors Affecting Arterial Concentration (Fa)
V/Q distribution and uptake
Ventilation < perfusion
blood leaving shunt dilutes PA from normal lung
induction with low solubility agent will be delayed
little difference with soluble agents (slow anyway)
Ventilation > perfusion
uptake is decreased which enhances rise in FA
may speed induction for soluble agents
less difference with low solubility agents (fast anyway)
Factors Affecting Elimination
1. Biotransformation: cytochrome P-450
2. Transcutaneous loss: insignificant
3. Exhalation: most important
Elimination of rebreathing, high fresh gas flows, low anesthetic-circuit volume, low absorption by anesthetic circuit, decreased solubility, high cerebral blood flow, increased ventilation, length of time
Metabolism
Drug | Liver | Enzyme | Kidney |
Halothane | 25% | CYP2E1, CYP2A6, CYP3A4 | minimal |
Sevoflurane | 5% | CYP2E1 | <1%, Some metabolism |
Isoflurane | 0.025% | CYP2E1 | none |
Desflurane | minimal | CYP2E1? | none |
Enflurane | <1% | CYP2E1 (minor) | 2%, Major place, F- toxicity no longer on market |
Pharmacodynamics
Mechanism of Action
We don’t know… much, but let me tell you about what we do know…
Meyer-Overton hypothesis
The MAC of a volatile substance is inversely proportional to its lipid solubility (oil:gas coefficient) , in most cases. This is the Meyer-Overton hypothesis.
MAC is inversely related to potency i.e. high mac equals low potency.
The hypothesis correlates lipid solubility of an anaesthetic agent with potency (1/MAC) and suggests that onset of anaesthesia occurs when sufficient molecules of the anaesthetic agent have dissolved in the cell's lipid membranes, resulting in anaesthesia.
Critical Volume Hypothesis
The Critical Volume Hypothesis is a modification of Meyer-Overton that states anesthesia occurs when a “critical region” volume is sufficiently changed by a certain degree that anesthesia results
- This also doesn’t seem to be true
Myer-Overton Rule predicts/implies that anesthesia will occur when a specific number of anesthetic molecules dissolve (implies actual binding sites)
- This doesn’t seem to be true
Membrane Hypotheses
Membrane Hypotheses
Receptor Theory
Mechanism – Bottom Line
No one knows
Likely more than one site
Neuronal transmission is disrupted
Pre-synaptic, post-synaptic and extra synaptic effects are found
MAC
Minimum Alveolar Concentration = MAC
Anesthetic potency is measured in MAC
1 MAC is the Minimum Alveolar Concentration at which 50% of humans have no response (movement) to surgical stimulus (skin incision)
MACawake is the alveolar concentration when 50% of persons will awake to vocal stimulus
MAC is directly proportional to the partial pressure of the anesthetic agent in the CNS
MAC is consistent within a species and between species
MAC is different for each inhaled agent
MAC
Activity | Level of MAC |
Awake | < 0.2 |
Memory and Learning | 0.3 to 0.6 |
Anesthesia | 0.9 to 3.0 |
No Movement | 1.2 to 1.4 |
MAC
MAC
MAC
Agent | [agent] 1 MAC (ED50, STP) |
Halothane | 0.75 % |
Isoflurane | 1.46 % |
Sevoflurane | 1.80% |
Desflurane | 6.60 % |
Nitrous Oxide | 104% |
Factors increasing MAC
Hyperthermia
Chronic ETOH abuse
Hypernatremia
Increased CNS transmitters
MAOI
Amphetamine
Cocaine
Ephedrine
L-DOPA
Factors decreasing MAC
Clinical pharmacology
Cardiovascular Effects
Halthane reduces HR
Sevo and Enf are neutral
Des >> Iso can cause an Initial tachycardia
Cardiovascular Effects
Contractility
All agents are depressants
At 1 MAC the approximatel order is:
Halo = Enfl >> Des = Iso = Sevo
Des and Iso > rest
Cardiovascular Effects
Vasculature
All inhaled agents are smooth muscle relaxants
All cause vasodilation (decreased SVR)
Variable effects on different vascular
leading to hypotension
via Protein Kinase C inhibition – cAMP and Ca Troponin binding
Life threatening hypotension can result at high enough doses – threshold varies for each patient
Cardiovascular Effects
All inhaled agents are cardio toxic will lead to death at high enough concentrations
Arrhythmias are induced by all anesthetic agents
ED50 of epinephrine at 1.25 MAC
Cardiovascular Effects
Isoflurane shown to be potent coronary vasodilator
Sevoflurane and Desflurane seem to be less potent in animal models (not all tissue beds behave the same)
Concern that blood can be directed away from stenotic coronaries
Coronary Steal theoretically possible
Respiratory Effects
Patients will only willingly breath Sevoflurane and Halothane
All other agents are respiratory irritants
Tidal Volume is decreased
Respiratory rate is increased
Minute ventilation is decreased
No change in mucociliary clearance
Respiratory Effects
Chemoreceptors
Response to CO2 blunted
Apneic Threshold raised
PCO2 raised during spontaneous ventilation
Hypoxic drive abolished early at about 0.1 MAC
Respiratory Effects
Musculature
Reduction in Vagal Tone
Inhibit Protein Kinase C
Dose Dependent reduction in Airway Resistance (RAW) occurs
Isoflurane thought best
Respiratory Effects
PVR is decreased
Hypoxic pulmonary vasoconstriction impaired
Increased shunting
Gas exchange is less efficient (decreased FRC, increased shunt)
Shunt and oxygenation largely not affected by one lung ventilation
Changes in PVR
Difficult to assess
Effects of many things affect numbers
Positon
Cardiac Output
PA pressure
Nitrous oxide worsens pulmonary hypertension - causes increased PVR
Central nervous system effects
auto regulation of cerebral blood flow is impaired
Via blood flow
Via induced hypercapnea
Sleep apnea
Narcotics add synergistically
Benzodiazepines add synergistically
Central nervous system effects
Decreased Amplitude
Increased Latency
EEG is flat line at high concentrations
Useful in the treatment of status epilepticus
Must give a very deep anesthetic
Do deep anesthetics cause memory impairment?
BIS = Bispectral Index (Aspect Medical)
uses EEG changes to monitor depth of anesthesia
AKA – BIS, Entropy, Evoked Potentials
Central nervous system effects
Intraoperative Awareness
Estimated at 0.15% of all cases
Risk Factors
Patient Factors
Drugs Used
Kidney Effects
Kidney
Renal blood flow
GFR
Urine Output
Central nervous system effects
Some agents (enflurane, sevoflurane) can be toxic due to F- production during metabolism in liver or in the kidney
Fluoride nephrotoxicity
Sevoflurane produces Compound A which is a renal toxin
Anesthetized patients are heavily dependent on renin - angiotensin system to regulate volume status
Other Organs
Potentate NMBA
Skeletal Muscle is relaxed by inhaled AA
MH
Liver
Hepatic blood flow decreased
Most agents cause a transient increase in LFT’s
Cause is unknown
Obstetrics
Nitrous Oxide little effect acutely
Halogenated inhaled AA
Waking Up
Age
Mental state (MR, Alzheimer's…)
Medical condition (sepsis, Parkinson’s)
Other Medications
All agents, especially soluble agents, dissolve in fat creating a depot of drug
Waking Up in OR
Waking Up – Complex Tasks
Waking Up – Level of MAC
Nitrous Oxide
Depress myocardial contractility
Arterial BP, CO, HR: unchanged or slightly↑ due to stimulation of catecholamines
Constriction of pulmonary vascular smooth muscle increase pulmonary vascular resistance
Peripheral vascular resistance: not altered
Higher incidence of epinephrine-induced arrhythmia
Nitrous Oxide
Respiratory rate: ↑
Tidal volume: ↓
Minute ventilation, resting arterial CO2: minimal change
Hypoxic drive (ventilatory response to arterial hypoxia): depressed
CBF, cerebral blood volume, ICP: ↑
Cerebral oxygen consumption (CMRO2): ↑
Nitrous Oxide
Not provide significant muscle relaxation
Not a triggering agent of malignant hyperthermia
Increase renal vascular resistance
Renal blood flow, glomerular filtration rate, U/O: ↓
Hepatic blood flow: ↓
Postoperative nausea and vomiting
Nitrous Oxide
Almost all eliminated by exhalation
Biotransformation < 0.01%
Irreversibly oxidize Co in vit.B12 inhibit vit.B12-dependent enzymes interfere myelin formation, DNA synthesis
Prolonged exposure bone marrow suppression, neurological deficiencies
Avoided in pregnant patients
Nitrous Oxide
Contraindications
N2O diffuse into the cavity more rapidly than air (principally N2) diffuse out
Pneumothorax, air embolism, acute intestinal obstruction, intracranial air, pulmonary air cysts, intraocular air bubbles, tympanic membrane grafting
Avoided in pulmonary hypertension
Drug interactions
Due to high MAC, combination with more potent agents decrease the requirement of other agents
Potentiates neuromuscular blockade
Halothane
Halogenated alkane
Cardiovascular
Direct myocardial depression 🡪 dose-dependent reduction of arterial BP
Coronary artery vasodilator, but coronary blood flow↓ due to systemic BP↓
Blunt the reflex: hypotension inhibits baroreceptors in aortic arch and carotid bifurcation 🡪 vagal stimulation↓🡪 compensatory rise in HR
Sensitzes the heart to the arrhythmogenic effects of epinephrine (<1.5μg/kg)
Systemic vascular resistance: unchanged
Halothane
Rapid, shallow breathing
Alveolar ventilation: ↓
Resting PaCO2: ↑
Hypoxic drive: severely depressed
A potent bronchodilator, reverses asthma-induced bronchospasm
Depress clearance of mucus promoting postoperative hypoxia and atelectasis
Halothane
Cerebral
Neuromuscular
Halothane
Renal blood flow, GFR, U/O: ↓
Part of this can be explained by a fall in arterial BP and CO, preoperative hydration limits these changes
Hepatic blood flow: ↓
Oxidized in liver by cytochrome P-450
In the absence of O2 hepatotoxic end products
Halothane hepatitis is extremely rare (1/35,000)
Halothane
Contraindications
Unexplained liver dysfunction following previous exposure
No evidence associating halothane with worsening of preexisting liver disease
Intracranial mass lesion, hypovolemic, severe cardiac disease…
Myocardial depression is exacerbation by β-blockers and CCB
With aminophylline serious ventricular arrhythmia
Isoflurane
Pungent ethereal odor
A chemical isomer of enflurane
Cardiovascular
Minimal cardiac depression
HR: ↑ due to partial preservation of carotid baroreflex
Systemic vascular resistance: ↓🡪 BP: ↓
Dilates coronary arteries 🡪 coronary steal syndrome or drop in perfusion pressure 🡪 regional myocardial ischemia 🡪 avoided in patients with CAD
Isoflurane
Respiratory depression, minute ventilation: ↓
Blunt the normal ventilatory response to hypoxia and hypercapnia
Irritate upper airway reflex
A good bronchodilator
CBF, ICP: ↑, reversed by hyperventilation
Cerebral metabolic oxygen requirement: ↓
Relaxes skeletal muscle
Isoflurane
Renal blood flow, GFR, U/O: ↓
Total hepatic blood flow: ↓
Limited metabolism
Severe hypovolemia
Epinephrine (4.5μg/kg)
Potentiate nondepolarizing NMBAs
Desflurane
Systemic vascular resistance: ↓ BP: ↓
CO: unchanged or slightly depressed
Rapid increases in concentration lead to transient elevation in HR, BP, catecholamine levels
Not increase coronary artery blood flow
Desflurane
RESPIRATORY
Tidal volume: ↓, respiratory rate: ↑
Alveolar ventilation: ↓, resting PaCO2: ↑
Depress the ventilatory response to ↑PaCO2
Pungency and airway irritation
Vasodilate cerebral vasculature CBF, ICP: ↑, lowered by hyperventilation
Cerebral metabolic rate of oxygen: ↓ vasoconstriction moderate the increase in CBF
Desflurane
Neuromuscular
Dose-dependent decrease in the response to train-of-four and tetanic peripheral nerve stimulation
No evidence of any nephrotoxic effects
No evidence of hepatic injury
Desflurane
Contraindications
Severe hypovolemia, malignant hyperthermia, intracranial hypertension
Drug interactions
Potentiate nondepolarizing NMBAs
Not sensitize myocardium to arrhythmogenic effects of epinephrine (4.5μg/kg)
Emergence associated with delirium in some pediatric patients
Sevoflurane
Mildly depress myocardial contractility
Systemic vascular resistance, arterial BP: ↓
CO: not maintained well due to little rise in HR
Prolong QT interval
Sevoflurane
Depress respiration
Reverse bronchospasm
CBF, ICP: slight ↑
Cerebral metabolic oxygen requirement: ↓
Adequate muscle relaxation for intubation of children
Renal blood flow: slightly ↓
Associated with impaired renal tubule function
Sevoflurane
Portal vein blood flow: ↓
Hepatic artery blood flow: ↑
Liver microsomal enzyme P-450
Degraded by alkali (barium hydroxide lime, soda lime), producing nephrotoxic end products (compound A)
Fresh gas flows be at least 2 L/min
Not be used in patients with preexisting renal dysfunction
Sevoflurane
Severe hypovolemia, susceptibility to malignant hyperthermia, intracranial hypertension
Potentiate NMBAs
Not sensitize the heart to catecholamine-induced arrhythmias
Metabolism of Inhaled anesthetics and gases��
Metabolism
Drug | Liver | Enzyme | Kidney |
Halothane | 25% | CYP2E1, CYP2A6, CYP3A4 | minimal |
Sevoflurane | 5% | CYP2E1 | <1%, Some metabolism |
Isoflurane | 0.025% | CYP2E1 | none |
Desflurane | minimal | CYP2E1? | none |
Enflurane | <1% | CYP2E1 (minor) | 2%, Major place, F- toxicity no longer on market |
Toxicity - Hepatitis
Reported since first use of halogenated anesthetics
Most common cause of post operative jaundice is hematoma resorbtion
“Halothane hepatitis” was reported very shortly after anesthetic introduced
Incidence 1:10 000 with halothane
Usually requires multiple exposures
Most patients given halothane have evidence of liver injury
Not as common with newer anesthetic agents
Hepatitis and Pancreatitis are known complications of surgery estimated rate ca. 1: 1 000 000
Hepatic Toxicity
Njoku, Anest Analg 1997; 84:173.
Toxicity – Malignant Hyperthermia
producing a myopathy
Most patients are aware of family history of condition
More common Europeans (northern)
Some patients can receive triggering agents and have no reaction – case reports of up to six exposures prior to MH reaction
Reactions tend to occur at extremes of age
In some cases, a rise in Cpk following anesthesia is the only symptom of condition
Stress
Succinyl choline
Toxicity – Malignant Hyperthermia
Fluoride Nephrotoxicty
[F-] = 50 mol/l
F- opposes ADH leading to polyuria
methoxyflurane 2.5 MAC-hours (no longer used)
enflurane 9.6 MAC-hours
Toxins – Sevoflurane and Compound A
Sevoflurane reacts with soda lime used in anesthetic circuit to form “compound A”
fluoromethyl-2-2-difluoro-1-(trifluoromethyl) vinyl ether
Some reports of fires and explosions
Compound A is renal toxin
Large amounts are produced at low gas flow rates
Recommended 2 L / min flow rate
Little evidence of harm unless
Some evidence for changes in markers of damage but not clinically significant
Anesthetics and CO
All anesthetic agents react with soda lime to produce CO
CO is toxic and binds to Hgb in preference to oxygen
Des > enfl >>> iso > sevo >halo
Risk Factors
In general, not clinically significant
No deaths reported
Do you want your anesthetic first Monday morning?
Toxicities – Nitrous Oxide
N2O antagonizes B12 metabolism
inhibition of methionine-synthetase
Decreased DNA production
RBC production depressed post a 2 h N2O exposure ca. 12 later
Leukocyte production depressed if > 12 h exposure
Megoloblastic anemia
Marked depression if exposure longer than 24 hours
Toxicities – Nitrous Oxide
Neurologic
Long term exposure to N2O (vets, dentists and assistants) is hypothesized to result in neurologic disease similar to B12 deficiency
Evidence only shows an association
Increased risk of spontaneous abortion in dental/vetrinarian and OR personel (RR 1.3)
Teratogenic in rats (prolonged exposure of weeks)
Other Toxicity Issues
Reproduction
Teratogenicity
Carcinogenicity
Pharmacoeconomics
Anesthesia is usually second most expensive department in hospital
Volatile anesthetic agents ca. 20% of budget
OR time is ~$2400 per hour
Saved OR time needed to pay for bottle
Pharmacoeconomics
Low flow anesthesia
Use of Circle – re-breathing gas circuits
Agent switching during case
Agent Choice
THANK YOU!�