Inhaled Anesthetics Flashcards
What and when was the first public successful anesthesia performed?
On october 16, 1846, the dentist William T. G. Morton administered diethyl ether for a surgery at the Massachusetts General Hospital to remove a tumor from Ebenezer Hopkins Frost’s neck
What is the importance of brain:blood partition coefficient?
The brain:blood partition coefficient is an important consideration for the induction of and recovery from general anesthesia because the nervous system is the major target organ. Lower tissue solubility will lead to more rapid equilibration from the blood and, by extension, from alveoli to that tissue.
Explain the concentration effect and the second gas effect
As nitrous oxide diffuses out of the alveoli, the uptake of nitrous oxide into blood and the reduction in alveolar volume concentrates the coadministered volatile anesthetic. For a volatile anesthetic, if 50% of the agent diffuses into the blood, its FA will decrease by 50% because the corresponding decrease in alveolar volume is negligi- ble. However, if nitrous oxide is administered at 80 vol% of a gas mixture and half of it (40% of alveolar volume) is taken up into the blood, the remaining alveolar volume is 60%, so the FA has changed from 0.8 (80/100) to 0.67 (40/60). The concurrent change in alveolar volume with uptake of nitrous oxide serves to increase nitrous oxide delivery as fresh gas replaces the absorbed anesthetic. This phenomenon, known as the concentration effect, increases the rate of rise of FA/FI for nitrous oxide relative to volatile anesthetics with similar blood-gas coefficients, explaining, in part, its rapid induction profile.17
A similar principle applies to the effect that high concentrations of nitrous oxide have on other inhaled anesthetics. The substantial decrease in alveolar volume as nitrous oxide diffuses into the blood partly offsets the uptake of a coadministered volatile anesthetic and concentrates the remaining anesthetic within the alveoli. Thus the rate of rise of FA/FI for a volatile anesthetic is greater in the presence of nitrous oxide than without it, a phenomenon known as the second gas effect
MAC (CAM in pt) definition
The minimum alveolar concentration (MAC) is defined as the concentration of an inhaled anesthetic required to produce immobility in response to a noxious stimulus in 50% of the population.
Describe MAC as volume concentration for the diferentes inhaled anesthetics
Agent MAC (vol%)
Halothane 0.75
Enflurane 1.68
Isoflurane 1.15
Methoxyflurane 0.16
Sevoflurane 2.10
Desflurane 7.25
Nitrous oxide 104
Xenon 71
When two inhaled anesthetics are used, MAC values are additive ou synergistic?
additive
How much MACs standard deviations are needed to produce immobilization to a surgical stimulus in 95% of pacients?
2 ( increase in the dose of
20% over MAC)
Therefore, 1,2 MAC
(The standard deviation for MAC across anesthetics is about 0.1 (i.e., 10% of the concentration defining MAC)
MAC-awake for isoflurane,
sevoflurane, and desflurane
MAC-awake is about one-third of MAC
Definition of MAC-awake: the end-tidal anesthetic concentration that allows a patient to respond meaningfully (in the absence of noxious stimuli).
MAC-amnesia definition
Is the concentration to prevent recall in 50% of a population.
OBS.: this value is not as well defined, but it is likely
less than MAC-awake, and it is assumed that conscious
recall is abolished at anesthetic concentrations preventing a meaningful response (again, when measured in the
absence of noxious stimuli).
MAC BAR definition
MAC at which 50% of a population will not mount an adrenergic response, evidenced by tachycardia, hypertension, and other signs, in response to a surgical stimulus.
The MAC-BAR is approximately 1.5 to 1.6 times MAC
- BAR = Blunted autonomic response
Factors that increase MAC
Factors Increasing MAC
Drugs
* Amphetamine (acute use)
* Cocaine
* Ephedrine
* Ethanol (chronic use)
Age
* Highest at age 6 months
Electrolytes
* Hypernatremia
Hyperthermia
Red hair
Factors that decrease MAC
Factors Decreasing MAC
Drugs
* Propofol
* Etomidate
* Barbiturates
* Benzodiazepines
* Ketamine
* α2-Agonists (clonidine, dexmedetomidine)
* Ethanol (acute use)
* Local anesthetics
* Opioids
* Amphetamines (chronic use)
* Lithium
* Verapamil
Age
* Elderly patients
Electrolyte disturbance
* Hyponatremia
Other factors
* Anemia (hemoglobin <5 g/dL)
* Hypercarbia
* Hypothermia
* Hypoxia
* Pregnancy
How to adjust the inhaled anesthetic concentration to achive 1 MAC at different ages?
MAC values are generally
referenced to a specific age, usually 40 years.
Increasing age reduces MAC by 6% to 7% for each decade.
This trend is broken for infants less than 1 year of age, where MAC increases from neonates to older children.
Describe the Meyer–Overton correlation
The lipophilicity of inhaled anesthetics led to theories that attributed anesthetic action to disruption of lipid membranes. Early experimental support for
this concept at the turn of the 20th century correlated anesthetic potencies with their oil–water partition coefficients, which was known as the Meyer–Overton correlation for the two pharmacologists involved
OBS.: inhaled anesthetics do not affect lipid membrane
properties at clinically relevant concentrations, so direct
membrane-mediated effects are unlikely to explain the
clinical effects of anesthetics
Inhibition of which enzime shown to correlate with inhaled anesthetic potency?
purified luciferase
Describe the mechanism of action of inhaled anesthetics
Despite 175 years of using inhaled anesthetics, the
molecular mechanisms leading to amnesia, unconsciousness, and immobility remain elusive.
A variety of voltage- and ligand-gated ion channels are
modulated by inhaled anesthetics and are thought to represent their critical neuronal targets for their neurophysiologic effects
(GABAA receptor; Glycine receptor; nACH (muscle) receptor; nACH (neuronal) receptor; 5-HT3 receptor; Na+
channels; Ca 2+ channels; Background K+ channels; AMP receptor; NMDA receptor)
These effects can be divided into
presynaptic and postsynaptic targets. Postsynaptically, volatile anesthetics potentiate inhibitory GABAA and glycine receptors, causing hyperpolarization and thus inhibiting action potential generation; however, these channels are not modulated by the inhaled anesthetics nitrous oxide or xenon.
All the inhaled anesthetics inhibit acetylcholine,
α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid
(AMPA), and N-methyl-D-aspartate (NMDA) receptors.
Voltage-gated ion channels are also modulated by volatile
anesthetics. Two-pore potassium channels are potentiated, causing hyperpolarization of neurons, thus inhibiting depolarization and action potential generation and propagation. Voltage-gated sodium and calcium channels are also targets of volatile anesthetics.
Studies have yielded
conflicting results for anesthetic effects on synaptic vesicle
exocytotic SNARE proteins. Volatile anesthetics also inhibit
mitochondrial function, in particular by inhibiting complex
I of the electron transport chain. Notably, patients with
mutations in complex I exhibit a substantial increase in
sensitivity to volatile anesthesia, confirming involvement
of this target in potentiating anesthetic potency.
Where is the local of action associated with the immobility caused by volatile anesthesia?
spinal cord is the primarily
responsible for mediating the immobility caused by volatile anesthesia
How volatile anesthesia alters the EEG?
With increasing doses of volatile anesthetics, neuronal activity is progressively inhibited. These effects can be readily observed by EEG, which shows a transition to higher-amplitude and lower-frequency electrical patterns, primarily in the alpha (8 to 13 Hz) and slow delta (1 Hz) frequencies, with theta oscillations (5 to 8 Hz) appearing at MAC doses of anesthetics. Further increases beyond typical surgical levels of anesthesia
produce burst suppression and, ultimately, an isolectric EEG
- At sub-MAC concentrations, beta frequencies (13 to 24 Hz) are reduced and alpha and delta (8 to 13 and 1 to 4 Hz, respectively) frequencies predominate. Increasing anesthetic concentration further causes theta frequencies (4 to 7 Hz) to emerge. At doses of 1.3 times MAC and
above, burst suppression can be observed
Which dose of volatile anesthesia inhibits cerebral blood flow autoregulation?
Cerebral autoregulation is inhibited by relatively high
doses (above 1.5 times MAC) of halothane, isoflurane, and
desflurane, while sevoflurane affects autoregulation less
Volatile anesthesia effects on cerebral blood flow
Whether CBF is increased
depends on the relative effects on vasodilation and suppression of cerebral metabolic rate of O2 (CMRO2).
Volatile anesthetic concentrations below MAC generally do not cause an increase in CBF or intracranial pressure (ICP) because vasodilation is offset by the decreased CMRO2 .
However, above MAC, the vasodilatory effects predominate and ICP increases
Describe, in decrescent order, the reduction of systemic vascular resistance caused by volatile anesthetics
isoflurane > desflurane > sevoflurane > halothane
The depressed cardiac function caused by volatile anesthetics may be partially offset by reduced SVR; for instance, at 2.0 times MAC of sevoflurane, cardiac index normal- izes despite reduced contractility because afterload is also decreased
T or F
T
Volatile anesthetics effects on pulmonary system
- Increase respiratory frequency
- Reduce tidal volume and minute ventilation
- Reduce hypoxic ventilators response
- Profoundly inhibits peripheral chemoreceptors to hypoxia
- Cause bronchodilation
- Mucociliary clearance is decreased
- May decreased surfactant production
Describe the diffusion hypoxia
Once nitrous oxide is discontinued, the partial pressure of nitrous oxide in blood exceeds the partial pressure of nitrous oxide in the alveoli; the resulting diffusion of nitrous oxide from blood to alveoli causes dilution of other alveolar gases. Dilution of oxygen, known as diffusion hypoxia, can pre- dispose patients to hypoxemia on emergence from nitrous oxide anesthesia. However, this process also contributes to the rapid emergence profile of nitrous oxide
How does nitrous oxide affects the metabolism of B12?
Nitrous oxide inhibits methionine synthetase. Prolonged use in patients with vitamin B12 deficiency can promote neuropathy and megaloblastic anemia. Homocysteine levels may also be increased by nitrous oxide, which has raised concern for increased cardiovascular morbidity because of the deleterious effects of elevated homocysteine
PONV risk factors
opioid use, being a nonsmoker, having a history of PONV or motion sickness, female sex, type and duration of surgery, age, and the use of volatile anesthesia
PONV pathogenesis
is likely the result of anesthetic and surgical effects affecting serotoninergic, dopaminergic, and μ opioid receptors of the area postrema of the brainstem, with vagal and vestibular afferents contributing. It is unclear how volatile anes- thetics specifically affect these pathways
Most common etiology of malignant hyperthermia
mutations in the ryanodine receptor 1 (RyR1) isoform, but about 25% of patients have mutations in other genes, such as the CACNA1 gene that encodes the L-type voltage-gated calcium channel responsible for triggering the opening of RyR1 in skeletal muscle
Most common etiology of malignant hyperthermia
mutations in the ryanodine receptor 1 (RyR1) isoform, but about 25% of patients have mutations in other genes, such as the CACNA1 gene that encodes the L-type voltage-gated calcium channel responsible for triggering the opening of RyR1 in skeletal muscle
How to manage a Malignant Hyperthermia crisis?
1- Stop potent inhalation agents
2- Do not repeat succinylcholine if it has been previously administered
3- Increase minute ventilation to lower ETCO2
4- Get help
5- Prepare and administer dantrolene (2.5 mg/kg initial dose; Every 10–15 min until acidosis, pyrexia, muscle rigidity are resolving)
6- Begin cooling measures if hyperthermic (Use intravenous normal saline at 4°C; Ice packs to all exposed areas; More aggressive measures as needed)
7- Stop cooling measures at 38.5°C (101.3°F)
8- Treat arrhythmias as needed (Amiodarone is the first choice; Lidocaine; Do not use calcium channel blockers)
9- Secure blood gases, electrolytes, creatine kinase, blood, and urine for myoglobin
10- Continue dantrolene (1 mg/kg every 4–8 h for 24–48 h; Alternatively and only if recrudescence occurs, dantrolene at 2.5 mg/kg bolus)
11- Ensure urine output of 2 mL/kg/h (Mannitol, Furosemide, Fluids as needed)
12- Evaluate need for invasive monitoring and continued mechanical ventilation
13- Observe patient in intensive care unit
14- Refer patient and family for MH testing
Volatile anesthetics can inhibit the immune response, raising concern for worsened outcomes after resections for cancer. Is this risk real?
A recent meta analysis of nine retrospective analyses and a single RCT reported greater recurrence free and overall survival using total intravenous anesthesia (TIVA) as opposed to volatile anesthesia. However, the authors noted that substantial heterogene- ity of study design and outcomes weakened the conclu- sion. In the single RCT included in the meta analysis there was no difference at 2 years in women randomized to receive propofol and remifentanil or sevoflurane for breast cancer resection; however, the relatively short follow-up and small trial size (80 patients) may have limited the ability of the trial to detect survival diferences. Large RCTs are underway to better assess whether volatile anesthesia worsens cancer outcomes compared with TIVA
The propensity to generate CO is dependent on the makeup of the absorbent and the volatile anesthetic used. Describe the bases and volatile anesthetics more associated with CO formation
KOH > NaOH»_space; Ba(OH)2 > Ca(OH)2
primarily desflurane and isoflurane
The theoretical risk of injury associated with compound A has led to the recommendation to maintain a fresh gas flow of at least
1 L min−1 if used for over 2 MAC-hours
Describe th percentage of the volatile anesthetics that is metabolized and how they are metabolized
The modern volatile anesthetics isoflurane, sevoflurane, and desflurane are minimally metabolized (0.2%, 5%, and 0.02%, respectively). Halothane, however, undergoes substantial hepatic metabolism (46%).
Metabolism occurs primarily by the cytochrome P450 system in the liver, specifically by CYP2E1, although other enzymes contribute to other volatile anesthetics. The breakdown of volatile anesthetics liberates fluoride.
Only methoxy- flurane has been shown to release sufficient fluoride to generate clinical renal injury
