Minimum alveolar concentration (mac)

Minimum Alveolar
Concentration (MAC)
and its related problems
Moderator- Dr.KAILASHNATH REDDY
Professor and HOD
Dept of Anesthesiology and Critical Care
Presenter-Dr.S.SARAH SHAHNAZ
First year postgraduate

Synopsis
• History
• Introduction
• Definition
• Meyer-Overton
hypothesis
• Exception to Meyer
Overton rule
• MAC derivatives
• Neural inertia
• Neurobiology of MAC
• Factors affecting MAC
• MAC vs Potency
• Advantages and
limitations of MAC and
its derivatives
• MAC and clinical
outcomes
• MAC and EEG changes
• Take away points

History
• Between 1840s and 1960s,newer agents were
introduced in anesthesia that demanded
comparison to determine potency and
adequacy of drug dosing
• Depth of anesthesia was assessed using
clinical observation
• Guedel –Stages of Anesthesia(breathing,
muscle tone, pupil diameter, lacrimation and
eyelid reflex)

• Woodbridge-Nothria (includes mental and
motor inactivity coupled with insensibility)
• In 1963,the study was done on animals
comparing two agents
• In 1964,the study was extended to halothane
anesthesia in human subjects
• In 1965, Eger et al. introduced the concept of
minimum alveolar concentration
• Hence MAC was described to compare various
anesthetic agent in 1965

Introduction
• It is a standard measure of potency for volatile
anesthetic agent.
• It mirrors brain partial pressure of the gaseous
agents
• MAC relates the concentration or partial
pressure of inhaled anesthetics to a single
clinically relevant endpoint of general
anesthesia i.e.immobility to surgical stimulus

Definition
• It is the minimum alveolar concentration of an
inhaled anesthetic at 1 atm pressure (sea
level) in 100% oxygen equilibrium ,at which
50% of patients do not produce any apparent
purposeful movement in response to a
standardised noxious stimuli (e.g. surgical skin
incision)
• It is expressed in terms of percentage

• According to Avogadro’s hypothesis, ’Volume
that a gas occupies at a given temperature
and pressure is related to the number of
molecules of gas present in a sample’
• the partial pressure is directly proportional to
number of molecules of gas present in a given
sample
• The inhaled and exhaled concentrations are
measured as volume percentage

• volume percentage=partial pressure of gas
atmospheric pressure
Hence 1% isoflurane means 7.6mmhg at sea
level
Synonyms for MAC includes
• EC50 for immobility
• MAC-movement
• Minimum alveolar partial pressure
• Median alveolar concentration

• The volatile anesthetics inhibit mobility largely
through action on spinal cord
• It also produces amnesia and hypnotic effects
by its action on brain
• The concentration of volatile anesthetic
needed to prevent development of explicit
memory and to produce unconsciousness is
usually lower than the concentration needed
to prevent movement in response to surgery

• MAC assumes that the end-tidal anesthetic
partial pressure is an accurate reflection of
alveolar partial pressure which in turn reflects
partial pressure at effect site
• It is the quantitative measure of potency of
anesthetic anesthetic agents
• It does not increase with stimulus intensity
beyond a certain point as supramaximal
stimulation
• Volatile anesthetics bind to protein target

Meyer –Overton hypothesis
• There are two coefficients which determines with
diffusion of the gases across the membranes to
act on target proteins. These are
Blood :gas partition coefficient
Lipid :gas partition coefficient
• Meyer –Overton hypothesis establishes the
striking correlation between the lipid solubility
properties of general anesthetic molecules and
their potency i.e lipid-gas partition coefficient.

• It states-”the greater the lipid solubility of the
compound in olive oil (lipid) the greater is its
anesthetic potency”
• Meyer concluded that all chemically
indifferent, fat-soluble agents, would function
as anesthetics
• Later in the century, further experimentation
showed that proteins were the likely site of
action

• It implies that MAC is inversely proportional to
lipid solubility of the inhaled anesthetic agent
• MAC is estimated from the equation
MAC *λ =1.82 atm
• λ implies olive oil/gas partition coefficient
• Thus if lipid solubility decreases MAC
increases
• Hence if a new volatile anesthetic was
introduced with a MAC of 9% we conclude
that it is less potent and less soluble than
desflurane (MAC is 6%)

Exception to Meyer-Overton rule
• Enflurane and isoflurane are structural
isomers and have similar oil:gas partition
coefficients but the MAC for isoflurane is
only approximately 70% of that for enflurane.
• Complete halogenation, or complete end-
methyl halogenation of alkanes and ethers
results in decreased anaesthetic potency and
the appearance of convulsant activity.

• For a given MAC reduction, plasma levels of
morphine, alfentanyl, sufentanyl and fentanyl
vary around 5000 fold. Levels of these four
agents in brain lipid vary 10 fold.
thus, studies of the reduction in MAC by
opioids suggests two sites of action: the
opioid receptor and some hydrophobic site.
• D-medetomidine, alpha-2-agonist results in a
marked reduction in MAC, whereas its optical
isomer, with identical lipid solubility, has no
effect.

• Mullins expanded the Meyer-Overton rule
by adding the 'Critical Volume Hypothesis'.
He stated that the absorption of
anesthetic molecules could expand the
volume of a hydrophobic region within the
cell membrane and subsequently distort
channels necessary for sodium ion flux
and the development of action potentials
necessary for synaptic transmission.

• The iconic Meyer-
Overton correlation was
initially interpreted as
evidence that lipids of
nerve membranes were
the principal anesthetic
target sites based on
the correlation between
anesthetic potency and
lipid-water partition
coefficient

• Equipotent administration of different agents
has enabled comparison of pharmacological
effects on physiological variables to be
described such as respiratory rate and blood
pressure
• One of the most striking feature is 6%
decrease in MAC per decade of age ,regardless
of volatile anesthetic
• MAC of 1.3 would prevent 95% patients from
moving and is termed EC95

This ﬁgure illustrates the relatively narrow
inter person variability in the anesthetic
concentration required to suppress
movement. Factors that shift the curve to the
left (i.e. decrease MAC) and to the right (i.e.
increase MAC) are shown in the arrows.
Population effective concentrations are shown
for 5% (EC5), 50% (EC50) and 95% (EC95) of
the population. The EC50 is synonymous with
MAC. SD, standard deviation.

MAC Derivatives
• The derivatives of MAC are usually inferred from
the surrogates of unresponsiveness or amnesia
• To determine the potency in terms of other
clinical endpoints of general anesthesia like
unconsciousness
• MAC awake
• MAC amnesia
• MAC bar
• MAC unawake
• MAC intubation

MAC awake
• It is defined as the anesthetic concentration
needed to suppress a voluntary response (eg-
eye opening)to verbal command in 50% of
patients
• MAC awake studies have been conducted with
volunteers who were not exposed to noxious
stimuli and hence it does not imply that 50%
of patients are unconscious but just
unresponsive in the absence of noxious stimuli

• MAC awake reflects the point at which one
both loses and regains consciousness
• The ratio MAC awake /MAC varies for different
volatile agent and it describes emergence from
anesthesia clinically
• The ratio closer to 1 implies patient will
recover responsiveness sooner
• Value of MAC awake=0.5-0.6

MAC amnesia
• The anesthetic concentration required to
suppress the recollection of a noxious
stimulus in 50% patients is defined as MAC
amnesia
• The primary goal of anesthetist is to suppress
the explicit episodic memory of surgical or
procedural events, which if not done ,may
lead to the development of post traumatic
stress disorder

• Several studies have shown that the value of
MAC awake is lesser than that of MAC
• According to Meyer-Overton hypothesis –
isoflurane-most potent amnesic agent and
halothane was the least potent.
• Administering both inhalational and
intravenous agents often prevent
consolidation of episodic memories

MAC Bar
• The minimum alveolar concentration of volatile
anesthetic that blocks autonomic responses to
surgical incision in 50% patients
• The autonomic responses to define MAC Bar are
pupil dilation ,heart rate and blood pressure
• It is the actual measure of adrenergic response to
skin incision which can be obtained by the level
of catecholemines in venous blood
• Value=1.5 MAC

MAC unawake
• The alveolar concentration of volatile
anesthetic at which 50% of patients remain
responsive verbal commands when the
anesthetic concentration is increased (the
induction pathway)

MAC intubation
• The minimum alveolar concentration at which
there is inhibition of movement and cough
reflexes during endotracheal intubation
• Value=1.3 MAC

NEURAL INERTIA
• Neural inertia is defined as the tendency of the
central nervous system to resist transition
between arousal state
• The path-dependent dose-response curves also
illustrate greater variability in responsiveness to
anesthetic concentration for emergence than for
induction.
• Anesthetic concentration predicts loss of
responsiveness much more reliably than recovery
of responsiveness.

Relationship between
isoﬂurane
concentration and
absence of righting
reﬂex during
induction of and
emergence from
anesthesia

• The gap between MAC-unawake and MAC
awake in anesthetised patient could provide a
safety limit
• The intense noxious stimulation could shift
the MAC awake and MAC amnesia curves such
that wakefulness and memory consolidation
occur at higher than expected concentration
of volatile anesthetic agent

• Mechanism of action of inhaled anesthetics
in producing generalised anesthesia by its
action on the spinal cord and the cerebral
cortex
• When preferentially delivered to the brain, the
partial pressure of anesthetic agent required
to suppress movement was greater than when
delivered to the whole body
• They suppress both sensory processing of
noxious stimuli and motor neuron reflex
responses to prevent movement

• The regions of the brain, such as the
amygdala, hippocampus and cortex,
contributing to the formation of explicit
episodic memory,may be targets for the
amnesic effects of inhaled anesthetics.
• Actions on subcortical structures, which
modulate sleep-wake cycles, probably
mediate effects on arousal.
• actions on thalamocortical and corticocortical
networks are thought to inhibit subjective
experience.

Uptake is a function of both
MAC and solubility of the
anesthetic in blood and
tissues. Thus, the 5-fold
higher MAC for desflurane
than isoflurane is offset by a
3-fold lower solubility,
which produces less than a
2-fold difference in uptake
at any point in time. Uptake
for all anesthetics initially
declines rapidly as a
function of the rate at
which the vessel-rich group
equilibrates. The further
decline after 5 to 10
minutes is a function of the
approach to equilibration of
the muscle group

• When a factor increases MAC in an individual,
volatile anesthetics have decreased potency
for that person.
• the presence of these factors will require a
higher concentration of the volatile agent
• Hence factors that decrease MAC will have
increased potency so those patients will
require a lower concentration of the volatile
agent
Factors influencing MAC

The factors altering MAC are classified as
• Physiological factors
• Pharmacological factors
• Pathological factors

Physiological factors
• Inversely proportional to age
MAC peaks at 6 months of age after which
it decreases
it is measured as MACage calculated as
MACage is the MAC at a given age and
MAC40 is the MAC value at age 40

• A positive linear relationship between
temperature and MAC is seen
for body temperatures of 32–37 °C, a
decrease by 1 °C resulted in a 5% decrease in
MAC for isoﬂurane
• Hypernatremia or hyponatremia will increase
and decrease MAC respectively
• osmolality in cerebrospinal ﬂuid may alter
MAC

• Genetically, mutations in the melanocortin-1
receptor (MCR-1) gene are associated with
increased MAC
• Obesity has been,controvertialy,considered to
be a modifier of MAC

Pharmacological factors
• Drugs administered in the peri-operative
setting often increase the potency of
inhalational anesthetic agents
• Midazolam premedication results in dose-
dependent reductions in MAC
• intravenous drugs that potentiate or activate
GABAA, including propofol, also decrease MAC

• it is important to emphasize that these drugs
might all alter MAC, but not similarly affect
other MAC derivatives
• drugs that increase catecholamine release in
the CNS, such as cocaine, increase MAC during
acute intoxication
• chronic cocaine exposure is associated with a
decrease in MAC for isoﬂurane

Pathological factors
• patients with a depressed level of
consciousness due to trauma or
cerebrovascular insult may have decreased
anesthetic requirements
• dementia or other neuro-degenerative
changes may also affect MAC
• Alzheimer’s disease confers a resistance to the
hypnotic actions of inhaled anesthetics

Decrease in MAC
• Hypothermia
• Hyperthermia-if temprature>42 deg celcius
• Elderly
• Acute alcohol intoxication
• Anemia where hematocrit < 10%
• PaO2 <40 mmhg and PaCO2>95mmHg

• Mean arterial pressure <40 mmHg
• Hypercalcemia
• Hyponatremia
• Pregnancy- MAC decrease by 1/3rd at 8 weeks
of gestation and come to normal
• Drugs-all local anesthetic except cocaine
opioids
ketamine
barbiturates
benzodiazepines

• Drugs (continued)
verapamil
lithium
sympatholytics like methyldopa
dexmeditomidine
clonidine
chronic amphetamine intake

Increase in MAC
• Young patients
• Chronic alcohol abuse
• Hypernatremia
• Drugs-cocaine
acute amphetamine toxicity
ephedrine
MAO inhibitors
levodopa

Factors causing NO change in MAC
• gender
• Hypothyroidism
• Hyperthyroidism
• Hypercalcaemia
• Metabolic alkalosis
• Duration of inhaled anesthetics use

Advantages and limitations of MAC
and MAC derivatives
Advantages of MAC
• It mirrors brain’s partial pressure after a
sufficient period of time
• Only small level of inter-individual variance is
seen
• The ability to quantify MAC for various
anesthetics allowed to compare and contrast
side-effects with speciﬁc anesthetics at MAC
equivalent multiples

Disadvantages or limitations
• MAC is not a reliable indicator of hypnosis or
unconsciousness
• MAC-awake, is unreliable due to the
behavioral component of the response
• MAC – a measure of responsiveness – may
not necessarily be informative regarding the
state of consciousness

• use of neuromuscular blockade to produce
paralysis makes the concentration of inhaled
anesthetic required to suppress movement
uninformative
• In multimodal or balanced anesthetic
techniques, the utility of MAC as a ‘pure’
measure of anesthetic effect is markedly
curtailed.

MAC and clinical outcomes
• clinical outcomes in surgical patients includes
intraoperative awareness with explicit recall
(AWR) and postoperative mortality.
• Efforts to prevent AWR events have focused
on attaining adequate depth of anesthesia by
adjustment of anesthetic dosing in response
to MAC or electroencephalographic measures

• bispectral index (BIS) values in the prevention
of AWR have been implemented-Michigan
Awareness Control Study, a randomized
comparative effectiveness trial
• Some trials showed the intraoperatively if
there is a combination of concurrent
low end-tidal levels (< 0.7 MAC) ,
low blood pressure (mean arterial pressure <
75 mmHg) and
low bispectral index values (BIS < 40)
was associated with a fourfold increase in
postoperative mortality

TAKE AWAY POINTS
• MAC is standard measure of potency of
volatile anesthetics
• MAC is inversely proportional to potency
• Mirrors brain partial pressure of gaseous agnts
• It acts on both the spinal cord and brain
causing largely immobility,amnesia to explicit
memory and unconsciousness

• It follows Meyer-Overton hypothesis which
says MAC is directly proportional to lipid
solubility of inhaled anesthetic agent
• There is a 6% decrease in MAC per decade of
age for all local anesthetic and the maximum
value is attained at 6 months
• MAC derivatives-MAC awake, MAC amnesia,
MAC bar, MAC unawake, MAC intubation
• MAC amnesia aims at prevention of incidence
of posttraumatic stress disorder

• MAC awake value is lesser than that of MAC
• Hypo or hyperthyroid state will not affect the
MAC value
• Mutation in melanocortin-1 receptor gene is
associated with increase in MAC values
• Intravenous agents used in anesthesia
potentiate or activate the GABA a and thereby
decrease the MAC value

• Drugs that release catecholeamine ,such as
cocaine causes increase in MAC on acute
intoxication
• Alzheimer’s disease confers resistance to
hypnosis caused by inhaled agents
• Pregnancy- MAC decrease by 1/3rd at 8 weeks
of gestation and come to normal
• The clinical outcomes of MAC enables
assessing intraoperative awareness and
postoperative mortality

References
• Miller’s anesthesia by Ronald D Miller-7th
edition and 8th edition
• Review article on,”Minimum Alveolar
Concentration: ongoing relevance and clinical
utility” by A.Aranake et al
• http://www.frca.co.uk/article.aspx?articleid=1
00341: Mechanism of action of inhaled
anesthetic agent-Meyer Overton correlation

Minimum alveolar concentration (mac)

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