Joseph Priestly – discovers N2O in 1773

Crawford W. Long – 1842. Country Dr. in Georgia first used ether for neck surgery. Did not publicize.Tried to claim credit after Morton’s demonstration but…Important lesson learned – if you don’t publish it, it didn’t happen.

Sir Humphrey Davy – experimented with N2O, reported loss of pain, euphoria

Horace Wells 1844. Demonstrated N2O for tooth extraction –deemed a failure because patient “reacted”.

History of Anesthesia

WORLD ANAESTHESIA DAY

16TH OCT 1846

W.T.G.MORTON

John Collin Warren

Gilbert Abortt

How do Inhalational Anesthetics Work?

Surprisingly, the mechanism of action is still largely unknown.

"Anesthetics have been used for 160 years, and how they work is one of the great mysteries of neuroscience," James Sonner, M.D. (UCSF)

Lipid Theory

Membrane Stabilization Theory

Promiscuous Receptor Agonist Theory:

Anesthetics may act at GABA receptors, NMDA receptors, other receptors

Modifying functions of ION CHANNELS (opening of

inhibitory ion channels (Cl- or K+) and closing of excitatory ion channels (Na+)

Speed(extremely rapid action and fast changes in level of anesthesia)

Faster turnover/recovery times

Route of administration- lungs (get 100% of cardiac output)

Margin of safety

The main target of inhalation anesthetics is the brain.

Goal

To develop and maintain a satisfactory

partial pressure or tension of anesthetic at

the site of anesthetic action in brain.

Alveolar concentration of anesthetic gas is

indirectly reflects brain concentration.

PA PB

Vaporizer

Breathing Circuit

Alveoli (lungs)

Arterial Blood

Tissues (VRG [brain], MUS,FAT)

Venous blood (coming back to lungs)

Alveoli (lungs, again)

Breathing Circuit (to be rebreathed)

Time constant

Uptake and distribution of anestheticgases

FI

FA

FD

MAC

Brain Partial pressure

drives depth of

anesthesia

Equilibrates

Ventilation

λB/G

CO

PA - PV

λT/BTissue blood flow

[Parterial - PTissue]

12

FA/FI

Concentration and

second gas effects

Time constant

VRG

The absorption phase is usually called -

uptake

The metabolic phase is usually called -

biotransformation

The excretion phase is usually called –

elimination.

lowering of drug concentration in one compartment by delivery into another compartment is called

redistribution

Partial Pressure-the pressure a gas exerts- proportional

its fractional mass

AdditivePatm = PO2 + PN2

=160mmHg + 600mmHg

= 760mmHg

Ptotal= Pgas1+ Pgas2+ ….+Pgas N

(Dalton’s law)

Same pressure each gas would have if

IT ALONE occupied the same volume

Pressure- gas phase

Concentration – amount of gas

dissolved in a solution.

Solubility = volume of gas

volume of liquid

(at standard temperature)

What is “ PARTIAL PRESSURE OF GAS” in

solution?

Reflects a “force” of gas to escape

out of solution ( think of CO2 in a bottle

of soda)

Gasses equilibrate based on partial pressures, not on

concentrations

By convention, we use fractional concentration(F) instead

of partial pressure(P)

Ex: We could say FO2= 21% instead of PO2= 160 mmHg

Thus, F is proportional to P

Physiologically, our body needs the partial

pressure, not the fractional concentration!!!

Henry”s law: Cg = k Pg

Cg - is concentration of gas in solution

k - is a solubility constant

Pg - is the partial pressure of the gas

Physiologically,

Anesthetic gases work based on partial

pressure in the brain, not fractional

concentration

Anesthetic gases work based on partial

pressure in the brain, not fractional

concentration !

The vaporizers are calibrated to deliver a set

partial pressure, NOT a set fractional

concentration!SEVO vaporizer only delivers 1% sevoflurane

when P atm= 760mmHg.

But it will always deliver(appr) the correct partial

pressure of sevoflurane at any altitude.

True for ALL vaporizers EXCEPT DESFLURANE

Getting agent from the anesthesia

machine into the brain so the patient goes to sleep!!!

Goal: achieve “steady state” of anesthetic partial pressures throughout the system

Vaporizer adds agent to the fresh gas flow at a fixed concentration

Fresh gas mixes with circuit gas (bag, tubing canister, piping), dilutes concentration of agent

Compartments equilibrate and concentration of agent in the circuit rises

Fractional concentration of agent leaving the

circuit is Fi (fraction inspired)

Fractional concentration of agent in the lungs is FA (fraction alveolar)

Initially, FA/Fi = 0 because Fa is a 0

No agent in the lungs yet

These compartments will also equilibrate over time

You will be at EQ when FA=Fi, or FA/Fi=1

Fast induction is defined as FA/Fi → 1 quickly

ANAESTHESIC

MACHINE BREATHING

CIRCUIT

LUNGS

ARTERIAL

BLOOD

VENOUS

BLOOD

BRAIN

FGF

FI

FA

Fa

Path of anesthetic

FFGO -is the fraction of inspired

anesthetic in the gas leaving the fresh

gas outlet.

T - is time.

τ - is a time constant.

The time constant is simply the

volume or “capacity” of the circuit

(VC) divided by the fresh gas flow (FGF) or τ = VC/FGF.

Concentration in the circuit (FI) will

rise according to first-order kinetics:

Concentration of (FA) will rise

analogous to Fi

FA -is the alveolar concentration

T - is time.

τ -is a time constant.

The time constant for raise of FA

concentration and equals FRC/VA

FRC-functional residual capacity

VA- minute ventilation

The time required for flow through a

container to equal the capacity of the

container.

TC is volume (capacity)/flow.

The time constant for the lungs is

FRC/Valveolar.

The time constant for the anesthesia circuit

is circuit capacity/FGF.

If 10 liter box is initially filled with oxygen and 5

l/min of nitrogen flow into box then,

TC is volume (capacity)/flow.

TC = 10 / 5 = 2 minutes ( 1 Time Constant)

So, the nitrogen concentration at end of 2

minutes is 63%.

O2 10 Lt5

Lt/min

2 Mts 4 Mts 6 Mts 8 Mts

63% 86% 95% 98%

N2

Time Constant at Lungs

Time Constants and Brain Equilibration

Time constant Brain Equilibration time

Isoflurane 3-4 mins 10-15 mins

Sevoflurane 2 mins 6 mins

Desflurane 2 mins 6 mins

Nitrous Oxide 2 mins 6 mins

equilibration with any tissue takes 3 time constants

a) The inspired concentration (FI)Inspired concentration - FA/FI

b) The alveolar ventilation (Valveolar)- Minute alveolar ventilation - FA/FI

- Larger the FRC - slows raise of alveolar concentration

c) The time constant

d) Anesthetic uptake by the blood

e) The concentration and second gas effects

1) Fresh Gas Flow rate:↑ FGF → ↑ speed of induction & recovery.

2) Volume of breathing circuit (apparatus dead space): incr. ↑volume → slower induction (dilution of anesthetic gases.)

3) Absorption by the breathing circuit: rubber tubing absorbs ˃plastic & silicon.

Increase in

Minute alveolar ventilation

Increases FA/FI

The change is greatest for

more soluble anesthetics

methoxyflurane - increases by 75%

isoflurane - by 18%

desflurane - by only 6%.

negative feedback that results

from respiratory depression

high ventilation → rapid

induction → hypoventilation

Increase FA/FI Decrease FA/FIComment

Low blood solubility High blood solubility

As the blood solubility

decreases, the rate of rise in

FA/FI increases.

Low cardiac output High cardiac output The lower the cardiac

output, the faster the rate of

rise in FA/FI

High minute ventilation Low minute ventilation The higher the minute

ventilation, the faster the

rate of rise in FA/FI

Factors that Increase or Decrease the Rate of Rise of FA/FI

Uptake from the lung = Blood solubility x Cardiac Output x [PA-PV]

Bar. pressure

50%O2

50%N2O2Lt

2Lt

4Lt

33%N2O

66%O2

3Lt

2Lt

1Lt

Uptake of half

of the N2O

38%N2O

62%O2

1Lt of N2O

1 Lt

50%O2 + 50%N2O

Ventilation Effect Inspired Gas

1.5Lt

4Lt

2.5Lt

The higher the inspired

concentration, the more rapid the

rise in alveol. concentration

.

The concentration effect is only significant for gases present in high

concentrations (e.g. nitrous).

.

Two components:

1.the concentrating effect 2.an augmented gas inflow effect

Administration of 70% nitrous oxide produces a more rapid rise in the

FA/FI ratio of nitrous oxide than

administration of 10% nitrous oxide

The FA/FI ratio for 0.5% halothane rises more rapidly when given with

70% nitrous oxide than when given with 10% nitrous oxide.

Concentration effect

Second gas effect

Factors raising the alveolar concentration (FA/FI )

a) The inspired concentration (FI)

b) The alveolar ventilation (Valveolar)

c) The time constant

d) Anesthetic uptake by the blood

e) The concentration and second gas effects

Factors determining uptake by blood

A. Solubility in blood

B. Cardiac Output

C. The mixed venous anesthetic concentration

d. Tissue uptake of anesthetic

Uptake from the lung = Blood solubility x Cardiac Output x [PA-PV]

Barometric pressure

U Lung = λB/G x Q x ((PA-Pvenous)

Barometric pressure

Fick equation

λB/G - blood:gas partition coefficient

Q - cardiac output

PA - alveolar partial pressure of anesthetic

Pv - mixed venous partial pressure of anesthetic

PB is barometric pressure.

Solubility is defined in terms of the partition coefficient

Partition coefficient is the ratio of the

amount of substance present in one phase compared with another, the two phases

being of equal volume and in equilibrium

[λB/G = CB ]

CG

Gas

Blood

Partition Coefficient = Ratio of Concentration

Concentrations Equilibirates

Partial pressure Equalize

CG =CB

PG = PB

Halothane

λB/G = CB = 2.5 = 2.5

CG 1

Equal volume

Partial pressures are equal but concentrations are not !!!

Blood has 50 balls of halothane/ml Gas has 20 balls of halothane / ml

Halothane blood / gas partition coefficient = 2.5

No net diffusion when

partial pressures are

equal.

Blood has 8 balls / ml desflurane Gaseous desflurane has 20 balls /ml

Desflurane blood / gas partition coefficient = 0.42

No net diffusion when

partial pressures are

equal.

Higher solubility (λB/G>1)= more agent in the blood and less in the gas phase.

A lower solubility (λB/G<1)= less agent in the blood and more in the gas phase.

Other partition coefficients:

-Brain:Blood, Muscle:Blood, Fat:Blood(describe movement of gas from one

environment to another)

Blood-GasBrain-

Blood

Liver-

Blood

Kidney-

Blood

Muscle-

Blood

Fat-

Blood

Desflurane 0.42 1.3 1.4 1.0 2.0 27

Nitrous oxide 0.47 1.1 0.8 — 1.2 2.3

Sevoflurane 0.65 1.7 1.8 1.2 3.1 48

Isoflurane 1.17 1.6 1.8 1.2 2.9 45

Enflurane 1.8 1.4 2.1 — 1.7 36

Halothane 2.4 1.9 2.1 1.2 3.4 51

Diethyl ether 12 2.0 1.9 0.9 1.3 5

Methoxyfluran

e15 1.4 2.0 0.9 1.6 38

PARTITION CO-EFFICIENT

The more soluble the anesthetic

The more drug will be taken up

by the blood

The slower the rise in alveolar

concentration

15

1.4

0.65

0.47Poor solubility Rapid induction

High solubility Slow induction

Greater the cardiac output

The more drug will be taken up

by the blood

The slower the rise in alveolar

concentration

Cardiac output is lowered

cerebral circulation

less maintained (shock)

Induction Induction

slower rapid

An increase in CO from 2 to 18 L/min

will decrease the alveolar anesthetic

concentration by augmenting

uptake, thereby slowing the rise of the FA/FI ratio.

B.Cardiac Output(Perfusion Effects)

More soluble anesthetics (halothane)

- effect is more prominent

Positive feedback - as inspired

concentration increases, greater cardiovascular depression reduces

anesthetic uptake and actually

increases the rate of rise of FA/FI.

The difference between partial pressure in the alveoli and that in venous blood

Partial pressure in venous blood depends on tissue uptake of anesthetic

At equilibrium, (no tissue uptake)

The venous partial pressure = arterial partial pressure = alveolar partial pressure

PA – PV = 0

Rate of rise of the mixed venous concentration depends on the tissue uptake of the anesthetic

AT EQUILIBRIUM

No

tis

sue

up

tak

e

PA

PV

PA – PV = 0

PA = PV

FA/FI

FAT

VRG

MG

4-8mts

2-6Hrs

3-4 days

1. The tissue/blood partition coefficient (tissue solubility)

2. The tissue blood flow.

3. The tissue anesthetic concentration

Tissue Uptake = Tissue solubility x Tissue blood flow x [Parterial - PTissue]

Atmospheric pressure

Gas

BloodTissue

Concentrations Equilibirates

Partial pressure Equalize

CG =CB = CT

PG = PB = PT

Equal volume

Brain has 19 balls halothane / ml Blood has 10 balls halothane / ml

Halothane brain / blood partition coefficient = 1.9

No net diffusion

when partial

pressures are

equal.

Brain has 11 balls N2O / ml Blood has 10 balls N2O / ml

N2O brain / blood partition coefficient = 1.1

No net diffusion

when partial

pressures are

equal.

Blood-GasBrain-

Blood

Liver-

Blood

Kidney-

Blood

Muscle-

Blood

Fat-

Blood

Desflurane 0.42 1.3 1.4 1.0 2.0 27

Nitrous oxide 0.47 1.1 0.8 — 1.2 2.3

Sevoflurane 0.65 1.7 1.8 1.2 3.1 48

Isoflurane 1.17 1.6 1.8 1.2 2.9 45

Enflurane 1.8 1.4 2.1 — 1.7 36

Halothane 2.4 1.9 2.1 1.2 3.4 51

Diethyl ether 12 2.0 1.9 0.9 1.3 5

Methoxyfluran

e15 1.4 2.0 0.9 1.6 38

PARTITION CO-EFFICIENT

The rate of rise in tissue anesthetic concentration is

proportional to tissue blood flow and inversely

proportional to the tissue capacity.

The tissue capacity = tissue solubility х tissue volume

Just as discussed for the lungs, the tissues have a time

constant too:

Time Constant = Tissue solubility x Volume

Flow

Equilibration of

the VRG complete

in 4 to 8 minutes

After 8 minutes,

the Muscle group

(MG) determines

most of uptake.

Once MG

equilibration is

complete Fat

group (FG)

determines the

uptake

Two important characteristics of

Inhalational anesthetics which govern

the anesthesia are :

Solubility in the blood(blood : gas partition co-efficient)

Solubility in the fat

(oil : gas partition co-efficient)

It indicates the amount of gas that is

soluble in oil phase.

It is a measure of lipid solubility of

anesthetic.

It is a measure of anesthetic potency

Higher the lipid solubility – potent anesthetic.

(e.g., halothane)

Meyer – Overton Rule

Anesthetic potency

correlates with lipid

solubility

Holds true across species

Because inhalation agents act through the lipid-rich

CNS cells, anesthetic potency increases with

lipid solubility.

OIL GAS PARTITION CO-EFFICIENT

Higher the Oil: Gas Partition

Co-efficient lower the MAC .

E.g., Halothane

1.4 220

0.8

Inhalation

Anesthetic

MAC value % Oil:Gas partition

Co

Nitrous oxide 104 1.4

Desflurane 6.6 19

Sevoflurane 1.8 47

Isoflurane 1.17 91

Halothane 0.75 220

Oil:Gas Partition Co-efficient and

MAC

At EQ:PA(alveoli)= Pblood =PCNS

Rapid transfer of gases:

alveoli > blood > CNS

F is proportional to P, so

1% SEV in the alveoli = 1% SEV in the CNS

At EQ, if you know PA of a gas, then

you know PCNS

Recovery from anesthesia, like induction, depends on:

anesthetic solubility- is the primary determinant of the rate of fall of FA

cardiac output

minute ventilation

Loss of inhaled anesthetics via skin, gastrointestinal viscera and the pleura are insignificant

The greater the solubility of inhaled anesthetic, the

larger the capacity for absorption in the bloodstream

and tissues.

The “reservoir” of anesthetic in the body at

the end of administration depends on:

1. Tissue solubility (which determines the capacity)

2. The dose

3. Duration of anesthetic (which determine how

much of that capacity is filled).

Low solubility→Rapid recoveryDesflurane>Sevoflurane>Isoflurane

Recovery from anesthesia, or

“washout,” is usually

expressed as the ratio of

expired fractional

concentration of anesthetic

(FA) to the expired

concentration at time zero

(FA0) when the anesthetic was discontinued (or FA/FA0).

During the 120-minute period after ending the

anesthetic delivery, the elimination of sevoflurane and

desflurane is 2 to 2.5 times faster than isoflurane or

halothane

The longer the duration of a highly soluble anesthetic, the greater

the reservoir of anesthetic in the body, and the higher the curve

seen in the right half( slow recovery)

INDUCTION RECOVERY

Induction can be accelerated by

Over Pressure( which offset solubility and uptake)

The inspired concentration

cannot be reduced below zero

All the tissues initially have the

same anesthetic partial

pressure—zero

On recovery, the tissue partial

pressures are variable

100%60% 10%

0% Recovery

As long as an arterial-to-tissue partial pressure gradient exists, muscle and fat will absorb anesthetic(especially fat).

After discontinuation of anesthesia, muscle and fat may continue to absorb anesthetic, even hours later.

The redistribution continues until blood/alveolar anesthetic partial pressure falls below tissue partial pressure.

1. Increased solubility slows recovery

2. Increasing ventilation may help the recovery

from potent agents

3. Prolonged anesthesia delays recovery

4. There is no concentration effect on

emergence

Diffusion hypoxiaAlso called as Fink effect.

Alveolar hypoxia can cause hypoxemia, and alveolar hypocarbia can depress respiratory drive, which may exacerbate hypoxemia

N2O

N- 79%

O2-21%O2-21%

N- 79%

N2O

O2-16%

N-70%

N2O-14%

PULMONARY CAPILLARY

MAC - is the alveolar concentration of

an anesthetic at 1 atm that prevents

movement in response to a surgical

stimulus in 50% of patients.

Analogous to the ED50 expressed for

intravenous drugs.

MAC value is a measure of inhalational

anesthetic potency.

AGENT MAC POTENCY

Methoxy-flurane 0.16% Most potent

Halothane 0.74%

Isoflurane 1.17%

Enflurane 1.7%

Sevoflurane 2.05%

Desflurane 6.0%

Nitrous oxide 104% Least potent

The lower the MAC– the more potent the agent!

Standard MAC values are roughly additive !!!

Administering 0.5 MAC of a potent

agent and 0.5 MAC of nitrous

oxide is equivalent to 1 MAC of

potent agent.

MAC effects for other response parameters are

not necessarily additive !!!

Combining 0.6 MAC of nitrous

oxide with 0.6 MAC of isoflurane

produces less hypotension than

1.2 MAC of isoflurane alone.

MAC awake: MAC allowing voluntary response tocommand in 50% of patients(0.15 – 0.5 MAC)

MAC 95%: MAC that prevents movement in 95 % ofpatients (1.2-1.3 MAC or +25% of MAC)

MAC intubation: MAC that allows intubation withoutmuscle relaxant, coughing or bucking in 50% ofpatients.

MAC-BAR (1.7-2.MAC or +50% of stand. MAC), whichis the concentration required to block autonomicreflexes to nociceptive stimuli.

MAC in Subjects Ages 30 to 60

Inhaled

Anesthetics

In O2 60%-70%

N2O

MACAWAKE MAC BAR

Desflurane 6.6% 2.83% 2.42% 1.45 MAC

Sevoflurane 1.8% 0.66% 0.61% 2.24 MAC

Isoflurane 1.17% 0.56% 0.39% 1.30 MAC

Halothane 0.75% 0.29% 0.41% 1.30 MAC

MAC decreases with

age - 6% per decade

(similar between agents)

MAC- is maximum at 6

months

Duration of inhaled anesth. administration

Gender

Type of surgical stimulation

Thyroid function

Hypo- or hypercarbia

Metabolic alkalosis

Hyperkalemia

And magnesium levels

Red-haired females have a 19% increase in MAC compared with dark-haired females. These data suggest involvement of mutations

of the MCIR(melanocyte stimulating hormone receptor) allele.

Classification of inhalational anaesthetics

Outdated Gases Volatile agents

Ether

trilene

Methoxyflurane

Cyclopropane

chloroform

Nitrous oxide

Xenon

Halothane

Enflurane

Isoflurane

Sevoflurane

Desflurane

Structural activity-relationship

2-chloro,bromo

1-trifluro ethane.

Methyl –isopropyl

ether.

2-fluro,1-trifluro

methyl ethyl ether.

2-chloro 1-trifluro

methyl-ethyl ether.

1-chloro ,fluro

2-difluro methyl-

ethyl ether.

All agents cause CBF, causing ICP(especially Halothane) and impair autoregulation of vascular tone( least with sefoflurane at<1MAC)

Volatile agents cerebral metabolic rate, N2O may

Desflurane and isoflurane at < 1 MAC can suppress status epilepticus while sevoflurane concentrations associated whith epileptiform EEG.

All agents SEP/MEP signals.(sensory-evoked potentials and motor-evoked potentials (MEPs).

All agents decreases CMRO2 :

Desflurane=Isoflurane=Sevoflurane>Halothane

Cerebral Metabolic Rate and Electroencephalogram

EEG an isoelectric-no further decreases in CMR are

generate, however:

Desflurane-induced isoelectric EEG reverts to

continuous activity with time, despite an unchanging

MAC, a property unique to Desflurane

All of the potent agents depress CMR to

varying degrees !!!

Isoflurane abolishes EEG activity at doses

used clinically, while Sevoflurane and

Desflurane at 2 MAC

Desflurane and Isoflurane at < 1 MAC

can suppress status epilepticus while

Sevoflurane concentrations associated whith

epileptiform EEG.

All of the potent agents increase CBF in a time-

dependent as well as dose-dependent manner !!!

Desflurane=Isoflurane=Sevoflurane<Halothane

The increase in CBF with increasing dose caused by the

potent agents occurs despite decreases in CMR -

cerebral uncoupling .

↓CMR→ vasoconstrictia (physiologicly), with VA

vasodilatory effect

Because the volatile anesthetics are direct

vasodilators, all are considered to diminish

autoregulation in a dose-dependent fashion.

Sevoflurane preserves autoregulation up to approx.1MAC.

At 1.5 MAC sevoflurane preserves better than isoflurane(This

may be a result of less of a direct vasodilator effect of

sevoflurane).

0.5 MAC desflurane reduced autoregulation and

isoflurane did not. At 1.5 MAC, both anesthetics

substantially reduced autoregulation.

Significant hypercapnia is associated with

dramatic increases in CBF whether or not

volatile anesthetics are administered.

Hypocapnia can blunt or abolish volatile

anesthetic-induced increases in CBF

depending on when the hypocapnia is

produced.

The increase in CBF→ ↑ICP

Isoflurane, sevoflurane and desflurane >1 MAC

produce mild increases in ICP, paralleling their mild increases in CBF.

All three potent agents may be used at appropriate

doses, especially with adjunctive and compensatory

therapies, in just about any neurosurgical procedure.

Isoflurane does not appear to alter CSF production, but may increase, decrease, or leave unchanged the resistance to resorption depending on dose.

Sevoflurane at 1 MAC depresses CSF production up to 40%.

Desflurane at 1 MAC leaves CSF production unchanged or increased.

In general, anesthetic effects on ICP via changes in CSF dynamics are clinically far less important than

anesthetic effects on CBF.

A common effect of the potent

volatile anesthetics has been a dose-related decrease in arterial

blood pressure

Primary mechanism to decrease

blood pressure with increasing dose

is lowering regional and systemic

vascular resistance.

Sevoflurane up to about 1 MAC results in minimal, if any, changes in

steady-state heart rate while

enflurane, isoflurane, and

desflurane increase it 5 to 10% from

baseline

Isoflurane, desflurane, and sevoflurane resulted in

a dose-dependent depression of myocardial function

with no differences between the three anesthetics.

Despite the small reduction in

baseline contractility, the

volative anesthetics did not

affect the ability of the

myocardium to respond to an

acute increase in cardiac preload.

Most of the volatile anesthetics have been studied

during both controlled and spontaneous ventilation.

Spontaneous ventilation(SV) reduces the high

intrathoracic pressures from positive pressure

ventilation.

The negative intrathoracic pressure during the

inspiratory phase of spontaneous ventilation augments

venous return and cardiac filling and improves cardiac

output and, hence, blood pressure.

SV is associated with higher PaCO2, causing cerebral

and systemic vascular relaxation. This contributes to an

improved cardiac output via afterload reduction.

It has been suggested that spontaneous ventilation

might improve the safety of inhaled anesthetic

administration because:

Concentration of a VA that produces

cardiovascular collapse > the conc. that

results in apnea.

Oxygen consumption is decreased approximately 10 to 15% during general anesthesia.

The distribution of cardiac output also is altered by anesthesia. Blood flow to liver, kidneys, and gut is decreased, particularly at deep levels of anesthesia.

- In contrast, blood flow to the brain, muscle, and skin is increased or not changed.

Sinoatrial node discharge rate is slowed by the volatile anesthetics. Conduction in the His-Purkinje system also is prolonged by the volatile anesthetics.

Isoflurane (and most other potent volatile anesthetics)

increases coronary blood flow many times beyond

that of the myocardial oxygen demand, thereby

creating potential for “steal.”

Steal is the diversion of blood from a myocardial bed

with limited or inadequate perfusion to a bed with

more adequate perfusion.

Neither isoflurane, sevoflurane, or desflurane at

concentrations up to 1.5 MAC cause steal effect.

There are only minor effects on decreasing minute ventilation.

The ventilatory effects are dose-dependent.

Their net effect of a gradual decrease in minute ventilation has been associated with increasing resting Paco2.

All volatile anesthetics decrease tidal volume

↓(TV) and increase respiratory rate ↑(RR)

Isoflurane does not

increase respiratory rate

above 1 MAC.

N2O increases respiratory

rate as much or more than

the inhaled anesthetics.

Desflurane results in the

greatest increase in

Paco2 .

In awake humans, changes in arterial CO2 such that

minute ventilation increases 3 L/min per a 10-mm Hg

increase in Paco2.

All inhaled anesthetics produce a dose-dependent depression of the ventilatory

response to hypercarbia!

The threshold at which

breathing stops, called the

apneic threshold.

It is generally 4 to 5 mm Hg below

the prevailing resting Paco2

Ing.Anesth., including nitrous oxide, produce a dose-

dependent attenuation of the ventilatory response to

hypoxia.

Has important clinical implications.

The short-acting sevoflurane and

desflurane may prove

advantageous - more rapid

washout and their minimal effect

on hypoxic sensitivity at

subanesthetic concentrations.

Bronchoconstriction under anesthesia occur:

direct stimulation of the laryngeal and tracheal areas

administration of adjuvant drugs that cause histamine

release

noxious stimuli activating vagal afferent nerves

The reflex response to these stimuli may be enhanced :

- in lightly anesthetized patients

- in patients with known reactive airway disease

including those requiring bronchodilator therapy

- chronic smoking histories.

Bronchoconstriction - via M2 and M3 muscarinic

receptors, which initiate increases in intracellular

cyclic guanosine monophosphate(cGMP).

Bronchiolar muscle relaxation – adrenergic β2-

receptors → an increase in intracellular cyclic

adenosine monophosphate(cAMP).

The volatile anesthetics relax airway smooth muscle primarily by directly depressing smooth muscle

contractility and indirectly inhibiting the reflex

neural pathway!

Volatile anesthetics have been used effectively to treat

status asthmaticus when other conventional treatments

have failed!

Sevoflurane may be a better choice.

Smokers have impaired mucociliary function compared

with nonsmokers.

and the combination of a volatile anesthetic in a smoker

who is mechanically ventilated sets up a scenario for

inadequate clearing of secretions, mucus plugging,

atelectasis, and hypoxemia.

Volatile anesthetics and nitrous oxide reduce ciliary movement and alter the characteristics

of mucus.

Inadequate hepatocyte oxygenation (oxygen supplyrelative to oxygen demand) is the principal mechanismresponsible for hepatic dysfunction following anesthesiaand surgery.

The liver has two blood supplies:

1 Hepatic artery(well-oxygenated).

2 Portal vein( poorly oxygenated).

Postoperative liver dysfunction has been associated with

most volatile anesthetics, with halothane receiving the

most attention.

HBF-Desflurane=Isoflurane=Sevoflurane<Halothane

The ether-based anesthetics

(isoflurane, sevoflurane, desflurane)

maintain or increase hepatic artery

blood flow while decreasing (or not changing) portal vein blood flow.

Halothane decreases in both

portal vein and hepatic artery

blood flow, thereby significantly compromising total hepatic artery

blood flow.

Altered liver function tests have been used as an

index of hepatic injury during anesthesia.

ALT, AST, GST

Increases in the ALT or AST are not uniquely

specific to the liver.

The centrilobular area of the liver is most

susceptible to hypoxia.

A more sensitive measure GST(α-glutathione S-

transferase), since it is distributed primarily in the

centrilobular hepatocytes.

The inhaled anesthetics have two important actions on neuromuscular function:

1. Directly relax skeletal muscle(nitrous oxide does not).

2. Potentiate the action of neuromuscular blocking drugs.

All of the potent volatile anesthetics serve as triggers for malignant

hyperthermia (MH)!!!

While N2O is considered safe in MH-susceptible

patients!!!

Uterine smooth muscle tone is diminished by volatile

anesthetics.

There is a dose-dependent decrease in spontaneous

myometrial contractility.

Uterine relaxation/atony can become problematic at

concentrations of volatile anesthesia >1 MAC, and

might delay the onset time of newborn respiration.

Consequently, a common technique used to provide

GA for urgent CS is to administer low concentrations of the VA, such as 0.5 to 0.75 MAC, combined with N20

Volatile anesthetics produce similar dose-related

decreases in renal blood flow, glomerular

filtration rate, and urine output.

These changes most likely reflect the effects of

volatile anesthetics on systemic blood pressure and

cardiac output.

Preoperative hydration attenuates or abolishes many

of the changes in renal function associated with

volatile anesthetics.

Physical properties: It is a laughing gas,colorless and odorless

It is only inorganic anesthetic gas in clinical use.

Non Explosive and Non Inflammable

Gas at room temperature and can be kept as a liquid under pressure.

It is relatively inexpensive.

low potency (MAC = 104%) and is relatively insoluble in blood

Nitrous oxide does not produce significant skeletal muscle relaxation, but it does have analgesic effects.

Elimination: almost 100% exhalation.

It causes post operative Nausea and Vomiting

Oxidizes Co atom in vitamin B12, inactivates

methinoine synthetase Affects myelin formation →peripheral neuropathies,

neurotoxicity.

Homocysteine accumulation

Inhibits thymidylate syntetase(DNA

syntesis)→teratogenicity.

Bone marrow depression-megaloblastic anemia

Air embolism

Pneumothorax

Acute Intestinal Obstruction

Tension Pneumocephalus

Tympanic membrane grafting

75% nitrous oxide can expand a pneumo-

thorax to double or triple its size in 10 and

30 minutes!!!

Physical Properties:

It is halogenated alkene.

Sweet, non-pungent.

Non Inflammable and Non explosive.

Least expensive .

CV: myocardial depression

- ↓BP and CO by up to 50%

- causes slowing of SA node conduction resulting in bradycardia

Resp: ↑RR, ↓↓TV, ↓MV, ↓↓hypercapnic drive, potent bronchodilator.

CEREBRAL:

It increases cerebral blood flow.

NEUROMUSCULAR:

Relaxes skelatal muscle and potentiates Non depolarizing neuro-muscular blocking agents.

RENAL:

Reduces renal blood flow, glomerular filtration rate and urinary output.

Hepatic

↓hepatic blood flow: impaired hepatic drug clearance.

-Liver oxidation→trifluoroacetic acid(TFA)

- 20% metabolised

- 1in 5 adults hepatotoxicity(lethargy, nausea,fever)

likely related to changes in HBF.

-”Halothane hepatitis”(rare): massive hepatic necrosis.

likely immune mechanism(eosinophilia, rash, fever)

Contraindications:

Unexplained liver dysfunction.

Intra-cranial mass lesions.

Hypovolemic patient with severe cardiac diseases

Isoflurane is a halogenated methyl ethyl ether

Clear, nonflammable liquid at room temperature.

Has a high degree of pungency.

It has become the “gold standard” anesthetic since its

introduction in the 1970s

Contraindications:

No such contraindication.

Patient with severe hypovolemia may not tolorate its

vasodilating effects.

It is the most potent of the volatile

anesthetics in clinical use.

Sevoflurane is a sweet-smelling, completely fluorinated methyl isopropyl ether

Non-pungent, low solubility- exellent for inhalation induction

+muscle relaxation(enough for peds intubation) potentiates NMBA.

Elimination:

-5%-liver metabolism

BaOH, soda lime- Compound A

-nephrotoxic in rats

-but has not been associated with renal injury in human volunteers or patients, with or without renal impairment, even when fresh gas flows are 1 L/min or less.

Very similar to Isoflurane in structure but much less

soluble, less potent.

Very high vapor pressure - requires special vaporizer.

- can boil at normal OR temperature.

- special vaporizer heats it to a gas and then blends it

with the FGF.

Desflurane is the most pungent

of the VA !!!

and if administered via the face mask results in:

coughing,salivation,breath holding,and laryngospasm.

Desflurane has the lowest blood:gas

solubility of the potent VA

Is an inert gas, difficult to obtain, and hence extremely expensive.

It has many characteristics approaching those of an “ideal” inhaled anesthetic.

Nonexplosive, nonpungent, and odorless, and thus can be inhaled with ease.

Its blood:gas partition coefficient is 0.14, and unlike the other potent VA , xenon provides some degree of analgesia.

Does not produce significant myocardial depression.

Because of its scarcity and high cost, new anesthetic systems need to be developed to provide for recycling of xenon.

Differential Physiologic Effects of Inhaled Anesthetics

N2O Halothane Isoflurane Sevoflurane Desflurane

HR or or

SVR

CO or or

Contractility

HBF

HBF- hepatic blood flow, HR- heart rate, CO-cardiac output, SVR-systemic vascular resist.,

and -slight or mild change, - significant decrease, - no change.