Inhalational Anaesthetics
Dr. Swadheen kumar Rout
2nd year P.G
Dept. of Anaesthesiology
M.K.C.G College & hospital
HISTORY:- Surgery Before Anesthesia
HISTORY:-
Surgical pain relief
• Alcohol
• Opium
• Unconsciousness (blow to head, strangulation)
No single individual can be said to have discovered anaesthesia.
The speciality of anaesthesia rests on discoveries made from several scientific disciplines. Major discoveries were often made by small groups of curious individuals with diverse backgrounds.
1773 - Joseph Priestly discovers N2O
1798 - Sir Humphrey Davy experimented with N2O, reported loss of pain, euphoria.
Recreational drug
1540 - ethyl ether was first created in a laboratory by a German scientist named Valerius Cordus,
Termed “laughing gas”
1830’s – 1840’s – Gardner Colton & othersInvolved in Nitrous oxide & ether fun and frolics.
1842 - Crawford W. Long –first used ether for neck surgery. Did not publicize, in part because of concerns about negative fallout from “frolics”. Tried to claim credit after Morton’s demonstration but…Important lesson learned – if you don’t publish it, it didn’t happen.
1844 - Nitrous oxide is used by Horace Wells for tooth extraction - demonstration at The Massachusetts General Hospital - deemed a failure because patient “reacted”. -
1846 – William Morton (apprentice under Horace Wells) First public demonstration of ether administration on October 16.
Dr. john collins warren painlessly removed a tumor from the neck of a Mr. Edward gilbert abbott.
He added a few harmless impurities to the ether to disguise its smell and named it the secret concoction Letheon.
His attempted disguise however failed - a patent was then useless, & no one had a financial claim on the use of ether, within months ether was being used in Europe and all over the United States
1847 - David Waldie at Edinburgh Medical school England suggested Chloroform as an alternative agent.
1853 – Dr. John Snow administers chloroform to Queen Victoria popularizes anesthesia for childbirth in UK.
1951 - Halothane was synthesised by Suckling and introduced into clinical practice in 1956.
1959 - 1966 - Terrell and colleagues at Ohio medical products synthesised more than 700 products .347th and 469th compounds were Enflurane & Isoflurane
1929 - Cyclopropane was discovered accidentally and was very popular for almost 30 yrs.
1990 - Sevoflurane was introduced into clinical practice initially in Japan. 1993 – Desflurane introduced ,- rapid onset and offset due to its low solubility in blood.
PHARMACODYNAMICS:- the study of drug action, including toxic responses, i.e - how a drug affects a body.
Mechanism of action:- still largely unknown
• "Anaesthetics have been used for 160 years, and how they work is one of the great mysteries of neuroscience,
• The effects of inhaled anaesthetics cannot be explained by a single molecular mechanism. Rather, multiple targets contribute to the effects of each agent.
• The immobilizing effect of inhaled anaesthetics involves a site of action in the spinal cord, whereas sedation hypnosis & amnesia involve supraspinal mechanisms.
• No comprehensive theory of anaesthesia describes the sequence of events leading from the interaction between an anaesthetic molecule and its targets to the behavioral effects.
Theories of Anaesthetic action:-
1) Lipid Solubility- Overton & Meyer rule
2) Alterations to Lipid Bilayers.
i) lipid perturbation – dimensional change - lipid phase transition, i.e: gel to liquid crystalline state ii) lipid-protein interactions
LIPID BASED PROTEIN BASED
Alteration to Protein Function
Molecular level
Lipid Solubility-
Unitary Hypothesis:- proposes that all inhalation agents share a common mechanism of action at the molecular level.
• Myriad of molecular species - Different size, different chemical properties
• This is supported by the observation that the anaesthetic potency of inhalation agents correlates directly with their lipid solubility – olive oil (Meyer–Overton rule).
Oil / gas partition coefficient X MAC = k(Constant)
- varies little over ~ a 100,000 fold range MAC
• There is a strong linear correlation between lipid solubility and anesthetic potency (MAC)
The lesser the MAC the greater the potency
i..e -the drug potency increases as the oil:gas solubility increases
The implication is that anaesthesia results from molecules dissolving at specific lipophilic sites, when a critical number of anaesthetic molecules occupy a crucial hydrophobic region resulting in the disturbance of the physical properties of cell membranes in CNS.
Meyer-Overton rule postulates that it is the number of molecules which are present at the site of action which is important and not their type thus, this hypothesis supports the additive nature of anaesthetic agents.
Exceptions to the Meyer-Overton Rule:-
1) HALOGENATED COMPOUNDS- Enflurane and Isoflurane are structural isomers and have similar oil:gas partition coefficients, however, the MAC for isoflurane is only ~ 70% of that for enflurane
• Complete halogenation, or complete end-methyl halogenation on alkanes & ethers results in decreased anaesthetic potency
2) CUTOFF EFFECT-• Increasing homologues of alkane series display a cutoff point, beyond which anaesthetic potency sharply decreases.• one postulate is that the larger members of a series are to large to fit into the "anaesthetic site“.
Increased lipid solubility increases anaesthetic potency
Alterations to Lipid Bilayers:-• Biological membranes consist of a cholesterol-phospholipid bilayer, having a thickness of ~ 4 nm.
• Peripheral proteins are weakly bound to the exterior hydrophilic membrane &integral proteins are deeply imbedded in, or pass through the lipid bilayer.
• Synaptic membranes are ~ 50:50 lipid bilayer & protein by weight.
Lipid perturbation:- Effects on Membrane Dimension
• Anaesthetic binding significantly modify membrane structure, effect is exerted through some perturbation of the lipid bilayer.
changes in curvature/elasticity
• Several types of bilayer perturbations were proposed to cause anaesthetic effect
changes in phase separation
changes in bilayer thickness
Critical volume hypothesis:-lipid bilayer expansion hypothesis
• Bulky and hydrophobic anaesthetic molecules accumulate inside the hydrophobic (or lipophilic) regions of neuronal lipid membrane causing its distortion and expansion (thickening) due to volume displacement.
• Accumulation of anaesthetic causes volume of the hydrophobic region to expand beyond some critical volume sufficient to reversibly alter function of membrane ion channels thus providing anaesthetic effect.
Changes in bilayer thickness:-
Greater the anaesthetic effect.
Actual chemical structure of the anaesthetic agent not important
Molecular volume more important
More space within membrane is occupied by anaesthetic
• Based on this theory, in 1954 Mullins suggested that the Meyer-Overton correlation with potency can be improved if molecular volumes of anaesthetic molecules are taken into account.
• This theory was supported by experimental fact that increases in atmospheric pressure reverses anaesthetic effect (pressure reversal effect).
Fluidization theory of anaesthesia-
Changes in phase separation:-
• Phospholipid membranes undergo a gel-liquid crystalline transition of the lipid matrix with increasing temperature , associated with an increase in the molar volume of the lipid.• Trudell et al. (1973) showed that in the presence of anaesthetic agents this transition occurs at a lower temperature, and over a wider temperature range.
An alternative proposal, is the "lateral phase separation hypothesis“
• NMR & ESR techniques,show anaesthetic agents cause a local disordering of the phospholipid matrix and reduce the number of molecules which simultaneously alternate between the gel & liquid crystalline states.
• Reducing such fluctuations, these agents thereby reduce the magnitude of fluctuations in volume which probably occur in dynamic biological membranes which allow conformational change in ion channels.
• Both the fluidization and lateral phase separation hypotheses suggest that anaesthesia results from making the membrane more disorganised or fluid.
• This anaesthetic-induced effect on lipids interacts in the basis of conformational changes in proteins that may be the basis for such membrane events as decreased permeability, ion gating, synaptic transmitter release, and transmitter binding to receptors resulting in anaesthetic action.
1) Stereoisomers of an anaesthetic drug have very different anaesthetic potency whereas their oil/gas partition coefficients are similar
.2) Certain drugs that are highly soluble in lipids, and therefore expected to act as anaesthetics, exert only one constituent of the anaesthetic action (amnesia) and do not suppress movement (and therefore were called nonimmobilizers).ex-fluorthyl
3) A small increase in body temperature affects membrane density and fluidity as much as general anaesthetics, yet it does not cause anaesthesia.
4) Increasing the chain length in a homologous series of straight-chain alcohols or alkanes increases their lipid solubility, but their anaesthetic potency stops increasing beyond a certain cutoff length .
All these lipid theories generally suffer from four weaknesses
Modern lipid hypothesis:-• States that anaesthetic effect happens if solubilization of general anaesthetic in the bilayer causes a redistribution of membrane lateral pressures.
• Each bilayer membrane has a distinct profile of how lateral pressures are distributed within it. Most membrane proteins especially ligand-gated ion channels are sensitive to changes in this lateral pressure distribution profile.
• General anaesthesia likely involves inhibition of the opening of the ion channel in a postsynaptic ligand-gated membrane protein.
• Oleamide (fatty acid amide of oleic acid) is an endogenous anaesthetic found in vivo (in the cat’s brain) and it is known to potentiate sleep and lower the temperature of the body by closing the gap junction channel connexion.
An example of how bilayer lateral pressure redistribution influences the ion-channel is
• Oleamide (fatty acid amide of oleic acid) is an endogenous anaesthetic found in vivo (in the cat’s brain) and it is known to potentiate sleep and lower the temperature of the body by closing the gap junction channel connexion.
Theories of Anaesthetic action:-
1) Lipid Solubility- Overton & Meyer rule
2) Alterations to Lipid Bilayers.
i) lipid perturbation – dimensional change - lipid phase transition, i.e: gel to liquid crystalline state ii) lipid-protein interactions
LIPID BASED PROTEIN BASED
Alteration to Protein Function
PROTEIN BASED THEORIES OF ANAESTHESIA:-
• In the early 1980s, Franks and Lieb demonstrated that the Meyer-Overton correlation can be reproduced using a soluble protein.
• These are luciferases, and cytochrome P450. Remarkably, inhibition of these proteins by general anaesthetics was directly correlated with their anaesthetic potencies.
• Demonstrated that general anaesthetics may also interact with hydrophobic protein sites of certain proteins, rather than affect membrane proteins indirectly through nonspecific interactions with lipid bilayer as mediator.
PROTEIN BASED THEORIES OF ANAESTHESIA:-
• Anaesthetics alter the functions of many cytoplasmic signalling proteins, including protein kinase C, however, the proteins considered the most likely molecular targets of anaesthetics are ion channels.• Bind directly only to small number of targets in CNS mostly ligand(neurotransmitter)-gated ion channels in synapse and G-protein coupled receptors altering their ion flux.• Cys-loop receptors are plausible targets for general anaesthetics that bind at the
interface between the subunits.
Inhibitory receptors (GABA A, GABA C, glycine receptors)
Eexcitatory receptors (Ach,5HT3 & glutamate NMDA receptor)
• Anaesthetics alter the functions of many cytoplasmic signalling proteins, including protein kinase C, however, the proteins considered the most likely molecular targets of anaesthetics are ion channels.• Bind directly only to small number of targets in CNS mostly ligand(neurotransmitter)-gated ion channels in synapse and G-protein coupled receptors altering their ion flux.• Cys-loop receptors are plausible targets for general anaesthetics that bind at the
interface between the subunits.
Inhibitory receptors (GABA A, GABA C, glycine receptors)
Excitatory receptors (Ach ,5HT3 & glutamate NMDA receptor)
Potentiation Inhibition
Effects Of Inhaled Anesthetics
Action of the inhaled agents on synaptic transmission may be due to alteration of either,
In summary, the predominant effects of the volatile agents cannot at present beexplained by depletion, production, or release of a single neurotransmitter.
MACROSCOPIC SITES OF ACTION:-
Anesthetic induced ablation of movement in response to pain is mediated primarily
by spinal cord..
Anesthetic induced amnesia is mediated by higher brain structures ( hippocampus).
Anesthetic induced sedation mediated by tuberomammillary nucleus of hypothalamus.
Measures of Anesthetic Potency:-MINIMUM ALVEOLAR CONCENTRATION:- MAC
• The minimum alveolar concentration of anaesthetic, at equilibrium, at 1 Atm pressure, which produces immobility in 50% of subjects exposed to a standard noxious stimulus, which, for humans is surgical incision of the skin.
• It is used as an index to measure the potency and relate the potency of other agents & provides a standard for experimental evaluations .
Rationale for this measure of anaesthetic potency is,
a) Alveolar concentration can be easily measured.
b) Near equilibrium, alveolar and brain tensions are virtually equal.
c) The high cerebral blood flow produces rapid equilibration.
• MAC represents only one point on the dose–response curve—it is the equivalent of a median effective dose (ED50) for IV drugs.
• 1.3 MAC of any of the volatile anesthetics prevent movement in about 95% patients surgical incision( ED95)
• The MAC values for different anaesthetics are roughly additive. For example, a mixture of 0.5 MAC of nitrous oxide and 0.5 MAC of halothane approximates the degree of central nervous depression of 1.0 MAC of isoflurane..
• In contrast to CNS depression, the degree of myocardial depression may not be equivalent at the same MAC: 0.5 MAC of halothane causes more myocardial depression than 0.5 MAC of nitrous oxide.
MAC VARIANTS:-• MAC Awake = MAC of anaesthetic that would allow opening of eyes on verbal commands during emergence from anaesthesia (0.3-0.4 MAC )
• MAC Intubation = MAC that would inhibit movement and coughing during endotracheal intubation.(1.3 MAC)
• MAC Bar = MAC of anaesthetic necessary to prevent adrenergic response to skin incision, as measured by conc. of catecholamine in venous blood (1.5 MAC) .
• When different agents are compared the ratio of MAC skin incision to MAC intubation or MAC awake is relatively constant.
Factors Which Affect MAC:-
Increase MAC
i) Hyperthermia - if > 42°C
ii) Hypernatraemia
iii) Drug induced elevation of CNS catecholamine stores. (amphetamine. Cocaine. Ephedrine. MAO inhibitors. Levodopa)
iv) Chronic alcohol / opioid abuse
Decrease MAC:-i) Hypothermia – (halothane MAC27°C ~ 50% MAC37°C)ii) Hyponatraemiaiii) Increasing age – (6% decrease in MAC per decade of age) iv) Hypoxaemia – (PaO2 < 40 mmHg)v) Hypotension – (MAP < 40 mm Hg)vi) Anaemia – (Hematocrit < 10%)vii) Pregnancyviii) CNS depressant drugs - opioids - benzodiazepines - major tranquilizers - TCA'six) Other drugs - lithium - lignocaine - magnesium-x) Acute alcohol abuse.
No Change in MAC:-
i) Sex, Species
ii) Weight, BSA
iii) Duration of anaesthesia
iv) Hypo/hyperkalaemia
v) Hypo/hyperthyroidism
• In Dehradun , the % MAC of sevoflurane will be higher than in puri, but the partial pressure will be the same (2 % X 760 = 15.2 mm Hg) which is constant.
• Atm. pressure decrease with altitude, so taking dehradun Atm. Pressure = 600 mm Hg, %MAC of sevoflurane = (15.2/ 600 = 2.5%)
• MAC is a concentration expressed as vol % but anaesthetic effect is produced by partial pressures.
PP = C * ATM
Pharmacokinetics:- Relationship between a drug’s dose, tissue concentration, and
elapsed time. (i.e- how a body affects a drug ).• Absorption.
• Distribution.
• Metabolism.
• Excretion.
Inhalational anaesthesia ultimate effect depends on attainment of a therapeutic tissue concentration in the central nervous system.
For a better understanding of the factors that govern induction and recovery from anaesthesia.
Some Basic concepts:-
Partial Pressure in gaseous phase
Partial pressure of a gas in a mixture of gases is the pressure it would have if it alone occupied the entire volume. This pressure is proportional to its fractional mass in the mixture of gases.
Partial pressure in Solution
Since pressure of a gas can only be measured in gaseous phase, while in solution we measure concentration as an indicator of amount of gas.
Partial pressure of a gas in solution, therefore refers to the pressure of the gas in the gas phase (if it were present) in equilibrium with the liquid.Why speak in
terms of partial pressure ?
Partial pressures assume importance because gases equilibrate based on partial pressures, not concentrations.
• A series of partial pressure gradients exists from the anaesthetic machine to brain tissue.
• Diffusion occurs from a region of higher concentration to a region of lower concentration (down a concentration gradient).
• Concentration of a gas is directly proportional to its partial pressure.
Pgas = Cgas x Atm Dalton's law of partial pressures
• FGF = Fresh Gas Flow
• FI = Inspired gas Concentration
• FA = Alveolar gas Concentration.
• Fa = Arterial gas Concentration.
2) Transfer from Inspired Air to Alveoli
3) Transfer from Alveoli to Arterial Blood
4) Transfer from Arterial Blood to Tissues
1) Transfer from machine to Inspired air
Anaesthetic gases administered via the lungs diffuse into blood until the partial pressures in alveoli and
blood are equal.
.
Transfer of anaesthetic from blood to target tissues also proceeds
toward equalizing partial pressures
Because gases equilibrate throughout a system based on partial pressures
Monitoring the alveolar concentration of inhaled anaesthetic provides an index of their effects in the brain
PALVEOLI=PBLOOD=PCNS
To put it in another way, faster rise in alveolar concentrations of a given anaesthetic herald a faster
induction
PBLOOD < A
PALVEOLI= A
PBLOOD = A
Pulmonary artery
Pulmonary vein = arterial blood
=
Pulmonary capillary
P inhaled = 2A
Equilibration is complete across AC membrane.
Induction
FACTORS AFFECTING INSPIRATORY CONCENTRATION (FI) :-
• The patient does not necessarily receive the same concentration set on the vaporizer as there are numerous intervening factors which vary the concentration.1) Fresh gas flow rate (FGF rate) = Depend on vaporizer & flowmeter settings
Higher the rate of FGF, closer the inspired gas concentration will be to fresh gas concentration.(FI =FGC). Induction can be accelerated with the use of high inflow rates
2) Breathing Circuit Volume: (apparatus dead space)
Smaller the volume, closer the inspired gas concentration will be to the fresh gas concentration.
• Avg. Volume of circle system is 4-5lts. Reservoir bag 2lts. Total vol. to wash out is 6-7lts.To wash out this vol. with FGF at 5lts/min may take 5-6minutes.
FI =FGC at 5-6mins
FACTORS AFFECTING INSPIRATORY CONCENTRATION (FI) :-
3) Circuit absorption: Rubber tubing absorbs plastic & silicon ˃
• Lower the circuit absorption, closer the inspired gas concentration will be to the fresh gas concentration.
4) The Effect of Rebreathing: Inspired gas is actually fresh gas + exhaled gas
• In rebreathing the inspired gas mixtures may be diluted by residual gases in the system
• Lower the rebreathing, closer the inspired gas concentration will be to the fresh gas concentration.
Clinically, these attributes translate into faster induction and recovery times.
FACTORS AFFECTING ALVEOLAR CONCENTRATION (FA) :-
Anaesthetic Uptake
Alveolar ventilation
Concentration Of
Anaesthetic agent
FACTORS AFFECTING ALVEOLAR CONCENTRATION (FA) :-
1) Uptake:- Alveolar membrane poses no barrier to the transfer of anaesthetic gases to pulmonary circulation.
• The FA / alveolar partial pressure determines the partial pressure of anaesthetic in the blood and, ultimately, in the brain which determines clinical effect.
Uptake
• FA depends on uptake of anaesthetic by pulmonary circulation. If this uptake is poor, whatever anesthetic is inspired is accumulating in the alveoli. thus FA increases rapidly towards FI . i.e. FA / FI =1.0
Greater the uptake
Slower the rate of rise FA
Lower the FA:FI ratio
Slower the rate of induction
• Fick’s equation:
VB = ∂b/g x Q x PA-PV / PB VB = Blood uptake
∂b/g = blood / gas partition co-efficient. Q = Cardiac output PA = Alveolar partial pressure Pv = Mixed venous partial pressure PB = Barometric Pressure
should any of these components = 0, then uptake will = 0.
Anesthetic uptake
Solubility in blood (blood/ gas partition coefficient)
Alveolar blood flow(Cardiac output)
Partial pressure difference between
alveolar gas & venous blood.
• The solubility of a gas in liquid is given by its Ostwald solubility coefficient.
SOLUBILITY OF THE AGENT:-
• Relative solubility of an anaesthetic in air, blood and tissues are expressed as partition co-efficients.
• Describes the relative affinity of an anaesthetic for two phases & each coefficient is the ratio of the concentrations of the anesthetic gas in each of two phases when equilibrium has been achieved.
• For example, halothane has a blood/gas partition coefficient of 2.4, indicating that at equilibrium, halothane‘s concentration in blood is 2.4 times its concentration in the gas (alveolar) phase.
• In another way , a value of 2.4 means that each ML of blood holds 2.4 times as much halothane as a ML of alveolar gas.
Blood has 48 balls of halothane / ml
Gas has 20 balls of halothane / ml
Halothane blood / gas partition coefficient = 2.4
No net diffusion when partial pressures are equal.
Partition Coefficients of Volatile Anesthetics at 37°c
Greater the co-efficient, more the solubility
More the solubility, greater the uptake
Greater uptake means longer time required for FA to approach FI
More the time required for FA to approach FI,
longer it takes for induction to be achieved.
N20 Halothane
ALVEOLAR BLOOD FLOW:-• In the absence of pulmonary shunting—is essentially equal to cardiac output.
• Determines the rate at which agents pass from gas to blood.
Cardiac output increases
Greater passage of blood through the lungs removes
more anesthetic
Uptake increases
longer time required for FA to approach FI
, Induction is delayed
This effect is greater with soluble agents (Eg.halothane) ˃ insoluble agents (N2O).
Children with shunt (F4) → rapid induction due to ↓ pulmonary blood flow.
Rt. to lt. shunts - A portion of the pul. blood flow will not come in contact with inspired gas..
Uptake decreases
faster FA to approach FI
Faster Induction
• Increased CNS anaesthetic concentration leads to reduced cardiac output. Reduced cardiac output as noted above, would be associated with a more rapid rise in FA/FI . • If we decrease blood flow (CO) by 50%, we
have the effect of concentrating the anaesthetic in that volume(less). In this case, arterial (in equilibrium with the alveolar anaesthetic), partial pressure would be doubled.
• The doubling in alveolar concentration(FA) would mean ultimately that the brain will "see" a double than expected number of anaesthetic molecules transferring in and so there is a greater likelihood of anaesthetic-mediated cardio-respiratory depression.
• Patients with shock - agents with relatively low blood: gas solubility might be preferable as the alveolar concentration(FA) of these agents would not be especially sensitive to cardiopulmonary changes.
• Nitrous oxide, a sparingly soluble agent, is often used in anaesthetic management in patients with shock.
In shock already reduced CO
Soluble agent further reduce CO
Rapid increase in FA
Concentration of inspired agent be decreased in anticipation
Partial pressure difference between alveolar gas and venous blood:-
• This gradient depends on tissue uptake. Tissues act like sponge absorbing anaesthetic agent. Movement of agent from blood into tissues is “distribution.”
• If no tissue uptake, the venous blood returning to the lungs would contain as much anaesthetic as it had when it left the lungs as arterial blood.( i.e- alveolar which equals arterial partial pressure & venous partial pressure become identical resulting in no uptake.
Encouraging greater alveolar uptake.
Tissues uptake from blood
Partial pressure of the anaesthetic in venous blood decreases relative to alveoli
Gradient between the alveoli and blood
Pvenous = Parterial = Palveolar
when tissues are saturated.Uptake stops when distribution stops, equilibration happens
• The transfer of anaesthetic from blood to tissues is determined by three factors analogous to systemic uptake:
1) Tissue solubility of the agent (tissue/blood partition coefficient),
2) Tissue blood flow,
3) Difference in partial pressure between arterial blood and the tissue.
• Tissues can be divided into four groups based on their solubility and blood flow
Highly perfused vessel rich group- Brain, Heart, Liver, Kidney, Endocrine organs- Limitations -moderate solubility, smaller volume- High perfusion -these tissues take
up first and get saturated. - Equilibration with arterial pp of
anaesthetic is> 90% complete with in 8 mts
Muscle Group- Skin, muscle- low perfusion - lower uptake- But due to -larger volumes -greater capacity-sustained uptake for hours. (Equilibration)
Fat Group- Final large reservoir of anaesthetic agent-Tremendous solubility of anesthetic leads to a total capacity that would take days to fill.
Vessel poor group - Tendons, ligaments, cartilage, teeth and hair.-No pharmacodynamic significance.
19/75=1/4 6/19=1/3
ANAESTHETIC UPTAKE GRAPH
• The initial steep rate of uptake is due to unopposed filling of the alveoli by ventilation.• The rate of rise slows as the vessel-rich group—and eventually the muscle group—reach their capacity
FACTORS AFFECTING ALVEOLAR CONCENTRATION (FA) :-
Anaesthetic Uptake
Alveolar ventilation
Concentration Of
Anaesthetic agent
Alveolar ventilation:-• Each inspiration delivers some anaesthetic to the lung and, if unopposed by uptake into the blood, normal ventilation would increase FA/FI to 95-98% in 2 minutes.
• Greater the FRC, the slower the rise in FA.
• FRC is less in supine position, pregnancy and obesity. ↓ FRC → Faster Induction and recovery
•The lowering of alveolar partial pressure(FA) by uptake can be countered by increasing alveolar ventilation.
Greater the Uptake
More needs to be replaced
Ventilation has to be increased
Increasing ventilation rapidly makes more sense for soluble anaesthetics as their uptake is faster. (is of little consequence if anesthetic is less soluble)
Effect of Concomitant Changes in Ventilation and Perfusion:-
If Cardiac output is doubled
Uptake (transfer from the alveolar volume to the blood) also be doubled
Reduce the rate of rise in FA/ FI by half
Ventilation rate were doubled
Rate of rise in FA/ FI would be doubled.
Effects should cancel each other .No change in FA/FI
Doubling anaesthetic delivery to the lungs
• This ignores one other factor in the equation that defines uptake. An increase in cardiac output accelerates the narrowing of the alveolar to venous partial pressure difference (PA-vGas) and thereby reduces the impact of the increase in cardiac output on uptake. • Thus, a proportional increase in ventilation and cardiac output increases the rate of rise of FA/FI.
Ultimately reducing uptake.
Tissues uptake from blood increased
Alveolar/mixed venous tension difference progressively falls as
tissue tension rises
Narrowing of Gradient between
the alveoli and blood (PA-vGas)
Cardiac output increased
Faster tissue equilibration with blood
Increases the rate of rise of FA / FI
Diffusion ∝ tension difference, the rate of diffusion SLOWS
PA=Pv =Ptissue
VA= ventilation Q= cardiac output
• The magnitude of the acceleration of rise in FA/FI depends in part on distribution of the increase in cardiac output. The effect is relatively small if the increase in cardiac output is distributed proportionately to all tissues (i.e., if cardiac output is doubled, all tissue blood flows are doubled)
Enhanced cardiac output and ventilation rate might be associated with thyrotoxicosis or hyperthermia. In this situation it is unlikely that a significant change in anaesthesia would be noted as a result of modifying FA/FI
Vessel-rich groups preferentially perfused
Rapid equilibration
Blood returning from the VRG has the same partial pressure as it had when it left lungs
PA = Pv
No PA-vGas gradient – No uptake Rapid rise in FA/FI
• In children, especially infants there appears to be a greater degree of vessel-rich tissue group perfusion compared to the adults. • So, in children and infants more rapid anesthesia development might be expected. • Additional factor is that there may be relatively higher CNS (brain) perfusion.
• Increased perfusion of vessel rich groups and increased ventilation rates will cause a more substantial FA/FI rate of rise.
Significant increase in halothane FA/FI rate of rise
FACTORS AFFECTING ALVEOLAR CONCENTRATION (FA) :-
Anaesthetic Uptake
Alveolar ventilation
Concentration Of
Anaesthetic agent
Concentration Of Anaesthetic Agent:-
• Increased uptake tends to decrease FA. To counter this, Inspired concentration can be increased. (“Over pressurisation”: analogous to Intravenous bolus)Two consequences of this are:-
Increasing FI increases FA
Increasing FI increases rate of rise of FA / FI
Concentration Effect results of two Phenomena: • Concentrating effect
• Augmented Inflow effect
“Concentration Effect”
N2O:80
O2
:20
N2O : 40
O2
:20
N2O 20
O2
:80
N2O 10
O2
:80
→ →
Concentrating effect:-
10/90=11% 40/60=67%
• The first one represents a lung containing 20% N2O (20 parts per 100 volumes gas) If 50 % of N2O (10 parts) is taken up the pulmonary
circulation, Remaining 10 parts N20 exist in a total gas of 90 parts, for a concentration of 11%• The 2nd one represents a lung containing 80% N2O (80 parts
per 100 volumes gas)
1) 2)
Inspired air
Alveolar air
Alveolar concentration will be 67% (40 parts N2O remaining in total volume of 60 parts gas)• Even though 50% of the anesthetic is taken up in both examples, increasing the inspired concentration 4-fold results in 6-fold increase in alveolar concentration( disproportionately higher alveolar concentration)• Anesthetic is concentrated following uptake because the remaining gases are “concentrated” in a smaller volume (CONCENTRATING EFFECT)
50% N20 taken up
50% N20 taken up
AUGMENTED INFLOW EFFECT:-
N2O 20
O2
:80
N2O 10
O2
:80
Inspired air
Alveolar air→
10/90=11%
50% N20 taken up
→Inspiration
CONTAINING 20% N2O, 80% O2
N20 10
O2 80
N20 2
02
8
89%
10 parts of absorbed gas(N2O) must be replaced by an equal volume of the 20% mixture to prevent alveolar collapse
Thus alveolar concentration becomes 12 % (10 + 2 parts of anesthetic in a total of 100 parts of gas)
N20 = 10+2/100 (12%)
• In contrast in the 80 % gas mixture, 40 parts of 80 parts N20 must be replaced by an equal volume of the 80% mixture, Replaced by 40 parts gas containing 80 % N20 (80% / 40 parts =32 parts N20)
Alveolar concentration becomes 40 parts N20 remaining + 32 parts N20 coming in total 100 parts of gas i.e 72%
• Alveolar concentration increases from 11% to 12% in 1st case & from 67% to 72% in 2nd case. this is augmented inflow effect.
Second gas effect:-
•The factors that govern the concentration effect also influence the concentration of any gas given concomitantly. The concentration effect of one gas upon another is called the second gas effect.
• This second gas effect applies to halothane or enflurane when it is administered with nitrous oxide.
• The loss of volume associated with the uptake of nitrous oxide concentrates the halothane or enflurane (2nd gas).
• Replacement of the gas taken up by an increase in inspired ventilation augments the amount of halothane or enflurane (2nd gas) present in the lung.
• Effect is more significant with nitrous oxide than with the volatile anesthetics, as the former can be used in much higher concentrations.
Second gas effect:-
50 % N20 taken up (40 PARTS)
Remaining total gas - 100 -40 = 60 PARTS
Concn. N20 = 40PARTS / 60 PARTS (66.7%) SECOND GAS = 1 PART / 60 PARTS (1.7%)
Replaced by 40 parts gas
Containing N20 : 80% / 40 part = 32% SECOND GAS : 1% / 40 part = 0.4 %
Uptake of half the N2O does not halve the concentration of N2O, and the reduction in volume thereby increases the concentration of the second gas.
Restoration of the lung volume by addition of gas at the same concentration will increase the N2O concentration & add to the amount of the second gas present in the lung.
Because of the large concn of N2O molecules administered, significant alveolar to blood transfer occurs despite relatively low solubility
• The FA/FI for nitrous oxide rose more rapidly when 70 percent nitrous oxide was inspired than when 10 percent was inspired (the concentration effect)
• Similarly, the FA/FI ratio for halothane rose more rapidly when 70 percent nitrous oxide was inspired than when 10 percent was inspired (second gas effect).
On the basis of blood: gas solubility, one might predict that desflurane should exhibit a more rapid rate of rise in FA/FI than N2O. N2O more soluble, more uptake so must be less alveolar concn than desflurane.
However, when one takes into account is substantially higher concentration of nitrous oxide delivered, the importance of the concentration effect is clear and is responsible for the rapid increase in FA/FI seen with nitrous oxide.
The clinical consequence of both concentration and second gas effects is to decrease induction time.
Factors Affecting Arterialconcentration (Fa):-
Ventilation/Perfusion Mismatch:-
• General assumption: Partial Pressure alveoli = Partial pressure arterial circulation( FA = Fa )
• Diseases such as emphysema and atelectasis, as well as congenital cardiac defects, produce substantial deviations from equilibration.
1) Ventilated non-perfused areas:
2) Perfused non-ventilated areas
↓ Parterial gas
i.e: the Alveolar–Arterial difference /gradient (PA-a gas) increases
(1) Increases the Alveolar (end-tidal) anaesthetic partial pressure (PAgas).
(2) Decreases the Arterial anaesthetic partial pressure.(Pagas)
Normal lung
PA gas = Pa gas
Non-ventilated lung
↑ PAlveoli gas↓ Parterial gas ↑PAlveoli-arterial gas
Ventilation/Perfusion Mismatch:-
Ventilation/Perfusion Mismatch:-
• The relative change depends on the solubility of the anesthetic.• With a poorly soluble agent, the end-tidal concentration (PAgas). is slightly increased, but the arterial partial pressure .(Pagas) is significantly reduced. The opposite occurs with a highly soluble anaesthetic.
For poorly soluble agents:
• Ventilation/perfusion ratio abnormalities increase ventilation relative to perfusion of some alveoli, whereas in other alveoli, the reverse occurs
increase in ventilation relative to perfusion does not appreciably increase the alveolar partial pressure issuing from those alveoli . When ventilation is absent(segment
of atelectatic lung)Blood from the segment has no additional anaestheticAnesthetic deficient blood mixes with Normal Anesthetic containing blood from the ventilated segments Mixing leads to dilutionSignificant reduction of Arterial partial pressure
For highly soluble agents: Initially increased Alveolar Partial Pressure (PAgas).
• Alveoli receiving more ventilation relative to perfusion, the Alveolar partial pressure rises to a higher level than usual.
Blood from these alveoli has increased anaesthetic content
Mixing with unventilated blood with no anaesthetic to maintain a near normal anaesthetic content in blood
Slight reduction of Arterial partial pressure
FACTORS AFFECTING ELIMINATION:-• Recovery from any anesthesia depends on lowering the brain anaesthetic concentration, indirectly rate at which the alveolar anaesthetic partial pressure declines. This elimination can happen secondary to
• Biotransformation (more with soluble agents)• Transcutaneous loss (minimal)• Exhalation (Most important)
Biotransformation:- Anaesthetic gas undergo metabolism which determins the rate at which the alveolar anesthetic partial pressure declines.
• Greatest impact is on the elimination of soluble anaesthetics that undergo extensive metabolism (eg, methoxyflurane).• The greater biotransformation of halothane compared with isoflurane accounts for halothane's faster elimination,even though it is more soluble. • The cytochrome P-450 (CYP) group of isozymes (specifically CYP 2EI) appears to be important in the metabolism of some volatile anesthetics.
Exhalation:- The most important route for elimination of inhalation anesthetics is the alveolus. Many of the factors that speed induction also speed recovery.
• Factors affecting the elimination of an anaesthetic agent are identical to those for uptake and distribution
Differences Between Induction and Recovery :-
• First, on induction, alveolar anaesthetic concentration can be raised by increasing the inspired anaesthetic concentration .No such luxury is available during recovery; the inspired concentration cannot be reduced below zero.
• Second, on induction, all the tissues initially have the same anaesthetic partial pressure = zero. On recovery, the tissue partial pressures are variable.
Recovery:-Recovery in general is faster than induction because apart from those compartments (brain) that take up anesthetic agent quickly, there are other compartments (eg: MG & Fat) which take up anesthetics slowly and therefore over a prolonged duration.
Implication is that long after administration of Inhalational agent is stopped, these compartments (fat) are still in process of saturating themselves by taking up anesthetic from blood.
Results in drop in Arterial partial pressure of anaesthetic
To equilibrate partial pressures blood tends to take up more anaesthetic from
the alveoli
Decrease in partial pressure of anaesthetic in alveoli
So with increased uptake, progressive decrease in alveolar partial pressure ensues
Hastens Recoverymore rapid than
induction
Recovery:-
Solubility:-
• If it is prolonged anaesthesia (>4 hours), there is enough time to saturate all compartments and consequently the rate of decline in alveolar partial pressures is less i.e. recovery takes a longer time.
Conclusion: Recovery depends on duration of anaesthesia
influences the rate at which the alveolar anaesthetic partial pressure declines.
During recovery exhalation clears anaesthetic from the alveoli lowering alveolar concentration.
Opposed by Alveolar – venous partial pressure gradient (drives anaesthetic into
alveoli)• A greater reserve exists in blood for the highly soluble agent—that is, far more anaesthetic is available at a given partial pressure for transfer to the alveoli thus opposing the lowering of alveolar concentration.
• Solubility affects the rate of fall in the alveolar partial pressure thereby affecting the rate at which recovery occurs.
• Poorly soluble agents( N2O,desflurane,sevoflurane) have a faster recovery compared to soluble agents (halothane, isoflurane) .
• This is one of the reasons why nitrous oxide is usually a component of an inhaled anaesthetic regimen. The rapid elimination of this component permits at least a portion of recovery to be rapid.
Desflurane solubility< sevoflurane solubilitiy
Diffusion Hypoxia:-
• N2O is 30 times more soluble than N2 in the blood.
• At the end of anaesthesia after discontinuation of N2O,(first 5-10 mins) N2O diffuses from blood into the alveoli much faster than N2 diffuses from alveoli into the blood.
↑ Total volume of gas in the alveolus
Dilutes alveolar oxygen and CO2
Directly affect oxygenation by displacing oxygen
Diluting alveolar CO2 decreases respiratory drive & hence ventilation.
HYPOXIA.
• Advisable to use 100% O2 after discontinuation of N2O (5-10 mins)
The ideal inhalational anaesthetic should have the following properties:
a) Rapid and pleasant induction and emergence from anaesthesia.
b) Rapid and easily identified changes in the depth of anaesthesia.
c) Adequate relaxation of skeletal muscles.
d) A wide margin of safety.
e) Absence of toxic or other adverse effects at normal doses.
f) High degree of specificity of action.
g) Technically easy to administer.
h) Useful for all age groups.
