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PHARMACOKINETICS OF INHALATION ANAESTHETIC AGENTS IN THE HORSE
45.
P~IAFUUGOKINETICS OF INHALAT IOB AXAESTHETTC AGZXTS IX TiIE TORS%
B. M.
Q.
Wearer
\rlellcoin? Comparative A n a e s t h e t i c s L a b o r a t o r y , Department o f V e t e r i n a r y S u r g e r y , U n i v e r s i t y o f B r i s x
P-harmacokinetics i s concerned. w i t h t h e f a c t o r s a f f e c t i n g t h e way
iii
,which the c o n c e n t r a t i o i i at thf: s i t e
rJf
a c t i o c v a r i a s with time f o l l o w i n g ir!jectic.r; o r i n h a l a t i o r , of a dru..
l'ha,-maccdgnarr.ics, cn t h e other. hand, i s a
s t u d y of t h e r e l a t i o n s h i ? between t h e c o n c 5 n t r a t i o n a t t h e s i t e of a c t i o n m d i t s e f f e z t . Tc fazi-l.ita-te phaririacoki.netic s t u d i e s , v a r i o u s models
have been i n t r o d u c e d .
"he
t e r n rnodei i s used. t o d e s c r i S e
scmething wkick behaves l i k e , b u t
~;:F;E
not necessarily i z i
any o t h e r way resemble, tl;e something thtLt i t i s a c t i n g like.
I t i s a s i m p l i f i c a t i o n o f tk.e s o m i t h i n g o r p o c e s s
i t i s designed
t3
imitate.
Exaniples o f n o i e l s used i n
pharmac okine t i c st u d i e s m e t h o s e cone errled w i t h
of
7 olumes
d i s t r i b u t i o n , e l e c t r i c analogues and 52.giI;d computer
models. E m p i r i c a l models are based o r s t r u s t u r e d o n o b s e r v z t i o n and expariment, and t h u s a r e q J a n t i f i o d
D;T
keing f i t t e d t o
e x p e r i m e n t a l data which i s u s u a l l y i n t h e f o r m of idasma concentratioas.
They a r e r e l a t i - e i y easy t o u s e , biit
hecaus-, t h e y a r s e m p i r i c a l , i . e . based. on o S s e r u a t i o n ,
they p e r t a i n o n l y
t o t h e circulnstances pre-irailing
w?ien t h e
This has t o b e l ~ o r n cj.n n i n d i f t h e y
2.zta were d b t a i n e d .
. i r e u s e d t o mzke p r e d i c t i o r i s , s i r i c e aiq c h a n g e in c i r c u m s t a r c e c o u l d i c v a l i d a t e th.t? n o d e 1 es botk. Beck ( 1 8 8 7 ) ar:d
Sear ( 1 3 P 3 ) h a v e laade c l 2 a r . Piodeli; d e v c l o T e d f r o i n t h e o r y , however, Zi?? t h e phy-
s i c l o g i c a l l y b a s e d oiies, 2 n d t h e y
.
SO
.
t h a n ti-e e r q . i r ; c a l
p r e d i . c t i o n s with more ce:rtai:!".g
They- a r e lie"
bt. xed t o n a k c
CI::
c o n v e n i e n t t? i:se,
cnes.
twza7xt, t h e y ha-re first
t o b e q u n n t i f i e 3 i n t e r m s o f t,li!, ph;*:;it:o-c!i?r.ii c a l F r o p e r t i w of t h e dr:iF;
m d -;hzn i- tel.liis o f ' t h e
Llr?;Tsi3?
0g12a? cl-,arac-
t e r < s t ? . c s (13Lke body; f o r e x a i ~ p l e , hccy c ; r c > o s i t i o n ,
s of t h e ; i i . i . ~ i . c . orgsas zcd t i s s u e s . To i , ~ t h i s foz dr,.igs t i l a ;
2cc:cunt has +.c 'Lie
t?.!:BT1
cf :
~ilss3Cia:Lion con..t m t s , e x c r . ? t i o n by t;.e kI.?ne-fs. a g e n t s , m c : e i n t h ? - bcti;,
irk i i i j e c t e i in-,o t,l::,
t-!!o
ir
factor:
1i srr ,
b3Cy
as p r c , t s i * i Siridiilg.
. .
?i Io t-.a;s f 3r~ia:L O C
and
T3,9wt\vi?l', ~;:tk: l n b a i 3 . t i o n r l the gas
t;iF,suF!
?artition coeffici-
e n t s f o r e a c h a g e n t ;ire t h e most, i m p o r t a n t o f t h e p h y s i c o c h e m i c a l j r o p a r t i e e , and p h y s i o i o g i cal m o d e l l i n g its ].ela t i v e l y s t r a i g h t - f o r w a r d and e a s i e r t h a n i s t h e c a s e Tor injected agents. This paper d e s c r i b e s t h e g e n e r s l p r l n c i p l e s involved
i n t h e u p t a k e , d i s t r i b u t i o n and n l i m i i i a t i o . ? of i n h a l e d a a e s t h e t i c +aiIts
in the horsa.
2 h y s i o l o g i c a l . l y based
model c o n c e = t s are used by way o f i l l u s t r a t i o n . The a g e n t s most commonly u s e d f o r i n h a l a t i o n n n a e s t h e i ii. iii
t n e h o r s e a t t h e p r e s e n t time a r e h a l o t h a n e and n i t r o u s
oxide.
T h e s e two a g e n t s w i l l f o r m t h e b a s i s o f t h i s
discussion.
47.
S e l e c t i o n of rn i n h a l a t i o n a g e n t o r a g e n t s for t h e h o r s e depends on t h e p r o p e r t i e s of e a c h a g e n t a v a i l a b l e and how t l ~ e s smatch up t o a ' t h e o r e t i c a l ' i d e a l one which would i n c l u d e all. t h e f o l l o w i n g f e a t u r e s : 1.
Low b l o o d g a s and body t i s c u e s o l u b i i i t y which e n a b l e s b r a i n t e n s i o n s t o be r a i s e d or lowered r a p i d l y according t c requirement. This i e a h i g h l y d e s i r a b l e f e a t u r e f o r t h e h o r s e
i n order
trJ
g e t t h s s u b j e c t a s l e e p q u i c k l y and sub-
s e q u e n t l y a c h i e v e emergence fron! a n a e s t h e s i a w i t h a minirrin p e r i o d o f d i s o r i e n t a t i o n and i n c o - o r d i n a t i o n . N i t r o u s oxide and cyclopropsne have low bloo?/gas and bra.in/blood s o l u b i l i t i e s which are good f e a t u r e s ( E g e r , 1974).
D i e t h y l e t h e r a ? d methoxyflurarie cn t h e
o t h e r h a n l a r e v e r y r , o l u b l e ir: blood and hence a r e u r d e s i r a b l e a g e n t s f o r tile h c r s e .
Chloroform
i.3
l.esa
s o l l i b l e , b u t h-.l!:)thans oven L e s s sc and is l y s c r i t e r i as 8
niedium z o l u b l e ager--t.
T k s s l u b i l i t y c.f h a l o t h a n e
i n hor:Se b l o o d . i s 1 - 7 6 (Web?, a n d Wezver, 1981). Er,Plurane and i s o f l u r a n e a r e l e s s soluble I n blood t h a n
is halothaxe.
A f i g u r c cf
2.3 f c r er-flurane i n t h e
h o r s e i s quoted by S t e f f e y e t d. (1977) frcm work by Giri.
Our p z e s e n t r e s u l t s , howa'v'e?, i n d i c a t e t h a t it
nag be lovler t h a n t h i s .
2.
h o w Minimum -klveolar r : o n c e n t r z t i , m (M.A.c.).
T h i s g j ves
the c c n c e n t r a t i o n re+.lred
i n t h e a1:re-
o l i t c p r e v e n t r e s p s n s e t o noxious s t i m u l i i n 50X of
48
s u b j e c t s (Eger, 1974).
The a c t u a l a l v e o l a r concen-
t r a t i o n r e q u i r e d i s u s u a l l y i n t h e o r d e r of 1.3 M.A.C. However, t h e lower t h e M.A.C.
t h e l e s s is t h e amount of
a n a e s t h e t i c r e q u i r e d t o produce t h e n e c e s s a r y d e p t h of a n a e s t h e s i a and t h i s i s obviously d e s i r a b l e i n t h e h o r s e Eger (1974) g i v e s M.A.C.
v a l u e s f o r man; f i g u r e s f o r
t h e h o r s e a r e given by S t e f f e y e t a l . (1977) a s 0.88
f o r h a l o t h a n e , 2.12 f o r e n f l u r m e and 1.3 f o r i s o flurane.
M.A.C.
i s t h e r e f o r e a measure of potency
which is high f o r h a l o t h a n e b u t u n f o r t u n a t e l y t h i s agent does n o t provide s p e c i f i c a n a l g e s i a .
Nitrous
oxide, on t h e o t h e r hand, i s n o t a p o t e n t a n a e s t h e t i c b u t is a good a n a l g e s i c .
3.
High s a t u r a t e d vapour p r e s s u r e ( S . V . t . ) . The importance of t h i s f e a t u r e i s t h a t it should be h i g h i n r e l a t i o n t o M.A.C.
For example, t h e S.V.F.
of h a l o t h a n e a t 20°C i s 243.3 mm Hg g i v i n g a concent r a t i o n of 32% whereas t h e S.V.P.
of methoxyflurane at
2OoG i s only 22.8 mm Hg so t h a t a l t h o u g h t h i s a g e n t
has a low M.A.C.,
t h e maximum c o n c e n t r a t i o n a v a i l a b l e
a t o r d i n a r y temperatures i s around 3%.
4.
Low t o n i l r e s p i r a t o r y and c a r d i o v a s c u l a r d e p r e s s i o n . Halothane does cause r e s p i r a t o r y and c a r d i o v a s c u l a r d e p r e s s i o n and s o i s n o t good i n t h i s r e s p e c t .
49 -
5.
Non-inflammability. Halothane is not inflammable and thus when it was introduced in the 1950's it provided a very good reason
for discontinuing cyclopropane.
6. Chemical stability. This applies in the main to inhalation agents in general.
Some metabolism and biotransformation does
take place but it represents such a small proportion of the agent administered that it can be ignored for practical purposes.
7. Non-toxic. This 2rovided an excellent reason f o r discontinuing chloroform when cyclopropane and then halothane became available; nevertheless this agent has left behind it a remarkably high record of successful use in the horse.
8. LOW cost.
This is an ideal not likely to be realised with agents presently used.
The cost of halothane, for
example, at around E l l per 250 mls, is n'ot inconsiderable but has become accepted in view of its value as a maintenance agent.
The uptake and distribution of inhaled anaesthetics is a complex process involving many factors and in this brief review of the general principles it will not be possible to describe them all in detail.
They are, however,
concerned with four features: 1.
The anaesthetic apparatus and breathing system.
2.
The ventilation of the lungs.
3.
The circulation
4.
The solubility of the anaesthetic agent or agents in
- tissue perfusion.
the body tissues.
Since horses usually weigh several hundred kilograms, circle or to-and-fro rebreathing systems are mandatory because of the practical difficulty of supplying the large minute volumes which would be required if non-rebreathing systems were used.
In addition, unacceptable levels of
operating theatre pollution would occur. Non-rebreathing systems have enjoyed much popularity in human and small animal anaesthesia mainly because inspired concentrations of anaesthetic are equivalent to the flowmeter and vaporiser settings and thus are known. In recent years there has been a revival of interest in rebreathing and closed systems generally, and much work has been done on the prediction of gas and vapour concentrations when, in particular, low fresh gas flows and truly closed systems a r e used.
The d i f f i c u l t y with r e b r e a t h i n g systems a r i s e s from a s s e s s i n g t h e d i f f e r e n c e between t h e composition of t h e f r e s h g a s flow i n t o t h e system, and t h e i n s p i r e d c o n c e n t r a t i o n s of oxygen and a n a e s t h e t i c a g e n t , s i n c e t h e s e a r e i n f l u e n c e d by a number o f f a c t o r s :
a.
Nitrogen.
There i s always l i k e l y t o b e some n i t r o g e n
i n t h e i n s p i r e d m i x t u r e , a l t h o u g h o f c o u r s e t h e r e is none i n t h e f r e s h gas flow. l i k e l y t o c o n t a i n a b o u t 18
A h o r s e b r e a t h i n g air i s
-
24 l i t r e s o f n i t r o g e n a t
a t e n s i o n of a b o u t 578 mm H g , and some o f t h i s is i n
t h e f u n c t i o n a l r e s i c u a l c a p a c i t y (F.R.C.).
According
t o t h e work o f Spence e t a l . (1981), even i f t h e system i s flushed with nitrogen-free
gas before conncetion t o
t h e p a t i e n t , t h e r e i s l i k e l y t o be some 20% o r more n i t r o g e n i n t h e r e s p i r e d mixture.
With t h e b e s t of
c i r c l e d e s i g n s t h i s may be reduced t o 5% w i t h h i g h f r e s h g a s flows.
Such f l o w s would be a t l e a s t 3 i i t r e s /
min f o r a human b u t , f o r t h e h o r s e , could be 24 l i t r e s / min, and t h u s u n a c c e p t a b l y h i g h .
Barton and Nunn
(1975) found that even i f p a t i e n t s b r e a t h e d n i t r o g e n f r e e g a s for 20 minutes b e f o r e connection t o a n i t r o g e n f r e e system, t h e c i r c l e c o n c e n t r a t i o n o f t h i s g a s c o u l d n o t be k e p t at l e s s t h a n 3%.
b.
The v o l a t i l e a g e n t , h a l o t h a n e .
Difficulty here a r i s e s
from t h e f a c t that i f t h e v a p o r i s e r i s o u t s i d e t h e c i r c u i t (V.O.C.)
t h e n t h e mass o f h a l o t h a n e t h a t needs
52.
to be delivered into the system at the beginning of an anaesthetic is high, i.e. about 1 litre of vapour p e r minute for the first 5 minutes or so if the inspir-
ed concentration of about 1% is to be maintained
(Spence et al., 1981).
This actually is not a real
practical problem in equine anaesthesia since initial
and even maintenance flows may be several litres/min and Fluotec (Cyprane) vaporizers for veterinary use are stated to give 8% and are likely to be delivering at least 6% vapour when turned to ' 8 % ' .
To avoid the need for initial high fresh gas flows, l o d resistance vaporizers in circuit ( V . 1 . c . )
developed and became popular for a time. well provided the vaporizer is
were
These work
very efficient and
provided the patient is breathing spontaneously.
c.
Nitrous oxide.
The addition of nitrous oxide is of
considerable value in adding an analgesic component to halothane.
Furthermore, at the start of the anaesthetic
its second gas and concentration effects are useful features. However, at all times, care must be taken to ensure the inspired mixture contains adequate oxygen and this is especially so when maintenance of anaesthesia continues after nitrous oxide has virtually equilibrated with the animal's tissues.
53.
Oxygen.
d.
If t h i s i s t h e sole c a r r i e r g a s for h a l o -
thane ( i . e .
t h e v o l a t i l e a g e n t ) , t h e r e is l i t t l e l i k e -
l i h o o d of a hypoxic i n s p i r e d m i x t u r e b e i n g a d m i n i s t e r e d b u t it should be remembered t h a t a v a r i a b l e amount of n i t r o g e n w i l l be p r e s e n t .
e.
Water vapour.
The e f f e c t o f t h i s , which s a t u r a t e s
e x p i r e d g a s , h a s n o t been f u l l y a s s e s s e d .
In g e n e r a l w i t h c l o s e d o r n e a r l y c l o s e d r e b r e a t h i n g systems, t h e e x p i r e d g a s which i s r e - i n h a l e d ,
even assuming
a l l t h e carbon d i o x i d e i s s a t i s f a c t o r i l y removed, w i l l ,
a f t e r t h e f i r s t few minutes, c o n t a i n some a n a e s t h e t i c . The a c t u a l amount i s dependent on t i s s u e uptake which i n t u r n v a r i e s with time. amount o f n i t r o g e n .
It w i l l also contain a v a r i a b l e
Thus, as i n h a l a t i o n p r o c e e d s , i t can
be expected t h a t i n s p i r e d oxygen (FI02) w i l l b e l e s s t h a n that of t h e f r e s h gas flow. A l s o t h e i n s p i r e d a n a e s t h e t i c
c o n c e n t r a t i o n (P,an)
will be g r e a t e r t h a n t h a t o f t h e
f r e s h g a s Plow w i t h a lob s o i u b i l i t y a g e n t such as n i t r o u s oxide o r i f a V.1.C.
i s used.
P a r t i c u l a r c a r e h a s 'to be
t a k e 1 t h e r e f o r e , a s .inhalation continues, t o ensure t h a t the
FI02
i s s a t i s f a c t o r y and t h a t t h e PIan
dces n o t r i s e
above t h e i n t e n d e d c o n c e n t r a t i o n of t h e v o l a t i l e a g e n t .
In a d d i t i o n t o t h e b r e a t h i n g s y s t w i , t h e iuptake, d i s t r i b u t i o n and :wbseqiient; e l i n j n a t i o n o f i n h a l e d a a e s t n e t i c s i? dependcnt upon a c.mtir.uoa:: i n t e r a c t i o n of
54.
t h e v e n t i l a t i o n o f t h e l u n g s , t i . s s u e p e r f u s i o n and t h e solubility
of t h o a n a e s t h e t i c iri. t h e t i s s u e s .
A g r e a t e - u n d e r s t a n d i n g of t h e p r o c e s s e s involved can
be achieved a s a l r e a d y mentioned by t h e u s e of p h y s i o l o g i c a l models.
This approach t o t h e s t u d y o f t h e pharma-
c o k i n a t i c s of i n h a l e d a n a e s t h e t i c a g e n t s i s n o t a new one and Kety (1951) i n h i s c l a s s i c p a p e r e n t i t l e d “The Theory and A p p l i c a t i o n o f t h e Exchaige o f I n e r t Gas a t t h e Lungs aqd T i s s u e s + ’ , i n c l u d e s a comprehensive r e v i e w o f all r e l a t e d e a r l i e r . work.
Kety s i m p l i f i e d t h e p h y s i o l o g i c a l s i t u a t i o n by h a v i n g
a s i n g l e compartment model, n o t i n c l u d i n g t h e l u n g , r e p r e s e x t i r i g a l l t h e body t i s s u e s w i t h a volume e q u a l t o t o t a l body volume, and
E
perfusion equal t o t h e czrdiac output.
I n t h i s way he bad a s i n g l e t i s s u e t e n s i o n .
K e t y ’ s eqxa-
t i o n , d e r i v e d from h i s mathematical model, showed t h a t t h e a r t e r i a l t e n s i o n o f a n a e s t h e t i c approaches t h a t of t h e i n s p i r e d t e n s i o n i n t h e f o r m o f two e x p o n e n t i a l decays w i t h d i f f e r e n t t i m e c o n s t a n t s and amplitudes.
These a r e
f u n c t i o n s o f .the a l v e o l a r and body volumes, a l v e o l a r v e n t i l a t i o n , c a r d i a c o u t p u t and t i s s u e s o l u b i l i t y of t h e anaesthetic.
K e t y + s s i m p l e s i n g l e compartment model
severely l i m i t s t h e accuracy o f p r e d i c t i o n s , but h i s complex mathematical e q u a t i o n developed t h e c l a s s i c a l upt a k e curve w i t h i - t s v a r i a t i o n s for low and h i g h s o l u b i l i t y anaesthetics.
I t a l s o made c l e a r f o r t h e f i r s t time t h s
r e l a t i v e irnportance o f t h e v e n t i l a t i o n of t h e l u n g s , t h e c a r d i a c o u t p u t and t h e b l o o d / g a s p a r t i t i o n c o e f f i c i e n t s .
55.
Copperman, as c i t e d by Kety (1951),
developed K e t y ' s equa-
t i o n t o a l l o w f o r any number o f t i s s u e s , and as a r e s u l t h i s model c o n t a i n e d many e x p o n e n t i a l s .
T h i s made t h e
s o l v i n g o f t h e e q u a t i o n f o r any s i i e c i f i c s i t u a t i o n i m p r a c t i . c a b l e w i t h o u t t h e a i d o f a computer.
Price e t a l .
(1960) were t h e f i r s t workers t o u s e a computer i n s t u d y -
i n g t h e problem of t h e d i n t r i b u t i o n of a n a e s t h e t i c s i n -:he body, a l t h o u g h t h e y s t u d i e d thiope.ntone and n o t i n h a h d anaesthetics.
Since thm, a number o f workers have s t u d i e d
mathematical models of %he u p t z k e and d i s t r i b u t i o n a n a e s t h z t i c s n o t a b l y Plaplescn ( 1 963).
of
I t wes r e a l i s e d
t h a t a sirn2le e l e c t r i c a l c i r c u i t c o n s i s t i n g of c a 2 a c i t o r s and r e s i s t o r s c o u l d b e a r r a r g e d s o t h a t t h e movement o f
e l e c t r i c i t y represented t h e d i s t r i b u t i c n of anaesthetic i n t h e body as i l l u s t r a t e d by t h e c l e c t r i c analogue o f Mapieson (1971) i n F i g u r e 1 . storage capacity
Each c a p a c i t o r r e p r e s e n t s t h e
of a body compartment, and each r e s i s t o r
r e p r e s e n t s e i t h e r t h e v e n t i l a t i o n cr t h e blood f1c.w t i m e s t h e blood-gas p a r t i t i o n c o e f f i c i e n t o f t h e a n a e s t h e t i c . W i t ' n . t h a wide v a r i e t y o f s i z e s c f c a p a c i t o r s and r e s i s t o r s
a v a i l a b l e commercially, Mapleson h a s been a b l e t o cons t r u c t h i s e l e c t r i c a l a7alogue i n such a way t h a t has enabled him t o u s e i t t o compute q u a n t i t a t i v e l y t h e approach t o e q u i l i b r i u m o f t h e l u n g t e n s i o n ( i . e . o r a r t e r i a l tension) with the ins?ired tension.
alveolar T h i s has
been c a r r i e d o u t € o r a number o f a n a e s t h e t i c s where t h e inspired
t e n s i o n i s k e p t c o n s t a n t , as shown i n F i g u r e 2.
56.
The time scale is logarithmic and it can be seen that the low soluSility age,itnitrous oxide does approach equilibrium fairly quickly, although full equilibrium in fact fakes several h o u r s .
A similar approach to equilibrium
with the medium soluble agent halothane takes several hours, and full equilibrium would only be reached if the anaesthetic were to be continued for several days.
The
failure of trichlorethylene to equilibrate is due to account being taken of th2 considerable metabolism this a g x t undergoes. Foll.owing the work of Ccpperman, Mapleson (1963) initially used an eight compartment model but he found that, with his analogue models, equally good agreement could be obtained using a three compartment model.
The
comgartrnents represent body tissues grouped together on the basis of perfusion End tissue/blood partition coefficients. These compartments, in addition to the lungs, are:1.
The vessel rich or visceral compartment, i.e. brain, heart, lungs, liver and kidneys.
2.
The vessel poor or lean compartment, represented mainly by muscle and skin.
7.
Adipose tissue, the very poorly perfused fat.
Kapleson has also used his electric analogue to compute quantitatively results for specific situa%ions such as a change in cardiac output or in ventilation.
Eowever,
not everyone, and certainly not every anaesthetist, has the
57.
n e c e s s a r y knowledge o f e l e c t r i c i t y f o r t h i s analogue t o r e p r e s e n t something which is familiar t o him o r h e r . F o r t h i s r e a s c n , Mapleson (1970 and 1972) developed a n o t h e r b a s i c a l l y simple znalogue model, t h e , d a t e r analogue, and s i n c e t h e p r i n c i p l e o f t h i s o r e r e s t s on t h t f a c t t h a t w a t e r f i n d s i t s own l e v e l , i t i s r e a d i l y inrlerstood by everyone ( P i g u r e 3 ) .
This nodel is e x c e l l e c t f o r v i s u a l -
i z i n g t h e d i s t r i b u t i o n o f i n h a l e d a n a e s t h e t i c s i n t h e body a n d , a l t h o u g h it h a s been more d i f f i x i t t o do t h a n with
t h e e l e c t r i c analogue, Mapleson h a s made t h e diagrams cf h i s water analogue model f u l l y q u a z t i t a t i v e i n terms rlf tine t o t a l body volume and how it i s s h a r e d amongst t h e t i s s u e s , a l v e o l a r v e n t i l a t i o n , t o t a l c a r d i a c oxitput and how t h i s i s s h a r f d amongst t h e t i s s u e s , and t h e s o l u b i l i t y o f t h e *-aesthetic
i n blood and t h e o t h e r t i s s u e s o f t h e
body. I t can be s e e n as a l r e a d y d 2 s c r i b e d f c r t h e e l e c t r i c analogue t h a t t h i s i s a t h r e e conpartmest model p l u s t h e lungs.
The 'mouth' vessel s e e n as overflowing, r e p r e s o n t s
a constant inspired tension of 'water'
0-
anaesthetic.
When t h e lower t a p i a opened t h e water (representj-iiE; t h e a n a e s t h e t i c ) f l o w s i n t o t k e l u n g vessel, arLd the p i p e c o n n e c t i n g t h e 'mouth' and ' l u n g ' vefisels r s p r e s e n t s t h e v e n t i l a t i o n which conveys t h e a n a e s t h e t i c t o t h e l u n g s . The o t h e r p i p e s r e p r e s e n t t h e blood f l o w s conveying a n a e s t h e t i c from t h e l u n g s t o t h e t h r e e body compartments. The v i s c e r a l compartment ( h e a r t , l i v e r , b r a i n , k i d n e y s ) i s r e p r e s e n t e d by a small v e s s e l and a l a r g e p i p e t h u s t h e
58..
a n a e s t h e t i c t e n s i o n h e r e follows t h e l u n g t e n s i o n very closely.
The l e a n o r v e s s e l poor compartment i s r e p r e s -
ented by a l a r g e c a p a c i t y v e s s e l and a small p i p e conveying the anaesthetic t o it, thus the anaesthetic l e v e l i n t h i s compartment can r i s e o n l y s l o w l y , and l a g s far behind t h e a n a e s t h e t i c tensi.on I n t h e lung v e s s e l .
This
i s l i k e l y t o be a g r e a t e r f a . c t o r f o r t h e h o r s e t h a n f o r
=an and o t h e r a n i m a l s , s i n c e muscle p e r f u s i c n i n t h e h c r s e is lower %ban i n o t t e r a n i m a l s which have been s t u d i e d , =id
v e r y l o w Fndaed d u r i n g a a a e s t h e s i a (Veaver and Staddon,
1984).
The f a t conpzrtm=.nt can be d e s c r i b e d as similar t o
t h e n u s c l e compartment i n havirig a l a r g e c a p a c i t y a n d a poor p e r f u s i o n , o n l y much more s o .
A s a n a e s t h e s i a proceeds
e q u i l i b r a t i o n e v e n t u a l l y o c c u r s beveeen a l i t h e compartments m d t h e i n s p i r e d t e n s i o n o f a n a e s t h e t i c and t h i s can 'be r e a d i l y a p p r e c i a t e & i n . t h e water analogue.
Figure
4 shows hcw d i f f e r e n t v e r s i o n s o f the water analogue model
can r s p r e s e n t t h e d i s p o s i t i o n o f a p o o r l y s o l u b l e mazst h e t i c and one which i s n i g h l y s o l - J b l e . The p r o p o r t i o n o f t h e p i p e s t r a n s p s r t i n g a n a e s t h e t i c t c t h e compmtments and t h e r e l a t i v e s i z e s o f t h e v e s s e l s a r e maintained i n b o t h v e r s i o n s .
For the highly soluble
m a e s t h e t i c , however, t h e y a r e l a r g e r a l t h c u g h t h e s i z e o f t h e v e n t i l a t i o n p i p e remains t h e s m e .
Thus i t i s
immediately c l e a r t h a t f o r a. h i g h l y s o l u b l e a n a e s t h e t i c ,
a much l a r g e r q u a n t i t y o f t h e a n a e s t h e t i c h a s t o e n t e r t h e body t h a n w i t h
a low s o l u b i l i t y a g e n t b e f o r e e q u i l i b r a t i o n
w i t h t h e i n s p i r e d t e n s i o n can be approached.
With a low
59.
solubility agent like nitrous oxide, therefore, it is relatively easy to raise the brain (visceral) tension. sowever, with both low ana high sclubility anaesthetics, the pip$ supplying the visceral compartment (and hence the brain) is large and so, in both cases the visceral (brain) tensioa fcllo3h's, fairly cloee?.y,the lung tension.
With
the high solubility agent, drainage away to the muscle and fat compartment occurs more quickly than with the low solubility agent since the pipes supplying these vessels for this situation are comparable in size to the ventilation pipe. When administering an inhaled anaesthetic to an individual there is a certain inspired concentration of the agent required to maintain anaesthesia at a certain depth once equilibration with the inspired tension is approached. Initially, however, when using a high or medium solubility agent, the tension in the visceral compartment is slow to rise and the anaesthetist can overcome this problem by using the technique of 'overpressure' (Eger, 1974) as illustrated by another version o f the water analogue (Figure 5).
A high inspired tension is used to raise the
l u n g and fience brain tensions rapidly.
Once the desired
level is achieved, the inspired tension must be reduced (represented by a dotted line, Figure 5) to a level which will just balance the drainage away to the muscle and fat compartments and cleaxly must be further reduced as anaesthesia proceeds and these compartments progressively fill UP. Thus during anaesthesia with the medium soluble agent
60.
h a l o t h a n e , t h e l u n g and t h e r e f o r e brain t e n s i o n s o f a n a e s t h e t i c l i e somewhere between t h a t of t h e i n s p i r e d t e n s i o n and t h a t o f t h e muscle compartment.
If t h e r e i s
an i n c r e a s e i n v e n t i l a t i o n , t h e l u n g s a r e p u t i n t o b e t t e r communication w i t h t h e i n s p i r e d t e n s i o n and, a c c o r d i n g l y , t h e l u n g and hence b r a i n t e n s i o n s r i s e and t h e h o r s e becomes more d e e p l y a n a e s t h e t i s e d .
Respiratory depression
t h e n o c c u r s and tine c o n s e q u e n t i a l red-dcti;n i n v e n t i l a : , i o ~ r e s u l t s i n a l i g h t e n i n g of t h e l e v e l of a n a e s t h e s i a .
s o l o n g as t h e m i m a 1
i3
dence,
b r e a t h i n g spontanaously, a some-
v h a t p r o t e c t i v e , n e g a t i v e feedback system c p e r a t e s . I f , however, under t h e same c i r c u n s t a n c e s , r e s p i r a -
t i o n s a r e c o n t r o l l e d , t h i s n e g a t i v e feedback system i s l o s t , and w i t h deepening a n a e s t h e s i a t h e c a r d i a c o u t p u t w i l l fall.
T h i s w i l l have t h e e f f e c t of r e d u c i n g t h e
p e r f u s i o n t o t h e muscle and f a t compartments b u t p e r f u s i o n t o t h e b r a i n may be mainta.ined by t h e a u t o - p e r f u s i o n regul a t i n g mechanism.
When t h i s h a p p a r s t h e n e g a t i v e f e e d -
back mechanism i s r e p l a c e d by a p o s i t i v e feedback one and a n a e s t h e s i a can e a s i l y become d a n g e r o u s l y deep.
A
r e d u c t i c n i n c a r d i a c ouC,put l e a d s t o a deepening o f anaest h e s i a and t h i s i s f r e q u e n t l y s e e n i n a n a e s t h e t i s e d h o r s e s when i t i s n e c e s s a r y t o t u r n them from one s i d e t o t h e o t h e r ; w h i l s t on t h e i r backs, venous r e t u r n t o t h e h e a r t is r e duced by t h e weight of t h e abdominal c o n t e n t s , hence c a r d i a c o u t p u t i s r s d u c e d and a n a e s t h e s i a becomes d e e p e r . Changes i n v e n t i l a t i o n and i n t h e c a r d i a c o u t p u t can
51.
t h e r e f o r e have a marked e f f e c t wi-th a rredium s o l u b l e agerit s-och as h a l o t h a n e .
I t i s i n t e r e s t i n g t o n o t e t h a t as long
ago as 1924, Haggarc showed e x p e r i m e n t a l l y t h a t t h e r a t e o f u p t a k e and e l i m i n a t i o n o f t h e h i g h l y soluble a g e n t d i -
e t h y l e t h e r wzs a l m o s t e n t i r e l y dependent on t h e v e n t ilation.
On t h e o t h e r hand, w i t h a p o o r l y s o l u b l e a g m t
such as n i t r s u s o x i d e , t h e v i s c e r a l ( b l a i n ) and lung t e n s i o n s remain allout equal t o t h e i n s p i r e d t e n s i o n f o r
much o f t h e d u r a t i o n o f a n a e s t h e s i a , and s o long as r e s p i r a t i c n s do n o t s t o p c o m p l e t e l y , changes In v e n t L i a t i o n anc. c i r c u l a t i o n have v e r y l i t t l e e f f e c t .
In a n a e s t h e t i s e d horses, l a r g c a l v e o l a r - a - t e r i a l t e n s i o n d i f f e r e n c e s o r shzn-ts have been shown t o occur (Weaver and Wally, 1975) m d right t o l e f t s h u n t can be i l l u s -
t r a t e d w i t h t h e water analogue (Figu.re 6 ) .
It can bc
s e e n t h a t t h e e f f e c t i s t o mix up t h e compartments scmewliat and t o reuiice t h e t e n s i o n ciiffererizes betw::en
thex.
The si;nple 2-rIalogue p h y s i u l o g i c a l models c m t e a g r e a t helip
ii;
understanaing t h e d i s t r i b u t i o n of ir-haled
a n a e f i t h e t i c s i n t h e body and, p r o p e r l y q u a n t i f i e d , t h e y a r e c a p a b l e o f computirig a c z u r a t e l y t h e d i s t r i b u t i o n p a t t e r n s t h a t occur.
They do, howeve:.,
h ~ v el i m i t a t i c n s
.
F o r exanple :-
:.
They dc n o t r e p r e s e n t , t h e time d e l a y t h a t o c c u r s f o r blood t o c i r c u l a t e from t h e i.ungs t o a t i s s u e compartment and back t o t h e l u n g s and t h i s car. be a ~ p r e c i a b l ei n R h o r s e .
62.
2.
It h a s been shown t h a t some d i r e c t d i f f u s i o n o f a n a e s t h e t i c can t a k e p l a c e between c o m p r t m e n t s a n d t h i s i s n o t r e p r e s e n t e d (Rackow e t a l . , 1965; P e r 1 e t al., 1965; A l l o t t e t a l . , 1976; Mapleson, 1977).
3.
The ' c o n c e n t r a t i o n e f f e c t ' i s n o t r e p r e s e n t e d .
This
w m s c named by Eger (1974) b u t would perhaps be b e t t e r termed t h e ' u 9 t a k e - v e n t i l a t i o n '
e f f e c t as s u g g e s t e d
i n o t h e r words, t h e u p t a k e of a n a e s t h e t i c
by Mapleson.
by t h e blood t e n d s t o r e d u c e t h e v o l u n e o f gas i n t h e
lungs and t o y r e . r e c t t h i s h a p p e r i n g i n s p i r e d a l v e o l a v e n t i l a t i o n exceeds t h e e x p i r e d a l v e o l a r v e n t i l a t i o n .
I t car& be a p p r e c i a t e d t h a t with a p p r o x i m a t e l y 1% h a l o t h a n e Tra;our t h i s e f f e c t woilld b e n e g l i g i b l e but w i t h scmething l i k e 20% n i t r o u s o x i d e it can be cons i d e r a b l e and, es a cor?se.iuence, t h e ' s e c m d - g a s e f f e c t ' comes i n t o p l a y whereby, f c . r example, t h e i n c r e a s e i n i r i s p i r e a e l v e o l a r g a s volume e m i n c r e a s e t h e r a t e of 'halotk:.ans i n p u t ' i n t o t h e lungs.
4.
I n h a l e d a n a a s t i ? e t i c s nay l o t always obey Henry's Law as h a s been s h o m t o be t h e c a s e w i t h cyclopropane ( E E e r , 1974)
5.
-
V a r i a t j o n s i n t h e F u c c t i o n a l R e s i d u a l C a p a c i t y (F.R.C.) a r e n o t represented.
Horses w i t h c h r o n i c o b s t r u c t i v e
pulmonary d i s e a s e (1S.O.P.D.)
may have l a r g e i n c r e a s e s
63.
i n F.R.C.
The e f f e c t o f t h i . s i s t o d e l a y t h e r i s e i n
a l v e o l a r t e n s i o n of a n a e s t h e t i c dhich w i l l be more apparent with a high concentration, e.g.
50
- 70%
n i t r o u s o x i d e , t h a n w i t h aboiiC, 1 % Iialcthane. as w e l l a s i n d u c t i o n w i l l ,
Recovery
o f c o u r s e , be d e l a y e d .
&cause o f t h e l i m i t . a t , i o n s o f tiialogue models m o m d e t a i l e r i s t u d i e s have irivolvcd t h e m e of d i g i t a l comp u t e r models and i n t973 t a e c o n p u t a t i o n ~f t i s s u e conc e n t r a t i o s s of a n a . e s t h e t i c was nacle mor? a c c u r a t e by t h e i n t r o d v c t i o n o f c i r c u l a t i o n - t i m e models (Mapleson, 1 9 7 5 ) .
Nore r e c e n t l y , th:.s (Eavie
t y p e of niodel has been e l a b o r a t e d
2nd Plap1e;-Ior, 1981 ) , ar:d i t i s This model. which
has been developed f o r t h e h o r s e (Wsaver e t a l . , 1982).
i n conc:Iusion, i t should. be c o t e d t h - a t t h e m a j x i t y of ecjuine p a t i e n t s 8 r e n e t a b c , l i c a l l y f i t and ll.a.-~~e f z.irly
s o n s t a n t an6 p r e d i c t a b l e a n a e s t h e t i c requiremf:n;;,
?'ri~is
t h e i r m a e s t h e t i c r:ianagemsnnt, i s reasona.bly e t r a i g l r t f b r w a r d . T h i s i s n o t t h + c a s e , howe-
Furthermore, i f i n h a l a t i o n a d -
m i n i s t r a t i o n i s p r a c t i s e d lnrith low f l o w ( r e l a t i v e l y s p e a k i n g i n t h e c a s e of t h e h o r s e ) and a t r u l y c l o s e d 3:J:;teIIl
( f r e e of t h e considerable l e a k s t h a t so e a s i l y
occur w i t h e x i s t i n g l a r g e > n i m a l s y s t e m s ) e v e r y t h i n g i.n t h e system w i l l be d e l i v e r e d t o t h e h o r s e and t h e ' d o s e '
64.
o f a n a e s t h e t i c j s similar t o an i n t r a v e n o u s i p j e c t i o n . a V.I.C.
i s u s e d , however, tile ' d o s e ' w i l l vary w i t h
ventila5ion.
To b- s u c c e s s f u l w i t h t h i s t e c h n i q u e and
w i t h t h e poor-risk c'iise, i t w i l l become n e c e s s a r y t o p r e d i c t d e l i v e r e s azd r e q u i r e d t e n s i o n s o f a n a e s t h e t i c
more a c c u r a t e l y than i s p o s s i b l e a t p r e s e n t .
If
ACKNOWLEDGEMENTS G r a t e f u l thanks a r e due t o P r o f e s s o r 'd. el. iblapieson
f o r a s s i s t a n c e w i t h t h i s pa>er and t o E x c e r p t a Medi-ca, Amste-dam, Springer-Verlag K . G . Cornpan:;
(Inc.)
f o r permission t o
avd L i t t l e , Brown & UJS'
f i . g u r e s from
P r o f e s s o r DIapleson's p u b l i s h e d wcrks. A s t u d y of the. p h a r m a c o k i n e t i c s o f ink;aled a n a e s t h e t i c
a g e n t s i n t h e h o r s e h a s been made p o s s i b l e by gensrous SUIJport f r o m t h e Wellconie T i u s t .
1mper:ial Shemical
I n d u s t r i e s Limited. have k i n d l y p r o v i c e d hsl;.otharie f o r t h i s
study
ar,d enflurarie h a s been k i n d l y p r o v i d e d Sy Abbott
L a b o r a t o r i e s Limited. ? i n a l l y , t h e a x t h o r i s m o s t g r a t e f u l t o P.lessre. iq. P a r s o n s and J. Conibear f o r p r e p a r i n g t h e i l l u s t r a t i o n s end
t3
Mrs M . iiughes f o r typing t h e manuscript.
66.
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Bger, E . I . , :I. (1cJ74). A n a e s t h e t i c Uptake and Action Tha W i l l i a m s & Wilkins C o . , B a l t i n o r e , Xaryland. Kety, 3 . S .
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3-0
621.
t r i c e , H.L., Ko-mat, P.J., S a f e r , J.!J., C o m e r , E.H. & ? r i c e , M.L. (1960). ;].in, Fhzrmacol. Therap. 1,16. Rackow, IT., S a l m i t r e , E . , E p s t e i n , R.M., Wolf, G.L. P e r l , W. (1965). J. Appl. P h y s i o l . 20, 611. S e a r , 3.#. (1983).
Proc. Ass. Vet. hnaes.
Spenca, A.A., A l l i s o n , X.H. J. Anaas-th. 6%.
z,
a(
2
e(
( i n press).
Wishart, H.Y. (1981).
Br.
S t e f f e y , E.?., Howland, I)., G i r i , S. & EgPr, 5.1. (1977). Am. J . Vet. Res. 3 8 , No. 7 , 1037. Weaver, B.M.Q. & W a l l i y , R.V. (1975). 7, No. 1 , 9.
-
Equine Vet. J .
Weairer, B.N.Q., Luna, C.E.N., M a p l e s o n , W . W . 5 S t a d d o n , G.E. (1982). A.V.A. P r n c e e d i n g s lo, 248.
Weaver, B.M.Q., Lunn, C.E.1VI. & Staddon, G.E. (19843. E q u i n e Vet. J. 16, No. 1, 66. Webb, A . I .
53,
& Weaver,
479.
B.N.Q. (3931).
E r . J. d n a ? s t l i .
68.
W. W. Mapleson (1971)
Figure 1. E l s c f r i c analogue o f t h e d i e t r i b a t i o n o f ir:haled
a n a e s t h e t i c s in t h e body. (From Mapleson, 1971 .)
1
2 3 5 10 20
60
rnin
I hours
2 3 5 7 dzys
wryks
Time
Mapleson, W.W.
(1972).
Figure 2. C o m p u t a t i m s rnade with t h e e l e c t r i c analogue showij.ig t h e approach t o equilibriuni of l u n g t e n s i o n w i t h i n s p i r e d
t e n s i o n where t h e i n s p i r e d t a n s i o n i s k.ept const-ant. The time s c a l e i s l o g a r i t h m i c .
(Froin Mapleson, 1972.)
_-----Fat
Mapleson, W, W. (1972)
.
Figure 3 . The water a r a l c g u e o f t h e d i s t r i b u 1 . i o n o f inhaled a n a e s t h e t i c s i n t h e body. (From klaplescn, 1972.)
Fat
Mapleson , W.W.
(1972).
F i g u r e 4. Two v e r s i o n s o f t h e water analogue r e p r e s e n t i n g i n h a l e d a n a e s t l z e t i c s of high a n d l o w s o l u b i l i t y . (From Mapleson, 1972.)
70.
--.-~
desired level of anaesthesia
-.--r
.
Mapleson, W.W.
Fat
(1972).
Figure 5 . A v s r s i o i r o f t h e w a t e r znalo@e r e p r e s e n t i n g the t e c h nique o f ' o v e r prfessure' t o hasten induction o f anaesthesia u s i n g an a g e n t o f medium or h i g h s o l u b i l i t y .
Mapleson, W.W,
(1972).
Figure 6 .
Water analogue r e p r e s e r i t i n g t h e r i g h t t o l e f t s h u n t o f blood p a s t t h e l u n g s .
(From Mapleson, 1 9 7 2 . )
P~IAFUUGOKINETICS OF INHALAT IOB AXAESTHETTC AGZXTS IX TiIE TORS%
B. M.
Q.
Wearer
\rlellcoin? Comparative A n a e s t h e t i c s L a b o r a t o r y , Department o f V e t e r i n a r y S u r g e r y , U n i v e r s i t y o f B r i s x
P-harmacokinetics i s concerned. w i t h t h e f a c t o r s a f f e c t i n g t h e way
iii
,which the c o n c e n t r a t i o i i at thf: s i t e
rJf
a c t i o c v a r i a s with time f o l l o w i n g ir!jectic.r; o r i n h a l a t i o r , of a dru..
l'ha,-maccdgnarr.ics, cn t h e other. hand, i s a
s t u d y of t h e r e l a t i o n s h i ? between t h e c o n c 5 n t r a t i o n a t t h e s i t e of a c t i o n m d i t s e f f e z t . Tc fazi-l.ita-te phaririacoki.netic s t u d i e s , v a r i o u s models
have been i n t r o d u c e d .
"he
t e r n rnodei i s used. t o d e s c r i S e
scmething wkick behaves l i k e , b u t
~;:F;E
not necessarily i z i
any o t h e r way resemble, tl;e something thtLt i t i s a c t i n g like.
I t i s a s i m p l i f i c a t i o n o f tk.e s o m i t h i n g o r p o c e s s
i t i s designed
t3
imitate.
Exaniples o f n o i e l s used i n
pharmac okine t i c st u d i e s m e t h o s e cone errled w i t h
of
7 olumes
d i s t r i b u t i o n , e l e c t r i c analogues and 52.giI;d computer
models. E m p i r i c a l models are based o r s t r u s t u r e d o n o b s e r v z t i o n and expariment, and t h u s a r e q J a n t i f i o d
D;T
keing f i t t e d t o
e x p e r i m e n t a l data which i s u s u a l l y i n t h e f o r m of idasma concentratioas.
They a r e r e l a t i - e i y easy t o u s e , biit
hecaus-, t h e y a r s e m p i r i c a l , i . e . based. on o S s e r u a t i o n ,
they p e r t a i n o n l y
t o t h e circulnstances pre-irailing
w?ien t h e
This has t o b e l ~ o r n cj.n n i n d i f t h e y
2.zta were d b t a i n e d .
. i r e u s e d t o mzke p r e d i c t i o r i s , s i r i c e aiq c h a n g e in c i r c u m s t a r c e c o u l d i c v a l i d a t e th.t? n o d e 1 es botk. Beck ( 1 8 8 7 ) ar:d
Sear ( 1 3 P 3 ) h a v e laade c l 2 a r . Piodeli; d e v c l o T e d f r o i n t h e o r y , however, Zi?? t h e phy-
s i c l o g i c a l l y b a s e d oiies, 2 n d t h e y
.
SO
.
t h a n ti-e e r q . i r ; c a l
p r e d i . c t i o n s with more ce:rtai:!".g
They- a r e lie"
bt. xed t o n a k c
CI::
c o n v e n i e n t t? i:se,
cnes.
twza7xt, t h e y ha-re first
t o b e q u n n t i f i e 3 i n t e r m s o f t,li!, ph;*:;it:o-c!i?r.ii c a l F r o p e r t i w of t h e dr:iF;
m d -;hzn i- tel.liis o f ' t h e
Llr?;Tsi3?
0g12a? cl-,arac-
t e r < s t ? . c s (13Lke body; f o r e x a i ~ p l e , hccy c ; r c > o s i t i o n ,
s of t h e ; i i . i . ~ i . c . orgsas zcd t i s s u e s . To i , ~ t h i s foz dr,.igs t i l a ;
2cc:cunt has +.c 'Lie
t?.!:BT1
cf :
~ilss3Cia:Lion con..t m t s , e x c r . ? t i o n by t;.e kI.?ne-fs. a g e n t s , m c : e i n t h ? - bcti;,
irk i i i j e c t e i in-,o t,l::,
t-!!o
ir
factor:
1i srr ,
b3Cy
as p r c , t s i * i Siridiilg.
. .
?i Io t-.a;s f 3r~ia:L O C
and
T3,9wt\vi?l', ~;:tk: l n b a i 3 . t i o n r l the gas
t;iF,suF!
?artition coeffici-
e n t s f o r e a c h a g e n t ;ire t h e most, i m p o r t a n t o f t h e p h y s i c o c h e m i c a l j r o p a r t i e e , and p h y s i o i o g i cal m o d e l l i n g its ].ela t i v e l y s t r a i g h t - f o r w a r d and e a s i e r t h a n i s t h e c a s e Tor injected agents. This paper d e s c r i b e s t h e g e n e r s l p r l n c i p l e s involved
i n t h e u p t a k e , d i s t r i b u t i o n and n l i m i i i a t i o . ? of i n h a l e d a a e s t h e t i c +aiIts
in the horsa.
2 h y s i o l o g i c a l . l y based
model c o n c e = t s are used by way o f i l l u s t r a t i o n . The a g e n t s most commonly u s e d f o r i n h a l a t i o n n n a e s t h e i ii. iii
t n e h o r s e a t t h e p r e s e n t time a r e h a l o t h a n e and n i t r o u s
oxide.
T h e s e two a g e n t s w i l l f o r m t h e b a s i s o f t h i s
discussion.
47.
S e l e c t i o n of rn i n h a l a t i o n a g e n t o r a g e n t s for t h e h o r s e depends on t h e p r o p e r t i e s of e a c h a g e n t a v a i l a b l e and how t l ~ e s smatch up t o a ' t h e o r e t i c a l ' i d e a l one which would i n c l u d e all. t h e f o l l o w i n g f e a t u r e s : 1.
Low b l o o d g a s and body t i s c u e s o l u b i i i t y which e n a b l e s b r a i n t e n s i o n s t o be r a i s e d or lowered r a p i d l y according t c requirement. This i e a h i g h l y d e s i r a b l e f e a t u r e f o r t h e h o r s e
i n order
trJ
g e t t h s s u b j e c t a s l e e p q u i c k l y and sub-
s e q u e n t l y a c h i e v e emergence fron! a n a e s t h e s i a w i t h a minirrin p e r i o d o f d i s o r i e n t a t i o n and i n c o - o r d i n a t i o n . N i t r o u s oxide and cyclopropsne have low bloo?/gas and bra.in/blood s o l u b i l i t i e s which are good f e a t u r e s ( E g e r , 1974).
D i e t h y l e t h e r a ? d methoxyflurarie cn t h e
o t h e r h a n l a r e v e r y r , o l u b l e ir: blood and hence a r e u r d e s i r a b l e a g e n t s f o r tile h c r s e .
Chloroform
i.3
l.esa
s o l l i b l e , b u t h-.l!:)thans oven L e s s sc and is l y s c r i t e r i as 8
niedium z o l u b l e ager--t.
T k s s l u b i l i t y c.f h a l o t h a n e
i n hor:Se b l o o d . i s 1 - 7 6 (Web?, a n d Wezver, 1981). Er,Plurane and i s o f l u r a n e a r e l e s s soluble I n blood t h a n
is halothaxe.
A f i g u r c cf
2.3 f c r er-flurane i n t h e
h o r s e i s quoted by S t e f f e y e t d. (1977) frcm work by Giri.
Our p z e s e n t r e s u l t s , howa'v'e?, i n d i c a t e t h a t it
nag be lovler t h a n t h i s .
2.
h o w Minimum -klveolar r : o n c e n t r z t i , m (M.A.c.).
T h i s g j ves
the c c n c e n t r a t i o n re+.lred
i n t h e a1:re-
o l i t c p r e v e n t r e s p s n s e t o noxious s t i m u l i i n 50X of
48
s u b j e c t s (Eger, 1974).
The a c t u a l a l v e o l a r concen-
t r a t i o n r e q u i r e d i s u s u a l l y i n t h e o r d e r of 1.3 M.A.C. However, t h e lower t h e M.A.C.
t h e l e s s is t h e amount of
a n a e s t h e t i c r e q u i r e d t o produce t h e n e c e s s a r y d e p t h of a n a e s t h e s i a and t h i s i s obviously d e s i r a b l e i n t h e h o r s e Eger (1974) g i v e s M.A.C.
v a l u e s f o r man; f i g u r e s f o r
t h e h o r s e a r e given by S t e f f e y e t a l . (1977) a s 0.88
f o r h a l o t h a n e , 2.12 f o r e n f l u r m e and 1.3 f o r i s o flurane.
M.A.C.
i s t h e r e f o r e a measure of potency
which is high f o r h a l o t h a n e b u t u n f o r t u n a t e l y t h i s agent does n o t provide s p e c i f i c a n a l g e s i a .
Nitrous
oxide, on t h e o t h e r hand, i s n o t a p o t e n t a n a e s t h e t i c b u t is a good a n a l g e s i c .
3.
High s a t u r a t e d vapour p r e s s u r e ( S . V . t . ) . The importance of t h i s f e a t u r e i s t h a t it should be h i g h i n r e l a t i o n t o M.A.C.
For example, t h e S.V.F.
of h a l o t h a n e a t 20°C i s 243.3 mm Hg g i v i n g a concent r a t i o n of 32% whereas t h e S.V.P.
of methoxyflurane at
2OoG i s only 22.8 mm Hg so t h a t a l t h o u g h t h i s a g e n t
has a low M.A.C.,
t h e maximum c o n c e n t r a t i o n a v a i l a b l e
a t o r d i n a r y temperatures i s around 3%.
4.
Low t o n i l r e s p i r a t o r y and c a r d i o v a s c u l a r d e p r e s s i o n . Halothane does cause r e s p i r a t o r y and c a r d i o v a s c u l a r d e p r e s s i o n and s o i s n o t good i n t h i s r e s p e c t .
49 -
5.
Non-inflammability. Halothane is not inflammable and thus when it was introduced in the 1950's it provided a very good reason
for discontinuing cyclopropane.
6. Chemical stability. This applies in the main to inhalation agents in general.
Some metabolism and biotransformation does
take place but it represents such a small proportion of the agent administered that it can be ignored for practical purposes.
7. Non-toxic. This 2rovided an excellent reason f o r discontinuing chloroform when cyclopropane and then halothane became available; nevertheless this agent has left behind it a remarkably high record of successful use in the horse.
8. LOW cost.
This is an ideal not likely to be realised with agents presently used.
The cost of halothane, for
example, at around E l l per 250 mls, is n'ot inconsiderable but has become accepted in view of its value as a maintenance agent.
The uptake and distribution of inhaled anaesthetics is a complex process involving many factors and in this brief review of the general principles it will not be possible to describe them all in detail.
They are, however,
concerned with four features: 1.
The anaesthetic apparatus and breathing system.
2.
The ventilation of the lungs.
3.
The circulation
4.
The solubility of the anaesthetic agent or agents in
- tissue perfusion.
the body tissues.
Since horses usually weigh several hundred kilograms, circle or to-and-fro rebreathing systems are mandatory because of the practical difficulty of supplying the large minute volumes which would be required if non-rebreathing systems were used.
In addition, unacceptable levels of
operating theatre pollution would occur. Non-rebreathing systems have enjoyed much popularity in human and small animal anaesthesia mainly because inspired concentrations of anaesthetic are equivalent to the flowmeter and vaporiser settings and thus are known. In recent years there has been a revival of interest in rebreathing and closed systems generally, and much work has been done on the prediction of gas and vapour concentrations when, in particular, low fresh gas flows and truly closed systems a r e used.
The d i f f i c u l t y with r e b r e a t h i n g systems a r i s e s from a s s e s s i n g t h e d i f f e r e n c e between t h e composition of t h e f r e s h g a s flow i n t o t h e system, and t h e i n s p i r e d c o n c e n t r a t i o n s of oxygen and a n a e s t h e t i c a g e n t , s i n c e t h e s e a r e i n f l u e n c e d by a number o f f a c t o r s :
a.
Nitrogen.
There i s always l i k e l y t o b e some n i t r o g e n
i n t h e i n s p i r e d m i x t u r e , a l t h o u g h o f c o u r s e t h e r e is none i n t h e f r e s h gas flow. l i k e l y t o c o n t a i n a b o u t 18
A h o r s e b r e a t h i n g air i s
-
24 l i t r e s o f n i t r o g e n a t
a t e n s i o n of a b o u t 578 mm H g , and some o f t h i s is i n
t h e f u n c t i o n a l r e s i c u a l c a p a c i t y (F.R.C.).
According
t o t h e work o f Spence e t a l . (1981), even i f t h e system i s flushed with nitrogen-free
gas before conncetion t o
t h e p a t i e n t , t h e r e i s l i k e l y t o be some 20% o r more n i t r o g e n i n t h e r e s p i r e d mixture.
With t h e b e s t of
c i r c l e d e s i g n s t h i s may be reduced t o 5% w i t h h i g h f r e s h g a s flows.
Such f l o w s would be a t l e a s t 3 i i t r e s /
min f o r a human b u t , f o r t h e h o r s e , could be 24 l i t r e s / min, and t h u s u n a c c e p t a b l y h i g h .
Barton and Nunn
(1975) found that even i f p a t i e n t s b r e a t h e d n i t r o g e n f r e e g a s for 20 minutes b e f o r e connection t o a n i t r o g e n f r e e system, t h e c i r c l e c o n c e n t r a t i o n o f t h i s g a s c o u l d n o t be k e p t at l e s s t h a n 3%.
b.
The v o l a t i l e a g e n t , h a l o t h a n e .
Difficulty here a r i s e s
from t h e f a c t that i f t h e v a p o r i s e r i s o u t s i d e t h e c i r c u i t (V.O.C.)
t h e n t h e mass o f h a l o t h a n e t h a t needs
52.
to be delivered into the system at the beginning of an anaesthetic is high, i.e. about 1 litre of vapour p e r minute for the first 5 minutes or so if the inspir-
ed concentration of about 1% is to be maintained
(Spence et al., 1981).
This actually is not a real
practical problem in equine anaesthesia since initial
and even maintenance flows may be several litres/min and Fluotec (Cyprane) vaporizers for veterinary use are stated to give 8% and are likely to be delivering at least 6% vapour when turned to ' 8 % ' .
To avoid the need for initial high fresh gas flows, l o d resistance vaporizers in circuit ( V . 1 . c . )
developed and became popular for a time. well provided the vaporizer is
were
These work
very efficient and
provided the patient is breathing spontaneously.
c.
Nitrous oxide.
The addition of nitrous oxide is of
considerable value in adding an analgesic component to halothane.
Furthermore, at the start of the anaesthetic
its second gas and concentration effects are useful features. However, at all times, care must be taken to ensure the inspired mixture contains adequate oxygen and this is especially so when maintenance of anaesthesia continues after nitrous oxide has virtually equilibrated with the animal's tissues.
53.
Oxygen.
d.
If t h i s i s t h e sole c a r r i e r g a s for h a l o -
thane ( i . e .
t h e v o l a t i l e a g e n t ) , t h e r e is l i t t l e l i k e -
l i h o o d of a hypoxic i n s p i r e d m i x t u r e b e i n g a d m i n i s t e r e d b u t it should be remembered t h a t a v a r i a b l e amount of n i t r o g e n w i l l be p r e s e n t .
e.
Water vapour.
The e f f e c t o f t h i s , which s a t u r a t e s
e x p i r e d g a s , h a s n o t been f u l l y a s s e s s e d .
In g e n e r a l w i t h c l o s e d o r n e a r l y c l o s e d r e b r e a t h i n g systems, t h e e x p i r e d g a s which i s r e - i n h a l e d ,
even assuming
a l l t h e carbon d i o x i d e i s s a t i s f a c t o r i l y removed, w i l l ,
a f t e r t h e f i r s t few minutes, c o n t a i n some a n a e s t h e t i c . The a c t u a l amount i s dependent on t i s s u e uptake which i n t u r n v a r i e s with time. amount o f n i t r o g e n .
It w i l l also contain a v a r i a b l e
Thus, as i n h a l a t i o n p r o c e e d s , i t can
be expected t h a t i n s p i r e d oxygen (FI02) w i l l b e l e s s t h a n that of t h e f r e s h gas flow. A l s o t h e i n s p i r e d a n a e s t h e t i c
c o n c e n t r a t i o n (P,an)
will be g r e a t e r t h a n t h a t o f t h e
f r e s h g a s Plow w i t h a lob s o i u b i l i t y a g e n t such as n i t r o u s oxide o r i f a V.1.C.
i s used.
P a r t i c u l a r c a r e h a s 'to be
t a k e 1 t h e r e f o r e , a s .inhalation continues, t o ensure t h a t the
FI02
i s s a t i s f a c t o r y and t h a t t h e PIan
dces n o t r i s e
above t h e i n t e n d e d c o n c e n t r a t i o n of t h e v o l a t i l e a g e n t .
In a d d i t i o n t o t h e b r e a t h i n g s y s t w i , t h e iuptake, d i s t r i b u t i o n and :wbseqiient; e l i n j n a t i o n o f i n h a l e d a a e s t n e t i c s i? dependcnt upon a c.mtir.uoa:: i n t e r a c t i o n of
54.
t h e v e n t i l a t i o n o f t h e l u n g s , t i . s s u e p e r f u s i o n and t h e solubility
of t h o a n a e s t h e t i c iri. t h e t i s s u e s .
A g r e a t e - u n d e r s t a n d i n g of t h e p r o c e s s e s involved can
be achieved a s a l r e a d y mentioned by t h e u s e of p h y s i o l o g i c a l models.
This approach t o t h e s t u d y o f t h e pharma-
c o k i n a t i c s of i n h a l e d a n a e s t h e t i c a g e n t s i s n o t a new one and Kety (1951) i n h i s c l a s s i c p a p e r e n t i t l e d “The Theory and A p p l i c a t i o n o f t h e Exchaige o f I n e r t Gas a t t h e Lungs aqd T i s s u e s + ’ , i n c l u d e s a comprehensive r e v i e w o f all r e l a t e d e a r l i e r . work.
Kety s i m p l i f i e d t h e p h y s i o l o g i c a l s i t u a t i o n by h a v i n g
a s i n g l e compartment model, n o t i n c l u d i n g t h e l u n g , r e p r e s e x t i r i g a l l t h e body t i s s u e s w i t h a volume e q u a l t o t o t a l body volume, and
E
perfusion equal t o t h e czrdiac output.
I n t h i s way he bad a s i n g l e t i s s u e t e n s i o n .
K e t y ’ s eqxa-
t i o n , d e r i v e d from h i s mathematical model, showed t h a t t h e a r t e r i a l t e n s i o n o f a n a e s t h e t i c approaches t h a t of t h e i n s p i r e d t e n s i o n i n t h e f o r m o f two e x p o n e n t i a l decays w i t h d i f f e r e n t t i m e c o n s t a n t s and amplitudes.
These a r e
f u n c t i o n s o f .the a l v e o l a r and body volumes, a l v e o l a r v e n t i l a t i o n , c a r d i a c o u t p u t and t i s s u e s o l u b i l i t y of t h e anaesthetic.
K e t y + s s i m p l e s i n g l e compartment model
severely l i m i t s t h e accuracy o f p r e d i c t i o n s , but h i s complex mathematical e q u a t i o n developed t h e c l a s s i c a l upt a k e curve w i t h i - t s v a r i a t i o n s for low and h i g h s o l u b i l i t y anaesthetics.
I t a l s o made c l e a r f o r t h e f i r s t time t h s
r e l a t i v e irnportance o f t h e v e n t i l a t i o n of t h e l u n g s , t h e c a r d i a c o u t p u t and t h e b l o o d / g a s p a r t i t i o n c o e f f i c i e n t s .
55.
Copperman, as c i t e d by Kety (1951),
developed K e t y ' s equa-
t i o n t o a l l o w f o r any number o f t i s s u e s , and as a r e s u l t h i s model c o n t a i n e d many e x p o n e n t i a l s .
T h i s made t h e
s o l v i n g o f t h e e q u a t i o n f o r any s i i e c i f i c s i t u a t i o n i m p r a c t i . c a b l e w i t h o u t t h e a i d o f a computer.
Price e t a l .
(1960) were t h e f i r s t workers t o u s e a computer i n s t u d y -
i n g t h e problem of t h e d i n t r i b u t i o n of a n a e s t h e t i c s i n -:he body, a l t h o u g h t h e y s t u d i e d thiope.ntone and n o t i n h a h d anaesthetics.
Since thm, a number o f workers have s t u d i e d
mathematical models of %he u p t z k e and d i s t r i b u t i o n a n a e s t h z t i c s n o t a b l y Plaplescn ( 1 963).
of
I t wes r e a l i s e d
t h a t a sirn2le e l e c t r i c a l c i r c u i t c o n s i s t i n g of c a 2 a c i t o r s and r e s i s t o r s c o u l d b e a r r a r g e d s o t h a t t h e movement o f
e l e c t r i c i t y represented t h e d i s t r i b u t i c n of anaesthetic i n t h e body as i l l u s t r a t e d by t h e c l e c t r i c analogue o f Mapieson (1971) i n F i g u r e 1 . storage capacity
Each c a p a c i t o r r e p r e s e n t s t h e
of a body compartment, and each r e s i s t o r
r e p r e s e n t s e i t h e r t h e v e n t i l a t i o n cr t h e blood f1c.w t i m e s t h e blood-gas p a r t i t i o n c o e f f i c i e n t o f t h e a n a e s t h e t i c . W i t ' n . t h a wide v a r i e t y o f s i z e s c f c a p a c i t o r s and r e s i s t o r s
a v a i l a b l e commercially, Mapleson h a s been a b l e t o cons t r u c t h i s e l e c t r i c a l a7alogue i n such a way t h a t has enabled him t o u s e i t t o compute q u a n t i t a t i v e l y t h e approach t o e q u i l i b r i u m o f t h e l u n g t e n s i o n ( i . e . o r a r t e r i a l tension) with the ins?ired tension.
alveolar T h i s has
been c a r r i e d o u t € o r a number o f a n a e s t h e t i c s where t h e inspired
t e n s i o n i s k e p t c o n s t a n t , as shown i n F i g u r e 2.
56.
The time scale is logarithmic and it can be seen that the low soluSility age,itnitrous oxide does approach equilibrium fairly quickly, although full equilibrium in fact fakes several h o u r s .
A similar approach to equilibrium
with the medium soluble agent halothane takes several hours, and full equilibrium would only be reached if the anaesthetic were to be continued for several days.
The
failure of trichlorethylene to equilibrate is due to account being taken of th2 considerable metabolism this a g x t undergoes. Foll.owing the work of Ccpperman, Mapleson (1963) initially used an eight compartment model but he found that, with his analogue models, equally good agreement could be obtained using a three compartment model.
The
comgartrnents represent body tissues grouped together on the basis of perfusion End tissue/blood partition coefficients. These compartments, in addition to the lungs, are:1.
The vessel rich or visceral compartment, i.e. brain, heart, lungs, liver and kidneys.
2.
The vessel poor or lean compartment, represented mainly by muscle and skin.
7.
Adipose tissue, the very poorly perfused fat.
Kapleson has also used his electric analogue to compute quantitatively results for specific situa%ions such as a change in cardiac output or in ventilation.
Eowever,
not everyone, and certainly not every anaesthetist, has the
57.
n e c e s s a r y knowledge o f e l e c t r i c i t y f o r t h i s analogue t o r e p r e s e n t something which is familiar t o him o r h e r . F o r t h i s r e a s c n , Mapleson (1970 and 1972) developed a n o t h e r b a s i c a l l y simple znalogue model, t h e , d a t e r analogue, and s i n c e t h e p r i n c i p l e o f t h i s o r e r e s t s on t h t f a c t t h a t w a t e r f i n d s i t s own l e v e l , i t i s r e a d i l y inrlerstood by everyone ( P i g u r e 3 ) .
This nodel is e x c e l l e c t f o r v i s u a l -
i z i n g t h e d i s t r i b u t i o n o f i n h a l e d a n a e s t h e t i c s i n t h e body a n d , a l t h o u g h it h a s been more d i f f i x i t t o do t h a n with
t h e e l e c t r i c analogue, Mapleson h a s made t h e diagrams cf h i s water analogue model f u l l y q u a z t i t a t i v e i n terms rlf tine t o t a l body volume and how it i s s h a r e d amongst t h e t i s s u e s , a l v e o l a r v e n t i l a t i o n , t o t a l c a r d i a c oxitput and how t h i s i s s h a r f d amongst t h e t i s s u e s , and t h e s o l u b i l i t y o f t h e *-aesthetic
i n blood and t h e o t h e r t i s s u e s o f t h e
body. I t can be s e e n as a l r e a d y d 2 s c r i b e d f c r t h e e l e c t r i c analogue t h a t t h i s i s a t h r e e conpartmest model p l u s t h e lungs.
The 'mouth' vessel s e e n as overflowing, r e p r e s o n t s
a constant inspired tension of 'water'
0-
anaesthetic.
When t h e lower t a p i a opened t h e water (representj-iiE; t h e a n a e s t h e t i c ) f l o w s i n t o t k e l u n g vessel, arLd the p i p e c o n n e c t i n g t h e 'mouth' and ' l u n g ' vefisels r s p r e s e n t s t h e v e n t i l a t i o n which conveys t h e a n a e s t h e t i c t o t h e l u n g s . The o t h e r p i p e s r e p r e s e n t t h e blood f l o w s conveying a n a e s t h e t i c from t h e l u n g s t o t h e t h r e e body compartments. The v i s c e r a l compartment ( h e a r t , l i v e r , b r a i n , k i d n e y s ) i s r e p r e s e n t e d by a small v e s s e l and a l a r g e p i p e t h u s t h e
58..
a n a e s t h e t i c t e n s i o n h e r e follows t h e l u n g t e n s i o n very closely.
The l e a n o r v e s s e l poor compartment i s r e p r e s -
ented by a l a r g e c a p a c i t y v e s s e l and a small p i p e conveying the anaesthetic t o it, thus the anaesthetic l e v e l i n t h i s compartment can r i s e o n l y s l o w l y , and l a g s far behind t h e a n a e s t h e t i c tensi.on I n t h e lung v e s s e l .
This
i s l i k e l y t o be a g r e a t e r f a . c t o r f o r t h e h o r s e t h a n f o r
=an and o t h e r a n i m a l s , s i n c e muscle p e r f u s i c n i n t h e h c r s e is lower %ban i n o t t e r a n i m a l s which have been s t u d i e d , =id
v e r y l o w Fndaed d u r i n g a a a e s t h e s i a (Veaver and Staddon,
1984).
The f a t conpzrtm=.nt can be d e s c r i b e d as similar t o
t h e n u s c l e compartment i n havirig a l a r g e c a p a c i t y a n d a poor p e r f u s i o n , o n l y much more s o .
A s a n a e s t h e s i a proceeds
e q u i l i b r a t i o n e v e n t u a l l y o c c u r s beveeen a l i t h e compartments m d t h e i n s p i r e d t e n s i o n o f a n a e s t h e t i c and t h i s can 'be r e a d i l y a p p r e c i a t e & i n . t h e water analogue.
Figure
4 shows hcw d i f f e r e n t v e r s i o n s o f the water analogue model
can r s p r e s e n t t h e d i s p o s i t i o n o f a p o o r l y s o l u b l e mazst h e t i c and one which i s n i g h l y s o l - J b l e . The p r o p o r t i o n o f t h e p i p e s t r a n s p s r t i n g a n a e s t h e t i c t c t h e compmtments and t h e r e l a t i v e s i z e s o f t h e v e s s e l s a r e maintained i n b o t h v e r s i o n s .
For the highly soluble
m a e s t h e t i c , however, t h e y a r e l a r g e r a l t h c u g h t h e s i z e o f t h e v e n t i l a t i o n p i p e remains t h e s m e .
Thus i t i s
immediately c l e a r t h a t f o r a. h i g h l y s o l u b l e a n a e s t h e t i c ,
a much l a r g e r q u a n t i t y o f t h e a n a e s t h e t i c h a s t o e n t e r t h e body t h a n w i t h
a low s o l u b i l i t y a g e n t b e f o r e e q u i l i b r a t i o n
w i t h t h e i n s p i r e d t e n s i o n can be approached.
With a low
59.
solubility agent like nitrous oxide, therefore, it is relatively easy to raise the brain (visceral) tension. sowever, with both low ana high sclubility anaesthetics, the pip$ supplying the visceral compartment (and hence the brain) is large and so, in both cases the visceral (brain) tensioa fcllo3h's, fairly cloee?.y,the lung tension.
With
the high solubility agent, drainage away to the muscle and fat compartment occurs more quickly than with the low solubility agent since the pipes supplying these vessels for this situation are comparable in size to the ventilation pipe. When administering an inhaled anaesthetic to an individual there is a certain inspired concentration of the agent required to maintain anaesthesia at a certain depth once equilibration with the inspired tension is approached. Initially, however, when using a high or medium solubility agent, the tension in the visceral compartment is slow to rise and the anaesthetist can overcome this problem by using the technique of 'overpressure' (Eger, 1974) as illustrated by another version o f the water analogue (Figure 5).
A high inspired tension is used to raise the
l u n g and fience brain tensions rapidly.
Once the desired
level is achieved, the inspired tension must be reduced (represented by a dotted line, Figure 5) to a level which will just balance the drainage away to the muscle and fat compartments and cleaxly must be further reduced as anaesthesia proceeds and these compartments progressively fill UP. Thus during anaesthesia with the medium soluble agent
60.
h a l o t h a n e , t h e l u n g and t h e r e f o r e brain t e n s i o n s o f a n a e s t h e t i c l i e somewhere between t h a t of t h e i n s p i r e d t e n s i o n and t h a t o f t h e muscle compartment.
If t h e r e i s
an i n c r e a s e i n v e n t i l a t i o n , t h e l u n g s a r e p u t i n t o b e t t e r communication w i t h t h e i n s p i r e d t e n s i o n and, a c c o r d i n g l y , t h e l u n g and hence b r a i n t e n s i o n s r i s e and t h e h o r s e becomes more d e e p l y a n a e s t h e t i s e d .
Respiratory depression
t h e n o c c u r s and tine c o n s e q u e n t i a l red-dcti;n i n v e n t i l a : , i o ~ r e s u l t s i n a l i g h t e n i n g of t h e l e v e l of a n a e s t h e s i a .
s o l o n g as t h e m i m a 1
i3
dence,
b r e a t h i n g spontanaously, a some-
v h a t p r o t e c t i v e , n e g a t i v e feedback system c p e r a t e s . I f , however, under t h e same c i r c u n s t a n c e s , r e s p i r a -
t i o n s a r e c o n t r o l l e d , t h i s n e g a t i v e feedback system i s l o s t , and w i t h deepening a n a e s t h e s i a t h e c a r d i a c o u t p u t w i l l fall.
T h i s w i l l have t h e e f f e c t of r e d u c i n g t h e
p e r f u s i o n t o t h e muscle and f a t compartments b u t p e r f u s i o n t o t h e b r a i n may be mainta.ined by t h e a u t o - p e r f u s i o n regul a t i n g mechanism.
When t h i s h a p p a r s t h e n e g a t i v e f e e d -
back mechanism i s r e p l a c e d by a p o s i t i v e feedback one and a n a e s t h e s i a can e a s i l y become d a n g e r o u s l y deep.
A
r e d u c t i c n i n c a r d i a c ouC,put l e a d s t o a deepening o f anaest h e s i a and t h i s i s f r e q u e n t l y s e e n i n a n a e s t h e t i s e d h o r s e s when i t i s n e c e s s a r y t o t u r n them from one s i d e t o t h e o t h e r ; w h i l s t on t h e i r backs, venous r e t u r n t o t h e h e a r t is r e duced by t h e weight of t h e abdominal c o n t e n t s , hence c a r d i a c o u t p u t i s r s d u c e d and a n a e s t h e s i a becomes d e e p e r . Changes i n v e n t i l a t i o n and i n t h e c a r d i a c o u t p u t can
51.
t h e r e f o r e have a marked e f f e c t wi-th a rredium s o l u b l e agerit s-och as h a l o t h a n e .
I t i s i n t e r e s t i n g t o n o t e t h a t as long
ago as 1924, Haggarc showed e x p e r i m e n t a l l y t h a t t h e r a t e o f u p t a k e and e l i m i n a t i o n o f t h e h i g h l y soluble a g e n t d i -
e t h y l e t h e r wzs a l m o s t e n t i r e l y dependent on t h e v e n t ilation.
On t h e o t h e r hand, w i t h a p o o r l y s o l u b l e a g m t
such as n i t r s u s o x i d e , t h e v i s c e r a l ( b l a i n ) and lung t e n s i o n s remain allout equal t o t h e i n s p i r e d t e n s i o n f o r
much o f t h e d u r a t i o n o f a n a e s t h e s i a , and s o long as r e s p i r a t i c n s do n o t s t o p c o m p l e t e l y , changes In v e n t L i a t i o n anc. c i r c u l a t i o n have v e r y l i t t l e e f f e c t .
In a n a e s t h e t i s e d horses, l a r g c a l v e o l a r - a - t e r i a l t e n s i o n d i f f e r e n c e s o r shzn-ts have been shown t o occur (Weaver and Wally, 1975) m d right t o l e f t s h u n t can be i l l u s -
t r a t e d w i t h t h e water analogue (Figu.re 6 ) .
It can bc
s e e n t h a t t h e e f f e c t i s t o mix up t h e compartments scmewliat and t o reuiice t h e t e n s i o n ciiffererizes betw::en
thex.
The si;nple 2-rIalogue p h y s i u l o g i c a l models c m t e a g r e a t helip
ii;
understanaing t h e d i s t r i b u t i o n of ir-haled
a n a e f i t h e t i c s i n t h e body and, p r o p e r l y q u a n t i f i e d , t h e y a r e c a p a b l e o f computirig a c z u r a t e l y t h e d i s t r i b u t i o n p a t t e r n s t h a t occur.
They do, howeve:.,
h ~ v el i m i t a t i c n s
.
F o r exanple :-
:.
They dc n o t r e p r e s e n t , t h e time d e l a y t h a t o c c u r s f o r blood t o c i r c u l a t e from t h e i.ungs t o a t i s s u e compartment and back t o t h e l u n g s and t h i s car. be a ~ p r e c i a b l ei n R h o r s e .
62.
2.
It h a s been shown t h a t some d i r e c t d i f f u s i o n o f a n a e s t h e t i c can t a k e p l a c e between c o m p r t m e n t s a n d t h i s i s n o t r e p r e s e n t e d (Rackow e t a l . , 1965; P e r 1 e t al., 1965; A l l o t t e t a l . , 1976; Mapleson, 1977).
3.
The ' c o n c e n t r a t i o n e f f e c t ' i s n o t r e p r e s e n t e d .
This
w m s c named by Eger (1974) b u t would perhaps be b e t t e r termed t h e ' u 9 t a k e - v e n t i l a t i o n '
e f f e c t as s u g g e s t e d
i n o t h e r words, t h e u p t a k e of a n a e s t h e t i c
by Mapleson.
by t h e blood t e n d s t o r e d u c e t h e v o l u n e o f gas i n t h e
lungs and t o y r e . r e c t t h i s h a p p e r i n g i n s p i r e d a l v e o l a v e n t i l a t i o n exceeds t h e e x p i r e d a l v e o l a r v e n t i l a t i o n .
I t car& be a p p r e c i a t e d t h a t with a p p r o x i m a t e l y 1% h a l o t h a n e Tra;our t h i s e f f e c t woilld b e n e g l i g i b l e but w i t h scmething l i k e 20% n i t r o u s o x i d e it can be cons i d e r a b l e and, es a cor?se.iuence, t h e ' s e c m d - g a s e f f e c t ' comes i n t o p l a y whereby, f c . r example, t h e i n c r e a s e i n i r i s p i r e a e l v e o l a r g a s volume e m i n c r e a s e t h e r a t e of 'halotk:.ans i n p u t ' i n t o t h e lungs.
4.
I n h a l e d a n a a s t i ? e t i c s nay l o t always obey Henry's Law as h a s been s h o m t o be t h e c a s e w i t h cyclopropane ( E E e r , 1974)
5.
-
V a r i a t j o n s i n t h e F u c c t i o n a l R e s i d u a l C a p a c i t y (F.R.C.) a r e n o t represented.
Horses w i t h c h r o n i c o b s t r u c t i v e
pulmonary d i s e a s e (1S.O.P.D.)
may have l a r g e i n c r e a s e s
63.
i n F.R.C.
The e f f e c t o f t h i . s i s t o d e l a y t h e r i s e i n
a l v e o l a r t e n s i o n of a n a e s t h e t i c dhich w i l l be more apparent with a high concentration, e.g.
50
- 70%
n i t r o u s o x i d e , t h a n w i t h aboiiC, 1 % Iialcthane. as w e l l a s i n d u c t i o n w i l l ,
Recovery
o f c o u r s e , be d e l a y e d .
&cause o f t h e l i m i t . a t , i o n s o f tiialogue models m o m d e t a i l e r i s t u d i e s have irivolvcd t h e m e of d i g i t a l comp u t e r models and i n t973 t a e c o n p u t a t i o n ~f t i s s u e conc e n t r a t i o s s of a n a . e s t h e t i c was nacle mor? a c c u r a t e by t h e i n t r o d v c t i o n o f c i r c u l a t i o n - t i m e models (Mapleson, 1 9 7 5 ) .
Nore r e c e n t l y , th:.s (Eavie
t y p e of niodel has been e l a b o r a t e d
2nd Plap1e;-Ior, 1981 ) , ar:d i t i s This model. which
has been developed f o r t h e h o r s e (Wsaver e t a l . , 1982).
i n conc:Iusion, i t should. be c o t e d t h - a t t h e m a j x i t y of ecjuine p a t i e n t s 8 r e n e t a b c , l i c a l l y f i t and ll.a.-~~e f z.irly
s o n s t a n t an6 p r e d i c t a b l e a n a e s t h e t i c requiremf:n;;,
?'ri~is
t h e i r m a e s t h e t i c r:ianagemsnnt, i s reasona.bly e t r a i g l r t f b r w a r d . T h i s i s n o t t h + c a s e , howe-
Furthermore, i f i n h a l a t i o n a d -
m i n i s t r a t i o n i s p r a c t i s e d lnrith low f l o w ( r e l a t i v e l y s p e a k i n g i n t h e c a s e of t h e h o r s e ) and a t r u l y c l o s e d 3:J:;teIIl
( f r e e of t h e considerable l e a k s t h a t so e a s i l y
occur w i t h e x i s t i n g l a r g e > n i m a l s y s t e m s ) e v e r y t h i n g i.n t h e system w i l l be d e l i v e r e d t o t h e h o r s e and t h e ' d o s e '
64.
o f a n a e s t h e t i c j s similar t o an i n t r a v e n o u s i p j e c t i o n . a V.I.C.
i s u s e d , however, tile ' d o s e ' w i l l vary w i t h
ventila5ion.
To b- s u c c e s s f u l w i t h t h i s t e c h n i q u e and
w i t h t h e poor-risk c'iise, i t w i l l become n e c e s s a r y t o p r e d i c t d e l i v e r e s azd r e q u i r e d t e n s i o n s o f a n a e s t h e t i c
more a c c u r a t e l y than i s p o s s i b l e a t p r e s e n t .
If
ACKNOWLEDGEMENTS G r a t e f u l thanks a r e due t o P r o f e s s o r 'd. el. iblapieson
f o r a s s i s t a n c e w i t h t h i s pa>er and t o E x c e r p t a Medi-ca, Amste-dam, Springer-Verlag K . G . Cornpan:;
(Inc.)
f o r permission t o
avd L i t t l e , Brown & UJS'
f i . g u r e s from
P r o f e s s o r DIapleson's p u b l i s h e d wcrks. A s t u d y of the. p h a r m a c o k i n e t i c s o f ink;aled a n a e s t h e t i c
a g e n t s i n t h e h o r s e h a s been made p o s s i b l e by gensrous SUIJport f r o m t h e Wellconie T i u s t .
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L a b o r a t o r i e s Limited. ? i n a l l y , t h e a x t h o r i s m o s t g r a t e f u l t o P.lessre. iq. P a r s o n s and J. Conibear f o r p r e p a r i n g t h e i l l u s t r a t i o n s end
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66.
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W. W. Mapleson (1971)
Figure 1. E l s c f r i c analogue o f t h e d i e t r i b a t i o n o f ir:haled
a n a e s t h e t i c s in t h e body. (From Mapleson, 1971 .)
1
2 3 5 10 20
60
rnin
I hours
2 3 5 7 dzys
wryks
Time
Mapleson, W.W.
(1972).
Figure 2. C o m p u t a t i m s rnade with t h e e l e c t r i c analogue showij.ig t h e approach t o equilibriuni of l u n g t e n s i o n w i t h i n s p i r e d
t e n s i o n where t h e i n s p i r e d t a n s i o n i s k.ept const-ant. The time s c a l e i s l o g a r i t h m i c .
(Froin Mapleson, 1972.)
_-----Fat
Mapleson, W, W. (1972)
.
Figure 3 . The water a r a l c g u e o f t h e d i s t r i b u 1 . i o n o f inhaled a n a e s t h e t i c s i n t h e body. (From klaplescn, 1972.)
Fat
Mapleson , W.W.
(1972).
F i g u r e 4. Two v e r s i o n s o f t h e water analogue r e p r e s e n t i n g i n h a l e d a n a e s t l z e t i c s of high a n d l o w s o l u b i l i t y . (From Mapleson, 1972.)
70.
--.-~
desired level of anaesthesia
-.--r
.
Mapleson, W.W.
Fat
(1972).
Figure 5 . A v s r s i o i r o f t h e w a t e r znalo@e r e p r e s e n t i n g the t e c h nique o f ' o v e r prfessure' t o hasten induction o f anaesthesia u s i n g an a g e n t o f medium or h i g h s o l u b i l i t y .
Mapleson, W.W,
(1972).
Figure 6 .
Water analogue r e p r e s e r i t i n g t h e r i g h t t o l e f t s h u n t o f blood p a s t t h e l u n g s .
(From Mapleson, 1 9 7 2 . )