Neuroleftanalgesics: 2. Laboratory evaluation of

NEUROLEPTANALGESICS: 2. LABORATORY EVALUATION OF COMBINATION OF ANALGESICS AND NEUROLEPTICS

WITH NITROUS OXIDE '!

A L ~ - B. DOBmN, M.D., PETEa K. Y. LEE, X~.D., ANLI, PF.rm~ H. BYLES, M.B.

Is ~ OO~NtrmG SE~C~ for anaesthetic agents which produce the minimum disturbance of the normal physiology yet are cl~aica]][y effective, a major irnpedhrlent to a truly scientfl~c approach, rather than empiricism, is the fact that there is stil| a serious lack of precise knowledge of how quite minor changes in drug molecular structure may produce such profound changes in pharmacological action, and of how different agents interact wiflh one another, x How- ever, we have found that the combination of certafila drugs does complement our a~rn clinically and oftentimes reduces the undesirable effect of using a large dose of a single agent. ~-~

Janssen recently introduced two groups of drugs. ~,6 One, the butyrophenones, has neuro- and psycho-sedative properties similar to tiaose of the phenothiazines. The other (meperfdine-like) has analgesic properties of great potency, and was at first thought to be without the propensity to cause addiction, but now is known to be addictive. These have been reinvestigated in detail in America during t~he past two years. 7-~e The expression "mineralized" has also been used to describe the state produced by iniection of these drugs in combination into humans) 3 and this state is felt by some to be appropriate to the needs of a surgical[ operation.

Recently, also, Harris and Pierson of Winthrop-Slter|ing Research Institute have studied a number of compounds that are in the benzomorphan series and are rather similar to nalorphine. 14 Pentazocine (Win 20, 228) has about one- third 'the analgesic potency of morphine, whereas cyclazocine is at least five times a~s potent as morphine. The subjective effects of morphine and pentazocine appear to be similar, causing restlessness, itchiness, dizziness, grogginess, nausea, and talkativeness. Cyclazocine differs only in that it appears to be somewhat more likely to produce hallucinations. The respiratory depressant effect of both new compounds is felt to be similar to that produced by equianalgesic doses of morphine. Unfortunately, if respiratory depression is produced by these compounds, it is not antagonized by nalorphine. Cuss and associates recently reported that 10entazocine produces satisfactory pain re][ief of approximately 2 hours' duration with less side-effects than morphine? 5 ]Lasagna has reported the same effect with cyclazocineJ ~ Of significant interest is that pentazocine appears to have no addicting properties, but this has been the unsubstantiated claim for every new analgesic except ~?or methotrimeprazine, rz

From the Department of Anesthesiology, Statl. University of New York, Upstate Medical Center, Syracuse, New York, 13210. Presented at the Annual Meeting of the Canadian Anaesthetists' Society at Montebe]]o, Quebec, Canada, in May 1964.

39

Can. Anaes. Soc. J., voL 12, no. 1, january, 1965

40 CANADIAN ANAESTHETISTS' SOCIETY JOURNAL

Two well-known phenothiazine derivatives, methotrimeprazine (levomepromazine, Nozinan| and promazine ($parine| were included in this Study because they are powerful neuroleptics. Methotrimeprazine has a wide range of properties that are useful in anaesthesia, including a purported powerful analgesic effect that is said to be equivalent to that of morphineY -a9 The properties of promazine are very similar to those of chlorpromuzine, but it might be less likely to cause hypotensi0n when given during anaesthesia, z~

Chlorprothixene (Taractan| Tarasan| was used because it is also a potent neuroleptic belonging to the thioxanthene group of drugs, whi(~h is c~.osely related in structure to the phenothiazines. In laboratory and clinical tests of this compound, we have found that it hardly differs from chlorpromazine in those properties that might be useful in anaesthesia. 21-23

The pharmacology of the individual drugs used in this study is summarized in Figure 1.

The object of this study was to test various mixtures of these analgesic and neuroleptic drugs to determine whether tlhey provide satisfactory anaesthetic conditions and to compare these with some mixtures which we have already tested in animals and in man. s.9.2~

MATERIAL AND METHODS

Following preliminary experiments to devise appropriate drug mixtures, 12 combinations that appeared to be satisfactory were selected for controlled tests and were used for comparison with mixtures previously tested-thiopental- curare, fentanyl-droperidol, and thiopenta]l-rnethotrimeprazine. Wil:h these, 115 experiments of the crossover type were carried out on 30 dogs weighing approximately 20 kg. (18 to 26 kg. ). Groups of 5 or 10 dogs were used depending on whether the experiment was proceeding well. Each animal was premedicated with atropine 0.5 rag. and scopolamine 0.51 rag. intramuscularly, an hour before injection of the anaesthetic drugs. An intralvenous infusion of 0.9 per cent saline was started in a forepaw. Succinylcho]ine '20 rng. was injected and, after hyperventilation with oxygen, the trachea was intubated with a cuffed endotracheal tube lubricated with 4 per cent lidocaine ointment and the tube was connected to a Takaoka respirator. 24 Pulmonary ventilation of each animal was set at 400 ml. gas/kg, body weight using a 2:1 mixture of nitrous oxide and oxygen. A Wright respirometer was interposed between the tube and l_he respirator to check and adjust the minute ventilation. 25

With local infiltration anaesthesia (1.5 per cent lidocaine), plastic catheters were placed in the femoral artery ~ and vein and threaded into ~he aorta and inferior vena cava in order to record blood pressures via Statham Istrain gauges. These were flushed as required with small amounts of hepariniz~d saline. (No glucose was administered during any of the experiments.) After preliminary preparations were completed, the dog was placed in the later;al recumbent position on the laboratory table. I

The rate of respiration was derived from the tracing usinlg a belt-type pneumotaehygraph. A rectal thermometer,,, urinary catheter with calibrated trap,

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42 CANADXAN ArqAE, Sa~aTsTS' SOCmTZ JOURNAL

and lead 2 of the E.C.G. were attached to record body temperature, urine output, and cardiac rate and rhythm d~ring the experiment. E.C.G., blood pressures, and respiration rate were recorded continuously and simultaneously throughout each experiment on a Grass polygraph ink recorder.

In each experiment, 20 per cent oI~ the calculated dose was injected through the saline infusion at the beginning of the study and, after 1(} minutes, the remainder was similarly injected. During preliminary experiments with some of the mixtures, it was found that the dos~ selected was not sufficient to provide smooth anaesthesia, so supplemental doses were given and the close selected was revised during subsequent tests untia a ,~atisfactory one was reached and employed in the comparative experirnents ~ Sixi~ minutes after the flail dose was administered, artificial respiration with nitrous oxide and oxygen was discontinued and 100 per cent oxygen was insufllated into the end0tracheal tube. The hind paw was pinched at 5-minute intervals until the dog responded physically; then all recording apparatus was removed, the procedure was terminated, and the dog was placed on tlhe laboratory floor. The animals were then kept under direct observation until they were fully recovered from the anaesthetic and were able to ambulate. The occurrence of retching, vomiting. defaecation, and rate of recovery were rlecorded.

Arterial blood samples were drawn at the beginning and end of each anaesthetic and again when the animals became responsive. These were analysed for pH, pCO.~, and pO2 using an Epsco Medical Blood Parameter Analyzer which uses a constant-temperature bath set at 37 ~ C., a Metrohm constant-temperature pH electrode, a Clark platinum silver membrane-covered electrode for measuring oxygen tension, and a carbon dioxide tension electrode. -~6-2s Venous blood samples were drawn before and at the end of anaesthesia to measure the haematocrit, blood sugar, blood urea niltrogen, serum potassium, SGOT, and SGPT.Z9-.~'-,

Digital tables were prepared showing a summary of the data from the tracings and laboratory procedures from each experiment. These were analysed for each group of anaesthetic tests and evaluated to determine the over-all efficacy of the anaesthetic mixture, and its probable value as a clinical anaesthetic technique.

RESULTS

Tables I to XV show the analysed serial effects of each drug mixture on vital signs. In Tables XVI to XXX, the corresponding effects on metabolism are shown. The data in the Tables I-XXX are summarized in Tables XXXI and XXXII to show the specific changes that were induced by each anaesthetic mixture, so that they can be ,compared easily.

As previously reported, the mixture elf fentanyl and droperidol (Innovar~) and the mixture of methotrimeprazine and thiopental provide satisfactory anaesthetic conditions without causing any appreciable cardiovascular or metabolic upset, s Similar satisfactory anaesthetic conditions were provided with all of the mixtures containing thiopental (with anileridine, fentanyl, meperidine,

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37

.9

~-~. 6 3

7.4

3

7.0

3

6.7

3

6.4

~

g~

. 2

In each

ex

pe

rime

nt 20 p

er cent o

f the calcu

lated d

ose w

as giv

en at th

e beg

inn

ing

and

the re

ma

ind

er w

as giv

en after 10 m

inu

tes.

TA

BL

E

VI].

EF

FE

CT

OF M

EP

ER

IDIN

E (10 m

.p.k

.) q-- I~IE

TItO

TR

IME

PRA

ZIN

E

(2.5 m.p

.k.) oN

V~T

AL

StuN

S (t4E

AN

O~ 5 D

OG

S)

Co

ntro

l 10 m

in.

20 rain. 30 rain.

40 rain. 50 rnin.

60 min

. 70 rain.

Aro

usal

Sy

stolic B

.P.

(ram.

Hg)

187 161

132 137

139 137

128 130

"~ 124

S.D

, 10

10 ~

7

27 ~

102 '~

83 88

88 82

80 83

~ 75

- C

A

O

5 .~

.~ 11

~ 8

a)

147 ~

122 ~

99 104

tO4

leo

9~

99 O

92

7 -e_

_'~ 10

4 7

4.5

~r

4 4

~ 4

.0

4,0

4,2

5.8

4

,7

4.2

~

4.4

0

9 ~

~ 0

.5

"~ 0

,5

,-~ e

180 ~

189 ~

156 171

!79

186

191 191

"~ 189

~3

-

24 43

~

49

38

.7

3S

.6

38

,0

37

.9

37

.6

37

.4

37

.5

36

.9

;~

Diastolic B

.P.

(mm

. H

g) S

.D.

Mean

B

,P.

(ram,

Hg)

S.D

.

Ven

ou

s B.P

, (ram

. H

g)

S.D

.

Card


S.D

.

Rectal tem

peratu

re (~ C

.)

]n each exp

erimen

t 20 per cent of th

e calculated

do

se was g

iven

at the b

egin

nin

g an

d

the rem

aind

er was g

iven

after 10 min

utes.

r,..~xr~r_..~,, ~

V '~,,. E

FF

EC

T _~,~ M

~*

,~,D

,~...

.......... (10 m

.t).k.). . -~-. PRO

MA

ZIN

E (i0

m.p

.k.) O

N V

ITA

L S

tuNS

(~fEA

N O

F 5 DO

<S)

Co

ntro

l 10 rain.

20 rain. 30 rain.

40 rain. 50 rain.

60 min

. 70 rain.

Aro

usal

Sy

stolic B

,P.

(ram, H

g)

197 S

.D.

!4

Diastolic B

.P.

(ram.

Hg)

119 S

.D.

13

~"- B

P (ram

, H

g)

145 Iv

1 e

aii

. --,

S.D

. 14

Ven

ou

s B.P

. (ram

. H

g) 4

.0

S.D

. 1

.7

Card


143 S

.D.

28

Rectal tem

peratu

re (~ C

.) 3

8.5

15i

8g o

*,=4

hi0

O

19 tl3

O)

o 108

e

O

3.8

~-

O

O

169

38

.3

116 I1

7

!!2

115 113

115 ~

104

4 ~

13

09 67

63 63

62 65

~

53 4

.~ T

M

7

85 83

79 80

79 82

~ 70

4 ~

8 Z

3

.8

3.s

5.0

3

.8

3.s

o.s

0.s

0 152

140 169

!62

t7

9

170 ~

191 ~

34

38

.0

37

.7

37

.5

37

.2

37

.0

36

.8

~ 3

6.6

In each exp

erimen

t 20 per cent of th

e calculated

do

se was g

iven

at the b

egin

nin

g an

d

the rem

aind

er was g

iven

after 10 m

inu

tes.

TA

BL

E

IX.

EF

FL

C3

O

F [V

[LPf'R

IDtN

E

{5 m,p

.k.)

q- !ItI(~

PE

NrA

L

(20

n

t.p.k

)oN

V

I"rAL

SIG

NS

(M

EA

N

OF

[0

DO

GS

)

Co

ntro

l 10 m

i~.

20 min

. 30 m

in. 40 m

in.

50

min

. 6

0m

ia. 7

0m

in,

Aro

usal

2t5

204

125 143

171 196

194 192

~ 190

37 27

=

119 I21

79 94

111 120

124 I20

5 1!7

6 12

g

Sy

stolic B

.P.

(n3m. H

g) S

.D.

Diastolic B

,P.

(ram, IA

g) =

; S

.D.

.>- .->

b.c em

co

09 M

ean

B,P

. (m

m.

Hg)

!~52 ~

148 ~

94 S

.D,

19 "~

Ven

ou

s B.P

. (ram

. Hg

) 3

.6

2 3

.6

~ 2

.0

S.D

. ! .0

'~

"~

Card

iac rate (per m

in.)

141 ~

14g m

~ 1,75

S.D

. 28

Rectal tem

peratu

re (~ C

,) 3

8,7

3

8,6

38

"~

112 131

I42

147

2.2

2

.4

2,6

2

.6

166 !67

167 166

3S

4 38

2 3

8,0

3

7.8

144 O

142

I 13

O

Z

2.6

~

2.6

1

.2

i~

O

162 .~

168 37

4.a

5 ~

37

.6

37.

In each ex

perim

ent 20 per cen

t of the calcu

lated d

ose w

as giv

en at th

e beg

inn

ing

and

th

e remain

der w

as giv

en after 10 m

inu

tes.

TA

BL

E

X.

EF

FE

CT

OF P

EN

TA

ZO

CIN

E

(5 m.p

.k.)

+ D

RO

PE

RID

OL

(0

.5

m.p

.k.)

oN

V

ITA

L S

IGN

S

(ME

AN

OF

5 D

OG

S)

Co

ntro

l 10 rain.

20 min.

30 min,

40 rain, 50 rain,

60 rain. 70 m

ln,

Aro

usal

Sy

stolic B

.P.

(ram. H

g)

20,q I97

i80

172

163 161

159 158

"~ 170

S.D

. 23

27

g

Diastolic B

.P,

(ram.

Hg)

126 g

100 ~

96 87

82 78

75 76

~ 87

S,D

, 16

.>

.-> i4

.,~

Mean

B

,P.

(mm

. H

g) 15a

" 132

~" O

114

o o

i24

115

109 106

103 104

S.D

, 18

w

~ 17

*, Z

V

eno

usB

,P,

(mm

. Hg

) 3

,8

~ 4

4 ~

4,6

4

.7

4.5

4

.6

4.6

4

,5

~ 3

.5

S.D

, 0

.3

~5 ~d

0.6

Card

iac rate (p

er rain.) 144

~ 117

~ 123

123 122

123 132

130 "2~

151 r

c~9 S

. D,

22 39

e-

Rectal tem

peratu

re (~ C

) 3

8,9

3

8.6

3

8.4

3

8.3

3

8,2

3

8.2

3

8,2

3

8.0

;~

38

.2

In each ex

perim

ent 20 per cen

t of the calcu

lated d

ose w

as giv

en at th

e beg

inn

ing

and

the rem

aind

er was g

iven

after 10 m

inu

tes.

"FA

BL

E

X|.

Ev

v~

c~ o

~ P~N

ZA

ZO

C~N

Z (5 m

.p.k

.) +

C

nL

o~

ego

rH~

xn

rq~

. (2 m.p

.k.)

ON

V~

w~

SraN

s (M

EA

N O

F 5 DO

NS)

Co

ntro

l 10 rain

. 20 m

in.

30 min

. 40 rain

. 50 rain

. 60 rain

. 70 rain

. A

rou

sal

Sy

stolic B

.P.

(ram. H

g)

199 180

172 153

149 163

153 154

~ 147

S.D

. 26

17 =

13

e-

D~

astolic B.P

. fro

m. H

g)

121 09=

87 ~=

69 71

70 83

77 76

~ 68

S.D

. 14

>

>

17 ~

14 tx0

~ "Z7

09

tD

rvlean B.P

. (m

m.

Hg

) 147

$ 118

~ 111)

98 96

110 102

102 O

94

O

[ S

.D.

17 "~

-o 16

O

13

Ven

ou

s B.P

, (ram

, H

g)

4.3

c

4.0

~

4.9

4

.4

4.5

4

,5 4

.4

4.!

~ 3

.8

S.D

. 1

,7

~5 ~5

t.6

~ 1

.6

Card

iac rate (p

er rain.)

186 ~

227 ~

226 2

10

2

10

192

194 199

"- 198

' ~

QO

4

-0

S.D

. 28

39 ~

31

Recta] te

mp

era

ture

(~ C

.) 3

7.5

3

7.4

3

7.2

3

7.0

3

6.8

3

6.7

3

6.5

3

6.3

~

36

.3

In each

ex

pe

rime

nt 20 p

er cent o

f the calcu

lated d

ose w

as giv

en at th

e beg

inn

ing

and

the re

ma

ind

er w

as giv

en a

fter

l0 m

inu

tes.

TA

BL

E

Xtt.

EF

FE

Ct O

~ F~NT

AZ

OC

INE

(5 m.p

.k.)

+

~r (2.5 m

.p.k

.) oN

VIT

AL

SrGN

S (,M

EA

N O

F 5 DO

GS

)

m

~.ontro~

~u rain

. 20 m

in.

au m

in.

§ m

in.

t)u rain.

ou

mir~.

~tl rain.

Aro

usal

Sy

stolic B

.P.

(mm

. H

g)

199 1

7!

157 !4

9

16

i !5

6

152 147

"~ 140

S, D

. 34

20 =

18

Diasto

lic B.P

. (ram

. Hg

) 123

09= 81

09= 71

70 72

72 68

67 o

66 S

.D.

22 .-~

.~

6 ~

8 m

0 ~

Mean

B

.P.

(mm

. H

g)

148 ~

111 ~

100 96

102 100

96 94

~ 90

S.D

. 26

"~ ~

5 O

5

Ven

ou

s B.P

. (m

m. H

g)

5.4

~

5.6

~

5.5

5

.4

5.6

5

.5

5.6

5

.3

x: 4

.8

S.D

. 4

.6

~d ~

4.I

~ 4

.1

Card

iac rate (p

er min

.) 186

~ 196

m

~ 186

182 185

182 183

179 '~

171

S.D

. 22

31 ~

37 4,,.I

Rectal te

mp

era

ture

(~ C

.) 3

8.0

3

7.6

3

7.6

3

7.3

3

7.1

3

6.9

3

6.8

3

6.6

;~

3

6.9

In each ex

per[m

en~

20 per cen

t of th

e calculated

do

se wa,~

giv

en at th

e beg

inn

ing

and

th

e rem

ain

de

r was g

iven

after 10 min

utes.

TA

BL

E

XI[I,

EF

FE

CT

OF P

EN

TA

ZO

CIN

E

(0.6

m

.p.k

.) q- "]['H

[(_)PI'~NTA

L (20 m

.p.k

,) O

N V

I'rAL

SIG

NS

(M

EA

N O

F 10 DO

GS

)

" "

" R

ft ~

O

l~.t[il*

Co

ntro

l l0

rain.

20

min

. 3

0 ram

. 4

0 m

m.

50 ram.

,,~ rain.

~a ~

:_

Aro

usal

Sy

stolic

B.P

. (ram

. H

g)

216

Diasto

lic B

.P.

(nu

n.

Hg

) 127

S.D

. 18

Mean

B

.P.

(ram.

Hg

) S

.D.

22

2

20

7

206 2

12

2

13

2

12

2

13

29

114 116

1[3

113

115 21

157 160

145 148

147 t4

6

148 22

22

Ven

ou

s B

.P.

(ram.

Hg

) 4

S.D

. 1

= 129

= ~ 14

>

;> ~a0 o9

Ia) o

o 145

4.a .,l=./.

2 o

4.4

~

40

19! ~

I92

r

cm

3.g

3_6

3,7

3

.8

Card

iac rate

(per rain.)

189 193

!92

190

190 189

S.D

. 1i6

!8 3.6

1

.1

Rectal

temp

erature

(~ C.)

38 2

38

.0

37

.7

37

.5

37

.4

37

.0

;37.0 3

6.8

x~ 2

13

r

3,9 r o

114 r

22

147 2a

Z

-= 3

.2

O

�9 .~ 185

r 16

4~

36

.7

In each

exp

erimen

t 2

0 p

er cent of th

e calcu

lated

do

se was g

iven

at

the

beg

inn

ing

an

d

tl~e remain

der

was g

iven

after

10 min

utes.

TA

BL

E

XIV

. E

FF

E~:I O

F TH

IOPE

NT

AL

(20 m.p

.k.)

+ bIE

TH

OT

RIM

EP

RA

ZiN

E (0.5 m

.p.k

.) oN

VtT

az S

tuN

s (M

EA

N

OF

1

0

DO

GS

)

Co

ntro

l 10 rain.

20

rain. 3

0 rain,

40

rain. 50

rain. 60 m

in.

70

min

. A

rou

sal

Sy

stoiic

B.P

. (m

m.

Hg

) 2

00

138

154 15g

I61 162

166 166

~ 158

~.i).

i4

2i

~ 2

2

4-0 r~

S.D

. 13

.>

,>

14 .~

15

Mean

B

.P,

(mm

H

g)

149 m

~

O

115 e

116 115

12t) 120

I21 123

122 j

�9

S,D

. I3

_~

xa~ 15

O

16 ca

Ven

ou

s B

.P.

(ram.

Hg

) 4

.7

~ 4

.2

~ 4

.1

4.1

4

.0

4.1

4

0 3

.9

~ 3

.2

�9 *" 1

.3

"- 1

7

S.D

. 1

.3

r o

~ �9

Card

iac rate

(per

min

.) 168

~ 194

~ 192

189 184

181 178

177 "~

169 S

.D.

21 36

--~ 4

3

Rectal

temp

erature

(~ C.)

38

.6

37

.7

37

.5

37

.2

36

.9

36

.7

36

.4

36

.1

;~

35

.4

In each

exp

erimen

t 20 p

er cen

t of th

e calcu

lated

do

se was g

iven

at

the b

egin

nin

g

and

th

e remain

der

was g

iven

after 10 m

inu

tes.

-AB

LE

X~,"

�9

+ #-

~FYF+C? .O

F 7

m,'

,+.~

,+,,

'"

" rr

, o

l,'

" +

"""~

" '"

"

,.,.

-,,,

.-~

,_,.,

-+

,, ...

...

u~

iL

! :'

+'

,,+,.,

~,~.

,,,.,.

',7

0 '"'

V'"'.

; "J

r- +.

e'~L

'~O

Ct{~

.-t?,

~t',t

5 ""

""

'

' ""

,,

. k.,

,,,.+

, li:

Jr).,

x,,t

ON

<t'i'"

~'!

Q~f:"

,'tr

i~Z~

'.. r

.",-,"

,+ J.J

t.+G~

.+

Cont

rol

10 ra

in.

2~ ra

in.

30 m

iz+.

+? r

ain.

50

rain

. 6+

3 mir:

. 70

rai

n.

Aro

um!

c,,,

r+

++8

i73

"~"

+0'

"++

+~"+~

i ~

i,5

i "o

I,~

+ ,,+

s++,

,+ B

F. (

ram

, Ilg

) ,

+ .

11/+

Jt

~,.,

t.N

.+

.+~

++

S,l::'

, N

~:

~ 32

lo

~.,:m

. H~;

) +3

+ ~..

ii

9 :

6i

~ 90

94

93

99

o

120

S i6

0"

. oo

},,ie

an B

,P.'

Hg'

+

'* ""

"

tram

. )

lg:5

o

i37

" ++

N

+-

"m

I(;~

110

110

i41

L+KI

"-'+-

I +

S, ~.

. ~,+

~ ~

~ 29

.,+,

25

'~ Z

4-'

,,'.+

,,~

o ,

o ~

'> .3.

,5 ,+

0 4.

o

4 +

++ "

"

ve,.o

us

H,P

, ra

m,

5.,0

+.

, ~.

6 ,-

,.,

.+,

. .

,~

.-

,,+

, .,

,. tl, J

"~

tJ

,. t

..l

S,O,

~+0

+"

+ oo

,-

, C'

O

"'+

+ ~:

CN

' 0

,+r

" r"

.

' 1~

1N

I~

- !0

0 16

2 16

t. ~o

t.;

a.d,

ac r

ate

(per

ram

.) r

I~3

o .,~

'.<

"~++

+ S,

D.

14

~ |

22.

2 .~t O

i.,I I,,.t

+"0

~ +

( C.}

384

,,~ ~,

3~0

O 3; ~,

'+

xa:+

af t

,+m

pera

,ure

o

,++1

,~

+m

- .+

.

o+

.,

37.+

37 o

37,6

>

+- ca

tc,x

lat~

'4

gi

. '

:,+-

'+'

In e

ach

,,..~

r;m.o

nt N

per

cen

t oi

the

'

' '

" ""

'

' ,~

ose

~+,as

~,

en at

the

be_

,+.,.n

.,.~ an

~ m

e re

mai

nder

u.+

,s g~

'+:en

af+e

r l0

mm

utP,

s.

DOBKIN et al.: NEUltOLEPTICS W l T g NYI~OIJS OXIDE 51

TABLE XVI

EFFECT OF ANILERIDINE (2.5 M.P.K.) + Ctt'LORPROTHIXENI~, (2 M.P.K.) ON METABOLISM (MEAN OF 5 DOGS)

Control 70 rnin. Arousal

pH at 37.5 ~ C. 7.43 7.35 S.D. 0.08 0.09

Arterial pCO2 (ram. Hg) 25 27 S.D. 4 6

Plasma HCOa-/ (mM./L. ) 15.2 13.7 S.D. 0.5 0.~

Arterial pO~ (mm. Hg) 152 153 S.D. 26 30

Venous haematocrit 46 37 S.D. 3 6

Serum potassium (mEq./L.) 4.9 4.0 S.D. 0.4 0.6

Blood sugar (rag./100 ml.) 127 220 S.D. 16 42

Blood urea nitrogen (rag./100 ml.) 12.2 11.8 S.D, 2.9 2.g

SGO-T units 40 37 S.D. 5.2 6.2

SGP-T units 27 29 S.D. 7.0 3.5

7.23 0.05

43 4

16.6 1.6

328 63

35 5

"FABLE XVI l

EFFECT OF ANILERIDINE (2.5 M.V.K,) + METHOTRIMEPRAZINIE (2 M.P.K.) ON METABOLISM (MEAN OF 5 DOGS)

Control 70 rain. Arousal

pH at 37.5 ~ C. S.D.

Arterial pCO~ (ram. Hg) S.D.

Plasma HCOa- / (mM./L. ) .<;. D.

Arterial pO~ (ram. Hg) S.D.

Venous haenmtocrit ,<i.D.

Serum potassium (mEq./L.') ,~. I).

Blood sugar (rag./100 ml.) S.D,

Blood urea nitrogen (rag./100 ml.) S.D.

SGO-T units S.D.

SGP-T units 5;, D.

7.37 0 07

28 7

15 3 0 7

143 24

42 10

4.9 0.3

108 16

10.6 0.5

3g 10.2

30 12.5

7.38 7.27 0.09 0.05

28 42 7 2

15.3 18.3 0.9 2.9

137 298 25 73

36 37 6 4

4.1 O. 8

138 43

1(). 0 0.7

37 3.7

29 14.2

52 CANADIAN ANAF_~THETISTS' SOCIETY JOURNAL

TABLE X V I I I

EFFECT OF ANILERIDINE (2.0 M.P,K,) + THIOPENTAL (20 M.P.K.) ON METABOLISM (MEAN Olq 10 DOGS)

Control 70 min. Arousal

pH at 37.5 ~ C. 7.42 7.45 S.D. 0.05 0.07 Arterial pCO2 (ram. Hg) 26 24 S.D. 4 4

Plasma HCO~- (mM./L.) 16,.0 15.7 S.D. 2,. 2 2 .0

Arterial pO,, (ram. Hg) 187 150 S.D. 108; 18


Serum potassium (mEq./L.) 5.1 4 .2 S.D. 0 .4 0 .3

Blood sugar (mg./100 ml.) 121 133 S.D. 20 19

Blood urea nitrogen (rag./100 ml,) 11,5 11.5 S.D. 2 .4 2 .3

SGO-T units 44 42 S.D. - 7.3 7 .0

SGP-T units 40 42 S.D. 7.8 8 .2

7.28 0 .05

42 5

18.1 2 .7

347 69

45 8

TABLE X I X

EVFECT OF FENTANYL (0.01 M.P.K.) + DROPERIDOL (0.5 M.P.K.) ON METABOLISM (MEAN ()F 10 DOGS)


pH at 37.5 ~ C. '7.40 7.39 S.D. 0.05 0.05


Plasma HCO3-- (mM./L.) 14.3 12.2 S.D. 2.6 2 .2

Arterial pO.~ (ram. Hg) 138 139 S.D. 21 14


Serum potassium (mEq./L.) 4.5 3 .6 S.D. 0 .4 0 .4


Blood urea nitrogen (rag./100 ml.) 11.4 10.7 S.D. 2 .5 2 .4

SGO-T units 39 44 S.D. 6 .6 6 .7

SGP-T units 37 43 S.D. 8 .7 10.4

7.27 0.05

33 7

14.2 2 .8

267 96

37 4

DOBrIN e t al.: NEUROLEPTICS WITI" I lglTlil.OlJS OXIDE 53

TABLE XX

EFFECT OF FENTANYL (0.02 M.P.K.) @ THIOPENTAL (20 ml'.K.) oN METABOLISM (MEAN OF 10 DOGS)

2 ~


pH at 37.5 ~ C. 7.47 S.D. 0.06

Arterial pCO2 (mm. Hg) 23 S.D. 1

Plasma HCOa- (mM./L.) 15.4 S.D. 1.9

Arterial pO2 (mm. Hg) 184 S.D. 121

Venous haematocrit 53 S,D. 8

Serum potassium (mEq./L.) 5.1 S.D. 0.4

Blood sugar (rag./100 ml.) 112 S.D. 18

Blood urea nitrogen (rag./100 ml.) 12.0 S.D. 2 7

SGO-T un{ts 46 S.D. 18.1

SGP-T units 41 S.D. 21.7

7.48 9.07

22 3

15.0 1.4

201 146

45 5

4.1 0.4

125 18

11.1 2 3

45 19.1

42 21.6

7.30 0.07

40 8

18.3 2.5

315 72

50 5

"FABLE XXI

EFFECT OF MEeER~DINE (10 M.ea(.) + CHLOReROTmXENE (2 M.P.IC) ON ME'rABOLmM (MEAN OF 5 DOGS)

pH at 37.5 ~ C. S.D.

Arterial pCO2 (ram. Hg) S.D.

Plasma HCOa- (mM./L.) S.D.

Arterial pO,, (mm. Hg) S.D.

Venous haematocrit S.D.

Serum potassium (mEq./L.) S.D.

Blood sugar (mg./100 ml.) S.D.

Blood urea nitrogen (rag./100 ml.) S.D.

SGO-T units S,D.

J

SGP-T units S.D.

Control

7.39 0 09

28 7

15 7 0 9

166 22

46 4

4.7 0.2

117 11

11 0 2 3

37 8.5

31 3.9

70 rain.

7.33 0.09

29 9

13.7 0.9

175 25

38 4

3.4 0.1

150 16

10.4 2.1

37 6.5

34 3.6

Arousal

7.22 0.03

41 3

15.6 0.7

296 75

37 5

54 CANADIAN ANAESTHETI$'I$' SOlSalgT'I JOURNAL

TABLE N X I I

EFFECT OF MEeERIDINE (10 M.P.K.) + MET~OIRIMEPR~ZINE (2.5 M.P.m) ON MF.TABOLmM (MEAN O~ 5 DOGS)


pH at 37.5 ~ C. 7.37 7.32 S.D. 0.04 0.09

Arterial pCO2 (mm. Hg) 28 30 S.D. 5 5

Plasma HCOa- (mM./L.) 15 .3 14.6 S.D. 2 6 3.0

Arterial pO2 (mm. Hg) J~49 145 S.D. 22 36

Venous haematoerit 37 35 S.D. 11 6

Serum potassium (mEq./I. .) 4. g 3.5 S.D. 0.6 0 .6


Blood urea nitrogen (mg./100 ml.) 12.5 11.5 S.D. 1.9 1.9

SGO-T units 36 34 S.D. 5 0 5.3

SGP-T units 27 29 S.D. 3 3 4.7

7.30 0.06

32 5

15.3 3.3

239 87

34 6

TABLE XXII l[

EFFECT OF ~IEPERXDINE (10 M.P.K.) .4. PKOMAZINE (10 M.P.K.) ON METABOLISM (MEAN OF ~ DOGS)


pH at 37.5 ~ C. 7.41 7.34 S.D. 0 .08 0 .04

Arterial pC02 (ram. Hg) 26 28 S.D. 1 4

Plasma HCOa- (mM./L.) 15.9 14.0 S.D. 1 5 2.0

Arterial pO2 (ram. Hg) 152 162 S.D. 16 31

Venous haematocrk 4g 40 S.D. 7 5



Blood urea nitrogen (mg./100 mI.) 10 11 S.D. 1.8 2.g

SGO-T units 40 44 S.D. 15.8 14.7

SGP-T units 33 39 S.D. 18.2 18.8

7.24 0.04

39 4

15.5 1 7

326 55

39 6

DoBKn~ et ed.: NLXraOLm~CS w r r a l~-rraous oxm~. 5 5

TABLE X X I V

EFFECT OF MEPERIDINE (5 M.P.K.) ~- THIOPENTAL (20 M.F.K.) ON METABOLISM (MEAN OF 10 DOGS)


pH at 37.5 ~ C. 7.46 7.39 S.D. 0.09 (). 10

Arterial pCO2 (mm. Hg) 26 30 S.D. 6 6

Plasma HCO3- (mM./L.) 17.0 17'. 0 S.D. 3 .6 3.8

Arterial pO~ (ram. Hg) 152 134 S.D. 18 3(]1


Serum potassium (mEq./L.) 5.1 4.3 S.D. 0.3 0 .6

Blood sugar (mg./100 ml.) 108 123, S.D. 21 18

Blood urea nitrogen (mg./100 ml.) 11.2 11.7 S.D. 2.3 2,. 4

SGO-T units 40 4(]1 S.D. 12.6 12.1

SGP-T units 35 38; S.D. 8 .7 8;. 3

7.30 0,07

41 7

18.6 4 .3

228 122

54 6

TABLE XXV

EFFECT OF PENTAZOCINE (5 M.P.K.) Jr" DROPERIDOL (0.5 M.P.K.) ON METABOLISM (MEAN OF 5 DOGS)

h ' I


pH at 37.5 ~ C. S.D.

Arterial pCO2 (mm. Hg) S.D.

Plasma HCOa- (mM./L.) S.D.

Arterial pO2 (ram. Hg) S.D.



Blood sugar (rag./100 ml.) S.D.

Blood urea nitrogen (mg./100 ml.) S.D.

SGO-T units S.D.

SGP-T units S.D.

7.49 7'. 33 0.07 0.11

22 27' 6 10

15.2 13.0 3.1 2.6

164 172 I0 15,

52 48, 5 4

5.8 3 .5 0 .4 0.5

114 176 18 79

11.4 10.8 2.0 2 .0

49 57 6.0 11.3

39 50 6.0 7'.1

I . . . . .

7.33 0.06

26 5

13.0 2 .4

299 76

45 4

56 soazrz Iomu

TABLE X X V I

EFFECT OF PENTAZOCINE (5 M.P,K.) "~- CHLORPROTHIXENE (2 M.P.K.) ON METABOLISM (MEAN OF 5 DOGS)


pH at 37.5 ~ C. S.D.

Arterial pCO2 (mm. Hg) S.D.

Plasma HCO3 (mM./L.) S.D.

Arterial pO2 (mm. Hg) S.D.



Blood sugar (rag./100 ml.) S.D.


SGO-T units S.D. "~

SGP-T units S.D.

7.41 7.27 0 . 0 4 0 . 0 5

23 34 4 5

14.8 9 .9 4 .8 3.1

191 171 70 19

52 38 7 5

4 .5 3 .3 O.4 O.8

102 234 27 40

14.8 14.6 4 .9 4 .8

40 42 10.3 6 .5

36 40 10.4 5 .9

I . . . . . . . . . . . . . . .

7.21 0.06

39 8

11.0 3 .8

177 35

37 5

TABLE X X V I I

EFFECT OF PFNTAZOCINE (5 M.P.K.) + METRO'reIMEPRAZZNE (2.5 M.e.K.) ON METABOLISM (MEAN OF 5 DO~S)

pH at 37.5 ~ C. S.D.

Arterial pCO2 (ram. Hg) S.D.

Plasma HCO3- (mM./L.) S.D.

Arterial pO2 (mm. Hg) S.D.



Blood sugar (mg./100 ml.) S.D.


SGO-T units S.D.

SGP-T units S.D.

I . . . . . . . .

Control 70 min.

7.42 7.31 0. O5 0. O2

21 22 4 4

12.6 10.4 1 .4 1 .6

155 169 23 26

47 37 8 4

4 .6 2 .7 0.1 0 .3

112 230 10 25

14.0 14.4 2 .7 2 .6

16 34 15.1 13.5

33 41 21.8 11.7

Arousal

7.19 0 .04

33 7

12.0 1.9

274 53

40 6

DOBK!N et al.: NEUBOLEPTICS WITtt NI~IltOU.~; OXIDE 57

TABLE XXVII I

EFFECT OF PENTAZOCINE (0.8 M,P.K.) At- TttIOPENTAL (20 ~.V.K.) O~ METABOLISM

. . . . . ' , , , , ' , ,,

(MEAN OF 1(1 DOGS) - " : : : " , 1 '

Control

pH at 37.5 ~ C. 7,38 S.D. 0.06

Arterial pCO2 (ram. Hg) 23 S.D. 4

Plasma HCOa- (mM./L.) 12.6 S.D. 1 1

Arterial pO~ (ram. Hg) 152 S.D. 27

Venous haematocrit 51 S.D. 4

Serum potassium (mEq./L.) 4.4 S.D. 0.5

Blood sugar (rag./100 ml.) 121 S.D. 27

Blood urea nitrogen (mg./100 ml.) 15.1 S,D. 4.2

SGO-T units 41 S.D. 14.9

SGP-T units 52 S.D. 22. l

70 rain.

7.34 0.06

23 5

11.8 1.5

164 33

48 5

3.0 0.5

150 36

14,1 3.6

47 15.4

54 21 8

Arousal

7.23 0.05

36 8

13.9 1.7

217 77

50 5

TABLE X X I X

EFFECT OF THIOPENTAL (20 M.P.K.) ~- METHOTRIMEPRAZINE ({).5 M.P.K.) ON METABOLISM (MEAN OF 10 DOGS)

I- Control 70 mln. Arousal

pH at 37.5 ~ C. 7.40 7.41 S.D. 0.04 0.07


Plasma HCO,s- (mM./L.) 14.7 14.3 S.D. i 9 2.2

Arterial pO~ (mm. Hg) 1125 143 S.D. 30 11



Blood sugar (rag./100 mt.) 140 178 S.D. 22 30

Blood urea nitrogen (rag./100 ml.) 12.3 12.2 S.D. 3.1 3.1

SGO-T units 41 39 S.D. 9.4 16.2

SGP-T units 40 40 S.D. 18.4 17.3

7 9

43 13

17 2

290 21

36 4

.25

.09

.2

.1

CANM)IAN . ~ I A E ~ ' ~ JOURNhL

TABLE XXX

EFFECT OF THIOPENTAL (25 M.P.K.) "-~ d'TUBOCtrRAR[NE (0.75 M.P.K.) ON MI~TABOLISM (MEAN OF 10 DOGS)

Control 70 rain. . . . . . . . . . . . . . . . I . . . .

pH at 37.5 ~ C. 7.30 7.30 S.D. 0.05 0.10

Arterial pCO~ (ram. Hg) 33 30 S.D. 8 10

Plasma HCO.q- (mM./L.) ] 4.7 13.3 S.D. 2.0 3.3

Arterial pO2 (ram. Hg) 137 143 S.D. 19 21




Blood urea nitrogen (rag./100 ml.) 110.6 10.6 S.D. 2.1 2.1

SGO-T units ~6 36 S.D. 8.7 14.3

SGP-T units 34 42 S.D. 114 .5 20.8

J i

:'i , " . . . . . .

Arousal J

6.96 0.23

104 54

179 91

50 14

pentazocine, and d'tubocurarine). In all of these tests, induction of anaesthesia was smooth and the dogs remained relatively quiet throughout the anaesthetic period. A few animals blinked their eyes from time to time in response to noise and some moved when blood samples were drawn, but, for the most part, the anaesthetics were considered adequate.

Among the above mixtures, the least post-aaaaesthetic respiratory depression was observed with the fentanyl-droperidot mb~ture (pC02 rose 8 ram. at the time of recovery) and the most depression was: consistently observed when the thiopental-d'tubocurarine mixture (Baird's solution z) was used (p CO2 rose 74 mm. ). The change was remarkably consistent with the other mixtures (pCO2 rose 13 to 18 mm.). No significant changes occurred in the blood pressure, and the heart rate usually decreased.

The mixtures containing the analgesics anileridine, meperidine, and pentazocine combined with the neuroleptics chlorprothixene, droperidol, methotrimeprazine, and promazine all proved to be unsatisfactory for one reason or aaaother, even after considerable manipulation of the dosages in preliminary experiments. The most prominent undesirable feature was our awareness that the level of anaesthesia frequently became so light that from moment to moment we did not know whether we could hold back the administration of a supplementary dose of the mixture in order to maintain smooth anaesthesia, as evidenced by the dog blinking its eyes, gazing about, moving his limbs, chewing on the endotracheal tube, and raising the head in response to noise while, at the same time, the mean blood pressure was reduced at least to a level which we considered

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DOBKIN e t al. : NEUtlOLEPTICS WITH NYJlTROUS OXIDE 61

excessively below the control reading (>30%). Very often additional drugs had to be given to keep the animals quiet.

In none of the experiments did the electrocardiogra m (lead 2) show alterations that have any significance.

Rectal temperature was invariably decreased during the course of all of the experiments, usually in excess of 1~ C.

Defaecation occurred during a few experiments: One dog had a bloody stool during anaesthesia with anileridine-thiopental and one with meperidine-dfio- pental, and two dogs passed a stool during fentanyl-thiopental anaesthesia. Most of the dogs defaecated during recovery after termination of the tests. None of the dogs had diarrhoea.

None of the dogs had retching or vomiting durlng the recovery period~ A brief red flush of the forepaw occurred when the mixture of meperidine-thiopental was injected (3 dogs ).

During anaesthesia, urine output was satisfactory those containing meperidine, and the anileridine-ch ml. urine). All of the mixtures except those conta appreciable rise in the blood sugar, This observatio viously, s Although there was a consistent reduction in anaesthesia with all the mixtures tested, only with per. change appreciable and probably excessive. The e remains obscure, s

vith all the mixtures except srprothixene mixture ( <:50 thing thiopental caused an

has been mentioned pro- the serum potassium during tazocine-droperidol was the xplanation for this change

In all of the experiments, the changes in blood urea nitrogen, SGOT, and SGPT were negligible and of no clinical significance~

All the animals were awake within 30 minutes after the nitrous oxide was discontinued except those that received thiopental-d'tubocurarine. However, they were invariably unable to ambulate for a variable period of time after they were awake, extending from 30 minutes to some hours after the tests, usually because of weakness of the hind limbs. Since the femoral vessels were can- ulated in each dog, we were undecided as to whether the difficulty in ambula- tion was caused by the anaesthetic alone. All of the animals appeared to be quite normal the following day, although most of them slept on and off for several hours after each test. There did not appear to be any consistent difference in the recovery responses that could be spdcifically attributed to any of the mixtures.

Tests were repeated at intervals of not less than .0no veeek on the individual clogs, ~md with the preliminary tests most dogs had 8 anaesthetics, but none of the animals seemed to develop an aversion to the tests that might be interpreted as attributable to an unhappy psychic or sensory experience following a previous experiment.

DISCUSSXON

The evaluation of the efficacy of intravenous anaesthetic agents presents a problem in semantics which is even more complex than that related to the study of analgesics 33 and inhalation agents. 34 Quantitative and qualitative testing involves more than merely measuring the responses of a number of physiological and pharmacological parameters and then stating: "this is good, and that is not

62 CAN.4~IAN ANAF~'I/I/EI'IS'I~' SOCIETY JOURNAL

good." When,we combine two or more intravenous agents to accomplish a smooth anaesthetic state, we are certainly dealing with a far more complicated situation that at the present time can only be evaluated empirically on the basis of the occurrence of undesirable responses. 1

In the concluding remarks of his Joseph Clover Lecture in 1954, T. C. Gray said:

The speed of pharmacological discovery and the sudden impact of ~aew conceptions such as hypotension and h othermia i s aptl indeed to create occasional bewilderment. YP : o There is a temptation to react by de~elopJing a nostalgia for the old days when we were able to produce so much~indeed, f a r t o o much~with only one agent. If we succumb to this temptation, we talk 9.t? polypharmacy and tend to sneer perhaps a little at the 'cocktail' mentality which isl developing. I have attempted to draw attention to the desirable principle, now t the nervous system controlled by the ana~ uncontrolled and therefore undesirable disi: calls for, in American terminology, a new I would answer those who, in dismay at th~ anaesthesia?' by quoting the great St. Aug it idly round about these senses of ours, but

,racticable, of differential disintegration of .~sthetist, as opposed ~to the indiscriminate ategration of ten years ago. This approach "conceptual system,' a new thinking, and

; effort required, ask the question "Whither ustine, "Time, sirs, doth not rest, nor rolls it worketh strange changes in the mind. "s5

I have quoted Professor Gray on this subject for his words fit well into the current dilemma, which he foresaw.

As new and more potent analgesics and neurosedatives (neuroleptics) have been developed, we have become acct~stomed to the basic "cocktail" concept of Laborit and I-Iuguenard. 36 This idea has certainly permeated the everyday practice of anaesthesia during the past decade, as most of us now use potent sedatives, muscle relaxants, analgesics, and hypnotics in combinations to accom-

L plish satisfactory surgical anaesthesia, without a second thought, although we may attach a different name to it. 37

There is a new question which should now be answered: Is it reasonable to combine these potent agents for intravenous administration into fixed mixtures? In clinical medicine, such a practice has not yet been o~cial~y condoned by the AMA Council of Drugs, for, as Isaac Starr has stated clearly, when two active drugs are needed, they should be given separately so that their dosages can be manipulated separately in accordam:e with the needs Of the patient, as Nevertheless, some skilled anaesthetists are accustomed to using drug mixtures; they have been using them for a great many years, and they may be in the best position to test the efficacy of new drugs in combinations. Whenever their use proves unworthy of a situation, the anaesthetist can easily revert to using the specific single drug that seems to be indicated. It is only when one becomes rigid in the use of mixtures that serious problems can and do arise.

In evaluating the above series of comblinations, we have kept the disadvantages of using a fixed mixture foremost in our minds and have come to the conclusion that for initiating an anaesthetic it is not inconvenient to employ a predetermined combination of drugs of evident usefulness. Thereafter, the supplementary requirements can be evaluated and judged best during the progress of a case by administering the individual compomads singly to fit the needs of the moment.

From the data reported above, it appears to us, at present, that six of the

VOBXIN et al.: NEUBOLEPTICS WITH NITROUS OXIDE 63

combinations of a potent analgesic and a neurolepti!c tested seem to be saris- factory for inducing clinical anaesthesia when used along with nitrous oxide. One is the fentanyl-droperidol (1:50) mixture. Thi!~ m~ture is the only one tested for which the term "neuroleptanalgesia" can be applied as coined by the French psychiatrist Jean Delay, 39 and first putt: into clinical practice by DeCastro and Mundeleer and by Nilsson. 4~ They conceived neuroleptanalgesia as a state of central ne1-eous system depression and sensory deprivation which is produced without the use of barbiturates or volatilb anaesthetic agents. 43 The state created is one of total indifference in a consciou,,~ person who remains responsive to auditory stimuli and can deny awarenelss to painful sti'muli. Since we feel, along with others, that there is no advantage to having the patient awake during a surgical operation, there is also no particular reason for eliminating the use ot? an ultra-short-acting barbiturate, such a,,l: thiopental. After all, this was one of the earliest of the drugs that have now come to be known as neurosedatives or neuroleptics, for, as long ago als 1936, Horsley employed thiopental for therapeutic psychotherapy (narco-analysis).44 Since thiopental is also a potent hypnotic of relatively short action, and, in very low dosage, acts also as a neurosedative, it is not surprising that satisfactory anaesthetic conditions and a smooth recovery were provided when it Was combined with pofent analgesic drugs (anileridine, fentanyl, meperidine, methotrimeprazine, and pentazocine). For years now, it has been used successfully with d'tubocurare and/or nitrous oxide for a wide variety of surgical procedures. 2,45-4s

As the efficacy of each pair of agents is analysed, it is apparent that there is some characteristic of each which we do not especially like and there is little we can do to prevent or counteract the undesirab]le feature without bringing a new element into the considerations. For this reason alone, we must weigh carefully every advantage and disadvantage these drug mixtures may present before using them indiscriminately in man. We reiterate that if intravenous mixtures such as are described above come into clin.~lcal use, we must remember that once injected they are irretrievable and one Cannot as easily counteract an untoward response as is possible with an inhalation agent. It is also more di~cult to know what antidote to use ha a given case since we are always dealing with at least two drugs with rather,different properties. ~,s,~ Perhaps the most disconcerting problem that arises when such rnixtures are employed in man is the possibility of psychoneurological reactions, especially when they occur several hours or days after the anaesthetic. 9

Addiction is a problem that may only arise in a patient who needs repeated anaesthetics, and can be averted by changing the ana][gesic agent when subsequent operations are required. Extrapyramidal reactions and neuramusr dys]cinesias, although seldom recognized in animals, occur in man more olften than some are willing to admit. Although these reactions can be controlled by drugs, the effect is sometimes frightening and the patient must be closely observed for at least one day after such aLn anaesthetic. In the case of the butyrophenones, such reactions are frequently delayed as much as two days. HaUuci- nations also occur with some of the potent analgesic ~. ugs. Unfortunately, i]heir occurrence cannot be studied in animals and it re qmres several days of Close

64 C.~tADIAN ANAESTHETIS~II~' SOCIETY IOUtiNAL

follow-up of psychic responses of the patient for them to be revealed. We are remiss in our duty in the care of our patients ff this reaction is not sought out, for the long-term effect of such a reaction may be more incapacitating to the patient than the disease for which the surgical procedure and anaesthetic was given in the first place.

SUMI~ARY AND CONCLUSIONS

Mixtures of several analgesic and neurloleptie drugs were devised and used in su~cient dosage to provide smooth anaesthesia in dogs. The response of the cardiorespiratory system, metabolic reactions, and postanaesthetic recovery were compared from recordings of the vital signs, blood analyses, and direct observation. These data show that the mixtures of anileridine-thiopental (1:10), fentanyl-droperidol (1:50), fentanyl-thiopental (1:1000), meperidine-thiopental (1:4), pentazocine-thiopental (1:33), and methotrimeprazine-thiopental (1:40) provide satisfactory anaesthetic conditions when used along with the inhalation of nitrous oxide and oxygen, and pulmonary ventilation is controlled during the period of anaesthesia. The thiopental-d'tubocurarine mixture would have been included if it had not caused severe poslL-anaesthetie respiratory depression. It is suggested that similar conditions may be reproduced clinically with all of these mixtures, but there are two maior disadvantages to using such an anaesthetic technique: controllability is difl3cult to maintain and delayed reactions may be highly undesirable.

~svM~

On a utflis6 des m61anges de plusieurs m~dicaments analg~siques et neuro- lepfiques A des doses su~santes pour produire une anesth~sie l~;gbre chez des chiens. Les effets sur le syst~me cardio-re~piratoire, les r~actions m~taboliques et l~volution postanesth~sique ont 6t6 compares d'aprbs les trac6s des signes vitaux, les analyses de sang et l'observation directe. Ces donn~es montrent que les m61anges de ani]~r~dine-thiopental ( 1:10 ), fentanyl-drop~ridol (1:50), fentanyl- thiopental (1:1000), m@~ridine-thiopental (1:4), pentazocine-thiopental ( 1:33 ), m6thotrim@razine-thiopental (1:40) procurent des conditions anesth6siques satisfaisantes lorsqu'ils sont combin~s ~ une in_halation de proto~l~de d'azote et d'oxyg~ne, et que la ventilation est contrS16e durant ranesth~sie. Nous aurions ajout~ le m61ange thiopental-d-tubocurarine, mais il produit une grave d~pression respiratoire postanesth6sique. On est d'avis que tous ces m6Ianges peuvent produire cliniquement de telles conditions, mais que cette technique d'anesth~sie pr6sente deux inconv6nients s6rieux: il est diff~cile de contrSler la ventilation et il peut se produire des r~actions tardives ind6sirables.

ACKNOWLEDC~EWrS

The authors are indebted to Rona]d Welgan for technical assistance in the animal laboratory and to Mrs. Arekie Canton in the biochemistry laboratory.

DOBKIN et al.: NEUROLEPTICS WITI{ NITROUS OXIDE 165

This work Was supported by grants-in-aid frbm McNeil ]Laboratories, inc. (D r. E. C. Hessert), Winthrop-Sterling Research Institute (Dr. ]. G. Bird), apd Abbott Laboratories (Dr. N. Wheeler).

Methotrimeprazine was provided by The AmeriCan Cyanamid Company- Lederle Division.

Pentazocine was provided by Winthrop-Sterling Research Institute. Innovar, fentanyl, and droperidol were provided by McNeil Laboratories, Inc. Chlorprothixene was provided by Hoffmann-La Rodhe, Inc. (Dr. J. C. Howard,

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