Document 71M4knm9GYnzqXR6687BwY646
JH.CT. /fer?
lack of sleep on < <,, \.
tetabolism of norm.d \,,,
est 34: 1092, 1955.
refer, R. E., DuBois, a, i,
nd Carlsen, E.: The _
ty and Pulmonary Fun, t
III,, The Year Bunk p,
5.
nninants of tissue
e. 16: 666, 1957.
rt, A. G., and Fenn, W. u
uring respiratory
t
535, 1952.
'`
id Schneider, R. A.: Stm!
if awareness: nnosi.i
rit. M. J. 1: 449, 1952.
mith, H.: Studies on rrgul,
on in acute hypoxia, Au.
v. 24: 293, 1952.
ges in alveolar CO; tenMm
iring sleep, J. Physiol. 122
> . i
aley, R. D., Crump, C. II
M.: Alveolar gas tension
ation and blood pH during
in normal subjects, J. Clm
1958.
Kellogg, R. H.: Chances ,
se to COi during uutui.i! .
vel and altitude, }. Ai>t>l (
, 1958.
I
ANESTHESIA LX: THE ANESTHETIC PROPERTIES Of 1,1,1-TRICHLOROETHANE
j.uts C. Krantz, Jr., Ph.D., Chung S. Park, M.D., Johnson S. L. Ling, Ph.D.
Ihkhk has been a revival of interest in the use ,,f luilogenated hydrocarbons and ethers as aesthetic agents.1- 2 Some years ago one of
(J. C. K., Jr.) with Forman3 studied 1,1,1trit hloroethane (TCE) in laboratory animals .is an anesthetic agent but abandoned the ex periments owing to the toxicity of the comlmnd. More recently TCE has been prepared in a pure form and is available at low cost. Therefore we were prompted to restudy its anesthetic properties. Lazarew,4 using mice, found the ratio between the concentration of vapor causing the loss of reflexes and death from chloroform to be 15, and that of TCE, 20.
TCE is a clear, colorless mobile liquid which hods at 74.1 C., and is nonflammable. The odor of its vapors resembles chloroform. The density of TCE is about 1.44 at 20 C. The liquid is preserved against deterioration by the addition of 0.01 per cent of thymol.
utes, and was, as a re'?, tranquil. The quanti ties of TCE required were approximately equal to those of chloroform needed to produce comparable anesthesia.
Anesthetic Index. The anesthetic index of TCE was determined on monkeys and dogs as previously described.8'7 The data shown in tables 1 and 2 indicate that TCE is a potent anesthetic agent. In the dog and monkey there is no statistically significant difference between the anesthetic index of TCE and Fluothane.7 The potency lies between those of Fluoromar and Fluothane. The difference between the means of the volumes required to produce respiratory arrest and surgical anes thesia in the dog is 0.26 ml.Ag. Our corre sponding value for chloroform vvas 0.27-0.17 or 0.1 ml./kg.* This is indicative of a greater margin of safety for TCE than for chloroform.
Electrocardiographic Studies (Monkeys and Uogs). Six dogs and 2 monkeys were oTiCS*
Experimental
Observation Anesthesias. Four dogs and 2 Macacus rhesus monkeys were anesthetized with TCE. The technique employed has been described previously.* The period of induc tion was short and resembled that with chlor oform. During induction there was breath holding in some animals. Salivation was minimal, and the bronchial tree remained free from mucus during the anesthesia period of 30 minutes. Surgical anesthesia was unevent ful; breathing was deep and regular and often stertorous. Relaxation of the abdominal mus culature and extremities was good. Occa sionally an animal exhibited incoordiuuted leg movements during anesthesia. Pain reflexes were absent during surgical anesthesia, and analgesia appeared to extend into the recovery |x'riod. Recovery from anesthesias of 20 to 30 minutes' duration occurred in 2 to 5 mtn-
Accepted for publication May 6, 1959. The authors arc in the Department of Pharmacology, I nivcrsitv of Maryland School of Medicine, Balti more, Md.
TABLE 1
Anesthetic Index* of Twchloroethane in Does
Dog
i 2 3 4 5 o 7 8 !> 10 a
Mean 9
c.v.
Weight Induction Retoapryira* Anesthetic (ml./It*.) Failure Index (ml,. It*.}
7.0 0.36 0.68 1.90
a.o 0.36 0.57 1.56
17.0 0.29 0.62 2.10 17.0 0.17 0.2!) 1.75
8.2 0.37 0.55 1.50 9.3 0.43 0.62 1.44 9.3 0.38 0.73 1.93 11.5 0.22 0.35 1.00 7.8 0.45 0.93 2.07 7.8 0.38 0.90 2.33 8.3 0.30 0.39 1.30
0.34 0.90
26.47
0.60 0,21
35.00
1.77 0.33 18.64
* The anesthetic index is obtained by dividing the volume of agent in ml./kg. required for respiratory failure by the volume in nil. kg. required for induc tion of tlie animal into surgical anesthesia.
036638 Sis
m
iNmUMi
J
636
KRANTZ, PARK, AND LING
s*p?<-o^T'
--
- ft 5
TABLE 2
circuit technique. The blood pressure was n
Anesthetic Index* of Triciilohoethane W Monkeys (Macacus rhesus)
corded by a mercury manometer from tin carotid artery. The respiration was measures
Monkey
Respira
Weight (kg,)
Induction (ml./kg.)
tory Failure
Anesthetic Index
(ml./kg.)
by a tambour connected to the trachea. Fro-. figure 2 it is cb .r that anesthesia with T( i elicited a depressor response. At the point <! respiratory arrest the blood pressure was n
i 3.5 0.21 0.43 2.00 dueed to approximately one-half of its noniu!
2 2.1 0.23 0.60 2.4!) value. This is in contrast to ethyl ether am v
3 4
2.7 2.0
0.28 0.38
0.56 1.00
2.00 2.66
thesia, as shown in the figure, where at
5 2.1 0.24 0.60 2.50 threatened respiratory arrest the blood prevail i
6 2.7 0.28 0.46 1.66 is only slightly depressed.
7 3.5 0.29 0.50 1.75 Effect on the Perfused Heart of the Fret,
8 9
3.5 2.7
0.21 0.28
0.43 0.65
2.00 2.33
TCE was dissolved in Howell-Ringer's solution
10 2.1 0.36 0.71 2.00 and perfused through the frog's heart in situ.
Solutions containing 10, 20 and 40 mg. per
Mean
V c.v.
0.28
0.06 21.42
0.59 0.17 28.81
2.15 0.33 15.34
* The anesthetic index is obtained by dividing the
cent were employed on 6 frogs. It is apparent from figure 3 that concentrations up to 20 mg. per cent produce little diminution in the ampli tude of heart beat. Forty milligrams per cent
i
volume of agent in mL/kg. required for respiratory concentration decreased the amplitude of heart
Fir- 2. Blood
*4 failure by the volume in ml./kg. required for indue- beat to approximately one-third of normal.
rthd ether anest
!. tion of the animal into surgical anesthesia.
...
| Effect on Oxygen Uptake of Rat Heart !
aneshesia; i3) t ether. (1) Lighi
('II*1
Rats were deeply anesthetized with TCE or ,
respiratory arrest.
ithetized with TCE by a closed technique. chloroform for an interval of one hour, where
3>
'*!
Deep surgical anesthesia was maintained tor upon the heart ot each animal was immediateh i jigr-Srant. Chlorofoi
60 minutes. Electrocardiograms were recorded removed. Cardiac ventricular slices were i awc-'u utilization of tl
and compared with those observed prior, to promptly prepared and the oxygen uptake * ,-atci by a 29.5 per ce
anesthesia (fig. 1). The pattern of the elec over a one-hour interval was measured, using | L-.vr Function Tes-
! trocardiogram was essentially unaltered. The the Warburg technique with a glucose sub j .L'cf w ere subjected to heart rate was increased under anesthesia and strate. These data were compared with thaw x'.i.c.on test. Prior to
the T-wave was either flattened or inverted. from unanesthetized control rats. In 4 control j :ui;v.:tes oi anesthesia
The electrocardiographic pattern at the point experiments the mean Q,-,.. was 9.76 0.43. repeated. After 24 an
of respiratory arrest showed depressed ST- In 6 experiments with TCE-anesthetized rat' ' lYn.-r.nod again. Thi
segments; tachycardia was absent and mild the mean Q0, was 6.51 . 1.06. In 6 addi
i 'bradycardia prevailed.
tional experiments using chloroform the mean
Blood Pressure Studies (Dogs). Blood pres sure studies were conducted on dogs anes thetized with TCE and ethyl ether by a closed
Qo2 was 6.8S 0.S3. TCE anesthesia evoked a 33.3 per cent diminution in tire oxygon up take of the myocardium which was considered
!
!
I. NORM
2.TCE
I 3.TCE
I 4. NORM
Fic. 1. Electrocardiogram of dog under trichlorocthane (TCE) anesthesia.
Lead II. (1) Nonnal dog; (2) TCE surgical anesthesia; (3) TCE respiratory arrest.
5. TCC Fi
SL 036639
mm 1
1
Anr-thf-i,.! , Sept.-Oct. 1'/.,
pressure was n nometer from tinlion was measure d the trachea. From ?sthesia with T( K ?. At the point <>1 ! pressure was n-. -half of its norm.il ethyl ether aimsfigure, where at the blood pressure
leart of the Fro
11-Ringer's solution rog's heart in situ. > and 40 nig, per igs. It is apparent tions up to 20 mg. ution in the amplinilligrams per cent amplitude of heart ird of normal, fce of Rat Heart. zed with TCE or : one hour, where,1 a :____ J_T m slices were
oxygen uptake s measured, using th a glucose submpared with those irats. In 4 control was 9.76 0.43. ^-anesthetized rats 1.06. In 6 addioroform the mean anesthesia evoked in the oxygen upch was considered
Volume 20
Number S
ANESTHESIA LX
637
I.F. mmm
t-A '
"
""
'
' ----
t
23
4
ltd
Fig. 2. Blood pressure and respiration of the dog under trichloroethane (TCE) and ethyl ether anesthesia. Left--TCE. (1) Light surgical anesthesia; (2) deep surgical anesthesia; (3) threatened respiratory arrest, and (4) respiratory arrest. Right--diethyl
ether. (1) Light surgical anesthesia; (2) deep surgical anesthesia, and (3) threatened respiratory arrest.
significant. Chloroform also depressed the oxygen utilization of the heart muscle as indi cated by a 29.5 per cent decrement.
Liver Function Tests in the Dog. Three dogs were subjected to the Bromsulfalein liver function test. Prior to and one hour after 60 minutes of anesthesia with TCE the test was repeated. After 24 and 72 hours the test was performed again. The percentage of dye ex
creted in no case was significantly greater than the preanesthetic values.
Plaa et al.10 developed a new method of de tecting hepatic damage produced by halogenated hydrocarbons. Using mice, these in vestigators measured the increase in sleeping time evoked by a subcutaneous injection of the halogenated compound in oil when pentobar bital was administered. Of seven compounds
1. NORMAL 2.TCE 40mg.
3.7 CE 20mg.
4. NORMAL
thesia. iratory
5. TCE lOmg.
Fic. 3. Perfused frog heart with trichloroethane (TCE). Mg. = milligrams per cent.
i
638
KRANTZ, PARK, AND LING
>T/t f> * ,, . ,
N,,- ;
TABLE 3
R`. ziratory E
Oxygen Consumption of Monkey Under Tr(chlcjroethi>\e (T< Ei Ane-thesu
The data in tab
Normal
TCE anesthesia
TCE
Different
oxygen consump
2.1 kg. 1
Respirations/ Minute 5G
Oi Uptake (mU/kg./hour)
3,238
Hfipimtioim Minute 55
Oa (Tpuk(rnl./kit. ln>ur)
2,095
Mip'it* -u
* bj l J)t c , j*#r
--1.14-- 135.3
Beneict-Roth n jnesv.-t'.zed by until ii.r quar.tit per cent of tha spiraiory arrest,
M 2-
58
3,428
61
2,857
+3
-5t;
| was measured ai
(16.7
1 during which a
the administrab
3
54 `
2,380
69
1,714
+ 15
(28.0
minute.
The depressioi
2.7 kg. 1
52
2,370
58
1,925
+5
--44i
anesthesia is ap
(18.8
that under Fluoi
M2
79
3,555
77
2,074
_ 2 --1,481 parable to the
(41.7
under chlorofon
respectively.1
3 34 1,857 58 1,037 +24 -8H { Irritation of ti
(44.0
i first approximati
3.5 kg. 1
52
1,942
61
1,571
+9
-47t
of TCE. the ag
,, I (19.1 instilled into the
` ** * *t '7
F2
68
2,628
66
2,342
o
-2M (10.9
Solutions of 5 j pared and comp
chloroform. On
3 76
3,428
75
1,771
- 1 -1,757 used in one ey
;S
(51.3
rofonn solution
Mean
conjunctivas we 26.7
a 12-hour perio
S.D.
14-5
emia elicited by
able to that pro
tested by this method, including chloroform and trichloroethylene, TCE was found to be the least hepatotoxic.
Repeated Anesthesia in the Rat. Four rats were anesthetized with TCE for 1 hour on three consecutive days, 4 rats on six consecu tive days and 4 rats on nine consecutive days. One animal died after 6 anesthesias and an other after 8 anesthesias. All animals were ultimately sacrificed and histologic studies were made of the brain, spinal cord, liver and kidneys. No significant pathologic changes were present with the exception of those found in the liver of one rat exposed to 9 anesthesias. In this specimen there was evidence of midzonal necrosis of the hepatic parenchyma.
Clotting Time and Hemolysis of Blood in the Dog. The clotting time of blood was determined in 4 normal dogs by the capillary
tube method. The average clotting time was
about 60 seconds. Under deep surgical anes
thesia with TCE of 60 minutes' duration, the }
clotting time was again determined. No sig- I
nificant change was noted.
[
Volumes of 10 ml. of TCE of varying con i
centrations in normal salt solution, to which was added 0.1 ml. of defibrinated dog's blood. I
were maintained at 23 C. for 24 hours. No
hemolysis was observed by concentrations ol
50, 100 and 150 mg. per cent of TCE.
Preanesthetic Medication. In 2 dogs, in j
ducing TCE anesthesia with nitrous oxide-
oxygen or cyclopropane-uxx gen mixture w.w
uneventful. Preanesthetic medication will'
pentobarbital sodium or morphine was found
to be compatible with TCE anesthesia in -
dogs.
Flammability is not flammablt
Sclubility in mined the solul 0.27 cm. (0.19 ferring to the c water solubility coefficient, the was found to physical constai potency which studies.
Haring com: December 1. T ministered TCE a volunteer, ag' and anesthesia for 30 minutes electrocardiogra sia. The blou<
SL 036641
4
Ane.sih^jn)i>tv
Sepl. <Jtt, |<>.
tNE (TCK) Anesthesia
Difference
fce tour)
UeaApliinrauttieofi*, '
-0
'
! +3
i + 15
5 +5
4 -2
17 +24
'1 + 9
12 - 2
-1
;an ).
Ot I fititk* 0>er friii)
-1.142 (35.3)
-- 571 (16*7)
-66t; (28.0)
-444 (18.8)
-1,481 (41.7)
-814 (44.0)
-471 (19.1)
-285 (10.9)
--1,757 (51.3)
26.7
14.5
. The average clotting time was onds. Under deep surgical am sl'CE of 60 minutes' duration, the : was again determined. \To sin ge was noted, >f 10 ml. of TCE of varying eonin normal salt solution, to which hi ml. of defibrinated dog's blood, lined at 25 C. for 24 hours. No ms observed by concentrations ot 150 mg. per cent of TCE. die Medication. In 2 dogs, inE anesthesia with nitrous oxidecyclopropane-oxygen mixture "">
Preanesthetic medication nilh a! sodium or morphine was found vatihle with TCE anesthesia in -
Volume 20 Number S
ANESTHESIA LX
639
Respiratory Effect Under Deep Anesthesia. The data in table 3 show the effect of deep TCE anesthesia on the respiratory rate and oxygen consumption of the monkey, using a Benedict-Roth respirometer. The animal was anesthetized by the anesthetic index technique until the quantity of TCE administered was 50 per cent of that previously required for re spiratory arrest. The oxygen consumption was measured again for a period of 6 minutes, during which anesthesia was maintained by the administration of 0.05 cc. of TCE per minute.
The depression of oxygen uptake under TCE anesthesia is approximately twice as great as that under Fluoromar 1 anesthesia and is com parable to the depressions of oxygen uptake under chloroform and Fluothane anesthesias, respectively.2
Irritation of the Mucous Membranes. As a first approximation of the irritative properties of TCE, the agent dissolved in com oil was instilled into the conjunctival sac of six rabbits. Solutions of 5 per cent by volume were pre pared and compared with a similar solution of chloroform. One drop of the oil solution was used in one eye and one drop of the chic roform solution in the contra-lateral eye. The conjunctivas were observed periodically over a 12-hour period. The chemosis and hyper emia elicited by TCE appeared to be compar able to that provoked by chloroform.
Flammability of Vapor. The vapor of TCE is not flammable.
Solubility in Water, van Arkel11 deter mined the solubility of TCE in water to be 0.27 gm. (0.19 ml.) in 100 ml. at 30 C. Re ferring to the curve of Carr et al.,x- in which water solubility is plotted against oil/water coefficient, the oil,/water coefficient of TCE was found to be approximately 100. This physical constant bespeaks a high anesthetic potency which was observed in all our animal studies.
Having completed these experiments, on December 1, 1957, Dr. Paul R. Hackett ad ministered TCE by a closed circuit method to a volunteer, aged 30. Induction was smooth and anesthesia was maintained uneventfully for 30 minutes. There were no significant electrocardiographic changes during anesthe sia. The blood pressure dropped to 70 per
cent of preanesthetic level. Recovery was slow, but uneventful. The individual com plained of being tired for several hours after the anesthesia.
Summary
Trichloroethane is a volatile liquid with po tent anesthetic properties comparable to those of chloroform. No functional hepatic impair ment was shown in the dog by the Bromsulfalein test, nor did repeated anesthesias in the rat with TCE produce kidney or liver damage except in one animal after nine anesthesias. The electrocardiogram of the monkey and dog failed to change significantly, but the blood pressure of the dog was markedly depressed by TCE. Oxygen uptake was depressed in the monkey by anesthesia with TCE.
This first approximation of the anesthetic properties of TCE warrants its cautious trial in man.
This investigation was supported by a grant from the Ohio Chemical & Surgical Equipment Co. (a Division of Air Reduction Company, Inc.), New York, New York.
REFERENCES
1. Lu, G., Ling, J. S. L., and Krantz, J. C., Jr.. Anesthesia; anesthetic properties of certain fiuorinated hydrocarbons and ethers, Anes thesiology, 14: 466, 1953.
2. Raventds, J.: Action of Fluothane; new volatile anesthetic, Brit. J. Pharmacol. 11: 394, 1956.
3. Forman, S. E.: Personal communication. 4. Lazarew, N. W.: Narcotic activity of vapors
of chlorinated methane, ethylene and ethane. Arch, Exper. Pathol. 141: 20, 1929, 5. Krantz, J. C., Jr,, Carr, C. J., Forman, S. E., and Evans, \V. E., Jr.: Anesthesia; anesthetic action of cyclopropyl methyl ether, J. Phar macol. It Exper. Therap, 69 : 207, 1940. 8. Krantz, J. C., Jr., Carr, C. J., Lu, G., and Bell, F. K.: Anesthesia; anesthetic action of tvifluoroethyl vinyl ether, J. Pharmacol. & Exper. Therap. 108; 488, 1953. 7. Krantz, J. C., Jr., Park, C. S., Truitt, E. B,, Jr., and Ling, A. S. C.: Anesthesia; further study of anesthetic properties of 1,1,1trifluoro-2,2-brofnochlorethane (Fluothane), ANEsnie.sioi.ocY 19: 38, 1958. 8. Krantz, J. C,, Jr., Carr, C. J., Forman, S. E., Evans, W. E., Jr., and NVollenwebcr, H.: Anesthesia; anesthetic action of cyclopropyl ethyl ether, J. Pharmacol. & Exper. Therap. 72: 233, 1941. 9. Pearson, O. H., Hastings, A. B., and Bunting, J.; Metabolism of cardiac muscle; utilizu-
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6642
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KRANTZ, PARK, AND LING
Anesthestaliidv Sept.-Oct. !>,.;
tion of Cw labelled pyruvate and acetate by rat heart slices. Am. J, Physiol. 158: 251, 1949. 10. Plaa, G. L., Evans, E. A., and Hine, C. H.: Relative hepatotoxicity of seven halngenated hydrocarbons, J. Pharmacol. & Exper. Therap. 123: 224, 1958.
PREANESTHETIC ROOM A distinctive feature of a large, cheerfully painted preanes thetic room is a painting of a detailed scene on the ceiling illuminated indirectly from valences. Of 100 patients questioned 80 per cent noted and most liked it. A variety of reasons why and how it helped alleviate anxiety is ad vanced. Very few patients had no memory of seeing it, (Steel, G. C.: Decoration of the Anesthetic Room. A Study of Patients' Por tions, Brit. M. ]. 1; 43 (Jan. 3) 1959.)
DIRTY SHOES Cultures were made from 15 surgeons' and 15 obstetricians' shoes taken from lockers in surgery and obstetrics. Cul tures from every pair of shoes had multiple colonies including 23 strains of hemolytic
11. van Arkel, A. E., and Vies, S. E,: Solubility of organic compounds in water. Rev. fr,u chim. 55: 407, 1936.
12. Carr, C. J., Kibler, D., and Kraut/, J. Jr : Anesthesia; study of certain physical prupet ties of isopropcnyl vinyl ether, Anestukskh ooy 5: 495, 1944.
staphylococci, 5 strains of Proteus, 50 beta, hemohtic gram-positive rods, and numerous fungi. The antibiotic resistance of these or ganisms indicated that they were lately asso ciated with clinical infections treated with antibiotics during which resistance developed. These were shoes which were kept in the delivery or surgical suite so that hospital dirt would not be tracked into the operating or delivery suites. The plea is made that shoes should be placed in a washing machine at tinend of an operation or delivery or sterilized with ultra-violet sterilization. The alternative would be the use of easily laundered cloth covers in pediatric, obstetric and surgical areas. (Casey, A. E,, and others: Shoes as a Potential Hazard to Surgical and Obstetrical Patients, South. M. J. 52: 384 (April) 1959.)
the effect of F
OF VARIOUS VAS'
Edmond I. Egkr II,
(lveoTENsioN lias lx-< patients who previi .-serpine. The fall respond satisfactorih as phenylephrine bi blocking agents sucl viium.1 Hypotensioi dia has also been rej with a barbiturate a reived reserpine.was undertaken to t ] administration of ri
j commonly used vas> ) these decreased ii
j reserpine.
Ik
Epinephrine, nonmethoxamine, meph methamphetamine below.
Mongrel dogs wt were anesthetized 15 mg. per kg.). E | intubated with a cu the cuff inflated. 3 perventilated throu: cither an Emerson The femoral artery' ethylene catheter ai tire abdominal aort. oeeted to a U-typ< the damped pressu it appropriate inti figure. A needle ' and a slow constant in water was allov experiment. The : illowed to stabilize <>f mercury pressur before an injection rf 45 or more min
Accepted for pul authors are in the D
Ipartmcnt of Surgery University of Iowa, ;
0366&3