SEPTEMBER, 1936
103 I
IKDUSTRIAL -4UD ENGINEERIKG CHEMISTRY
sumption that the reaction rate constant is determined by lii K = -a/T b. Finally, it must be realized that the results presented here apply only to individual reactions and not to a complex heterogeneou. process which is the resultant of several reactions. In the latter case the dependence of the over-all rate constant on temperature may not be given by In K = -a’T +b.
+
Acknowledgment
E+)
e = base of natural logarithms = integral logarithm of 2
F (a, b, c, 2) = hypergeometric function 1
H(r) =
integration.
Nomenclature
+
a , b = constants in the equation In K = -a/T b, expressing the rate of a reaction as a function of the temperature
ds
” L 5
i=m Ja(z) = aero’th order Bessel function KT = rate constant at temperature T Y = frequency of temperature oscillation T = absolute temperature t = time
Literature Cited
The author wishes to express his appreciation to Selson
K. Taylor a t whose suggestion this paper was written, and to P. L.Smith and B. Ellefson for checking the f0rmUkis O f
lo-;
F,lmas, c, , I;vD, ESG. CHEII,, 23,534 (1931), (2) Jahnke, E,, a n d ~ ~ F,, “dT a b l e~s of , ti^^^," znd e d , , pp. 83-5, 278, €3. G. Teubner, 1933. ( 3 ) K i n n e y , 6. P . , Bur. Mines, Tech. Paper 442 (1929). (4) Taylor, H. S., “ T r e a t i s e on P h y s i c a l Chemistry,” 2nd ed., Tol. 2, Chaps. XI\-and XV, New York, D. V a n N o s t r a n d Co., 1931. RECEIYED
>ray 29. 1936.
ANESTHESIA Clinical Application of Recent Chemical Contributions JOHN S. LUNDY Mayo Clinic, Rochester, Minn.
C
HERIISTS hare supplied clinical anesthetists with a number of anesthetic agents in the last few years which have interesting physiologic effects and are meeting a long-felt need in medicine. S o doubt there will be some variation of opinion among medical men concerning the relative value of various anesthetic agents in clinical practice. The ideas expressed here are those of the author and do not represent general opinion on the subject. There has been a progressive demand in the last few years for special agents and methods of anesthesia over ordinary agents and methods; this is illustrated by experience a t the Mago Clinic (Table I). A great deal of progress has been made in the development of new anesthetic agents to meet this demand. Table I1 shows these special agents and methods used a t the clinic, when they appeared, and when certain of them were supplanted by others or when their use was
discontinued. Regional anesthesia produced by local anesthetic agents has continued to be a popular method, in spite of some unsatisfactory results which have been obtained with certain agents introduced in the period here reviewed.
Local Anesthetics
SUPERCAISE. Of the local anesthetic agents used in recent years, nupercaine or “percaine” (a-butyloxy cinchoninic acid y-diethylenediamide hydrochloride) is one of an unusual type; it was applied clinically as a spinal anesthetic 18) in a concentration of 1 t o 200. The dose of nupercaine was measured directly in the syringe, and spinal fluid was then aspirated into the syringe to secure a dilution of 1 to 800. Injection was carried out at a rate of 0.5 cc. per second. The use of nupercaine for spinal anesthesia, however, did not prove as satisfactory a t this clinic as it evidently did later in the experience of Jon& ( 3 ) . He injected a solution of nupercaine and spinal fluid in a coiicentration of 1 to 1500. The desirability of Attention is called to trends in the use of special anesthetic injecting a local anesthetic agent agents and methods of administering them in the last ten which is also a surface anesthetic intrigues the clinician into trying such years, including certain new local anesthetics, general inhalaagents, always in the hope that one tion, anesthetics (both gaseous and volatile), intravenous will finally become a v a i l a b l e to anesthetics (especially those of *the thiobarbituric acid series supply all needs. Then full attenand evipal soluble), and rectal anesthesia. The author extion can be deiroted to a complete presses his own ideas and does not pretend that they repreand thorough understanding of the physiologic action of the agent so that sent the general opinion of clinicians. The paper contains a it may become generally used and tinclinical evaluation of the drugs only. The author’s reasons derstood. Since, however, nuperfor liking or disliking agents is expressed briefly together with caine is essentially a quinine derivahis ideas of their clinical usefulness. tive and may produce e x t r e m e l y toxic effects, I have discarded it.
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INDUSTRIAL AND ENGINEERING CHEMISTRY
TABLE I. COMPARISOX OF SPECIAL AND ORDIXARY AGENTS (IN PERCENT) Specialagentsandmethods Ordinary agents and methods
1935 1934 1933 1932 1931 1930 1929 1928 1927 1926 1925 5 2 . 3 3 5 . 2 30.9 3 0 . 1 31.6 28.9 1 9 . 4 14.6 12.9 16.3 1 5 . 9 47.7 64.8 8 9 . 1 69.9 6 8 . 4 7 1 . 1 8 0 . 6 85.4 8 7 . 1 83.7 8 4 . 1
TABLE 11. SPECIAL AGENTSAND METHODS(IN PERCENT) Regional block Oil-ether colonic Acetylene Tribromoethyl alcohol and barbiturates Barbiturates (by rectum) Barbiturates (intravenously) Tribromoeth 1 aloohol Intratr acbea? anesthesia Intrapharyngeal anesthesia Cyclopropane Divinyl ether
1935 58.3
1934 1933 1932 1931 1930 1929 79.9 81.1 80.8 86.7 8 3 . 8 7 9 . 1 .. 0 . 1 . . .. .. .. 0.2 .. .. .. .. 0.2 1.0 .. .. .. 0.03 0 . 0 9 0:01 0 . 4 0.4 14:s 2 : s 0 : 3 0:6 1 . 4 8 . 9 15.2 0.03 0 . 2 0.7 0.8 0.3 1.3 2.2 10.2 1 4 . 8 16.2 1 5 . 5 1 0 . 4 5 . 2 2.9 0.1 0.3 0.5 0.6 0.7 0.3 0.2 16.3 1.7 .. .. 0.3 0.01 .. 0 . 1 .. ..
..
I
PANTOCBISE. The next drug used a t the clinic was pantocaine (butylaminobenzoic acid P-dimethylaminoethyl ester monohydrochloride), Following a number of experimental studies on animals carried out a t the Institute of Experimental Surgery and Pathology in Rochester (Y), this drug was found to be much safer than nupercaine and was used clinically in a number of cases. The potency and toxicity of both nupercaine and pantocaine, however, are much greater than that of procaine, but it was believed that the use of these drugs would be safe if correspondingly smaller doses of each were used. This supposition, however, has not been clearly demonstrated. I n all probability there is a systemic effect in spinal anesthesia which is produced during transportation of the anesthetic from the spinal fluid by way of the blood stream to the liver, where it is destroyed. This is the only apparent explanation for the otherwise untoward results obtained during spinal anesthesia with these agents. Pantocaine is a surface anesthetic, and it has been tried in gels and in ointments for the purpose of producing a painrelieving dressing. This result has been accomplished and the agent has given satisfactory results in the treatment of many superficial wounds in civil cases; no doubt it will accomplish the same purpose in military cases. The suggestion that pantocaine be used with procaine for spinal anesthesia has been made by Tovell (11) and by McCuskey ( 9 ) , but general experience n i t h pantocaine has not been such as to bring it into universal faror, although its use is fairly common. METYCAIXE.Benzoyl-y-(2-methy1piperidino)-propanolhydrochloride, or metycaine, has giren general satisfaction. I t s manufacturers have been wise in not pushing its use clinically. I n gels and ointments, combined with an antiseptic such as merthiolate, it has given excellent results in relieving the distress of superficial wounds; in climates of extreme heat and cold such preparations n ill probably be serviceable when solutions of the agents in water might not be. Metycaine, which has a surface anesthetic as well as an antiseptic effect, comes closest to giving the clinician a good all-round preparation of any yet used, although the writer is not yet in a position to pass final judgment on it. Since metycaine is also injectable and may be used for spinal anesthesia, it is generally more applicable than other local anesthetic agents. DIOTHANE.This hydrochloride of piperidinopropanediol has been satisfactory as a surface anesthetic in urologic cases. It was somewhat irritating when first used, but it is apparently less so a t present. Its use by injection is not advisable, at least in or near diseased tissue; indeed the advisability of using any local anesthetic agent in such tissue is questionable. Diothane has also been used in ointments, but it has no advantages over metycaine for this purpose. ADDITIOSAGENTS. I n local or infiltration anesthesia the
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addition of epinephrine (adrenaline) to the local anesthetic agent definitely improves the quality of the anesthesia, its duration, and its local hemostasis. Certain individuals, such as those suffering from exophthalmic goiter and from marked hypertension and those in a highly excited condition at the time of operation, do not tolerate epinephrine well, and for them it is said that cobefrin may be better tolerated. The action of cobefrin in respect to hemostasis is similar to that of epinephrine, and it may be given by mouth. Ephedrine is valuable in sustaining blood pressure during spinal anesthesia.
Inhalation Anesthetics
-
VIXETHENE. Of the general inhalation anesthetic agents which have been used, vinethene, or divinyl oxide, has not been found as satisfactory as diethyl ether. Vinethene does not regularly bring about good relaxation or quiet gentle breathing even when an intratracheal tube is inserted. Bourne ( 1 ) reported using it in obstetric cases, but the writer has not yet felt entirely justified in using it in such cases. The explanation for the limited use of vinethene a t this clinic is either that it was not administered properly or that it was not used in a sufficient number of cases to obtain an accurate idea as to its true value. CYCLOPROPANE. This has definitely taken the place of acetylene for inhalation anesthesia. While the mixture of cyclopropane and oxygen that produces anesthesia is explosive, and the mixture of ethylene and oxygen that produces anesthesia in inflammable, there can be no doubt that cyclopropane has entirely displaced acetylene and will largely also displace ethylene. Cyclopropane, however, will not displace nitrous oxide because the latter carries with it less fire hazard; in the present wide clinical application of the diathermy machine, the electric scalpel, and electric devices for cauterizing malignant lesions, methods of anesthesia carrying no increased fire hazard are in demand. When a general anesthetic is to be administered, and when ether is contraindicated and an inflammable gas may be used, cyclopropane is the best anesthetic available. Use of this gas in both
Grains FIGCRE 1 . RELATIOX BETWEEN DOS.4GE AND EFFECTO F SODIUM AMYTALGIVEN IXTRAVENOUSLY IN THE AVERAGE HEALTHY .~DULT
SEPTEMBER, 1936
INDUSTRIAL AND ENGINEERING CHEMISTRY
surgical and dental cases has made it possible to operate on selected individuals with a feeling of security M hen there might otherwise have been considerable risk with some other agent. If ether is to be avoided and nitrous oxide or ethylene is used, then a degree of anoxemia may be produced which may be detrimental to the patient under the conditions of the operation or the disease from which the patient is suffering. This is especially true if debility is marked and if the erythrocytes are greatly reduced in number. The administration of cyclopropane is associated with considerable capillary oozing, as is true also of ethylene; in many cases such oozing seems to be greater with cyclopropane than with ethylene. Cyclopropane as a n adjunct to nitrous oxide has not been given the clinical trial it deserves. Cyclopropane can be added to nitrous oxide and oxygen just as ether can be, and the quiet and depressed respiration which is associated with deep cyclopropane anesthesia is of considerable advantage in operating on the thorax and diaphragm and on patients who are subject to those diseases, one of the symptoms of which may be dyspnea. CARBONDIOXIDE ABSORPTIOS. The use of a canister of soda lime for the absorption of carbon dioxide has reduced the expense of administering inhalation anesthetics to the lowest point in history and has also made it possible to extend the use of such agents even into small communities where previously it was felt they could not be afforded and where they were looked on as luxuries to be used only in well-endowed institutions or for wealthy people. The use of the carbon dioxide-absorption technic has also decreased the fire hazard in connection with the administration of ethylene and cyclopropane, and without doubt this has been responsible for the immediate clinical success of cyclopropane, for while the cost of a cylinder of cyclopropane may be high, the cost of anesthetizing each patient is relatively low. HELIUM.Because of its low molecular weight, helium reduces the average molecular weight of the inspired mixture when it is used as a vehicle for oxygen or other anesthetic agents. It has been found of real value to patients suffering from acute asthma and for those with pathologic obstruction in the airway passages, especially if the trachea has been compressed by a thoracic tumor or goiter. I n all probability it will be incorporated as a standard agent in many gas machines. It is available a t this clinic and can be used in the gas machines.
Intravenous Anesthetics BARBITURATES. The intravenous method of anesthesia has been revived by the recent appearance of two very shortacting barbiturates : (1) sodium n-methylcyclohexenylmethylmalonylurea (“evipal soluble”) which was introduced in Europe as “evipan,” and ( 2 ) sodium ethyl-(1-methylbutyl) thiobarbituric acid (“pentothal sodium”), formerly called “barbiturate A” and “thionembutal” (6). Clinically there are now three types of barbiturates, and they are classified according to the degree of anesthesia they produce-namely, prolonged, sustained, and short. -4barbiturate of the first type is sodium amytal and one of the second type is pentobarbital sodium (“nembutal”) ; barbiturates of the third type are evipal soluble, pentothal sodium, and perhaps also “seconal” (sodium propyl methyl carbinyl allyl barbiturate). There are certain definite characteristics exhibited by all these barbiturates regardless of m-hether they produce a prolonged, sustained, or short effect. These effects may or may not be noticeable, depending on the rapidity with which the patient passes through the various stages of the effect of a specific drug. Figure 1 illustrates the various effects which are produced by the administration of sodium amytal, and which can be produced by any of the other barbiturates. The scale has a
”
~~
V-ctrte
1033
L-:urve
U-c,rve
Vulverebil.ty
c il: ~ e s
FIQTJRE 2. DOSEOF EVIPAL SOLUBLE(INTRAVENOUSLY) FOR A MAN40 YEARSOLD WEIQHINO150 POUNDS (68 KO.),AND 5.5 FEETTALL
illustrates the safe dose for a short operation. U shows the nonfatal result of a moderate overdose. respiration is almost completely depressed for a short time and the remvery is prompt if no more is given. It shows t h a t the period’of anesthesia is longer than when a small dose is given and this period of anesthesia is coincidental with respiratory depression. Curve L illustrates the overdose, nhich is large enough t o be fatal
triple meaning. If we are thinking in terms of dosage, the scale may be read in grains; in terms of induction, it should be read in minutes (the maximal time used for producing the effect); in terms of recovery, it should be read in hours. The figures in the black area indicate the stage of effect of the barbiturate. First is the stage of hypnotic effect, the second the stage of inebriation, the third the stage of anesthesia, and the fourth the premortem stage from overdose. Only a small percentage of patients recover from the fourth stage if an overdose has been given. Induction is frequently hastened to only a fraction of the time indicated. Sodium amytal can be used intravenously in medical cases for the relief of the convulsions of tetanus and of strychnine poisoning, where the effect of the barbiturate must be prolonged and the demand is for an immediate effect. Pentobarbital sodium has been used intravenously a t the clinic in surgical cases, although it is now given by mouth as a preliminary medicament and for this purpose has been a favorite for two or three years. Evipal soluble has also been given intravenously for surgical anesthesia with satisfactory results. Instead of employing the technic of administration originally recommended, varying amounts are given intermittently as needed, following the principle used in administering ether by the open-drop method. The method of giving a single dose of evipal soluble until surgical anesthesia is produced seems as absurd as attempting to give ether by the opendrop method in sufficient amount in the first few niinutes to supply anesthesia for the whole operation; as a rule the operation would certainly outlast the period of anesthesia produced under these circumstances. I n the first six months of 1934, evipal soluble was used intravenously in a limited number of cases; in June the writer began to compare its effect with that of pentothal sodium. The increased potency of the latter was so evident that it was soon preferred. The relative margin of safety of the two agents is about the same if the intermittent method of administration is employed (Figure 2 ) and if the difference in potency is taken care of by varying the d o s a g e t h a t is, if from half to two-thirds as much pentothal sodium as evipal soluble is used. The toxicity of these agents is shown clinically in depression of respiration; small doses of either drug tend t o
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INDUSTRIAL AUD ENGISEERING CHEMISTRY
produce this effect. The relative toxicity and potency of pentothal sodium and evipal soluble are as 1 to 0.66. It was soon found that, if these short-acting barbiturates are given in large doses, the resulting period of recovery from anesthesia is prolonged and some of the undesirable features associated with the use of sodium aniytal and pentobarbital sodium by the intravenous method are present. Therefore, preliminary medicati-n is usually advisable so that minimal quantities of these short-actirg barbiturates will suffice. Evipal soluble and pentothal sodium x-ere injected in 10 per c e n t concentrations. When either of these drugs was injected extravenously, it caused irritation of the tissue, but this condition was fairly well controlled by the application of moist heat. I n time, veins in the back of the hand were used in preference to those of the arm so that extravenous i n j e c t i o n s w o u l d b e noticed quickly and m i n i m a l amounts of the drug would thus be used. However, there seemed to be a definite although small number of patients who complained of discomfort after injection, especially of pentothal FIQURE 3. SCHEME FOR sodium. It was therefore found SAFE -ADMIPJISTRATION O F necessary to inject p e n t o t h a 1 BARBIT URATES sodium in 5 rather than 10 per cent concentration. I n connection with the intravenous use of these drugs, it soon became apparent that the principal sign of anesthesia was shallow respiration. Although the clinic has never advised the use of these agents by the inexperienced, the intravenous method seems to be easily mastered by the newest physicians. A scheme was then adopted which seemed to add considerable safety to the use of these agents (6) (Figure 3). d butterfly of cotton is fastened to the patient’s upper lip so that one wing is over his lips and the other below his nostrils. The anesthetist then never administers the anesthetic in sufficient quantity to stop entirely the motion of this cotton. I n this way untoward results probably can be avoided. To guard further against undue respiratory depression, the writer incorporated a respiratory stimulant in the same solution with the intravenous anesthetic. The first one used was pyridine P-carbonic acid diethylamide (coramine) ; it was added to the solution in the proportion of one part of coramine to four of pentothal sodium. There usually was a definite difference in the volume and character of the respiration when coramine was used and when it was not used, especially in cases in which patients had been prepared for operation and anesthesia by the oral administration of a barbiturate and hypodermic injection of morphine and atropine. The other known respiratory stimulants are being investigated in order to determine which one is best. Another barbiturate used intravenously was sodium allyl sec-butyl thiobarbituric acid (“barbiturate B” or “thiosebutal”). Its potency was about that of evipal soluble, and, since it did not give the clinical satisfaction obtained with pentothal sodium, it was subjected to only a short clinical trial. Pentothal sodium was tried as a preliminary medicament by mouth before operation, but it was not as satisfactory for this purpose as pentobarbital sodium. Seconal was also tried as a preliminary medicament. It was given for a few weeks during very warm weather; more patients were nauseated from i t than from the other barbiturates, so that no
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further clinical applications were attempted. It is said t o be short-acting, but as yet the writer has not heard of it.. being used intravenously for producing surgical anesthesia,
Rectal Anesthesia The rectal method of anesthesia has been advocated for many years. Attempts to secure anesthesia with ether by this method, however, were unsatisfactory until 1913 when Gwathmey (a) suggested a combination of ether and olive oil. This method was not considered to be uniformly safe when full surgical anesthesia was produced, and its greatest clinical application and usefulness probably occurred in obstetric cases when it was used as an analgesic rather than an anesthetic. Tribromoethyl alcohol (“avertin”) came into use in 1926 as a rectal anesthetic to replace ether, since ether is volatile, is eliminated by the lungs, and hence cannot be controlled easily. It was thought that avertin, which was detoxified by the liver, might solve the problem. I n the early cases in which full surgical anesthesia was attempted with this agent (6),there were a few fatalities. However, rectal anesthesia with avertin solution was, and is, a satisfactory method of producing b@saldmesthesia,and it is used to advantage when circumstances’{ permit the surgeon to complete the operation under suppl6mentary anesthesia with small amounts of a local, inhalation, or intravenous anesthetic. Magill’s method ( I O ) of using a large-bore soft-rubber intratracheal tube as a n airway in connection with the administration of inhalation anesthetics has largely eliminated the need for rectal anesthesia by means of avertin. However, in small doses avertin is satisfactory and valuable when the intratracheal method cannot be used. It fills a definite place in the medical armamentarium, and, although there is seldom a case in which it is the anesthetic agent of choice, it should not be given up entirely.
Literature Cited B o u r n e , W., Lancet, 1, 566-7 (March l i , 1934).
Gwathmey, J. T., 2, 1756-8 (1913). Jones, W.H., Brit.J . Anaesthesia, 7 , 99-113 (April, 1930). L u n d y , J. S., Proc. Sta.f Meetings M u y o Clinic. (Suppl.), 4 , 370-80 (Dec. 18, 1929). Ibid.,10,536-43 (1935). ( 6 ) Ibid., 10, 791-2 (1935). ( 7 ) L u n d y , J. S . , a n d Essex, H. E., Ibid., 6,376-80 (1931). ( 8 ) L u n d y , J. S., a n d Torell, R. M., Ibid., 9, 221-40 (1934). (9) M c C u s k e g , C. F., Anesthesia and Analgesia, 12, 116-18 (1933). (10) Magill, I. W., Proc. R o y . SOC.Med. (Sect,. Anes.), 22, 1-6 (Dec., 1928). (11) Tovel1,’R. M., Can. Med. Assoc. J . , 28, 404-9 (1933). RECEIVED June 8, 1936. Presented before the Division of Medicinal Chemistry a t the 9 l s t Meeting of the American Chemical Society, Kansas City, >lo., April 13 to 17, 1936.
APPARATUS USED IN GRINDING GLAXDS OR LIVER, LABOR.4TORIES O F ELI LILLYAND COMPlNY
