EFFECTS OF ALPHAeLOBELIN ON RESPIRATION

AN EXPERIMENTAL STUDY*

ROBERT A. WILSON, M.D., F.A.C.S. AND M. ALLEN TORREY, M.D.

BROOKLYN, N. Y.

SPHYXIA is a frequent probIem A of medicine. The arrest of puImo- nary activity is an ever-present

danger with our highIy specialized surgica1 procedures. There is aIways the possibiIity of faiIure of the respiratory center during spina anesthesia or from overdosage with ether or chIoroform. In the heId of in- dustria1 medicine, asphyxia is frequentIy encountered, particuIarIy foIIowing poison- ing with carbon monoxide or iIIuminating gas. Intentional or accidental overdosage with drugs, such as morphine and veronaI, must be considered, aIthough this is Iess frequentIy seen than formerIy.

ProbabIy the obstetrician is confronted with asphyxia more frequentIy than other members of the profession. It is certain that asphyxia accounts for a Iarge number of infant deaths. In some cases the as- ph yxia occurs so earIy in Iabor that nothing is of any avai1, but in other cases, a’ reIiabIe method of combatting it wouId save many babies and materiaIIy Iower the infant death rate.

A review of the present methods of treating respiratory faiIure Ieads to the concIusion that none of them is perfect. ArtificiaI respiration is vaIuabIe, yet often impractica1. Another method is the use of chemicaIs and aIkaIoids, the most impor- tant being caffeine, atropine and aIpha- IobeIin. Caffeine may be administered with safety but cIinicaIIy it is a poor respiratory stimuIant. Atropine, in suf- ficient quantity to produce a respiratory response, has so many undesirabIe side effects that its use is seIdom practica1. LogicaIIy, it would seem that the natura1 respiratory center stimuIant wouId be the

best. It is improbabIe however, that asphyxia occurring in the presence of high tensions of carbon dioxide in the bIood, wouId be reIieved by the administration of more carbon dioxide. That such a condition does exist has been shown by Eastman. The foIIowing quotations are taken from Eastman’s paper, recentIy published.

The reIativeIy high carbon dioxide tension of foetaI bIood as it exists in utero seems difficult to reconciIe with a state of apnoea, and at present this phenomenon can onIy be expIained by assuming that the sensitivity of the foetal respiratory center, in respect to this gas at Ieast, is markedIy depressed.

. . . since the tension of carbon dioxide in the bIood of asphyxiated infants is usuaIIy aImost twice that found in norma babies, the use of this gas as a resuscitating agent seems to us superfluous and possibIy harmfu1, inasmuch as it may tend to intensify an already existing acidosis.

Eastman and other investigators have shown that in many cases of asphyxia neonatorum high tensions of carbon dioxide in the bIood can be demonstrated. In such cases it wouId seem that the use of carbon dioxide wouId be contraindicated. We do not know with any degree of certainty whether or not this condition exists in other types of asphyxia.

The stimuIating action of the nicotine group on the respiratory center has Iong been known, but the high toxicity of these drugs has made their use impractical. Quite recentIy a hydrochIoric saIt of an aIkaIoid of LobeIia inffata has been pro- duced which, whiIe possessing a stimuIating action on the respiratory center, is said to Iack toxicity. This drug under the name

* From the Department of Obstetrics and GynecoIogy, the Long Island CoIlege of Rledicine.

426

NV\\ SPHIRS Vnr.. XXIII, No. 3 Wilson & Torrey--Alpha-LobeIin Amcric;m Journal of Surgery 427

of alpha-Iobelin has become moderateIy popular in recent years, ahhough it is stiII an infant therapeuticaIIy, there being

ested in comparing the principa1 act ions of aIpha-IobeIin with nicotine. The herb LobeIia inff ata was First recognized in 18 I 3

FIG. 1. Response to intravenous injection of gr. go of aIpha-Iobelin. After nine seconds, there is an initial deep inspiration folIowed by a few excursions of irregular Iength; an increase in rate and, in generaI, a lower fixation of diaphragm which sIowIy returns to its original position. As effects of drug wear off, rate progressively decreases and amplitude increases. (See Table II, Number I.)

a Iack of detaiIed and reIiabIe knowledge of its cIinica1 action. This paper deaIs only experimentaIIy with a phase of its pharma- coIogic action. Before proceeding further, a brief discussion of the historica aspects seems proper.

HISTORY

LobeIia inffata is the herb from which aIpha-IobeIin is obtained. It is a member of the nicotine group, and it has Iong been known that a smaI1 dose of nicotine acts as a brief stimuIant of the respiratory center. Nicotine is not used for this purpose because of its toxicity and other iI effects. It is aIso known that injections of nicotine raise the bIood pressure because of vaso- constriction from combined stimmation of the vasomotor center and the periphera1 gangIia. This rise in bIood pressure Iasts onIy a few minutes. These brief facts are mentioned for those who might be inter-

FIG. 2. Response to gr. No. Characteristics are same as those of Figure I, onIy more marked. Descent of diaphragm is greater and more prolonged. BIood pressure changes are shown in third tracing. There is a maximum rise of 38 mm. of mercury above normal which is sustained for thirty-nine seconds. (See TabIe III, Number 7 and Table v, Number 7.)

by CutIer, who used it in the treatment of asthma. It had been used for many years however by the Indians as a substitute for tobacco.

The principa1 aIkaIoid is IobeIine, which unti1 recentIy had been isoIated onIy in the form of impure amorphous saIts. In 1916 WeiIand succeeded in preparing a pure crystaIIine hydrochloric salt, and it is this preparation that was used in our experiments. It differs from the previousIy mentioned amorphous saIts in that it has no emetic action. In addi- tion to Iobeline, which has the formula C22HzTN02, four other aIkaIoids are found in the pIant, which are known as IobeIid-

428 American hrd of Surgery W&on & Torrey-AIpha-Lobelin MARCH, 19x4

ine, C20H2jN02, IobeIanidine Ct2H29N02, IobeIanine C2,H,,N02 and isoIobeIanine &.H2,N02. Salts can aIso be formed of

FIG. 3. Copy of an origina graph showing response to gr. 3{0. Here there is a rapid and marked descent of diaphragm with first an irreguIarity and then a compIete cessation of respirations. This apnea, with diaphragm in extreme inspiratory position, is main- tained for 105 seconds. After this there is a partia1 reIease of diaphragmatic spasm, with respirations for a time rapid and totaIIy irreguIar. Later rhythm is reestablished with both ampIitude and rate in excess of OriginaI. FoIIow tracing in 1-3-z-4 order. (See Table III, Number I I .)

these aIkaIoids, but the hydrochIoride of IobeIine is the most readiIy purified. It meIts at 182’~. Those who are interested further in its chemistry, are referred to the appended bibliography.

It might be interesting to give a few quotations from the standard textbooks of pharmacoIogy regarding this drug. SoIis- Cohen and Githers state that pure IobeIine has a stimuIating action on the respiratory center and does not cause vomiting even in Iarge doses; that smaI1 doses from 0.5 to I mg. when injected into pigeons cause a marked increase in respiratory rate and

voIume of tidal air. The increase may run as high as 50 per cent. This effect is especiaIIy marked if the respiratory center has been poisoned with morphine, veronaI, etc. ; it never produces a centra1 paraIysis and even in Iarge doses the vomiting center is not excited. They aIso state that the crystaIIine saIt shouId be given great consideration as a respiratory stimuIant, because it has none of the depressing and nauseating properties of the crude drug and in proper doses acts onIy on the respiratory center. SoIImann states that if 0.5 mg. per kg. is injected into the rabbit the carbon dioxide threshold is Iowered and this produces a marked stimu- Iation of respiratory movements; that for rabbits which had been deepIy morphinized it was necessary to use as much as 5 mg. per kg. This author aIso states that I mg. per kg. in the cat causes an increase of bIood pressure with some acceIeration of the heart. Meyer and GottIieb state that the hydrochIoride stimuIates the respira- tory center and may be given intravenousIy or intramuscuIarIy to strengthen the res- pirations and make them more rapid. They fee1 that it is particuIarIy usefu1 in respiratory paraIysis during narcosis.

The preceding quotations were searched for after our experiments had been con- cIuded and are given for those who may be interested in comparing them with our resuIts.

It is our purpose first, to determine whether or not the drug is a respiratory stimuIant; second, to anaIyze the mechani- ca1 reaction to its use; third, to consider its toxicity; fourth, to endeavor to isoIate the Iocus of its action. In a few cases simuI- taneous bIood pressure tracings have been taken. These wiI1 be briefly discussed.

METHOD

The mechanica arrangement empIoyed for recording the respiratory changes is a modification of the weII-known diaphragm method. A smaI1 Iinear incision is made through the Iinea aIba beginning about 5 cm. beIow the tip of the zyphoid process.

KS w Se1uts VOL. XXIII, No. 3 WiIson & Torrey-AIpha-Lobelin A-ncrican Journal of Surgery 429

This incision is made purposeIy smaI1 to prevent air exposure of the abdomina1 contents. A smaI1 hook is introduced and inserted in the under surface of the diaphragm, as high up in the dome as possible. A fine cord, which was previousIy threaded to this hook, is then carried to one arm of an equa1 armed Lever and fastened there. From the other arm of this lever another cord is carried around a puIIey whose axis is in the vertica1. The Iever is mounted on a standard in such a manner that variation in the Iine of puI1 is possibIe through rather wide Iimits. The puIIey is freeIy movabIe and of such a weight that inertia is practicaIIy negIigibIe. The cord is finaIIy attached to the short arm of an unequa1 armed lever (ratio 3 : I). The Iong arm of this Iever carries a scribing point which writes on the drum.

It is obvious that the position of the hook in the diaphragm wiI1 vary somewhat in difFerent experiments. However, once placed, its position remains the same for the duration of any given experiment. The error, then, for each experiment is a constant. The movable standard carrying the equa1 armed Iever makes possibIe the eIimination of friction between the cord from the diaphragm hook and the sides of the abdomina1 incision. The movements of the diaphragm are faithfuIIy recorded with such an arrangement but are exagger- ated as to excursion by means of the unequa1 armed Iever.

After many triaIs we abandoned the usua1 laboratory methods for recording respirations, since in our opinion they a11 possess error factors that cannot be eIimi- nated. The usua1 diaphragm method using a singIe cord to a muItipIying Iever re- quired such carefu1 adjustment that ac- curate tracings were obtained more by accident than design. The carboy and pneumographic methods as commonly used empIoy tambours for recording. The ac- curacy of these tambours depends primariIy on the condition of the rubber, a very uncertain factor. Gross change is not shown we11 by either method. The sharp-

ness of the m-essure changes is eliminated bv the cus&oning effectoof the air. The c&boy method is essentially a rebreathing

FIG. 4. Rq ,_” . an initial increas: in rate and aG&tude with a sIight descent of diaphragm. As effects of drug wear off, rate and amp&de diminish. Comparison with Figure I, shows difference in magnitude of diaphragm change with peripheral sensory arc cut. iScc Table I\-, Number 3.)

one. The stimuIation of the center by carbon dioxide must steadiIy increase as the experiment progresses, thus distorting the tracing.

Blood pressure tracings were obtained in the approved Iaboratory manner. A carotid cannuIa was inserted and con- nected with a mercury manometer, the scribing point of which was arranged to write on the drum.

We used cats weighing approximateIS 3 kg., anesthetizing them with sodium

430 American JournaI of Surgery Wilson & Torrey-AIpha-Lobelin MARCH, 1934

amytaI given intraperitoneahy. Sufficient of the drug was used to produce good

in one direction onIy.

muscuIar reIaxation. The alpha-Iobelin In most cases, particuIarIy those in

which a smaI1 dose of aIpha-IobeIin was

FIG. 5. Compo Iine) with

site graph comparing average puImonary ventiIation after various doses of alpha. norma ventiIation (straight Iine). (This graph is compiled from a11 Tables except

-1obeIin (brc IV and v.)

was injected into the femoraI vein in doses ranging from gr. J& to gr. 3f0,

EXPERIMENTAL DATA

Certain of our tabuIations are arbitrary and require expIanation. IndividuaI ex- cursions of the Iever have been carefuIIy measured as to phase in time and from this the average tota phase has been deter- mined. It wiI1 be noticed that in every case preceding the administration of the drug, the expiratory phase is considerabIy Ionger than the inspiratory phase and this type of respiration we have caIIed n or normaI. In experiment number 3 foIIowing biIatera1 vagotomy this condition is reversed, the inspiratory phase being considerabIy Ionger (two seconds) than the expiratory phase. This type we have caIIed r or reversed. FoIIowing the administration of alpha- IobeIin, the tota phase has been reduced in every case, the greatest reduction occurring in the expiratory phase in a11 but experi- ment 3. The tabuIations under amplitude indicate miIIimeters of excursion, measured

used, we found that the visibIe changes resuIting from its use were initiated by a very deep inspiration.

Since respiratory efficiency depends on both rate and amplitude, particuIarIy of the diaphragmatic excursions, we have chosen to caIcuIate efficiency in terms of both these factors. This efficiency factor is tabuIated as ventijation index and is obtained by taking the sum of individua1 ampIitudes for a given period of time. It wiI1 be noticed that this factor varies in the norma from experiment to experiment, probabIy because the hook in the diaphragm is never in exactIy the same position in any two cases. This variation pIays no part in the fina resuIt since the hook once pIaced is never changed during any given experiment.

FoIIowing the administration of aIpha- IobeIin, irrespective of the dose, effects are obtained in from six to eIeven seconds. The maximum effect is reached very rapidIy, occurring in a11 our experiments within the first minute. The visibIe effects of the drug seIdom Iast more than four minutes. With the smaher doses (gr. +&

NEW SERIES VOL. XXIII, No. , W&on & Torrey-AIpha-Lobelin America” Journal of $urgcry 4; I

and gr. x0) there is considerabIe change in ventilation index.

Grain s/40 (3 Cases)

The reaction to the drug was rapid with an increase in the respiratory rate (5 1.9 per cent above the norma during the first minute and 25.7 per cent above the norma during the second minute) and a decrease in the ampIitude of the excursion (5.59 per cent beIow the norma during the first minute and 12.49 per cent beIow the norma during the second minute). The rate showed an average tota increase of 38.8 per cent, and the ampIitude an average decrease of 9.04 per cent. ‘I he ventiIation index showed an immediate increase above the norma during the first minute foIIowed by a drop from this high point during the second minute. It was, however, stiI1 above the norma during the second minute in a11 but number 8. The average ventiIation index was 43 per cent above the norma during the first minute and IO. I 6 per cent above the norma during the second minute, an average tota increase of 26.58 per cent for the two minutes.

The reduction in the duration of the expiratory phase observed during the first minute was not maintained during the second minute, there being a tend- ency for both phases (inspiratory and expiratory) to reestabIish their origina reIationship.

Grain 450 (3 Cases)

The response to the drug was aImost immediate, the respiratory rate increased (75.7 per cent above the norma during the first minute and 5 1.9 per cent above the norma during the second minute) and the ampIitude decreased (27.39 per cent beIow the norma during the first minute and 34.195 per cent beIow the norma during the second minute). The tota rate increase averaged 63.8 per cent above the normal and the total amphtude decrease averaged 30.79 per cent beIow the normaI. The ventiIation index averaged 44 per cent above the norma during the

first minute and 25.7 per cent above the normal during the second minute. The average tota ventilation index was 34.85 per cent above the normal.

TABLE 1

ANALYSIS OF MECHANICAL RESPONSE TO GRAIN x,-, OF

ALPHA-LOBELIN ADMINlSTERED INTRAVENOUSLY

Number ._._. _. 2 15 ‘8 Dose.. $60 ‘Si, :x0 Normalr/m .__.........___.._ 1x6,s 19 18 Type. In

I /

n ” Exp. phase. 2.i 2.j I

iz. 3 nspasc h ..I o.7j iI

Total phase., 3.5 13.2j i3.3

Amplitude.. ~36 13 ;51 Initiating Ins.. .‘40 30 Vent. index.. 594 1247 I918

Rate 1st ml”. Rate 2nd mm., _. Av. amp. rst min. Vent. index 1st min.. Av. amp. 2nd ml”. Vent. index 2nd min.,

28 128 25

24 124 119

30.1 ‘14.45 843 406 K

.,30.4 ,12.25 i42.7

,173’ I294 $12

Av. amplitude and vent. index 31 .o-218 13.837 144.2-310 at 15 sec. intervals for the 29.7-208 r4.5-IOZ 47.1-269 two minutes following injec- 30.0-210 14.5-102 44.1-265 tion of the drug. 29.2-205 lg.o-ro5 40.6244

30.1-181 13.&82 40.8-204 ‘30.3-182 ,12.x-73

1st min EXD. ohase.. . . Ins. phase..

2nd min. Exp. phase. Ins. phase.,

Vent. index rel. to normal rst ml” . .._. . . 2nd ml”. .

Rate rel. to normal 1st ml*. . . . . 2nd ml”. _. _. .

Amp. rel. to normal 1st In‘“. . 2nd mm.. ,_ __ _. .

.!f41.9% +23.o%

+69.4% .lf45.4%

:iZ:::zy

i-64.3% +lg.o%

i-22.8% - I I 5 rj

Av. vent. index rel. to normal ’ 1st m1n. . . . . . 2nd min.. _. . . . . . . . .

Av. rate rel. to normal 1st m1n. . . . . . 2nd ml”. . . _.

Av. amp. rel. to normal 1st ml” . . . . . . 2nd ml”. _. . _.

I I . ~+43.0% I

‘+ro.r6%1

....... ‘+51.9% ’

....... +25.7% / I

........

....... ,I 5.59% . 12.49%

Av. total vent. index rel. to I normal. ............................ ‘+26.58%

Av.totaIratereI. tonormal ............ ~+38.8% Av. total amp. rel. to normal ............ - 9.04%

I -

Grain 3io (I case) Grain 3so (I case)

Grain pi0 (I case)

FoIIowing grain 3& and grain 340 there was a marked increase in rate (83.3 per cent; 166.6 per cent), which increase was

432 American J~~r”al of Surgery Wilson & Torrey-Alpha-Lobelin MARCH, 1934

maintained during the first two minutes. With grain j?io the rate sIowed almost immediateIy and in fifteen seconds an apnea deveIoped which Iasted for the

TABLE II

ANALYSIS OF MECHANICAL RESPONSE TO GRAIN $‘&j OF

ALPHA-LOBELIN ADMINISTERED INTRAVENOUSLY

I I Number.. Dose. Norma1 r/m. Type. . Exp. phase. Ins. phase.,

Total phase Amplitude

Initiating ins Vent. index

, . . . I 16 I.2

>$o ‘340 lfio 17.5 I8 ,9

. n ” n

‘., 3.35 2.3 I.75 . ..o.g , ‘I

3.85 . 3.3 ‘2.75

32.25 ‘.. 45 2:

,4 32

563 666 266

Rate IStmr”......

Rate 2nd min.

Av. amp ,St min..

Vent. index ,St min

Av. amp. 2nd m,n, Vent. index 2nd min..

. . . 29 '31 36 25 23 33

,.. 25.4 31.7 II.3 ‘.. 739 984 408 . 23.7 32.6 9.8 . 588 (815 1323

Av. ampIit”de and vent. index 26.8-~15 4o.z-282 atxgsec. intervalsforthetwo 27.1--19026.2--210 minutes foIlowing injection of 25.4-178 30.9-247 the drug. 23.o--16130.6-245

22.5-158 29.6-237 123.3-,403,.0-,86

10.8-87 ,2.3--I,, ,,.o_99 ,,.,-,,I

8.9-7, ,o.o-go 10.0-8, 10.1-8,

1st min. Exp. phase..

Ins. phase.. 2nd min.

Exp. phase. Ins. phase. _.

1 I 0.7 0.75 0.5 0.7

,.3 1.6 0.5 . 0.75 0.7 I

Vent. index rel. to normal ,st rn,“. I.. 2nd min

Rate rel. to normal 1st min. _. 2nd m,n..

Amp. rel. to normal ,st mm. 2nd m,“.

+3,.0% +47.?% + 4.4%1+22.3%

i-65.6% -t72.2% +42.8% +38.8%

-21.2% -14.3% . -26.5% -11.89%

+89.4% +74.x%

-19.28% -30.0%

Av. vent. index rel. to normal 1st “xl”. . 2nd nun., _. _, _.

Av. rate ret. to normal ,st rn,“. 2nd min.. .

Av. amp. rel. to normal ,st nun.. . . . . 2nd mm.. . . ..,..,..

Av. total vent. index rel. to normal. . . . . . . . . . . . . .

Av. total rate ret. to normal. .I. Av. total amp. rel. to normal.. (. .

-+-44-O% -tZ5.7%

i-75.?% +5,.97o

-27.39%

-34.195%

remainder of the first minute and during the entire second minute. At the end of two minutes rapid shaIIow respirations began. During the next eight minutes the rate graduaIIy diminished and the amplitude graduaIIy increased unti1 norma respira- tory relationships were again established.

The amplitude was reduced in al1 3 cases, the greatest reduction occurring with grain 9$0 (36.81 per cent) and grain 3io (90.95 per cent). The reduction with grain 950 was 22.03. per cent.

TABLE III

ANALYSIS OF MECHANICAL RESPONSE TO GRAIN 940,

GRAIN so AND GRAIN yfo OF ALPHA-LOBELIN

ADMINISTERED INTRAVENOUSLY

Number.. I IO lap,

‘7 Dose. 14&l Normal r/m ‘24 2,

iii0

Type.. . _. n I” ” Exp.phase r.75 ‘2 ‘I.5 Ins. phase.. 0.3 I 0.5 Total phase 2.2 3 2

Amplitude.. 35 I, ‘9 Initiating ins 44 29 Vent. index. 840 23, 456

,- Rate ,st min.. 44 56 5 Rate and mio 44 56 0

Av. amp ,Sf min. . 22.3 9,25 3.45 Vent. index ,st min. . 982.3 521.17 16.25

Av. amp. 2nd min.. 2, .g 7.9 0

Vent. index 2nd min.. 965.8 447.34 o

Av. amplitude and vent. 29.7-326.7 ,2.7-179.38 13.8-16.25 index at 15 sec. intervals 23. o-253 10.6I49.7 O-0 for the two minutes fol- ,8.3-w, .3 6.7-94.63 o-o lowing injection of the ,8.3-2or.3 6.9-97.46 o-o

drug. 19.5-214.5 6.2-87.5 o-o *o.o--220 9.5-134.180-0 23.8-261.8 8.7-122.880-0

!24.5-269.5 7.1-,02.780-0

,st min. Exp. phase.. . . 0.5

Ins. phase.. . 0.5 1:::: :.5

2nd min. Exp. phase.. 1.0 0.55 0 Ins. phase.. . 0.5 0.50 0

Vent. index re1. to normal

,st min . +,6.9% +,25.6% -96.6% 2nd min.. . . +,4.g% + 94.9% -100%

Rate ret. to normal ,st nun.. . . . +83.3% +,66.6% -79.1% zndmin . . . . . . . . . . . . . . . +83.3% +166.6% -100%

Amp. ret. to normal ,st min ._._._... . . -36.2% - 15.9% -81.9% 2nd min . . -37.42% - 28.18% - 100%

Av. vent. index rel. to normaI ,............... -l-15.9% +,,o.zj% -98.3%

.A”. rate ret. to normal.. . . +83.3 % +x66.6% -89.55% Av. amp. rel. to normal... -36.81% - 22.04% -90.95%

Because of the high rate maintained with grain 350 and the reIatively smaII reduction in the ampIitude the ventijation index showed a huge increase (I 10.25 per cent). With grain 950 the ventiIation index increased 15.9 per cent whiIe with grain 3i0 it decreased 98.3 per cent. The marked decrease with grain ${o resuIted from the proIonged apnea.

With doses Iarger than grain 340 the inspiratory phase as we11 as the expiratory

Vagi lntnct h’,,mhrr Kate /ill> Type... Exp. phase Ins. phase. Total pIuw A111pl:t,l<l? Vent. inrlex

3 16

2.j

3.5

30 180

6

.,.

., -__

R:rte /m. Type. Exp. phase. Ins. phase., Total phase. Amplitude.. Vent. index.

vagi Cut

3

8 45

Rate 1st min.,

Nate 2nd min., Av. amplitude 1st min. Vent. index 1st min.

Av. amplitude 2nd min Vent. index. _.

Grain fo

;i’ 37.5 369 32.75 202

.......... .... ...........

............ 396.j 43

30’ I_ Av. amplitude and vent. index at I 5 sec. intervals for the

twc minutes following injection of the drug. .I 46-92

45-X12.5

43-64.5 45-67.5 44-66 43-86 43-86

42-63

34.5--138 44. o--88 ;i.5--77

33. w-66 34.5-69 33. s--67 3 I g--63 3 I 5-63

............ ........ .... ...... ......

.......... .........

1st min. Exp. phase.. Ins. phase.

2nd min. Exp. phase Ins. phase., _.

1st min. Exp. phase.

I Ins. phase.

2nd min. Exp. phase .’ Ins phase..

3 2.j

3 3.5

2.5

3

2.5 5

Following Double Vagotomy Vent. index decrease. . . Rate decrease. Amplitude increase. . .

Grain >io Vent. index increase..

43.3% 62.5% 50 %

. Av. total.

46.8% 11.4%

Av. total.. 16.6% 16.6%

Av. total..

0.590 4.4%

. Av. total..

36.6% 2.9%

. Av. total..

50% 1 33.3%

Av. total.. . 16.6%

37.4%

29.1% Rel. to normal. l-27.45%

16.67 Rel. to normal -56.2 %

1st mm. _, 2nd min..

Rate increase. 1st min.. 2nd min..

Amplitude decrease 1st min... 2nd min.. _.

Grain fir. Vent. index increase.. _. .

1st mm., 2nd min. _.

Rate increase. 1st min.. 2nd min

Ampiitude decrease. 1st m*n. _. 2nd min..

.

.

. . .

2.45:; (Kel. to normal. ._ 1+46.2%

16.85% ReI. to normaI.. -34.27 %

41.65% Rel. to normal ‘-46.8% .

2-s Rel tonormal.. :+17%

phase has shown reduction. The diminu- been Iess during the second minute than tion of both phases aIso tended to be during the first minute (gr. >iO, 3.1 per greater than with the smaIIer doses. cent; gr. $50, 3.4 per cent; gr. 3/40, I.7 per

The average amplitude for a11 cases has cent; gr. 350, 14.3 per cent). A comparison

434 American Journal of Su rgery Wilson & Torrey-AIpha-LobeIin MARCH, 1934

of these figures with the swing back observed in the ventiIation index for the same periods shows a striking simiIarity.

Grain >d,-, and Grain $50 with Double Vagotomy

Following doubie vagotomy the rate decreased 6245 per cent. The ampIitude increased 50 per cent. The ventiIation index decreased 43.3 per cent. This decrease resuIted from faiIure of the ampIitude increase to counterbaIance the decrease in rate. The folIowing percentages are all figured on post-vagotomy values except where otherwise indicated.

FoIIowing grain ,>io the rate increased 16.6 per cent for both the first and second minutes, giving an average tota increase of 16.6 per cent. This rate was minus 56.2 per cent when compared with the origina norma before vagotomy. The ampIitude decreased 0.5 per cent during the first minute and 4.4 per cent during the second minute, an average totaI decrease of 2.4-j

per cent. This amplitude was pIus 46.2 per cent when compared with the original normaI. The ventiIation index showed an average tota increase of 29.1 per cent, which compared with the origina norma was minus 27.45 per cent.

FolIowing grain >40 the rate increased so that during the first minute it was pIus 50 per cent and during the second minute plus 33.3 per cent, an average tota increase of 41.65 per cent. This rate compared with the origina normaI was minus 46.6 per cent. The ampIitude during the first minute decreased 16.6 per cent and during the second minute 37.4 per cent, an average tota decrease of 27 per cent. This ampIi- tude compared with the origina norma was pIus I 7 per cent. The ventiIation index showed an average total increase of 16.85 per cent, which compared with the origina norma was minus 34.27 per cent.

Blood Pressure

In cases I, 2, 3, 5, and 7 simultaneous bIood pressure tracings were taken.

Experiment 3 was. the vagotomized anima1 and wiI1 be considered separateIy.

TABLE V

BLOOD PRESSURE FINDINGS FROM TRACINGS TAKEN

SIMULTANEOUSLY WITH RESPIRATORY CURVES

Number ................... Dose ...................... Rate/m ................... Pulse pressure ..............

ko 165 4.5

Blood pressure rise above . . . . . . . . . . .._.. 8

Rate.. . . . . . . . . . . .._.. 170

P&e pressure .............. I Duration of rise ............ 75 sec. Fall below normal 4 min. later 4

Rate ...................... 160

Pulse pressure .............. I

16

165 5.5 42 sec. 26

I55 3

Following Double Vagotomy Number ................... 3 Dose. ..................... fro Rate/m.. ................. 130

Puke pressure. ............. 4

Blood pressure rise above normal .................. 44

Rate/m ................... 150

Puke pressure .............. 6 Duration of rise ............. 90 sec. Fall below normal 4 min. later I I

Rate.. .................... 115

Pulse pressure .............. 4

40 I70

4 45 sec. 16

130 1.5 --

Cases I, 2, 5 and 7 showed a rise in systoIic bIood pressure foIlowing the injec- tion of aIpha-IobeIin. RoughIy the pressure

TABLE VI

COMPOSITE TABLE SHOWING AVERAGE PERCENTAGE

CHANGE IN VENTlLATlON INDEX, RATE AND AMPLITUDE

DURING FIRST TWO MINUTES OF ACTION OF

ALPHA-LOBELIN

Dose

Vent. index.. . -I- 43.0 + 10.16 + 26.58 Rate.. _. . . + 51.9 + 25.7 i- 38.8 Amplitude.. . - 5.59 - ‘2.4.9 - 9.04

Vent. index.. . + 44.0 + 25.7 Rate . . . . . . . . . . . + 75.7 + 51.9 : 2::2

Amplitude.. . . - 27.39 - 34.195 - 30.79

Rate . . . . . . . . . . +166.6 - 28.18

- 98.3 - 89.55 - 90.95

I

rose proportionateIy with the size of the dose. The heart rate and pulse pressure during the rise were not characteristic; in

NE\V SLXIES VOL. XXIII. No. 3 Wilson & Torrey-AIpha-Lobelin American Journal ol Surgcr y 433

some cases increasing, in others showing no change. The duration of the rise was short, the Iongest recorded interva1 being seventy-five seconds. In a11 cases the rise was folIowed by a faI1 in systoIic pressure below normaI. During the fal1 the puIse pressure changes were not characteristic. The heart rate decreased in every case, the greatest decrease occurring with the Iargest dose.

TABLE VII

COMPOSITE TABLE OF VAGOTOMIZED ANIMALS, SHOWING

AVERAGE PERCENTAGE CHANGE IN VENTILATION

INDEX, RATE AKD AMPLITUDE DURING FlRST

TWO MINUTES OF ACTION OF

ALPHA-LOBELIN

1st Min. 2nd Min. AVerZig.

(Per Cent) 1

(Per Cent), (Per Cent)

I With Double Vanotonw I I

I

Vent. index. : 1 +46.8 Grains0 Kate __.. ..,,. ( +16.6

fII.4 +29.x +16.6 +16.6

1 Amplitude. .I - 0.3 - 4.4 - 2.45 -:

With Double Vagotomy Vent. index.

Grain $l” Rate.. - 2.9 +16.85

+33.3 +41.65 -37.4 -27

In case 3 the bIood pressure, puIse pressure and heart rate a11 increased foIIow- ing the administration of the drug. In this case the Iongest duration of the rise was observed (ninety seconds), aIthough the dose was reIativeIy smaI1 (gr. $50). FoIIow- ing the rise, a faI1 was observed with a decrease in heart rate (150-115), and a return of the puIse pressure to the same vaIue as observed before injection.

DISCUSSION

From a study of our experimenta data we are convinced that the use of aIpha- Iobelin produces increased respiratory efficiency. This conviction is based princi- paIIy on an anaIysis of ventiIation index, which is a reIiabIe index of respiratory efhciency. AIphaJobeIin produces a definite increase in puImonary ventiIation within certain Iimits which is evidenced by the rise in the ventiIation factor, caIcuIated from rate and amplitude. In some cases this factor has been more than twice the normaI.

The ampIitude of each respiratory excursion is diminished but the rate is disproportion- ateIy increased. The tota amount of tida1 air passing per minute is therefore increased. AI1 our data were obtained with intravenous injections. The efficiency and action of the drug when given intra- muscuIarIy or subcutaneousIy wiI1 not be discussed.

We find that any dose, which is not Iess than grain ?,io or greater than grain

350 wiI1 produce a definite increase in pulkonary ventiration in cats weighing approximateIy 3 kg. In this dosage range the increase has been as high as I IO per cent. This ventiIation increase has been roughIy proportionate to the size of the dose, with the exception of grain Fi,. We do not know why this amount, which is intermediate between grain f 6 0 and grain 350, does not produce an increase greater than grain $50 and Iess than grain 350. We have found a marked decrease in puImonary ventiIation with doses of grain ${o and over which has been manifested by a proIonged apnea as in experiment I I.

The margin is smaI1 between that close which produces the most marked voIume index increase and that which produces a decrease because of apnea. However, short of this maximum efficient dose, there is a wide range of dosage producing considera- ble ventiIation increase. This makes it un- necessary to even approach the use of a quantity productive of apnea.

The apnea observed in experiment I I is of great importance because it demon- strates what may be expected if the dose is too Iarge, for experimentaIIy, at Ieast, too great a dose defeats the purpose for which it is given. This apnea seems to be a Iink in the explanation of the drug’s action. It is the end resuIt of a chain of events that is evident when aIpha-IobeIin iS used. As the drug beings to act, the position of the diaphragm changes, assum- ing a Iower position, nearer to the position of inspiration than expiration. This phe- nomenon increases as the dose is increased thus suggesting that tone in the muscIes of

436 * m&can Journal of Surgery W&on & Torrey-AIpha-Lobelin MARCH. 1~x4

respiration increases proportionateIy with the amount of the drug. Tone in the muscIes of inspiration is in excess of tone in the muscIes of expiration. Moreover it wiI1 be noted that the amplitude of each excursion decreases from experiment to experiment as the dose is increased, unti1 finaIIy ampIitude ceases and apnea resuIts. In other words, the diaphragm progres- siveIy approaches the position of inspira- tion, both in its gross position and in its excursions and when apnea has fuIIy de- veIoped, the diaphragm is fixed in the inspiratory position. Tone has increased to such an extent that the reIaxation phase of the muscIe has grown shorter and shorter. FinaIIy there is no reIaxation phase. This phenomenon seems to be cIoseIy reIated to the one observed when a muscIe-nerve preparation is stimuIated to compIete tetanus with progressiveIy in- creasing stimuIi.

Our data aIso shows that, in generaI, the respiratory rate increases as the ampIi- tude diminishes, this increase of rate hav- ing aIways been more than sufficient to baIance the decrease of ampIitude up to and including the administration of grain x0. This is shown by the maintenance of an increased ventiIation index. With Iarger doses however the rate and ampIitude have both faiIed and the ventiIation index has finaIIy dropped to zero. This points to increased sensitivity of the apparatus that governs respiration, to interna and ex- terna stimuli. ExternaI stimuIi pIay an important part in producing this mass effect, this being shown by the percentage difference obtained in vagotomized animaIs as compared with that obtained with the vagi intact, using the same dose in each case. With the vagi intact the percentage change is greater than with the vagi cut, although the duration of the action is the same. We can say then that, due to exces- siveIy increased sensitivity, the muscIes of inspiration no Ionger possess a reIaxation phase, thus ceasing to do work in the physica sense, and puImonary ventiIation comes to a standstiI1. A condition of

overstimuIation exists which is objectiveIy evident in the mechanica part of the respiratory act.

It is probabIe that the principa1 effect of aIpha-Iobelin is to Iower the threshoId of the respiratory center to its norma stimuIant, carbon dioxide. As far as its abiIity to respond is concerned, the center under the infIuence of the drug is in the same reIation to usua1 tensions of carbon dioxide as the norma center is to increased tensions. The resuIting hyperactivity of the center effects, probabIy through its connections, the somatic motor side which brings about increased muscuIar activity. We cannot say at present whether or not this is the whoIe story of its action. It may aIso act directIy on the somatic motor and sensory centers as we11 as on the respiratory center, thus resuIting in a hyper&icity.- It is probabIe the neighbor- inn nucIei share with the center in the effects of the drug.

Considering the action of the drug from a practica1 standpoint, puImonary ventiIa- tion can be definitely and strongly in- creased within certain Iimits. The ventiIa- tion index rises steadiIy unti1 the maximum beneficia1 action is obtained after which there is a sudden drop, and puImonary ventiIation rapidIy diminishes and soon stops. The Iower position of the diaphragm is an advantage because this change in position of the floor of the puImonary cavity means that more aIveoIi are open and working activeIy. The aeration surface is thus increased and the possibiIity of gaseous interchange is much greater. The amount of tida1 air per respiratory cycIe is reduced, but the cycles are occurring at such an increased rate that the tida1 air for a given period is much greater. This is a decided advantage, particuIarIy when the carbon dioxide tension in the bIood is high and the oxygen tension is Iow. On the other hand, in those cases in which the center is partiaIIy paraIyzed or poisoned, at Ieast to such an extent that the amount of carbon dioxide normaIIy present is no Ionger effective, aIpha-IobeIin may diminish

NEW 5~x1~s VOL. XXIII, No. 3 Wilson & Torrey-AIpha-Lobelin American Journal of Surgery 437

the threshoId of the center to such an oId to, and hence increasing its ability extent that it wiII respond even in its to respond to, existing carbon dioxide poisoned condition. tensions in the bIood.

We shaI1 next consider the question of dosage and toxicity. If our reasoning is correct, a dose that wiI1 produce a Iong apnea does not do so because of toxicity, the apnea being simpIy an exaggeration of conditions existing in Iesser degree with smaIIer doses. A dose that produces stop- page of the respiratory act is not neces- sariIv a fata one, as exempIified by expeiiment I I in which respiration started again and eventua1Iy resumed a norma rhythm. StiII Iarger doses wiI1 proIong the apnea excessively, and the anima1 wiI1 die. In view of this, it seems best to cIassify dosage as Efficient Dose, Maxi- mum Efficient Dose and Dangerous Dose. The intravenous introduction of grain >io to grain 350 covers the efficient dose range. Grain 350 is the maximum eflicient dose. Grain ?,<< and over ranges from a dangerous to a fata dose. AI1 this appIies, of course, to the norma anima1, but with a paraIyzed or poisoned center the dosage range might change considerabIy. We have just finished an investigation of this phase and hope to report our findings in a Iater communication.

3. Its action is comparativeIy transient. Prolonged stimuIation cannot be obtained with a singIe dose.

4. The most efficient action with max- imum safety is obtained with doses not exceeding grain ?io. This dose produces the greatest increase of ventiIation index (I 10.65 per cent).

5. The margins of safety in its use are wide.

6. The mechanica reaction is whoIIy desirabIe within certain Iimits.

7. Cessation of the respiratory act as a resuIt of an overdose is not due to paraIysis or poisoning of the respiratory center, but rather to increased centra1 sensitivity which resuIts in over stimuIation of the center.

The bIood pressure tracings taken dur- ing some of our experiments show nothing of particuIar importance. There is a transient rise in the pressure which is soon foIIowed by a faI1 beIow normaI. Neither the rise nor the faI1 has been excessive but in generaI, they increase with the dose. However wisdom wouId dictate the use of as smaI1 a dose as possibIe in the presence of bIeeding or damaged vesseIs.

8. Vomiting and other undesirabIe side effects were not observed at any time.

9. The bIood pressure changes are not important except, possibIy, in the presence of hemorrhage or vesse1 pathology.

The authors wish to express their apprecia- tion to Dr. John C. CardweII and Dr. George H. Roberts for their aid in the outlining and pur- suit of this study and are grateful to Dr. AIfred C. Beck and the Iate Dr. John 0. Polak for their valuable suggestions.

REFERENCES

I.

2.

3. 4.

RANDALL. Am. Med. Bat., I: 183, 1817.

L.EWIS, W. H. D. Am. J. Pharmacol., 7: 154, 1878. VON ROSEN, H. Am. J. Pharmacol., 16: 224, 1886. DKESER, H. Arch. j. esper. Patb. u. Pbarmakol.,

26: 237, 1889.

5.

6.

WIELAP~‘D, H. Arch. j. exper. Patb. u. Tberapie, 79:

95, 1916.

7. 8.

CONCLUSIONS

ECKSTEIN, RohIINGER, and WIEL.~ND. Zta-hr. j. Kinderbeilk., 28: 208, 1921.

OVERBECK, A. Med. J. dv Rec., 122: 40, 1925.

WILSON, R. A. Am. J. Obs. Ed Gyn. 16: 379, Sept., 1928.

I. AIpha-IobeIin results in powerfu1 res- piratory stimulation in the anesthetized, non-asphyxiated Iaboratory animaI pro- ducing aImost immediate resuIts when administered intravenousIy.

2. It acts primariIy on the respiratory center. It does this by Iowering its thresh-

9. IO.

II. 12.

13. 14. 15.

BONSMANN, N. R. Klin. Wcbnscbr., p. 2127, 1924.

v. MILTNER, T. Monatscbr. j. Geburtsb. u. Gyniik., Heft 62, 1923.

HELLWIG, A. Zentralbl. f. Cbir., p. 72 I, 1~2 I. GRILL, w. Klin. Wchns~br., p..4&, 15)24. _ PETERS. K. Med. J. u Rec.. March 18. 1024 GWATHMEY, J. T. J. A. M. ‘A., p. 77, Aug.,‘~ 921. WIELAND, H., and MEYER, R. Arch. j. Path. u.

Pbarmakol., 42: 195, 1922. [For Remainder of References see p. 418.1

418 American Journd of Surgery Frank--Carcinoma

perforation of a Iarge bIood vesseI but even worse it may produce recta1 orvesica1 f%tuIa of the very worst type.

And so aIso with deep x-ray therapy; this cannot be secured with the ordinary x-ray outfit. The apparatus must be abIe to generate 250,000 to 300,000 volts, it must be caIibrated and the dosage prescribed with as much care and precision as the dosage of any dangerous agent. It is quite IikeIy that herein Iies one reason for not onIy the great diversity of resuIts but aIso the faiIure to generaIIy achieve improvement in treatment.

RecentIy we were much impressed by a medica student who accompanied a physi- cist to our hospita1 in an effort to Iocate some Iost radium. NaturaIIy we were curious to know why a medica student was traveIing about with a physicist. The answer: he was preparing himseIf to do radiation therapy and was therefore major-

ing in the study of the physics of roent- genoIogy and radium for the purpose of preparing himseIf for his speciaIty. More credit to him and his Iike.

So we beIieve with BIoodgood that one of the essentiaIs in bettering the resuIts in treatment of cervica1 carcinoma is a Iarge number of trained radioIogists and that they shouId have a cIinica1 surgica1 training in addition. There is a Iarge fieId for such men and there are now in this country four or five unexceIIed pIaces where training may be secured with vast cIinica1 observation. With such preliminary experience upon the part of the radioIogist, with attention by the surgeon and famiIy physician to earIy diagnosis and their cIose cooperation with the pathologist we may hope to bring the unfortunate carcinoma patient under treat- ment at a time which wiI1 or shouId enabIe us to save 80 per cent at Ieast. It a11 de- pends upon the profession.

REFERENCES

BLOODGOOD, J. C., Am. J. Cancer, 16: 1238, 1932. SCHILLER, W. Surg., Gynec. Obst., 56: No. 2, 210, 1933. CUTLER, M. Surg., Gynec. Obst., 55: No. 4, 1932. GRAVES, W. P. Surg., Gynec. Obst., 56: No. 2A, 317,

NEWELL, Q. U. B&l. St. Louis M. Sot., 27: No. 25, 1933. 1933. DESJARDINS, A. U. J. A. M. A., gg: No. 25, p. 2133, BRODERS, A. C. J. A. M. A., gg: 1670. 1932.

Dec. 12, 1932. MCFARLAND, J., and MEADE, T. S. Am. J. M. SC., 184:

BRODERS, A. C. N. York M. J., 32: 667, 1932. 60. 1932.

REFERENCES OF DRS. WILSON AND TORREY”

16. NIELSEN, G. Proc. Oklahoma Acad. .I%., vol. 58: 24. WHITEHEAD, R. W. J. Pbarmacol. 0 Eqer. 1926.

17. MENNET. Zentralb1.j. Gynak., Tberap., 31: 145-176, 1927.

p. 2703, 19-q. 18. MENNET. Zentralbl. j. Gyniik., p. 1522,

1926. 25. CURTIS, F. R., and WRIGHT, S. Lancet, pp. 1255-

rg. LANG. Zentralbl. j. Gyniik., p. 1465, 1926. 1258, Dec. 18, 1926.

20. PFEILSTICKER. Med. Corr . Blatt f. Wuerttembera. 26. SOLIS-COHEN, S., and GITHENS, T. S. Pharmaco- _. Jan. 8, 1927.

21. EASTMAN, N. J. Bull. Jobns Hopkins Hosp., 50: therapeutics, Materia Medica and Drug Action,

39-50, 1932. pp. I7g8-1801, 1928.

22. NORRIS, V. H., and WEISS, S. J. Pbarmacol. @ 27. SOLLMANN, T. A Manual of Pharmacology, pp. Exper. Tberap., 31: 43-63, 1927. 416-417, 1926.

23. SMITH, R. G. J. Pbarmacol. @ Exper. Tberap., 33: 28. MEYER, H. H., and GOTTLIEB, R. Exper. Pbar- 147-165, 1928. macol., pp. 362-363, 1926.

* Continued from p. 437.