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The action of quinine and quinidine on patients with transient ventricular fibrillation
T
HE purpose of t,his study was to drter~uine the clinical manifestations and the successive changes in the rhythm of the heart following the intravenous administ,ration of graded doses of quinine dihydrochloride and quinidine sulphate to 1)atient.s with a.nricrrloverttrieular dissociation subject to transient seizures of ventricular fibrillation. These drugs have been used both orally and intravenously with moderate success in the treatment and pre\rention of ctrtairl forms of the transknt t,ypes of ventricular tachycardias.1-5 Thrir administration in one form or another has been strongly advocatetl in the treatment and prclvention of transient seizures of ventricular tibrillat.ion on t.he ground that t,he frequency of such seizures would be greatly diminished by their use.” Indeed, it has been suggested by Morawitz’ and other+ o that quinidine might be used with success as a prophylaet,ic tlrug in patients regarded as liable to sudden death as a, rflsult, of vent,ricular fibrillation. The assumption t,hat these tlrugs would be of therapeutic value in such patients seems to us to be basecl on retry meager c*linical c~sperieuccl. For while both qGninel”9 I1 and and in fact mostly on hypothesis. quinidine12 have been demonstrated to have an inhibitory c4fect~ upon ventricular fibrillation produced in the expc~rimental animal as a result of timed electrical stimuli, such kansft1l.s of practice arc not applkablc to human brings. On the contrary, it ~onltl appear from the very fe\\ c+linical reports in the literaturr that, cl1~initlinc~ may rrsnlt in tbr clevclopment of transient. vcntriciilar tibrillation.
In 1921, Kerr and Render’” reported observations on a male, sixt.yeight years of age, who was observed over a year, during which time there were several attacks of cardiac syncope following the administration of quinidine sulphate. Electrocarc~iograms obtained during some of these attacks revealed transient, ventricular fibrillation. They eoneluded that quinidine therap?- was dangerous in such patients. Unfortunately, some of t.heir observations were made at a time xvhen the ventricular rate varied between 40 and 70 beats per minute and when the ventricular rhyt,hm was totally irregular. It is well established
3IETIIOD
Two from subjects
patients rtw7rrent of
with stntly.
SW-l)T
of
vtwtricnlar
aluric7tlovelltricular
t~ransirnt this
OF
srieures The
natural
tlissociation wwse
of
who
were
fibrillation the
development,
suffering f0rm of
the thei
attacks and the successive changes in the rhythm of their hearts were studied by us carefully over a period of several years. During this entire time they were in the Jlontefiorr Hospital, anti hundreds of COTrelated observations were mado on their heart rhythms at the same time that electrocardiograms w-rrc vbtaintxl These experiments were carrietl out iIt ii time when it was certain that the patients had not had any transirnt. seizures of ventricular It was definitely detrrminetl fibrillation for at least twenty-fonr hours. from constant study of both the hear-t rate and thrl pulse, with the patients attached in the clectrc)cardiograplIjc (knit., that the bask Tentrkular rate was fairly constant for at lrast four hJUrS prior to the onsrt of an experiment. A basic vt7ltricular rate that was almost regallar and ditl not vary more than tirtl fJ&%tS prr minut(A was consitlered Whrn the basic iin essential condition before initiating itli cJsprrinicnt. A~ythrn
was intermptrd
spontaneously
hy thr appearance
of prtmature
vcntrieular beats, the nunibrr of such extrasystolic c~ontractions \vas c+ountetl each minute for at. Irust tf>n niinntrs prior to tht> iise of an> tlrug. The patients were kept in l~cl all the tinit,. ant1 no other mrdication was administeretl to them throughout, the entire period of thrse studies. In one instam inhalations of amy nitrite were given aftchx quinidine had been used. On several occasions ilIlt frrqurntl~ brfore the drugs were used, the effects of the intravenoils injection of 1 cc. of either distilled water or J-,hysiological saline wer’r determined in ortlrr to rule out any abnormal changes in the rhythm of the heart, or in thr c&oruplesesof the elrctrocardiograms that might follow the injection (Jf the fluid itself. One of us timed the clinical manifestations following the injection of the tlrugs, while the other recorded the time intervals at which changes appeared in the electrocardiograms. All studies were carried out with liead II only. Sncccssirc changes in the rhythm of the heart, were recorded as frequently as it. was thought necessary? and observations of the movements of the galvanomrter strin, 0 were followed for several hours after t,he use of the drug unless ttic condition of the patient made it, impossible to do so, in which case reliance was placed so,lely upon the clinical manifestations. The minimal dose of the drugs that was necessary to produce transient changes in the rhythm of the heart was arrived at by the method of t,rial and error. St,arting w&h very minute quantities, the dosage was gradually increased in repeated preliminary experiments until it. was determined how much was neecleti to produce a pharmacological effect. The final amount used was based on the average amount required to give a specific effect. although innumerable obsefrvations were made from time to time, we ha.ve thought it advisable to describe only some of the typical protocols.
Each one of these demonstrates some mode of action of the drugs to which we direct particular attention. Since the effeds on the\ heart rhythms ha-\-e been somewhat variable each time, the sequence of t,he experiments has been rearrailged so as to form a. consecutive st,cq. Refore describing these alterati(Jns. however, it is important. to call attention to the successive changes in the cardiac mechanism which take place when transient ventricular fibrillation develops spontanronsly in patients with aaricul~~ventricl~l~~r dissoeiatiou so that comparisons van be made with such alterations iu the rhythm of the heart which may bc at,tributed t,cl the infurnvc: of tbr tlr~~ps. THE
AI~‘l’ERA’L’IC)NS
IS
THE
R.HYTI~M
OF
TLII’,
HEART
I’RM’EI~IXG
TRASSIES’r
‘&I alttlmhJIIS iu the rhythm of the bePtrt that prcvetle transient periods of ventricular fibrillation during the presence of anricdo~entricular dissociation are eflected through (a) an increase in tbe basic idioventricnlar rate and ib) the interposition of I)rc‘niature ventricular beats eithrr singly or in proups. These eventually lead to the development, of short recurrent runs (If aberrant ~entricnlar oscillations whidi, in the final analysis, are short runs of vnitricrdxr fibrillation.
Prolonged obserx3tious on our two patients during their ” qniescrnt ” periods, when thy are free from symptoms, re~aletl that, there was a marked fixation of the inherent, v~ntriuular rate from day to (lay and at. times from month to month. In both casesthe alrerage ventricular rate of from 27 to :il beats l)er minnt.e did not vtq more iban 5 beats per minute at, the most at, any one time. This relatively “fixed” ventricular rate was fow~l to be the same during deep sleep as well RS tluring undue exertion. excitement, or emotional tl isturbancr. 1243piratious tlitl not at&et it and tbr use of adequate dosesof ntropine snlpbate (gr. 1 420 intramuscularly j did not. infinenc!c it. imlicatiug that at SIICII times the uu~icnlo~rntric~nlill paeemakrr in them was not rcgulat~ecl I,the extrinsic cardiac nervous mechanism. In both of these patients, mben the increase in the basic ventricular rate appeared prior to the development of a transient seizure of vent,ricular fibrillation, the changes in the rate were gradual. Occasionally, such variations mere easily appreciated by the patients. who complained of precorclial distress. [n
The changes in tbth rat<, of tltv idiorettt~i(~ttlat. Itacettiakt~r in thrtttselves are not sufficient. to I)rrc’il)itatt~ thts tyl)r c~f ventricular Hbrillation with which me arr concernrcl. Soowr or latfv, c>ifher in the presence of a basically accelcrafec( \rnfrit*ular Jxtv or freclitently in its absence. premature ventrjwlslr r,eats bcgiti to a]‘]‘WJ’. ‘l’hC-‘w lltN)a1 first alternate so as to I)roclnve a typical t)ig:‘(Gnal r$~thnt, or the)- may increase in freqilency the itttvrpositicm of abrlrrant vcrttricnlat* oscillations begins to tiisrupt thv rtt!-thm. ‘I’~cw ventricular oscillations can be apprrckted clinically by thv fact thitt only the first few beats associated with them are andibl(~ at fhr al)iea I portion of the heart 01 l)alpa.ble at the wrist. The!so frllstt u.tr itt vharactrr tltat, they at’t’ insufficient. to open the wcWtic orifit7~. atttl ~otthH~tlPtlf1~ ct’rt!hYill anc~tttia sets in when they last for a ptlriotl iottgt~r than Ftvttt eight to ten secontls. Jf they last as lonp as forty st~c~otlcls or lttor(‘, it typical Stokes-Atlams seiziirtA occurs? with pallot. of the skin ant1 favch, tttt~~oIis~iottsItc~ss. kitertorous breathing, incontinPucr of f~v~c’s cbt’ ttJ*irlc~, it clrol’ in blootl pressure, and finall?- iIl”tf’itT with intt~ttst~ v~auosis tltttl to asphysiil. Sollt~ of these phenomena has t>vtLr IJ~I~~I swtl to apI)tkat’ withottt the previous interruption of the basic jclioveitt dcnlill~ Yit\-~httl I,.,t’f’(‘lLlY’t’itt d1lJt.i periods of ventricular osc4lations wttivh. in tltc>ir fillill anal+, art’ short runs of ~c~ntricnlar fibrillation. Siitiilat. itltPJ’?3tiOllS in the c+arcliat* me&anjsm hare 111’vpr btvn olwrrvrtl lay 11s tcb Foll~~W tlte intrarenotts injection of pitlrtv tlistilletl water t)t* ~Jlt~siolopic~wl salitiv sollttiott. brfore
ilr?
itlttl
Patients with transient seiznres of vc~tltrivitlat* librillat~ion occurring during auriculovcntri~iila,~ tlissociatiotr ~a1e.v in their response to the same close of quininr tlihyd~ochloritlc~ from time to time. The speed of injection does not influencv this in any way when tlie same dose is used. The immediate result following the injection of qoantitics of up to 1,/i C.C. of the solution (l:%j gra,ins of the clrng) is usnally a sensation of warmth which the patietlt feels all ~JWI the hotly. At times large beads of perspiration appear on the forehead. and the skin feels moist and clammy. Occasionally a sense of constrktion is Pelt in the midst~ernal region. and with this thrrc> is a shorl. l)eriod of rcu;tlessness that ma> be followed immediately by profound disturbances in the rhythm of the heart. On one occasion. at a time when the basic ventriealar rate averaged 31 beats per minute. the administration of 1/z C.C. (1s’~ gr.) of quinine clihydroehloride resultetl in the appearance of only two premature ventricular heats nine minutes after the iujection of the tlrug. Rowerer, when an acltlitional close of (ml>- ‘!k C.C. (Tk gr.) was injected forty-five
minutes after the tirst dose, there was an immediat,e but transitory increase in bot,h the auricular and the ventricular rates from 100 and At the same time 31 brats per minute to 125 and 43 beats respeetirely. the v&ric+ular complexes, which had previously been all of the upright form, UIIV became variable in direction, assuming tra.nsit.ionnl changes from destrograms to levograms. Oue minute later there was a bigeminal rhythm due to prematurr Ibeats of the ventricles. The auricular rate, however, was now lowered to 100 beats, and four minutes later there was a further reduction in the auricular rate to 8:1 beats per minute and in the rentricular rate to PG. Within fix miuutes. howe~r. the rhythm assumed a bigeminy again, ant1 exactly forty-five minutes after the injection uf the second tlose vf the tlrug a transient pdotl of ventricular fibrillation was ushered in by a pre-fibrillator~ mechanism consisting at first, of a bigeminal rhythm and then of a few short r11ns of aberrant ventricular oscillations brfure a t)-pica1 Stolrcls-Adams sciaurca developed. There were repeated srizurrs uf syncope after this that lasted for not more than one miuute each before the rhythm returned to its original basic level of 31 beats per minute, about two ant1 one-half hours after the beginning c&’ the experiment. (in another occasion, after a control p&ocl during which the ventricular rate was fairly fixed and ayeraged 30 beats per minute, the iujectiun of $$ c’.c. (l:‘,.i gr.) of quinine clihytlro~hloride resulted within six minutes in the development of a short pre-fibrillator~~ mechanism and one minute later in a t~ypical Stokes-Adams seizure due t.0 transient ventricular fibrillation. i\ftrr recovery from this attack, the patient complained of palpitation of the heart due to irregular beat,ing which, however, lasted only a few minut’es before there was a return to the basic itlioventricular rhythm with a regular rat,e of 38 beats per minute. This persisted for approximately one-half hour before another StokesI\dan~s seizure appeared. This was ushered in by a few alternating premature beats of t,he vrntricl~~ with a rrry short run of grouped beats hefore the major attack devrlopc~tl. For the nest, hour t,hese abnormal rhythms alternated with the basically regular rhythm until there \vas finally a restoration to the basic* rll~thm two hours after the injection of t,he drug. A third observation in the presence nf a fixed vent,ricular rate averaging 31 beats per minute was followed within three minutes after the injection of ‘/ii C.C. (l$/~ gr.) of the drug bp a short run of ventricular fibrillation. There were two similar attacks five and stqTmteen minutes later, before t,hese abnormal rhythms and their precursory mechanism disappeared altogether. Sot unt,il fifty minutes a,fter the injection of Ihr drug Teas the patient free from any irregularities of t,he head,. Then t,he basic rhythm with a ventricular rate of :Sl heats per minute returned and rnnainerl regular after that.
111 another observation, at a time when alternate premature beats of the ventricle constantly int,errul)t.ecl the basic* a~~riculoventricular dissociated rhyt.hm, the iqjection of variable ctoses of the drug rang&g from 1/i to l/z c.e. resultetl within a few minutes in the tlevelopinrnt of short, runs of multiple prematruy ventricular beats or in the appraranuc IZ~ the pre-fibrillatory mechanistkr xhich tlisappri~retl~ howvrvcr. within from one-half to one IU)II~ after the in.jc&ou.
I
I
G
--t. ~-.--- --.T-
__ ._
H
B’ig.
...___.--: _-._ _L
_._-_
i
Fig. l.--Portions of continuous strips (Lead IT) showing the clevelopulent uf a transient seizure of ventricular fibrillation following immediately the intravenous injection of I/< of a grain of yuinidine suipbatr. A, Control, the basic ventricular z,hxthm : B, the pm-tibrillatol‘y mechanism ; C, the rneclmnism initiating ventricular fibrillation ; J) and l3, records obtained during a. G, the in.te!mediary idioventricular rhythm following Stokes-Adams seizure : P and ventricular fibrillation ; H, the gust-Abritlatory tuchysystotr : I. the gradual restoration to the basic rhythm. THE
EFFECTS
OF GRADED TRAKSIENT
DOSES
OF QUIXIDINE VENTRICVLAR
SL%PHATE
ON
PATIENTS
WITH
FIBRJLLATIOS
The intravenous injections of 1 cc. ($4 gr.) of yuinidine sulphate to a patient whose vexltricu1a.r rate averaged 28 beats per minute and who showed only one premature beat of the ventricles during a control period in which the rate was counted every minute for one and one-
‘1’1 11 K - __s:;i.i
P.ll I.
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P.11 I., P.~l 1. I'.\1 P.X ‘. ,‘.hl L. I’.,%,I.
x:00-3:o P.11.
1
I.
3 : In“ I’.hl 3 : 0:4 I’.11 x:03-:::o P.31. .3:05 ,‘.\I
4
:: :OG I’.hl 3 :Cli
3 :08
.I P.31 .'
:::10 3:11
P.11 .I P.11 I’.\1
3:13
P.?I
R:ll 3:19
P.hl
3:20 3 :25 3:30
P.31 P.11 P.iv P.\I
32 32
-
33 33
Regular. Regular.
i Pulse small, hardly i pererptiblt~, gradually. . in- . I m2asnlg 111 Intensity with the return of the ~ regularity of the rhythm. I
,Comfortable.
Sl’MhIAli\-
AHD
I’OSt’T,TISIONS
1. C&nine (lili~drotrliloricle and qninidine sutphste were administered intravenously iii gratlecl doses to two patients with anricnloventricular tlissoeiatioti who were stibjcct to transirnt. wizrtres of ventricular fibrillation. 3. The drugs were ittjcdetl ;-lt it tittx (it) when the basic itlioventricnlar rate clicl not. Till')- J11Ot’e than fivt> beats per minute over a period of several hours prior to t.itcJir use. ant1 ( TV1 wbw premature ventricular beats interrnpted the basic rhythm. Tlte nnntber of these was counted fur each minute clnring the hour pwwtling thy iqjections., Tbe tests were carried uut at a time wltc~n it was tlrfinitrly liiiown that the patients had been i’rce from syn~opal seixiircs for at. least twenty-four hours prior to the injections of the tlrug. 3. It. was c~cterntinttl that such patients with transiwt srizures of I-entricnlar fibrillation twpond(~tl variably to thr same close of both quinine ciili~~lrc)clilori~l~ attcl ijnittitlinc~ snlphat~e at clifferent times. 1. The intrarenons atlministratiott of small dosw c.tf qninine dihydrochloridr (nix&iiim tlow : 1 :!I grains i anal cluinitline snlphate (masimum dose: I,$ grain) resulted in the devc~lopment of eit.lter a prefibrillatory mwbanism or transient periods of ventricular fibrillation within from one to nine minutes after the injection.
Hecht. A. F., and Zweig, W.: Uebcr rinen Fall x-on ventrikulawn und pnroxgsmaler Anfallen van I<;ut~mc~rnul onratic und dercn Beinflussune. Wien. klin. Wvlmscl~r. 30: 167. 1917.
Extrasystolic tll~~r:~T~~~~~tis~~l~~~
12. 13.
cardiograms 0bt:lincd Prool a Paticllt \Vitll Auriculo-T’cnl rivulnr l)issoci;ll ion and Rwurrent S)-ncopal .2ttnvks. Arch. Int. Med. 49: 252. 1!1::!2. 1.5. Davis, I)., and Sprague, II. B. : T’ciitricul:tr Yibrillation. Its l<~~l:ltion to TT(‘:crt Block, Aar. HEART’ .J. 4: 6ii9> 19%. ,I. : Studies on Trxnnicnt \-c~lltri~~nl:rr l~‘iIri~illntion. 16. Schrvnrtz, 8. I’., and Jczer, C. Observations on the 211tcrations in the Rhgtllm of tllc Ilcnrt T’rec-cdillg St;vncopal Seizures in ;I P:lticSnt \Yith Sormal Sinus 1111) tllm. i\nl. .T. 31. $v. 4: 17. 18.
19.
lYS,
1934.
HE purpose of t,his study was to drter~uine the clinical manifestations and the successive changes in the rhythm of the heart following the intravenous administ,ration of graded doses of quinine dihydrochloride and quinidine sulphate to 1)atient.s with a.nricrrloverttrieular dissociation subject to transient seizures of ventricular fibrillation. These drugs have been used both orally and intravenously with moderate success in the treatment and pre\rention of ctrtairl forms of the transknt t,ypes of ventricular tachycardias.1-5 Thrir administration in one form or another has been strongly advocatetl in the treatment and prclvention of transient seizures of ventricular tibrillat.ion on t.he ground that t,he frequency of such seizures would be greatly diminished by their use.” Indeed, it has been suggested by Morawitz’ and other+ o that quinidine might be used with success as a prophylaet,ic tlrug in patients regarded as liable to sudden death as a, rflsult, of vent,ricular fibrillation. The assumption t,hat these tlrugs would be of therapeutic value in such patients seems to us to be basecl on retry meager c*linical c~sperieuccl. For while both qGninel”9 I1 and and in fact mostly on hypothesis. quinidine12 have been demonstrated to have an inhibitory c4fect~ upon ventricular fibrillation produced in the expc~rimental animal as a result of timed electrical stimuli, such kansft1l.s of practice arc not applkablc to human brings. On the contrary, it ~onltl appear from the very fe\\ c+linical reports in the literaturr that, cl1~initlinc~ may rrsnlt in tbr clevclopment of transient. vcntriciilar tibrillation.
In 1921, Kerr and Render’” reported observations on a male, sixt.yeight years of age, who was observed over a year, during which time there were several attacks of cardiac syncope following the administration of quinidine sulphate. Electrocarc~iograms obtained during some of these attacks revealed transient, ventricular fibrillation. They eoneluded that quinidine therap?- was dangerous in such patients. Unfortunately, some of t.heir observations were made at a time xvhen the ventricular rate varied between 40 and 70 beats per minute and when the ventricular rhyt,hm was totally irregular. It is well established
3IETIIOD
Two from subjects
patients rtw7rrent of
with stntly.
SW-l)T
of
vtwtricnlar
aluric7tlovelltricular
t~ransirnt this
OF
srieures The
natural
tlissociation wwse
of
who
were
fibrillation the
development,
suffering f0rm of
the thei
attacks and the successive changes in the rhythm of their hearts were studied by us carefully over a period of several years. During this entire time they were in the Jlontefiorr Hospital, anti hundreds of COTrelated observations were mado on their heart rhythms at the same time that electrocardiograms w-rrc vbtaintxl These experiments were carrietl out iIt ii time when it was certain that the patients had not had any transirnt. seizures of ventricular It was definitely detrrminetl fibrillation for at least twenty-fonr hours. from constant study of both the hear-t rate and thrl pulse, with the patients attached in the clectrc)cardiograplIjc (knit., that the bask Tentrkular rate was fairly constant for at lrast four hJUrS prior to the onsrt of an experiment. A basic vt7ltricular rate that was almost regallar and ditl not vary more than tirtl fJ&%tS prr minut(A was consitlered Whrn the basic iin essential condition before initiating itli cJsprrinicnt. A~ythrn
was intermptrd
spontaneously
hy thr appearance
of prtmature
vcntrieular beats, the nunibrr of such extrasystolic c~ontractions \vas c+ountetl each minute for at. Irust tf>n niinntrs prior to tht> iise of an> tlrug. The patients were kept in l~cl all the tinit,. ant1 no other mrdication was administeretl to them throughout, the entire period of thrse studies. In one instam inhalations of amy nitrite were given aftchx quinidine had been used. On several occasions ilIlt frrqurntl~ brfore the drugs were used, the effects of the intravenoils injection of 1 cc. of either distilled water or J-,hysiological saline wer’r determined in ortlrr to rule out any abnormal changes in the rhythm of the heart, or in thr c&oruplesesof the elrctrocardiograms that might follow the injection (Jf the fluid itself. One of us timed the clinical manifestations following the injection of the tlrugs, while the other recorded the time intervals at which changes appeared in the electrocardiograms. All studies were carried out with liead II only. Sncccssirc changes in the rhythm of the heart, were recorded as frequently as it. was thought necessary? and observations of the movements of the galvanomrter strin, 0 were followed for several hours after t,he use of the drug unless ttic condition of the patient made it, impossible to do so, in which case reliance was placed so,lely upon the clinical manifestations. The minimal dose of the drugs that was necessary to produce transient changes in the rhythm of the heart was arrived at by the method of t,rial and error. St,arting w&h very minute quantities, the dosage was gradually increased in repeated preliminary experiments until it. was determined how much was neecleti to produce a pharmacological effect. The final amount used was based on the average amount required to give a specific effect. although innumerable obsefrvations were made from time to time, we ha.ve thought it advisable to describe only some of the typical protocols.
Each one of these demonstrates some mode of action of the drugs to which we direct particular attention. Since the effeds on the\ heart rhythms ha-\-e been somewhat variable each time, the sequence of t,he experiments has been rearrailged so as to form a. consecutive st,cq. Refore describing these alterati(Jns. however, it is important. to call attention to the successive changes in the cardiac mechanism which take place when transient ventricular fibrillation develops spontanronsly in patients with aaricul~~ventricl~l~~r dissoeiatiou so that comparisons van be made with such alterations iu the rhythm of the heart which may bc at,tributed t,cl the infurnvc: of tbr tlr~~ps. THE
AI~‘l’ERA’L’IC)NS
IS
THE
R.HYTI~M
OF
TLII’,
HEART
I’RM’EI~IXG
TRASSIES’r
‘&I alttlmhJIIS iu the rhythm of the bePtrt that prcvetle transient periods of ventricular fibrillation during the presence of anricdo~entricular dissociation are eflected through (a) an increase in tbe basic idioventricnlar rate and ib) the interposition of I)rc‘niature ventricular beats eithrr singly or in proups. These eventually lead to the development, of short recurrent runs (If aberrant ~entricnlar oscillations whidi, in the final analysis, are short runs of vnitricrdxr fibrillation.
Prolonged obserx3tious on our two patients during their ” qniescrnt ” periods, when thy are free from symptoms, re~aletl that, there was a marked fixation of the inherent, v~ntriuular rate from day to (lay and at. times from month to month. In both casesthe alrerage ventricular rate of from 27 to :il beats l)er minnt.e did not vtq more iban 5 beats per minute at, the most at, any one time. This relatively “fixed” ventricular rate was fow~l to be the same during deep sleep as well RS tluring undue exertion. excitement, or emotional tl isturbancr. 1243piratious tlitl not at&et it and tbr use of adequate dosesof ntropine snlpbate (gr. 1 420 intramuscularly j did not. infinenc!c it. imlicatiug that at SIICII times the uu~icnlo~rntric~nlill paeemakrr in them was not rcgulat~ecl I,the extrinsic cardiac nervous mechanism. In both of these patients, mben the increase in the basic ventricular rate appeared prior to the development of a transient seizure of vent,ricular fibrillation, the changes in the rate were gradual. Occasionally, such variations mere easily appreciated by the patients. who complained of precorclial distress. [n
The changes in tbth rat<, of tltv idiorettt~i(~ttlat. Itacettiakt~r in thrtttselves are not sufficient. to I)rrc’il)itatt~ thts tyl)r c~f ventricular Hbrillation with which me arr concernrcl. Soowr or latfv, c>ifher in the presence of a basically accelcrafec( \rnfrit*ular Jxtv or freclitently in its absence. premature ventrjwlslr r,eats bcgiti to a]‘]‘WJ’. ‘l’hC-‘w lltN)a1 first alternate so as to I)roclnve a typical t)ig:‘(Gnal r$~thnt, or the)- may increase in freqilency the itttvrpositicm of abrlrrant vcrttricnlat* oscillations begins to tiisrupt thv rtt!-thm. ‘I’~cw ventricular oscillations can be apprrckted clinically by thv fact thitt only the first few beats associated with them are andibl(~ at fhr al)iea I portion of the heart 01 l)alpa.ble at the wrist. The!so frllstt u.tr itt vharactrr tltat, they at’t’ insufficient. to open the wcWtic orifit7~. atttl ~otthH~tlPtlf1~ ct’rt!hYill anc~tttia sets in when they last for a ptlriotl iottgt~r than Ftvttt eight to ten secontls. Jf they last as lonp as forty st~c~otlcls or lttor(‘, it typical Stokes-Atlams seiziirtA occurs? with pallot. of the skin ant1 favch, tttt~~oIis~iottsItc~ss. kitertorous breathing, incontinPucr of f~v~c’s cbt’ ttJ*irlc~, it clrol’ in blootl pressure, and finall?- iIl”tf’itT with intt~ttst~ v~auosis tltttl to asphysiil. Sollt~ of these phenomena has t>vtLr IJ~I~~I swtl to apI)tkat’ withottt the previous interruption of the basic jclioveitt dcnlill~ Yit\-~httl I,.,t’f’(‘lLlY’t’itt d1lJt.i periods of ventricular osc4lations wttivh. in tltc>ir fillill anal+, art’ short runs of ~c~ntricnlar fibrillation. Siitiilat. itltPJ’?3tiOllS in the c+arcliat* me&anjsm hare 111’vpr btvn olwrrvrtl lay 11s tcb Foll~~W tlte intrarenotts injection of pitlrtv tlistilletl water t)t* ~Jlt~siolopic~wl salitiv sollttiott. brfore
ilr?
itlttl
Patients with transient seiznres of vc~tltrivitlat* librillat~ion occurring during auriculovcntri~iila,~ tlissociatiotr ~a1e.v in their response to the same close of quininr tlihyd~ochloritlc~ from time to time. The speed of injection does not influencv this in any way when tlie same dose is used. The immediate result following the injection of qoantitics of up to 1,/i C.C. of the solution (l:%j gra,ins of the clrng) is usnally a sensation of warmth which the patietlt feels all ~JWI the hotly. At times large beads of perspiration appear on the forehead. and the skin feels moist and clammy. Occasionally a sense of constrktion is Pelt in the midst~ernal region. and with this thrrc> is a shorl. l)eriod of rcu;tlessness that ma> be followed immediately by profound disturbances in the rhythm of the heart. On one occasion. at a time when the basic ventriealar rate averaged 31 beats per minute. the administration of 1/z C.C. (1s’~ gr.) of quinine clihydroehloride resultetl in the appearance of only two premature ventricular heats nine minutes after the iujection of the tlrug. Rowerer, when an acltlitional close of (ml>- ‘!k C.C. (Tk gr.) was injected forty-five
minutes after the tirst dose, there was an immediat,e but transitory increase in bot,h the auricular and the ventricular rates from 100 and At the same time 31 brats per minute to 125 and 43 beats respeetirely. the v&ric+ular complexes, which had previously been all of the upright form, UIIV became variable in direction, assuming tra.nsit.ionnl changes from destrograms to levograms. Oue minute later there was a bigeminal rhythm due to prematurr Ibeats of the ventricles. The auricular rate, however, was now lowered to 100 beats, and four minutes later there was a further reduction in the auricular rate to 8:1 beats per minute and in the rentricular rate to PG. Within fix miuutes. howe~r. the rhythm assumed a bigeminy again, ant1 exactly forty-five minutes after the injection uf the second tlose vf the tlrug a transient pdotl of ventricular fibrillation was ushered in by a pre-fibrillator~ mechanism consisting at first, of a bigeminal rhythm and then of a few short r11ns of aberrant ventricular oscillations brfure a t)-pica1 Stolrcls-Adams sciaurca developed. There were repeated srizurrs uf syncope after this that lasted for not more than one miuute each before the rhythm returned to its original basic level of 31 beats per minute, about two ant1 one-half hours after the beginning c&’ the experiment. (in another occasion, after a control p&ocl during which the ventricular rate was fairly fixed and ayeraged 30 beats per minute, the iujectiun of $$ c’.c. (l:‘,.i gr.) of quinine clihytlro~hloride resulted within six minutes in the development of a short pre-fibrillator~~ mechanism and one minute later in a t~ypical Stokes-Adams seizure due t.0 transient ventricular fibrillation. i\ftrr recovery from this attack, the patient complained of palpitation of the heart due to irregular beat,ing which, however, lasted only a few minut’es before there was a return to the basic itlioventricular rhythm with a regular rat,e of 38 beats per minute. This persisted for approximately one-half hour before another StokesI\dan~s seizure appeared. This was ushered in by a few alternating premature beats of t,he vrntricl~~ with a rrry short run of grouped beats hefore the major attack devrlopc~tl. For the nest, hour t,hese abnormal rhythms alternated with the basically regular rhythm until there \vas finally a restoration to the basic* rll~thm two hours after the injection of t,he drug. A third observation in the presence nf a fixed vent,ricular rate averaging 31 beats per minute was followed within three minutes after the injection of ‘/ii C.C. (l$/~ gr.) of the drug bp a short run of ventricular fibrillation. There were two similar attacks five and stqTmteen minutes later, before t,hese abnormal rhythms and their precursory mechanism disappeared altogether. Sot unt,il fifty minutes a,fter the injection of Ihr drug Teas the patient free from any irregularities of t,he head,. Then t,he basic rhythm with a ventricular rate of :Sl heats per minute returned and rnnainerl regular after that.
111 another observation, at a time when alternate premature beats of the ventricle constantly int,errul)t.ecl the basic* a~~riculoventricular dissociated rhyt.hm, the iqjection of variable ctoses of the drug rang&g from 1/i to l/z c.e. resultetl within a few minutes in the tlevelopinrnt of short, runs of multiple prematruy ventricular beats or in the appraranuc IZ~ the pre-fibrillatory mechanistkr xhich tlisappri~retl~ howvrvcr. within from one-half to one IU)II~ after the in.jc&ou.
I
I
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Fig. l.--Portions of continuous strips (Lead IT) showing the clevelopulent uf a transient seizure of ventricular fibrillation following immediately the intravenous injection of I/< of a grain of yuinidine suipbatr. A, Control, the basic ventricular z,hxthm : B, the pm-tibrillatol‘y mechanism ; C, the rneclmnism initiating ventricular fibrillation ; J) and l3, records obtained during a. G, the in.te!mediary idioventricular rhythm following Stokes-Adams seizure : P and ventricular fibrillation ; H, the gust-Abritlatory tuchysystotr : I. the gradual restoration to the basic rhythm. THE
EFFECTS
OF GRADED TRAKSIENT
DOSES
OF QUIXIDINE VENTRICVLAR
SL%PHATE
ON
PATIENTS
WITH
FIBRJLLATIOS
The intravenous injections of 1 cc. ($4 gr.) of yuinidine sulphate to a patient whose vexltricu1a.r rate averaged 28 beats per minute and who showed only one premature beat of the ventricles during a control period in which the rate was counted every minute for one and one-
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i Pulse small, hardly i pererptiblt~, gradually. . in- . I m2asnlg 111 Intensity with the return of the ~ regularity of the rhythm. I
,Comfortable.
Sl’MhIAli\-
AHD
I’OSt’T,TISIONS
1. C&nine (lili~drotrliloricle and qninidine sutphste were administered intravenously iii gratlecl doses to two patients with anricnloventricular tlissoeiatioti who were stibjcct to transirnt. wizrtres of ventricular fibrillation. 3. The drugs were ittjcdetl ;-lt it tittx (it) when the basic itlioventricnlar rate clicl not. Till')- J11Ot’e than fivt> beats per minute over a period of several hours prior to t.itcJir use. ant1 ( TV1 wbw premature ventricular beats interrnpted the basic rhythm. Tlte nnntber of these was counted fur each minute clnring the hour pwwtling thy iqjections., Tbe tests were carried uut at a time wltc~n it was tlrfinitrly liiiown that the patients had been i’rce from syn~opal seixiircs for at. least twenty-four hours prior to the injections of the tlrug. 3. It. was c~cterntinttl that such patients with transiwt srizures of I-entricnlar fibrillation twpond(~tl variably to thr same close of both quinine ciili~~lrc)clilori~l~ attcl ijnittitlinc~ snlphat~e at clifferent times. 1. The intrarenons atlministratiott of small dosw c.tf qninine dihydrochloridr (nix&iiim tlow : 1 :!I grains i anal cluinitline snlphate (masimum dose: I,$ grain) resulted in the devc~lopment of eit.lter a prefibrillatory mwbanism or transient periods of ventricular fibrillation within from one to nine minutes after the injection.
Hecht. A. F., and Zweig, W.: Uebcr rinen Fall x-on ventrikulawn und pnroxgsmaler Anfallen van I<;ut~mc~rnul onratic und dercn Beinflussune. Wien. klin. Wvlmscl~r. 30: 167. 1917.
Extrasystolic tll~~r:~T~~~~~tis~~l~~~
12. 13.
cardiograms 0bt:lincd Prool a Paticllt \Vitll Auriculo-T’cnl rivulnr l)issoci;ll ion and Rwurrent S)-ncopal .2ttnvks. Arch. Int. Med. 49: 252. 1!1::!2. 1.5. Davis, I)., and Sprague, II. B. : T’ciitricul:tr Yibrillation. Its l<~~l:ltion to TT(‘:crt Block, Aar. HEART’ .J. 4: 6ii9> 19%. ,I. : Studies on Trxnnicnt \-c~lltri~~nl:rr l~‘iIri~illntion. 16. Schrvnrtz, 8. I’., and Jczer, C. Observations on the 211tcrations in the Rhgtllm of tllc Ilcnrt T’rec-cdillg St;vncopal Seizures in ;I P:lticSnt \Yith Sormal Sinus 1111) tllm. i\nl. .T. 31. $v. 4: 17. 18.
19.
lYS,
1934.