- Email: [email protected]
Electroencephalographic and circulatory responses to megimide in normal subjects
ELECTROENCEPHALOGRAPHYAND CLINICAL NEUROPHYSlOLOGY
I1
ELECTROENCEPHALOGRAPHIC AND CIRCULATORY RESPONSES TO MEGIMIDE IN N O R M A L SUBJECTS 1 ULLA SELLD[N AND BROR SODERHOLM, M . D .
Laboratoriesfor Clinical Neurophvsiology and Clinical Physiology, Sahlgrenska Sjukhuset, G6teborg (Sweden) (Accepted fo,t publication: December 6, 1963)
The excitatory effect of Megimide (/~,~-methylethyl-glutarimide) on the electroencephalogram has been amply demonstrated by investigations on humans as welt as by experimental studies on animals. Since cardiovascular centers have both a cortical and a subeortical representation in the cerebrum (Penfield and Rasmussen 1950; Kaada 1951; Folkow 1955; Rushmer and Smith 1959) it is conceivable that Megimide activation may produce undesirable side effects on the peripheral circulation. Blomberg el al. (1961) found no appreciable effect of Megimide activation on the heart rate and blood pressure in patients with various neurological disorders, whereas Delay et al. (1956a and b) reported slightly elevated values for these two factors. Hypotensive effects associated with bradycardia and asystole have also been reported (Margerison 1958; Peters6n et al. 1960). In these investigations blood pressures were measured by arm cuff and sphygmomanometer. There has been some discussion ofthe possible correlation between EEG changes and effects on the peripheral circulation. On the basis of animal experiments involving coincident recording of EEGs, ECGs and intra-arterial blood pressure, Morin and Corriol (1955 and 1957) contend that a paroxysmal discharge is essential to get a cardiovascular reaction. In contrast, Delgado (1960) and Delgado et al. 0960), using a depth recording technique in humans, claim to have demonstrated that paroxysmal discharges and cardiovascular effects may occur independently of each other. This is supported by their observations in patients with spontaneous 3 c/see wave 1 This investigation was supported by grants from the Faculty of Medicine, Gothenburg, and Svenska Sitllskapet f6r Medicinsk Forskning, Stockholm.
and spike attacks, whose heart rates and blood pressures showed no appreciable fluctuation. The chief purpose of the present investigation was to determine whether Megimide activation may give rise to detectable effects on the peripheral circulation. Another aim was to find out whether certain sensations of discomfort which frequently attend injection of Megimide were correlated with any form of cardiovascular reaction. A normal series ~vasconsidered best suited for an investigation of this type. MATERIAL AND METHODS
The investigation comprised twenty-two normals, nine females and thirteen males, none of whom had any history of, or showed any evidence of, cerebral, cardiovascular or other disease of significance. The source of tile subjects, the electroencephalographic recording, the activation technique and the classification of EEG responses were the same as is reported in the foregoing paper on repeated activation with Megimide in normals (Selld6n 1964). Electroencephalographic findings were normal in all subjects except two (cases 4 and 21).who exhibited a certain amount of theta activity with left preponderance in fronto-temporal leads. Brachial artery pressure was recorded from an indwelling polythene tube (Berneus et al. 1954). Pressures were registered by strain gauge manometers on a 4-channel direct writing recorder (Mingograf, EIema). A point 5 cm dorsal to the sternal angle was used as reference level. EEGs were taken concurrently. Injection of Megimide was started at least 1 h after catheterization. Systolic and diastolic pressures and heart rates were calculated prior to Megimide injection and after each dose. The vafi,~tions were expressed Electroenceph. clin. NeurophysioL, 1964, 17:i1-16
12
u. SELLDI~N AND B. SODERiIOLM
as the pooled estimate for the standard deviations within individuals. Differences between the pre~-and post-injection heart rates and blood p~essures were anatyz~d both in the series as a whole (Table 11) and in groups and subgroups f~rmed on the basis of: 1. Subjective reaction to Megimide activation (Table ll); 2. Type o f EEG response to Meg'.'.mide activation (Table ll); and 3. EEG responses grouped with respect to subjective reactions (Table Ill). Cases in which Megimide failed to affect the EEG were omitted from the analyses in groups 2 and 3 above, since they numbered only three. The statistical analyses were carried out with the use of Student's t test at the 5% level. The mean differences and their standard deviations are reported.
RESULTS In Table I the series is detailed with respect to age, sex, resting EEG, EEG response to activation, and relevant threshold doses; total dose o f Megimide administered, and subjective reactions to the injection; systolic and diastolic blood pressures and heart rate p~ior to Megimide injection, at the onset o f a n effect of non-paroxysmal type, and after activation. Tables II and III present the results of statistical analyses of the differences between the preand post-injection blood pressures and heart rates. Fig. ! illustrates concurrently recorded EEGs, ECGs and blood pressures in a typical case (case 3).
Eiectroencephalographic responses and subjective reactions In three cases no EEG t.hanges were obtained,
TABLE l For explanatory text ~e Results Case Sex
Rest- Total
no.
in8 dose of None =:'A B EEG Megimide Threshold dose m$
I 2 3 4 5 6 7 8 9 i0 II 12 13 14 15
16 17 18 19 20 21 22
and age
~19 N ~19 N ~24 N ~ 26 Abn. ~33 N ~ 37 N c~42 N ~44 N ~51 N ~ 19 N ~ 20 N ~ 22 N (~ 22 N (~ 26 N ~ 26 N ~29 N ~ 29 N ~ 37 N d~ 39 N (~41 N (~49 Abn. ,~ 51 N
150 g0 80 30 90 80 40 60 60 100 80 80 150 130 100 150 50 80 140 140 80 120
EEG response
II0 60 50 20 80
it0
40 40 60 100 50 40 70 140 70 130 X 80 150 30 X 70 140 90 40
Blood pressures (BA)
fort on mm H8 activation Before On act. After M M
I~:F
80 40 60
X
Discern-
~÷ 0 0 + +~ oF 0 0 + +~ 0 0 0 ++ 0 0 -F + ++ 0 0 0
124/56 130/60 126/60 111/56 111/57 107/56 119~55 120/55 119/55 101/52 99153 99155 119/66 117/66 117/66 140/59 136/64 106163 107•65 99/47 110/53 109/54 140178 139/74 135/74 1581102147/84 175/108 156/86 159/93 165f93 152/96 162j92 166/96 148/83 156198 156/96 136182 140186 144182 145/88 138/86 119/68 113/73 116/78 131/82 126/75 128/7~ 139/83 146184 130/66 130/72 117r'81 149/97 159/101 157/98 125/78 !!9/72 125176 140/86 146/88
Heart rate
beats per rain Before On act. After M M 64 66 82 54 78 82 74 72 62 72 60 62 74 72 68 56 64 68 84 60 56 70
70 74 82 54 76 72 54 84 70 60 72 64 58 58 82 58 54
74
74 84 54 76 80 76 72 54 82 72 57 72 70 62 78 54 78 74 60 56
67
A: Nvn-paroxysmal effect; B: Paroxysmal effect; M: Megimide activation; BA: Brachial artery; N: Normal; Abn.: Abnormal; + : Slight; + + : Considerable.
Electroenceph. clin. Neurophysiol., 1964, 17:11-16
13
EEG A N D C I R C U L A T O R Y RESPONSES T O MEGIMIDE
T A B L E II For explanatory textsee Results
Differences between pr¢- and post-injection values Total series S
Number o f cases Mean difference Sdm. tvalue
D
N o discomfort on activation
S
HR
22 2.0 2.8 i.2 -t-7.34-5.3-t-2.5 !.312.45"2.22"
D
Discomfort on activation
HR
12 3.4 1.9--0.5 !6.34-5.7-4-7.9 1.88 !.16 0.22
S
D
EEG response type A
HR
l0 0.4 3.8 3.2 ±8.54-4.9:[:7.8 0.152.46" !.30
S
D
EEG response type B
HR
17 !.2 0.8 0.5 4-6.44-7.4-4-5.8 0,76 0.46 0.33
S
D
HR
9 3.3 5,0 1.9 -4-9.64-5.2:£-9.3 !.042.88" 0.61
A: Non-paroxysmal effect; B: Paroxysmaleffect; S: Systolic blood pressure (ram Hg); D: Diastolic blood pressure ~mm Hg); HR: Heart rate (beats/min). * Statistically significant at the 5% level. TABLE 111 For explanatory text see Results
Differences between pre- and post-injection values EEG response type A
Number of cases
Mean difference sdin. t value*
EEG response type B
No discomfort on activation
Discomfort on activation
No discomfort on activation
Discomfort on activation
S
S
S
S
D
HR
D
II
2.2 1.3 -2.2 t6.7 t6.5 ±3.6 1.09 0.66 2.01
HR 6
D
HR 5
-0.7 0 5.3 t5.8 =[:9.2 ±6.0 0.3 0 2.16
D
HR
4
5.8 3.4 3.4 0.3 7.0 0 t7.1 ±4.8 tl0.7 ±12.5±5.6 £:8.3 1.83 !.58 0.71 0.05 2.50 0
A: Non-paroxysmal effect; B: Paroxysmal effect; S: Systolic blood pres,~ure (ram Hg); D: Diastolic blood pressure (mm HS); HR: Heart rate (l~als/min), * N o levelsof statistical siBniflcance. subjective distress necessitating discontinuance of the injection at doses of 80, 100 and 120 mg respectively. An effect of non.paroxysmal type was noted in seventeen cases, seven of which showed paroxysmal activity as well. Each of the other two subjects (cases 6 and 7) exhibited paroxysmal activity. In case 6 no significant increase of non-paroxysmal low frequency activity was recorded, and case 7 was not evaluable because of artefacts associated with the injection. The paroxysmal changes in this series were consistently of bilaterally synchronous type and occurred in one or more episodes, usually of 2-4 sec duration. Ten of the subjects experienced discomfort, which varied in type and intensity, but which was described as essentially a form of dizziness, accompanied by a rocking or floating sensation
as well as some disorientation in space. Several had twitching sensations, particularly around the eyes; in these cases palpebral tremor was objectively discernible. No nystagmus was observed. Four subjects (cases 6, i !, 15 and 19) reported a sensation of imminent syncope.
Circulatory responses in relation to electroencephalographic findings and subjective reactions From the pre- and post-injection values listed in Table I it is evident that neither heart rate nor blood pressu~'e underwent any major fluctuations. Only in six subjects (cases 10-13, 16 and 19) did the heart rate change by more than 10 beats per rain and the blood pressure by more than 10 m m Hg. After Megimide there was no systematic change in the systolic pressure, whereas the diastolic showed a significant increase averaging Eleetroenceph. clin. Neurophysiol., 1964, 17:11-16
U. SELLDI~NAND B. S~DERHOLM
14
~om0
BLood pressure 11glS$ mm HO
160
~
All
120155mmH9
'
' 60 m 9
•
119155 mrnH
30cmlmin
ECG Heart Rote 831 rain
621rain
II/,I rain
Fig. I The figure illustrates the course of activation with Megimide in one typical case (No. 3). the EEG first showing a non.paroxysmal effect (A) and then paroxysmal activity (B). Simultaneously recorded arterial blood pressure and ECG appear below each EEG section,
2.8 mm Hg, concomitant with a significant eleva- alographic activation may produce detectable tion of the heart rate by 1.2 beats/min (Table II). effects on the peripheral circulation, it was of On the basis of all recorded fluctuations in interest to find out whether the EEG phenomena blood pressure and heart rate associated with which result from the injection are attended by Megimide in the total series the pooled estimates heart rate and blood pressure changes of for the standard deviations were found to be 4.0 sufficient magnitude to be of clinical significance. The possible rote of subjective distress has mm Hg for the systolic pressure, 3.5 mm Hg for the diastolic, and 4.1 beats/rain for the heart been taken up for discussion because this factor could influence the cardiovascular functions via rate. It is evident from Table l[ that, although there at least two conceivable mechanisms. In the was no systematic change in heart rate and systol- first place, the dysphoria which is likely to ic pressure, a significant elevation of diastolic accompany pronounced distress could welt give pressure occurred in the groups with subjective ris¢ to cardiovascular effects; and, secondly, the discomfort and paroxysmal activity. No signif- disagreeable sensations could themselves stem icant differences emerged on subdivision of the from excitatory discharges which in turn affect cerebral structures with cardiovascular represeries as in Table IlL sentation. The latter hypothesis is prompted by DISCU~ION the fact that Penfield and Rasmussen (1950), on This investigation was designed to ascertain stimulation of the temporal lobe and insular whether injection of Megimide for electroenceph- cortex in humans, noted subjective sensations Electroenceph. elin. Neurophysiol., 1964, 17:11-16
EEG AND CIRCULATORYRESPONSESTO MEGIMIDE
similar in type to those produced by Megimide in this series. Delgado and Hamlin (1958) also observed such phenomena in their investigation with depth electrodes. They den-.onstrated, moreover, that paroxysmal patterns could be induced by stimulation of deep cerebral structures without involvement of superficial structures. The distress caused by Meg[re[de can possibly be attributed, therefore, to excitatory phenomena that do not lend themselvesto registration by scalp electrodes. It is, however, evident that with the Meg[re[de doses used in the present investigation only minor changes in heart rate and blood pressure occurred. Although the series as a whole showed a statistically significant elevation of heart rate and diastolic blood pressure during the course of the injection, the rise was apparently not substantial enough to be of biological significance. The same may be said of the statistically significant rise of diastolic pressure in the paroxysmal activity group and in subjects distressed by the injection. When the series was broken down with respect to the EEG response, then subdivided according to the subjective reaction, differences of statistical significance no longer emerged. This suggests that another factor (e.g. individual reactions to the injection procedure per se) contributed to the observed effects. The discrepancies noted on comparison of the present results with those of other authors (Margerison 1958; Peters~n et al. 1960; Blomberg et al. 1961) may be attributable largely to differences in size and composition of the respective
series. The investigations reported by these workers have been mainly concerned with EEG responses, and the results do not permit general conclusions as to effects on the circulation. SUMMARY Electroencephalographic and circulatory responses to Megimide were studied in 22 normals,
nine females and thirteen males, aged 19-51. Megimide was injected intravenously in doses of 10 mg/min up to a maximum of 150 mg (mean 95 ~ 37 rag), and EEGs, ECGs and brachial artery pressures were continuously recorded in connection with the injection. With the onset of paroxysmal effects, increasing focal abnormality, or subjective distress the injection was discontinued.
l
After each injected dose of Megimide the heart rate and the systolic and diastofic blood pressures showed, with few exceptions, slight fluctuations around the initial values. The pooled estimates for the star~dard deviations within individuals wore 4.1 bcats/min and 4.0 and 3.5 mm Hg, respectively. These changes showed no significant correlation either with the type of EEG response or with the characteristic sensations of discomfort that were noted in approximately one half of the cases. This investigation indicates that Megimide in the doses here employed for EEG activation does not affect to an appreciable degree the circulatory conditions, as evaluated from the ECG and the brachial artery pressure. R~UM~ RI~PONSES I~LECTROENCI~PHALOGRAPHIQUESEl" CIRCULATOIRES AU MI~GIMIDE CHEZ DES SUJETS NORMAUX
Les r~ponses ~lectroenc6phalographiques et circulatoires au M6gimide ont 6t~ ~tudi~es chez 22 sujets normaux, neuf femmes et treiz¢ hemrues ag6s de 19 ~ 51 ans. L'EEG, rECG et la pression sanguine, prise dam l'art~re brachiale, ont ~t6 enregistr6s continueilement pendant rinjection intraveineuse du M6gimide. Cette preparation a ~t6 administr6e en doses de 10 rag/rain; maximum 150 mg (dose moyenne 95 :[= 37 rag). L'activation a ~t~ interrompue lorsqu'ont apparu dos activit~s paroxysmales, un accroissement des anormalit~s focales ou des malaises chez le sujet. La fr~quence du pouls et la press[on sanguine systolique et diastolique, enregistr~es aprbs ['injection de chaque dose de M~gimide, ont r~v~16, avec de rares exceptions, des variations l~#,res autour des valeurs [nit[ales constat6es l'occasion de l'activation. La moyenne estim~e de 1'6cart normal, bas~e sur l'cnsemble des essais, ~tait de 4.1 battements/min et de 4.0 et 3.5 mm Hg respectivement. I! n'existe aucune correlation certaine entre ces ~carts et le type de r~ponse EEG ou les sensations de malaise caract~ristiques du M~gimide et qui ont t~t~ constat~es darts environ la molt[6 des cas. En r~sum6, it r~sulte de ces essais que les conditions circula~oires, enregistr~es par l'~lecE/ectroenceph. clin. NeurophysioL, 1964, 17:!1-16
16
U. SELLDI~N A N D B. SODERHOLM
FOLgOW,B. Nervous control of the blood vessels. Physiol. Rev., 1955, 35: 629-663. FOOtDA, B. R. Somato-motor, au,,,aomic and electrocorticographic responses to electrical stimulation of rhinencephalic and other ~tructures in primates, cat and dog; Acra ~ . - ~ a n d . , ". . . . . . . . . ~ ~. 1-285. MARCEnJSON,J. H. The effect of bemegride ("Megimide") REFERENCES on normal people. Electroenceph. clin. Nearophysiol., BERNEUS,B., CARLSTEN,A., HOLMGREN,A. and SELDINGER 1958, 10: 541-545. S.L Percutaneous catheterization of peripheral arteries MOroN, G. et CORnlOL,J. Sur ie m6canisme de l'hyperas method for blood sampling. Stand. J. olin. Lab. tension art6rielle produite par Vinjection intraveineuse Invest., 19~4~6: 217-221. de cardiazol chez le chien curaris~, chloralos~ ou non BLOMBERG,L. H., FEGEt~TEN, L., FLODMARK, S. and chloralos~. C. R. So¢. Biol. (Paris), 1955, 149: 748-P~aS~N, I. Electrocnccphalographic responses to 751. combined injections of Megimide aad Xylocaine. Acta MontH, G. et CORRtOL,J. Relations entre les effets hyperpsychiat, stand., 1961, 36: 5%68. tenseurs et ~pileptog6nes du penta-methyl6ne-tc~trazol. DELAY, J., SCUULLER,E., DROSSOPOULO,G., H^tM, A., Arch. int. Pharmacodyn., 1957, 109: 157-170. CHANOtT,P., V~RD~AUX,G. et V~RDEAUX,J. Un nouvei PENFIELD, W. and RASMUSSEN,TH. The cerebral cortex of activant de I'¢.L!ectroen~phalogramme: le N.P. 13. man. Macmillan, New York, 1950: "/7-86. C.R. $oc. Biol. (Paris), 1956a, 150: 242-243. DELAY,J., VERDEAUX,G. et J., DROSSOPOULO,G., SCHUL- PFT~nStN, I., SELLDtN, U., STEINWALL,O. and SODEaHOLM,B. Bradycardia and asystole on administration L~R, E. et CHANmT, P. Un neurostimulant 6pileptoof Megimide (~d~-methyl-ethyl glutarimide) for elec. @ne: La M6gimide.Pressem~d., 1956b, 64: 1525-1527. troencephalographic activation. Electroenceph. clin. DI~LGADO,J. M. R. Circulatory effects of cortical stimulaNeurophysiol., 1960, 12: 497-501. tion. Physiol. Rev., 1960, 40, suppl. 4: 146-171. RUSHM~R, R. F. and SMm~, JR., O. A. Cardiac control, DELG^DO0J. M. R. and HAMLIN,H. Direct recording of Physiol. Rev., 1959, 39: 41-68. spontaneous and evoked seizures in epileptics. ElecS~LLt~[N, U. Repeated activation with Megimide in nortroeneeph, din. Neurophysiol., 1958, 10: 463-486. mal subjects: electroencephalographi¢ responses and Dl~l.o^tm, J. M, R., MmAILOVlC,L. and SEVILLANO,M. threshold doses. Electroenceph. clin. Neurophysiol., Cardiovascular phenomena during ~eizure activity. J. herr. ment. Dis., 1960, 130: 477-487. 1964, 17: 1-10.
troenc6phalograph¢ et la pression sanguine prise sur l'art6r¢ brachiale, ne subissent aucune influence notable par l'injection des doses de M6gimide utilis6es pour activation 61ectroenc6phalographique suivant le proc6d6applique.
Reference: SELLDI~N,U. ANDS~DERHOLM,B, Electroencephalographic and circulatory responses to Megimide in normal subjects. Electroenceph. olin. Nearophysiol., 1964, 17: ! 1-16.
I1
ELECTROENCEPHALOGRAPHIC AND CIRCULATORY RESPONSES TO MEGIMIDE IN N O R M A L SUBJECTS 1 ULLA SELLD[N AND BROR SODERHOLM, M . D .
Laboratoriesfor Clinical Neurophvsiology and Clinical Physiology, Sahlgrenska Sjukhuset, G6teborg (Sweden) (Accepted fo,t publication: December 6, 1963)
The excitatory effect of Megimide (/~,~-methylethyl-glutarimide) on the electroencephalogram has been amply demonstrated by investigations on humans as welt as by experimental studies on animals. Since cardiovascular centers have both a cortical and a subeortical representation in the cerebrum (Penfield and Rasmussen 1950; Kaada 1951; Folkow 1955; Rushmer and Smith 1959) it is conceivable that Megimide activation may produce undesirable side effects on the peripheral circulation. Blomberg el al. (1961) found no appreciable effect of Megimide activation on the heart rate and blood pressure in patients with various neurological disorders, whereas Delay et al. (1956a and b) reported slightly elevated values for these two factors. Hypotensive effects associated with bradycardia and asystole have also been reported (Margerison 1958; Peters6n et al. 1960). In these investigations blood pressures were measured by arm cuff and sphygmomanometer. There has been some discussion ofthe possible correlation between EEG changes and effects on the peripheral circulation. On the basis of animal experiments involving coincident recording of EEGs, ECGs and intra-arterial blood pressure, Morin and Corriol (1955 and 1957) contend that a paroxysmal discharge is essential to get a cardiovascular reaction. In contrast, Delgado (1960) and Delgado et al. 0960), using a depth recording technique in humans, claim to have demonstrated that paroxysmal discharges and cardiovascular effects may occur independently of each other. This is supported by their observations in patients with spontaneous 3 c/see wave 1 This investigation was supported by grants from the Faculty of Medicine, Gothenburg, and Svenska Sitllskapet f6r Medicinsk Forskning, Stockholm.
and spike attacks, whose heart rates and blood pressures showed no appreciable fluctuation. The chief purpose of the present investigation was to determine whether Megimide activation may give rise to detectable effects on the peripheral circulation. Another aim was to find out whether certain sensations of discomfort which frequently attend injection of Megimide were correlated with any form of cardiovascular reaction. A normal series ~vasconsidered best suited for an investigation of this type. MATERIAL AND METHODS
The investigation comprised twenty-two normals, nine females and thirteen males, none of whom had any history of, or showed any evidence of, cerebral, cardiovascular or other disease of significance. The source of tile subjects, the electroencephalographic recording, the activation technique and the classification of EEG responses were the same as is reported in the foregoing paper on repeated activation with Megimide in normals (Selld6n 1964). Electroencephalographic findings were normal in all subjects except two (cases 4 and 21).who exhibited a certain amount of theta activity with left preponderance in fronto-temporal leads. Brachial artery pressure was recorded from an indwelling polythene tube (Berneus et al. 1954). Pressures were registered by strain gauge manometers on a 4-channel direct writing recorder (Mingograf, EIema). A point 5 cm dorsal to the sternal angle was used as reference level. EEGs were taken concurrently. Injection of Megimide was started at least 1 h after catheterization. Systolic and diastolic pressures and heart rates were calculated prior to Megimide injection and after each dose. The vafi,~tions were expressed Electroenceph. clin. NeurophysioL, 1964, 17:i1-16
12
u. SELLDI~N AND B. SODERiIOLM
as the pooled estimate for the standard deviations within individuals. Differences between the pre~-and post-injection heart rates and blood p~essures were anatyz~d both in the series as a whole (Table 11) and in groups and subgroups f~rmed on the basis of: 1. Subjective reaction to Megimide activation (Table ll); 2. Type o f EEG response to Meg'.'.mide activation (Table ll); and 3. EEG responses grouped with respect to subjective reactions (Table Ill). Cases in which Megimide failed to affect the EEG were omitted from the analyses in groups 2 and 3 above, since they numbered only three. The statistical analyses were carried out with the use of Student's t test at the 5% level. The mean differences and their standard deviations are reported.
RESULTS In Table I the series is detailed with respect to age, sex, resting EEG, EEG response to activation, and relevant threshold doses; total dose o f Megimide administered, and subjective reactions to the injection; systolic and diastolic blood pressures and heart rate p~ior to Megimide injection, at the onset o f a n effect of non-paroxysmal type, and after activation. Tables II and III present the results of statistical analyses of the differences between the preand post-injection blood pressures and heart rates. Fig. ! illustrates concurrently recorded EEGs, ECGs and blood pressures in a typical case (case 3).
Eiectroencephalographic responses and subjective reactions In three cases no EEG t.hanges were obtained,
TABLE l For explanatory text ~e Results Case Sex
Rest- Total
no.
in8 dose of None =:'A B EEG Megimide Threshold dose m$
I 2 3 4 5 6 7 8 9 i0 II 12 13 14 15
16 17 18 19 20 21 22
and age
~19 N ~19 N ~24 N ~ 26 Abn. ~33 N ~ 37 N c~42 N ~44 N ~51 N ~ 19 N ~ 20 N ~ 22 N (~ 22 N (~ 26 N ~ 26 N ~29 N ~ 29 N ~ 37 N d~ 39 N (~41 N (~49 Abn. ,~ 51 N
150 g0 80 30 90 80 40 60 60 100 80 80 150 130 100 150 50 80 140 140 80 120
EEG response
II0 60 50 20 80
it0
40 40 60 100 50 40 70 140 70 130 X 80 150 30 X 70 140 90 40
Blood pressures (BA)
fort on mm H8 activation Before On act. After M M
I~:F
80 40 60
X
Discern-
~÷ 0 0 + +~ oF 0 0 + +~ 0 0 0 ++ 0 0 -F + ++ 0 0 0
124/56 130/60 126/60 111/56 111/57 107/56 119~55 120/55 119/55 101/52 99153 99155 119/66 117/66 117/66 140/59 136/64 106163 107•65 99/47 110/53 109/54 140178 139/74 135/74 1581102147/84 175/108 156/86 159/93 165f93 152/96 162j92 166/96 148/83 156198 156/96 136182 140186 144182 145/88 138/86 119/68 113/73 116/78 131/82 126/75 128/7~ 139/83 146184 130/66 130/72 117r'81 149/97 159/101 157/98 125/78 !!9/72 125176 140/86 146/88
Heart rate
beats per rain Before On act. After M M 64 66 82 54 78 82 74 72 62 72 60 62 74 72 68 56 64 68 84 60 56 70
70 74 82 54 76 72 54 84 70 60 72 64 58 58 82 58 54
74
74 84 54 76 80 76 72 54 82 72 57 72 70 62 78 54 78 74 60 56
67
A: Nvn-paroxysmal effect; B: Paroxysmal effect; M: Megimide activation; BA: Brachial artery; N: Normal; Abn.: Abnormal; + : Slight; + + : Considerable.
Electroenceph. clin. Neurophysiol., 1964, 17:11-16
13
EEG A N D C I R C U L A T O R Y RESPONSES T O MEGIMIDE
T A B L E II For explanatory textsee Results
Differences between pr¢- and post-injection values Total series S
Number o f cases Mean difference Sdm. tvalue
D
N o discomfort on activation
S
HR
22 2.0 2.8 i.2 -t-7.34-5.3-t-2.5 !.312.45"2.22"
D
Discomfort on activation
HR
12 3.4 1.9--0.5 !6.34-5.7-4-7.9 1.88 !.16 0.22
S
D
EEG response type A
HR
l0 0.4 3.8 3.2 ±8.54-4.9:[:7.8 0.152.46" !.30
S
D
EEG response type B
HR
17 !.2 0.8 0.5 4-6.44-7.4-4-5.8 0,76 0.46 0.33
S
D
HR
9 3.3 5,0 1.9 -4-9.64-5.2:£-9.3 !.042.88" 0.61
A: Non-paroxysmal effect; B: Paroxysmaleffect; S: Systolic blood pressure (ram Hg); D: Diastolic blood pressure ~mm Hg); HR: Heart rate (beats/min). * Statistically significant at the 5% level. TABLE 111 For explanatory text see Results
Differences between pre- and post-injection values EEG response type A
Number of cases
Mean difference sdin. t value*
EEG response type B
No discomfort on activation
Discomfort on activation
No discomfort on activation
Discomfort on activation
S
S
S
S
D
HR
D
II
2.2 1.3 -2.2 t6.7 t6.5 ±3.6 1.09 0.66 2.01
HR 6
D
HR 5
-0.7 0 5.3 t5.8 =[:9.2 ±6.0 0.3 0 2.16
D
HR
4
5.8 3.4 3.4 0.3 7.0 0 t7.1 ±4.8 tl0.7 ±12.5±5.6 £:8.3 1.83 !.58 0.71 0.05 2.50 0
A: Non-paroxysmal effect; B: Paroxysmal effect; S: Systolic blood pres,~ure (ram Hg); D: Diastolic blood pressure (mm HS); HR: Heart rate (l~als/min), * N o levelsof statistical siBniflcance. subjective distress necessitating discontinuance of the injection at doses of 80, 100 and 120 mg respectively. An effect of non.paroxysmal type was noted in seventeen cases, seven of which showed paroxysmal activity as well. Each of the other two subjects (cases 6 and 7) exhibited paroxysmal activity. In case 6 no significant increase of non-paroxysmal low frequency activity was recorded, and case 7 was not evaluable because of artefacts associated with the injection. The paroxysmal changes in this series were consistently of bilaterally synchronous type and occurred in one or more episodes, usually of 2-4 sec duration. Ten of the subjects experienced discomfort, which varied in type and intensity, but which was described as essentially a form of dizziness, accompanied by a rocking or floating sensation
as well as some disorientation in space. Several had twitching sensations, particularly around the eyes; in these cases palpebral tremor was objectively discernible. No nystagmus was observed. Four subjects (cases 6, i !, 15 and 19) reported a sensation of imminent syncope.
Circulatory responses in relation to electroencephalographic findings and subjective reactions From the pre- and post-injection values listed in Table I it is evident that neither heart rate nor blood pressu~'e underwent any major fluctuations. Only in six subjects (cases 10-13, 16 and 19) did the heart rate change by more than 10 beats per rain and the blood pressure by more than 10 m m Hg. After Megimide there was no systematic change in the systolic pressure, whereas the diastolic showed a significant increase averaging Eleetroenceph. clin. Neurophysiol., 1964, 17:11-16
U. SELLDI~NAND B. S~DERHOLM
14
~om0
BLood pressure 11glS$ mm HO
160
~
All
120155mmH9
'
' 60 m 9
•
119155 mrnH
30cmlmin
ECG Heart Rote 831 rain
621rain
II/,I rain
Fig. I The figure illustrates the course of activation with Megimide in one typical case (No. 3). the EEG first showing a non.paroxysmal effect (A) and then paroxysmal activity (B). Simultaneously recorded arterial blood pressure and ECG appear below each EEG section,
2.8 mm Hg, concomitant with a significant eleva- alographic activation may produce detectable tion of the heart rate by 1.2 beats/min (Table II). effects on the peripheral circulation, it was of On the basis of all recorded fluctuations in interest to find out whether the EEG phenomena blood pressure and heart rate associated with which result from the injection are attended by Megimide in the total series the pooled estimates heart rate and blood pressure changes of for the standard deviations were found to be 4.0 sufficient magnitude to be of clinical significance. The possible rote of subjective distress has mm Hg for the systolic pressure, 3.5 mm Hg for the diastolic, and 4.1 beats/rain for the heart been taken up for discussion because this factor could influence the cardiovascular functions via rate. It is evident from Table l[ that, although there at least two conceivable mechanisms. In the was no systematic change in heart rate and systol- first place, the dysphoria which is likely to ic pressure, a significant elevation of diastolic accompany pronounced distress could welt give pressure occurred in the groups with subjective ris¢ to cardiovascular effects; and, secondly, the discomfort and paroxysmal activity. No signif- disagreeable sensations could themselves stem icant differences emerged on subdivision of the from excitatory discharges which in turn affect cerebral structures with cardiovascular represeries as in Table IlL sentation. The latter hypothesis is prompted by DISCU~ION the fact that Penfield and Rasmussen (1950), on This investigation was designed to ascertain stimulation of the temporal lobe and insular whether injection of Megimide for electroenceph- cortex in humans, noted subjective sensations Electroenceph. elin. Neurophysiol., 1964, 17:11-16
EEG AND CIRCULATORYRESPONSESTO MEGIMIDE
similar in type to those produced by Megimide in this series. Delgado and Hamlin (1958) also observed such phenomena in their investigation with depth electrodes. They den-.onstrated, moreover, that paroxysmal patterns could be induced by stimulation of deep cerebral structures without involvement of superficial structures. The distress caused by Meg[re[de can possibly be attributed, therefore, to excitatory phenomena that do not lend themselvesto registration by scalp electrodes. It is, however, evident that with the Meg[re[de doses used in the present investigation only minor changes in heart rate and blood pressure occurred. Although the series as a whole showed a statistically significant elevation of heart rate and diastolic blood pressure during the course of the injection, the rise was apparently not substantial enough to be of biological significance. The same may be said of the statistically significant rise of diastolic pressure in the paroxysmal activity group and in subjects distressed by the injection. When the series was broken down with respect to the EEG response, then subdivided according to the subjective reaction, differences of statistical significance no longer emerged. This suggests that another factor (e.g. individual reactions to the injection procedure per se) contributed to the observed effects. The discrepancies noted on comparison of the present results with those of other authors (Margerison 1958; Peters~n et al. 1960; Blomberg et al. 1961) may be attributable largely to differences in size and composition of the respective
series. The investigations reported by these workers have been mainly concerned with EEG responses, and the results do not permit general conclusions as to effects on the circulation. SUMMARY Electroencephalographic and circulatory responses to Megimide were studied in 22 normals,
nine females and thirteen males, aged 19-51. Megimide was injected intravenously in doses of 10 mg/min up to a maximum of 150 mg (mean 95 ~ 37 rag), and EEGs, ECGs and brachial artery pressures were continuously recorded in connection with the injection. With the onset of paroxysmal effects, increasing focal abnormality, or subjective distress the injection was discontinued.
l
After each injected dose of Megimide the heart rate and the systolic and diastofic blood pressures showed, with few exceptions, slight fluctuations around the initial values. The pooled estimates for the star~dard deviations within individuals wore 4.1 bcats/min and 4.0 and 3.5 mm Hg, respectively. These changes showed no significant correlation either with the type of EEG response or with the characteristic sensations of discomfort that were noted in approximately one half of the cases. This investigation indicates that Megimide in the doses here employed for EEG activation does not affect to an appreciable degree the circulatory conditions, as evaluated from the ECG and the brachial artery pressure. R~UM~ RI~PONSES I~LECTROENCI~PHALOGRAPHIQUESEl" CIRCULATOIRES AU MI~GIMIDE CHEZ DES SUJETS NORMAUX
Les r~ponses ~lectroenc6phalographiques et circulatoires au M6gimide ont 6t~ ~tudi~es chez 22 sujets normaux, neuf femmes et treiz¢ hemrues ag6s de 19 ~ 51 ans. L'EEG, rECG et la pression sanguine, prise dam l'art~re brachiale, ont ~t6 enregistr6s continueilement pendant rinjection intraveineuse du M6gimide. Cette preparation a ~t6 administr6e en doses de 10 rag/rain; maximum 150 mg (dose moyenne 95 :[= 37 rag). L'activation a ~t~ interrompue lorsqu'ont apparu dos activit~s paroxysmales, un accroissement des anormalit~s focales ou des malaises chez le sujet. La fr~quence du pouls et la press[on sanguine systolique et diastolique, enregistr~es aprbs ['injection de chaque dose de M~gimide, ont r~v~16, avec de rares exceptions, des variations l~#,res autour des valeurs [nit[ales constat6es l'occasion de l'activation. La moyenne estim~e de 1'6cart normal, bas~e sur l'cnsemble des essais, ~tait de 4.1 battements/min et de 4.0 et 3.5 mm Hg respectivement. I! n'existe aucune correlation certaine entre ces ~carts et le type de r~ponse EEG ou les sensations de malaise caract~ristiques du M~gimide et qui ont t~t~ constat~es darts environ la molt[6 des cas. En r~sum6, it r~sulte de ces essais que les conditions circula~oires, enregistr~es par l'~lecE/ectroenceph. clin. NeurophysioL, 1964, 17:!1-16
16
U. SELLDI~N A N D B. SODERHOLM
FOLgOW,B. Nervous control of the blood vessels. Physiol. Rev., 1955, 35: 629-663. FOOtDA, B. R. Somato-motor, au,,,aomic and electrocorticographic responses to electrical stimulation of rhinencephalic and other ~tructures in primates, cat and dog; Acra ~ . - ~ a n d . , ". . . . . . . . . ~ ~. 1-285. MARCEnJSON,J. H. The effect of bemegride ("Megimide") REFERENCES on normal people. Electroenceph. clin. Nearophysiol., BERNEUS,B., CARLSTEN,A., HOLMGREN,A. and SELDINGER 1958, 10: 541-545. S.L Percutaneous catheterization of peripheral arteries MOroN, G. et CORnlOL,J. Sur ie m6canisme de l'hyperas method for blood sampling. Stand. J. olin. Lab. tension art6rielle produite par Vinjection intraveineuse Invest., 19~4~6: 217-221. de cardiazol chez le chien curaris~, chloralos~ ou non BLOMBERG,L. H., FEGEt~TEN, L., FLODMARK, S. and chloralos~. C. R. So¢. Biol. (Paris), 1955, 149: 748-P~aS~N, I. Electrocnccphalographic responses to 751. combined injections of Megimide aad Xylocaine. Acta MontH, G. et CORRtOL,J. Relations entre les effets hyperpsychiat, stand., 1961, 36: 5%68. tenseurs et ~pileptog6nes du penta-methyl6ne-tc~trazol. DELAY, J., SCUULLER,E., DROSSOPOULO,G., H^tM, A., Arch. int. Pharmacodyn., 1957, 109: 157-170. CHANOtT,P., V~RD~AUX,G. et V~RDEAUX,J. Un nouvei PENFIELD, W. and RASMUSSEN,TH. The cerebral cortex of activant de I'¢.L!ectroen~phalogramme: le N.P. 13. man. Macmillan, New York, 1950: "/7-86. C.R. $oc. Biol. (Paris), 1956a, 150: 242-243. DELAY,J., VERDEAUX,G. et J., DROSSOPOULO,G., SCHUL- PFT~nStN, I., SELLDtN, U., STEINWALL,O. and SODEaHOLM,B. Bradycardia and asystole on administration L~R, E. et CHANmT, P. Un neurostimulant 6pileptoof Megimide (~d~-methyl-ethyl glutarimide) for elec. @ne: La M6gimide.Pressem~d., 1956b, 64: 1525-1527. troencephalographic activation. Electroenceph. clin. DI~LGADO,J. M. R. Circulatory effects of cortical stimulaNeurophysiol., 1960, 12: 497-501. tion. Physiol. Rev., 1960, 40, suppl. 4: 146-171. RUSHM~R, R. F. and SMm~, JR., O. A. Cardiac control, DELG^DO0J. M. R. and HAMLIN,H. Direct recording of Physiol. Rev., 1959, 39: 41-68. spontaneous and evoked seizures in epileptics. ElecS~LLt~[N, U. Repeated activation with Megimide in nortroeneeph, din. Neurophysiol., 1958, 10: 463-486. mal subjects: electroencephalographi¢ responses and Dl~l.o^tm, J. M, R., MmAILOVlC,L. and SEVILLANO,M. threshold doses. Electroenceph. clin. Neurophysiol., Cardiovascular phenomena during ~eizure activity. J. herr. ment. Dis., 1960, 130: 477-487. 1964, 17: 1-10.
troenc6phalograph¢ et la pression sanguine prise sur l'art6r¢ brachiale, ne subissent aucune influence notable par l'injection des doses de M6gimide utilis6es pour activation 61ectroenc6phalographique suivant le proc6d6applique.
Reference: SELLDI~N,U. ANDS~DERHOLM,B, Electroencephalographic and circulatory responses to Megimide in normal subjects. Electroenceph. olin. Nearophysiol., 1964, 17: ! 1-16.