- Email: [email protected]
The use of noludar in pediatric electroencephalography
THE
USE
OF NOLUDAR
IN
PEDIATRIC
ELECTROENCEPHALOGRAPHY
D o s L. WtNmELD, P h . D . a n d JAMES G. HUGHES, M . D .
Departments o[ Neurology and Psychiatry and Pediatrics, University ol Tennessee, College o~ Medicine, Memphis, Tennessee (Received for publication: Febl'uary 10, 1957)
Various drugs and hypnotics have been used to induce sleep. This report is concerned with the use of Nohldar.1 I t is a newly developed hypnotic, distinguished by high therapeutic activity and low toxicity. N o l u d a r is a central nervous system depressant which is non-alkaloid'll. I t is a piperidine derivative mid does not belong either to the b a r b i t u r i c acid or the ureide groups. Chemically, N o l u d a r is 3,3-diethyl-5lnethyl-2,4-plperldinedione. E x p e r i m e n t a l studies with animals and clinical studies with h u m a n s reveal that N o l u d a r is distinctly less toxic t h a n phenobarbital. I n adults, N o l u d a r is well tolerated and effective with a fairly rapid onset and a short duration of effect. I n view of the reportedly quick action of Noludar, it was decided to see how effective this would b~, as nn a g e n t to induce sleep ill children referred for electroeneephalographic study. I t was also investigated froln tile point of vi~,w as to the amount of fast •lctivity produced ill the record and as to its qufi'tillg influence on those chihlrcn who "ire often stinlulated by the barbitul't~tes. METHOD The N o l u d a r ill the elixir f o r m was used. The taste is pleasant to children and uot as objectioml/)h, as the taste of some sedatives. F u r t h e r m o r e , children are more prone to accept a sedative in tile elixir fornl l"tther t h a n as a tablet. P r e f e r a b l y , a short period of waking activity was obtained, then the N o l u d a r was admilfistered, followed by a 3 mill. period of hyperventil'~tion by those p a t i e n t s who would co',)p¢,rate. Tho~e p a t i e n t s who a p p e a r e d to be difficult to lmlldle aml the very y o u n g i n f a n t s were given the N o l u d a r prior to the application of the electrodes. Early ill the study "~n attenlpt was made to administer a dosage of N o h n l a r which w~s believL,d to a l T r a x i l n n t e the equivalent amolmt of N e m b u t a l which Kellaway and F o x (1952) found effective ill their sleep study of chihlren. As more experien/'e with N o l u d a r wag g'lined, tlLe dosage given "lCcording t~, the child's age was as follows: 1 Noludar used in the study was supplied through the courtesy of Dr. Thomas C. Fleming, Department of Clinical Research, Hoffman-La Roche Inc., Nutley, N. J.
2 13 2~,~ 4 10
Me.. lyr .......... Me. - 29 me . . . . . . . . . . Yr. - 3 yr . . . . . . . . . . . . . . . Yr. - 9 y r . . . . . . . . . . . . Yr. - 15 yr . . . . . . . . . . . . . . .
50 75 100 150 200
rag. rag. rag. rag. rag.
Usually, if sleep had not ensued within 30 rain. f r o m the tinle of the original dosage, half of this dose was again given the patient. This r e p o r t is Col,eel'ned with the results obtained f r o m a study of 278 consecutive E E G s on children between the ages of 2 m o n t h s and 15 years. Only those children whose condition contraindicated the use of sedatives were omitted d u r i n g the course of the investigation. No a t t e m p t w:,s made to select the patients, although the age, weight, a n d provisional diagnosis were recorded. One p u r p o s e of the study was to evaluate the effectiveness of Nolud'lr on all types of pediatric referrals. RESULTS Two h a l , h ' e d ~tll~l twenty-three of tile 278 patients had sleep spindles in their records. The average length of time to obtain spindles in their records was 26.41 rain. with an average dosage of 150.90 mg. of Noludar. The average length of time before the ternlill'ltiOl~ L)f tile record of tile non-sleepers was 51.16 rain. with an average dosage of 211.36 mg. of Noludar. F i f t y - t h r e e of the p a t i e n t s with sleep spindh, s had rei,c,ated doses of Nohldar. The second dose generally w:ls about ~.', of the initial dose. F o r t y - t h r e e of the mm-sleepillg p a t i e n t s had repeated doses of Noludar. The average age of the sleeping and non-sleeping g r o u p s was npproxilnately six ?'ears "~lld weight differences were small b u t not significantly so. T h i r t y - f o u r (71 per cent) of 48 behavior problem referrals slept, 132 (83 per cent) of 160 convulsive disorder referrals slept and 53 (76 per cent) of 70 p a t i e n t s with other CNS disorders slept. E i g h t y per cent of the total g r o u p slept and 81 per cent had a b n o r m a l E E G s . 'Ellis is interpreted as a favorable response to the medication as compared with the results reported ill other studies using other sedatives
[ 713 ]
7]4
DON L. W I N F I E L D and JAMES G. HUGHES Age ~^
150 m g . N o l u d a r
1:15
P.M.
LF -RE R
F
-
LT-RE 9 0 ~ v
L I1
E
~
sec.
Sleep spindle stage
RT-LE Time of sample-l:27 P.M.
Time of sample-l:46 P.M.
LP-RE
RO-LE
Age
4
150 rag. Noludar 2:20 P.M. IF-LE RF-~E LT-LE 50 )u~ ~_1 sec. --
Parietal hump stage of early sleep
RT-RETime of sample- 2:31 P.M.
A ~ ~ Time of sample-2:39 P.M.
RP-~
LO-LE RO-PE
~ "
- v
~"
(Gibbs and Gibbs 1946; Kellaway 1950; Kellaway and Fox 1952; Levin 1952; Winfield 1955). This is particularly true since no special preparations were taken with the patients prior to the examination.
Since the purpose of this study was not to investigate the clinical side effects of Noludar (that having been done extensively by previous investigators - - Loughlin et al. 1955), no systematic attempt was
715
NOLUDAR I N P E D I A T R I C EEG made to collect such data. In a few instances it was noted that a non-sleeping child who was administered rather large doses of Noludar appeared to be a little unstable and dizzy. Very rarely did a child appenr to be stimulated by the Noludar, per se. On the contrary, in many instances, those children who in our experience would probably have been stimulated by the barbiturates were quieted by Noludar. The EEGs in this study were examined with refer(~nce to the amount of fast activity present. Of the 278 p~tients in this study, 186 patients had no fast activity or negligible amounts in their EEGs (fig. 1). Forty-one patients had some fast activity which appeared to be accentuated by the Noludar. Thor(, were 38 other patients known to be on anticonvulsant medication (barbiturates alone or in combination with other medication) at the time of their brain wave tracing. I n this group, the fast activity present was believed to be either barbiturate induced or else activity characteristic of these children. In most instances the fast activity appeared to 1)c potentiated by the Noludar. Thirteen other patient~ were believed to have abnormally fast EEGs. As with barbiturates, the fast activity is generally potentiated in drowsiness and light sleep. An analysi~ of the data would indicate that by giving 200 rag. of Noludar beginning at the age of 8 years instead of 10, as done in this study, would probably increase the percentage of sleep records. CONCLUSIONS In general it would appear that Noludar is a good hypnotic for the induction of sleep in pediatric electroencephalography. In the recommended doses, it produces sleep in a reasonable length of time in most patients. Furthermore, it does not generally in-
duee fast activity in the record, although it appears to enhance fast waves already present whether they be barbiturate induced or characteristic of a given patient. Since 81 per cent of the patients had abnormal EEGs, it would appear unlikely that Noludar would be considered a depressant of abnormal brain wavc activity. Noludar appears to be particularly effective with behavior problem referrals and with those children who are generally excited by the barbiturates. No significant undesirable side effects were noted during the study, although no systematic attempt was made to investigate them. REFERENCES GIBBS, E. I,. and GIBBS, F. A. Diagnostic and localizing value of electroencephalographic studies in sleep. ICes. P u b L Ass. herr. qnc~t. Dis., 1946, 26: 366-376. ](ELLA\VAY, P. The use of sedative induced sleep as an aid to electroencephalographic diagnosis in children. J. Fed., 1950, 37: 862-877. ~ELLA~VAY, I). and Fox, B. J. Electroencephalographic diagnosis of cerebral pathology in infants during sleep. I. J. Ped., 1952, 4 I : 262-287. I~.~.DWIG, H. A. An electroencephalographic study of Doriden. A . M . A . Arch. Ncurol. Psychiat., 1955, 74: 351-355. LEVIN, Paul M. Dormison as a hypnotic in clinical electroenccphalography. Presented at the 5th Annual Meeting of the Southern EEG Society. .Nov. 10-11, 1952, Miami, Florida.
I~OUGHLIN, E. ~., ~ULLIN, ~V. G., SCttWlMMER, J. and SCHWIM.~IER, M. Clinical studies on toxicity and on hypnotic and sedative effects of Rol6463% Noludar (3,3-diethyl-2,4-dioxo-5-methylpiperidine). I n t e r n a t . Rec. Med. 1955, 168: 52-60. WINFIELD, O. L. A comparison of oral and rectal chloral induced sleep in clinical electroencephalography. E E G Clin. Nc~rophy.¢foZ.. 1955. 7: 424.
t,'cf,.rcncc: WINFIELD, D. :L. and ttVOHES, J. G. Tile use of Noludar in pediatric electroencephalography. E E G Clin. Neurophysiol., 1957, 9: 713-715.
USE
OF NOLUDAR
IN
PEDIATRIC
ELECTROENCEPHALOGRAPHY
D o s L. WtNmELD, P h . D . a n d JAMES G. HUGHES, M . D .
Departments o[ Neurology and Psychiatry and Pediatrics, University ol Tennessee, College o~ Medicine, Memphis, Tennessee (Received for publication: Febl'uary 10, 1957)
Various drugs and hypnotics have been used to induce sleep. This report is concerned with the use of Nohldar.1 I t is a newly developed hypnotic, distinguished by high therapeutic activity and low toxicity. N o l u d a r is a central nervous system depressant which is non-alkaloid'll. I t is a piperidine derivative mid does not belong either to the b a r b i t u r i c acid or the ureide groups. Chemically, N o l u d a r is 3,3-diethyl-5lnethyl-2,4-plperldinedione. E x p e r i m e n t a l studies with animals and clinical studies with h u m a n s reveal that N o l u d a r is distinctly less toxic t h a n phenobarbital. I n adults, N o l u d a r is well tolerated and effective with a fairly rapid onset and a short duration of effect. I n view of the reportedly quick action of Noludar, it was decided to see how effective this would b~, as nn a g e n t to induce sleep ill children referred for electroeneephalographic study. I t was also investigated froln tile point of vi~,w as to the amount of fast •lctivity produced ill the record and as to its qufi'tillg influence on those chihlrcn who "ire often stinlulated by the barbitul't~tes. METHOD The N o l u d a r ill the elixir f o r m was used. The taste is pleasant to children and uot as objectioml/)h, as the taste of some sedatives. F u r t h e r m o r e , children are more prone to accept a sedative in tile elixir fornl l"tther t h a n as a tablet. P r e f e r a b l y , a short period of waking activity was obtained, then the N o l u d a r was admilfistered, followed by a 3 mill. period of hyperventil'~tion by those p a t i e n t s who would co',)p¢,rate. Tho~e p a t i e n t s who a p p e a r e d to be difficult to lmlldle aml the very y o u n g i n f a n t s were given the N o l u d a r prior to the application of the electrodes. Early ill the study "~n attenlpt was made to administer a dosage of N o h n l a r which w~s believL,d to a l T r a x i l n n t e the equivalent amolmt of N e m b u t a l which Kellaway and F o x (1952) found effective ill their sleep study of chihlren. As more experien/'e with N o l u d a r wag g'lined, tlLe dosage given "lCcording t~, the child's age was as follows: 1 Noludar used in the study was supplied through the courtesy of Dr. Thomas C. Fleming, Department of Clinical Research, Hoffman-La Roche Inc., Nutley, N. J.
2 13 2~,~ 4 10
Me.. lyr .......... Me. - 29 me . . . . . . . . . . Yr. - 3 yr . . . . . . . . . . . . . . . Yr. - 9 y r . . . . . . . . . . . . Yr. - 15 yr . . . . . . . . . . . . . . .
50 75 100 150 200
rag. rag. rag. rag. rag.
Usually, if sleep had not ensued within 30 rain. f r o m the tinle of the original dosage, half of this dose was again given the patient. This r e p o r t is Col,eel'ned with the results obtained f r o m a study of 278 consecutive E E G s on children between the ages of 2 m o n t h s and 15 years. Only those children whose condition contraindicated the use of sedatives were omitted d u r i n g the course of the investigation. No a t t e m p t w:,s made to select the patients, although the age, weight, a n d provisional diagnosis were recorded. One p u r p o s e of the study was to evaluate the effectiveness of Nolud'lr on all types of pediatric referrals. RESULTS Two h a l , h ' e d ~tll~l twenty-three of tile 278 patients had sleep spindles in their records. The average length of time to obtain spindles in their records was 26.41 rain. with an average dosage of 150.90 mg. of Noludar. The average length of time before the ternlill'ltiOl~ L)f tile record of tile non-sleepers was 51.16 rain. with an average dosage of 211.36 mg. of Noludar. F i f t y - t h r e e of the p a t i e n t s with sleep spindh, s had rei,c,ated doses of Nohldar. The second dose generally w:ls about ~.', of the initial dose. F o r t y - t h r e e of the mm-sleepillg p a t i e n t s had repeated doses of Noludar. The average age of the sleeping and non-sleeping g r o u p s was npproxilnately six ?'ears "~lld weight differences were small b u t not significantly so. T h i r t y - f o u r (71 per cent) of 48 behavior problem referrals slept, 132 (83 per cent) of 160 convulsive disorder referrals slept and 53 (76 per cent) of 70 p a t i e n t s with other CNS disorders slept. E i g h t y per cent of the total g r o u p slept and 81 per cent had a b n o r m a l E E G s . 'Ellis is interpreted as a favorable response to the medication as compared with the results reported ill other studies using other sedatives
[ 713 ]
7]4
DON L. W I N F I E L D and JAMES G. HUGHES Age ~^
150 m g . N o l u d a r
1:15
P.M.
LF -RE R
F
-
LT-RE 9 0 ~ v
L I1
E
~
sec.
Sleep spindle stage
RT-LE Time of sample-l:27 P.M.
Time of sample-l:46 P.M.
LP-RE
RO-LE
Age
4
150 rag. Noludar 2:20 P.M. IF-LE RF-~E LT-LE 50 )u~ ~_1 sec. --
Parietal hump stage of early sleep
RT-RETime of sample- 2:31 P.M.
A ~ ~ Time of sample-2:39 P.M.
RP-~
LO-LE RO-PE
~ "
- v
~"
(Gibbs and Gibbs 1946; Kellaway 1950; Kellaway and Fox 1952; Levin 1952; Winfield 1955). This is particularly true since no special preparations were taken with the patients prior to the examination.
Since the purpose of this study was not to investigate the clinical side effects of Noludar (that having been done extensively by previous investigators - - Loughlin et al. 1955), no systematic attempt was
715
NOLUDAR I N P E D I A T R I C EEG made to collect such data. In a few instances it was noted that a non-sleeping child who was administered rather large doses of Noludar appeared to be a little unstable and dizzy. Very rarely did a child appenr to be stimulated by the Noludar, per se. On the contrary, in many instances, those children who in our experience would probably have been stimulated by the barbiturates were quieted by Noludar. The EEGs in this study were examined with refer(~nce to the amount of fast activity present. Of the 278 p~tients in this study, 186 patients had no fast activity or negligible amounts in their EEGs (fig. 1). Forty-one patients had some fast activity which appeared to be accentuated by the Noludar. Thor(, were 38 other patients known to be on anticonvulsant medication (barbiturates alone or in combination with other medication) at the time of their brain wave tracing. I n this group, the fast activity present was believed to be either barbiturate induced or else activity characteristic of these children. In most instances the fast activity appeared to 1)c potentiated by the Noludar. Thirteen other patient~ were believed to have abnormally fast EEGs. As with barbiturates, the fast activity is generally potentiated in drowsiness and light sleep. An analysi~ of the data would indicate that by giving 200 rag. of Noludar beginning at the age of 8 years instead of 10, as done in this study, would probably increase the percentage of sleep records. CONCLUSIONS In general it would appear that Noludar is a good hypnotic for the induction of sleep in pediatric electroencephalography. In the recommended doses, it produces sleep in a reasonable length of time in most patients. Furthermore, it does not generally in-
duee fast activity in the record, although it appears to enhance fast waves already present whether they be barbiturate induced or characteristic of a given patient. Since 81 per cent of the patients had abnormal EEGs, it would appear unlikely that Noludar would be considered a depressant of abnormal brain wavc activity. Noludar appears to be particularly effective with behavior problem referrals and with those children who are generally excited by the barbiturates. No significant undesirable side effects were noted during the study, although no systematic attempt was made to investigate them. REFERENCES GIBBS, E. I,. and GIBBS, F. A. Diagnostic and localizing value of electroencephalographic studies in sleep. ICes. P u b L Ass. herr. qnc~t. Dis., 1946, 26: 366-376. ](ELLA\VAY, P. The use of sedative induced sleep as an aid to electroencephalographic diagnosis in children. J. Fed., 1950, 37: 862-877. ~ELLA~VAY, I). and Fox, B. J. Electroencephalographic diagnosis of cerebral pathology in infants during sleep. I. J. Ped., 1952, 4 I : 262-287. I~.~.DWIG, H. A. An electroencephalographic study of Doriden. A . M . A . Arch. Ncurol. Psychiat., 1955, 74: 351-355. LEVIN, Paul M. Dormison as a hypnotic in clinical electroenccphalography. Presented at the 5th Annual Meeting of the Southern EEG Society. .Nov. 10-11, 1952, Miami, Florida.
I~OUGHLIN, E. ~., ~ULLIN, ~V. G., SCttWlMMER, J. and SCHWIM.~IER, M. Clinical studies on toxicity and on hypnotic and sedative effects of Rol6463% Noludar (3,3-diethyl-2,4-dioxo-5-methylpiperidine). I n t e r n a t . Rec. Med. 1955, 168: 52-60. WINFIELD, O. L. A comparison of oral and rectal chloral induced sleep in clinical electroencephalography. E E G Clin. Nc~rophy.¢foZ.. 1955. 7: 424.
t,'cf,.rcncc: WINFIELD, D. :L. and ttVOHES, J. G. Tile use of Noludar in pediatric electroencephalography. E E G Clin. Neurophysiol., 1957, 9: 713-715.