some the anticonvulsive action of paraldehyde* · produced a convulsive attack and the injection of...

J. Neurol. Neurosurg. Psychiat., 1949, 12, 19.

SOME EXPERIMENTAL AND CLINCAL OBSERVATIONS ON THE

ANTICONVULSIVE ACTION OF PARALDEHYDE*BY

F. J. DE ELtO, P. G. DE JALON -and S. OBRADOR

From the Instituto de Investigaciones M6dicas,f the Instituto de Farmacologia Experimental,*and the Instituto de Neurocirugia,§ Madrid

In the practice of neurosurgical operations theconvulsions occasionally elicited during corticalmanipulations or produced by electrical stimulationsmay sometimes be difficult to control, and may giverise in some cases to dangerous convulsive statesthat may even end fatally. Barbiturates and othercommon drugs may fail to stop such convulsionsquickly, as we have observed in some of our cases.We have recently tried paraldehyde by intra-

venous injection in the treatment of such convulsivestates, and the good results obtained have been thebasis for an experimental and clinical study of ithisdrug. In the literature we have found that Cervello(1884) was the first to use paraldehyde by mouth and-rectum for narcosis. Nitzescu and lacobovici (1934)recommended paraldehyde by intravenous injection(0-15 to 0-2 c.cm. per kg.) as a basal anaestheticbefore the administration of ether. Wechsler (1940)has also successfully employed the slow intravenousinjection of 1 c.cm. of paraldehyde for the treatmentof status epilepticus.

ToxicityParaldehyde has relatively little toxicity by the

intravenous route. Experimentally 0-5 c.cm. perkg. in cats produces only a small and transitoryreduction of the blood pressure and respiration.With smaller doses (01 to 0-2 c.cm. per kg.)injected into rabbits, cats, and dogs there are nochanges in respiration or circulation.

In human beings the intravenous injection of1 to 3 c.cm. does not alter the pulse, blood pressure,or consciousness. There may be a slight fall inblood pressure lasting a few minutes. Frequentlythere is intense coughing for two to five minutesafter the injection, with individual variations andcaused by the irritation of the bronchial tree dueto the partial elimination of the paraldehyde throughthe lungs. Usually there is also a stimulation of therespiration with hyperpnoea.

Higher doses of 6 c.cm. of intravenous paral-dehyde in adults (about 0 1 c.cm. per kg.) produce anarcotic effect with some diminution of conscious-

ness and a tendency to sleep, although the subjectwill still react to painful stimuli. There is also aslight fall in tlood pressure. With bigger doses(9 to 12 c.cm. in adults) the narcotic action is moremarked- and usually the patients fall asleep at theend of the injection. The cough does not appear,the blood pressure falls slightly, and there is anincrease in the rhythm and amplitude of therespirations.

Action on the Motor Responses of theCerebral Cortex

In cats under dial anesthesia the motor area wasstimulated and the contractions of the contralateraltibialis anterior muscle were isometrically recorded.Condenser discharges of 10 m.sec. duration andwith a frequency of 50 per second were appliedthrough a bipolar electrode during periods of5 seconds.The same type of stimulation was employed in'

five patients submitted to neurosurgical operations,where the stimulation was necessary because ofepileptic disorders or for delimitation of the motorarea in cortical removals for athethosis.

Paraldehyde in small doses (0-05 to 0-1 c.cm. incats and 1 to 3 c.cm. in men) produced a cleardiminution of the motor responses of the, cortex,with great elevation of the threshold of stimulationand even a complete abolition of the responses.Experimentally we have determined that thedepressive action on the motor cortex lasted for20 to 30 minutes, and afterwards the excitabilityrecovered slowly although the diminution persistedfor some time.

In some clinical cases the cortical stimulationproduced a convulsive attack and the injection ofparaldehyde stopped the convulsions immediately.Further stimulations were completely negative, andonly with intense stimuli some slight clonicdischarges were obtained in one epileptic patient.

Action on the Electrical Activity of theCerebral Cortex

Cats under nembutal were used for recording theelectrical activity of the cortex with electrodesinserted in the skull and in contact with the dura.A Grass electroencephalograph of four channelswas employed for recording.

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* Read before the Society of British Neurological Surgeons, DublinMeeting, July, 1948.

t Prof. C. Jimenez Diaz.- Prof. B. L. Velazquez.

§ Dr. S. Obrador.

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F. J. DE ELIO, P. G.. DE JALON AND S. OBRADORThe spontaneous activity of the cortex typical of

the cat under nembutal with frequencies of 4 to12 per-second and 50 to 200 microvolts was notapparently modified by small doses of paraldehyde(0 05 c.cm. per kg.). Greater doses (0 1 c.cm. perkg.) produce, however, an obvious diminution ofthe spontaneous cortical activity that appears at20 or 30 seconds from the injection time (Fig. 1).This effect lasts about 15 to 20 minutes, followed byslow recovery. Using higher amounts of paral-dehyde (015 to 0-2 c.cm. per kg.) the completeelimination of activity is very striking, as we shallsee later (Fig. 3).

Paraldehyde also stops the convulsive activity-ofthe cortex elicited by intravenous injection ofleptazol (300 to 600 mg.). These convulsi-vedischarges of very large voltage and high frequencyappear a few seconds after leptazol injection, andparaldehyde abolishes such activity immediately(Fig. 2). The convulsive discharges may continuefor several minutes in the control experiments.Sometimes paraldehyde in bigger doses (0'2 c.cm.

A

per kg.) not only stops the convulsive activity, butmay also abolish completely all signs of electricalactivity in the brain (Fig. 3). This completedepression of the cortex lasted two minutes andafterwards some isolated discharges of spontaneouswaves reappear, but it takes about 15 minutes beforea marked recovery is noticed.

In several epileptic patients in the course ofroutine electroencephalographic studies, paralde-hyde was injected intravenously in small doses of2 to 3 c.cm. In some cases there was no noticeablechange in the activity of the electroencephalogram,probably because of the small amount injected.But even these doses produced in two cases adiminution of the abnormal activity. Furtherstudies are still necessary, injecting larger amountsof paraldehyde.

Anticonvulsive ActionThe anticonvulsive action of paraldehyde has

been studied experimentally in rabbits and cats.

B

FIo. 1.-Electrical activit of a cat's cerebral cortex under Nembutal, before (A) and after (B) a small dose ofparaldehyde (0 1 c.cm. per kg.).

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ANTICONJ.ULSIVE ACTION OF PARALDEHYDE

This drug, in doses of 01 to 0-2 c.cm., is veryeffective in preventing and immediately stoppingthe very severe and lasting convulsions producedby large doses. of leptazol and strychnine. Theconvulsions elicited by local applications of strych-nine on the motor cortex of the cat under nembutalanesthesia are also stopped to a striking degree byparaldehyde (Fig. 4). An animal injected withparaldehyde is compleiely protected even againstvery large doses of several mg. of strychnine. Theanticonvulsive action appears also in the decere-brate rahd spinal preparation of the cat.

Clinically we have also confirmed the intenseanticonvulsive action of paraldehyde in severalcases of epileptic attacks during or after neuro-surgical operations. Even in cases under combinedrectal avertin and intravenous pentothal anmsthesiawe have seen convulsive fits during removal of scars

or' other cortical lesions that have quickly stoppedwith'doses of 2 to 4 c.cm. of intravenous paral-dehyde. Serious and prolonged status epilepticushas also been controlled by an injection of paral-dehyde that sometimes had to be repeated- once or

even twice in the course of several hours. We havenever seen any complications or secondary effectsafter the use of paraldehyde.

Other Pharmacological ActionsThe action of paraldehyde has also been studied

on some pharmacological preparations. On thenerve and-muscle preparation of the rat's diaphrag(Builbring, 1946) this substance reduces the muscularresponses to the electrical stimulation of the phrenicnerve (Fig. 5). The same depression has beenobserved on the nerve and muscle preparation of thesciatic nerve of the cat (Fig. 6). In the perfusion ofthe superior cervical sympathetic ganglion of thecat with the technique of Kibjakow (1933), modifiedby Feldberg and Gaddum (1934), the paraldehydeproduces also a marked depression on the ganglionicsynapse (Fig. 7).

DiscussionOur experimental and clinical observations on

the effects of paraldehyde demonstrate very clearlythe great depressive action of this drug on different

dCW,''.U

-FIG. 2.-onvulsive activity of the cat's cortex after leptazol (A) abolished by paraldehyde (B).

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F. J. DE ELIO, P. G. DE JALON AND S. OBRADOR

levels of the nervous system-peripheral, spinal,and cerebral. The action seerns, however, moremarked on the cerebral cortex, where paraldehydecan completely eliminate for several minutes allsigns of electrical activity in the cat.The mechanism of action of this substance is

unknown to us, and in some preliminary experi-ments-using the preparations of guinea-pig intestineand the rectus muscle of the frog we have seen thatparaldehyde does not antagonize the action ofacetylcholine.From a theoretical point of view, the great anti-

convulsive action of paraldehyde has some interestbecause of the similarity of this substance to otherorganic aldehydes that are normaly formed in thecomplicated steps ofthe hydrocarbonate metabolism.Perhaps we may presume that paraldehyde actssomething like other substances (glucose, carbondioxide, pyruvic acid, etc.) that are considered as" physiological" anticonvulsants and regulators ofthe neuronal discharges. We hope to extend this

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line of investigation, comparing the anticonvulsiveaction-ofparaldehyde with other organic compoundsand especially those related to the carbohydratemetabolism, although it is well known that themajority of the compounds that take a part in suchmetabolism are very unstable.From a practical standpoint we believe that

intravenous paraldehyde is actually the best agentthat we have to stop an epileptic discharge immedi-ately. It can also be used as a prophylactic drugagainst operative convulsions in cortical. operations-on epileptic patients. The small toxicity of thissubstance is a very important factor if a repetitionof the injection is necessary. We recommend as afirst dose about 005 c.cm. to 0 1 c.cm. per kg., andif the convulsions reappear the injection may berepeated one or two hours later. Although, as wehave seen in our experimental studies, the markedaction lasts only fifteen to thirty minutes', it is onlynecessary to inject the paraldehyde once to breakthe epileptic state and usually the convulsions do>

B

FIG. 3.-Convulsive activity (A) arrested by paraldehyde (02 c.cm. per kg.), and all electrical activity alsoabolished (B).

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ANTICONVULSIVE ACTION OF PARALDEHYDE

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FiG. 4.-Electrocorticogram to illustrate theabolition of strychnine convulsions after theintravenous injection of paraldehyde at P.

FIG. 5.-The effect of paraldehyde in reducing themuscular response of the isolated diaphragmof the rat to electrical stimulation of thephrenic nerve.

FIG. 6.-Contractions of the gastrocnemius muscleof the cat (under chloralose) elicited, bystimulation of the sciatic nerve. Depressionof contractions following the administrationof paraldehyde at P.

W.IIFiG. 7.-Superior cer-vical ganglion of thecat isolated and,perfused with Lockesolution. Stimula-tion ofpreganglionic

- fibres causing con-E- El__8N vitraction of the11_{_1 canictitating mem-

brane of the cat'seye. Depression oftransmission of im-pulses by injectionof paraldehyde intothe fluid perfusingthe ganglion at P.

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F. J. DE ELIO, P. G. DE JALON AND S. OBRADOR

not recur. An annoying side effect is the coughthat follows the injection and that may last severalminutes with great intensity in some individuals.

SummaryParaldehyde is a substance with little toxicity

that can -be injected intravenously in doses of upto, 0-2 c.cm. per kg. without any ill-effects. Largedoses have a narcotic action.The motor responses- of the cerebral cortex of

the cat and human beings are greatly reduced orabolished by small doses of paraldehyde. Theconvulsive attacks produced' in the course ofneurosurgical -operations by cortical stimulationare immediately stopped by paraldehyde.

Paraldehyde reduces or abolish for some minutesthe spontaneous cortical activity of the cat accordingto the dose employed. Convulsive discharges ofthe cortex elicited by leptazol disappear immedi-ately with the injection of paraldehyde.The anticonvulsive action is also very striking

in animals injiected with different convulsant drugs.A dose of paraldehyde protects an animal againstlarge doses of'strychnine and leptazol. The anti-

convulsive action appears also in the decerebrateand . pinal preparations. Clinically, paraldehydehas been used in many cases to stop operative, orpostoperative convulsions that in some cases mayreach serious proportions.The depressing action of paraldehyde has also

been demonstrated on the peripheral neuromuscularjunctions- and on the ganglion synapses, althoughthe action is more marked on the cerebral cortex.The theoretical implications and mechanism of

action of paraldehyde are briefly discussed. Thissubstance is recommended in doses of 005 to0-1 c.cm. per kg. intravenously as the best agentthat we actually have to break and stop a convulsivedischarge. The dose may be repeated if necessary.

REFERENCESBuilding, E. (1946). British J. Pharm. Chem., 1, 38.Cervello, V. (1884). From Adriani, J., " The Chemistry

of Ariesthesia." (1946). Oxford.Feldberg, W., and Gaddum, J. H. (1934). J. Physiol.,

81, 305.Kibjakow, A. W. (1933). Pflibg Arch., 232, 432.Nitzescu, I. I., and Iacobovici, I. (1934). Presse med.,

42, 331.Wechsler, I. S. (1940). J. Amer. med. Ass., 114, 2198.

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