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DIAZEPAM IN THE PROPHYLAXIS OF LIGNOCAINE SEIZURES
Br.J. Anaesth. (1976), 48, 309
DIAZEPAM IN THE PROPHYLAXIS OF LIGNOCAINE SEIZURES B. AUSIKSCH, M. H. MALAGODI AND E. S. MUNSON SUMMARY
Diazepam 0.05-0.25 mg/kg increased the dose of lignocaine required to cause seizures in Rhesus monkeys by 24-34%. Spontaneous ventilation was maintained adequately during lignocaine administration following diazepam treatment and no adverse cardiovascular effects occurred. Before the onset of lignocaine-induced seizures in non-treated animakj the unimals appeared to be drowsy. However, prior administration of diazepam masked this effect. Convulsions were controlled by smaller doses of diazepam in non-treated animals than in diazepam-treated animak Also, the animals that were pretreated with diazepam had a greater duration of depression after seizure.
We have measured the arterial plasma concentrations of lignocaine at which seizures occur following constant-rate infusion of the drug in Rhesus BATBA AUSTNSCH, M.D., MARJORIB H. MALAGODI, PH.D.,
EDWIN S. MUNSON, M.D., Departments of Anesthesiology
and Pharmacology and Therapeutics, University of Florida College of Medicine, Box 721, J. Hillis Miller Health Center, Gainesville, Florida 32610, U.S.A. Reprint requests to B. A. The research described in this report involved animals maintained in animal care facilities fully accredited by the American Association for the Accreditation of Laboratory Animal Care.
monkeys treated with diazepam. The effects of this treatment on the behavioural responses, cardiorespiratory function and acid-base state were evaluated before, during and after the administration of lignocaine. METHOD
Thirty-two experiments were performed on six Macaca mulatto, (weight 4.1-5.6 (mean 5.1) kg). Each animal was placed supine in a restraining chair without medication. Lignocaine was infused at a constant rate to groups of five or six animals, both with and without prior treatment with diazepam. Diazepam treatment was given in a random manner and all experiments in the same animal were separated by intervals of at least 8 days. Following control measurements, four diazepam treatments (0.1 or 0.25 mg/kg i.m. 45 min before lignocaine infusion; 0.05 or 0.10 mg/kg i.v. 1.5 min before lignocaine infusion) were conducted. On completion of the diazepam studies, the lignocaine seizure dose was reassessed without diazepam treatment. In each animal, a cannula was inserted percutaneously into a superficial limb vein for the continuous infusion of a glucose and balancedelectrolyte solution. Lignocaine was administered i.v. by an infusion pump, at a rate of 4 mg/kg/min, until electrical seizure activity began. The seizure dose was expressed as mg/kg body weight. At the onset of seizure activity the lignocaine infusion was stopped. After 5 min of seizure activity, diazepam 0.05 or 0.1 mg/kg was administered i.v., and this was repeated at 1 -min intervals until electrical seizure activity ceased. Bipolar scalp electrodes placed bilaterally over the sensory motor cortex recorded electrical brain activity. A single-lead e.c.g. recorded
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The effectiveness of diazepam in terminating seizures induced by local anaesthetic agents has been reported in both animals (Feinstein, Lenard and Mathias, 1970; de Jong and Heavner, 1971,1974; Munson and Wagman, 1972; Munson et al., 1975) and man (Munson, 1973). The administration of diazepam to animals before a rapid i.v. injection of lignocaine has been shown by de Jong and Heavner (1971, 1974) to increase the dose required to produce seizure activity. It is a common clinical belief that diazepam given before large doses of local anaesthetic agents may offer protection against the inadvertent, rapid intravascular injection of a local anaesthetic, although there is no information about its effect during relatively slow increases in the blood concentration of local anaesthetic agents. The effect of diazepam on the concentrations at which local anaesthetic seizures occur has not been studied. The prophylactic use of diazepam in modifying the systemic toxicity of local anaesthetic agents might be deleterious if its anticonvulsant action masks the prodromal signs of toxicity, or if recovery is prolonged. The combined effect of a potentially toxic dose of local anaesthetic agent plus that of diazepam on cardiorespiratory function is unknown also.
310
BRITISH JOURNAL OF ANAESTHESIA
RESULTS
Behavioural and electrical changes
Lignocaine infusion produced a generalized increase in brain electrical activity in all experiments. Behavioural changes were similar to previous findings (Munson and Wagman, 1969). The animals without diazepam treatment became drowsy and unresponsive to mild sensory stimuli just before the onset of seizure activity. The seizure pattern—a tonic phase followed by a donic phase with bursts of electrical activity interspersed with electrically silent periods—was not altered by diazepam treatment. However, while animals receiving prophylactic diazepam showed transient drowsiness without loss of consciousness, they appeared to be more sedated * by R. N. Boyes, PH.D., Astra Pharmaceutical Products, Inc., Worcester, Mass.
during the period before seizure compared with the control animals. This depression and loss of responsiveness tended to mask the early signs of lignocaine toxicity, usually characterized by sedation just before the onset of seizure activity. When electrical seizure activity occurred, diazepam 0.1 mg/kg i.v., or less, was successful in terminating seizures in 10 of 11 control experiments. However, in diazepam-pretreated animals, this dose of diazepam was effective in only 13 of 24 experiments (P<0.01). In addition, animals receiving diazepam for both prophylaxis and therapy recovered more slowly than did those receiving diazepam after the onset of seizure activity. Seizure dosage and threshold
The lignocaine seizure dose (mean + SD) in the absence of diazepam treatment was 22.5 + 4.4 mg/kg. Diazepam treatment with the four doses tested caused a significant (P<0.05) increase in the seizure dose (24-34%) compared with the control values (table I). Similarly, animals receiving 0.1 mg/kg diazepam i.v. showed a 27% increase (P< 0.05) in the lignocaine concentration at which seizures occurred. The seizure dose following completion of the diazepam experiments was not significantly different from the values obtained before the diazepam study. Cardiorespiratory responses
No significant changes were observed in heart or respiratory rates in either the control or diazepam groups during lignocaine infusion (table II). The mean arterial pressure increased in both groups during lignocaine administration; this was significant (P<0.05) in the diazepam group just before the seizure and at 1 min after the seizure. Blood-gas and acid-base data
Before lignocaine and diazepam 0.1 mg/kg administration, a mild respiratory alkalosis was observed (Munson, Gillespie and Wagman, 1970) (table III). Diazepam treatment resulted in a small but significant (P< 0.05) increase in Paoo, at the onset of lignocaineinduced seizure activity. The degree of metabolic acidosis in the diazepam-treated animals was less than in the control animals. P a ^ values in all the experiments ranged from 67 to 298 mm Hg. DISCUSSION
Our findings show that pretreatment with diazepam caused an increase in the lignocaine seizure dose of
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cardiac rate and rhythm. A pneumograph, consisting of expandable rubber tubing placed over the thorax and abdomen, recorded the rate of ventilation. In both the control and i.v. diazepam 0.1 mg/kg experiments, a cannula was inserted into the saphenous artery, under dilute procaine local anaesthesia (Munson, 1974) for the continuous recording of arterial pressure and the withdrawal of blood for measurement of lignocaine concentration, gas tensions, and pH, before, during and after the lignocaine infusion. Oxygen (5 litre/min) was delivered to a transparent hood which covered the animal's head. The inspired oxygen fraction (Flo,) was greater than 0.75. P a ^ P&ca, an< i pH were measured with a Radiometer (BMS 3) blood-gas analyser. The acid-base state was calculated using the method of Siggaard-Andersen (1963) as modified by Severinghaus (1971). Arterial plasma lignocaine concentrations were measured* using a Varian 1700 gas chromatograph. The lignocaine doses and blood concentration data were analysed using the analysis of variance. Student's t test was used to compare results between two groups when a significant F-ratio was determined. The effectiveness of diazepam in terminating seizure activity was tested using the binomial distribution, comparing the percentage of animals in which seizures were terminated with diazepam 0.1 mg/kg or less during control and experimental (diazepam treatment) conditions. The significance of differences between groups in respect of cardiorespiratory, blood-gas and acid-base changes were evaluated using Student's t test.
311
DIAZEPAM AND LIGNOCAINE SEIZURES TABLE I. Effect of diazepam treatment on lignocaine {infusion 4 mglkgjmm) seizure dose and threshold in Rhesus monkeys. Mean values ( ± SD) Diazepam dose (mg/kg)
Treatment Initial control Diazepam Diazepam Diazepam Diazepam Final control
Animals studied
—
6 5 6 5 5 5
0.05 i.v. 0.10 i.v. 0.10 i.m. 0.25 i.m. —
Seizure dose (mg/kg)
Seizure threshold
Increase (%) — 24 30 34 34 4
22.5 ±4.4 27.8 ±3.5*
293+ 3 A*
30.2 ±5.9* 30.1 + 6.3* 23.3 ±4.7
18.2 ±1.5 —
24.1 ±4.5* — — —
* Significantly (P<0.05) different from control values.
Heart rate (beats/min) Control Before lignocaine and diazepam After diazepam (0.5 min) After lignocaine (2 min) (4 min) Seizure After seizure (1 min) (5 min) (15 min)
Diazepam
Mean arterial pressure (mmHg) Control
Diazepam
Respiratory rate (b.p.m.) Control
171
178
94
101
42
±11
±16
±14
±7
±16_
Diazepam 53
±18
176
103
53
±16
±13
±18
163
175
95
98
46
46
±25
±13
±9
±6
±15
±5
170
178
102
±4
±10
±7
lll*t ±5
182
176
±5
±17
116* ±8
195
202
±15
±26
208
200
±18
±12
120* ±13 120* ±15
38
51
±6
±12
113
44
61
±9
±12
±21
141*f ±16 127* ±15
173
178
109
103
±7
±35
±15
±12
* P < 0.05 compared with control values before lignocaine and diazepam. t P<0.05 compared with corresponding lignocaine values.
24-34% above control values. The doses of diazepam employed caused only transient drowsiness without loss of consciousness when administered alone, before lignocaine infusion. The magnitude of the protective effect of diazepam is approximately one-third that reported by de Jong and Heavner (1971, 1974) who used bolus injections of lignocaine in cats and monkeys. These differences in lignocaine requirement may be explained by the method of drug administration and by the brief but profound hypotension that is known to accompany the rapid administration of lignocaine (de Jong and Heavner, 1973). In
contrast, during constant-rate administration of lignocaine, we observed a small but consistent and significant increase in arterial pressure. It is believed commonly that the prophylactic use of diazepam is desirable when large doses of local anaesthetic agents are employed. Although this increases the threshold for local anaesthetic seizures, thereby reducing the frequency of toxicity, the usual prodromal signs of impending central nervous system depression, usually present during the constant-rate infusion of lignocaine, are masked by the prior administration of diazepam. When seizures
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TABLE II. Effects of diazepam 0.1 mg/kg i.v. treatment on heart and respiratory rates and mean arterial pressure before, during and after lignocaine-induced seizures in five Rhesus monkeys. Mean values ( ± SD)
BRITISH JOURNAL OF ANAESTHESIA
312
TABLE III. Effects of diazepam 0.1 mg/kg i.v. treatment on arterial pH, P c o u P o , and base excess before, during and after lignocaine-induced seizures. Mean values ( ± SD) pH (units)
Before lignocaine
Control
Diazepam
7.43 ±0.01 (5)
7.42 ±0.02 (6)
(mmHg) Control
Diazepam
32.2 ±2.8 (5)
7.45 ±0.05 (5)
After diazepam (0.5 min)
30.9 ±1.2 (6)
Base excess (m-equiv/litre)
Pao< (mm Hg)
Control
Diazepam
Control
Diazepam
-3.2 ±2.4 (5)
-3.5 ±1.5 (6)
295 ±17 (5)
263 ±28 (6)
30.0 + 0.08 (5)
250 ±41 (5)
-3.5 ±2.0 (5)
7.42 + 0.04 (5)
31.0 ±2.1 (5)
36.7*t ±4.1 (5)
-2.4 ±1.9 (5)
-0.7* ±1.2 (5)
288 ±15 (5)
260 + 52 (5)
7.28* + 0.02 (5)
7.33*t + 0.03 (4)
46.5* ±3.1 (5)
47.2* ±3.7 (4)
-4.4 ±0.9 (5)
-1.2f ±1.2 (4)
246* ±26 (5)
207 ±46 (4)
(5 min)
7.12* ±0.09 (5)
7.17* ±0.06 (5)
71.1* ±15.8 (5)
69.5* ±11.5 (4)
-4.3 + 5.1 (5)
(15 min)
7.25* ±0.05 (4)
1.21* ±0.07 (4)
42.1 ±9.2 (4)
48.9* + 9.2 (4)
-8.6* ±2.8 (4)
-3.8 ±2.4 (5) -4.0t ±1.1 (4)
210 + 71 (5) 248 ±62 (4)
138* ±54 (5) 125*t ±67 (4)
After seizure (1 min)
* P< 0.05 from control values before lignocaine and diazepam; numbers in brackets = number of animals studied. t P < 0.05 from corresponding lignocaine values. developed, approximately 50% of the diazepampretxeated animals required additional diazepam in doses greater than 0.1 mg/kg i.v. to abort the seizure activity. It is not surprising that treatment is more difficult when these seizures occur, since the lignocaine doses and blood concentrations were much higher in the diazepam pretreatment groups. The combination of diazepam and the increased dose of lignocaine resulted in greater depression after seizure and prolonged recovery as compared with animals receiving only a single therapeutic dose of diazepam 0.1 mg/kg after the onset of seizure activity. Thus, diazepam pretreatment may interfere with the early recognition of impending seizure activity, and may complicate the treatment of those seizures which occur. The routine use of diazepam before the administration of large doses of local anaesthetic agents is attended by both advantages and disadvantages. The clinician who uses diazepam in this manner should be aware of these actions. ACKNOWLEDGEMENTS
The authors are grateful to William J. Embro for his valuable technical assistance.
This research was supported in part by grants from United States Public Health Service (grant numbers GM00427-12 and RR00421) and from Astra Pharmaceutical Products, Inc. REFERENCES
de Jong, R. H., and Heavner, J. E. (1971). Diazepam prevents local anesthetic seizures. Anesthesiology, 34, 523. (1973). Diazepam and lidocaine-induced cardiovascular changes. Anestfusiology, 39, 633. (1974). Diazepam prevents and aborts lidocaine convulsions in monkeys. Anesthesiology, 41, 226. Feinstein, M. B., Lenard, W., and Mathias, J. (1970). The antagonism of local anesthetic induced convulsions by the benzodiazepine derivative diazepam. Arch. Int. Pharmacodyn. Ther., 187, 144. Munson, E. S. (1973). Mepivacaine overdose in a child. Anesth. Analg. (Cleve.), 52, 422. (1974). Arterial cannulation in awake restrained monkeys. Lab. Anim. Sci., 24, 793. Gillespie, J. R., and Wagman, I. H. (1970). Respiratory blood-gases and pH in two species of unanesthetized monkeys. J. Appl. Physiol., 28, 108. Tucker, W. K-, Ausinsch, B., and Malagodi, M. H. (1975). Etidocaine, bupivacaine and lidocaine seizure thresholds in monkeys. Anesthesiology, 42, 471. Wagman, I. H. (1969). Acid-base changes during lidocaine induced seizures in Macaco, mulatto. Arch. Neurol., 20, 406.
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7.45 ±0.05 (5)
Seizure
DIAZEPAM AND LIGNOCAINE SEIZURES Severinghaus, J. W. (1971). Siggaard-Andersen alignment nomogram; in Respiration and Circulation (eds P. L. Airman and D. S. Dittmer), p. 222. Maryland: Federation of American Societies for Experimental Biology. Siggaard-Andersen, O. (1963). Blood acid-base alignment nomogram. Scand.J. Clin. Lab. Invest., 15, 211. LE DIAZEPAM DANS LA PROPHYLAXIE DES ATTAQUES PROVOQUEES PAR LA LIGNOCAINE RESUME
DIAZEPAM ALS PROPHYLAKTIKUM BEI LIGNOCAINE-KRAMPFEN ZUSAMMEKFASSUNG
Die Wirkung von Lignocain deburite einer Erganzung von 24-36% zusatzlich 0,05-0,25 mg/kg Diazepam, um beim Rhesusaffen Krampfanfalle zu verursachen. Die
Spontanatmung wurde wahrend der Verabreichung von Lignocain nach Diazepambenandlung optimal aufrecht erhalten, wobei sich keinerlei kardiovaskulSre Nebenwirkungen ergaben. Vor Einleitung der durch Lignocain ausgelosten Krampfe, erzeigten sich die unbehandelten Tiere als schlafrig, wfihrend die vorherige Verabreichung von Diazepam diese Erscheinung verbarg. Unbehandelte Tiere benotigten kleinere Dosierungen von Diazepam zur Beseitigung der Krarnpfe, als dicjenigen, die schon mit Diazepam behandelt worden waren. Weiterhin zeigten die mit Diazepam vorbehandelten Tiere langet andauerade, den Krfimpfen folgende Depressionen.
EL DIAZEPAM EN LA PROFILAXIS DE LOS ACCESOS DE LINOCAINA SUMARIO
El diazepam (de 0,05 a 0,25 mg/kg) incremento la dosis de linocaina necesaria para producir accesos en monos macacos en un porcentaje del 24 al 34%. Se mantuvo la ventilation espontanea de forma adecuada durante la administracion de linocaina despues del tratamiento de diazepam y no se produjeron efectos cardiovasculares adversos. Antes de los accesos de linocaina inducida en animales no tratados, los animales parecfan amodorrados. Sin embargo, una administraci6n previa de diazepam enmascani este efecto. Las convulsiones fueron controladas por pequenas dosis de diazepam en animales no tratados que en animales tratados con diazepam. Tambien, los animales que fueron previamente tratados con diazepam tuvieron una mayor duracion de depresi6n despues del acceso.
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Le diazepam a raison de 0,05-0,25 mg/kg augmente de 24 a 34% la dose de lignocaine requise pour provoquer des attaques chez les singes rhesus. La respiration spontanee a etc maintenue de la maniere appropriee pendant l'adininistration de lignocaine apres traitement au diazepam et il ne s'est produit aucun effet cardiovasculaire adverse. Avant le debut des attaques provoquees par la lignocaine sur les animairr n'ayant recu aucune medication prealable, ces animaux semblaient somnoler. Cependant l'administration prealable de diazepam a masque ces effets. Les convulsions ont etc maitrisees sur les animaux n'ayant recu aucune pre-medication par des doses plus faibles de diazepam que sur les animaux ayant recu un pre-traitement au diazepam. Egalementj les animaux qui avaient ete pre-traites au diazepam ont subi une periode de depression plus longue apres l'attaque.
313
DIAZEPAM IN THE PROPHYLAXIS OF LIGNOCAINE SEIZURES B. AUSIKSCH, M. H. MALAGODI AND E. S. MUNSON SUMMARY
Diazepam 0.05-0.25 mg/kg increased the dose of lignocaine required to cause seizures in Rhesus monkeys by 24-34%. Spontaneous ventilation was maintained adequately during lignocaine administration following diazepam treatment and no adverse cardiovascular effects occurred. Before the onset of lignocaine-induced seizures in non-treated animakj the unimals appeared to be drowsy. However, prior administration of diazepam masked this effect. Convulsions were controlled by smaller doses of diazepam in non-treated animals than in diazepam-treated animak Also, the animals that were pretreated with diazepam had a greater duration of depression after seizure.
We have measured the arterial plasma concentrations of lignocaine at which seizures occur following constant-rate infusion of the drug in Rhesus BATBA AUSTNSCH, M.D., MARJORIB H. MALAGODI, PH.D.,
EDWIN S. MUNSON, M.D., Departments of Anesthesiology
and Pharmacology and Therapeutics, University of Florida College of Medicine, Box 721, J. Hillis Miller Health Center, Gainesville, Florida 32610, U.S.A. Reprint requests to B. A. The research described in this report involved animals maintained in animal care facilities fully accredited by the American Association for the Accreditation of Laboratory Animal Care.
monkeys treated with diazepam. The effects of this treatment on the behavioural responses, cardiorespiratory function and acid-base state were evaluated before, during and after the administration of lignocaine. METHOD
Thirty-two experiments were performed on six Macaca mulatto, (weight 4.1-5.6 (mean 5.1) kg). Each animal was placed supine in a restraining chair without medication. Lignocaine was infused at a constant rate to groups of five or six animals, both with and without prior treatment with diazepam. Diazepam treatment was given in a random manner and all experiments in the same animal were separated by intervals of at least 8 days. Following control measurements, four diazepam treatments (0.1 or 0.25 mg/kg i.m. 45 min before lignocaine infusion; 0.05 or 0.10 mg/kg i.v. 1.5 min before lignocaine infusion) were conducted. On completion of the diazepam studies, the lignocaine seizure dose was reassessed without diazepam treatment. In each animal, a cannula was inserted percutaneously into a superficial limb vein for the continuous infusion of a glucose and balancedelectrolyte solution. Lignocaine was administered i.v. by an infusion pump, at a rate of 4 mg/kg/min, until electrical seizure activity began. The seizure dose was expressed as mg/kg body weight. At the onset of seizure activity the lignocaine infusion was stopped. After 5 min of seizure activity, diazepam 0.05 or 0.1 mg/kg was administered i.v., and this was repeated at 1 -min intervals until electrical seizure activity ceased. Bipolar scalp electrodes placed bilaterally over the sensory motor cortex recorded electrical brain activity. A single-lead e.c.g. recorded
Downloaded from http://bja.oxfordjournals.org/ at UQ Library on June 22, 2015
The effectiveness of diazepam in terminating seizures induced by local anaesthetic agents has been reported in both animals (Feinstein, Lenard and Mathias, 1970; de Jong and Heavner, 1971,1974; Munson and Wagman, 1972; Munson et al., 1975) and man (Munson, 1973). The administration of diazepam to animals before a rapid i.v. injection of lignocaine has been shown by de Jong and Heavner (1971, 1974) to increase the dose required to produce seizure activity. It is a common clinical belief that diazepam given before large doses of local anaesthetic agents may offer protection against the inadvertent, rapid intravascular injection of a local anaesthetic, although there is no information about its effect during relatively slow increases in the blood concentration of local anaesthetic agents. The effect of diazepam on the concentrations at which local anaesthetic seizures occur has not been studied. The prophylactic use of diazepam in modifying the systemic toxicity of local anaesthetic agents might be deleterious if its anticonvulsant action masks the prodromal signs of toxicity, or if recovery is prolonged. The combined effect of a potentially toxic dose of local anaesthetic agent plus that of diazepam on cardiorespiratory function is unknown also.
310
BRITISH JOURNAL OF ANAESTHESIA
RESULTS
Behavioural and electrical changes
Lignocaine infusion produced a generalized increase in brain electrical activity in all experiments. Behavioural changes were similar to previous findings (Munson and Wagman, 1969). The animals without diazepam treatment became drowsy and unresponsive to mild sensory stimuli just before the onset of seizure activity. The seizure pattern—a tonic phase followed by a donic phase with bursts of electrical activity interspersed with electrically silent periods—was not altered by diazepam treatment. However, while animals receiving prophylactic diazepam showed transient drowsiness without loss of consciousness, they appeared to be more sedated * by R. N. Boyes, PH.D., Astra Pharmaceutical Products, Inc., Worcester, Mass.
during the period before seizure compared with the control animals. This depression and loss of responsiveness tended to mask the early signs of lignocaine toxicity, usually characterized by sedation just before the onset of seizure activity. When electrical seizure activity occurred, diazepam 0.1 mg/kg i.v., or less, was successful in terminating seizures in 10 of 11 control experiments. However, in diazepam-pretreated animals, this dose of diazepam was effective in only 13 of 24 experiments (P<0.01). In addition, animals receiving diazepam for both prophylaxis and therapy recovered more slowly than did those receiving diazepam after the onset of seizure activity. Seizure dosage and threshold
The lignocaine seizure dose (mean + SD) in the absence of diazepam treatment was 22.5 + 4.4 mg/kg. Diazepam treatment with the four doses tested caused a significant (P<0.05) increase in the seizure dose (24-34%) compared with the control values (table I). Similarly, animals receiving 0.1 mg/kg diazepam i.v. showed a 27% increase (P< 0.05) in the lignocaine concentration at which seizures occurred. The seizure dose following completion of the diazepam experiments was not significantly different from the values obtained before the diazepam study. Cardiorespiratory responses
No significant changes were observed in heart or respiratory rates in either the control or diazepam groups during lignocaine infusion (table II). The mean arterial pressure increased in both groups during lignocaine administration; this was significant (P<0.05) in the diazepam group just before the seizure and at 1 min after the seizure. Blood-gas and acid-base data
Before lignocaine and diazepam 0.1 mg/kg administration, a mild respiratory alkalosis was observed (Munson, Gillespie and Wagman, 1970) (table III). Diazepam treatment resulted in a small but significant (P< 0.05) increase in Paoo, at the onset of lignocaineinduced seizure activity. The degree of metabolic acidosis in the diazepam-treated animals was less than in the control animals. P a ^ values in all the experiments ranged from 67 to 298 mm Hg. DISCUSSION
Our findings show that pretreatment with diazepam caused an increase in the lignocaine seizure dose of
Downloaded from http://bja.oxfordjournals.org/ at UQ Library on June 22, 2015
cardiac rate and rhythm. A pneumograph, consisting of expandable rubber tubing placed over the thorax and abdomen, recorded the rate of ventilation. In both the control and i.v. diazepam 0.1 mg/kg experiments, a cannula was inserted into the saphenous artery, under dilute procaine local anaesthesia (Munson, 1974) for the continuous recording of arterial pressure and the withdrawal of blood for measurement of lignocaine concentration, gas tensions, and pH, before, during and after the lignocaine infusion. Oxygen (5 litre/min) was delivered to a transparent hood which covered the animal's head. The inspired oxygen fraction (Flo,) was greater than 0.75. P a ^ P&ca, an< i pH were measured with a Radiometer (BMS 3) blood-gas analyser. The acid-base state was calculated using the method of Siggaard-Andersen (1963) as modified by Severinghaus (1971). Arterial plasma lignocaine concentrations were measured* using a Varian 1700 gas chromatograph. The lignocaine doses and blood concentration data were analysed using the analysis of variance. Student's t test was used to compare results between two groups when a significant F-ratio was determined. The effectiveness of diazepam in terminating seizure activity was tested using the binomial distribution, comparing the percentage of animals in which seizures were terminated with diazepam 0.1 mg/kg or less during control and experimental (diazepam treatment) conditions. The significance of differences between groups in respect of cardiorespiratory, blood-gas and acid-base changes were evaluated using Student's t test.
311
DIAZEPAM AND LIGNOCAINE SEIZURES TABLE I. Effect of diazepam treatment on lignocaine {infusion 4 mglkgjmm) seizure dose and threshold in Rhesus monkeys. Mean values ( ± SD) Diazepam dose (mg/kg)
Treatment Initial control Diazepam Diazepam Diazepam Diazepam Final control
Animals studied
—
6 5 6 5 5 5
0.05 i.v. 0.10 i.v. 0.10 i.m. 0.25 i.m. —
Seizure dose (mg/kg)
Seizure threshold
Increase (%) — 24 30 34 34 4
22.5 ±4.4 27.8 ±3.5*
293+ 3 A*
30.2 ±5.9* 30.1 + 6.3* 23.3 ±4.7
18.2 ±1.5 —
24.1 ±4.5* — — —
* Significantly (P<0.05) different from control values.
Heart rate (beats/min) Control Before lignocaine and diazepam After diazepam (0.5 min) After lignocaine (2 min) (4 min) Seizure After seizure (1 min) (5 min) (15 min)
Diazepam
Mean arterial pressure (mmHg) Control
Diazepam
Respiratory rate (b.p.m.) Control
171
178
94
101
42
±11
±16
±14
±7
±16_
Diazepam 53
±18
176
103
53
±16
±13
±18
163
175
95
98
46
46
±25
±13
±9
±6
±15
±5
170
178
102
±4
±10
±7
lll*t ±5
182
176
±5
±17
116* ±8
195
202
±15
±26
208
200
±18
±12
120* ±13 120* ±15
38
51
±6
±12
113
44
61
±9
±12
±21
141*f ±16 127* ±15
173
178
109
103
±7
±35
±15
±12
* P < 0.05 compared with control values before lignocaine and diazepam. t P<0.05 compared with corresponding lignocaine values.
24-34% above control values. The doses of diazepam employed caused only transient drowsiness without loss of consciousness when administered alone, before lignocaine infusion. The magnitude of the protective effect of diazepam is approximately one-third that reported by de Jong and Heavner (1971, 1974) who used bolus injections of lignocaine in cats and monkeys. These differences in lignocaine requirement may be explained by the method of drug administration and by the brief but profound hypotension that is known to accompany the rapid administration of lignocaine (de Jong and Heavner, 1973). In
contrast, during constant-rate administration of lignocaine, we observed a small but consistent and significant increase in arterial pressure. It is believed commonly that the prophylactic use of diazepam is desirable when large doses of local anaesthetic agents are employed. Although this increases the threshold for local anaesthetic seizures, thereby reducing the frequency of toxicity, the usual prodromal signs of impending central nervous system depression, usually present during the constant-rate infusion of lignocaine, are masked by the prior administration of diazepam. When seizures
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TABLE II. Effects of diazepam 0.1 mg/kg i.v. treatment on heart and respiratory rates and mean arterial pressure before, during and after lignocaine-induced seizures in five Rhesus monkeys. Mean values ( ± SD)
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TABLE III. Effects of diazepam 0.1 mg/kg i.v. treatment on arterial pH, P c o u P o , and base excess before, during and after lignocaine-induced seizures. Mean values ( ± SD) pH (units)
Before lignocaine
Control
Diazepam
7.43 ±0.01 (5)
7.42 ±0.02 (6)
(mmHg) Control
Diazepam
32.2 ±2.8 (5)
7.45 ±0.05 (5)
After diazepam (0.5 min)
30.9 ±1.2 (6)
Base excess (m-equiv/litre)
Pao< (mm Hg)
Control
Diazepam
Control
Diazepam
-3.2 ±2.4 (5)
-3.5 ±1.5 (6)
295 ±17 (5)
263 ±28 (6)
30.0 + 0.08 (5)
250 ±41 (5)
-3.5 ±2.0 (5)
7.42 + 0.04 (5)
31.0 ±2.1 (5)
36.7*t ±4.1 (5)
-2.4 ±1.9 (5)
-0.7* ±1.2 (5)
288 ±15 (5)
260 + 52 (5)
7.28* + 0.02 (5)
7.33*t + 0.03 (4)
46.5* ±3.1 (5)
47.2* ±3.7 (4)
-4.4 ±0.9 (5)
-1.2f ±1.2 (4)
246* ±26 (5)
207 ±46 (4)
(5 min)
7.12* ±0.09 (5)
7.17* ±0.06 (5)
71.1* ±15.8 (5)
69.5* ±11.5 (4)
-4.3 + 5.1 (5)
(15 min)
7.25* ±0.05 (4)
1.21* ±0.07 (4)
42.1 ±9.2 (4)
48.9* + 9.2 (4)
-8.6* ±2.8 (4)
-3.8 ±2.4 (5) -4.0t ±1.1 (4)
210 + 71 (5) 248 ±62 (4)
138* ±54 (5) 125*t ±67 (4)
After seizure (1 min)
* P< 0.05 from control values before lignocaine and diazepam; numbers in brackets = number of animals studied. t P < 0.05 from corresponding lignocaine values. developed, approximately 50% of the diazepampretxeated animals required additional diazepam in doses greater than 0.1 mg/kg i.v. to abort the seizure activity. It is not surprising that treatment is more difficult when these seizures occur, since the lignocaine doses and blood concentrations were much higher in the diazepam pretreatment groups. The combination of diazepam and the increased dose of lignocaine resulted in greater depression after seizure and prolonged recovery as compared with animals receiving only a single therapeutic dose of diazepam 0.1 mg/kg after the onset of seizure activity. Thus, diazepam pretreatment may interfere with the early recognition of impending seizure activity, and may complicate the treatment of those seizures which occur. The routine use of diazepam before the administration of large doses of local anaesthetic agents is attended by both advantages and disadvantages. The clinician who uses diazepam in this manner should be aware of these actions. ACKNOWLEDGEMENTS
The authors are grateful to William J. Embro for his valuable technical assistance.
This research was supported in part by grants from United States Public Health Service (grant numbers GM00427-12 and RR00421) and from Astra Pharmaceutical Products, Inc. REFERENCES
de Jong, R. H., and Heavner, J. E. (1971). Diazepam prevents local anesthetic seizures. Anesthesiology, 34, 523. (1973). Diazepam and lidocaine-induced cardiovascular changes. Anestfusiology, 39, 633. (1974). Diazepam prevents and aborts lidocaine convulsions in monkeys. Anesthesiology, 41, 226. Feinstein, M. B., Lenard, W., and Mathias, J. (1970). The antagonism of local anesthetic induced convulsions by the benzodiazepine derivative diazepam. Arch. Int. Pharmacodyn. Ther., 187, 144. Munson, E. S. (1973). Mepivacaine overdose in a child. Anesth. Analg. (Cleve.), 52, 422. (1974). Arterial cannulation in awake restrained monkeys. Lab. Anim. Sci., 24, 793. Gillespie, J. R., and Wagman, I. H. (1970). Respiratory blood-gases and pH in two species of unanesthetized monkeys. J. Appl. Physiol., 28, 108. Tucker, W. K-, Ausinsch, B., and Malagodi, M. H. (1975). Etidocaine, bupivacaine and lidocaine seizure thresholds in monkeys. Anesthesiology, 42, 471. Wagman, I. H. (1969). Acid-base changes during lidocaine induced seizures in Macaco, mulatto. Arch. Neurol., 20, 406.
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7.45 ±0.05 (5)
Seizure
DIAZEPAM AND LIGNOCAINE SEIZURES Severinghaus, J. W. (1971). Siggaard-Andersen alignment nomogram; in Respiration and Circulation (eds P. L. Airman and D. S. Dittmer), p. 222. Maryland: Federation of American Societies for Experimental Biology. Siggaard-Andersen, O. (1963). Blood acid-base alignment nomogram. Scand.J. Clin. Lab. Invest., 15, 211. LE DIAZEPAM DANS LA PROPHYLAXIE DES ATTAQUES PROVOQUEES PAR LA LIGNOCAINE RESUME
DIAZEPAM ALS PROPHYLAKTIKUM BEI LIGNOCAINE-KRAMPFEN ZUSAMMEKFASSUNG
Die Wirkung von Lignocain deburite einer Erganzung von 24-36% zusatzlich 0,05-0,25 mg/kg Diazepam, um beim Rhesusaffen Krampfanfalle zu verursachen. Die
Spontanatmung wurde wahrend der Verabreichung von Lignocain nach Diazepambenandlung optimal aufrecht erhalten, wobei sich keinerlei kardiovaskulSre Nebenwirkungen ergaben. Vor Einleitung der durch Lignocain ausgelosten Krampfe, erzeigten sich die unbehandelten Tiere als schlafrig, wfihrend die vorherige Verabreichung von Diazepam diese Erscheinung verbarg. Unbehandelte Tiere benotigten kleinere Dosierungen von Diazepam zur Beseitigung der Krarnpfe, als dicjenigen, die schon mit Diazepam behandelt worden waren. Weiterhin zeigten die mit Diazepam vorbehandelten Tiere langet andauerade, den Krfimpfen folgende Depressionen.
EL DIAZEPAM EN LA PROFILAXIS DE LOS ACCESOS DE LINOCAINA SUMARIO
El diazepam (de 0,05 a 0,25 mg/kg) incremento la dosis de linocaina necesaria para producir accesos en monos macacos en un porcentaje del 24 al 34%. Se mantuvo la ventilation espontanea de forma adecuada durante la administracion de linocaina despues del tratamiento de diazepam y no se produjeron efectos cardiovasculares adversos. Antes de los accesos de linocaina inducida en animales no tratados, los animales parecfan amodorrados. Sin embargo, una administraci6n previa de diazepam enmascani este efecto. Las convulsiones fueron controladas por pequenas dosis de diazepam en animales no tratados que en animales tratados con diazepam. Tambien, los animales que fueron previamente tratados con diazepam tuvieron una mayor duracion de depresi6n despues del acceso.
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Le diazepam a raison de 0,05-0,25 mg/kg augmente de 24 a 34% la dose de lignocaine requise pour provoquer des attaques chez les singes rhesus. La respiration spontanee a etc maintenue de la maniere appropriee pendant l'adininistration de lignocaine apres traitement au diazepam et il ne s'est produit aucun effet cardiovasculaire adverse. Avant le debut des attaques provoquees par la lignocaine sur les animairr n'ayant recu aucune medication prealable, ces animaux semblaient somnoler. Cependant l'administration prealable de diazepam a masque ces effets. Les convulsions ont etc maitrisees sur les animaux n'ayant recu aucune pre-medication par des doses plus faibles de diazepam que sur les animaux ayant recu un pre-traitement au diazepam. Egalementj les animaux qui avaient ete pre-traites au diazepam ont subi une periode de depression plus longue apres l'attaque.
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