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PLASMA LEVELS OF DIAZEPAM
1085
CORRESPONDENCE PLASMA LEVELS OF DIAZEPAM
Plasma diazepam levels found 90 minutes following administration of 10 mg (O) orally or ( # ) by intramuscular injection.
Plasma diazepam levels found by us following oral or intravenous administration of 10 mg doses to adults agree with the earlier results published by Baird and Hailey (1972), so we feel that the difference mentioned above is not due to variations in the method of analysis. The patients used in our study were young women resting in bed prior to minor gynaecological operations whereas the subjects of Baird and Hailey were students and may have been more active. This may have changed the rate of absorption. We intend to follow this up to see if muscular activity influences the plasma diazepam levels. J. A. S. GAMBLE J. S. MACKAY J. W. DUNDEE
Belfast Baird, E. S., and Hailey, D . M. (1972). Delayed recovery from a sedative: correlation of the plasma levels of diazepam with rliniral effects after oral and intravenous administration. Brit. J. Anaesth., 44, 803. Sir,—The results reported by Professor Dundee and his colleagues are interesting, and raise questions regarding the efficacy of diazepam when administered by the intramuscular route. We agree that the different results obtained are unlikely to b : due to the use of an alternative
analytical method. The difference in methodology would, in any case, not account for the difference found between the two groups of patients in the Belfast study. It is possible that there was some difference between the groups in the two studies, but we doubt whether this is accounted for by any increased mobility in the Liverpool group. The students in our trial received diazepam 10 mg injected into the vastus lateralis muscle on the outer aspect of the thigh. They remained recumbent throughout the first 2 hours following administration. We think it is unlikely that any mild activity in this resting position would have significantly enhanced distribution of the drug. Intramuscular diazepam has been reported to be satisfactory for premedication (Kyles, 1968) and it is hard to see how this could be so if plasma concentrations were very small. In our paper (Baird and Hailey, 1973), we drew attention to the rapid transfer of diazepam from mother to foetus following intramuscular administration. It is difficult to reconcile slow distribution of the drug from muscle tissue with the recent results of Erkkola, Kangas and Pekkarinen (1973), who found diazepam in maternal and foetal circulations in high concentrations 5 minutes after intramuscular administration to the mother. They also reported significant concentrations in both circulations 76-105 minutes after injection. The rate of diazepam distribution from muscle tissue is likely to be dependent on the site of injection. As the drug is highly lipid soluble, increased depots of adipose tissue would delay release. Possibly the subjects in the Belfast study had more adipose tissue at the injection site compared with the Liverpool group. Another possibility is that the samples taken at 90 minutes corresponded to a trough in the plasma level fall-off curve for most subjects. It would be instructive if Professor Dundee and his colleagues could quote plasma concentrations of both diazepam and desmethyldiazepam at other time intervals. The main purpose of our work using intramuscular diazepam was to extend previous studies on the delayed adverse effects of this drug (Baird and Hailey, 1972), particularly with regard to the outpatient. Therefore, we were mainly concerned with the plasma concentrations after several hours. In view of the current interest in the rate of distribution of the drug after intramuscular injection, we intend to measure plasma concentrations of diazepam over the first hour following administration. D.
Roche E.
M.
HAILEY
Products S.
Ltd
BAIRD
London REFERENCES
Baird, E. S., and Hailey, D . M. (1972). Delayed recovery from a sedative: correlation of the plasma levels of diazepam with clinical effects after oral and intravenous administration. Brit. J. Anaesth., 44, 803. (1973). Plasma levels of diazepam and its major metabolite following intramuscular administration. Brit. J. Anaesth., 45, 546. Erkkola, R., Kangas, L., and Pekkarinen, A. (1973). The transfer of diazepam across the placenta during labour. Acta obstet. gynec. scand., 52, 167. Kyles, J. R. (1968). Observations on the use of diazepam during anaesthesia; in Diazepam in Anaesthesia (eds. Knight, P. F., and Burgess, C. G.), p. 66. Bristol: John Wright and Sons.
Downloaded from http://bja.oxfordjournals.org/ at University of Tennessee ? Knoxville Libraries on August 14, 2015
Sir,—We read with great interest the recent article by Mr Baird and Dr Hailey (Brit. J. Anaesth. (1973), 45, 546) on blood diazepam and metabolite levels following intramuscular injection. Their findings are contrary to ours. We have found a very slow absorption rate following intramuscular diazepam. Plasma levels were consistently lower 90 minutes after an injection of 10 mg (mean 35 ng/ml) as compared with the same dose taken orally (mean 185 ng/ml) and our preliminary findings are shown in the accompanying graph.
BRITISH JOURNAL OF ANAESTHESIA
1086 NITROUS OXIDE AND INTRACRANIAL PRESSURE
block the alpha-vasoconstrictive reaction to surgical trauma or other forms of adrenergic stress whereas halothane does. Details of the volume-pulse plethysmographic studies of nitrous oxide and halothane have still to be reported. The clinical significance of these observations is a controversial subject. Some anaesthetists regard the vasodilator effect of die inhalational anaesthetics to be a contraindication to dieir use in neurosurgical patients. Other anaesthetists have used them successfully in these circumstances. Obviously, there are other factors to be considered in the protection of patients from the undesirable consequences of sudden increases in intracranial pressure. The placing of the patient in a slightly head-up position during the induction of anaesthesia with these agents will counteract the cerebral hyperaemic effect of alpha-vasodilatation by facilitating the pooling of blood in the dilated alpha vessels of the extremities. The deliberate lowering of the Paooi by passive hyperventilation during the induction of anaesthesia will ensure the rapid onset of cerebral vasoconstriction, and the avoidance of all factors which cause tachycardia will maintain a low cardiac output and a correspondingly low cerebral blood flow. In die study of the effects of anaesthetic agents on die intracranial blood vessels it should be remembered that the majority of die deeper vessels of die brain are autoregulatory and are not directly influenced to any great extent by changes in the activity of the sympathetic nervous system (Csillik et al., 1971). MICHAEL JOHNSTONE
Manchester REFERENCES
Adams, R. W., Gronert, G. A., Sundt, T. M., and Michenfelder, J. D. (1972). Halothane hypocapnia and cerebrospinal fluid pressure in neurosurgery. Anesthesiology, 37, 510. Csillik, B., Jancso, G., Toth, L., Kozma, M., Kalman, G., and Karcsu, S. (1971). Adrenergic innervation of hypothalamic blood vessels: a contribution to the problem of central diermodetectors. Acta anal. (Basel), 80, 142. Green, H. D., and Kepchar, J. H. (1959). Control of peripheral resistance in major systemic vascular beds. Physiol. Rev., 39, 617. Johnstone, M. (1968). Hypocapnic vasoconstriction. during halothane anaesthesia in surgical patients. Brit. J. Anaesth., 40, 607. (1972). The cardiovascular effects of oxytocic drugs. Brit. J. Anaesth., 44, 826.
CORRESPONDENCE CUIRASS VENTILATORS
Sir,—Our department is embarking on a reassessment of the use of the cuirass for assisted ventilation. In this region we have several old polio patients regularly using the cuirass. We are measuring its efficiency on these cases and hope to define its value in other situations, such as early acute or chronic respiratory failure and weaning from IPPR.
Our Electronics department is also attempting to devise a low cost negative/positive power unit based on a domestic vacuum cleaner. I would be most interested to hear from centres who have experience in the use of the cuirass, and grateful for any information or advice on indications, details of apparatus and practical management, cheap power units, etc. A. MARSHALL BARR
Printed In Great Britain br John Sbmtu & SOD Ltd, Pufc Road, Altrlncbam, Chahhc. WA14 SQQ
Reading
Downloaded from http://bja.oxfordjournals.org/ at University of Tennessee ? Knoxville Libraries on August 14, 2015
Sir,—Drs Henriksen and Jorgensen (Brit. J. Anaesth. (1973), 45, 486) observed that nitrous oxide increased the intracranial pressure as judged by intraventricular and epidural measurements in patients with intracranial disorders. Nitrous oxide also decreased the cerebral perfusion pressure. The intracranial hypertension caused by the nitrous oxide was counteracted efficiendy either by hyperventilation (moderate hypocapnia) or by the withdrawal of the nitrous oxide. They concluded that the most likely mechanism for the pressure elevation is vasodilatation with an increase in intracranial blood volume. I should like to confirm Drs Henriksen and Jorgensen's suggestion that nitrous oxide dilates at least some of the intracranial blood vessels. An extensive study of the effects of nitrous oxide on peripheral vascular behaviour by means of volume-pulse plethysmography has shown that nitrous oxide dilates the alpha-adrenoceptive (finger) blood vessels and constricts the betaadrenoceptive (forearm muscle) vessels in most patients. As the pial or meningeal vessels are alpha-adrenoceptive (Green and Kcpchar, 1959), their behaviour in patients anaesthetized with nitrous oxide will be similar to that of the blood vessels of the finger. The combination of effects, alpha-vasodilatation and beta-vasoconstriction, is characteristic of blockage or depression of the sympathetic innervation of the vascular beds and excludes the possibility of a direct depression of the vascular smooth muscle. Vasodilator drugs which depress the vascular smooth muscle directly are not selectively adrenoceptive and affect equally the alpha and the beta blood vessels Qohnstone, 1972). The alpha-vasodilatation of nitrous oxide anaesthesia is transient and is man'mnl in most patients for only a short time after the induction of anaesthesia. The initial surgical incision of the skip usually causes reflex alpha-vasoconstriction. This indicates that the depression of sympathetic activity caused by the nitrous oxide is not sufficient to control the adrenergic reactions to surgical trauma. The initial effects of nitrous oxide and of halothane on peripheral vascular behaviour are similar. Both cause alpha-vasodilatation and beta-vasoconstriction (Johnstone, 1972). Neither blocks the vasoconstrictive reaction of the cerebral and other blood vessels to hypocapnia induced by passive hyperventilation (Adams et al., 1972; Johnstone, 1968). The important difference between the two drugs, so far as their effects on peripheral vascular behaviour are concerned, is that nitrous oxide does not
CORRESPONDENCE PLASMA LEVELS OF DIAZEPAM
Plasma diazepam levels found 90 minutes following administration of 10 mg (O) orally or ( # ) by intramuscular injection.
Plasma diazepam levels found by us following oral or intravenous administration of 10 mg doses to adults agree with the earlier results published by Baird and Hailey (1972), so we feel that the difference mentioned above is not due to variations in the method of analysis. The patients used in our study were young women resting in bed prior to minor gynaecological operations whereas the subjects of Baird and Hailey were students and may have been more active. This may have changed the rate of absorption. We intend to follow this up to see if muscular activity influences the plasma diazepam levels. J. A. S. GAMBLE J. S. MACKAY J. W. DUNDEE
Belfast Baird, E. S., and Hailey, D . M. (1972). Delayed recovery from a sedative: correlation of the plasma levels of diazepam with rliniral effects after oral and intravenous administration. Brit. J. Anaesth., 44, 803. Sir,—The results reported by Professor Dundee and his colleagues are interesting, and raise questions regarding the efficacy of diazepam when administered by the intramuscular route. We agree that the different results obtained are unlikely to b : due to the use of an alternative
analytical method. The difference in methodology would, in any case, not account for the difference found between the two groups of patients in the Belfast study. It is possible that there was some difference between the groups in the two studies, but we doubt whether this is accounted for by any increased mobility in the Liverpool group. The students in our trial received diazepam 10 mg injected into the vastus lateralis muscle on the outer aspect of the thigh. They remained recumbent throughout the first 2 hours following administration. We think it is unlikely that any mild activity in this resting position would have significantly enhanced distribution of the drug. Intramuscular diazepam has been reported to be satisfactory for premedication (Kyles, 1968) and it is hard to see how this could be so if plasma concentrations were very small. In our paper (Baird and Hailey, 1973), we drew attention to the rapid transfer of diazepam from mother to foetus following intramuscular administration. It is difficult to reconcile slow distribution of the drug from muscle tissue with the recent results of Erkkola, Kangas and Pekkarinen (1973), who found diazepam in maternal and foetal circulations in high concentrations 5 minutes after intramuscular administration to the mother. They also reported significant concentrations in both circulations 76-105 minutes after injection. The rate of diazepam distribution from muscle tissue is likely to be dependent on the site of injection. As the drug is highly lipid soluble, increased depots of adipose tissue would delay release. Possibly the subjects in the Belfast study had more adipose tissue at the injection site compared with the Liverpool group. Another possibility is that the samples taken at 90 minutes corresponded to a trough in the plasma level fall-off curve for most subjects. It would be instructive if Professor Dundee and his colleagues could quote plasma concentrations of both diazepam and desmethyldiazepam at other time intervals. The main purpose of our work using intramuscular diazepam was to extend previous studies on the delayed adverse effects of this drug (Baird and Hailey, 1972), particularly with regard to the outpatient. Therefore, we were mainly concerned with the plasma concentrations after several hours. In view of the current interest in the rate of distribution of the drug after intramuscular injection, we intend to measure plasma concentrations of diazepam over the first hour following administration. D.
Roche E.
M.
HAILEY
Products S.
Ltd
BAIRD
London REFERENCES
Baird, E. S., and Hailey, D . M. (1972). Delayed recovery from a sedative: correlation of the plasma levels of diazepam with clinical effects after oral and intravenous administration. Brit. J. Anaesth., 44, 803. (1973). Plasma levels of diazepam and its major metabolite following intramuscular administration. Brit. J. Anaesth., 45, 546. Erkkola, R., Kangas, L., and Pekkarinen, A. (1973). The transfer of diazepam across the placenta during labour. Acta obstet. gynec. scand., 52, 167. Kyles, J. R. (1968). Observations on the use of diazepam during anaesthesia; in Diazepam in Anaesthesia (eds. Knight, P. F., and Burgess, C. G.), p. 66. Bristol: John Wright and Sons.
Downloaded from http://bja.oxfordjournals.org/ at University of Tennessee ? Knoxville Libraries on August 14, 2015
Sir,—We read with great interest the recent article by Mr Baird and Dr Hailey (Brit. J. Anaesth. (1973), 45, 546) on blood diazepam and metabolite levels following intramuscular injection. Their findings are contrary to ours. We have found a very slow absorption rate following intramuscular diazepam. Plasma levels were consistently lower 90 minutes after an injection of 10 mg (mean 35 ng/ml) as compared with the same dose taken orally (mean 185 ng/ml) and our preliminary findings are shown in the accompanying graph.
BRITISH JOURNAL OF ANAESTHESIA
1086 NITROUS OXIDE AND INTRACRANIAL PRESSURE
block the alpha-vasoconstrictive reaction to surgical trauma or other forms of adrenergic stress whereas halothane does. Details of the volume-pulse plethysmographic studies of nitrous oxide and halothane have still to be reported. The clinical significance of these observations is a controversial subject. Some anaesthetists regard the vasodilator effect of die inhalational anaesthetics to be a contraindication to dieir use in neurosurgical patients. Other anaesthetists have used them successfully in these circumstances. Obviously, there are other factors to be considered in the protection of patients from the undesirable consequences of sudden increases in intracranial pressure. The placing of the patient in a slightly head-up position during the induction of anaesthesia with these agents will counteract the cerebral hyperaemic effect of alpha-vasodilatation by facilitating the pooling of blood in the dilated alpha vessels of the extremities. The deliberate lowering of the Paooi by passive hyperventilation during the induction of anaesthesia will ensure the rapid onset of cerebral vasoconstriction, and the avoidance of all factors which cause tachycardia will maintain a low cardiac output and a correspondingly low cerebral blood flow. In die study of the effects of anaesthetic agents on die intracranial blood vessels it should be remembered that the majority of die deeper vessels of die brain are autoregulatory and are not directly influenced to any great extent by changes in the activity of the sympathetic nervous system (Csillik et al., 1971). MICHAEL JOHNSTONE
Manchester REFERENCES
Adams, R. W., Gronert, G. A., Sundt, T. M., and Michenfelder, J. D. (1972). Halothane hypocapnia and cerebrospinal fluid pressure in neurosurgery. Anesthesiology, 37, 510. Csillik, B., Jancso, G., Toth, L., Kozma, M., Kalman, G., and Karcsu, S. (1971). Adrenergic innervation of hypothalamic blood vessels: a contribution to the problem of central diermodetectors. Acta anal. (Basel), 80, 142. Green, H. D., and Kepchar, J. H. (1959). Control of peripheral resistance in major systemic vascular beds. Physiol. Rev., 39, 617. Johnstone, M. (1968). Hypocapnic vasoconstriction. during halothane anaesthesia in surgical patients. Brit. J. Anaesth., 40, 607. (1972). The cardiovascular effects of oxytocic drugs. Brit. J. Anaesth., 44, 826.
CORRESPONDENCE CUIRASS VENTILATORS
Sir,—Our department is embarking on a reassessment of the use of the cuirass for assisted ventilation. In this region we have several old polio patients regularly using the cuirass. We are measuring its efficiency on these cases and hope to define its value in other situations, such as early acute or chronic respiratory failure and weaning from IPPR.
Our Electronics department is also attempting to devise a low cost negative/positive power unit based on a domestic vacuum cleaner. I would be most interested to hear from centres who have experience in the use of the cuirass, and grateful for any information or advice on indications, details of apparatus and practical management, cheap power units, etc. A. MARSHALL BARR
Printed In Great Britain br John Sbmtu & SOD Ltd, Pufc Road, Altrlncbam, Chahhc. WA14 SQQ
Reading
Downloaded from http://bja.oxfordjournals.org/ at University of Tennessee ? Knoxville Libraries on August 14, 2015
Sir,—Drs Henriksen and Jorgensen (Brit. J. Anaesth. (1973), 45, 486) observed that nitrous oxide increased the intracranial pressure as judged by intraventricular and epidural measurements in patients with intracranial disorders. Nitrous oxide also decreased the cerebral perfusion pressure. The intracranial hypertension caused by the nitrous oxide was counteracted efficiendy either by hyperventilation (moderate hypocapnia) or by the withdrawal of the nitrous oxide. They concluded that the most likely mechanism for the pressure elevation is vasodilatation with an increase in intracranial blood volume. I should like to confirm Drs Henriksen and Jorgensen's suggestion that nitrous oxide dilates at least some of the intracranial blood vessels. An extensive study of the effects of nitrous oxide on peripheral vascular behaviour by means of volume-pulse plethysmography has shown that nitrous oxide dilates the alpha-adrenoceptive (finger) blood vessels and constricts the betaadrenoceptive (forearm muscle) vessels in most patients. As the pial or meningeal vessels are alpha-adrenoceptive (Green and Kcpchar, 1959), their behaviour in patients anaesthetized with nitrous oxide will be similar to that of the blood vessels of the finger. The combination of effects, alpha-vasodilatation and beta-vasoconstriction, is characteristic of blockage or depression of the sympathetic innervation of the vascular beds and excludes the possibility of a direct depression of the vascular smooth muscle. Vasodilator drugs which depress the vascular smooth muscle directly are not selectively adrenoceptive and affect equally the alpha and the beta blood vessels Qohnstone, 1972). The alpha-vasodilatation of nitrous oxide anaesthesia is transient and is man'mnl in most patients for only a short time after the induction of anaesthesia. The initial surgical incision of the skip usually causes reflex alpha-vasoconstriction. This indicates that the depression of sympathetic activity caused by the nitrous oxide is not sufficient to control the adrenergic reactions to surgical trauma. The initial effects of nitrous oxide and of halothane on peripheral vascular behaviour are similar. Both cause alpha-vasodilatation and beta-vasoconstriction (Johnstone, 1972). Neither blocks the vasoconstrictive reaction of the cerebral and other blood vessels to hypocapnia induced by passive hyperventilation (Adams et al., 1972; Johnstone, 1968). The important difference between the two drugs, so far as their effects on peripheral vascular behaviour are concerned, is that nitrous oxide does not