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CONCENTRATIONS OF ATRACURIUM AND LAUDANOSINE IN CEREBROSPINAL FLUID AND PLASMA IN THREE INTENSIVE CARE PATIENTS
British Journal of Anaesthesia 1990^ 65: 829-832
CONCENTRATIONS OF ATRACURIUM AND LAUDANOSINE IN CEREBROSPINAL FLUID AND PLASMA IN THREE INTENSIVE CARE PATIENTS
concentrations increase rapidly following an i.v. bolus dose of laudanosine 1 mg kg"1, and reach We have measured concentrations of atracurium 30-60% of plasma concentration within 10 min and laudanosine in cerebrospinal fluid (CSF) [4]. In comparison, when atracurium was used and plasma in three intensive care patients to provide neuromuscular block during intrareceiving atracurium infusions of 22.5-106 h cranial aneurysm surgery, after 2 h the mean duration to maintain neuromuscular block. Two CSF:plasma laudanosine ratio was 17% [7]. To patients had suffered severe closed head injuries date, no data have been published on the peneand the third patient had developed respiratory tration of laudanosine into the CNS when failure following the clipping of two intracranial atracurium infusions of more than 2 h duration aneurysms. The total dose of atracurium given are used. We have therefore studied CSF and plasma was 14.3-736.6mg kg-'; rate of infusion was 1 1 concentrations of atracurium and laudanosine in 0.6-1.38 mg kg' h' . Plasma concentrations of three patients who received infusions of atraatracurium and laudanosine were 0.73-3.11 ng curium for periods of 22.5, 44 and 106 h, remf-' and 0.48-8.65fig mt', respectively; CSF spectively. concentration of laudanosine was 70-440 ng SUMMARY
mt'. No adverse effects attributable to these concentrations of laudanosine were observed.
PATIENTS AND METHODS
The study was approved by the District Ethics Committee. Three patients were receiving atraCerebrospinal fluid: atracurium, laudanosine. Neuromuscular curium as part of the normal technique to facilitate relaxants: atracurium. laudanosine. controlled ventilation following cerebral injury. Sedation was provided using continuous infusions Concern has been expressed regarding possible of propofol or midazolam, and fentanyl. Ventiaccumulation of laudanosine during prolonged latory minute volume was adjusted to maintain infusions of atracurium [1]. Laudanosine has been PacOi at 3.5-4.0 kPa, and the ECG, arterial and shown to have cerebral excitatory properties in central venous pressures were monitored concats [2], mice and rats [3] and dogs [3-5]. In dogs, tinuously in all three patients. Core temperature the effects vary from EEG arousal patterns at was 36-38 °C. There were no other associated plasma concentrations of 2—4 (ig ml"1 to clonic injuries, and renal and hepatic function were seizures at approximately 17 ug ml"1. The greatest within normal limits. plasma concentration of laudanosine reported to date in man was 5.1 ng ml"1 [6] but no side effects C. L . GWINNUTT, M.D., B.S., F.F.A.R.C.S. J J. M . EDDLESTON, M.B., CH.B., F.F.A.R.C.S. ; Department of Anaesthesia, Hope were observed. The concentration of laudanosine in the central Hospital, Eccles Old Road, Salford M6 8HD. D . EDWARDS, B.SC.; B. J. POLLARD, M.B., B.S., F.F.A.R.C.S.; Department of nervous system determines cerebral toxicity, and Anaesthesia, Manchester Royal Infirmary, Oxford Road, accumulation in the CNS appears to differ Manchester. Accepted for Publication: June 8, 1990. Correspondence to C.L.G. depending on the species studied. In dogs, CSF KEY WORDS
Downloaded from http://bja.oxfordjournals.org/ at The University of British Colombia Library on July 12, 2015
C. L. GWINNUTT, J. M. EDDLESTON, D. EDWARDS AND B. J. POLLARD
BRITISH JOURNAL OF ANAESTHESIA
830
CASE REPORTS
Patient A A 56-yr-old, 65-kg female developed respiratory failure 24 h after uneventful clipping of a right anterior and left posterior communicating artery aneurysms. The decision was taken to ventilate her lungs artificially; this was facilitated by a bolus of atracurium 0.8 mg kg"1, followed by a constant infusion at 0.6 mg kg"1, with continuous infusions of fentanyl and midazolam for sedation. The lumbar subarachnoid drain inserted at the time of surgery was still functioning. Paired samples of arterial blood and CSF were obtained
after 12 and 22.5 h. The lumbar drain was removed at this time, but ventilation and the atracurium infusion were continued for a total of 7 days. The CSF samples were colourless and on subsequent analysis atracurium could not be detected. The total dose of atracurium given by 22.5 h was 0.93 g (table I). After resolution of a chest infection the patient made a slow neurological recovery. Focal epileptiform seizures occurred 9 and 10 days after stopping the atracurium infusion. These were treated successfully with clonazepam. CT scan showed the presence of a small cerebral infarct. Patient B A 25-yr-old, 80-kg male sustained a closed head injury in a road traffic accident. On admission, his Glasgow Coma Score was 6 and there were no other associated injuries. CT scan demonstrated multiple cerebral contusions. The decision was made to ventilate his lungs and an intraventricular catheter was inserted to monitor intracranial pressure. The patient was sedated with continuous infusions of fentanyl and midazolam. For the first 8 h, repeated boluses of atracurium were given to a total of 330 mg. An infusion of atracurium was started and adjusted to ensure abolition of the cough reflex during tracheal suction. For the first 6 h the infusion rate was 0.75 mg kg"1 h"1. It was then necessary to increase the rate to 1.0 mg kg"1 h"1, which was maintained for the next 30 h. Paired samples of arterial blood and CSF were obtained for assay 8, 14, 20, 32, 38 and 44 h after starting ventilation. The CSF samples were colourless, and on subsequent analysis no atracurium was detected. The total dose of atracurium given during the 44-h period was 3.09 g
TABLE I. Plasma and CSF atracurium and laudanosine concentrations for each patient Plasma Patient A B
C
CSF
Time (h)
Atracurium (ug ml"1)
Laudanosine (ug ml"1)
12 22.5 8 14 20 32 38 44 106
0.75 0.95 1.48 0.85 1.84 2.15 3.11 1.36 2.78
0.48 0.52 0.99 1.09 1.44 2.00 2.20 1.83 8.65
Atracurium (ug ml"1)
Laudanosine (ng ml"1)
CSF: plasma ratio
— — — — — — — —
100 120 — 70 110 140 190 170 440
0.21 0.23 0.06 0.07 0.07 0.09 0.09 0.05
Downloaded from http://bja.oxfordjournals.org/ at The University of British Colombia Library on July 12, 2015
Plasma concentrations of atracurium and laudanosine were measured in samples of blood obtained from an indwelling arterial catheter. Samples of CSF were obtained via a lumbar subarachnoid drain (patient A) and from ventricular catheters in the two other patients. The first 2 ml of blood and 1 ml of CSF were discarded to ensure fresh samples were obtained for analysis. Each pair of samples was centrifuged immediately at 13000£ for 1 min and 0.2 ml of the supernatant decanted into 0.8 ml of cooled sulphuric acid (pH 1.5) and frozen at - 2 0 °C. Concentrations of atracurium and laudanosine in plasma and CSF were assayed in duplicate using high pressure liquid chromatography [8]. The assay was sensitive to 20 ng ml"1 for atracurium and 10 ng ml"1 for laudanosine. The coefficients of variation for atracurium were 6.6% at 1000 ng ml"1, 2.7% at 2000 ng ml"1 and 4.0% at 4000 ng ml"1 and for laudanosine 7.6% at 100 ng ml"1, 2.8% at 200 ng ml"1, 2.3% at 1000 ng ml"1, 3.2% at 1500 ng ml"1 and 1.9% at 8000 ng ml"1.
CSF CUMULATION OF LAUDANOSINE (table I). The patient made a slow neurological recovery and there was no clinical evidence of epileptiform activity.
DISCUSSION
The plasma concentration of laudanosine causing toxic side effects has been measured in several animal species, but the corresponding values for man are not known. It has been assumed that they may be similar, although the data available suggest a species difference in penetration of laudanosine into the CNS. Previous studies in man have shown that CSF concentrations of laudanosine increase slowly, reaching 10-13 ng ml"1, 60 min after a single bolus of atracurium [9], and a mean of 203 ng ml"1 after an infusion of approximately 2 h duration [7]. In contrast, in dogs, CSF concentrations of laudanosine reached 210-640 ng ml"1 within 10 min of a bolus of laudanosine 1 mg kg"1 [4]. The reason for these differences is unlikely to be the large dose of laudanosine administered to dogs, as the resultant plasma concentrations of laudanosine were of the same magnitude as those seen in man when an infusion of atracurium was used. These observations may represent species variation in transfer into or
clearance from CSF, which in turn may account for the.lack of reports of laudanosine toxicity in man, despite plasma concentrations in the range causing CNS excitatory effects in dogs. In the present report, infusions of atracurium were used to facilitate ventilation in patients with cerebral injuries. The rate of infusion of atracurium and subsequent plasma concentrations of atracurium were similar to those described by Yate and colleagues for patients in a general ITU [6]. Patients B and C required increasing rates of infusion of atracurium to maintain a satisfactory degree of neuromuscular block, and this was described also by the above authors. The mechanism of this increased requirement is not known, but studies in dogs suggest that it may be related to the period of prolonged immobility [10]. The greatest CSF:plasma ratio occurred in patient A (0.23 after 22.5 h), who had undergone intracranial surgery, and is similar to those reported after 2 h in a series of patients at the time of surgery [7]. Although the CSF samples were obtained via a lumbar subarachnoid drain, this is unlikely to account for the difference between this patient and the two others, as it takes only 60-90 min for CSF in this region to mirror contamination of the ventricles with a foreign substance [11]. The presence of the drain is also likely to shorten this period by facilitating circulation of CSF. Although blood from the operative site may have increased the CSF concentrations of laudanosine, the samples were not blood stained or xanthochromic and atxacurium was not detected. The CSF:plasma ratios in patients B and C, who had sustained head injuries, were lower than in patient A, despite greater plasma concentrations of laudanosine. We postulate that the accumulation of laudanosine within the CNS in man may be dependent in part upon the underlying pathology. Following both subarachnoid haemorrhage [12] and head injury [13], the blood-brain barrier becomes more permeable. In addition, changes occur also in the rate of production of CSF [14]. Each of these factors may influence the final concentration of a foreign substance within the CNS. In patients with nonCNS pathology in which the integrity of the blood—brain barrier is preserved, the concentrations of laudanosine within the CNS may be even less for a given plasma concentration. This may explain the lack of reported side effects attributable to laudanosine when atracurium is used over long periods. Patients B and C also had lower
Downloaded from http://bja.oxfordjournals.org/ at The University of British Colombia Library on July 12, 2015
Patient C A 28-yr-old, 58-kg female sustained a closed head injury during a road traffic accident. On admission, her Glasgow Coma Score was 7; there were no other injuries. CT scan showed diffuse cerebral oedema, and the decision was made to ventilate her lungs artificially. An intraventricular catheter was inserted to monitor intracranial pressure. Continuous infusions of propofol and fentanyl were used for sedation. Control of ventilation was achieved with a bolus dose of atracurium 0.7 mg kg"1, followed by an infusion, initially at the rate of 0.86 mg kg"1 hr1, which was sufficient to abolish coughing during tracheal suction. After 14 and 32 h it was necessary to increase the rate of infusion of atracurium, first to l ^ l m g k g " 1 ^ 1 and then to 1.38 mg kg"1 h"1. This final rate remained constant until the infusion was stopped at 106 h. Paired samples of arterial blood and CSF were taken immediately before stopping the infusion of atracurium. The CSF sample was colourless and no atracurium was detected. The total dose of atracurium given was 7.92 g (table I). The patient made a good recovery and did not experience any fits.
831
BRITISH JOURNAL OF ANAESTHESIA
832
ACKNOWLEDGEMENTS This study was supported by grants from the Hope Hospital Neurosurgical Research Fund and the Wellcome Foundation. REFERENCES 1. Parker CJR, Jones JE, Hunter JM. Disposition of infusions of atracurium and its metabolite, laudanosine, in patients in renal and respiratory failure in an ITU. British Journal of Anaesthesia 1988; 61: 531-540.
2. Ingram MD, Sclabassi RJ, Stiller RL, Cook DR, Bennett MH. Cardiovascular and electroencephalographic effects of laudanosine in nephrectomised cats. Anesthesia and Analgesia 1985; 64: 232. 3. Chappel DJ, Miller AA, Ward JB, Wheatley PL. Cardiovascular and neurological effects of laudanosine. Studies in mice and rats and in conscious and anaesthetized dogs. British Journal of Anaesthesia 1987; 59: 218-225. 4. Hennis PJ, Fancy MR, Miller RD, Canfell C, Shi W-Z. Pharmacology of laudanosine in dogs. Anesthesiology 1984; 61: A305. 5. Lanier WL, Milde JH, Michenfelder JD. Cerebral effects of atracurium. Anesthesiology 1984; 61: A361. 6. Yate PM, Flynn PJ, Arnold RW, Weatherley RC, Simmonds RJ, Dopson J. Clinical experience and plasma laudanosine concentrations during atracurium infusions in the intensive therapy unit. British Journal of Anaesthesia 1987; 59: 211-217. 7. Eddleston JM, Harper NJN, Pollard BJ, Edwards D, Gwinnutt CL. Concentrations of atracurium and laudanosine in cerebrospinal fluid and plasma during intracranial surgery. British Journal of Anaesthesia 1989; 63: 525-530. 8. Simmonds RJ. Determination of atracurium, laudanosine and related compounds in plasma by high performance liquid chromatography. Journal of Chromatography 1985; 343: 645-675. 9. Fahey MR, Canfell C, Toaboada T, Shi W-Z, Miller RD, Hosobuchi Y. Cerebrospinal fluid concentrations of laudanosine after administration of atracurium. British Journal of Anaesthesia 1990; 64: 105-106. 10. Chappie DJ, Dodd P, Macleod DM, Withington PS, Yate PM. Requirements for neuromuscular blocking agents during prolonged anaesthesia in the anaesthetized dog. British Journal of Anaesthesia 1987; 59: 1321P-1322P. 11. Di Chiro G, Hammock MK, Bleyer WA. Spinal descent of cerebrospinal fluid in man. Neurology 1976; 26: 1-8. 12. White RP. Vasospasm. In: Fox JL, ed. Intracranial Aneurysms, vol. 1. New York: Springer-Verlag, 1983; 218-271. 13. Crockard A. Brain swelling, brain oedema and the bloodbrain barrier. In: Crockard A, Hayward R, Hoff JT, eds. Neurosurgery—The Scientific Basis of Clinical Practice. Oxford: Blackwell, 1985; 33-349. 14. Kosteljanetz M. Cerebrospinal fluid production in subarachnoid haemorrhage. British Journal of Neurosurgery 1988; 2: 161-168.
Downloaded from http://bja.oxfordjournals.org/ at The University of British Colombia Library on July 12, 2015
CSF concentrations of laudanosine than those seen in dogs, despite greater plasma concentrations (CSF:plasma ratios < 0.1 compared with 0.3-0.6, respectively). This further supports the concept of a species difference in distribution of laudanosine in the CNS. The plasma and CSF concentrations of laudanosine in patient C (8.65 ug ml"1 and 440 ng ml"1, respectively) are greater than reported previously, and considerably greater than those in the two other patients. This is most likely a reflection of the greater rate of infusion and total dose of atracurium used (7.92 g). Despite these concentrations, no CNS side effects were seen either during the infusion or immediately after discontinuation, although EEG was not monitored. The slight difference in the CSF:plasma ratios between patients B and C may reflect the difference in the pathology of the underlying head injuries. Patient B was known to have cerebral contusions, and patient C had generalized cerebral oedema. Laudanosine accumulated in both plasma and CSF during prolonged infusions of atracurium. The rate of increase and the final concentration of laudanosine within the CSF were smaller in man than in dogs. Concern about the use of prolonged infusions of atracurium based on results in dogs may therefore not be justified.
CONCENTRATIONS OF ATRACURIUM AND LAUDANOSINE IN CEREBROSPINAL FLUID AND PLASMA IN THREE INTENSIVE CARE PATIENTS
concentrations increase rapidly following an i.v. bolus dose of laudanosine 1 mg kg"1, and reach We have measured concentrations of atracurium 30-60% of plasma concentration within 10 min and laudanosine in cerebrospinal fluid (CSF) [4]. In comparison, when atracurium was used and plasma in three intensive care patients to provide neuromuscular block during intrareceiving atracurium infusions of 22.5-106 h cranial aneurysm surgery, after 2 h the mean duration to maintain neuromuscular block. Two CSF:plasma laudanosine ratio was 17% [7]. To patients had suffered severe closed head injuries date, no data have been published on the peneand the third patient had developed respiratory tration of laudanosine into the CNS when failure following the clipping of two intracranial atracurium infusions of more than 2 h duration aneurysms. The total dose of atracurium given are used. We have therefore studied CSF and plasma was 14.3-736.6mg kg-'; rate of infusion was 1 1 concentrations of atracurium and laudanosine in 0.6-1.38 mg kg' h' . Plasma concentrations of three patients who received infusions of atraatracurium and laudanosine were 0.73-3.11 ng curium for periods of 22.5, 44 and 106 h, remf-' and 0.48-8.65fig mt', respectively; CSF spectively. concentration of laudanosine was 70-440 ng SUMMARY
mt'. No adverse effects attributable to these concentrations of laudanosine were observed.
PATIENTS AND METHODS
The study was approved by the District Ethics Committee. Three patients were receiving atraCerebrospinal fluid: atracurium, laudanosine. Neuromuscular curium as part of the normal technique to facilitate relaxants: atracurium. laudanosine. controlled ventilation following cerebral injury. Sedation was provided using continuous infusions Concern has been expressed regarding possible of propofol or midazolam, and fentanyl. Ventiaccumulation of laudanosine during prolonged latory minute volume was adjusted to maintain infusions of atracurium [1]. Laudanosine has been PacOi at 3.5-4.0 kPa, and the ECG, arterial and shown to have cerebral excitatory properties in central venous pressures were monitored concats [2], mice and rats [3] and dogs [3-5]. In dogs, tinuously in all three patients. Core temperature the effects vary from EEG arousal patterns at was 36-38 °C. There were no other associated plasma concentrations of 2—4 (ig ml"1 to clonic injuries, and renal and hepatic function were seizures at approximately 17 ug ml"1. The greatest within normal limits. plasma concentration of laudanosine reported to date in man was 5.1 ng ml"1 [6] but no side effects C. L . GWINNUTT, M.D., B.S., F.F.A.R.C.S. J J. M . EDDLESTON, M.B., CH.B., F.F.A.R.C.S. ; Department of Anaesthesia, Hope were observed. The concentration of laudanosine in the central Hospital, Eccles Old Road, Salford M6 8HD. D . EDWARDS, B.SC.; B. J. POLLARD, M.B., B.S., F.F.A.R.C.S.; Department of nervous system determines cerebral toxicity, and Anaesthesia, Manchester Royal Infirmary, Oxford Road, accumulation in the CNS appears to differ Manchester. Accepted for Publication: June 8, 1990. Correspondence to C.L.G. depending on the species studied. In dogs, CSF KEY WORDS
Downloaded from http://bja.oxfordjournals.org/ at The University of British Colombia Library on July 12, 2015
C. L. GWINNUTT, J. M. EDDLESTON, D. EDWARDS AND B. J. POLLARD
BRITISH JOURNAL OF ANAESTHESIA
830
CASE REPORTS
Patient A A 56-yr-old, 65-kg female developed respiratory failure 24 h after uneventful clipping of a right anterior and left posterior communicating artery aneurysms. The decision was taken to ventilate her lungs artificially; this was facilitated by a bolus of atracurium 0.8 mg kg"1, followed by a constant infusion at 0.6 mg kg"1, with continuous infusions of fentanyl and midazolam for sedation. The lumbar subarachnoid drain inserted at the time of surgery was still functioning. Paired samples of arterial blood and CSF were obtained
after 12 and 22.5 h. The lumbar drain was removed at this time, but ventilation and the atracurium infusion were continued for a total of 7 days. The CSF samples were colourless and on subsequent analysis atracurium could not be detected. The total dose of atracurium given by 22.5 h was 0.93 g (table I). After resolution of a chest infection the patient made a slow neurological recovery. Focal epileptiform seizures occurred 9 and 10 days after stopping the atracurium infusion. These were treated successfully with clonazepam. CT scan showed the presence of a small cerebral infarct. Patient B A 25-yr-old, 80-kg male sustained a closed head injury in a road traffic accident. On admission, his Glasgow Coma Score was 6 and there were no other associated injuries. CT scan demonstrated multiple cerebral contusions. The decision was made to ventilate his lungs and an intraventricular catheter was inserted to monitor intracranial pressure. The patient was sedated with continuous infusions of fentanyl and midazolam. For the first 8 h, repeated boluses of atracurium were given to a total of 330 mg. An infusion of atracurium was started and adjusted to ensure abolition of the cough reflex during tracheal suction. For the first 6 h the infusion rate was 0.75 mg kg"1 h"1. It was then necessary to increase the rate to 1.0 mg kg"1 h"1, which was maintained for the next 30 h. Paired samples of arterial blood and CSF were obtained for assay 8, 14, 20, 32, 38 and 44 h after starting ventilation. The CSF samples were colourless, and on subsequent analysis no atracurium was detected. The total dose of atracurium given during the 44-h period was 3.09 g
TABLE I. Plasma and CSF atracurium and laudanosine concentrations for each patient Plasma Patient A B
C
CSF
Time (h)
Atracurium (ug ml"1)
Laudanosine (ug ml"1)
12 22.5 8 14 20 32 38 44 106
0.75 0.95 1.48 0.85 1.84 2.15 3.11 1.36 2.78
0.48 0.52 0.99 1.09 1.44 2.00 2.20 1.83 8.65
Atracurium (ug ml"1)
Laudanosine (ng ml"1)
CSF: plasma ratio
— — — — — — — —
100 120 — 70 110 140 190 170 440
0.21 0.23 0.06 0.07 0.07 0.09 0.09 0.05
Downloaded from http://bja.oxfordjournals.org/ at The University of British Colombia Library on July 12, 2015
Plasma concentrations of atracurium and laudanosine were measured in samples of blood obtained from an indwelling arterial catheter. Samples of CSF were obtained via a lumbar subarachnoid drain (patient A) and from ventricular catheters in the two other patients. The first 2 ml of blood and 1 ml of CSF were discarded to ensure fresh samples were obtained for analysis. Each pair of samples was centrifuged immediately at 13000£ for 1 min and 0.2 ml of the supernatant decanted into 0.8 ml of cooled sulphuric acid (pH 1.5) and frozen at - 2 0 °C. Concentrations of atracurium and laudanosine in plasma and CSF were assayed in duplicate using high pressure liquid chromatography [8]. The assay was sensitive to 20 ng ml"1 for atracurium and 10 ng ml"1 for laudanosine. The coefficients of variation for atracurium were 6.6% at 1000 ng ml"1, 2.7% at 2000 ng ml"1 and 4.0% at 4000 ng ml"1 and for laudanosine 7.6% at 100 ng ml"1, 2.8% at 200 ng ml"1, 2.3% at 1000 ng ml"1, 3.2% at 1500 ng ml"1 and 1.9% at 8000 ng ml"1.
CSF CUMULATION OF LAUDANOSINE (table I). The patient made a slow neurological recovery and there was no clinical evidence of epileptiform activity.
DISCUSSION
The plasma concentration of laudanosine causing toxic side effects has been measured in several animal species, but the corresponding values for man are not known. It has been assumed that they may be similar, although the data available suggest a species difference in penetration of laudanosine into the CNS. Previous studies in man have shown that CSF concentrations of laudanosine increase slowly, reaching 10-13 ng ml"1, 60 min after a single bolus of atracurium [9], and a mean of 203 ng ml"1 after an infusion of approximately 2 h duration [7]. In contrast, in dogs, CSF concentrations of laudanosine reached 210-640 ng ml"1 within 10 min of a bolus of laudanosine 1 mg kg"1 [4]. The reason for these differences is unlikely to be the large dose of laudanosine administered to dogs, as the resultant plasma concentrations of laudanosine were of the same magnitude as those seen in man when an infusion of atracurium was used. These observations may represent species variation in transfer into or
clearance from CSF, which in turn may account for the.lack of reports of laudanosine toxicity in man, despite plasma concentrations in the range causing CNS excitatory effects in dogs. In the present report, infusions of atracurium were used to facilitate ventilation in patients with cerebral injuries. The rate of infusion of atracurium and subsequent plasma concentrations of atracurium were similar to those described by Yate and colleagues for patients in a general ITU [6]. Patients B and C required increasing rates of infusion of atracurium to maintain a satisfactory degree of neuromuscular block, and this was described also by the above authors. The mechanism of this increased requirement is not known, but studies in dogs suggest that it may be related to the period of prolonged immobility [10]. The greatest CSF:plasma ratio occurred in patient A (0.23 after 22.5 h), who had undergone intracranial surgery, and is similar to those reported after 2 h in a series of patients at the time of surgery [7]. Although the CSF samples were obtained via a lumbar subarachnoid drain, this is unlikely to account for the difference between this patient and the two others, as it takes only 60-90 min for CSF in this region to mirror contamination of the ventricles with a foreign substance [11]. The presence of the drain is also likely to shorten this period by facilitating circulation of CSF. Although blood from the operative site may have increased the CSF concentrations of laudanosine, the samples were not blood stained or xanthochromic and atxacurium was not detected. The CSF:plasma ratios in patients B and C, who had sustained head injuries, were lower than in patient A, despite greater plasma concentrations of laudanosine. We postulate that the accumulation of laudanosine within the CNS in man may be dependent in part upon the underlying pathology. Following both subarachnoid haemorrhage [12] and head injury [13], the blood-brain barrier becomes more permeable. In addition, changes occur also in the rate of production of CSF [14]. Each of these factors may influence the final concentration of a foreign substance within the CNS. In patients with nonCNS pathology in which the integrity of the blood—brain barrier is preserved, the concentrations of laudanosine within the CNS may be even less for a given plasma concentration. This may explain the lack of reported side effects attributable to laudanosine when atracurium is used over long periods. Patients B and C also had lower
Downloaded from http://bja.oxfordjournals.org/ at The University of British Colombia Library on July 12, 2015
Patient C A 28-yr-old, 58-kg female sustained a closed head injury during a road traffic accident. On admission, her Glasgow Coma Score was 7; there were no other injuries. CT scan showed diffuse cerebral oedema, and the decision was made to ventilate her lungs artificially. An intraventricular catheter was inserted to monitor intracranial pressure. Continuous infusions of propofol and fentanyl were used for sedation. Control of ventilation was achieved with a bolus dose of atracurium 0.7 mg kg"1, followed by an infusion, initially at the rate of 0.86 mg kg"1 hr1, which was sufficient to abolish coughing during tracheal suction. After 14 and 32 h it was necessary to increase the rate of infusion of atracurium, first to l ^ l m g k g " 1 ^ 1 and then to 1.38 mg kg"1 h"1. This final rate remained constant until the infusion was stopped at 106 h. Paired samples of arterial blood and CSF were taken immediately before stopping the infusion of atracurium. The CSF sample was colourless and no atracurium was detected. The total dose of atracurium given was 7.92 g (table I). The patient made a good recovery and did not experience any fits.
831
BRITISH JOURNAL OF ANAESTHESIA
832
ACKNOWLEDGEMENTS This study was supported by grants from the Hope Hospital Neurosurgical Research Fund and the Wellcome Foundation. REFERENCES 1. Parker CJR, Jones JE, Hunter JM. Disposition of infusions of atracurium and its metabolite, laudanosine, in patients in renal and respiratory failure in an ITU. British Journal of Anaesthesia 1988; 61: 531-540.
2. Ingram MD, Sclabassi RJ, Stiller RL, Cook DR, Bennett MH. Cardiovascular and electroencephalographic effects of laudanosine in nephrectomised cats. Anesthesia and Analgesia 1985; 64: 232. 3. Chappel DJ, Miller AA, Ward JB, Wheatley PL. Cardiovascular and neurological effects of laudanosine. Studies in mice and rats and in conscious and anaesthetized dogs. British Journal of Anaesthesia 1987; 59: 218-225. 4. Hennis PJ, Fancy MR, Miller RD, Canfell C, Shi W-Z. Pharmacology of laudanosine in dogs. Anesthesiology 1984; 61: A305. 5. Lanier WL, Milde JH, Michenfelder JD. Cerebral effects of atracurium. Anesthesiology 1984; 61: A361. 6. Yate PM, Flynn PJ, Arnold RW, Weatherley RC, Simmonds RJ, Dopson J. Clinical experience and plasma laudanosine concentrations during atracurium infusions in the intensive therapy unit. British Journal of Anaesthesia 1987; 59: 211-217. 7. Eddleston JM, Harper NJN, Pollard BJ, Edwards D, Gwinnutt CL. Concentrations of atracurium and laudanosine in cerebrospinal fluid and plasma during intracranial surgery. British Journal of Anaesthesia 1989; 63: 525-530. 8. Simmonds RJ. Determination of atracurium, laudanosine and related compounds in plasma by high performance liquid chromatography. Journal of Chromatography 1985; 343: 645-675. 9. Fahey MR, Canfell C, Toaboada T, Shi W-Z, Miller RD, Hosobuchi Y. Cerebrospinal fluid concentrations of laudanosine after administration of atracurium. British Journal of Anaesthesia 1990; 64: 105-106. 10. Chappie DJ, Dodd P, Macleod DM, Withington PS, Yate PM. Requirements for neuromuscular blocking agents during prolonged anaesthesia in the anaesthetized dog. British Journal of Anaesthesia 1987; 59: 1321P-1322P. 11. Di Chiro G, Hammock MK, Bleyer WA. Spinal descent of cerebrospinal fluid in man. Neurology 1976; 26: 1-8. 12. White RP. Vasospasm. In: Fox JL, ed. Intracranial Aneurysms, vol. 1. New York: Springer-Verlag, 1983; 218-271. 13. Crockard A. Brain swelling, brain oedema and the bloodbrain barrier. In: Crockard A, Hayward R, Hoff JT, eds. Neurosurgery—The Scientific Basis of Clinical Practice. Oxford: Blackwell, 1985; 33-349. 14. Kosteljanetz M. Cerebrospinal fluid production in subarachnoid haemorrhage. British Journal of Neurosurgery 1988; 2: 161-168.
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CSF concentrations of laudanosine than those seen in dogs, despite greater plasma concentrations (CSF:plasma ratios < 0.1 compared with 0.3-0.6, respectively). This further supports the concept of a species difference in distribution of laudanosine in the CNS. The plasma and CSF concentrations of laudanosine in patient C (8.65 ug ml"1 and 440 ng ml"1, respectively) are greater than reported previously, and considerably greater than those in the two other patients. This is most likely a reflection of the greater rate of infusion and total dose of atracurium used (7.92 g). Despite these concentrations, no CNS side effects were seen either during the infusion or immediately after discontinuation, although EEG was not monitored. The slight difference in the CSF:plasma ratios between patients B and C may reflect the difference in the pathology of the underlying head injuries. Patient B was known to have cerebral contusions, and patient C had generalized cerebral oedema. Laudanosine accumulated in both plasma and CSF during prolonged infusions of atracurium. The rate of increase and the final concentration of laudanosine within the CSF were smaller in man than in dogs. Concern about the use of prolonged infusions of atracurium based on results in dogs may therefore not be justified.