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PLASMA CHOLINESTERASE AND MALIGNANT HYPERTHERMIA
Br.J. Anaesth. (1981), 53, 317
CORRESPONDENCE for the atypical gene (E" Ef). In none of the patients was the fluoride-resistant gene found. (We did not look for the C,+ variant of cholinesterase, but as none of the patients had higher than normal values of cholinesterase activity, it may be assumed that they were all normal (Harris et al., 1963).) The difference between our results and those of Whittaker, Spencer and Searle (1977) and Ellis, Cain and others (1978) is a matter of speculation. There is apparently a difference in frequency of the fluoride-resistant gene between the two populations, the frequency being 0.5% in England (Whittaker, Spencer and Searle, 1977) and only 0.23% in Denmark (Hanel, Viby-Mogensen and Schaffalitzky de Muckadell, 1978) but this would not explain the higher frequencies of the gene reported. Ellis investigated 25 patients but did not state the number of families to which they belonged. A high frequency of abnormal genes found in one or two large families might explain the high frequency found in the total population J. W. MOSTERT investigated. However, Whittaker found this combination of Pretoria, S. Africa genes in al least three and possibly five families. If we assume the MH-trait to be found in 1 of 14 000 persons and the frequency of thefluoride-resistantgene to be 0.23%, we should REFERENCES Humphrey, D., Downing, J. W., and Brock-Utne, J. G. (1980). expect to find this combination of genes in one of six million Johannesburg A-D circuit switch. Br. J. Anaesth., 52, 842. persons, provided that no association exists between the genes. In conclusion, our results do not indicate any association between the genes controlling susceptibility to MH and the fluoride-resistant gene controlling plasma cholinesterase in the Danish population. JOHANNESBURG A - D CIRCUIT SWITCH
HELLB 0RDING HENRK H. HANEL PLASMA CHOUNESTERASE AND MALIGNANT HYPERTHERMIA
Sir,—A surprisingly high frequency of the fluoride-resistant gene controlling plasma cholinesterase has been found in patients who survived malignant hyperthermia (Whittaker, Spencer and Searle, 1977) and in patients proved by in vitro tests of a muscle biopsy to be MH-susceptible (Ellis, Cain et al., 1978). We have determined activity and genotype of plasma cholinesterase in 26 consecutive patients from 13 different families in Denmark, referred to the Danish Malignant Hyperthermia Investigation Unit for investigation of susceptibility to MH. One patient had survived a severe attack of MH, six patients were referred because of spasm of the masseter muscle after suxamethonium and 19 patients were first degree relatives of patients who had died of MH. Susceptibility to MH was determined by in vitro investigaDon of a muscle biopsy according to the method described by Ellis, Harriman and colleagues (1978). Fifteen patients were found to be MHsusceptible and 11 patients were normal. Activity and genotype of plasma cholinesterase was determined as described by VibyMogensen and Hanel (1977), assessing the dibucaine, fluoride, chloride, scoline and urea numbers. The results are shown in table I. Normal cholinesterase activity and genotype (E°Bf) was found in 24 patients. One patient who was MH-positive was cither normal or heterozygous for the silent gene (E° E" or E,u E^ and one patient who was MH-negative was heterozygous
JORGBN VIBY-MOGENSEN
Copenhagen, Denmark
REFERENCES
Ellis, F. R., Cain, P. A., Harriman, D. G. F., and Toothill, C. (1978). Plasma cholinesterase and malignant hyperpyrexia. Br. J. Anaesth., 50, 86. Harriman, D. G. F., Currie, S., and Cain, P. A. (1978). Screening for malignant hyperthermia in susceptible patients; in Malignant Hyperthermia (eds J. A. Aldrete and B. A. Britt), p. 273. Grune & Stratton. Hanel, H. K., Viby-Mogenscn, J., and Schaffalitzky de Muckadell, O. B. (1978). Serum cholinesterase variants in the Danish population. Acta Anaesthesiol. Scand.^^22, 505. Harris, H., Hopkinson, D. A., Robson, E. B., and ^ ^ c a k e r , M. (1963). Genctical studies on a new variant of serum cholinesterase detected by clectrophoresis. Ann. Ham. Genet. Land., 26, 359. Viby-Mogensen, J., and Hanel, H. K. (1977). A Danish cholinesterase research unit. Acta Anaesthesiol. Scand., 21, 405. Whittaker, M., Spencer, R., and Searle, J. (1977). Plasma cholinesterase and malignant hyperthermia. Br.J. Anaesth., 49, 393.
Downloaded from http://bja.oxfordjournals.org/ at Stanford Medical Center on May 10, 2015
Sir,—Humphrey, Downing and Brock-Utne (1980) are less than accurate in describing the destiny of expiration switched to inspiration in the Johannesburg Circuit. They vaguely refer to experimental evidence gathered "while studying a similar system"—evidence which simply does not tally with known pharmacokinetic principles. With a fresh gas inflow of 70mlkg~' min"' in a patient weighing 65 kg, the time constant is circuit volume (certainly no more than 6 litre) plus a large functional residual capacity of 3 litre, divided by the 4.5 litre min" ' gasflow;at most 2 min for 63% clearance and 6min for 95% clearance. There is no possibility that washout could take "more than lOmin" in the given circumstances. I have just seen the Johannesburg Switch performing well in Holland and it would be a pity if its clinical use is discredited unfairly.
318
BRITISH JOURNAL OF ANAESTHESIA
TABLE I. Determination of plasma cholinesterase activity and genotype in 26 Danish patients investigatedfor susceptibility to malignant hyperthermia. Normal range in parentheses (Viby-Mogensen and Hanel, 1977)
Patient number
1
1
757
71
53
16
76
57
2 2
2 3
1365 1438
83 83
61 59
15 15
91 90
49 52
3 4
4 5
1008 1165
82 88
55 62
14 11
89 92
45 43
5 5
6 19
698 755
81 80
62 62
14 15
90 91
45 43
6 6 6
7 8 12
914 818 802
84 80 80
60 62 58
14 15 18
91 90 91
48 48 56
7 7 7
9 14 15
1158 894 787
83 82 85
59 63 60
17 7 12
91 92 94
47 42 45
8
10
1056
81
61
17
92
51
9 9 9 9
11 13 18 21 16
826 1391 874 850
82 86 85 83
58 59 64 58
11 15 14 13
88 91 91 90
43 51 47 54
1024
86
63
14
91
47
10
Dibucaine number (78-86)
Fluoride number (55-65)
Chloride number (1-22)
Scoline number (89-95)
Urea number (41-52)
Presumed genotype
(ErEr)
+ + + — + + + + — + + + + + + + +
E,UE,U
ErEr ErEr ErEr E,UE,U
ErEr ErEr ErEr E,uEr E,U Er ErEr E,UE,U
ErEr
E,UE,U
E,uEr ErEr
11
17
758
84
63
6
89
45
20 22 23 24
1059 967 822 788
83 84 80 85
58 61 62 61
13 15 11 13
53 51 52 48
h,
13
25
635
87
60
16
91 91 90 90 85
46
E, U E, U or E, U E,'
13
26
1166
82
61
18
88
53
ErEr
INDUCTION DOSE OF MIDAZOLAM
_
ErE? E,uEr ErEr ErEr
12 12 12 12
Sir,—We would agree with Forster and others (1980) that midazolam 0.15mgkg~ ' is insufficient to induce anaesthesia reliably in unprcmedicated patients. However, they imply that 0.2mgkg~' is satisfactory in 100% of such patients by referring to a study in which only 10 patients received that dose (Reves, Corssen and Holcomb, 1978). Neither the appropriate induction dose nor the degree of individual variation in response to this agent is yet established (Dundee, 1979). We have found 0.225mgkg~ ' to be inadequate for induction of anaesthesia in unpremedicated patients and consider 0.3mgkg" ' to be a more realistic dose. Furthermore, loss of the eyelash reflex may not be a reliable sign of induction of anaesthesia with midazolam. Conner and others (1978) found that loss of lid reflex was an unreliable sign of induction for patients in whom tracheal intubation was planned. Many of their patients made purposeful arm and hand movements after an apparently successful induction. We have frequently noted that unpremedicated patients who have
MHsusceptibility
ii,
E, U E, U
ErEr ErEr
—
received midazolam still respond to oral commands despite the loss of this reflex. J. B. ElSENKRAFT R. MILLER
New York
REFERENCES
Conner, J. T., Katz, R. L., Pagano, R. R., and Graham, C. W. (1978). RO21-3981 for intravenous surgical premedication and induction of anesthesia. Anesth. Analg. (Clevc.), 57, 1. Dundee, J. W. (1979). New i.v. anaesthetics. Br. J. Anaesth., 51,641. Forster, A., Gardaz, J.-P., Suter, P. M., and Gemperle, M. (1980). I.v. midazolam as an induction agent for anaesthesia: a study in volunteers. Br. J. Anaesth., 52, 907. Rcves, J. G., Corssen, G., and Holcomb, C. (1978). Comparison of two benzodiazepines for anaesthesia induction: midazolam and diazepam. Can. Anaesth. Soc. J., 25, 211.
Downloaded from http://bja.oxfordjournals.org/ at Stanford Medical Center on May 10, 2015
Family number
Cholinesterase activity (u. litre" 1 ) (677-1560)
CORRESPONDENCE for the atypical gene (E" Ef). In none of the patients was the fluoride-resistant gene found. (We did not look for the C,+ variant of cholinesterase, but as none of the patients had higher than normal values of cholinesterase activity, it may be assumed that they were all normal (Harris et al., 1963).) The difference between our results and those of Whittaker, Spencer and Searle (1977) and Ellis, Cain and others (1978) is a matter of speculation. There is apparently a difference in frequency of the fluoride-resistant gene between the two populations, the frequency being 0.5% in England (Whittaker, Spencer and Searle, 1977) and only 0.23% in Denmark (Hanel, Viby-Mogensen and Schaffalitzky de Muckadell, 1978) but this would not explain the higher frequencies of the gene reported. Ellis investigated 25 patients but did not state the number of families to which they belonged. A high frequency of abnormal genes found in one or two large families might explain the high frequency found in the total population J. W. MOSTERT investigated. However, Whittaker found this combination of Pretoria, S. Africa genes in al least three and possibly five families. If we assume the MH-trait to be found in 1 of 14 000 persons and the frequency of thefluoride-resistantgene to be 0.23%, we should REFERENCES Humphrey, D., Downing, J. W., and Brock-Utne, J. G. (1980). expect to find this combination of genes in one of six million Johannesburg A-D circuit switch. Br. J. Anaesth., 52, 842. persons, provided that no association exists between the genes. In conclusion, our results do not indicate any association between the genes controlling susceptibility to MH and the fluoride-resistant gene controlling plasma cholinesterase in the Danish population. JOHANNESBURG A - D CIRCUIT SWITCH
HELLB 0RDING HENRK H. HANEL PLASMA CHOUNESTERASE AND MALIGNANT HYPERTHERMIA
Sir,—A surprisingly high frequency of the fluoride-resistant gene controlling plasma cholinesterase has been found in patients who survived malignant hyperthermia (Whittaker, Spencer and Searle, 1977) and in patients proved by in vitro tests of a muscle biopsy to be MH-susceptible (Ellis, Cain et al., 1978). We have determined activity and genotype of plasma cholinesterase in 26 consecutive patients from 13 different families in Denmark, referred to the Danish Malignant Hyperthermia Investigation Unit for investigation of susceptibility to MH. One patient had survived a severe attack of MH, six patients were referred because of spasm of the masseter muscle after suxamethonium and 19 patients were first degree relatives of patients who had died of MH. Susceptibility to MH was determined by in vitro investigaDon of a muscle biopsy according to the method described by Ellis, Harriman and colleagues (1978). Fifteen patients were found to be MHsusceptible and 11 patients were normal. Activity and genotype of plasma cholinesterase was determined as described by VibyMogensen and Hanel (1977), assessing the dibucaine, fluoride, chloride, scoline and urea numbers. The results are shown in table I. Normal cholinesterase activity and genotype (E°Bf) was found in 24 patients. One patient who was MH-positive was cither normal or heterozygous for the silent gene (E° E" or E,u E^ and one patient who was MH-negative was heterozygous
JORGBN VIBY-MOGENSEN
Copenhagen, Denmark
REFERENCES
Ellis, F. R., Cain, P. A., Harriman, D. G. F., and Toothill, C. (1978). Plasma cholinesterase and malignant hyperpyrexia. Br. J. Anaesth., 50, 86. Harriman, D. G. F., Currie, S., and Cain, P. A. (1978). Screening for malignant hyperthermia in susceptible patients; in Malignant Hyperthermia (eds J. A. Aldrete and B. A. Britt), p. 273. Grune & Stratton. Hanel, H. K., Viby-Mogenscn, J., and Schaffalitzky de Muckadell, O. B. (1978). Serum cholinesterase variants in the Danish population. Acta Anaesthesiol. Scand.^^22, 505. Harris, H., Hopkinson, D. A., Robson, E. B., and ^ ^ c a k e r , M. (1963). Genctical studies on a new variant of serum cholinesterase detected by clectrophoresis. Ann. Ham. Genet. Land., 26, 359. Viby-Mogensen, J., and Hanel, H. K. (1977). A Danish cholinesterase research unit. Acta Anaesthesiol. Scand., 21, 405. Whittaker, M., Spencer, R., and Searle, J. (1977). Plasma cholinesterase and malignant hyperthermia. Br.J. Anaesth., 49, 393.
Downloaded from http://bja.oxfordjournals.org/ at Stanford Medical Center on May 10, 2015
Sir,—Humphrey, Downing and Brock-Utne (1980) are less than accurate in describing the destiny of expiration switched to inspiration in the Johannesburg Circuit. They vaguely refer to experimental evidence gathered "while studying a similar system"—evidence which simply does not tally with known pharmacokinetic principles. With a fresh gas inflow of 70mlkg~' min"' in a patient weighing 65 kg, the time constant is circuit volume (certainly no more than 6 litre) plus a large functional residual capacity of 3 litre, divided by the 4.5 litre min" ' gasflow;at most 2 min for 63% clearance and 6min for 95% clearance. There is no possibility that washout could take "more than lOmin" in the given circumstances. I have just seen the Johannesburg Switch performing well in Holland and it would be a pity if its clinical use is discredited unfairly.
318
BRITISH JOURNAL OF ANAESTHESIA
TABLE I. Determination of plasma cholinesterase activity and genotype in 26 Danish patients investigatedfor susceptibility to malignant hyperthermia. Normal range in parentheses (Viby-Mogensen and Hanel, 1977)
Patient number
1
1
757
71
53
16
76
57
2 2
2 3
1365 1438
83 83
61 59
15 15
91 90
49 52
3 4
4 5
1008 1165
82 88
55 62
14 11
89 92
45 43
5 5
6 19
698 755
81 80
62 62
14 15
90 91
45 43
6 6 6
7 8 12
914 818 802
84 80 80
60 62 58
14 15 18
91 90 91
48 48 56
7 7 7
9 14 15
1158 894 787
83 82 85
59 63 60
17 7 12
91 92 94
47 42 45
8
10
1056
81
61
17
92
51
9 9 9 9
11 13 18 21 16
826 1391 874 850
82 86 85 83
58 59 64 58
11 15 14 13
88 91 91 90
43 51 47 54
1024
86
63
14
91
47
10
Dibucaine number (78-86)
Fluoride number (55-65)
Chloride number (1-22)
Scoline number (89-95)
Urea number (41-52)
Presumed genotype
(ErEr)
+ + + — + + + + — + + + + + + + +
E,UE,U
ErEr ErEr ErEr E,UE,U
ErEr ErEr ErEr E,uEr E,U Er ErEr E,UE,U
ErEr
E,UE,U
E,uEr ErEr
11
17
758
84
63
6
89
45
20 22 23 24
1059 967 822 788
83 84 80 85
58 61 62 61
13 15 11 13
53 51 52 48
h,
13
25
635
87
60
16
91 91 90 90 85
46
E, U E, U or E, U E,'
13
26
1166
82
61
18
88
53
ErEr
INDUCTION DOSE OF MIDAZOLAM
_
ErE? E,uEr ErEr ErEr
12 12 12 12
Sir,—We would agree with Forster and others (1980) that midazolam 0.15mgkg~ ' is insufficient to induce anaesthesia reliably in unprcmedicated patients. However, they imply that 0.2mgkg~' is satisfactory in 100% of such patients by referring to a study in which only 10 patients received that dose (Reves, Corssen and Holcomb, 1978). Neither the appropriate induction dose nor the degree of individual variation in response to this agent is yet established (Dundee, 1979). We have found 0.225mgkg~ ' to be inadequate for induction of anaesthesia in unpremedicated patients and consider 0.3mgkg" ' to be a more realistic dose. Furthermore, loss of the eyelash reflex may not be a reliable sign of induction of anaesthesia with midazolam. Conner and others (1978) found that loss of lid reflex was an unreliable sign of induction for patients in whom tracheal intubation was planned. Many of their patients made purposeful arm and hand movements after an apparently successful induction. We have frequently noted that unpremedicated patients who have
MHsusceptibility
ii,
E, U E, U
ErEr ErEr
—
received midazolam still respond to oral commands despite the loss of this reflex. J. B. ElSENKRAFT R. MILLER
New York
REFERENCES
Conner, J. T., Katz, R. L., Pagano, R. R., and Graham, C. W. (1978). RO21-3981 for intravenous surgical premedication and induction of anesthesia. Anesth. Analg. (Clevc.), 57, 1. Dundee, J. W. (1979). New i.v. anaesthetics. Br. J. Anaesth., 51,641. Forster, A., Gardaz, J.-P., Suter, P. M., and Gemperle, M. (1980). I.v. midazolam as an induction agent for anaesthesia: a study in volunteers. Br. J. Anaesth., 52, 907. Rcves, J. G., Corssen, G., and Holcomb, C. (1978). Comparison of two benzodiazepines for anaesthesia induction: midazolam and diazepam. Can. Anaesth. Soc. J., 25, 211.
Downloaded from http://bja.oxfordjournals.org/ at Stanford Medical Center on May 10, 2015
Family number
Cholinesterase activity (u. litre" 1 ) (677-1560)