Background Altered Ca2+ homeostasis in skeletal muscle is a key molecular event triggering malign... more Background Altered Ca2+ homeostasis in skeletal muscle is a key molecular event triggering malignant hyperthermia (MH) in malignant hyperthermia-susceptible (MHS) individuals. Genetic studies have shown that mutations in the type 1 ryanodine receptor (RYR1) are associated with MH susceptibility. Because human B lymphocytes express the RYR1, it is hypothesized that Ca2+ homeostasis in B lymphocytes is altered in MHS individuals. Methods This study investigated the Ca2+ response of B cells to caffeine and 4-chloro-m-cresol in 13 MHS and 21 MH-negative (MHN) individuals who had been diagnosed by caffeine halothane contracture test (CHCT) and 18 healthy volunteers. Changes in [Ca2+]i in B cells were measured directly in fluo-3 loaded cells using a dual-color flow cytometric technique. Further, B cell phenotype was correlated with CHCT results in a family with the Val2168Met (G6502A) mutation. Results Caffeine-induced (50 mm) increases in [Ca2+]i in B cells were significantly greater in ...
Malignant hyperthermia (MH) is a complex pharmacogenetic disorder of muscle metabolism. To more c... more Malignant hyperthermia (MH) is a complex pharmacogenetic disorder of muscle metabolism. To more closely examine the complexities of MH and other related muscle disorders, the Malignant Hyperthermia Association of the United States recently sponsored a scientific conference at which an interdisciplinary group of experts gathered to share new information and ideas. In this Special Article, we highlight key concepts and theories presented at the conference along with exciting new trends and challenges in MH research and patient care. * See www.emhg.org for a listing of RyR1 mutations deemed causative for MH susceptibility by the European Malignant Hyperthermia Group (last accessed 3/11/11).
The time between the beginning of anesthetic administration and recognition of the first sign of ... more The time between the beginning of anesthetic administration and recognition of the first sign of malignant hyperthermia (MH) (MH onset time) could differ among anesthetic drugs. We examined the time of the first signs of suspected MH, anesthetic drugs administered, subject age, and year of event in Adverse Metabolic/Musculoskeletal Reaction to Anesthesia reports in the North American Malignant Hyperthermia Registry. Inclusion criteria were judgment by the reporting clinician that the event was possible or fulminant MH, documentation of the time when anesthetic administration began, and the time when the first MH sign was noted. Descriptive statistics, Kruskal-Wallis analysis, and nonparametric correlation were used to assess the difference in MH onset times under different conditions. Four hundred seventy-seven cases met inclusion criteria; 58.5% were possible MH and 41.5% fulminant MH. Inhaled anesthetic and succinylcholine were given in 53.9% of cases, inhaled anesthetic only in 41.7%, and succinylcholine without inhaled anesthetics in 2.9%. No causative anesthetic drugs were reported in 7 MH cases. In 394 patients exposed to only 1 of the 4 inhaled anesthetics, without regard for subject age, MH onset time was shorter in the presence of halothane than any of the other anesthetics and shorter after succinylcholine in all anesthetics. If succinylcholine was not given, MH onset was shorter during sevoflurane anesthesia than during desflurane or isoflurane. In 322 cases, 1 rather than multiple first signs of MH were reported with masseter spasm as the earliest MH sign. In 339 cases in which masseter spasm was not reported, there was no difference in MH onset time with or without succinylcholine. In 146 cases in which masseter spasm was not reported and succinylcholine was not given, MH onset was shorter during halothane anesthesia, than during exposure to desflurane, or isoflurane. MH onset time during sevoflurane was shorter than during desflurane or isoflurane. MH was reported later in the course of anesthesia after 1998, when halothane and succinylcholine were less often reported. MH occurred after succinylcholine administration in the absence of inhaled anesthetics. We could not separate an effect of age from that of other variables. The onset of MH has been observed later during desflurane and isoflurane anesthesia than during exposure to sevoflurane. Since 1998, MH signs have more often appeared later, in the second or third hour of anesthesia, than they did before 1998.
Atracurium, a non-depolarizing neuromuscular blocking drug with an intermediate duration of actio... more Atracurium, a non-depolarizing neuromuscular blocking drug with an intermediate duration of action, is metabolized by non-specific esterases and decomposes spontaneously via Hoftnann elimination (Basta et al., 1982; Merrett, Thompson and Webb, 1983). In vitro about two-thirds of atracurium is degraded by ester hydrolysis and one-third by the Hofmann reaction (Stiller, Brandom and Cook, 1985; Stiller, Cook and Chakravorti, 1985). Thus, each pathway plays an important role in the degradation of atracurium; laudanosine is the major end product of each pathway. Neither true-or pseudo-cholinesterase has any effect on the inactivation of atracurium, and the nature of the non-specific esterases has been poorly denned. In patients with liver disease, esterase activity may be reduced, the protein binding of drugs may be affected, body fluid compartments may be altered, and the renal excretion of drugs decreased (Duvaldestin et al., 1978). These changes could affect the pharmacokinetics of atracurium. In addition, age-related differences in dose requirements and duration of action of atracurium between infants, children and adults have been reported (Brandom, Rudd and Cook, 1983; Brandom et al., 1984). Since these changes could
Purpose: This study describes the effects of 0.3 mg.kg -~ mivacurium in 180 paediatric patients b... more Purpose: This study describes the effects of 0.3 mg.kg -~ mivacurium in 180 paediatric patients between the ages of one month and 13 yr. Methods: Alternate patients at each of two geographic sites received nitrous oxide-halothane or nitrous oxide-opioid anaesthesia. ...
... More recently, Girard et al. ... However, that day is not here yet. Charles D. Collard, MD‡. ... more ... More recently, Girard et al. ... However, that day is not here yet. Charles D. Collard, MD‡. Stanton K. Shernan, MD. Amanda A. Fox, MD. Martin N. Giesecke, MD. Simon C. Body, MB, Ch.B., MPH. ‡Texas Heart Institute, St. Luke's Episcopal Hospital, Houston, Texas. ...
Whole exome sequencing (WES) was used to determine the primary cause of muscle disorder in a fami... more Whole exome sequencing (WES) was used to determine the primary cause of muscle disorder in a family diagnosed with a mild, undetermined myopathy and malignant hyperthermia (MH) susceptibility (MHS). WES revealed the compound heterozygous mutations, p.Ile235Asn and p.Glu982Lys, in ATP2A1, encoding the sarco(endo)plasmic reticulum Ca 2+ ATPase type 1 (SERCA1), a calcium pump, expressed in fast-twitch muscles. Recessive mutations in ATP2A1 are known to cause Brody myopathy, a rare muscle disorder characterized by exercise-induced impairment of muscle relaxation and stiffness. Analyses of affected muscles showed the absence of SERCA1, but SERCA2 upregulation in slow and fast myofibers, suggesting a compensatory mechanism that partially restores the diminished Ca 2+ transport in Brody myopathy. This compensatory adaptation to the lack of SERCA1 Ca 2+ pumping activity within the muscle explains, in part, the mild course of disease in our patient. Diagnosis of MHS in this family was secondary to a loss of SERCA1 due to disease-associated mutations. Although there are obvious differences in clinical expression and molecular mechanisms between MH and Brody myopathy, a feature common to both conditions is elevated myoplasmic Ca 2+ content. Prolonged intracellular Ca 2+ elevation is likely to have led to MHS diagnosis in vitro and postoperative MHlike symptoms in Brody patient.
Background The authors determined associated cardiac arrest and death rates in cases from Canada ... more Background The authors determined associated cardiac arrest and death rates in cases from Canada and the United States as reported to The North American Malignant Hyperthermia (MH) Registry and analyzed factors associated with a higher risk of poor outcomes. Methods The authors searched the database for AMRA (adverse metabolic/musculoskeletal reaction to anesthesia) reports with inclusion criteria as follows: event date between January 1, 1987, and December 31, 2006; "very likely" or "almost certain" MH as ranked by MH Clinical Grading Scale; location in Canada or the United States; and one or more anesthetic agents given. The exclusion criterion was a pathologic condition other than MH independently judged by the authors. Severe MH outcomes were analyzed as regards clinical history and presentation, using Wilcoxon rank sum tests for continuous variables and Pearson exact chi-square tests for categorical variables. A Bonferroni correction adjusted for multiple co...
Neuromuscular blocking drugs are valuable adjuncts to the practice of pediatrics. Monitoring of d... more Neuromuscular blocking drugs are valuable adjuncts to the practice of pediatrics. Monitoring of drug effects is technically more difficult in the younger patient. Nevertheless, careful observation of drug effects will improve the usefulness of NMB and safeguard the patient from prolonged weakness. Although there are differences in neuromuscular function with age in the pediatric age range, the differences between the NMB currently available are greater than the differences between the patients. Thus, the only uniform finding across age and all drugs is that onset of drug effect is more rapid in the infant than in the child when circulatory function is normal. In general, children require more of all NMB on a mg/kg basis than do infants or adults to obtain the same effect. Children recover from NMB more rapidly than do patients of other ages. Infants, however, may recover more rapidly than do any other patients from the effects of drugs such as mivacurium which are metabolized in the plasma. Tables 4 and 5 summarize doses, onset of action, and duration of NMB. Please note in Table 4 that succinylcholine is only used for endotracheal intubation, whereas the other nondepolarizing muscle relaxants can be used for endotracheal intubation or to maintain some degree of muscle paralysis in the child whose trachea is already intubated. Nondepolarizing muscle relaxants (e.g., mivacurium, ORG 9426, atracurium, vecuronium) are used both for initial bolus for endotracheal intubation and maintenance of muscle relaxation. Long-acting drugs (e.g., pancuronium, pipecuronium, and doxacurium), however, are used more commonly in small incremental doses to maintain muscle paralysis in patients already intubated. The advantages of these long-acting drugs are minimal cardiovascular side effects (i.e., tachycardia or hypotension from histamine release) and longer dosing interval. In all children, the dosing interval should be adjusted to the needs of the individual. In children with renal insufficiency or in those receiving drugs which impair neuromuscular function (e.g., aminoglycosides), the interval at which supplemental doses are required is longer than normal.
In 30 children under balanced anaesthesia, we have determined dose-response curves and maintenanc... more In 30 children under balanced anaesthesia, we have determined dose-response curves and maintenance requirement of three dose ratio combinations of atracurium and vecuronium (10:1, 4:1 or 1.6:1 on a fig:^ig basis). Neuromuscular block was monitored by adductor pollicis EMG. An equipotent dose ratio (4:1) was most potent, with a mean (SEM) ED g5 of atracurium 95 (6) /xg kg' 1 with vecuronium 24 (1) fig kg~1. The sum of these doses is only 58% of an ED 95 value of one agent (? = 0.0001). The hourly requirement to maintain a 90-95% neuromuscular block was 2.0 (0.1) times an individual ED g5 dose of any combination. Recovery index was 8.9 (0.5) min. These results indicate that a combination of atracurium and vecuronium is supra-additive compared with the effects of each drug alone. However, all combinations maintained an intermediate character of neuromuscular block. Combining atracurium with vecuronium may reduce drug requirement by 40%. (Br.
We have compared the effects of two different frequencies of train-of-four stimulation of the uln... more We have compared the effects of two different frequencies of train-of-four stimulation of the ulnar nerve (2-Hz stimulation once every 10 or 20 s) on onset time and potency of atracurium, vecuronium and mivacurium during balanced anaesthesia. The adductor pollicis EMG was recorded simultaneously in both hands of 24 children aged 2-12 yr. After administration of an ED^ dose of each blocker, onset times were mean 21 (SEM 10) s shorter (? < 0.05) and decreases in neuromuscular function were 22 (3) % greater (P < 0.001) in the hand which was stimulated once every 10 s. We conclude that it is not possible to compare potency estimates of neuromuscular blocking agents if different stimulation patterns have been used. (Br.
Background Altered Ca2+ homeostasis in skeletal muscle is a key molecular event triggering malign... more Background Altered Ca2+ homeostasis in skeletal muscle is a key molecular event triggering malignant hyperthermia (MH) in malignant hyperthermia-susceptible (MHS) individuals. Genetic studies have shown that mutations in the type 1 ryanodine receptor (RYR1) are associated with MH susceptibility. Because human B lymphocytes express the RYR1, it is hypothesized that Ca2+ homeostasis in B lymphocytes is altered in MHS individuals. Methods This study investigated the Ca2+ response of B cells to caffeine and 4-chloro-m-cresol in 13 MHS and 21 MH-negative (MHN) individuals who had been diagnosed by caffeine halothane contracture test (CHCT) and 18 healthy volunteers. Changes in [Ca2+]i in B cells were measured directly in fluo-3 loaded cells using a dual-color flow cytometric technique. Further, B cell phenotype was correlated with CHCT results in a family with the Val2168Met (G6502A) mutation. Results Caffeine-induced (50 mm) increases in [Ca2+]i in B cells were significantly greater in ...
Malignant hyperthermia (MH) is a complex pharmacogenetic disorder of muscle metabolism. To more c... more Malignant hyperthermia (MH) is a complex pharmacogenetic disorder of muscle metabolism. To more closely examine the complexities of MH and other related muscle disorders, the Malignant Hyperthermia Association of the United States recently sponsored a scientific conference at which an interdisciplinary group of experts gathered to share new information and ideas. In this Special Article, we highlight key concepts and theories presented at the conference along with exciting new trends and challenges in MH research and patient care. * See www.emhg.org for a listing of RyR1 mutations deemed causative for MH susceptibility by the European Malignant Hyperthermia Group (last accessed 3/11/11).
The time between the beginning of anesthetic administration and recognition of the first sign of ... more The time between the beginning of anesthetic administration and recognition of the first sign of malignant hyperthermia (MH) (MH onset time) could differ among anesthetic drugs. We examined the time of the first signs of suspected MH, anesthetic drugs administered, subject age, and year of event in Adverse Metabolic/Musculoskeletal Reaction to Anesthesia reports in the North American Malignant Hyperthermia Registry. Inclusion criteria were judgment by the reporting clinician that the event was possible or fulminant MH, documentation of the time when anesthetic administration began, and the time when the first MH sign was noted. Descriptive statistics, Kruskal-Wallis analysis, and nonparametric correlation were used to assess the difference in MH onset times under different conditions. Four hundred seventy-seven cases met inclusion criteria; 58.5% were possible MH and 41.5% fulminant MH. Inhaled anesthetic and succinylcholine were given in 53.9% of cases, inhaled anesthetic only in 41.7%, and succinylcholine without inhaled anesthetics in 2.9%. No causative anesthetic drugs were reported in 7 MH cases. In 394 patients exposed to only 1 of the 4 inhaled anesthetics, without regard for subject age, MH onset time was shorter in the presence of halothane than any of the other anesthetics and shorter after succinylcholine in all anesthetics. If succinylcholine was not given, MH onset was shorter during sevoflurane anesthesia than during desflurane or isoflurane. In 322 cases, 1 rather than multiple first signs of MH were reported with masseter spasm as the earliest MH sign. In 339 cases in which masseter spasm was not reported, there was no difference in MH onset time with or without succinylcholine. In 146 cases in which masseter spasm was not reported and succinylcholine was not given, MH onset was shorter during halothane anesthesia, than during exposure to desflurane, or isoflurane. MH onset time during sevoflurane was shorter than during desflurane or isoflurane. MH was reported later in the course of anesthesia after 1998, when halothane and succinylcholine were less often reported. MH occurred after succinylcholine administration in the absence of inhaled anesthetics. We could not separate an effect of age from that of other variables. The onset of MH has been observed later during desflurane and isoflurane anesthesia than during exposure to sevoflurane. Since 1998, MH signs have more often appeared later, in the second or third hour of anesthesia, than they did before 1998.
Atracurium, a non-depolarizing neuromuscular blocking drug with an intermediate duration of actio... more Atracurium, a non-depolarizing neuromuscular blocking drug with an intermediate duration of action, is metabolized by non-specific esterases and decomposes spontaneously via Hoftnann elimination (Basta et al., 1982; Merrett, Thompson and Webb, 1983). In vitro about two-thirds of atracurium is degraded by ester hydrolysis and one-third by the Hofmann reaction (Stiller, Brandom and Cook, 1985; Stiller, Cook and Chakravorti, 1985). Thus, each pathway plays an important role in the degradation of atracurium; laudanosine is the major end product of each pathway. Neither true-or pseudo-cholinesterase has any effect on the inactivation of atracurium, and the nature of the non-specific esterases has been poorly denned. In patients with liver disease, esterase activity may be reduced, the protein binding of drugs may be affected, body fluid compartments may be altered, and the renal excretion of drugs decreased (Duvaldestin et al., 1978). These changes could affect the pharmacokinetics of atracurium. In addition, age-related differences in dose requirements and duration of action of atracurium between infants, children and adults have been reported (Brandom, Rudd and Cook, 1983; Brandom et al., 1984). Since these changes could
Purpose: This study describes the effects of 0.3 mg.kg -~ mivacurium in 180 paediatric patients b... more Purpose: This study describes the effects of 0.3 mg.kg -~ mivacurium in 180 paediatric patients between the ages of one month and 13 yr. Methods: Alternate patients at each of two geographic sites received nitrous oxide-halothane or nitrous oxide-opioid anaesthesia. ...
... More recently, Girard et al. ... However, that day is not here yet. Charles D. Collard, MD‡. ... more ... More recently, Girard et al. ... However, that day is not here yet. Charles D. Collard, MD‡. Stanton K. Shernan, MD. Amanda A. Fox, MD. Martin N. Giesecke, MD. Simon C. Body, MB, Ch.B., MPH. ‡Texas Heart Institute, St. Luke's Episcopal Hospital, Houston, Texas. ...
Whole exome sequencing (WES) was used to determine the primary cause of muscle disorder in a fami... more Whole exome sequencing (WES) was used to determine the primary cause of muscle disorder in a family diagnosed with a mild, undetermined myopathy and malignant hyperthermia (MH) susceptibility (MHS). WES revealed the compound heterozygous mutations, p.Ile235Asn and p.Glu982Lys, in ATP2A1, encoding the sarco(endo)plasmic reticulum Ca 2+ ATPase type 1 (SERCA1), a calcium pump, expressed in fast-twitch muscles. Recessive mutations in ATP2A1 are known to cause Brody myopathy, a rare muscle disorder characterized by exercise-induced impairment of muscle relaxation and stiffness. Analyses of affected muscles showed the absence of SERCA1, but SERCA2 upregulation in slow and fast myofibers, suggesting a compensatory mechanism that partially restores the diminished Ca 2+ transport in Brody myopathy. This compensatory adaptation to the lack of SERCA1 Ca 2+ pumping activity within the muscle explains, in part, the mild course of disease in our patient. Diagnosis of MHS in this family was secondary to a loss of SERCA1 due to disease-associated mutations. Although there are obvious differences in clinical expression and molecular mechanisms between MH and Brody myopathy, a feature common to both conditions is elevated myoplasmic Ca 2+ content. Prolonged intracellular Ca 2+ elevation is likely to have led to MHS diagnosis in vitro and postoperative MHlike symptoms in Brody patient.
Background The authors determined associated cardiac arrest and death rates in cases from Canada ... more Background The authors determined associated cardiac arrest and death rates in cases from Canada and the United States as reported to The North American Malignant Hyperthermia (MH) Registry and analyzed factors associated with a higher risk of poor outcomes. Methods The authors searched the database for AMRA (adverse metabolic/musculoskeletal reaction to anesthesia) reports with inclusion criteria as follows: event date between January 1, 1987, and December 31, 2006; "very likely" or "almost certain" MH as ranked by MH Clinical Grading Scale; location in Canada or the United States; and one or more anesthetic agents given. The exclusion criterion was a pathologic condition other than MH independently judged by the authors. Severe MH outcomes were analyzed as regards clinical history and presentation, using Wilcoxon rank sum tests for continuous variables and Pearson exact chi-square tests for categorical variables. A Bonferroni correction adjusted for multiple co...
Neuromuscular blocking drugs are valuable adjuncts to the practice of pediatrics. Monitoring of d... more Neuromuscular blocking drugs are valuable adjuncts to the practice of pediatrics. Monitoring of drug effects is technically more difficult in the younger patient. Nevertheless, careful observation of drug effects will improve the usefulness of NMB and safeguard the patient from prolonged weakness. Although there are differences in neuromuscular function with age in the pediatric age range, the differences between the NMB currently available are greater than the differences between the patients. Thus, the only uniform finding across age and all drugs is that onset of drug effect is more rapid in the infant than in the child when circulatory function is normal. In general, children require more of all NMB on a mg/kg basis than do infants or adults to obtain the same effect. Children recover from NMB more rapidly than do patients of other ages. Infants, however, may recover more rapidly than do any other patients from the effects of drugs such as mivacurium which are metabolized in the plasma. Tables 4 and 5 summarize doses, onset of action, and duration of NMB. Please note in Table 4 that succinylcholine is only used for endotracheal intubation, whereas the other nondepolarizing muscle relaxants can be used for endotracheal intubation or to maintain some degree of muscle paralysis in the child whose trachea is already intubated. Nondepolarizing muscle relaxants (e.g., mivacurium, ORG 9426, atracurium, vecuronium) are used both for initial bolus for endotracheal intubation and maintenance of muscle relaxation. Long-acting drugs (e.g., pancuronium, pipecuronium, and doxacurium), however, are used more commonly in small incremental doses to maintain muscle paralysis in patients already intubated. The advantages of these long-acting drugs are minimal cardiovascular side effects (i.e., tachycardia or hypotension from histamine release) and longer dosing interval. In all children, the dosing interval should be adjusted to the needs of the individual. In children with renal insufficiency or in those receiving drugs which impair neuromuscular function (e.g., aminoglycosides), the interval at which supplemental doses are required is longer than normal.
In 30 children under balanced anaesthesia, we have determined dose-response curves and maintenanc... more In 30 children under balanced anaesthesia, we have determined dose-response curves and maintenance requirement of three dose ratio combinations of atracurium and vecuronium (10:1, 4:1 or 1.6:1 on a fig:^ig basis). Neuromuscular block was monitored by adductor pollicis EMG. An equipotent dose ratio (4:1) was most potent, with a mean (SEM) ED g5 of atracurium 95 (6) /xg kg' 1 with vecuronium 24 (1) fig kg~1. The sum of these doses is only 58% of an ED 95 value of one agent (? = 0.0001). The hourly requirement to maintain a 90-95% neuromuscular block was 2.0 (0.1) times an individual ED g5 dose of any combination. Recovery index was 8.9 (0.5) min. These results indicate that a combination of atracurium and vecuronium is supra-additive compared with the effects of each drug alone. However, all combinations maintained an intermediate character of neuromuscular block. Combining atracurium with vecuronium may reduce drug requirement by 40%. (Br.
We have compared the effects of two different frequencies of train-of-four stimulation of the uln... more We have compared the effects of two different frequencies of train-of-four stimulation of the ulnar nerve (2-Hz stimulation once every 10 or 20 s) on onset time and potency of atracurium, vecuronium and mivacurium during balanced anaesthesia. The adductor pollicis EMG was recorded simultaneously in both hands of 24 children aged 2-12 yr. After administration of an ED^ dose of each blocker, onset times were mean 21 (SEM 10) s shorter (? < 0.05) and decreases in neuromuscular function were 22 (3) % greater (P < 0.001) in the hand which was stimulated once every 10 s. We conclude that it is not possible to compare potency estimates of neuromuscular blocking agents if different stimulation patterns have been used. (Br.
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