E. H. Flewellen

Dantrolene dose response in awake man: implications for management of malignant hyperthermia

Dantrolene sodium was administered intravenously to 12 adult volunteers to assess muscular and cardiopulmonary response. Pharmacokinetic results were obtained from whole blood drug concentration. Indirectly evoked thumb adduction was quantitated. Handgrip strength and subjective weakness score (10 equal to full strength, 0 equal to paralyzed) were assessed. Cardiopulmonary variables included forced vital capacity (FVC), peak expiratory flow rate (PEFR), percentage of end-tidal carbon dioxide (ETCO2), indirect mean arterial pressure (MAP), and heart rate (HR). Commercially available dantrolene for intravenous administration 0.33 mg/ml was administered in bolus doses of 0.1 mg/kg every 5 min until a plateau in twitch depression was achieved. Monitored variables were assessed either after each dose or following each cumulative 0.2 mg/kg dose over approximately 2 h. Intermittently during the subsequent 46 h, grip strength, subjective weakness, and blood levels were assessed. An average maximal twitch depression of 75% was reached at 2.2–2.5 mg/kg cumulative dantrolene dose. Significant depression of grip strength was observed after a dantrolene dose of 1.0 mg/kg and remained for 20 h. Subjective weakness score was 4.7 after dantrolene and slowly returned to 10 by 48 h. FVC and PEFR were not depressed significantly from control levels. ETCO2, MAP, and HR were unchanged. Maximum dantrolene blood level was 4.2 μg/ml at 2.9 h after the initial dantrolene dose. A near steady state existed for 5.5 h following the last dantrolene dose with a blood level of 3.6 μg/ml. Then blood levels declined slowly following first-order kinetics with a t 1/2 elimination of 12.1 h. Based on these results, the authors predict that the acute intravenous administration of dantrolene, 2.4 mg/kg, will achieve MH prophylaxis or therapeusis in humans.

Spectrum of Susceptibility to Malignant Hyperthermia-Diagnostic Dilemma

Utilizing established in vitro muscle contracture tests, we have identified three diagnostic contracture phenotypes for malignant hyperthermia susceptibility (MHS) among 103 patients. Phenotype H is an unequivocal diagnostic result for MHS, as is the nonsusceptible phenotype N. The third diagnostic group, phenotype K, represents an equivocal diagnostic response. To provide a basis for understanding relationships between contracture phenotypes and MHS, pigs with phenotypes H, K, and N were exposed to a standardized anesthetic protocol for assessing MHS. During the anesthetic challenge, phenotype H pigs developed a more severe form of the MH syndrome than did phenotype K pigs. Comparing phenotype H v K average responses, Vo2 increased four- v twofold; lactate increased 13− v 9-fold; and temperature increased 41.7°C v 39.2°C, respectively. These values either had no change or decreased in the phenotype N pigs. Results of this study suggest that a spectrum of MHS exists among the human population.

Halothane-succinylcholine induced masseter spasm: indicative of malignant hyperthermia susceptibility?

Masseter spasm (MS) after succinylcholine administration in adults and children receiving volatile anesthetics may herald the acute development of a malignant hyperthermia (MH) hypermetabolic crisis (1-3). Many clinicians observing MS immediately discontinue anesthesia, utilize the laboratory to monitor for biochemical derangements, and refer the patient to one of a few MH diagnostic centers (4,5). Several recent reports have shown that such children have subsequent muscle biopsy test results indicative of MH susceptibility (4-8). Eighteen children were referred to us for halothane-caffeine skeletal muscle contracture testing. All had developed MS immediately after anesthetic induction with inhalation of halothane followed by intravenous succinylcholine prior to attempted endotracheal intubation. Included in this study are six children we previously reported on. These 18 children represent 15% of referrals to our laboratory for MH evaluation.

Rationale for dantrolene vs. procainamide for treatment of malignant hyperthermia.

: The use of procainamide or procaine for treatment of malignant hyperthermia is commonly recommended. The skeletal muscle relaxant dantrolene has also been indicated for treatment of this complication during anesthesia. In the present study, effects of procainamide and dantrolene were compared in malignant hyperthemia-susceptible (MHS) pigs in vivo and on MHS muscle from human patients in vitro. The ED50 for dantrolene block of indirectly evoked twitch tension was 0.85 mg/kg in MHS pigs. A final cumulative dose of 2 mg/kg resulted in 68 per cent block of the twitch response. In contrast, procainamide at a final cumulative dose of 14 mg/kg had no effect on twitch response of the MHS pigs. Dantrolene, 3 micrometer, in vitro (approximately 0.8 mg/kg in vivo) was effective in preventing or reversing the abnormal halothane-induced contracture response of human MHS muscle strips. Procainamide, 0.11 mM, a dose approximating clinical levels (about 22 mg/kg), had no effect on basal twitch response or on the abnormal halothan-induced contracture of MHS human muscle. These results confirm the effectiveness of dantrolene and the lack of effectiveness of procainamide in the treatment of malignant hyperthemia.

Masseter spasm induced by succinylcholine in children: contracture testing for malignant hyperthermia: report of six cases.

We evaluated six boys who had developed isolated masseter muscle spasm following intravenous succinylcholine. All were receiving halothane by inhalation.In vitro muscle contracture tests utilizing halothane and caffeine were performed. Four of the six boys had contracture responses similar to those of malignant hyperthermia susceptible patients. Rigidity following succinylcholine should prompt the clinician to consider malignant hyperthermia but has been associated with other myopathic conditions as discussed.RéSUMéSix jeunes garçons qui avaient présenté un spasme n’impliquant que le masséter à la suite d’une injection de succinylcholine par la voie veineuse ont été étudiés. Tous ces malades recevaient de l’halothane. Des tests de contracture à l’halothane et à la caféine in vitro ont été effectués et ont démontré dans quatre cas sur six des contractures identiques à celles qu’on rencontre chez le sujet susceptible à l’hyperthermie maligne. La rigidité qui suit l’injection de succinylcholine devrait toujours faire suspecter l’hyperthermie maligne mais ne peut éliminer d’emblée d’autres myopathies.

Effect of Dantrolene on Neuromuscular Block by d-Tubocurarine and Subsequent Antagonism by Neostigmine in the Rabbit

The effects of dantrolene on neuromuscular blockade produced by d-tubocurarine (dTc) and subsequent reversal with neostigmine were studied in vivo in a rabbit model. Two groups of rabbits were given a constant rate of infusion of dTc at a concentration of 0.1 or 0.2 mg/ml to produce approximately 95 per cent twitch depression, as measured by plantar flexion of the hind foot in response to sciatic-nerve stimulation. An additional two groups of rabbits first received dantrolene, 1.5 mg/kg, producing approximately 60 per cent depression of twitch amplitude, and then received the dTc infusion to attain a combined 95 per cent twitch depression. The paralytic effects of initial dantrolene and subsequent dTc were additive. Prior dantrolene therapy produced greater twitch depression with initial doses of dTc, but as greater dTc-induced paralysis was achieved, the dantrolene effect became insignificant. It appears that dTc and dantrolene act on proximal and distal sites, respectively, in the process of muscle excitation, and that these sites are in tandem. Thus, there was no difference between the amounts of dTc (.2 mg/kg) necessary to produce 95 per cent twitch depression with and without prior administration of dantrolene. When neostigmine, .02 mg/kg, with atropine was administered, reversal was complete in rabbits receiving only dTc, but in those receiving prior dantrolene, neostigmine appeared to antagonize only the dTc effect, without influencing the dantrolene-induced block.

DOES PRIOR DANTROLENE AFFECT THE IN VITRO DIAGNOSIS OF MALIGNANT HYPERTHERMIA SUSCEPTIBILITY

SummaryA therapeutic and prophylactic dose of dantrolene administered to malignant hyperthermia-susceptible pigs had no effect on the abnormalin vitro contracture response of subsequent muscle biopsies. Thein vitro contracture response of MHS pig muscle to halothane and to caffeine was not altered by prior dantrolene treatment. It is concluded that prior dantrolene administration has no effect on the discrimination of porcine MHS byin vitro pharmacological testing.RésuméOn a administré à des porcs susceptibles ďhyperthermie maligne, une dose de 3.5 mg·kg-1 de dantrolène dans le but de produire une dépression maximale de la contraction provoquée de ľorteil. Des biopsies du muscle droit interne de la cuisse ont été prélevées avant et après ľadministration de la drogue pour évaluer les modifications qu’elle pourrait apporter aux épreuves diagnostiques basées sur ľévaluation in vitro de la contracture du muscle en contact avec ľhalothane, la caféine ou une combinaison de ces deux drogues. Les épreuves de contraction furent réalisées immédiatement, une heure ou deux après chaque biopsie.Lors de ľépreuve à ľhalothane, le dantrolène n’a eu aucun effet sur la réceptivité du muscle et la contracture se mesurait à 0.8 g en moyenne avant et à 0.7g après traitement. Au contact de ľhalothane la contracture augmentait avec la longueur de ľintervale qui séparait le prélèvement de ľépreuve et le dantrolène n’a pas modifié cet effet particulier. La concentration spécifique de caféine nécessaire pour une contracture isométrique mesurée à I g du muscle susceptible à ľhyperthermie maligne n’a pas été modifiée par le dantrolène (2.56 mM avant et 2.60 mM après dantrolène). Ľintervale entre le prélèvement et ľépreuve n’a pas affecté de façon significative la réponse à la caféine seule, alors que ľassociation halothane- caféine augmente ľeffet de contracture après dantrolène. On en conclut que ľadministration préalable de dantrolène n’a pas ďeffet sur le dèroulement des épreuves pharmacologiques in vitro de ľhypothermie maligne.

Is Theophylline, Aminophylline, or Caffeine (Methylxanthines) Contraindicated in Malignant Hyperthermia Susceptible Patients?

Based on animal data, aminophylline (theophylline ethylene diamine) and caffeine have been said to be contraindicated in patients susceptible to malignant hyperthermia (MH) (1,2). Aminophylline and theophylline are frequently indicated for bronchospastic disease and caffeine is found in many beverages. Intravenous preparations of aminophylline contain 7585% theophylline by weight (3). We diagnosed four MH susceptible patients by caffeine-halothane contracture response. Additional skeletal muscle fascicles from these patients were exposed in vitro to theophylline with and without the presence of 1% halothane. Results allow for recommendations concerning administration or consumption of these methylxanthines for known MH susceptible patients.

In vivo andIn vitro responses to magnesium sulphate in porcine malignant hyperthermia

Magnesium sulphate has previously been shown therapeutic in porcine malignant hyperthermia. It was given intravenously in doses of 99 mg·kg-1 before and 277 mg·kg-1 after an episode of malignant hyperthermia had been produced by halothane 1.5 per cent, in a group of four malignant hyperthermia susceptible swine. Two groups of four additional MH susceptible and MH resistant swine received a constant infusion of magnesium sulphate 10 mg·kg-1 until approximately 95 per cent depression of foretoe twitch was produced. Four hyperthermia susceptible controls received saline infusions. All were then immediately challenged with succinylcholine 2 mg·kg-1 and halothane 1.5 per cent. Muscle strips from three other malignant hyperthermia swine were exposedin vitro to magnesium sulphate with and without halothane, and response of twitch tension and contracture were measured. The malignant hyperthermia response to halothane 1.5 per cent was attenuated but not prevented by pretreatment with magnesium sulphate. It did not appear to be therapeutic in this group. Depression of toe twitch by magnesium sulphate was similar in MH susceptible and MH resistant pigs. Pretreatment with magnesium sulphate markedly attentuated the response to a succinylcholine-halothane challenge in MH susceptible pigs.In vitro magnesium sulphate depressed twitch and halothane contracture responses. We conclude that magnesium sulphate is partially prophylactic for the malignant hyperthermia challenge. The mechanism of this response is likely secondary to calcium ion antagonism at multiple sites. The muscle relaxant reponse to magnesium sulphate cannot be used as a diagnostic test for porcine malignant hyperthermia.RésuméĽefficacité thérapeutique du sulfate de magnésie a déjà été démontrée dans ľhyperthermie maligne du porc. On a administré cet agent aux doses de 99 mg·kg-1 et 277 mg·kg-1 avant et après déclenchement ďun épisode ďhyperthermie au moyen ďhalothane à 1.5 pour cent, ceci à quatre porcs rendus susceptibles à ľhyperthermic maligne. Deux autres groupes de quatre porcs respectivement susceptibles et résistants à ľhyperthermie maligne, ont reçu une perfusion continue de sulfate de magnésie (à raison de 10 mg·kg-1·min-1) jusqu’à la dépression de 95 pour cent de la contraction réflexe simple de ľorteil antérieur. Un autre groupe contrôle de quatre porcs susceptibles au syndrome a reçu une perfusion de soluté physiologique. On a alors tenté de déclencher un épisode chez tous ces animaux en administrant une dose de 2 mg·kg-1 de succinylcholine et une anesthésie à ľhalothane à 1.5 pour cent. Des fibres musculaires prélevées chez trois animaux susceptibles ont été exposées in vitro au sulfate de magnésie avec ou sans halothane, et ľon a mesuré leur réponse réflexe et leur tension de contracture.Les animaux susceptibles ont présenté une réaction à ľhalothane atténuée mais non abolie par ľadministration préalable de sulfate de magnésie. Le sulfate de magnésie ne semblait pas efficace chez ces animaux une fois la crise déclenchée. La dépression de la réponse de ľorteil antérieur était semblable chez les porcs susceptibles à ľhyperthermie et à ceux qui étaient résistants. Ľadministration préalable de sulfate de magnésie atténuait de façon importante la réponse à la stimulation à la succinylcholine avec halothane chez les animaux sensibles. In vitro, le sulfate de magnésie déprimait la réponse réflexe au stimulus simple, ainsi que la tension de contracture sous halothane. Nous concluons que le sulfate de magnésie est partiellement efficace comme mesure préventive de ľhyperthermie maligne. Cette action est probablement due à un antagonisme du calcium à différents sites. Le relâchement musculaire secondaire au sulfate de magnésie ne peut être utilisé comme test diagnostique de ľhyperthermie maligne chez le porc.