Succinylcholine Use and Dantrolene Availability for Malignant Hyperthermia Treatment
Marilyn Green LarachThomas T. KlumpnerBarbara W. BrandomMichelle T. VaughnKumar G. BelaniAndrew HerlichTae W. KimJanine LimoncelliSheila RiaziErica L. SivakJohn F. CapacchioneDarlene MashmanSachin KheterpalFabian O. KooijJanet WilczakRoy G. SotoJoshua R. BerrisZachary PriceS. M. B. LinsPeter ColesJohn HarrisKenneth C. CummingsMitchell F. BermanMasakatsu NanamoriBruce T. AdelmanChristopher WedevenJohn LaGorioPatrick J. McCormickSimon TomMichael F. AzizTraci CoffmanTerri A. EllisSusan MolinaWilliam PetersonSean MackeyWilton A. van KleiAdit A. GindeDaniel A. BiggsMark D. NeumanRobert M. CraftNathan L. PaceWilliam C. PaganelliMarcel E. DurieuxBala J. NairJonathan P. WandererScott MillerDaniel L. HelstenZachary A. TurnbullRobert B. Schonberger
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Abstract EDITOR’S PERSPECTIVE What We Already Know about This Topic Dantrolene effectively treats malignant hyperthermia, but there are discrepant recommendations for dantrolene availability in facilities that stock succinylcholine for airway rescue but do not use volatile anesthetics. What This Article Tells Us That Is New The authors performed an analysis of data from three databases and a systematic literature review. Providers frequently use succinylcholine, including during difficult mask ventilation. Succinylcholine given without volatile anesthetics triggered 24 malignant hyperthermia events, 13 of which were treated with dantrolene. Fourteen patients experienced substantial complications, and one died. Delayed dantrolene treatment worsened patient outcomes. Background Although dantrolene effectively treats malignant hyperthermia (MH), discrepant recommendations exist concerning dantrolene availability. Whereas Malignant Hyperthermia Association of the United States guidelines state dantrolene must be available within 10 min of the decision to treat MH wherever volatile anesthetics or succinylcholine are administered, a Society for Ambulatory Anesthesia protocol permits Class B ambulatory facilities to stock succinylcholine for airway rescue without dantrolene. The authors investigated (1) succinylcholine use rates, including for airway rescue, in anesthetizing/sedating locations; (2) whether succinylcholine without volatile anesthetics triggers MH warranting dantrolene; and (3) the relationship between dantrolene administration and MH morbidity/mortality. Methods The authors performed focused analyses of the Multicenter Perioperative Outcomes Group (2005 through 2016), North American MH Registry (2013 through 2016), and Anesthesia Closed Claims Project (1970 through 2014) databases, as well as a systematic literature review (1987 through 2017). The authors used difficult mask ventilation (grades III and IV) as a surrogate for airway rescue. MH experts judged dantrolene treatment. For MH morbidity/mortality analyses, the authors included U.S. and Canadian cases that were fulminant or scored 20 or higher on the clinical grading scale and in which volatile anesthetics or succinylcholine were given. Results Among 6,368,356 queried outcomes cases, 246,904 (3.9%) received succinylcholine without volatile agents. Succinylcholine was used in 46% (n = 710) of grade IV mask ventilation cases (median dose, 100 mg, 1.2 mg/kg). Succinylcholine without volatile anesthetics triggered 24 MH cases, 13 requiring dantrolene. Among 310 anesthetic-triggered MH cases, morbidity was 20 to 37%. Treatment delay increased complications every 10 min, reaching 100% with a 50-min delay. Overall mortality was 1 to 10%; 15 U.S. patients died, including 4 after anesthetics in freestanding facilities. Conclusions Providers use succinylcholine commonly, including during difficult mask ventilation. Succinylcholine administered without volatile anesthetics may trigger MH events requiring dantrolene. Delayed dantrolene treatment increases the likelihood of MH complications. The data reported herein support stocking dantrolene wherever succinylcholine or volatile anesthetics may be used.Keywords:
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Departments of Anesthesiology, Surgery, and Pediatrics, Dartmouth-Hitchcock Medical Center, Hanover, New Hampshire
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Ryanodine toxicity in animals has been suggested to constitute a model of malignant hyperthermia. Dantrolene is known to block the development of malignant hyperthermia triggered by halothane in susceptible swine. The authors studied the influences of dantrolene and halothane on the effects of ryanodine in vitro in isolated rat diaphragm muscle segments, and in vivo in mice, to explore the validity of this model. In the diaphragm experiments, dantrolene was found to block or delay the development of contractures produced by ryanodine and to delay the potentiation of ryanodine-induced contractures caused by halothane. In mice, ryanodine at various dosages was injected and animals surviving after one hour were examined. Such survivors appeared grossly to be normal, and may constitute a model for the malignant hyperthermia patient. They were found to be susceptible to halothane and to succinylcholine, being killed by treatment with these two agents at dosages that were not lethal to control mice. Pretreatment of mice for 48 hours with orally administered dantrolene, followed by injection of ryanodine and then halothane anesthesia, decreased the lethality of ryanodine but did not reduce the number of deaths caused by the subsequent exposure to halothane. That the effects of ryanodine in vitro and in vivo are diminished and potentiated by dantrolene and halothane, respectively, would suggest that the ryanodine toxicity model of malignant hyperthermia may have validity and is worthy of further study. A prediction from this model is that the terminal cisternae of skeletal muscle sarcoplasmic reticulum may be altered in MH.
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The effect of dantrolene on porcine malignant hyperthermia in the Pietrain pig was studied. Five out of six pigs were successfully treated with dantrolene and the alkaline solvent was found to have no therapeutic effect.
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Malignant Hyperthermia(MH) is a hypermetabolic syndrome which is quite rare in India. Inhalational anesthetics and succinyl choline have been reported as potent triggering agents of MH. Dantrolene remains the gold standard for treating this life-threatening syndrome.
We encountered a case of malignant hyperthermia in a 34-year-old male undergoing ventricular septal defect closure under general anesthesia. We successfully managed our patient by timely recognition of this syndrome and by administering prompt, effective symptomatic treatment and without dantrolene which was not available in our hospital. JMS 2018;21(1):40-43
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Malignant hyperthermia (MH) is a clinical syndrome of skeletal muscle that presents as a hypermetabolic response to volatile anesthetic gases, where susceptible persons may develop lethally high body temperatures. Genetic predisposition mainly arises from mutations on the skeletal muscle ryanodine receptor (RyR). Dantrolene is administered to alleviate MH symptoms, but its mechanism of action and its influence on the Ca2+ transients elicited by MH triggers are unknown. Here, we show that Ca2+ release in the absence of Mg2+ is unaffected by the presence of dantrolene but that dantrolene becomes increasingly effective as cytoplasmic-free [Mg2+] (free [Mg2+]cyto) passes mM levels. Furthermore, we found in human muscle susceptible to MH that dantrolene was ineffective at reducing halothane-induced repetitive Ca2+ waves in the presence of resting levels of free [Mg2+]cyto (1 mM). However, an increase of free [Mg2+]cyto to 1.5 mM could increase the period between Ca2+ waves. These results reconcile previous contradictory reports in muscle fibers and isolated RyRs, where Mg2+ is present or absent, respectively, and define the mechanism of action of dantrolene is to increase the Mg2+ affinity of the RyR (or "stabilize" the resting state of the channel) and suggest that the accumulation of the metabolite Mg2+ from MgATP hydrolysis is required to make dantrolene administration effective in arresting an MH episode.
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