title: Comparison of the therapeutic effectiveness of a dantrolene sodium solution and a novel nanocrystalline suspension of dantrolene sodium in malignant hyperthermia normal and susceptible pigs.
abstract: OBJECTIVE
  Stopping trigger agents and prompt administration of dantrolene are the cornerstones of treatment of malignant hyperthermia. However, significant time is lost in treatment of the condition because of the cumbersome preparation and administration of the commercially available dantrolene sodium for injection. A potential improvement has become available in the form of a novel nanocrystalline dantrolene sodium suspension (DSS), which is 150 times more concentrated (50 mg ml(-1)) than the standard dantrolene sodium solution (0.33 mg ml(-1)). The aims of this study were to measure the effects of DSS on clinical and laboratory variables in malignant hyperthermia normal pigs and to compare the therapeutic management and clinical effectiveness of DSS with standard dantrolene sodium in a fulminant malignant hyperthermia crisis in susceptible pigs. The pig model is a well accepted method of studying the malignant hyperthermia crisis and is an ideal way to evaluate the variables of interest in this study.
  
  
  METHODS
  Seven malignant hyperthermia normal and 10 malignant hyperthermia susceptible pigs were studied. Malignant hyperthermia susceptible pigs (body weight approximately 24 kg) were allocated to a dantrolene sodium group or a DSS group. After induction of anaesthesia, a 22-gauge catheter was placed in an ear vein and trigger-free anaesthesia was performed. After achieving stable conditions, administration of halothane was started with 0.1% and then 0.15%. Halothane was discontinued after the administration of 0.2% (malignant hyperthermia normal pigs) or when a fulminant malignant hyperthermia crisis was achieved (malignant hyperthermia susceptible pigs). After halothane was discontinued, FIO2 was set to 1.0, respiratory minute volume was doubled and sodium bicarbonate 2 mmol kg(-1) was administered. The time required to prepare and administer each formulation was measured. To simulate the administration of the substances under typical clinical conditions for a child weighing approximately 24 kg, dantrolene sodium (5 mg kg(-1)) or DSS (5 mg kg(-1)) was prepared and injected via the intravenous 22-gauge cannula. Bolus administrations of dantrolene sodium or DSS were repeated after 24 min.
  
  
  RESULTS
  Arterial pH, arterial pCO2, mean arterial pressure and arterial lactate concentration remained stable during the experiment with DSS in malignant hyperthermia normal pigs. A significant decrease in cardiac index and increases in systemic vascular resistance and serum potassium concentration occurred after administration of DSS. In all malignant hyperthermia susceptible animals, the inhaled administration of halothane 0.15% led to a fulminant malignant hyperthermia crisis. The therapeutic regimens with administration of dantrolene sodium or DSS were successful in treating the malignant hyperthermia crisis in all animals. The course of the malignant hyperthermia crisis and the therapeutic effects of dantrolene sodium or DSS were comparable in the two groups. The time needed to prepare DSS for administration was significantly shorter (51 ± 9 s) compared to dantrolene sodium (860 ± 202 s). The time taken to inject DSS (4 ± 2 s) was significantly shorter than for dantrolene sodium (472 ± 51 s).
  
  
  CONCLUSIONS
  The therapeutic action of DSS in a malignant hyperthermia crisis in pigs was effective and comparable to that of standard dantrolene sodium. However, preparation and administration of DSS were significantly faster, which may offer a clinically significant advantage in the treatment of a fulminant malignant hyperthermia crisis and may result in a reduction in stress for the anaesthesia team.
authors.affiliation: Department of Anaesthesiology and Intensive Care Medicine, Hospital Cologne Merheim, University of Witten/Herdecke, Cologne, Germany. schuettej@kliniken-koeln.de
authors.forename: Jan K
authors.initials: JK
authors.lastname: Schütte
authors.forename: Sandra
authors.initials: S
authors.lastname: Becker
authors.forename: Sascha
authors.initials: S
authors.lastname: Burmester
authors.forename: Alexander
authors.initials: A
authors.lastname: Starosse
authors.forename: Daniel
authors.initials: D
authors.lastname: Lenz
authors.forename: Lars
authors.initials: L
authors.lastname: Kröner
authors.forename: Frank
authors.initials: F
authors.lastname: Wappler
authors.forename: Mark U
authors.initials: MU
authors.lastname: Gerbershagen
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood; D002626:Chemistry, Pharmaceutical; D003620:Dantrolene / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D004195:Disease Models, Animal; D006221:Halothane; D006439:Hemodynamics / Q000187:drug effects; D007275:Injections, Intravenous; D019344:Lactic Acid / Q000097:blood; D008305:Malignant Hyperthermia / Q000097:blood / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D009119:Muscle Contraction / Q000187:drug effects*; D009125:Muscle Relaxants, Central / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000503:physiopathology; D053758:Nanoparticles; D019999:Pharmaceutical Solutions; D011188:Potassium / Q000378:metabolism; D013552:Swine; D013997:Time Factors
chemical_list: D015415:Biomarkers; D009125:Muscle Relaxants, Central; D019999:Pharmaceutical Solutions; D019344:Lactic Acid; D003620:Dantrolene; D011188:Potassium; D006221:Halothane