ryanodex,a new dantrolene formulation

Un nuovo farmaco contro lrsquoipertermia maligna

Claudio MelloniAnestesista Libero professionista

melloniclaudioliberoit

Dichiarazione di assenza di conflitto di interessi

bull Non viene riferito alcun conflitto di interessi

MECHANISM OF ACTION

Dantrolene

bull The only specific drug to manage MH isdantrolene sodium a specific ryanodinereceptor antagonist that inhibits the pathologically increased calcium release from the sarcoplasmic reticulum in the affectedindividualsndash Inan S Wei H The cytoprotective effects of dantrolene a ryanodine

receptor antagonist Anesth Analg 2010 111 140010

ndash Kurihara T Brooks JE Excitationcontraction uncoupling The effect of hyperosomolar glycerol solution and dantrolene sodium on mammalianmuscle in vitro Arch Neurol 1975 32 927

dantroleneCa++ flux

VGCCvoltage gated Ca++ channels

NMDArN methyl d aspartic receptors

AMPARalpha amino hydroxyl metYl idroxazole propionate

IP3Rinositol tryphosphate

RYRryanodine receptors

Mechanism of action 2bull Dantrolene inhibits ryanodine receptors (RYR) bull RYR are intracellular Ca2+ -release channels expressed on the surface of the

sarcoendoplasmic reticulumbull RYR are regulated by theCa2+ -dependent protein calmodulin (CaM) bull Three different RYR isoforms have been identified in mammalian tissues bull They have specific sites of expression all three RYRs can be found in the brain but

ndash RYR1 is found predominantly in skeletal muscle

bull RYR2 predominantly in cardiac muscle ndash RYR3 is expressed at comparatively low levels in a variety of tissues ncluding the brain

and smooth muscles cells 11

bull Dantrolene acts directly on the RYR1 and RYR3 to reduce channelactivation by CaM and thereby decreasing the Ca2+ -sensitivity of the channel activation 12

bull RYR2 is not inhibited by dantrolene This fortuitous selectivity explains why the drug has no negative inotropic effect on the heart

bull Binding of dantrolene to the RYRs in the brain may protect neurons from disruptions in Ca2+ -homeostasis Dantrolenehas recently been used in cellmodels and animal models to diminish cell death resulting froma multitude of neuronal injuries including ischemia epileptic seizures and spinal cord injury

Exogenous substances acting on RyR

Dantrolene

Procaine

Tetracaine

Ruthenium red

Caffeine

4 chlor meta cresol

RyR

DANTROLENE THERAPY IS NOTLIMITED TO MH

bull Circulation 2014 Feb 25129(8)834-6 doi 101161CIRCULATIONAHA113007657 Epub2014 Jan 8

bull Dantrolene from better bacon to a treatment for ventricular fibrillation

bull Roden DM1 Knollmann BC

Dantrolene improves survival after ventricular fibrillation by mitigating impaired calcium handling in animal models

Circulation 2014 Feb 25129(8)875-85Zamiri N Masseacute S Ramadeen A Kusha M Hu

X Azam MA Liu J Lai PF Vigmond EJ Boyle PM Behradfar E Al-Hesayen A Waxman MB Backx P Dorian P Nanthakumar K

bull Resistant ventricular fibrillation refibrillation and diminished myocardial contractility are important factorsleading to poor survival after cardiac arrest We hypothesized that dantrolene improves survival after ventricularfibrillation (VF) by rectifying the calcium dysregulation caused by VF

bull METHODS AND RESULTSbull VF was induced in 26 Yorkshire pigs for 4 minutes Cardiopulmonary resuscitation was then commenced for 3

minutes and dantrolene or isotonic saline was infused at the onset of cardiopulmonary resuscitation Animalswere defibrillated and observed for 30 minutes To study the effect of VF on calcium handling and its modulation by dantrolene hearts from 14 New Zealand rabbits were Langendorff-perfused The inducibility of VF afterdantrolene administration was documented Optical mapping was performed to evaluate diastolic spontaneouscalcium elevations as a measure of cytosolic calcium leak The sustained return of spontaneous circulation (systolicblood pressure ge60 mm Hg) was achieved in 85 of the dantrolene group in comparison with 39 of controls(P=002) return of spontaneous circulation was achieved earlier in dantrolene-treated pigs after successfuldefibrillation (21 plusmn 6 s versus 181 plusmn 57 s in controls P=0005) The median number of refibrillation episodes waslower in the dantrolene group (0 versus 1 P=004) In isolated rabbit hearts the successful induction of VF wasachieved in 83 of attempts in controls versus 41 in dantrolene-treated hearts (P=0007) VF caused diastoliccalcium leaks in the form of spontaneous calcium elevations Administration of 20 μmolL dantrolene significantlydecreased spontaneous calcium elevation amplitude versus controls (0024 plusmn 0013 versus 012 plusmn 002 arbitraryunit [200-ms cycle length] P=0001)

bull CONCLUSIONSbull Dantrolene infusion during cardiopulmonary resuscitation facilitates successful defibrillation improves

hemodynamics postdefibrillation decreases refibrillation and thus improves survival after cardiac arrest The effects are mediated through normalizing VF-induced dysfunctional calcium cycling

DANTROLENE IN OTHERHYPERTHERMIC SYNDROMES

CJEM 2010 Sep12(5)435-42Dantrolene in the treatment of MDMA-related hyperpyrexia

a systematic reviewGrunau BE1 Wiens MO Brubacher JRbull OBJECTIVE

bull The use of dantrolene in the treatment of hyperpyrexia related to MDMA (34-methylenedioxymethamphetamine) iscontroversial with little data available to guide clinical decision-making Although the treatment is recommended by severalpoison control centres published data are primarily in the form of case reports and animal and in vitro experiments Weconducted a systematic review to investigate the published evidence regarding the safety and benefits of dantrolene for MDMA-related hyperpyrexia in humans

bull DATA SOURCESbull A systematic search of Embase and MEDLINE was conducted from the earliest possible date to November 2008bull STUDY SELECTIONbull All human trials and case reports of MDMA related hyperpyrexia were consideredbull DATA EXTRACTIONbull Data were abstracted systematically and characteristics including use of dantrolene adverse reactions attributed to dantrolene peak temperature complications from MDMA-related

hyperpyrexia and survival were recordedbull DATA SYNTHESIS

bull Our search yielded 668 articles of which 53 reporting 71 cases of MDMA-induced hyperpyrexia met our inclusion criteria No

clinical trials randomized controlled trials observational studies or meta-analyses were identified Dantrolene wasused in 26 cases Patient characteristics were similar in the dantrolene and no dantrolenegroups The proportion of survivors was higher in the dantrolene group (2126) than in the no dantrolene group (2545) This difference was especially pronounced in those with extreme (ge 42degC) and severe (ge 40degC) fever with a survival rate of 8 of 13 and 10 of 10 respectively in the dantrolene groupcompared with 0 of 4 and 15 of 27 in the no dantrolene group There were no reports of adverse events attributable to dantrolene with the exception of a possible association with an episode of transient hypoglycemia

bull CONCLUSION

bull Our systematic review suggests that dantrolene is safe for patients with MDMA-related hyperpyrexia Dantrolene may alsobe associated with improved survival and reducedcomplications especially in patients with extreme (ge 42degC) or severe (ge 40degC) hyperpyrexia although this conclusion must be interpreted with caution given the risk of reporting or publication bias

Neuroleptic syndromebull Crit Care 200711(1)R4bull Managing an effective treatment for neuroleptic malignant

syndromebull Reulbach U1 Duumltsch C Biermann T Sperling W Thuerauf N

Kornhuber J Bleich Sbull Author information

bull Neuroleptic malignant syndrome (NMS) is a rare but sometimes fatal adverse reaction to neuroleptics characterized principally by fever and rigor The aim of this study was to prove the efficacy of different NMS treatment strategies focusing on the efficacy of dantrolene

bull METHODSbull Altogether 271 case reports were included These cases were categorized into four treatment groups and compared to each other according to effectiveness of therapy within 24 hours mortality

complete time of remission in days effectiveness due to increase of dosage relapse on the basis of decrease of dosage and improvement of symptomsbull RESULTSbull Between the four treatment groups the complete time of remission was significantly different (analysis of variance F = 402 degrees of freedom = 3 p = 0008) In a logistic regression with adjustment

for age gender and severity code no significant predictor of the treatment for the complete time of remission (dichotomized by median) could be found However if the premedication was a monotherapy with neuroleptics the complete time of remission was significantly shorter with dantrolene monotherapy (t = -297 p = 0004)

bull CONCLUSION

bull The treatment of NMS with drugs that are combined with dantrolene is associated with a prolongation of clinical recovery Furthermore treatment of NMS with dantrolene as monotherapy seems to be associated with a higher overall mortality Therefore dantrolene does not seem to be the evidence-based treatment of choice in cases of NMS but might be useful if premedication consisted of a neuroleptic monotherapy

bull Comment inbull Conclusions regarding the efficacy of treatments for neuroleptic malignant syndrome

should be tempered given poor quality data regardless of the analysis conducted [Crit Care 2007]

bull PMID 17222339 [PubMed - indexed for MEDLINE] PMCID PMC2151884 Free PMC Article

Dantrolenechemistry

bull Dantrolene sodium is a highly lipid soluble small moleculethat is rather water insoluble which led to the delay of the development of the intravenous (IV) formulation

bull Dantrolene was initially only available as an oralmedication

bull One vial of dantrolene IV (60ml) contains 20 mg dantrolene sodium and 3000 mg mannitol and sodiumhydroxide to yield a pH of 95 to assist with solubility

bull The resulting solution is irritating to veins and should be injected preferably via a central venous catheter or large bore peripheral IV catheter

Pharmacokinetics

bull Peak plasma time 5 hrbull Concentration 100 to gt600 ngmLbull Half-life elimination 4-8hr the plateau maximal depression of muscle twitch response

(75 depression) and grip strength (42 depression) was accomplished afteradministration of an accumulative dose of 24 mgkg body weight

bull This resulted in a dantrolene plasma concentration of 42 μgml (approximately 10μM)

bull Duration 3 hr or longerThe residual dantrolene plasma concentration at 24 hours after such a dose was 1 μgml

bull Protein Bound substantialbull Metabolism microsomally livervia oxidative and reductive pathways Oxidation to 5-hydroxy

derivative results in hydroxylation of the hydantoin ring to 5-hydroxydantrolene (5HD) whilereduction leads to the formation of aminodantrolene which is then acetylated to the reducedacetylated derivative (RAD) of dantrolene The metabolites themselves can have some musclerelaxant properties

bull Excretion Urine (25) feces (45-50) 79 excreted as 5HD 17 as RAD while 4 of the dose cleared unchanged in the urine

Anesthesiology 1988 Dec69(6)900-4Plasma levels of dantrolene following oral administration in

malignant hyperthermia-susceptible patientsAllen GC1 Cattran CB Peterson RG Lalande M

bull Reports of the lack of protection following oral dantrolene prophylaxis have led some authors to recommend only intravenous administration of dantrolene for prophylaxis against malignant hyperthermia at induction of anesthesia The authors determined whether a specific regimen of preoperative oral dantrolene would result in protective blood levels at induction of anesthesia and in the postoperative period

bull Ten malignant hyperthermia-susceptible (MHS) patients were given a total dose of 5 mgkg-1 of oral dantrolene in three or four divided doses every 6 h with the last dose 4 h preoperatively

bull Plasma dantrolene levels were determined by reverse phase high pressure liquid chromatography at induction of anesthesia and every 6 h thereafter for 48 h

bull All ten patients had plasma dantrolene levels over 28 microgramsml-1 at induction of anesthesia for at least 6 h and in three patients up to 18 h after induction

bull Every patient had an uneventful perioperative course Side effects (drowsiness weakness) occurred in seven patients

bull An elimination half-life of 158 +- 60 h was determined In contrast to intravenous dantrolene this specific oral dantrolene regimen resulted in protective plasma levels for 6-18 h after induction of anesthesia These results were likely due to the relatively high bioavailability of oral dantrolene and possibly to continued absorption of dantrolene in the postoperative period

Plasma dantrolene levels in 10 MH susceptible patients

Protracted protective levels for 12-18 h following oral adm

total dose of 5 mgkg-1 of oral dantrolene in three or four divided doses every 6 h with the last dose 4 h

preoperatively

Data from iv dantrolene

bull prophylactic plasma concentrations of dantrolene in humans are between 28 and 42 mgL and are able to depress the response of a single muscle twitch by 70ndash75

bull Peak dantrolene plasma concentrations of 42 mgL were obtained3 h after administering bolus injections of 01 mgkg until a twitchdepression plateau was reached (22- to 25-mgkg cumulative dose)

bull Plasma elimination half-life t is 10 ndash13 h in adults and 10 +- 26 h in childrenndash Flewellen EH Nelson TE Jones WP et al Dantrolene dose response in

awake man implications for management of malignanthyperthermia Anesthesiology 198359275ndash80

ndash Lerman J McLeod ME Strong HA Pharmacokinetics of intra- venousdantrolene in children Anesthesiology 198970625ndash9

Anesthesiology 1989 Apr70(4)625-9Pharmacokinetics of intravenous dantrolene in children

Lerman J1 McLeod ME Strong HAbull 10 children 2-7 yr of age scheduled for minor elective surgery were studied

bull After induction of anesthesia and tracheal intubation dantrolene (24 mgkg) was administered iv over 102 +- 083 min

bull Venous blood samples (3 ml) were obtained 1 5 10 20 and 30 min and 1 2 4 8 12 and 20 h after the dantrolene infusion

bull Whole blood concentrations of dantrolene 5-hydroxydantrolene and nitroreducedacetylated dantrolene were measured by high-performance liquid chromatography

bull The whole blood concentration of dantrolene decreased rapidly from a mean (+- SD) of 603 +- 093 microgramml 1 min after the end of the dantrolene infusion to 356 +- 049 microgramml at 1 h Between 1 and 4 h the concentration of dantrolene either remained constant or increased slightly Thereafter the concentration of dantrolene decreased slowly with an elimination half-life (mean +- SD) of 100 +- 26 h The mean (+- SD) time for the concentration of dantrolene to decrease to 30 microgramsml was 655 +- 288 h

bull The whole blood concentration of 5-hydroxydantrolene reached a maximum of 060 +- 018 microgramml approximately 7 h after the dantrolene and decreased thereafter with an elimination half-life of 90 +- 25 h

bull The concentration of nitroreduced acetylated dantrolene was below the limit for detection at all times All children recovered without complications Intravenous dantrolene 24 mgkg produces safe and predictable blood concentrations in children similar to those reported in adults


Lerman J1 McLeod ME Strong HA





Anesth Analg 2005 Dec101(6)1695-9Compartmental pharmacokinetics of dantrolene in adults do malignant

hyperthermia association dosing guidelines workPodranski T1 Bouillon T Schumacher PM Taguchi A Sessler DI Kurz A

bull Current dosing recommendations are based on noncompartmental analyses and are largely empiricbull They are also divergent as evidenced by differing recommendations from the Malignant Hyperthermia

Association of the United States (MHAUS) and European Sources bull We determined the compartmental pharmacokinetics of dantrolene simulated the concentration time

course based on currently recommended dosing and suggest an optimal regimenbull 9 volunteers (55-89 kg) received IV infusions of dantrolene (5 mgkg over 30 min followed by 005 mgkg(-1)

h(-1) for 5 h)bull Venous blood samples were drawn for up to 60 h and dantrolene plasma concentrations were determined

by reverse phase high-performance liquid chromatographybull One two and three compartmental models were fitted to the data and a covariate analysis was performed

All calculations were performed with NONMEM using the population approach bull The data were adequately described by a two-compartment model with the following typical variable values

(median +- se) volumes of distribution V1= 324 +- 061 L V2= 229 +- 153 L plasma clearance CL el= 003 +- 0003 Lmin and distributional clearance CL dist= 124 +- 022 Lmin All parameters were scaled linearly with weight

bull Simulations of European recommendations for treatment of MH lead to plasma concentrations converging to 14-18 mgL within 24 h Simulating MHAUS guidelines (intermittent bolus administration) yielded peak and trough plasma concentrations ranging from 67-226 mgL

bull Based on our findings we propose an infusion regimen adjusted to the initial bolus dose(s) required to control symptoms This strategy maintains the individualized therapeutic concentrations and improves stability of plasma concentrations

Figure 1 Measured dantrolene plasma concentrations (dots) The thin lines represent the predicted concentrations based on the individual values The

bold line depicts the concentration time course of the median patient (Inset enlargement of the first 120 min)

dantrolene (5 mgkg over 30 min followed by 005 mgkg(-1) h(-1) for 5 h)

copy 2005 International Anesthesia Research Society Published by International Anesthesia Research Society2

Table 1

Compartmental Pharmacokinetics of Dantrolene in Adults Do Malignant Hyperthermia Association Dosing Guidelines WorkPodranski Tobias Bouillon Thomas Schumacher Peter MS PhD Taguchi Akikio Sessler Daniel Kurz Andrea

Anesthesia amp Analgesia 101(6)1695-1699 December 2005DOI 10121301ANE000018418440504F3

Table 1 Pharmacokinetic Parameters for Dantrolene

Bassa estrazionebassoVdma durante crisi di MH con ampie fluttuazioni di tempGCflussomuscolareche succede alla PK e PD



Anesth Analg 2005 Dec101(6)1695-9Compartmental pharmacokinetics of dantrolene in adults do malignant hyperthermia association dosing guidelines workPodranski T1 Bouillon T Schumacher PM Taguchi A Sessler DI Kurz A



Dantrolene Plasma elimination half life

bull 103 h Anesth Analg 2005 Dec101(6)1695-9Compartmental pharmacokinetics of dantrolene in adults do

malignant hyperthermia association dosing guidelines workPodranski T1 Bouillon T Schumacher PM Taguchi A Sessler DI Kurz A

bull 12+-2

bull 10+-3 (children)

Time to first sign and dantroleneClinical

Presentation Treatment and Complications of Malignant Hyperthermia in North America from 1987 to 2006Marilyn Green LarachGerald A Gronert Gregory C Allen MD Barbara W Brandom MErik B

Lehman (Anesth Analg 2010110498 ndash507)

bull 15-60 min median 30 min

bull The likelihood of complication increased 161 times for every 30 min increase in time between Ist sign and first dantrolene dose

Dantrolene dosage

bull Initial dose24 mgkg

bull Total median dose59 mgkg

bull Vials(20 mgvial)17 median number

bull But 25 of cases requiredgt 36 vials

bull Obesity epidemics may require gt 36 vials

Anesth Analg 2014 Feb118(2)381-7 Malignant hyperthermia in Canada characteristics of index anesthetics in 129 malignant

hyperthermia susceptible probandsRiazi S1 Larach MG Hu C Wijeysundera D Massey C Kraeva N

Anesth Analg 2014 Feb118(2)381-7 Malignant hyperthermia in Canada characteristics of index anesthetics in 129

malignant hyperthermia susceptible probandsRiazi S1 Larach MG Hu C Wijeysundera D Massey C Kraeva N

Anesth Analg 2014 Feb118(2)381-7Malignant hyperthermia in Canada characteristics of index anesthetics in 129 malignant hyperthermia susceptible probandsRiazi S1 Larach MG Hu C Wijeysundera D Massey C Kraeva N

Time needed for dantrolene dilution

bull Rcommendations offered by the different scientific societies rather vague

Plan for MH treatment

bull Know the risksbull Recognize warning signsbull Stop anesthesiabull Mix dantrolenebull Get helpbull Tout teamworkbull React and reassessbull Apply cooling measuresbull Transfer

MH Task Cards

bull Malignant hyperthermia can strike at a moments notice and a timely response by your staff can mean the difference between life and death for the stricken patient To ensure your staff responds asquickly as possible give members of your MH team task cards to wear around their necks The cards are printed on colored paperand placed in clear plastic holders hung from lanyards They outlinethe essential duties of each assigned role mdash the recorder chargenurse circulator dantrolene nurse cooling nurse medication nurse anesthesia providers and additional runners mdash so they focus on what matters most when every second counts

bull Kristi Plank RN BSN Cartersville (Ga) MedicalCenter kristiplankhcahealthcarecom

Task Cards

bull The MH box contains individual task cards for MH crisis management

bull Give each available staff member a card (or two) and ask them to complete the self-explanatory instructions

bull There are multiple high priority tasks buthelliphellipDantrolene administration is the priority

bull (Assign as many staff as possible to this task)

deas That Work Cool IdeaKeep Ice Ready for MH Emergencies

CategoryOutpatient Surgery News and Trends gt Ideas and Tips

COOL IDEA Keep Ice Ready for MH EmergenciesYou know those bags of ice you have on stand-by for placing around patients in the event of a malignanthyperthermia emergency Have a staff member break them up occasionally otherwise theyll freeze intoblocks that are impossible to form to a strickenpatients anatomy

WITHIN ARMS REACHMH Kit Essentials

bull Keep a malignant hyperthermia response kit in your anesthesia workroomor in an easily accessible location It should contain

bull 36 dantrolene vialsbull mini spikes for dantrolene vialsbull sterile water IV bagsbull syringes (60ml)bull IV tubing and bag spikesbull stopcocksbull supplies for drawing bloodbull illustrated MH treatment algorithmsbull drug dosing calculation and charting formsbull Malignant Hyperthermia Association of the United States hotline (800-

644-9737)bull Note Also wheel in your crash cart during MH emergencies for accessing

medications to treat arrhythmias acidosis and electrolyte disorders

Reconstitution instructions

bull Each vial of Dantrium Intravenous should be reconstituted by adding 60 mL of sterile water for injection USP (without a bacteriostatic agent) and the vial shaken until the solution is clear 5 Dextrose Injection USP 09 Sodium ChlorideInjection USP and other acidic solutions are notcompatible with Dantrium Intravenous and should not be used The contents of the vial must be protected from direct light and used within 6 hours after reconstitution Store reconstitutedsolutions at controlled room temperature (59degF to 86degF or 15degC to 30degC)

Mixingsimulation video

bull httpwwwdartmouth-hitchcockorgwebpagecfmsite_id=2amporg_id=152ampmorg_id=0ampsec_id=0ampgsec_id=42609ampitem_id=42614

bull Fake dantroleneerythromycin or Simulateddantrolene was prepared using used empty vialsof dantrolene filled with a powder made by mixing yellow aniline dye and uncoloured jellypowder in a rate of 1 2

Mixing dantrolene can be time consuming and rapidadministration is critical

bull bull As many as 36 vials may be required in the acute treatment of a large adultbull Staff should practice mixing dantrolene with expired stockbull The attached dantrolene task card demonstrates ONE method of

reconstituting dantrolenebull Newer stocks of Dantrolene may be easier to reconstitute due to a different

freeze drying process bull Newer stocks are identified by the ldquoflip offrdquo plastic top and Dantrium

written in orange (the old stock has Dantrium written in blue)bull As many staff as possible should be assigned to mixing dantrolene (hence

three task cards) Ensure that ALL other tasks cards are assigned beforegivingout extra dantrolene cards to staffndash Vial Access NeedleThe BAXA ported ldquoTwo-fer drawing up needlerdquo has been

recommended for this purpose It is a 16G short needle with a Huber point It isavailable to order from St Ives Medical PO Box 65-069 Mairangi Bay Auckland 10 New Zealand Phone or fax +64 (9) 479-6038 Another alternative is the BBraun Micro Pin (product code MP2000)

J Clin Anesth 2006 Aug18(5)339-42Dantrolene reconstitution can warmed diluent make a differenceQuraishi SA1 Orkin FK Murray WBCan J Anaesth 2003 Feb50(2)127-30Warmed diluent speeds dantrolenereconstitutionMitchell LW1 Leighton BLAANA J 2007 Apr75(2)101-6The Icaruseffect the influence of diluent warmingon dantrolene sodium mixing timeBakerKR1 Landriscina D Kartchner H Mirkes DM

Ist trick

Warming the water

bull J Clin Anesth 2006 Aug18(5)339-42Dantrolene reconstitution can warmed diluent make a differenceQuraishi SA1 Orkin FK Murray WB

bull Can J Anaesth 2003 Feb50(2)127-30Warmed diluent speeds dantrolene reconstitutionMitchell LW1 Leighton BL

bull AANA J 2007 Apr75(2)101-6The Icarus effect the influenceof diluent warming on dantrolene sodium mixing timeBakerKR1 Landriscina D Kartchner H Mirkes DM

Time to complete dissolution 1 ampoule (LandriscinaQuraishi et al )

bull 22Co

bull 94 sec

bull 56 min

bull 41Co

bull 54 sec

bull 35 min

1 person10 mgkgpersonal exp90-130 sec for

one ampoule at room temp

Video on mixing dantrolene

bull Metapharm Canadanice flip offbut mixing with needle+ shaking

bull Mixing the Antidote For Malignant Hyperthermia ndashYouTube

wwwyoutubecomwatchv=zhtPQvhrxTI

bull 27ott2010 ndash from MHAUS video

bull Mixing the Antidote For Malignant Hyperthermia MHAUSvideo The Preparation of Dantrolene by

Links useful but open to criticism

bull httpyoutubezssXPLOfNXwvideo della MHAUS

bull httpyoutubekSOvl1IzSNYvideo AAGBI4 min for dissolving a 20 ml ampoule

bull httpyoutubeWfmvyrkWqeEvideo JHP new rapidly dissolving Dantrium

Malignant Hyperthermia (MH) Cart Suggested medication and equipment1

bull 36 ampules dantrolene sodium (ie Dantrium) bull IV (20-mg vials) bull 4 500-mL bottles sterile water (preservative free) bull 6 50-mEq syringes sodium bicarbonatebull 2 50-mL syringes 50 dextrosebull 2 4-mL vials furosemide (10 mgmL) bull 2 500-mL bottles 20 mannitolbull 2 prefilled syringes 2 lidocaine bull 6 20-mL ampules procainamide (1 g) bull 3 10-mL vials heparin (1000 units) bull 2 semiautomatic dispensing syringesbull 2 stopcocks (3-way) bull 4 60-mL syringesbull


bull Other equipment bull

bull 6 10-mL syringesbull 6 18-gauge needlesbull 6 alcohol prep padsbull 1 4-oz bottle povidone-iodine paintbull 2 10-each boxes 4 x 4 sterile gauzebull 2 tourniquets bull 2 radial artery cathetersbull 1 arterial line monitoring kit bull 1 central venous pressure line kit bull 2 sets cassette tubing for IV pumps bull 2 sets of IV tubing (pediatric and adult) bull 2 sets IV extension tubingbull 10 medication labelsbull 2 wrist splints (1 each pediatric and adult sizes) bull

bull Tubes for laboratory tests bull

bull 6 5-mL heparinized blood gas syringes or bull ABG kits bull 2 urine specimen containers bull 1 bottle urine test strips for myoglobinbull 6 light blue stoppered tubes (pediatric andbull adult sizes) bull 6 lavender stoppered tubes (pediatric andbull adult sizes) bull 10 gold stoppered tubes with gel bull 10 red stoppered tubes bull Refrigerated regular insulin bull Ice


bull Cooling equipment bull

bull 2 nasogastric tubes (pediatric and adult sizes) bull 2 30-mL balloon 3-way Foley catheters (2 each bull pediatric and adult sizes) bull 2 closed-system Foley catheter traysbull 2 peritoneal lavage traysbull 2 sets cystoscopy tubingbull 2 60-mL catheter tip syringesbull 2 5-in-1 connectorsbull 2 Y-connectorsbull 2 plastic buckets to hold ice bull 10 medium- and large-size plastic bagsbull

bull Anesthesia equipment bull (Have on cart or immediately available) bull

bull 2 breathing circuits (pediatric and adult sizes) bull 2 breathing circuit adapters bull 2 pressure bagsbull 2 soda lime canistersbull

bull Miscellaneousbull

bull 1 sharps container bull 2 Ambu bags (pediatric and adult sizes) bull 1 MH cart medicationssupplies checklist bull 1 Malignant Hyperthermia Association of bull the United States (MHAUS) label on front of bull cart listing hotline telephone number (ie [800] bull 644-9737 ask for Index Zero) bull

bull At the time cart is requested add bull Refrigerated lV normal saline solution (1000-mL bull bags) bull Refrigerated normal saline for irrigation (3000-ml bull bags)

recommended contents of an MH Box1

bull Dantrolenendash bull 24 x 20 mg vials of Dantrolene

ndash bull Sterile water for injection (2000ml)clearly labelled as unsuitable for IV infusioneg 250 ml bag from BBraun or

ndash 100ml bottles of sterile water for parenteral injections (Pfizer)

ndash bull Drawing up needles (see above)

ndash bull 60 ml syringes 5-10

ndash Include information on where to obtain additionaldantrolene

bull Drugsndash 84 sodium bicarbonate (1mmolml)

ndash 50 dextrose 50 ml

ndash Lignocaine 1

ndash Amiodarone 300mg

ndash Cold Box in fridge

ndash 2 litres normal saline for IV use

ndash Actrapid insulin


Blood tubes for haematology coagulation profile electrolytes creatinine urea creatine kinase (CK)

bull crossmatchbull blood gas syringesbull Urine sample pot for myoglobinbull Pathology forms (pre-written)bull Task Cardsbull As described in the MH Resource kit instructionsbull If space in your MH Box allowsbull (otherwise have instructions on where to find)bull Urinary catheterbull Urinary catheter and hourly urine bagbull Monitoring equipmentbull Arterial line equipmentbull Central line catheter

MHAUSMALIGNANT HYPERTHERMIAASSOCIATION OF THE UNITED STATES

Time consumingand cumbersome

AAGBI

NEW SUGGESTIONS

Dantrolene preparation

bull Bag 1000 ml water for injection without preservativesprewarmed if possible

bull Put the bag inside a pressure infuser set at 250 mmhGbull I v gravity set connected to the bag(before

pressurizing)three way stopcock terminal attachedbull Connect the syringe 60 ml to the stopcockbull Withdraw 60 ml from the pressurized bag with the three

way stopcockbull Inject the60 ml of water into the dantrolene powder

ampoule through a short 16 needle or ardquominispike ventedrdquobull Repeat for the needed 10-12 ampoules

RYANODEX

bull Ryanodex was granted priority review status by the FDA in March 2014 a regulatory review process that expedites the review of drugs that treat life threatening and serious conditions and provide a significant improvement in safetyor effectiveness over the existing therapies Ryanodex will be available to orderthrough national and regional drug wholesalers in August with product shippingshortly after For more information about Ryanodex please visit RYANODEXCOM

bull About Ryanodexbull Ryanodex (dantrolene sodium) is a novel formulation of the antidote for

management of malignant hyperthermia (MH) a potentially fatal disorderdescribed in more detail below Ryanodex is available in single-use vials containing250mg of dantrolene sodium in lyophilized powder form It is formulated for rapidreconstitution and administration in less than one minute to patients in malignanthyperthermia crisis Ryanodex should be administered by continuous rapidintravenous push beginning with a loading dose of 25 mgkg and continuing untilsymptoms subside Ryanodex is the first significant enhancement to the management of malignant hyperthermia in more than three decades and has the potential to become the new standard of care in malignant hyperthermiamanagement

RYANODEXreg (dantrolene sodium)

bull injectable suspension is a sterile lyophilizedpowder

bull RYANODEX is supplied in 20 mL vials containing250 mg dantrolene sodium and the followinginactive ingredients 125 mg mannitol 25 mg polysorbate 80 4 mg povidone K12 and sufficientsodium hydroxide or hydrochloric acid for pHadjustment When reconstituted with 5 mL sterile water for injection USP (without a bacteriostaticagent) this yields a suspension with a pH of approximately 103

Pharmacodynamics and pharmacokinetics

bull 122 Pharmacodynamicsbull The administration of intravenous dantrolene to human volunteers was associated with loss of grip strength and weakness in

the legs as well as subjective CNS complaints [see Warnings and Precautions (51)]

bull 123 Pharmacokineticsbull The pharmacokinetics of RYANODEX was investigated in healthy volunteers following single-dose administration as an

intravenous push over 60 seconds (dose range of 1 to 25 mgkg) via a peripheral catheter There was a dose-proportionalincrease in plasma exposure of dantrolene and its metabolite 5-hydroxydantrolene Table 2 presents pharmacokineticparameters of dantrolene after administration of single RYANODEX dose of 25 mgkg Time to peak dantrolene concentrationwas observed at the first time point collected (ie median Tmax is 1 minute post-dose)

bull When prophylactic intravenous dantrolene infusion was administered whole blood dantrolene concentrations remained at a near steady state level for 3 or more hours after the infusion was completed

bull Distributionbull Based on assays of whole blood and plasma slightly greater amounts of dantrolene are associated with red blood cells than

with the plasma fraction of blood Significant amounts of dantrolene are bound to plasma proteins mostly albumin and thisbinding is readily reversible Binding to plasma protein is not significantly altered by diazepam diphenylhydantoin orphenylbutazone Binding to plasma proteins is reduced by warfarin and clofibrate and increased by tolbutamide

bull Information concerning the passage of dantrolene across the blood-brain barrier is not available

bull Metabolismbull Dantrolene is found in measurable amounts in blood and urine Its major metabolites in body fluids are 5-hydroxy dantrolene

and an acetylamino metabolite of dantrolene Another metabolite with an unknown structure appears related to the latter Dantrolene may also undergo hydrolysis and subsequent oxidation forming nitrophenylfuroic acid Following RYANODEX 25 mgkg dose administration in healthy volunteers mean peak plasma concentration for the primary metabolite 5-hydroxydantrolene was 640 ngmL and was achieved by approximately 24 hours post-dose with an average metabolite-to-parent exposure ratio of 027 (AUC0-inf = 212 μghmL) Median t12 for 5-hydroxydantrolene was 10 hours the clearancewas estimated to be 89 Lhr and the terminal phase volume of distribution was 144 L

bull Dantrolene is metabolized by the liver and it is possible that its metabolism may be enhanced by drugs known to induce hepatic microsomal enzymes However neither phenobarbital nor diazepam appears to affect dantrolene metabolism

Ryanodex pharmacokinetics

The mean half-life (t12) for dantrolene was independent of the RYANODEX dose administered and ranged from 85 hours to 114 hours over the 1 to 25 mgkg dose range

Producer

bull Investors Eagle Pharmaceuticals Inc David E Riggs 201-326-5300 Chief Financial Officer driggseagleuscom or Media Ashley Moore 202-955-6222 amoorespectrumsciencecom

How many ampoules Anesth Analg 2014 Feb118(2)381-7

Malignant hyperthermia in Canada characteristics of index anesthetics in 129 malignant hyperthermia susceptible probands

Riazi S Larach MG Hu C Wijeysundera D Massey C Kraeva N

bull Our study of 229 MH episodes with documented dantrolene dosesfound a wide range with an initial median dantrolene dose of 24 mgkg and a total median dantrolene dose of 59 mgkg These dosesapproximate those recommended by the Malignant HyperthermiaAssociation of the United States(MHAUS) Our findings for initialdantrolene dose are similar to those of Kolb et al21 in their first multicenter study of dantrolene use in humans from 1977 to 1979 in which 11 MH patients received a dose of 25 05 mgkg The mediantotal vials of dantrolene required were 17 (first quartile 7 thirdquartile 36) Our data support current MHAUS recommendations for initial dantrolene treatment doses MHAUS recommendations for the availability of at least 36 dantrolene vials in anesthetizing locations were predicated on an average patient body weight of 70 kg However because 25 of our cases required 36 vialsof dantrolene and considering the current obesityepidemiclocal demographics may suggest that 36 vials be stocked where feasible and reasonable

Eur J Anaesthesiol 201128256 ndash 264Comparison of the therapeutic effectiveness of a dantrolene sodium solution and a novel nanocrystalline

suspension of dantrolene sodium in malignant hyperthermia normal and susceptible pigsJan K Schu tte Sandra Becker Sascha Burmester Alexander Starosse Daniel Lenz Lars Kro ner Frank

Wappler and Mark U Gerbershagen

bull A potential improvement has become available in the form of a novel nanocrystalline dantrolenesodium suspension (DSS) which is 150 times more concentrated (50 mg ml11130881) than the standard dantrolene sodium solution (033 mg ml11130881)

bull 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 clinicaleffectiveness of DSS with standard dantrolene sodium in a fulminant malignant hyperthermiacrisis in susceptible pigs

bull 7 malignant hyperthermia normal and 10 malignant hyperthermia susceptible pigs were studiedMalignant 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 01 and then 015 Halothane was discontinued after the administration of 02 (malignant hyperthermia normal pigs) or when a fulminant malignant hyperthermia crisis was achieved (malignant hyperthermia susceptiblepigs) After halothane was discontinued FIO2 was set to 10 respiratory minute volume was doubled and sodium bicarbonate 2 mmol kg11130881 was administered The time requirfor a child weighing approximately 24 kg dantrolene sodium(5 mg kg11130881) or DSS (5 mg kg11130881) was prepared and injected via the intravenous 22-gauge cannula

Eur J Anaesthesiol 201128256 ndash 264Comparison of the therapeutic effectiveness of a dantrolene sodium solution and a novelnanocrystalline suspension of dantrolene sodium in malignant hyperthermia normal and

susceptible pigs Jan K Schu tte Sandra Becker Sascha Burmester Alexander Starosse Daniel

Lenz Lars Kro ner Frank Wappler and Mark U Gerbershagen

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 malignanthyperthermia susceptible animals the inhaled administration of halothane 015 led to a fulminant manliganthyperthermia crisisThe 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 comparablein the two groups The time needed to prepare DSS for administration was significantly shorter (51 1113088 9 s) compared to dantrolene sodium (860 1113088 202 s) The time taken to inject DSS (4 1113088 2 s) was significantly shorter than for dantrolene sodium (472 1113088 51 s) ConclusionThe 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 clinicallysignificant advantage in the treatment of a fulminant malignant hyperthermia crisis and may result in a reduction in stress for the anaesthesia team

bull From the Department of Anaesthesiology and Intensive Care Medicine Hospital Cologne Merheim University of WittenHerdecke (JKS SB SB AS FW MUG) and University Hospital of Cologne Institute of Legal Medicine (DL LK) Cologne Germany

bull Correspondence to Jan Karl Schu tte MD Department of Anaesthesiology and Intensive Care Medicine Hospital Cologne Merheim University of Witten Herdecke Ostmerheimer Strasse 200 51109 Cologne GermanyTel +49 221 890718588 e-mail schuettejkliniken-koelnde

bull The average total preparation and administration time for DSS is55 s compared with 1332 s (gt 22 min) for dantrolene sodium

Critical times

Eur J Anaesthesiol 201128256 ndash 264

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 Jan K Schu tte Sandra Becker Sascha

Burmester Alexander Starosse Daniel Lenz Lars Kro ner Frank Wappler and Mark U Gerbershagen

Time to dantrolene dissolution

bull Old drug new drug

bull 860 plusmn 202 51plusmn9

Time to dantrolene injection


bull 472plusmn51 4plusmn2

suggestions

bull Practice response protocols

ndash Conduct mandatory annual MH drills for the entiresurgical team including anesthesia providers

ndash Use expired dantrolene or similar constitutedmaterial(see mock spain)

bull Recognize warning signs AA 2012

bull Call for help

bull Start treatment

bull Transfer for follow-up care

(Anesth Analg 2006103551ndash6)Use of Cognitive Aids in a SimulatedAnesthetic Crisis

T Kyle HarrisonTanja Manser Steven K Howard David M Gaba

bull a high-fidelity simulation of a malignant hyperthermia (MH) event facilitatedbull the correct and prompt treatment of MH We reviewed the management of 48bull simulated adult MH scenarios 24 involving CA 1 and 24 involving CA 2bull residents In the CA 1 group 19 of the 24 teams (79) used a cognitive aid butbull only 8 of the 19 teams used it frequently or extensively In the CA 2 group 18bull of the 23 teams (78) used a cognitive aid but only 6 of them used it frequentlybull or extensively The frequency of cognitive aid use correlated significantly withbull the MH treatment score for the CA 1 group (Spearman r 059 P 001) andbull CA 2 group (Spearman r 068 P 0001) The teams that performed the bestbull in treating MH used a cognitive aid extensively throughout the simulationbull Although the effect was less pronounced in the more experienced CA 2 cohortbull there was still a strong correlation between performance and cognitive aid usebull We were able to show a strong correlation between the use of a cognitive aidbull and the correct treatment of MH

The end

Dichiarazione di assenza di conflitto di interessi

bull Non viene riferito alcun conflitto di interessi

MECHANISM OF ACTION

Dantrolene




dantroleneCa++ flux















Dantrolene

Procaine

Tetracaine

Ruthenium red

Caffeine

4 chlor meta cresol

RyR





















bull CONCLUSION









bull CONCLUSION





Dantrolenechemistry





Pharmacokinetics



















preoperatively




































Table 1













bull 12+-2







Dantrolene dosage















MH Task Cards



Task Cards


























Ist trick

Warming the water





bull 22Co

bull 94 sec

bull 56 min

bull 41Co

bull 54 sec

bull 35 min





































ndash Lignocaine 1










AAGBI

NEW SUGGESTIONS







RYANODEX





















Producer




















Critical times










suggestions





bull Call for help






The end

MECHANISM OF ACTION

Dantrolene




dantroleneCa++ flux















Dantrolene

Procaine

Tetracaine

Ruthenium red

Caffeine

4 chlor meta cresol

RyR





















bull CONCLUSION









bull CONCLUSION





Dantrolenechemistry





Pharmacokinetics



















preoperatively




































Table 1













bull 12+-2







Dantrolene dosage















MH Task Cards



Task Cards


























Ist trick

Warming the water





bull 22Co

bull 94 sec

bull 56 min

bull 41Co

bull 54 sec

bull 35 min





































ndash Lignocaine 1










AAGBI

NEW SUGGESTIONS







RYANODEX





















Producer




















Critical times










suggestions





bull Call for help






The end

Dantrolene




dantroleneCa++ flux















Dantrolene

Procaine

Tetracaine

Ruthenium red

Caffeine

4 chlor meta cresol

RyR





















bull CONCLUSION









bull CONCLUSION





Dantrolenechemistry





Pharmacokinetics



















preoperatively




































Table 1













bull 12+-2







Dantrolene dosage















MH Task Cards



Task Cards


























Ist trick

Warming the water





bull 22Co

bull 94 sec

bull 56 min

bull 41Co

bull 54 sec

bull 35 min





































ndash Lignocaine 1










AAGBI

NEW SUGGESTIONS







RYANODEX





















Producer




















Critical times










suggestions





bull Call for help






The end

dantroleneCa++ flux















Dantrolene

Procaine

Tetracaine

Ruthenium red

Caffeine

4 chlor meta cresol

RyR





















bull CONCLUSION









bull CONCLUSION





Dantrolenechemistry





Pharmacokinetics



















preoperatively




































Table 1













bull 12+-2







Dantrolene dosage















MH Task Cards



Task Cards


























Ist trick

Warming the water





bull 22Co

bull 94 sec

bull 56 min

bull 41Co

bull 54 sec

bull 35 min





































ndash Lignocaine 1










AAGBI

NEW SUGGESTIONS







RYANODEX





















Producer




















Critical times










suggestions





bull Call for help






The end










Dantrolene

Procaine

Tetracaine

Ruthenium red

Caffeine

4 chlor meta cresol

RyR





















bull CONCLUSION









bull CONCLUSION





Dantrolenechemistry





Pharmacokinetics



















preoperatively




































Table 1













bull 12+-2







Dantrolene dosage















MH Task Cards



Task Cards


























Ist trick

Warming the water





bull 22Co

bull 94 sec

bull 56 min

bull 41Co

bull 54 sec

bull 35 min





































ndash Lignocaine 1










AAGBI

NEW SUGGESTIONS







RYANODEX





















Producer




















Critical times










suggestions





bull Call for help






The end





















bull CONCLUSION









bull CONCLUSION





Dantrolenechemistry





Pharmacokinetics



















preoperatively




































Table 1













bull 12+-2







Dantrolene dosage















MH Task Cards



Task Cards


























Ist trick

Warming the water





bull 22Co

bull 94 sec

bull 56 min

bull 41Co

bull 54 sec

bull 35 min





































ndash Lignocaine 1










AAGBI

NEW SUGGESTIONS







RYANODEX





















Producer




















Critical times










suggestions





bull Call for help






The end








bull CONCLUSION





Dantrolenechemistry





Pharmacokinetics



















preoperatively




































Table 1













bull 12+-2







Dantrolene dosage















MH Task Cards



Task Cards


























Ist trick

Warming the water





bull 22Co

bull 94 sec

bull 56 min

bull 41Co

bull 54 sec

bull 35 min





































ndash Lignocaine 1










AAGBI

NEW SUGGESTIONS







RYANODEX





















Producer




















Critical times










suggestions





bull Call for help






The end

Dantrolenechemistry





Pharmacokinetics



















preoperatively




































Table 1













bull 12+-2







Dantrolene dosage















MH Task Cards



Task Cards


























Ist trick

Warming the water





bull 22Co

bull 94 sec

bull 56 min

bull 41Co

bull 54 sec

bull 35 min





































ndash Lignocaine 1










AAGBI

NEW SUGGESTIONS







RYANODEX





















Producer




















Critical times










suggestions





bull Call for help






The end

Pharmacokinetics



















preoperatively




































Table 1













bull 12+-2







Dantrolene dosage















MH Task Cards



Task Cards


























Ist trick

Warming the water





bull 22Co

bull 94 sec

bull 56 min

bull 41Co

bull 54 sec

bull 35 min





































ndash Lignocaine 1










AAGBI

NEW SUGGESTIONS







RYANODEX





















Producer




















Critical times










suggestions





bull Call for help






The end












preoperatively




































Table 1













bull 12+-2







Dantrolene dosage















MH Task Cards



Task Cards


























Ist trick

Warming the water





bull 22Co

bull 94 sec

bull 56 min

bull 41Co

bull 54 sec

bull 35 min





































ndash Lignocaine 1










AAGBI

NEW SUGGESTIONS







RYANODEX





















Producer




















Critical times










suggestions





bull Call for help






The end




































Table 1













bull 12+-2







Dantrolene dosage















MH Task Cards



Task Cards


























Ist trick

Warming the water





bull 22Co

bull 94 sec

bull 56 min

bull 41Co

bull 54 sec

bull 35 min





































ndash Lignocaine 1










AAGBI

NEW SUGGESTIONS







RYANODEX





















Producer




















Critical times










suggestions





bull Call for help






The end









bull 12+-2







Dantrolene dosage















MH Task Cards



Task Cards


























Ist trick

Warming the water





bull 22Co

bull 94 sec

bull 56 min

bull 41Co

bull 54 sec

bull 35 min





































ndash Lignocaine 1










AAGBI

NEW SUGGESTIONS







RYANODEX





















Producer




















Critical times










suggestions





bull Call for help






The end






Dantrolene dosage















MH Task Cards



Task Cards


























Ist trick

Warming the water





bull 22Co

bull 94 sec

bull 56 min

bull 41Co

bull 54 sec

bull 35 min





































ndash Lignocaine 1










AAGBI

NEW SUGGESTIONS







RYANODEX





















Producer




















Critical times










suggestions





bull Call for help






The end










MH Task Cards



Task Cards


























Ist trick

Warming the water





bull 22Co

bull 94 sec

bull 56 min

bull 41Co

bull 54 sec

bull 35 min





































ndash Lignocaine 1










AAGBI

NEW SUGGESTIONS







RYANODEX





















Producer




















Critical times










suggestions





bull Call for help






The end

Task Cards


























Ist trick

Warming the water





bull 22Co

bull 94 sec

bull 56 min

bull 41Co

bull 54 sec

bull 35 min





































ndash Lignocaine 1










AAGBI

NEW SUGGESTIONS







RYANODEX





















Producer




















Critical times










suggestions





bull Call for help






The end






















Ist trick

Warming the water





bull 22Co

bull 94 sec

bull 56 min

bull 41Co

bull 54 sec

bull 35 min





































ndash Lignocaine 1










AAGBI

NEW SUGGESTIONS







RYANODEX





















Producer




















Critical times










suggestions





bull Call for help






The end

Warming the water





bull 22Co

bull 94 sec

bull 56 min

bull 41Co

bull 54 sec

bull 35 min





































ndash Lignocaine 1










AAGBI

NEW SUGGESTIONS







RYANODEX





















Producer




















Critical times










suggestions





bull Call for help






The end


bull 22Co

bull 94 sec

bull 56 min

bull 41Co

bull 54 sec

bull 35 min





































ndash Lignocaine 1










AAGBI

NEW SUGGESTIONS







RYANODEX





















Producer




















Critical times










suggestions





bull Call for help






The end



































ndash Lignocaine 1










AAGBI

NEW SUGGESTIONS







RYANODEX





















Producer




















Critical times










suggestions





bull Call for help






The end






AAGBI

NEW SUGGESTIONS







RYANODEX





















Producer




















Critical times










suggestions





bull Call for help






The end

NEW SUGGESTIONS







RYANODEX





















Producer




















Critical times










suggestions





bull Call for help






The end







RYANODEX





















Producer




















Critical times










suggestions





bull Call for help






The end


















Producer




















Critical times










suggestions





bull Call for help






The end



















Critical times










suggestions





bull Call for help






The end

suggestions





bull Call for help






The end




The end

ryanodex,a new dantrolene formulation

Health & Medicine