A new dantrolene formulation for the treatment of Malignant hyperthermia(MH).Receptors,pharmacokinetics,dosages,preparation of dantrolene,practical tips,advantages.
5. Dantrolene
• The only specific drug to manage MH is
dantrolene sodium, a specific ryanodine
receptor antagonist that inhibits the
pathologically increased calcium release from
the sarcoplasmic reticulum in the affected
individuals
– Inan S, Wei H. The cytoprotective effects of dantrolene: a ryanodine
receptor antagonist. Anesth Analg 2010; 111: 140010.
– Kurihara T, Brooks JE. Excitationcontraction uncoupling. The effect of
hyperosomolar glycerol solution and dantrolene sodium on mammalian
muscle in vitro. Arch Neurol 1975; 32: 927.
7. Mechanism of action 2
• Dantrolene inhibits ryanodine receptors (RYR)
• RYR are intracellular Ca2+ -release channels expressed on the surface of the
sarcoendoplasmic reticulum
• RYR are regulated by theCa2+ -dependent protein, calmodulin (CaM)
• Three different RYR isoforms have been identified in mammalian tissues.
• They have specific sites of expression: all three RYRs can be found in the brain, but
:
– RYR1 is found predominantly in skeletal muscle,
• RYR2 predominantly in cardiac muscle,
– RYR3 is expressed at comparatively low levels in a variety of tissues, ncluding the brain
and smooth muscles cells 11.
• Dantrolene acts directly on the RYR1 and RYR3 to reduce channel
activation by CaM, and thereby decreasing the Ca2+ -sensitivity of
the channel activation 12.
• RYR2 is not inhibited by dantrolene . This fortuitous selectivity explains why the
drug has no negative inotropic effect on the heart.
• Binding of dantrolene to the RYRs in the brain may protect neurons from
disruptions in Ca2+ -homeostasis. Dantrolenehas recently been used in cell
models and animal models to diminish cell death resulting froma multitude of
neuronal injuries, including ischemia , epileptic seizures , and spinal cord injury
8.
9. Exogenous substances acting on RyR
Dantrolene
Procaine
Tetracaine
Ruthenium red
Caffeine
RyR
4 chlor meta cresol
12. • Circulation. 2014 Feb 25;129(8):834-6. doi:
10.1161/CIRCULATIONAHA.113.007657. Epub
2014 Jan 8.
• Dantrolene: from better bacon to a
treatment for ventricular fibrillation.
• Roden DM1, Knollmann BC
13. Dantrolene improves survival after ventricular fibrillation by
mitigating impaired calcium handling in animal models.
Circulation. 2014 Feb 25;129(8):875-85.Zamiri N, Massé 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.
• Resistant ventricular fibrillation, refibrillation. and diminished myocardial contractility are important factors
leading to poor survival after cardiac arrest. We hypothesized that dantrolene improves survival after ventricular
fibrillation (VF) by rectifying the calcium dysregulation caused by VF.
• METHODS AND RESULTS:
• 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. Animals
were 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 after
dantrolene administration was documented. Optical mapping was performed to evaluate diastolic spontaneous
calcium elevations as a measure of cytosolic calcium leak. The sustained return of spontaneous circulation (systolic
blood pressure ≥60 mm Hg) was achieved in 85% of the dantrolene group in comparison with 39% of controls
(P=0.02). return of spontaneous circulation was achieved earlier in dantrolene-treated pigs after successful
defibrillation (21 ± 6 s versus 181 ± 57 s in controls, P=0.005). The median number of refibrillation episodes was
lower in the dantrolene group (0 versus 1, P=0.04). In isolated rabbit hearts, the successful induction of VF was
achieved in 83% of attempts in controls versus 41% in dantrolene-treated hearts (P=0.007). VF caused diastolic
calcium leaks in the form of spontaneous calcium elevations. Administration of 20 μmol/L dantrolene significantly
decreased spontaneous calcium elevation amplitude versus controls. (0.024 ± 0.013 versus 0.12 ± 0.02 arbitrary
unit [200-ms cycle length], P=0.001).
• CONCLUSIONS:
• 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
18. CJEM. 2010 Sep;12(5):435-42.
Dantrolene in the treatment of MDMA-related hyperpyrexia:
a systematic review.Grunau BE1, Wiens MO Brubacher JR.
• OBJECTIVE:
• The use of dantrolene in the treatment of hyperpyrexia related to MDMA (3,4-methylenedioxymethamphetamine) is
controversial, with little data available to guide clinical decision-making. Although the treatment is recommended by several
poison control centres, published data are primarily in the form of case reports and animal and in vitro experiments. We
conducted a systematic review to investigate the published evidence regarding the safety and benefits of dantrolene for MDMA-related
hyperpyrexia in humans.
• DATA SOURCES:
• A systematic search of Embase and MEDLINE was conducted from the earliest possible date to November 2008.
• STUDY SELECTION:
• All human trials and case reports of MDMA related hyperpyrexia were considered.
• DATA EXTRACTION:
• 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 recorded.
• DATA SYNTHESIS:
• 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 was
used in 26 cases. Patient characteristics were similar in the dantrolene and no dantrolene
groups. The proportion of survivors was higher in the dantrolene group (21/26) than in the no
dantrolene group (25/45). This difference was especially pronounced in those with extreme (≥
42°C) and severe (≥ 40°C) fever, with a survival rate of 8 of 13 and 10 of 10, respectively, in the dantrolene group
compared 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.
• CONCLUSION:
• Our systematic review suggests that dantrolene is safe for
patients with MDMA-related hyperpyrexia. Dantrolene may also
be associated with improved survival and reduced
complications, especially in patients with extreme (≥ 42°C) or
severe (≥ 40°C) hyperpyrexia, although this conclusion must be
interpreted with caution given the risk of reporting or
publication bias
19. Neuroleptic syndrome?
• Crit Care. 2007;11(1):R4.
• Managing an effective treatment for neuroleptic malignant
syndrome.
• Reulbach U1, Dütsch C, Biermann T, Sperling W, Thuerauf N,
Kornhuber J, Bleich S.
• Author information
• 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.
• METHODS:
• 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 symptoms.
• RESULTS:
• Between the four treatment groups, the complete time of remission was significantly different (analysis of variance, F = 4.02; degrees of freedom = 3; p = 0.008). 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 = -2.97; p = 0.004).
• CONCLUSION:
• 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.
• Comment in
• 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]
• PMID: 17222339 [PubMed - indexed for MEDLINE] PMCID: PMC2151884 Free PMC Article
20. Dantrolene;chemistry
• Dantrolene sodium is a highly lipid soluble small molecule
that is rather water insoluble, which led to the delay of
the development of the intravenous (IV) formulation.
• Dantrolene was initially only available as an oral
medication.
• One vial of dantrolene IV (60ml) contains 20 mg
dantrolene sodium and 3000 mg mannitol and sodium
hydroxide to yield a pH of 9.5, to assist with solubility.
• The resulting solution is irritating to veins, and should be
injected preferably via a central venous catheter or large
bore peripheral IV catheter.
21. Pharmacokinetics
• Peak plasma time: 5 hr
• Concentration: 100 to >600 ng/mL
• Half-life elimination: 4-8hr the plateau maximal depression of muscle twitch response
(75% depression) and grip strength (42% depression) was accomplished after
administration of an accumulative dose of 2.4 mg/kg body weight.
• This resulted in a dantrolene plasma concentration of 4.2 μg/ml (approximately 10μM).
• Duration: 3 hr or longer:The residual dantrolene plasma concentration at 24
hours after such a dose was 1 μg/ml.
• Protein Bound: substantial
• Metabolism: microsomally ,liver,via oxidative and reductive pathways. Oxidation to 5-hydroxy
derivative results in hydroxylation of the hydantoin ring to 5-hydroxydantrolene (5HD), while
reduction leads to the formation of aminodantrolene, which is then acetylated to the reduced
acetylated derivative (RAD) of dantrolene The metabolites themselves can have some muscle
relaxant properties
• Excretion: Urine (25%); feces (45-50%) :79% excreted as 5HD, 17% as RAD, while 4% of the dose
cleared unchanged in the urine
22. Anesthesiology. 1988 Dec;69(6):900-4.
Plasma levels of dantrolene following oral administration in
malignant hyperthermia-susceptible patients.
Allen GC1, Cattran CB, Peterson RG, Lalande M.
• 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.
• Ten malignant hyperthermia-susceptible (MHS) patients were given a total
dose of 5 mg.kg-1 of oral dantrolene in three or four divided doses, every 6
h, with the last dose 4 h preoperatively.
• Plasma dantrolene levels were determined by reverse phase high pressure
liquid chromatography at induction of anesthesia and every 6 h thereafter
for 48 h.
• All ten patients had plasma dantrolene levels over 2.8 micrograms.ml-1 at
induction of anesthesia, for at least 6 h and, in three patients, up to 18 h
after induction.
• Every patient had an uneventful perioperative course. Side effects
(drowsiness, weakness) occurred in seven patients.
• An elimination half-life of 15.8 +/- 6.0 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.
23. Plasma dantrolene levels in 10 MH
susceptible patients
Protracted protective levels for 12-18 h following oral adm.
24. total dose of 5 mg.kg-1 of oral dantrolene in three or four
divided doses, every 6 h, with the last dose 4 h
preoperatively
25. Data from iv dantrolene
• prophylactic plasma concentrations of dantrolene in humans are
between 2.8 and 4.2 mg/L and are able to depress the response of
a single muscle twitch by 70%–75%.
• Peak dantrolene plasma concentrations of 4.2 mg/L were obtained
3 h after administering bolus injections of 0.1 mg/kg until a twitch
depression plateau was reached (2.2- to 2.5-mg/kg cumulative
dose).
• Plasma elimination half-life t is 10 –13 h in adults and 10 +/- 2.6 h
in children
– Flewellen EH, Nelson TE, Jones WP, et al. Dantrolene dose response in
awake man: implications for management of malig- nant
hyperthermia. Anesthesiology 1983;59:275–80.
– Lerman J, McLeod ME, Strong HA. Pharmacokinetics of intra- venous
dantrolene in children. Anesthesiology 1989;70:625–9.
26. Anesthesiology. 1989 Apr;70(4):625-9.
Pharmacokinetics of intravenous dantrolene in children.
Lerman J1, McLeod ME, Strong HA.
• 10 children 2-7 yr of age scheduled for minor elective surgery, were studied.
• After induction of anesthesia and tracheal intubation, dantrolene (2.4 mg/kg) was
administered iv over 10.2 +/- 0.83 min.
• 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.
• Whole blood concentrations of dantrolene, 5-hydroxydantrolene, and nitroreduced
acetylated dantrolene were measured by high-performance liquid chromatography.
• The whole blood concentration of dantrolene decreased rapidly from a mean (+/- SD) of
6.03 +/- 0.93 microgram/ml 1 min after the end of the dantrolene infusion to 3.56 +/- 0.49
microgram/ml 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 10.0 +/- 2.6 h. The mean (+/- SD) time for the
concentration of dantrolene to decrease to 3.0 micrograms/ml was 6.55 +/- 2.88 h.
• The whole blood concentration of 5-hydroxydantrolene reached a maximum of 0.60 +/- 0.18
microgram/ml approximately 7 h after the dantrolene and decreased thereafter with an
elimination half-life of 9.0 +/- 2.5 h.
• The concentration of nitroreduced acetylated dantrolene was below the limit for detection
at all times. All children recovered without complications. Intravenous dantrolene, 2.4
mg/kg, produces safe and predictable blood concentrations in children similar to those
reported in adults
30. Anesth Analg. 2005 Dec;101(6):1695-9.
Compartmental pharmacokinetics of dantrolene in adults: do malignant
hyperthermia association dosing guidelines work?
Podranski T1, Bouillon T, Schumacher PM, Taguchi A, Sessler DI, Kurz A.
• Current dosing recommendations are based on noncompartmental analyses and are largely empiric.
• They are also divergent, as evidenced by differing recommendations from the Malignant Hyperthermia
Association of the United States (MHAUS) and European Sources.
• We determined the compartmental pharmacokinetics of dantrolene, simulated the concentration time
course based on currently recommended dosing, and suggest an optimal regimen.
• 9 volunteers (55-89 kg) received IV infusions of dantrolene (5 mg/kg over 30 min followed by 0.05 mg.kg(-1) .
h(-1) for 5 h).
• Venous blood samples were drawn for up to 60 h, and dantrolene plasma concentrations were determined
by reverse phase, high-performance liquid chromatography.
• 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.
• The data were adequately described by a two-compartment model with the following typical variable values
(median +/- se): volumes of distribution V1= 3.24 +/- 0.61 L; V2= 22.9 +/- 1.53 L; plasma clearance CL el= 0.03
+/- 0.003 L/min; and distributional clearance CL dist= 1.24 +/- 0.22 L/min. All parameters were scaled linearly
with weight.
• Simulations of European recommendations for treatment of MH lead to plasma concentrations converging
to 14-18 mg/L within 24 h. Simulating MHAUS guidelines (intermittent bolus administration) yielded peak
and trough plasma concentrations ranging from 6.7-22.6 mg/L.
• 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
31. 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
mg/kg over 30
min followed
by 0.05
mg.kg(-1) . h(-
1) for 5 h).
33. Anesth Analg. 2005 Dec;101(6):1695-9.
Compartmental pharmacokinetics of dantrolene in adults: do malignant
hyperthermia association dosing guidelines work?
Podranski T1, Bouillon T, Schumacher PM, Taguchi A, Sessler DI, Kurz A.
34. Anesth Analg. 2005
Dec;101(6):1695-9.
Compartmental
pharmacokinetics of
dantrolene in
adults: do
malignant
hyperthermia
association dosing
guidelines work?
Podranski T1,
Bouillon T,
Schumacher PM,
Taguchi A, Sessler
DI, Kurz A.
35. Anesth Analg. 2005 Dec;101(6):1695-9.
Compartmental pharmacokinetics of dantrolene in adults: do malignant
hyperthermia association dosing guidelines work?
Podranski T1, Bouillon T, Schumacher PM, Taguchi A, Sessler DI, Kurz A.
36. Dantrolene Plasma elimination half life
• 10.3 h Anesth Analg. 2005 Dec;101(6):1695-9.Compartmental pharmacokinetics of dantrolene in adults: do
malignant hyperthermia association dosing guidelines workPodranski T1, Bouillon T, Schumacher PM, Taguchi A, Sessler DI,
Kurz A.
• 12+-2
• 10+-3 (children)
37. Time to first sign and dantrolene:Clinical
Presentation, Treatment, and Complications of Malignant Hyperthermia in North America from 1987
to 2006.Marilyn Green Larach,Gerald A. Gronert, Gregory C. Allen, MD, Barbara W. Brandom, MErik B.
Lehman. (Anesth Analg 2010;110:498 –507)
• 15-60 min ;median 30 min
• The likelihood of complication increased 1.61
times for every 30 min increase in time
between I.st sign and first dantrolene dose.
38. Dantrolene dosage
• Initial dose:2.4 mg/kg
• Total median dose:5.9 mg/kg
• Vials(20 mg/vial):17 median number
• But 25% of cases required> 36 vials
• Obesity epidemics may require > 36 vials
39. Anesth Analg. 2014 Feb;118(2):381-7.
Malignant hyperthermia in Canada: characteristics of index anesthetics in 129 malignant
hyperthermia susceptible probands.
Riazi S1, Larach MG, Hu C, Wijeysundera D, Massey C, Kraeva N.
40. Anesth Analg. 2014 Feb;118(2):381-7.
Malignant hyperthermia in Canada: characteristics of index anesthetics in 129
malignant hyperthermia susceptible probands.
Riazi S1, Larach MG, Hu C, Wijeysundera D, Massey C, Kraeva N.
41. Anesth Analg. 2014 Feb;118(2):381-7.
Malignant hyperthermia in Canada: characteristics of index
anesthetics in 129 malignant hyperthermia susceptible
probands.Riazi S1, Larach MG, Hu C, Wijeysundera D, Massey C,
Kraeva N.
42. Time needed for dantrolene dilution
• Rcommendations offered by the different
scientific societies rather vague ......
43. Plan for MH treatment
• Know the risks
• Recognize warning signs
• Stop anesthesia
• Mix dantrolene
• Get help
• Tout teamwork
• React and reassess
• Apply cooling measures
• Transfer
44. MH Task Cards
• Malignant hyperthermia can strike at a moment's 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 as
quickly as possible, give members of your MH team task cards to
wear around their necks. The cards are printed on colored paper
and placed in clear plastic holders hung from lanyards. They outline
the essential duties of each assigned role — the recorder, charge
nurse, circulator, dantrolene nurse, cooling nurse, medication nurse,
anesthesia providers and additional runners — so they focus on
what matters most when every second counts.
• Kristi Plank, RN, BSN Cartersville (Ga.) Medical
Center kristi.plank@hcahealthcare.com
45.
46. Task Cards
• The MH box contains individual task cards for
MH crisis management:
• Give each available staff member a card (or
two) and ask them to complete the self-explanatory
instructions.
• There are multiple high priority tasks, but
……Dantrolene administration is the priority.
• (Assign as many staff as possible to this task)
47.
48. deas That Work: Cool Idea
Keep Ice Ready for MH Emergencies
Category:
Outpatient Surgery News and Trends > Ideas and Tips
COOL IDEA Keep Ice Ready for MH Emergencies
You know those bags of ice you have on stand-by for
placing around patients in the event of a malignant
hyperthermia emergency? Have a staff member break
them up occasionally, otherwise they'll freeze into
blocks that are impossible to form to a stricken
patient's anatomy.
49. WITHIN ARM'S REACH
MH Kit Essentials
• Keep a malignant hyperthermia response kit in your anesthesia workroom
or in an easily accessible location. It should contain:
• 36 dantrolene vials
• mini spikes for dantrolene vials
• sterile water IV bags
• syringes (60ml)
• IV tubing and bag spikes
• stopcocks
• supplies for drawing blood
• illustrated MH treatment algorithms
• drug dosing calculation and charting forms
• Malignant Hyperthermia Association of the United States' hotline (800-
644-9737)
• Note: Also wheel in your crash cart during MH emergencies for accessing
medications to treat arrhythmias, acidosis and electrolyte disorders.
50. Reconstitution instructions
• 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, 0.9% Sodium Chloride
Injection USP, and other acidic solutions are not
compatible 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 reconstituted
solutions at controlled room temperature (59°F
to 86°F or 15°C to 30°C).
51.
52. Mixing;simulation video
• http://www.dartmouth-hitchcock.
org/webpage.cfm?site_id=2&org_id=1
52&morg_id=0&sec_id=0&gsec_id=42609&item_
id=42614
• Fake dantrolene;erythromycin or .......Simulated
dantrolene was prepared using used empty vials
of dantrolene, filled with a powder made by
mixing yellow aniline dye and uncoloured jelly
powder in a rate of 1 : 2
53. Mixing dantrolene can be time consuming and rapid
administration is critical
• .
• As many as 36 vials may be required in the acute treatment of a large adult.
• Staff should practice mixing dantrolene with expired stock.
• The attached dantrolene task card demonstrates ONE method of
reconstituting dantrolene.
• Newer stocks of Dantrolene may be easier to reconstitute due to a different
freeze drying process.
• Newer stocks are identified by the “flip off” plastic top and Dantrium
written in orange (the old stock has Dantrium written in blue).
• As many staff as possible should be assigned to mixing dantrolene (hence
three task cards). Ensure that ALL other tasks cards are assigned before
givingout extra dantrolene cards to staff.
– Vial Access Needle:The BAXA ported “Two-fer drawing up needle” has been
recommended for this purpose. It is a 16G short needle with a Huber point. It is
available 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
B.Braun Micro Pin (product code MP2000).
54.
55.
56.
57. J Clin Anesth. 2006 Aug;18(5):339-
42.Dantrolene reconstitution: can warmed
diluent make a difference?Quraishi SA1,
Orkin FK, Murray WB.
Can J Anaesth. 2003 Feb;50(2):127-
30.Warmed diluent speeds dantrolene
reconstitution.Mitchell LW1, Leighton BL.
AANA J. 2007 Apr;75(2):101-6.The Icarus
effect: the influence of diluent warming
on dantrolene sodium mixing time.Baker
KR1, Landriscina D, Kartchner H, Mirkes DM
Ist trick !!!
58. Warming the water
• J Clin Anesth. 2006 Aug;18(5):339-42.Dantrolene
reconstitution: can warmed diluent make a
difference?Quraishi SA1, Orkin FK, Murray WB.
• Can J Anaesth. 2003 Feb;50(2):127-30.Warmed diluent
speeds dantrolene reconstitution.Mitchell LW1, Leighton BL.
• AANA J. 2007 Apr;75(2):101-6.The Icarus effect: the influence
of diluent warming on dantrolene sodium mixing time.Baker
KR1, Landriscina D, Kartchner H, Mirkes DM
59. Time to complete dissolution: 1
ampoule (Landriscina,Quraishi et al )
• 22Co
• 94 sec
• 56 min
• 41Co
• 54 sec
• 35 min
1 person,10 mg/kg..
:personal exp:90-130 sec for
one ampoule at room temp
60. Video on mixing dantrolene
• Metapharm Canada;nice flip off,but mixing with needle
+ shaking!
• Mixing the Antidote For Malignant Hyperthermia –
YouTube
www.youtube.com/watch?v=zhtPQvhrxTI
• 27/ott/2010 – from MHAUS video
• Mixing the Antidote For Malignant Hyperthermia.
MHAUSvideo .... The Preparation of Dantrolene by
61. Links useful ....but open to criticism....
• http://youtu.be/zssXPLOfNXw;video della
MHAUS
• http://youtu.be/kSOvl1IzSNY;video AAGBI;4
min for dissolving a 20 ml ampoule.!!!!!
• http://youtu.be/WfmvyrkWqeE;video JHP
:new rapidly dissolving Dantrium
64. Malignant Hyperthermia (MH) Cart
Suggested medication and equipment:2
• Other equipment
•
• 6 10-mL syringes
• 6 18-gauge needles
• 6 alcohol prep pads
• 1 4-oz bottle povidone-iodine paint
• 2 10-each boxes 4 x 4 sterile gauze
• 2 tourniquets
• 2 radial artery catheters
• 1 arterial line monitoring kit
• 1 central venous pressure line kit
• 2 sets cassette tubing for IV pumps
• 2 sets of IV tubing (pediatric and adult)
• 2 sets IV extension tubing
• 10 medication labels
• 2 wrist splints (1 each, pediatric and adult sizes)
•
• Tubes for laboratory tests
•
• 6 5-mL heparinized blood gas syringes or
• ABG kits
• 2 urine specimen containers
• 1 bottle urine test strips for myoglobin
• 6 light blue stoppered tubes (pediatric and
• adult sizes)
• 6 lavender stoppered tubes (pediatric and
• adult sizes)
• 10 gold stoppered tubes with gel
• 10 red stoppered tubes
• Refrigerated regular insulin
• Ice
65. Malignant Hyperthermia (MH) Cart
Suggested medication and equipment:3
• Cooling equipment
•
• 2 nasogastric tubes (pediatric and adult sizes)
• 2 30-mL balloon, 3-way Foley catheters (2 each,
• pediatric and adult sizes)
• 2 closed-system Foley catheter trays
• 2 peritoneal lavage trays
• 2 sets cystoscopy tubing
• 2 60-mL catheter tip syringes
• 2 5-in-1 connectors
• 2 Y-connectors
• 2 plastic buckets to hold ice
• 10 medium- and large-size plastic bags
•
• Anesthesia equipment
• (Have on cart or immediately available)
•
• 2 breathing circuits (pediatric and adult sizes)
• 2 breathing circuit adapters
• 2 pressure bags
• 2 soda lime canisters
•
• Miscellaneous
•
• 1 sharps container
• 2 Ambu bags (pediatric and adult sizes)
• 1 MH cart medications/supplies checklist
• 1 Malignant Hyperthermia Association of
• the United States (MHAUS) label on front of
• cart listing hotline telephone number (ie, [800]
• 644-9737; ask for Index Zero)
•
• At the time cart is requested, add:
• Refrigerated lV normal saline solution (1,000-mL
• bags)
• Refrigerated normal saline for irrigation (3,000-ml
• bags)
66. recommended contents of an MH Box:1
• Dantrolene
– • 24 x 20 mg vials of Dantrolene
– • Sterile water for injection (2000ml)clearly labelled as unsuitable for IV infusioneg 250 ml bag from
B/Braun or
– 100ml bottles of sterile water for parenteral injections (Pfizer)
– • Drawing up needles (see above)
– • 60 ml syringes 5-10
– Include information on where to obtain additionaldantrolene
• Drugs
– 8.4% sodium bicarbonate (1mmol/ml)
– 50% dextrose 50 ml
– Lignocaine 1%
– Amiodarone 300mg
– Cold Box in fridge
– 2 litres normal saline for IV use
– Actrapid insulin
67. recommended contents of an MH Box:2
Blood tubes for haematology, coagulation profile electrolytes, creatinine, urea,
creatine kinase (CK)
• crossmatch
• blood gas syringes
• Urine sample pot for myoglobin
• Pathology forms (pre-written)
• Task Cards
• As described in the MH Resource kit instructions
• If space in your MH Box allows:
• (otherwise, have instructions on where to find)
• Urinary catheter
• Urinary catheter and hourly urine bag
• Monitoring equipment
• Arterial line equipment
• Central line catheter
116. Dantrolene preparation
• Bag 1000 ml water for injection without preservatives
,prewarmed if possible
• Put the bag inside a pressure infuser set at 250 mmhG
• I v gravity set connected to the bag(before
pressurizing);three way stopcock terminal attached
• Connect the syringe 60 ml to the stopcock
• Withdraw 60 ml from the pressurized bag with the three
way stopcock
• Inject the60 ml of water into the dantrolene powder
ampoule through a short 16 needle or a”minispike vented”
• Repeat for the needed 10-12 ampoules
117.
118.
119.
120. RYANODEX
• 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 safety
or effectiveness over the existing therapies. Ryanodex will be available to order
through national and regional drug wholesalers in August with product shipping
shortly after. For more information about Ryanodex, please visit RYANODEX.COM.
• About Ryanodex
• Ryanodex (dantrolene sodium) is a novel formulation of the antidote for
management of malignant hyperthermia (MH), a potentially fatal disorder
described in more detail below. Ryanodex is available in single-use vials containing
250mg of dantrolene sodium in lyophilized powder form. It is formulated for rapid
reconstitution and administration in less than one minute to patients in malignant
hyperthermia crisis. Ryanodex should be administered by continuous rapid
intravenous push beginning with a loading dose of 2.5 mg/kg, and continuing until
symptoms 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 hyperthermia
management.
121.
122. RYANODEX® (dantrolene sodium)
• injectable suspension is a sterile lyophilized
powder.
• RYANODEX is supplied in 20 mL vials containing
250 mg dantrolene sodium and the following
inactive ingredients: 125 mg mannitol, 25 mg
polysorbate 80, 4 mg povidone K12 and sufficient
sodium hydroxide or hydrochloric acid for pH
adjustment. When reconstituted with 5 mL sterile
water for injection USP (without a bacteriostatic
agent), this yields a suspension with a pH of
approximately 10.3.
123. Pharmacodynamics and
pharmacokinetics
• 12.2 Pharmacodynamics
• 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 (5.1)].
• 12.3 Pharmacokinetics
• 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 2.5 mg/kg), via a peripheral catheter. There was a dose-proportional
increase in plasma exposure of dantrolene and its metabolite, 5-hydroxydantrolene. Table 2 presents pharmacokinetic
parameters of dantrolene after administration of single RYANODEX dose of 2.5 mg/kg. Time to peak dantrolene concentration
was observed at the first time point collected (i.e. median Tmax is 1 minute post-dose).
• 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.
• Distribution
• 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 this
binding is readily reversible. Binding to plasma protein is not significantly altered by diazepam, diphenylhydantoin, or
phenylbutazone. Binding to plasma proteins is reduced by warfarin and clofibrate and increased by tolbutamide.
• Information concerning the passage of dantrolene across the blood-brain barrier is not available.
• Metabolism
• 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 2.5
mg/kg dose administration in healthy volunteers, mean peak plasma concentration for the primary metabolite, 5-
hydroxydantrolene, was 640 ng/mL, and was achieved by approximately 24 hours post-dose, with an average metabolite-to-parent
exposure ratio of 0.27 (AUC0-inf = 21.2 μg*h/mL). Median t1/2 for 5-hydroxydantrolene was 10 hours, the clearance
was estimated to be 8.9 L/hr and the terminal phase volume of distribution was 144 L.
• 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.
124. Ryanodex pharmacokinetics
The mean half-life (t1/2) for dantrolene was independent of the RYANODEX dose
administered and ranged from 8.5 hours to 11.4 hours over the 1 to 2.5 mg/kg dose
range.
125. Producer
• Investors: Eagle Pharmaceuticals, Inc. David
E. Riggs, 201-326-5300 Chief Financial
Officer driggs@eagleus.com or Media: Ashl
ey Moore, 202-955-
6222 amoore@spectrumscience.com
126. How many ampoules ? Anesth Analg. 2014 Feb;118(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.
• Our study of 229 MH episodes with documented dantrolene doses
found a wide range with an initial median dantrolene dose of 2.4
mg/kg and a total median dantrolene dose of 5.9 mg/kg. These doses
approximate those recommended by the Malignant Hyperthermia
Association of the United States(MHAUS). Our findings for initial
dantrolene dose are similar to those of Kolb et al.21 in their first
multicenter study of dantrolene use in humans from 1977 to 1979, in
which 11 MH patients received a dose of 2.5 0.5 mg/kg. The median
total vials of dantrolene required were 17 (first quartile 7, third
quartile 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 vials
of dantrolene and considering the current obesity
epidemic,local demographics may suggest that 36
vials be stocked where feasible and reasonable.
127. Eur J Anaesthesiol 2011;28:256 – 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. Schütte, Sandra Becker, Sascha Burmester, Alexander Starosse, Daniel Lenz, Lars Kröner, Frank
Wappler and Mark U. Gerbershagen
• 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 mlﰀ1) than the standard
dantrolene sodium solution (0.33 mg mlﰀ1).
• 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.
• 7 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 kgﰀ1 was administered.
The time requirfor a child weighing approximately 24 kg, dantrolene sodium
(5 mg kgﰀ1) or DSS (5 mg kgﰀ1) was prepared and injected via the intravenous 22-gauge cannula
.
128. Eur J Anaesthesiol 2011;28:256 – 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. Schütte, Sandra Becker, Sascha Burmester, Alexander Starosse, Daniel
Lenz, Lars Kröner, 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 malignant
hyperthermia susceptible animals, the inhaled administration of halothane 0.15% led to a fulminant manligant
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 ﰀ 9 s) compared to dantrolene sodium (860
ﰀ 202 s). The time taken to inject DSS (4 ﰀ 2 s) was significantly shorter than for dantrolene sodium (472 ﰀ 51 s). Conclusion
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.
• From the Department of Anaesthesiology and Intensive Care Medicine, Hospital Cologne Merheim, University of
Witten/Herdecke (JKS, SB, SB, AS, FW, MUG) and University Hospital of Cologne, Institute of Legal Medicine (DL, LK),
Cologne, Germany
• Correspondence to Jan Karl Schütte, MD, Department of Anaesthesiology and Intensive Care Medicine, Hospital
Cologne Merheim, University of Witten/ Herdecke, Ostmerheimer Strasse 200, 51109 Cologne, Germany
Tel: +49 221 890718588; e-mail: schuettej@kliniken-koeln.de
• The average total preparation and administration time for DSS is
55 s compared with 1332 s (> 22 min) for dantrolene sodium
129.
130. Critical times
Eur J Anaesthesiol 2011;28:256 – 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
• Old drug new drug
• 860 ± 202 51±9
Time to dantrolene injection
• Old drug new drug
• 472±51 4±2
131. suggestions
• Practice response protocols.
– Conduct mandatory annual MH drills for the entire
surgical team, including anesthesia providers.
– Use expired dantrolene or similar constituted
material(see mock spain...)
• Recognize warning signs. AA 2012
• Call for help
• Start treatment
• Transfer for follow-up care
132. (Anesth Analg 2006;103:551–6).Use of Cognitive Aids in a Simulated
Anesthetic Crisis
T. Kyle Harrison,Tanja Manser, Steven K. Howard, David M. Gaba.
• a high-fidelity simulation of a malignant hyperthermia (MH) event facilitated
• the correct and prompt treatment of MH. We reviewed the management of 48
• simulated adult MH scenarios; 24 involving CA 1 and 24 involving CA 2
• residents. In the CA 1 group, 19 of the 24 teams (79%) used a cognitive aid, but
• only 8 of the 19 teams used it frequently or extensively. In the CA 2 group, 18
• of the 23 teams (78%) used a cognitive aid but only 6 of them used it frequently
• or extensively. The frequency of cognitive aid use correlated significantly with
• the MH treatment score for the CA 1 group (Spearman r 0.59, P 0.01) and
• CA 2 group (Spearman r 0.68, P 0.001). The teams that performed the best
• in treating MH used a cognitive aid extensively throughout the simulation.
• Although the effect was less pronounced in the more experienced CA 2 cohort,
• there was still a strong correlation between performance and cognitive aid use.
• We were able to show a strong correlation between the use of a cognitive aid
• and the correct treatment of MH
