Products / Dantrium IV / Dantrolen IV
MH is a rare but life-threatening muscle condition in which sustained muscle contractions and high temperatures of up to 43°C or more may occur in response to certain inhaled anaesthetics and skeletal muscle relaxants. MH susceptibility in patients is inherited and one which doctors and nurses can be unfamiliar with.
When malignant hyperthermia was first identified in 1962, there was a high mortality rate of nearly 80 percent. Treatment consisted of cooling the patient and treating each specific symptom, rather than the underlying cause.
Dantrium IV / Dantrolen IV (dantrolene sodium) has been available since 1979 and was the first specific drug therapy available for the treatment of MH, contributing to a massive decline in mortality. The syndrome must be identified and treated early for a successful outcome, but a greater awareness among anaesthetists and other medical professionals has resulted in earlier diagnosis and treatment.
Products / Malignant Hyperthermia
The name malignant hyperthermia comes from malignant, meaning fatal (not cancerous) and hyperthermia, meaning a very high temperature. Temperature was the most obvious clinical feature seen in the first case described in 1962 by Prof. Denborough and co-workers in Australia1. MH is a fulminant hypermetabolic crisis and is most likely to be induced by an increased and sustained release of ionised calcium in the muscle fibre. Triggers for MH include skeletal muscle relaxants such as succinylcholine and all volatile anaesthetic gasses, one example of which is halothane. Physiological and emotional stresses have also been implicated as triggering factors. The condition is undetectable until symptoms appear under anaesthesia during an operation.
- Tachycardia (often sudden and unexplained)
- Unstable/rising blood pressure
- Profuse sweating
- Respiratory and metabolic acidosis
- Cardiac arrhythmias
- Muscle stiffness/rigidity
- Rapid rise in core body temperature
- Dark urine due to myoglobinuria
- Elevation of serum muscle enzymes and various electrolyte abnormalities, notably hyperkalaemia.
Although accurate estimates of frequency of MH are difficult to make, it is likely to occur in the order of 1 per 10,000-15,000 anaesthetic procedures in a normal hospital population2 including both adults and children. Both sexes can be affected although it is seen more frequently in males, with reactions occurring commonly between the ages of 10-30 years old3. It is also important to note that a history of previous anaesthesia without complications does not exclude the possibility of MH.
Diagram of Normal Muscle
In MH patients, anaesthetic drugs interfere with the normal calcium regulation at a particular stage in the excitation-contraction (EC) coupling process, which relays impulses from the nerves to the muscles creating contraction and relaxation. The reaction appears to result from a sudden, but sustained increase in ionised calcium in the muscle cytoplasm (myoplasm). This is probably due to a failure of the fibres? sarcoplasmic reticulum to take up ionised calcium as normal. Other possible causes may be dysfunctional calcium channels on the sarcolemma and T-tubule (both external muscle membranes). It is also possible that more than one site in this complex chain of events is involved in MH.
This sustained high level of ionised calcium causes continual muscle contraction and a series of hypermetabolic reactions. These reactions result in increased heat production and increased membrane permeability. These processes, unless interrupted, cause more calcium ions to enter the muscle and a self-perpetuating cycle ensues from which the patient cannot recover.4
1. Denborough MA, et al: Anaesthetic deaths in a family. Br J Anaesth, 1962; 34: 395-396
2. Britt BA, Kalow W: Malignant Hyperthermia: A Statistical Review. Can Anaesth Soc J, 1970; 17: 293-315.
3. Malignant Hyperthermia, A Family Concern. Professor FR Ellis, Dr. PJ Halsall, Dr PM Hopkins.
4. Lucke JN, Hall GM, Lister D; Porcine Malignant Hyperthermia: I. Metabolic and Physiologic changes. Br J Anaesth, 1976; 48: 297-304.
Products / About Dantrium IV / Dantrolen IV
The only effective treatment of MH is the product Dantrium Intravenous / Dantrolen Intravenous (dantrolene sodium). This drug is a muscle relaxant which acts within the skeletal muscle and was originally used for the treatment of painful muscle spasms in certain neuromuscular disorders.
Dantrium IV / Dantrolen IV is used for the management of fulminant hypermetabolism of skeletal muscle, characteristic of a malignant hyperthermia crises. It is also indicated pre-operatively and sometime post-operatively to prevent or attenuate MH episodes in individuals who are judged to be MH susceptible (Dantrium IV / Dantrolen IV, (Abridged Product Information).
Site and Mode of Action
Dantrium IV / Dantrolen IV acts peripherally to lower the intracellular calcium concentration in skeletal muscle. This most likely occurs by decreasing the release of calcium ions from the sarcoplasmic reticulum and inhibiting the influx of calcium into the myoplasm. Therefore, it effectively slows or stops the cycle of MH.
Products / Treatment with Dantrium / Dantrolen
Method of Administration
As soon as an MH reaction is suspected, all anaesthetic agents should be discontinued and the correct treatment should be rapidly instituted. Failure to detect and diagnose a reaction early means the crisis is more likely to be fatal.
An initial Dantrium IV / Dantrolen IV dose of 1mg/kg should be rapidly administered into the vein. Dosage for children is the same as for adults. If the physiological and metabolic abnormalities persist or reappear, this dose may be repeated up to a cumulative dose of 10mg/kg. To date, clinical experience has shown that the average dose of Dantrium IV / Dantrolen IV required to reverse the manifestations of malignant hyperthermia has been 2.5mg/kg. If a relapse or recurrence occurs, Dantrium IV / Dantrolen IV should be re-administered at the last effective dose.
The size of the patient and the severity of the reaction will dictate the number of Dantrium IV / Dantrolen IV vials needed however, in some patients as much as 10mg/kg of Dantrium IV / Dantrolen IV intravenous has been needed to reverse the crisis. In a 70kg man, approximately 36 vials would be required for this dose. Because of this, facilities that use triggering agents may want to consider stocking a minimum of 36 vials of Dantrium IV / Dantrolen IV as recommended by the Malignant Hyperthermia Association of the United States (MHAUS). The European Malignant Hyperthermia Group (EMHG) recommends that dantrolene sodium be mobilised from any nearby source ? at least 36 to 50 vials for an adult patient.
Special Precautions for Storage
Unopened vials can be stored for three years. Once the powder has been reconstituted, the solution must be used within six hours. Do not store the product above 30°C, make sure not to refrigerate or freeze the product and protect all vials from direct light.
Because of the nature of the freeze drying process used to manufacture the product, the freeze dried cake of Dantrium IV / Dantrolen IV may have a mottled orange/white appearance or be in the form of loose aggregates. This is an entirely normal artefact and in no way compromises the stability of the product.
Example of Treatment Regimen
1) Call for help; management is complex and can be difficult for one person.
2) Stop anaesthesia and surgery immediately.
3) Hyperventilate patient with 100% oxygen.
4) Administer Dantrium IV / Dantrolen IV as soon as possible.
5) Initiate cooling (injection of fluids and surface cooling with wet, cold sheets, fans and ice packs in axillae and groin).
6) Treat serious arrhythmias.
7) Correct acidosis.
8) Treat hyperkalaemia.
9) Promote urine output.
10) Monitor patient until danger of subsequent episodes is past.
11) Administer oral Dantrium if desired.
How Can MH-Susceptible Patients be Identified?
Because MH is usually an inherited genetic disorder, all members of a family in which MH has occurred must also be considered MH susceptible and treated accordingly, unless proven otherwise. It is important that any family history of anaesthetic deaths or complications should be made known to the anaesthetist before undergoing surgery.
Is There a Test for MH?
There is currently no simple diagnostic test available for screening the general population (e.g., a blood test). The most accurate diagnostic test involves a biopsy of skeletal muscle from the thigh. It is usually reserved for those with a family history of MH or when a patient has had a previous suspicious reaction to anaesthesia.
Products / Useful Contacts
European MH Group website:
Contact details for SpePharm:
SpePharm Italia s.r.l.
SpePharm UK Ltd.
SpePharm Nordic AsP
Products / Abridged Product Information
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TRADE NAME OF THE MEDICINAL PRODUCT
Dantrium Intravenous / Dantrolen Intravenous
QUALITATIVE AND QUANTITATIVE COMPOSITION
Each vial contains 20 mg dantrolene sodium. For excipients, click here
Powder for solution for injection.
For the treatment of malignant hyperthermia.
Posology and Method of Administration
As soon as the malignant hyperthermia syndrome is recognised all anaesthetic agents should be discontinued. An initial Dantrium IV / Dantrolen IV dose of 1 mg/kg should be given rapidly into the vein. If the physiological and metabolic abnormalities persist or reappear, this dose may be repeated up to a cumulative dose of 10 mg/kg. Clinical experience to date has shown that the average dose of Dantrium IV / Dantrolen IV required to reverse the manifestations of malignant hyperthermia has been 2.5 mg/kg. If a relapse or recurrence occurs, Dantrium IV / Dantrolen IV should be readministered at the last effect dose.
Special Warnings and Precautions for Use
In some subjects as much as 10 mg/kg of Dantrium IV / Dantrolen IV has been needed to reverse the crisis. In a 70 kg man this dose would require approximately 36 vials. Such a volume has been administered in approximately one and a half hours.
Because of the high pH of the intravenous formulation of D Dantrium IV / Dantrolen IV, care must be taken to prevent extravasation of the intravenous solution into the surrounding tissues.
The use of Dantrium IV / Dantrolen IV in the management of malignant hyperthermia is not a substitute for previously known supportive measures. It will be necessary to discontinue the suspect triggering agents, attend to increased oxygen requirements and manage the metabolic acidosis. When necessary institute cooling, attend to urinary output and monitor for electrolyte imbalance.
Interactions with other Medicaments and other forms of Interaction:
The combination of therapeutic doses of intravenous dantrolene sodium and verapamil in halothane/alpha-chloralose anaesthetised swine has resulted in ventricular fibrillation and cardiovascular collapse in association with marked hyperkalaemia. It is recommended that the combination of intravenous dantrolene sodium and calcium channel blockers, such as verapamil, is not used during the reversal of a malignant hyperthermia crisis until the relevance of these findings to humans is established.
Pregnancy and Lactation:
The safety of Dantrium IV / Dantrolen IV in pregnant women has not been established; it should be given only when the potential benefits have been weighed against the possible risk to mother and child.
Effects on Ability to Drive and Use Machines
A decrease in grip strength and weakness of leg muscles, especially walking down stairs, can be expected post-operatively. In addition, symptoms such as ?lightheadedness? may be noted. Since some of these symptoms may persist for up to 48 hours, patients must not operate an automobile or engage in other hazardous activity during this time.
There have been occasional reports of death following malignant hyperthermia crisis even when treated with intravenous dantrolene sodium; incidence figures are not available (the pre-dantrolene mortality of malignant hyperthermia crisis was approximately 50%). Most of these deaths can be accounted for by late recognition, delayed treatment, inadequate dosage, lack of supportive therapy, intercurrent disease and/or the development of delayed complications such as renal failure or disseminated intravascular coagulopathy. In some cases there are insufficient data to completely rule out therapeutic failure of dantrolene sodium .
The administration of intravenous dantrolene sodium to human volunteers is associated with loss of grip strength and weakness in the legs, as well as subjective central nervous system complaints.
There are rare reports of pulmonary oedema developing during the treatment of malignant hyperthermia crisis in which the diluent volume and mannitol needed to deliver i.v. dantrolene sodium possibly contributed.
There have been reports of thrombophlebitis following administration of intravenous dantrolene sodium.
Hepatotoxic reactions have been noted in a small number of subjects given long-term oral dantrolene therapy.
The receptor molecule for dantrolene has not been identified. Radiolabelled dantrolene sodium binds to specific components of the striated muscle cell, namely the t-tubules and the sarcoplasmic reticulum. However, the kinetics of binding vary between these two organelles. The binding of ryanodine is thought to compete with the binding of calcium in these organelles; further evidence for the specificity of binding is that dantrolene inhibits the binding of ryanodine to heavy sarcoplasmic reticulum vesicles from rabbit skeletal muscle. Under some conditions, dantrolene will lower intra-sarcoplasmic calcium concentrations in the resting state. This may be more important in diseased muscle [e.g. in malignant hyperthermia in humans and swine stress syndrome] than in muscle with normal function.
Dantrolene does not bind to the same sites as calcium channel blocking drugs such as nitrendipine or calmodulin. There is no electrophysiological evidence that dantrolene interferes with the influx of calcium from outside the cell. This may be one reason why paralysis by dantrolene has never been reported in animals or man; the muscle cell has alternative sources of calcium which are not influenced by dantrolene.
Whatever the molecular mechanism, the cardinal property of dantrolene sodium is that it lowers intracellular calcium concentration in skeletal muscle. Calcium concentrations may be lower in both the quiescent state, and as a result of a reduction in the release of calcium from the sarcoplasmic reticulum in response to a standard stimulus. This effect has been observed in striated muscle fibres from several species, and is not seen in myocardium. Fast fibres may be more sensitive than slow fibres to the action of dantrolene sodium.
Diverse other properties of dantrolene sodium have been observed in vitro, and in animal studies. Dantrolene sodium may inhibit the release of calcium from the smooth endoplasmic reticulum of smooth muscle, but the significance of this observation is questionable; for example, dantrolene sodium has no effect on isolated human urinary bladder smooth muscle. Calcium dependent, pre-synaptic neurotransmitter release may also be inhibited by dantrolene sodium. Again, the clinical significance of this has not been demonstrated.
Studies on Isolated, Functional Muscle
Elevation of intracellular, free calcium ion concentration is an obligatory step in excitation-contraction coupling of skeletal muscle. Dantrolene sodium, therefore, acts as a muscle relaxant by a peripheral mechanism which is quite different, and easily distinguishable from neuromuscular junction blocking drugs. In contrast with compounds that relax skeletal muscle by acting principally on the central nervous system, dantrolene sodium acts directly on skeletal muscle cells. In rabbit atria, dantrolene sodium has no effect alone, but it may antagonise inotropic agents which act by increasing intramyocardial cell calcium e.g. anthopleurin-a.
Dantrolene sodium is a highly lipophobic drug. In addition, it lacks hydrophilicity. Dantrolene sodium binds to human serum albumin (HSA) with a molar ratio of 0.95 to 1.68 in vitro. The association constant in vitro is 2.3 to 5.4 x 10-5 per mol. In vitro dantrolene sodium can be displaced from HSA by warfarin, clofibrate and tolbutamide but these interactions have not been confirmed in humans (re. manufacturer's database). Single intravenous dose studies suggest that the primary volume of distribution is about 15 litres.
Metabolism and Excretion
The biological half life in plasma in most human subjects is between 5 and 9 hours, although half-lives as long as 12.1 + 1.9 hours have been reported after a single intravenous dose. Inactivation is by hepatic metabolism in the first instance. There are two alternative pathways. Most of the drug is hydroxylated to 5-hydroxy-dantrolene. The minor pathway involves nitro-reduction to amino-dantrolene which is then acetylated (compound F-490). The 5-hydroxy metabolite is a muscle relaxant with nearly the same potency as the parent molecule, and may have a longer half life than the parent compound. Compound F-490 is much less potent and is probably inactive at the concentrations achieved in clinical samples. Metabolites are subsequently excreted in the urine in the ratio of 79 5-hydroxy dantrolene : 17 compound F-490 : 4 unaltered dantrolene (salt or free acid). The proportion of drug excreted in the faeces depends upon dose size.
Preclinical Safety Data
Whilst there is no clinical evidence of carcinogenicity in humans, this possibility cannot be absolutely excluded. Dantrolene sodium has shown some evidence of tumourgenicity at high dose levels in Sprague-Dawley female rats, but these effects have not been seen in other studies in Fischer 344 rats or HaM/ICR mice.
Dantrium IV / Dantrolen IV should not be mixed with other intravenous infusions.
Three years. The reconstituted solution should be used within six hours.
Special Precautions for Storage
Unopened product: Do not store above 30C.Reconstituted solution: Do not store above 30C. Do not refrigerate or freeze. Protect from direct light.
Because of the nature of the freeze-drying process used in the manufacture of Dantrium IV / Dantrolen IV , the freeze-dried cake of Dantrium IV / Dantrolen IV may have a mottled orange/white appearance or be in the form of loose aggregates. This is an entirely normal artefact and in no way compromises the stability of the product.
Nature and Contents of Container
Type I glass vial with butyl rubber stopper and aluminium seal. Twelve vials per carton.
Instruction for Use/Handling
Each vial of Dantrium IV / Dantrolen IV should be reconstituted by adding 60ml of water for injection PhEur, and shaken until the solution is clear. Any unused portion of the reconstituted solution should be discarded. There are no special requirements relating to the disposal of the container or contents.