Ryanodex® – So easy to use, even a caveman can do it!

By Nubriel Hernandez, PharmD, PGY-1 Pharmacy Resident

 

Insurance policies can be life-saving, and many different kinds exist to help support things that we value including, but not limited to, health, life, auto, home, and even liability insurance. In the medical setting, drugs can serve in a similar role when utilized appropriately, especially those indicated for rare conditions such as malignant hyperthermia. In a Center for Medicare and Medicaid Services (CMS) mock survey in October 2016, the management of malignant hyperthermia was raised as a question and in response, our hospital acted to strengthen its current practice hospital wide by introducing Ryanodex® to replace Dantrium®.

 

What is Malignant Hyperthermia and why does it matter?

Malignant hyperthermia (MH) is an inherited skeletal muscular disorder commonly associated with the use of inhaled anesthetics and neuromuscular blockers, the most notorious agent being succinylcholine.1 A conformational change located on the ryanodine receptor subtype 1 (RYR1) at the sarcoplasmic reticulum facilitates release of calcium into the extracellular space, leading to uncontrolled muscle contractions, increased oxygen consumption, ATP hydrolysis, and carbon dioxide and heat production (Figure 1). Malignant hyperthermia occurs in 1 case out of every 100,000, but it is important to note that although the incidence rate is very rare, the outcome, if not treated, can be life-threatening.1 More importantly, a patient may not experience malignant hyperthermia from every exposure of inhaled anesthetics or neuromuscular blockers. Triggering MH might be in part a dose-dependent phenomenon, which is consistent with the inter-individual variability and graded incremental contracture response of MH susceptible muscles observed in vitro.2

Figure 1:

From Schneiderbanger D, et al. Management of malignant hyperthermia: diagnosis and treatment. Ther Clin Risk Manag. 2014;10:355-62.

 

What symptoms should we look for in patients with MH?

The early signs of MH are typically non-specific and include hyperthermia, muscle spasms/rigidity, tachycardia, tachypnea, hyperkalemia, and acidosis. Symptoms that appear later in the progression of the condition include rhabdomyolysis, acute kidney injury, myoglobinuria, and irregular heartbeat. If a patient is suspected to have malignant hyperthermia, it is important to stop the offending agent and switch to a safer option if possible (Table 1). A kit or cart must be made available within 10 minutes of the decision to treat MH as per our MH protocol. For MH diagnoses in the OR, the MH cart must be used and for MH diagnoses outside the OR, Pharmacy must be informed as soon as the diagnosis is made in order to deliver the MH kit. For further assistance, the Malignant Hyperthermia Association of the United States (MHAUS) may be contacted as well.

 

MHAUS serves as a non-profit organization with a mission to optimize care in those patients who experience MH. MHAUS currently recommends initially ventilating the patient who is under general anesthesia with 100% oxygen to flush the volatile agent and prevent further carbon dioxide buildup.1 Anesthesia can be maintained using intravenous opioids, sedatives, or non-depolarizing neuromuscular blockers until surgery is completed if certain that the cause is the inhaled agent.2 The very next step in the management of a MH crisis is administering dantrolene at 2.5 mg/kg IV push repeatedly until symptoms subside or a maximum of four doses is reached.3 Cumulative doses greater than 10 mg/kg may be necessary in some patients.1

Table 1:

Triggers for MH

Safer Alternatives

Inhaled General Anesthetics

Inhaled Non-Volatile Anesthetic

Sevoflurane

Nitrous Oxide

Methoxyflurane

Intravenous Anesthetics

Desflurane

Ketamine

Enflurane

Etomidate

Halothane

Propofol

Isoflurane

Midazolam

Depolarizing Neuromuscular Blocker

Non-Depolarizing Neuromuscular Blockers

Succinylcholine

Rocuronium

Vecuronium

Pancuronium

Cisatracurium

Atracurium

What’s so special about dantrolene?

Dantrolene has been our hospital’s insurance policy for MH for many years. It works by blocking the RYR1 receptor and thus inhibiting further release of calcium into the extracellular space, allowing for gradual calcium reuptake by the skeletal muscle cells.4 Currently, there are three formulations of dantrolene available commercially (Figure 2), and Dantrium® was the initial product that we stocked. Dantrium® is available as 20 mg vials that require 60 mLs of sterile water per vial and about 8 minutes to achieve dissolution of the dantrolene powder.5 Given the dose of 2.5 mg/kg, approximately 8 to 9 vials may be needed for an average adult patient weighing 70 kg. Due to the large number of vials needed and the extensive preparation time, Dantrium® may seem like a risky insurance policy. Another dantrolene formulation available is Revonto®. Revonto® is a powdered formulation of dantrolene that requires 20 to 30 seconds of reconstitution per vial but, nonetheless, requires the same number of vials as Dantrium®.6

 

A new formulation of dantrolene was introduced to our formulary in one of last year’s P&T meetings, named Ryanodex®. Ryanodex® is available as a 250 mg vial that requires only 5 mLs of sterile water and 15 to 20 seconds for reconstitution.3 A dose of 2.5 mg/kg requires only 1 vial for an adult patient weighing 70 kg. Due to the larger dosage strength per vial, MHAUS has recommended that only 3 vials of Ryanodex® be stocked in an emergency cart whereas 36 vials of both Dantrium® or Revonto® would be needed to be stocked instead.1 Furthermore, only two 10 mL vials of sterile water needed for all 3 vials of Ryanodex®. On the other hand, a minimum of twenty-two 100 mL vials would be needed to reconstitute 36 vials of Dantrium® or Revonto®. Emergency carts are required to stock sufficient medications and tools to help save lives but if space is being occupied by sterile water which only serves the one purpose of preparation, it begs the question, would we be utilizing all available space as efficiently as possible?

Figure 2:

Manufacturer

Par Pharmaceutical

US WorldMeds

Eagle Pharmaceuticals

Dose per vial

20 mg

20 mg

250 mg

# of vials for initial dose

8 vials

8 vials

1 vial

Sterile Water to reconstitute 1 vial

60 mL

60 mL

5 mL

Vials Required to Stock in Emergency Cart

36 vials

36 vials

3 vials

Reconstitution time per vial

8 – 10 minutes

20 – 30 seconds

15-20 seconds

Where can I access Ryanodex® if I ever witness a MH case?

Our hospital has approved the storage of Ryanodex® in the emergency cart located within the operating room (OR). Ryanodex® is also stored in an emergency kit located within the Main Pharmacy to serve the rest of the hospital. The kit contains two 20 mL and three 6 mL syringes, three Ryanodex® vials, five 20-gauge needles, a dosing schedule, and an instructional sheet for use (see Figure 3). In an emergency where MH is suspected within the hospital (except the OR) the pharmacy should be notified immediately to deliver the emergency kit containing Ryanodex® to the appropriate location. Time is of the essence and every second counts. Prompt delivery and preparation can ensure that a life-saving medication can be administered as quickly as possible. It takes 15 seconds to prepare, it’s no wonder even a caveman can do it!

Figure 3:

Take Home Points:

  • Malignant hyperthermia (MH) is an inherited skeletal muscular disorder commonly associated with the use of inhaled anesthetics and neuromuscular blockers, with the most notorious agent being succinylcholine.1
  • Be aware of the early signs of MH that include hyperthermia, muscle spasms/rigidity, tachycardia, tachypnea, hyperkalemia, and acidosis.1
  • Dantrolene works by blocking the RYR1 receptor and thus inhibiting further release of calcium into the extracellular space, allowing for gradual calcium reuptake by the skeletal muscle cells.4
  • In a MH crisis outside of the OR, contact the Main Pharmacy to obtain the MH kit.
  • The MHAUS Hotline is 800-644-9737 and the website URL: https://www.mhaus.org/ may be consulted for further assistance.
  • Dantrolene is the first line agent for MH and should be dosed at 2.5 mg/kg IV push repeated as frequently as needed until symptoms subside or until a maximum of four doses is given.3
  • Ryanodex® is the new formulation of dantrolene that allows for more rapid preparation due to its faster reconstitution time.

 

References:

1. MHAUS. Malignant Hyperthermia Association of the United States. http://www.mhaus.org/. Accessed July 20, 2017.

2. Schneiderbanger D, Johannsen S, Roewer N, Schuster F. Management of malignant hyperthermia: diagnosis and treatment. Ther Clin Risk Manag. 2014;10:355-62.

3. Ryanodex® [package insert]. Woodcliff Lake, NJ: Eagle Pharmaceuticals, Inc; 2014.

4. Lexicomp Online®, Lexi-Drugs®, Hudson, Ohio: Lexi-Comp, Inc.; accessed December 1, 2016

5. Dantrium® [package insert]. Spring Valley, NY: Par Pharmaceutical Companies, Inc; 2014.

6. Revonto® [package insert]. Louisville, KY: US WorldMeds, LLC; 2014.

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nhernandez

PGY-1 Pharmacy Practice Resident

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