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Malignant Hyperthermia Trigger Drug May Be Replaced

by MHAUS President Henry Rosenberg, MD

One of the most useful drugs in the armamentarium of anesthesia providers, and emergency medicine physicians is succinylcholine (also called Anectine). Succinylcholine is a drug that produces intense paralysis within seconds of injection which lasts (in most patients) for about 5-8 minutes. This is just perfect for procedures that required intense paralysis for only a few moments such as intubation of the trachea, orthopedic manipulation or brief relaxation to assist the surgeon. As such the drug gained widespread acceptance after it was introduced in 1952 especially since the alternative drug, curare had many problems in predicting response and duration.


It is well known that every medication has some undesirable side effects. This is especially true for succinylcholine. Within a few years of the introduction of succinylcholine clinicians noted that in some patients, paralysis would last for hours instead of minutes. If the patient were not anesthetized, s/he would be awake yet unable to move or communicate. Researchers discovered that the reason for the long duration of action in these patients was the presence of an inherited defective enzyme responsible for the degradation of the molecule.. After a while clinicians began to recognize this problem and when it occurred, would sedate the patient until the drug wore off. However routine screening for the altered enzyme was not economically feasible so one in 2500 patients receiving succinylcholine experience muscle paralysis for an hour or more. Parenthetically, the person who worked out this problem was a pharmacologist, Dr. Werner Kalow, who later in his career would work with Dr. Beverly Britt in describing the muscle biopsy contracture test for Malignant Hyperthermia.


Then in the 1960s, another life threatening problem was noted with succinylcholine. Some patients who were burned or had spinal cord injury would experience a cardiac arrest after receiving succinylcholine . Researchers found that these patients developed a massive rise in serum potassium. Normally, potassium levels are about 4meq/L, but in many of these patients the level quickly rose to 8 , 9 or more. When potassium levels are so high, the electrical conduction system of the heart is effected , throwing off the normal heart rhythm and producing a cardiac arrest. In some cases the patient was not able to be resuscitated. After the phenomenon was described and the cause noted , clinicians began to realize that succinylcholine should be avoided in burn and neurologically impaired patients (even those who had paralysis from a stroke)


Yet another life threatening problem was noted some years later. Some patients with an unrecognized or unappreciated muscle disorder, would also develop a cardiac arrest due to elevated potassium after receiving succinylcholine. In these cases it was because the patient, most often a young male child had an underlying, unrecognized muscle disorder such as Duchenne Muscular dystrophy. Older patients who are at risk to high potassium levels after succinylcholine have a different form of Muscular Dystrophy. Again, after a while most clinicians recognized that patients with muscle disease should not receive succinylcholine. However, there were always those patients, particularly young children, who had an underlying muscle disorder but because they were too young to walk the disorder was not recognized. Eventually the FDA required that the manufacturers place a â??black box warningâ?? in the package insert indicating that succinylcholine should not be used without indication in young children for fear of high potassium levels resulting in cardiac arrest in those with undiagnosed muscle disorders.


Yet other significant problems were noted. In some patients, particularly children, succinylcholine would produce intense jaw muscle rigidity making it almost impossible to open the mouth to insert an endotracheal tube. In those cases patients would also sustain significant muscle breakdown ( called rhabdomyolysis). Furthermore such intense jaw rigidity was noted to be a heralding sign of Malignant Hyperthermia.


Succinylcholine is also a trigger for MH. Animal studies and human experience demonstrated that succinylcholine could by itself a trigger for malignant hyperthermia. This meant that any anesthetizing location that has succinylcholine available even for emergency use only should also stock a full supply of dantrolene ( I wrote about this in my blog of May 2012.) even if they did not use the gas anesthetics that trigger MH. Despite some doubts, it is clear that this drug is a trigger for MH particularly when used with the gas anesthetics that are MH triggers.


In addition to these life threatening problems there are a host of other unpleasant side effects, such as muscle aches and pains and in some, non MH patients, a mild degree of muscle breakdown.


So why is succinylcholine still used routinely? For several reasons, but most of all, the properties of the drug in most patients, namely short onset, intense paralysis and short duration outweighed the other rarer problems. Furthermore, no other drug matched these properties. Meanwhile beginning in the 1980s a new series of muscle paralyzing drugs was introduced into anesthesia practice that had some of the desirable qualities of succinylcholine. Two such drugs were named vecuronium and rocuronium. These drugs do not lead to the life threatening increases in potassium as seen with succinylcholine nor do they precipitate MH. If given in high doses they could produce rapid onset of paralysis just like succinylcholine, however instead of the paralysis lasting about 5-6 minutes, it would last for more than 20 minutes. This is a problem if the procedure was a brief one.


One other important point about the alternative paralyzing drugs like vecuronium and rocuronium. The paralysis so produced could be â??reversedâ?? if the clinician waited a long enough period of time after drug administration or with administration of a competitive reversal drug , i.e. neostigmine. (It is actually more complex then this, but the point is the same). However, in general such reversal could not be effective in less than 20-30 minutes of administration.


If only it were possible to reverse the paralysis of these newer drugs quickly then the desired qualities of succinylcholine would be matched. Well a few years ago such a compound was developed. This agent, Sugammadex, could rapidly and completely reverse the paralysis of rocuronium in a unique manner. The reversal agent would actually â??trapâ?? the paralyzing drug molecule and block it from attaching to the cell surface where it exerted its effect. Furthermore the basic molecular structure of this new agent was similar to a complex sugar, so it was not associated with organ toxicity. I include a figure from Wikepedia of the molecular structure of the drug below. It demonstrates that Sugammadex was designed to trap the muscle paralyzing drug in its â??donut holeâ??.


Sugammadex was approved for use in most European countries, Australia and New Zealand in about 2008 and has lived up to its reputation of being a â??clean drugâ?? that reverses the action of rocuronium very rapidly from any level of muscle paralysis.


Patients do not become reparalyzed with time either.


So, if this drug is so great and can replace succinylcholine why is it not available yet ? I donâ??t have all the answers but it seems that after the drug was submitted to the FDA for approval, the agency wanted some additional studies to make sure there were no significant side effects when given in repeated doses as well as other studies on the possible side effects of the drug.


Recently the drug company that acquired Sugammadex completed the studies requested and resubmitted the drug to the FDA for reconsideration. A decision may be made within the next few months.


In those countries where the drug is available there is concern that routine use of rocuronium, because it can be reversed quickly with Sugammadex, would lead to increased drug costs since rocuronium is much more expensive than succinylcholine. So, it is unlikely that succinylcholine will be replaced entirely. Rather, in those cases where there is a question or suspicion that the patient may be at risk for MH , or where there is evidence of muscle disease, or where there are procedures that are very brief but intense paralysis is needed (such as procedures on the airway by ENT surgeons) the anesthesia provider will likely lean to use rocuronium in high doses to obtain rapid, deep paralysis, and then reverse the paralysis with Sugammadex.


In time, if the economic calculation of the cost of incurring a complication with succinylcholine exceeds the costs of using Sugammadex routinely, well then succinylcholine may not be used as often. Even now without Sugammadex, succinylcholine is not used routinely by most pediatric anesthesiologists in the US because of the concerns about unexpected high potassium levels in a patient with undiagnosed muscle disorder but is reserved for special indications.


Where there is a choice of several drugs that produce similar effects the clinicianâ??s decision to use one or another is rather complex. I have simplified the explanation of the factors leading to the decision to use Sugammadex. However, the main point is that it is there likely will be an acceptable alternative to succinylcholine, thereby lessening the chances of precipitating MH or other undesirable side effect of succinylcholine Time will tell.


Sugammadex molecule from Wikepedia

A rendering of the Sugammadex molecule. The molecular structure is such that the paralyzing drug is trapped in the donut hole of the compound.


Disclaimer: I have no personal financial interest in Merck or any company that manufactures Sugammadex. Neither does MHAUS receive support from any manufacturer of the drug.

This article is copyright by Henry Rosenberg MD

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  • MH and MHAUS Updates
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