**3. Sodium dantrolene**

### **3.1 Pharmacokinetics**

Flewellen et al showed that after an intravenous dose of dantrolene, therapeutic levels were rapidly achieved and remain stable for around 5.5h. Subsequently, the dantrolene blood level slowly declined following first order kinetics with a half-life elimination of 12h. The mean residual blood dantrolene concentration present 20h after the last dose was 1.7 mcg.ml-1 and, after 50h, that level was 0.3 mcg.ml-1 60. This same study evaluated neuromuscular effects of intravenous dantrolene in conscious patients and showed that

muscle relaxant succinylcholine triggers the syndrome49. Isoflurane, desflurane and sevoflurane appear to be less potent triggers than halothane, but these agents can produce a more gradual or fast onset of MH50-56. The onset may be explosive if succinylcholine is used57. Local anesthetics, nondepolarizing muscle relaxants, barbiturates, benzodiazepines, droperidol, ketamine, nitrous oxide, opioids, and propofol are all safe drugs to administer in

The commonest clinical presentation of MH is a hypermetabolic state in a genetically susceptible individual in response to certain anesthetic agents, notably succinylcholine or halogenated volatile anesthetics. One of the earliest clinical signs is MMR after succinylcholine. *In vitro* muscle testing in patients who have developed this sign alone reveals that 28–50% are susceptible to MH. In the full-blown syndrome there is a rapid and sustained rise in body temperature, without shivering, either in the operating theatre or in the recovery room, in the absence of any obvious cause such as infection or a hot and humid environment. Tachycardia, cyanosis, generalized muscle rigidity, and cardiac arrhythmias are common clinical signs. There may be heating and rapid exhaustion of the soda-lime canisters. Acidosis is an early finding and there may also be hyperkalemia, hyperphosphatemia, and hypocalcemia from muscle-cell breakdown. Rhabdomyolysis is an important feature of the syndrome and is best demonstrated by measuring serum CK, which usually peaks on the second or third day after the reaction. Tenderness and swelling of muscles may develop, especially in the thighs. Myoglobinemia and myoglobinuria are common and renal failure may result from the

rhabdomyolysis. Another complication is disseminated intravascular coagulation1.

uneventful while another in the same patient is not1.

the case-fatality rate is only 5%1.

**3. Sodium dantrolene 3.1 Pharmacokinetics** 

In less obvious cases, MH may present with one or any combination of the above clinical signs. The first indication of MH may be an unexplained cardiac arrest or cardiac arrhythmia. A rise in end-tidal CO2 is often the earliest indication of MH, and now that this is widely measured in clinical anesthesia MH may be picked up before the more florid signs develop. Previously apparently uncomplicated anesthesia with halothane and/or succinylcholine does not exclude the diagnosis of MH on a subsequent occasion. Factors such as the concentration of the anesthetic drugs used, the duration of the anesthesia, and the degree of MH susceptibility of the patient may explain why one anesthetic procedure is

When MH was first recognized as a complication of anesthesia the case-fatality rate was 70%. Today, with the use of a specific drug for MH and the introduction of an *in vitro* muscle-contracture test59 to identify susceptibility to MH in individuals and their relatives,

Flewellen et al showed that after an intravenous dose of dantrolene, therapeutic levels were rapidly achieved and remain stable for around 5.5h. Subsequently, the dantrolene blood level slowly declined following first order kinetics with a half-life elimination of 12h. The mean residual blood dantrolene concentration present 20h after the last dose was 1.7 mcg.ml-1 and, after 50h, that level was 0.3 mcg.ml-1 60. This same study evaluated neuromuscular effects of intravenous dantrolene in conscious patients and showed that

MH susceptible patients49.

**2.5 Clinical presentation** 

maximal depression of muscle twitch response (75% depression) and grip strength (42% depression) was accomplished after a cumulative dose of 2.4 mg.kg-1 body weight. Twenty four hours after such regimen, dantrolene levels were still high enough to cause strength reduction and a subjective weakness complaint only disappeared 48h after the last dose. On the other hand, spontaneous respiratory parameters (peak expiratory flow rate, vital capacity, end-tidal carbon dioxide and respiratory rate) did not change significantly during dantrolene administration. In children, the pharmacokinetic profile is similar, with a half-life of approximately 10 h61.

Metabolism of dantrolene is achieved microsomally in the liver via oxidative and reductive pathways. Oxidation results in hydroxylation of the hydantoin ring to 5-hydroxydantrolene (5HD), while reduction of the nitro group of dantrolene leads to the formation of aminodantrolene, which is then acetylated to the reduced acetylated derivative (RAD) of dantrolene62.

5HD is a metabolite with muscle relaxant effects. Compared with dantrolene sodium, it has a longer half-life (15,5h vs. 6h), but its activity is lower and its plasma levels are only 30-50% of its parent drug63. As a result, in healthy patients, 5HD can only be considered to play a minor role on the skeletal muscle relaxant properties of dantrolene therapy. The other metabolites have no relaxant effect.

After an oral dose, 70% of dantrolene is absorbed. Twenty-five percent of the dose is excreted in urine, most of it as 5HD (79%) or RAD (17%); only 4% is excreted as unchanged drug62. Biliary excretion accounts for 45-50% of the oral dose administered64. Specific and detailed excretion studies after intravenous dantrolene are lacking.

#### **3.2 Pharmacodynamics**

Dantrolene is a unique muscle relaxant. Unlike neuromuscular blocking agents (site of action of which is at the nicotinic receptor of the neuromuscular junction) or the nonspecific relaxants (which modulate spinal cord synaptic reflexes), several studies have shown that dantrolene interferes with excitation-contraction coupling by reducing the concentration of myoplasmic calcium65-69. Consequently, muscle contraction is decreased without an effect on the action potential patterns of the neuromuscular junction70.

However, the pathway by which dantrolene lowers myoplasmic Ca2+ is complex and still not fully understood. The ryanodine receptor of skeletal muscle (RyR1) has traditionally been thought to be the site of action of dantrolene66, and recent studies have located the molecular target of dantrolene to the area comprising amino acid residues 590 through 609 of RyR171, strengthening that hypothesis. Some controversy was shed on that assumption when purified RYR1 was incorporated into an artificial planar lipid bilayer and no effect of dantrolene was detected in channel activity or pharmacology72. As a consequence, to date, we lack evidence of a direct action of dantrolene on purified RyR1 channels studied in lipid bilayers, even in the presence of calstabin 1, ATP, and activating concentrations of Ca2+, suggesting that dantrolene's main action is to alter key protein-protein interactions73.

### **3.3 Side effects**

The two most frequently observed side-effects were muscle weakness in 22% and phlebitis in 10% of the patients.

Besides the intrinsic effect of dantrolene therapy, muscle weakness during MH may have a contribution of the muscle injury that is an integral part of the syndrome. Additionally, prolonged mechanical ventilation may, *per se*, exert deleterious effects on respiratory function. Although some authors objectively demonstrated strength reduction with clinically used doses of dantrolene60, no studies of pulmonary function have been performed in patients after MH crises, dantrolene therapy and intensive care management. As a result, careful attention with respiratory function is essential in these patients, especially during weaning of mechanical ventilation or in patients with borderline respiratory function, like those neuromuscular disorders. The clinicians treating an MH episode should request repeated measurement of creatine kinase until it returns to normal levels74.

Because of its high alkalinity (pH = 9.6) after reconstitution, dantrolene should be preferentially administered through a large bore peripheral or central venous access to avoid local inflammatory phlebitis at the infusion site. Moreover, the sites of infusion should be frequently inspected for signs of extravasation and tissue necrosis.

Besides these, the most commonly reported adverse effects can be grouped as of central (drowsiness, weakness, dizziness, malaise, fatigue, diplopia, dysarthria, seizures) and gastrointestinal (nausea, epigastric discomfort, diarrhea, constipation, abdominal pain) origin70. Gastrointesinal symptoms are more common with oral therapy75. Central nervous system symptoms may be worsened by sedatives and general anesthetics and it is not yet clear whether they are mediated by altered neuronal calcium homeostasis76.

The side-effects were more commonly reported at the initiation of oral therapy and frequently disappeared with continued therapy and dose titration, although in 2.5% of patients they may be severe and persistent enough to warrant discontinuation of therapy64.

Once the sarcoplasmic reticulum of heart muscle plays an essential role in the variable calcium release and uptake in excitation-contraction coupling, negative inotropic effects of dantrolene could be expected. The first studies to specifically address the effects of dantrolene on cardiovascular function evaluated healthy anesthetized dogs and showed no relevant effects on arterial pressure, central venous pressure, heart rate, coronary blood flow and cardiac output77-78. Later, other authors argumented that those results did not imply absence of effects on cardiovascular functions, since mechanisms of compensation may have had a role in maintaining the stability of the parameters investigated79. So, several authors began to study the effects of dantrolene in isolated animal cardiac muscle79-81, but these investigations resulted in divergent results. The human studies that addressed this issue did not show any relevant effects of therapeutic doses of dantrolene on cardiovascular function 60, even in patients with poor cardiac function82. Whether this stability was due to complete absence of action of dantrolene on human myocardium or due to the action of compensating cardiovascular mechanisms is still a matter of debate.

Another relevant cardiovascular issue has recently emerged in a two-decade registry analysis of the complications associated with dantrolene administration74. The authors found that the risk of any complication with dantrolene therapy increases with larger doses of dantrolene and fluid administration; on the other hand, this same study showed that the associated use of furosemide decreased that risk. Besides this, considering only the subset of patients with serious underlying disease or complex surgery (like liver transplant), there was a greater incidence of complications and these patients commonly presented more than one type of complication.

Besides the intrinsic effect of dantrolene therapy, muscle weakness during MH may have a contribution of the muscle injury that is an integral part of the syndrome. Additionally, prolonged mechanical ventilation may, *per se*, exert deleterious effects on respiratory function. Although some authors objectively demonstrated strength reduction with clinically used doses of dantrolene60, no studies of pulmonary function have been performed in patients after MH crises, dantrolene therapy and intensive care management. As a result, careful attention with respiratory function is essential in these patients, especially during weaning of mechanical ventilation or in patients with borderline respiratory function, like those neuromuscular disorders. The clinicians treating an MH episode should request

Because of its high alkalinity (pH = 9.6) after reconstitution, dantrolene should be preferentially administered through a large bore peripheral or central venous access to avoid local inflammatory phlebitis at the infusion site. Moreover, the sites of infusion should

Besides these, the most commonly reported adverse effects can be grouped as of central (drowsiness, weakness, dizziness, malaise, fatigue, diplopia, dysarthria, seizures) and gastrointestinal (nausea, epigastric discomfort, diarrhea, constipation, abdominal pain) origin70. Gastrointesinal symptoms are more common with oral therapy75. Central nervous system symptoms may be worsened by sedatives and general anesthetics and it is not yet

The side-effects were more commonly reported at the initiation of oral therapy and frequently disappeared with continued therapy and dose titration, although in 2.5% of patients they may be severe and persistent enough to warrant discontinuation of therapy64. Once the sarcoplasmic reticulum of heart muscle plays an essential role in the variable calcium release and uptake in excitation-contraction coupling, negative inotropic effects of dantrolene could be expected. The first studies to specifically address the effects of dantrolene on cardiovascular function evaluated healthy anesthetized dogs and showed no relevant effects on arterial pressure, central venous pressure, heart rate, coronary blood flow and cardiac output77-78. Later, other authors argumented that those results did not imply absence of effects on cardiovascular functions, since mechanisms of compensation may have had a role in maintaining the stability of the parameters investigated79. So, several authors began to study the effects of dantrolene in isolated animal cardiac muscle79-81, but these investigations resulted in divergent results. The human studies that addressed this issue did not show any relevant effects of therapeutic doses of dantrolene on cardiovascular function 60, even in patients with poor cardiac function82. Whether this stability was due to complete absence of action of dantrolene on human myocardium or due to the action of compensating

Another relevant cardiovascular issue has recently emerged in a two-decade registry analysis of the complications associated with dantrolene administration74. The authors found that the risk of any complication with dantrolene therapy increases with larger doses of dantrolene and fluid administration; on the other hand, this same study showed that the associated use of furosemide decreased that risk. Besides this, considering only the subset of patients with serious underlying disease or complex surgery (like liver transplant), there was a greater incidence of complications and these patients commonly presented more than

repeated measurement of creatine kinase until it returns to normal levels74.

clear whether they are mediated by altered neuronal calcium homeostasis76.

cardiovascular mechanisms is still a matter of debate.

one type of complication.

be frequently inspected for signs of extravasation and tissue necrosis.

The interpretation of these findings has to be undertaken in light of the administration peculiarities of dantrolene. Each vial with 20 mg of dantrolene contains 3 g of mannitol (to improve liposolubility) and has to be reconstituted with 60 mL of sterile water. Thus, the results of the registry analysis would suggest that the mannitol content of dantrolene formulations, when combined with fluid administration, would further aggravate the fluid shifts related to the pathophysiology of MH and major surgeries, justifying the occurrence of complications like pulmonary edema. On the other hand, the careful use of furosemide to maintain urinary output and regulate intravascular volume status decreased these complications and has long been suggested by many authors. In this registry analysis, two of the 386 enrolled patients (0.5%) presented a decrease in cardiac output, but the authors did not sufficiently describe these cases to determine if it may have been the result of direct negative inotropism of dantrolene or due to other possible causes, like fluid overload.

Liver transplantation is a very complex surgery and hepatorenal syndrome and cirrhotic cardiomyopathy are relatively common among liver transplant patients. Besides this, fluid management during liver transplantation, which is especially challenging because of massive bleeding and altered hemodynamics of cirrhotic patients, can become even more challenging with the occurrence of MH. As a result, dantrolene therapy may be especially prone to cardiovascular complications in this population. Because of these concerns, some authors suggest that documentation of cardiac filling pressures and cardiac output with continuous monitors such as echocardiography may improve management of critically ill subjects during MH treatment, although they were unable to demonstrate a reduction in dantrolene-associated complications with these measures. Furthermore, careful titration of the lowest effective dose regimen should always be sought.

Although rarely encountered, chronic oral dantrolene therapy has been linked to different grades of hepatic damage, including fatal hepatitis in 0.1-0.3% of patients20,83. As a result, it received a black box warning for hepatotoxicity in 1976, early after its release in 197484. Despite these facts, a few authors suggest that other concomitant therapies may have had a role in that toxicity75-76. In addition, *in vivo* experiments in mice have not revealed any toxicity to hepatocytes85-86. In fact, recently, it was argued that dantrolene, due to its properties of restoring calcium homeostasis in scenarios of its disruption (like models of ischemia, hypoxia, seizure, trauma, anesthesia, and neurodegenerative diseases), may have cytoprotective effects in different tissue culture or animal models of diseases involving cytotoxicity induced by disruption of intracellular calcium homeostasis in pathogenesis87.

Although the great majority of the studies agree that dantrolene may induce liver toxicity, the reports regarding intravenous short term dantrolene therapy are scarce, and most of the information is related to the oral long term dantrolene therapy in patients with spasticity disorders20. The only study that addressed the hepatic effects of intravenous dantrolene, found no significant differences in liver enzymes after its use, although it employed volunteers without any signs of MH60. In publications of oral therapy, some risk factors for dantrolene associated hepatitis have been identified like female sex, patients over the age of 35 years and greater accumulated doses20,88.

Although larger doses were identified as a risk factor, there is no agreement about the reactions involved in dantrolene hepatotoxicity and, until now, it is not known if the mechanism is dose-related or attributable to hypersensitivity (idiosyncratic reaction after a few doses)85,89-90. As described in the pathophysiology section, ryanodine receptors were recently discovered in hepatocytes38. Whether dantrolene causes liver toxicity through these receptors or during its metabolism is unclear.

Most of the patients with dantrolene hepatitis develop only mild and nonspecific symptoms (malaise, weakness, vomiting, fever, vomiting, jaundice)90, although fatal acute hepatic failure has been described93. Laboratory exams show different degrees of alterations in liver enzymes (alkaline phosphatase, AST, ALT) and bilirubin levels91. Histological findings of liver biopsies did not show a homogenous pattern, and multiple different descriptions were published (Table 1)20,88-90,92-95. If signs of hepatic injury develop during MH therapy, the treatment is mainly supportive and dantrolene should be stopped soon after control of the crisis, as dantrolene hepatitis is usually reversible after its withdrawal.

In the two available reports of the use of dantrolene sodium during liver transplantation, there were alterations in postoperative laboratory exams, but the liver graft recovered uneventfully56,96. Actually, although dantrolene may pose an additive threat in the large set of perioperative injuries to the graft, abnormal symptoms and laboratory exams may be masked in the routine postoperative course of hepatic transplantation. Besides this, biopsies may not be of great help because histological patterns of dantrolene hepatitis do not greatly differ from those usually observed postoperatively in liver grafts. Consequently, prevention of dantrolene-induced hepatic injury is crucial. So, if malignant hyperthermia happens during liver transplantation, it seems prudent to, besides supportive treatment, use the lowest effective dose of dantrolene for the shortest time possible.

Less commonly reported effects are acne-like rash, pruritus, urticaria, fever, hypersensitivity pleural effusion with pericarditis.
