Dantrolene, which binds to the ryanodine-receptor 1 (RyR1) and inhibits calcium release from the sarcoplasmic reticulum, is only indicated intravenously for the management of malignant hyperthermia (MH). MH is a pharmacogenetic disorder of skeletal muscle presenting as hyperthermia, tachycardia, tachypnea, metabolic acid–base disturbances, hyperkalemia, muscle rigidity, and rhabdomyolysis that occurs in response to exposure to volatile anesthetics or succinylcholine. MH is considered a hypermetabolic state, which is linked primarily to the RYR1 gene. Due to the high prevalence of RYRI genetic variations in the population, researchers suspect that other hypermetabolic states may also be associated with this gene. If this is the case, IV dantrolene may be useful for these conditions as well as it reduces mortality from 70% to 80% to <10% in MH.

A retrospective, descriptive study was conducted of the U.S. Veterans Health Administration national database from October 1, 2004, to September 30, 2014, to examine the frequency of use, associated diagnoses, clinical characteristics, and outcomes associated with the use of IV dantrolene for hypermetabolic states. All VA patients who received IV dantrolene during an inpatient admission were included in the study.

In the event of multiple admissions, only the last admission was included in the analysis. Patient profiles were screened for ICD-9 codes for 12 primary or secondary diagnoses associated with hypermetabolic syndromes, including MH, heatstroke, myopathies, diabetes with hyperosmolarity, neuroleptic malignant syndrome (NMS), Parkinson’s disease, serotonin syndrome, rhabdomyolysis, masseter muscle rigidity (i.e., muscle rigidity associated with difficulty opening the jaw), severe sepsis, stimulant abuse, and fever of unknown origin (FUO).

The reliability of a MH diagnosis was confirmed using the Malignant Hyperthermia Clinical Grading Scale. Use of medications that could possibly trigger a hypermetabolic syndrome, such as volatile anesthetics, succinylcholine, antipsychotics, antidepressants (excluding monoamine oxidase inhibitors [MAOIs]), MAOIs, anti-Parkinsonian drugs, and triptans, was determined starting 10 days prior to the use of IV dantrolene. A secondary analysis was also conducted to compare the frequency of death among patients with MH, NMS, severe sepsis, and heatstroke who received IV dantrolene compared with those who did not.

During the 10-year period, 304 patients received IV dantrolene nationwide (mean age: 60.8 years). The two most common diagnoses associated with IV dantrolene administration were NMS (35.53%) and severe sepsis (15.46%), with only 4.28% of patients receiving the drug for its labeled indication of MH. Therefore, more than 95% of cases of IV dantrolene administration were for off-label indications. More patients received IV dantrolene for a FUO (7.9%) and for an unclear indication (10.86%) than for its intended use. Among patients who had received IV dantrolene, 55.59% had received antipsychotics and 44.08% had received antidepressants in the previous 10 days. Succinylcholine and volatile anesthetic gases were only administered in 1.32% and 3.62% of patients, respectively.

Approximately one-quarter (24.01%) of patients who received IV dantrolene died, with deaths occurring in 7.69% of those with MH, 20.37% of those with NMS, and 42.55% of those with severe sepsis compared with 5.26%, 6.66%, and 41.9%, respectively, among those who did not receive IV dantrolene. The authors concluded that IV dantrolene does not improve survival in severe sepsis and may be associated with increased mortality in NMS.

This study can serve as justification for pharmacists to conduct medication-use reviews to determine the appropriateness of administration of IV dantrolene in their practice setting.

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