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Complications Associated with the Administration of Dantrolene 1987 to 2006: A Report from the North American Malignant Hyperthermia Registry of the Malignant Hyperthermia Association of the United States

Authors:
  • North American MH Registry of MHAUS

Abstract and Figures

Dantrolene is the only specific treatment for malignant hyperthermia (MH), a genetic disorder in which life-threatening temperature increase has been induced by inhalation anesthetics and succinylcholine. Because MH presents with nonspecific signs and delay of treatment can be fatal, dantrolene may be given as soon as MH is suspected. We report the complications associated with dantrolene administration as documented in AMRA (adverse metabolic/musculoskeletal reaction to anesthesia) reports submitted to the North American Malignant Hyperthermia Registry. AMRA reports were analyzed for differences between subjects with and without complications attributed to dantrolene. Documentation of dantrolene dose and subject weight were inclusion criteria. Because some reported complications were likely due to factors other than dantrolene, a reduced set of cases was also defined. We used χ(2) and Mann-Whitney tests. Logistic regression was applied to describe factors associated with increased risk of complications. In the full dataset of 368 subjects, the most frequent complications associated with dantrolene were muscle weakness (21.7%), phlebitis (9%), gastrointestinal upset (4.1%), and respiratory failure (3.8%). Logistic regression described a 29% increase in risk of any complication when the total dantrolene dose was doubled, a 144% increase in risk when fluid administration was part of treatment, an 83% decrease in risk in the presence of neurosurgery, and a 74% decrease in risk in the presence of oral surgery. In the dataset reduced by removal of some serious complications that were judged likely to have been due to preexisting disease or the MH event, there were 349 subjects. The most frequent complications associated with dantrolene were muscle weakness (14.6%), phlebitis (9.2%), and gastrointestinal upset (4.3%). In this reduced dataset, logistic regression described a 25% increase in risk of any complication when the total dantrolene dose was doubled, a 572% increase in risk in the presence of obstetric or gynecologic surgery, a 56% decrease in risk if furosemide was given, and no relationship with fluid administration or other types of surgery. Complications after dantrolene are common, but rarely life threatening. Unidentified factors in the surgical environment are associated with changes in the risk of complications. Fluid management, as part of the treatment of MH, has an important association with the risk of complications after dantrolene administration and should be monitored closely.
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Complications Associated with the Administration of Dantrolene
1987 to 2006: A Report from the North American Malignant
Hyperthermia Registry of the Malignant Hyperthermia
Association of the United States
Barbara W. Brandom, M.D.,
The North American Malignant Hyperthermia Registry of MHAUS in Mercy Hospital Department
of Anesthesiology, University of Pittsburgh Medical Center and the Department of
Anesthesiology, Pittsburgh, Pennsylvania
Marilyn Green Larach, M.D.,
The North American Malignant Hyperthermia Registry of MHAUS
Min-Shue Alvin Chen, M.D., and
University of Pittsburgh Medical Center
Michael C. Young, M.S.
University of Pittsburgh School of Medicine and The North American Malignant Hyperthermia
Registry of MHAUS
Corresponding Author: Barbara W. Brandom, M.D. The North American Malignant Hyperthermia Registry of MHAUS in Mercy
Hospital Department of Anesthesiology, University of Pittsburgh Medical Center and the Department of Anesthesiology, Pittsburgh,
Pennsylvania North American Malignant Hyperthermia Registry 1400 Locust Street, Room 8522-3, Ermire Building (B), 8th Floor
Pittsburgh, PA 15219 Phone: 1-888-274-7899 FAX: 412-232-7960 (fax) BrandomBW@anes.upmc.edu.
DISCLOSURES
Name: Barbara W. Brandom, MD
Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.
Attestation: Barbara W. Brandom, MD has seen the original study data, reviewed the analysis of the data, wrote and approved the
final manuscript, and is the author responsible for archiving the study files.
Conflicts of Interest: Barbara W. Brandom, MD received honoraria from MHAUS and reported a conflict of interest with MHAUS.
She also received reimbursement for travel to required meetings of MHAUS.
Name: Marilyn Green Larach, MD
Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.
Attestation: Marilyn Green Larach, MD has seen the original study data, reviewed the analysis of the data, and approved the final
manuscript.
Conflicts of Interest: Marilyn Green Larach, MD consulted for MHAUS. She received a consulting fee from MHAUS to develop an
ambulatory surgery center transfer of care document for MH patients and she was reimbursed by MHAUS for travel expenses to
present a paper at a scientific conference.
Name: Min-Shue Alvin Chen, MD
Contribution: This author performed initial data analysis and helped write the manuscript.
Attestation: Min-Shue Alvin Chen, MD has seen the original study data, reviewed the analysis of the data, and approved the final
manuscript.
Conflicts of Interest: Min-Shue Alvin Chen, MD reported no conflicts of interest. Name: Michael C. Young, MS
Contribution: This author analyzed the data and help write the manuscript.
Attestation: Michael C. Young, MS has seen the original study data, reviewed the analysis of the data, and approved the final
manuscript.
Conflicts of Interest: Michael C. Young, MS worked for MHAUS . He is funded by the Malignant Hyperthermia Association of the
United States. This organization receives funding from the manufacturers of dantrolene.
Conflict of Interest: See Disclosures at the end of the article
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Abstract
Background—Dantrolene is the only specific treatment for malignant hyperthermia (MH), a
genetic disorder in which life-threatening temperature increase has been induced by inhaled
anesthetics and succinylcholine. Because MH presents with nonspecific signs and delay of
treatment can be fatal, dantrolene may be given as soon as MH is suspected. We report the
complications associated with dantrolene administration as documented in
AMRA
(
a
dverse
m
etabolic/
m
usculoskeletal
r
eaction to
a
nesthesia) reports submitted to the North American
Malignant Hyperthermia Registry.
Methods—
AMRA
reports were analyzed for differences between subjects with and without
complications attributed to dantrolene. Documentation of dantrolene dose and subject weight were
inclusion criteria. Because some reported complications were likely due to factors other than
dantrolene, a reduced set of cases was also defined. Chi-square and Mann-Whitney tests were
used. Logistic regression was applied to describe factors associated with increased risk of
complications.
Results—In the full dataset of 368 subjects, the most frequent complications associated with
dantrolene were muscle weakness (21.7%), phlebitis (9%), gastrointestinal upset (4.1%) and
respiratory failure (3.8%). Logistic regression described a 29% increase in risk of any
complication when the total dantrolene dose was doubled, a 144% increase in risk when fluid
administration was part of treatment, an 83% decrease in risk in the presence of neurosurgery and
a 74% decrease in risk in the presence of oral surgery.
In the dataset reduced by removal ofsome serious complications that were judged likely to have
been due to preexisting disease or the MH event, there were 349 subjects. The most frequent
complications associated with dantrolene were muscle weakness (14.6%), phlebitis (9.2%) and
gastrointestinal upset (4.3%). In this reduced dataset, logistic regression described a 25% increase
in risk of any complication when the total dantrolene dose was doubled, a 572% increase in risk in
the presence of obstetric or gynecologic surgery, a 56% decrease in risk if furosemide was given
and no relationship with fluid administration or other types of surgery.
Conclusions—Complications after dantrolene are common, but rarely life threatening.
Unidentified factors in the surgical environment are associated with changes in the risk of
complications. Fluid management, as part of the treatment of MH, has an important association
with the risk of complications after dantrolene administration and should be monitored closely.
Introduction
Dantrolene, a skeletal muscle relaxant that reduces myoplasmic calcium,1,2 effectively treats
malignant hyperthermia (MH).3 Because MH presents with nonspecific signs4 and delay of
treatment can be fatal,5 dantrolene may be given as soon as MH is suspected. Also,
dantrolene has been used to treat spasticity,6 reduce the metabolic effects of fever in the
presence of neurologic injury,7 treat cerebral vasospasm,8 neuroleptic malignant syndrome,9
and 3,4-methylenedioxymethamphetamine (Ecstasy) intoxication.10
The medical literature provides limited data on dantrolene’s side effects. In a study of 6
control subjects and 6 MH-susceptible patients, Wedel et al. demonstrated that a 3 mg/kg
dose of IV dantrolene produced visual symptoms more commonly in control subjects than in
MH-susceptible subjects and that MH-susceptible subjects complained more frequently of
muscle weakness, dizziness, and fatigue. For all studied individuals, 7/12 experienced
nausea, 3/12 complained of dyspnea, and 1/12 developed a superficial phlebitis.11 Case
reports note a possible association of dantrolene and the development of muscle
weakness,12,13 respiratory distress,14-16 pleural effusion,17 hepatotoxicity,18 and
hyperkalemia in the presence of concomitant calcium channel blocking drugs.19,20 There
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have been no large postmarketing surveillance (Phase 4) studies of dantrolene’s adverse
effects.
Therefore, we examined the type and frequency of complications associated with dantrolene
as reported to The North American Malignant Hyperthermia Registry via the AMRA
(adverse metabolic/musculoskeletal reaction to anesthesia) Report. Additionally, we tested
the hypothesis that complications from dantrolene administration were associated with
clinical factors or subject characteristics.
This report serves as a benchmark for the experience of the past three decades. During this
time Dantrium®, recently manufactured by Proctor and Gamble, was the only formulation
of dantrolene that was clinically available. In 2008, the manufacturer sold this product.
Reports on the complications of dantrolene after 2008 may have different results specific to
the new formulations by new manufacturers.
Materials and Methods
IRB review deemed this study exempt. Five hundred eighty-two (582) AMRA reports
received by the North American Malignant Hyperthermia Registry as of December 31, 2006
were examined. Inclusion criteria were documentation of weight of the subject, initial or
total dantrolene dose, and treatment after December 31, 1986 in the United States or Canada.
These criteria were met by 368 reports.
The outcomes of interest, complications attributed by clinicians to dantrolene
administration, are specifically queried by checkbox on the AMRA reports. These
complications include phlebitis, muscle weakness, respiratory failure, excessive secretions,
gastrointestinal upset, and hyperkalemia. Health care providers completing the questionnaire
were given the option of writing in additional complications or adding comments (Online
Supplement).
Independent variables that were examined for possible association with complications
included subject sex, weight, age, total dose, total dose adjusted for weight, initial dose,
initial dose adjusted for weight, and whether the subject received more than one dantrolene
dose. Other variables noted on the AMRA reports (including the type of surgery during
which the MH episode occurred, signs of MH, intervals between events, laboratory tests
obtained during or after the MH episode and other procedures used to treat MH) were also
examined for possible association with complications attributed to dantrolene. The
relationship between the presence of complications attributed to dantrolene and the
likelihood of an MH event as documented by the clinical grading scale (CGS) was also
examined. The CGS estimates the qualitative likelihood that a MH event occurred, based on
observed signs and laboratory tests.21
Three datasets were analyzed. The larger set (full dataset) included all cases that met the
inclusion criteria and all complications reported on the AMRA reports in association with
dantrolene. The smaller subset (reduced dataset) removed complications that were likely due
to either underlying medical conditions or the acute MH episode itself rather than to
dantrolene administration. These judgments were made by the anesthesiologist investigators
with MH expertise (BWB and MGL). Cases were excluded if the only complication
associated with dantrolene was grave (respiratory failure, pulmonary edema, hyperkalemia,
low cardiac output) and review of the cases identified a potential medical cause other than
dantrolene for this complication. If muscle weakness was the only complication associated
with dantrolene and review of details by the anesthesiologist investigators with MH
expertise (BWB and MGL) concluded that this was likely due to serious preexisting disease,
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the MH episode itself, or severe rhabdomyolysis, the case was excluded from analysis.
Severe rhabdomyolysis was defined by the indicators for the process of muscle breakdown
in the CGS; creatine kinase more than 10,000 IU without exposure to succinylcholine and
more than 20,000 IU after exposure to succinylcholine. If rhabdomyolysis of this degree was
associated with muscle weakness, muscle weakness was not counted as a complication of
dantrolene in analysis of the reduced dataset. Hyperkalemia was removed as a complication
if the potassium level was ≤6.0 mEq/L, renal disease was present before dantrolene
administration, or the MH event was ranked as “very likely” or “almost certain.” For those
cases with both a serious complication likely due to factors other than dantrolene and other
complications, which may have been due to dantrolene, the case remained in the reduced
dataset but without the serious complications. The smallest dataset was created by
discounting technical drug administration complications (e.g., difficulty with mixing
dantrolene with diluent or the observation of precipitate in the IV tubing) as a dantrolene
complication in the reduced dataset.
Several methods were used to test the hypothesis that complications from dantrolene
administration were associated with clinical factors or subject characteristics in the full and
the reduced datasets. Because many of the variables occurred in very few cases or were not
distributed normally, nonparametric or exact tests were used to identify potentially
significant factors. For continuous variables, the Mann-Whitney test was used to compare
the mean values of the groups in which the complication occurred with that in which it did
not occur. For categorical variables, a Fisher exact test was used to assess the difference
between the groups. Variables with p<0.2 in these univariate tests that were reported at least
10 times in this dataset became candidates for entry into a multivariate logistic regression
model. Stepwise selection into a logistic regression was performed to minimize the -2 log
likelihood of the risk of any dantrolene complication. A Wald statistic with p< 0.05
indicated statistical significance. Logistic regressions were developed to assess the
association of all variables and their potential interactions with the outcome of any
complication reported with dantrolene. Correlation between variables of interest was
examined. Analysis was performed using SPSS for Windows release 16.0.1 (SPSS Inc.,
Chicago, IL).
Odds ratios were calculated from the logistic regression.
P
values less than 0.05 were
accepted as statistically significant. The mean is presented with standard deviation. The
median is presented with 1st and 3rd quartiles and range.
Results
Age and weight of the subjects and the CGS of the events are presented in Table 1. Doses of
dantrolene administered are summarized in Table 2.
Full Dataset
Data from the full set of 368, predominantly male (73.4%), subjects are presented in Tables
1 through 4. There were 95 (25.8%) subjects who received a single dose of dantrolene, 258
(70.1%) who received more than one dose, and 15 (4.1%) whose dose frequency was
unknown. Because each 20 mg vial of dantrolene requires 60 ml of sterile water diluent,
median, 1st and 3rd quartile total dantrolene doses required the co-administration of 702
(300, 1,800) ml of sterile water, respectively.
In 129 of the 368 subjects (35.1%) in the full dataset, a complication was noted with
dantrolene administration (Table 3; Figure 1). Of these, 37 (10.1%) had more than one
complication associated with dantrolene administration. In these 129 subjects the median
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number of complications was 1, as was the 1st quartile, while the 3rd quartile was 2 and the
range 1 to 5.
The logistic regression model that best described the risk of any complication associated
with dantrolene in these 368 cases included the natural log of the dose of dantrolene in mg,
and the binary variables: fluid administration, oral surgery and neurosurgery (Table 4).
Observations that were not part of the logistic regressions include the following: before or
during the adverse anesthetic reaction in 101 of 368 cases, either a central venous or
pulmonary artery catheter or a transesophageal echocardiogram probe was placed. There
was no significant difference in the frequency of dantrolene complications (P=0.46) between
those with and without these monitors.
Of the 80 subjects with muscle weakness, 5 were known to have either a history of muscle
weakness or a physical finding of generalized muscle weakness or myopathy before the
dantrolene administration. The median total dose of dantrolene was larger for those who
experienced muscle weakness (400 mg vs. 212 mg), P=0.002. Logistic regression indicated
that doubling the total dose of dantrolene increased by 27% the likelihood of a muscle
weakness complication, P=0.002. Of the 80 reports of muscle weakness, 33 had a
documented duration of dantrolene administration. Of these 33 subjects, 22 had received
dantrolene for at least 24 hours.
Twelve subjects were reported to have experienced hyperkalemia as a complication of
dantrolene (serum potassium of 5.2 to 9.9 mEq/L). Subjects with hyperkalemia had higher
CGS scores (P=0.005). Review of the hyperkalemia cases determined that preoperative renal
failure was present in 2 and none of the others received concomitant calcium channel
blockers. All subjects with hyperkalemia had experienced a “very likely” or “almost certain”
MH event.
There were also 14 cases with respiratory failure, 6 with pulmonary edema and 2 with low
cardiac output reported in association with dantrolene administration. One of the 14 subjects
with respiratory failure was known to have a myopathy before the dantrolene administration.
The 6 patients with pulmonary edema had all received fluid administration, volume
unknown, as part of their MH treatment. There were 18 subjects with one or more of these
grave complications reported in addition to the other complications associated with
dantrolene. In 12 of these patients, there was evidence of serious underlying disease or
complex surgery, such as concomitant administration of multiple vasoactive drugs and
recent cardiovascular surgery including cardiopulmonary bypass. In 2 of 18 patients there
was no evidence of such complicating factors. These two patients had CGS scores of 43 and
58, indicating that the events were “very likely” or “almost very likely or almost certain”
MH.
Four subjects were reported to have developed compartment syndrome as a complication of
dantrolene. After review of the
AMRA
reports, the anesthesiologist authors (MGL and
BWB) considered that these 4 cases of compartment syndrome were likely secondary to an
adverse reaction to anesthesia (including MH) or a preexisting condition (trauma) rather
than to dantrolene administration. This complication was still counted in the full dataset, but
not in the reduced dataset.
Figure 2 depicts the number of cases with and without fluid administration who experienced
a complication stratified by dantrolene dose in comparison with those who did not
experience a complication. In the 98 cases in which fluid administration was reported as part
of MH treatment, muscle weakness was 2.7 times more likely to be reported (P=0.003) and
succinylcholine given two times as often (P=0.005), the median absolute total dantrolene
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dose was 1.3 times larger (P=0.002), and the median total dantrolene dose/kg was 1.5 times
larger (P=0.015) in comparison with cases that did not report fluid administration as part of
therapy. Also, the median CGS score was higher in those receiving fluid administration (51,
“almost certain MH”) than those who did not (38, “very likely MH”), P<0.0005.
Reduced Dataset
Data from the reduced set of 349, predominantly male (72.8%), subjects is presented in
Tables 1 - 4. The relationship between dantrolene dose and complications is depicted in
Figure 3. There were 88 (25.2%) subjects who received a single dose of dantrolene, 232
(66.5%) who received more than one dose, and 29 (8.3%) whose dose number was
unknown. Median, 1st and 3rd quartile total dantrolene doses required the co-administration
of 666 (284, 1,800) ml of sterile water, respectively.
The reduced subset of cases had fewer complications, by definition, but muscle weakness
was still common and the incidence of phlebitis and gastrointestinal upset was unchanged
(Table 3). In the 83 subjects with at least one complication, the median number of
complications was 1, as was the 1st quartile, while the 3rd quartile was 2 and the range 1 to
4. In the reduced dataset, subjects with either a central venous or a pulmonary artery catheter
or a transesophageal echocardiography probe were 2.77 times less likely to experience a
dantrolene complication than those without such monitors, P=0.002.
Of the 51 reports of muscle weakness, 19 had a documented duration of dantrolene
administration. Of these 19 subjects, 13 had received dantrolene for at least 24 hours. Those
experiencing muscle weakness had received a significantly higher dose of dantrolene than
those who did not experience this complication (360 mg vs. 212 mg), P=0.011. Logistic
regression indicated that doubling the dantrolene dose increased by 25% the likelihood of a
muscle weakness complication, P=0.012. Figure 4 depicts the number of subjects who
received or did not receive furosemide and who did or did not develop a complication
stratified by total dantrolene dose. Those subjects treated with furosemide (n=106) received
a higher median total dantrolene dose (380 mg vs. 200 mg, P<0.0005) and a higher median
total dantrolene dose/kg (6.2 mg/kg vs. 4.0 mg/kg, P=0.002), although their CGS scores did
not differ.
The logistic regression model that best described the risk of any complication associated
with dantrolene administration in the reduced dataset of 349 cases included the natural log
of dose of dantrolene, obstetric or gynecologic surgery, and administration of furosemide
(Table 4).
When the reduced dataset is further reduced by discounting problems with mixing or
precipitate in the IV tubing as complications of dantrolene, the same number of cases
contributes to regression analysis, and the same variables appear in the model. The
coefficients of the variables in the logistic regression changed slightly, but not significantly.
Comparison of Models from the Two Datasets
When the statistically significant binary variables, fluid administration, furosemide
administration and some types of surgery, were added to the model of dantrolene
complications, the odds ratio for dantrolene complications decreased. There was no
difference in the effect of increasing the dose of dantrolene on the risk of complications as
described by logistic regression between the full and the reduced dataset. The coefficients of
the natural logarithm of the dose of dantrolene were not significantly different (Z=1.21).
The binary variables and the incidence of complications are presented in Table 5. The
presence of fluid administration was associated with a 144% increase in risk of reported
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dantrolene complications and administration of dantrolene during oral surgery or
neurosurgery was a protective factor only when the most severely ill patients (the full
dataset) are part of the model. In the reduced dataset none of these binary variables was
significant, however a new protective variable, furosemide administration, was associated
with a reduced risk of reported dantrolene complications and administration of dantrolene
during obstetric or gynecologic surgery greatly increased the risk of complications.
In both datasets weight, age, and dantrolene dose unadjusted for weight were very highly
correlated (Tables 6 and 7). If weight were forced into a model of dantrolene complications,
none of the doses of dantrolene would have sufficient power to enter the model. Age had the
same role in this dataset.
Discussion
We found that complications from dantrolene administration were associated with clinical
factors. The complications of dantrolene were related to the total dose administered, but not
to the initial dose or dose/weight. In these datasets, dantrolene dose, weight and age were
correlated. The likelihood of dantrolene-associated complications did not change with
increasing severity of the MH event as measured by either the CGS score or rank.
Complications were examined as a function of the subjects’ clinical status to create a
reduced dataset that represents a minimum estimate of the factors associated with
complications during dantrolene administration. This is in contrast to the full dataset that
provides a maximum estimate of the factors associated with complications associated with
dantrolene regardless of underlying medical or surgical conditions. While analysis of the
reduced dataset reduced the odds ratio for risk of increasing complications with increasing
dose of dantrolene, the observed change was not statistically significant.
The small numbers of cases of oral surgery, neurosurgery and obstetric and gynecologic
surgery make it difficult to identify any factors that could be expected to be responsible for
differences in risk of complications associated with dantrolene administration in these cases.
The lower risk of complications during neurosurgery may be related to details of the
anesthetic environment during this type of surgery, including fluid restriction. However, we
were unable to attribute the lower risk to either more intensive monitoring or shorter inhaled
anesthetic exposure. The
AMRA
report does not request data on the dose of potent inhaled
anesthetic or the specific details of fluid management beyond asking whether fluid
administration was used as a MH treatment. The low number of neurosurgical, oral surgery
and obstetric and gynecologic surgery cases, however, suggests that a larger dataset might
not produce the same conclusions.
The finding that administration of a fluid load is associated with increased risk of
complications associated with dantrolene when cases with grave cardiovascular, pulmonary
and/or renal conditions, including severe MH, are present is not surprising. Mannitol is part
of this formulation of dantrolene. There will be fluid shifts due to the pathophysiology of
MH and due to mannitol. Also, reconstitution of dantrolene for administration requires 3 ml
of sterile water for every 1 mg of dantrolene administered. 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 we were
unable to demonstrate a reduction in dantrolene-associated complications with their use in
the full dataset. Fluid management during treatment of MH may be challenging even in the
relatively healthy patient, since use of monitoring and administration of furosemide was
associated with reduced risk of complications in the reduced dataset of patients without
preexisting systemic disease.
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Muscle weakness was the most common complication of dantrolene administration and was
associated with total dose received. Flewellen et al. reported that maximum muscle
weakness in normal volunteers occurs at a dantrolene dose of 2.4 mg/kg, which produces a
plasma concentration near the therapeutic concentration of the drug.22 Therefore, it is not
surprising that muscle weakness was frequently reported in our subjects who received a
therapeutic dose of dantrolene. Since 80% of recrudescence events occurred within 16
hours23 of the initial MH treatment, it seems reasonable to suggest that if a patient receiving
dantrolene has muscle weakness and is metabolically stable 24 hours after initial therapy,
dantrolene could be administered at longer intervals or at a reduced infusion rate and then
stopped. Patients who experience acute MH may also experience muscle weakness as a
result of muscle injury that can be part of this syndrome. The clinician treating an MH
episode should request repeated measurement of creatine kinase until it returns to normal
levels. Patients with muscle weakness may require longer periods of postoperative positive
pressure ventilation, which has its own associated increase in morbidity and mortality.
The 9% incidence of phlebitis is unsurprising given dantrolene’s high pH (9.5) and relative
insolubility. The frequency of phlebitis does suggest that once an acute MH event is
controlled, efforts should be made to administer dantrolene via a large bore IV and all IV
sites should be carefully monitored. Gastrointestinal upset was reported in 4% of our
subjects. This side effect has been observed in humans.11, 22, 24 Dantrolene has been
demonstrated to interfere with excitation-contraction coupling of murine intestinal smooth
muscle cells25 and rat gastric fundus, and colon.26
The benefit of logistic regression is that it identified variables that contributed to a
statistically significant description of the risk of complications after administration of
dantrolene. It is noteworthy that the total dose of dantrolene is identified by logistic
regression as an important risk factor. However, in clinical practice dantrolene is usually
administered in a dose based on patient weight. Therefore heavier patients will usually
receive a larger total dose. There was not sufficient power to identify a significant
interaction between weight and dose in these logistic regression models.
Because the dose of dantrolene was related to the reported complications, we reviewed the
dantrolene dose administered by clinicians in this case series and what might have been their
rationale for this dosing. The initial dose of dantrolene per kilogram in this report was not
different from the dantrolene dose that has been recommended by the Malignant
Hyperthermia Association of the United States. This recommendation was based on the
results of the study by Kolb et al.3 Because recrudescence of MH occurs in a substantial
number of patients23 it is important to continue dantrolene administration after initial
therapy. There is a plateau phase in the plasma decay of dantrolene which lasts between four
and six hours.22, 27 Therefore, the recommendation is to administer an additional 1 mg/kg
every six hours after initial dosing to treat an acute MH episode, assuming that the patient is
clinically stable. Others have suggested administration of a continuous infusion of
dantrolene to produce more stable plasma concentrations.28 If the patient is not stable, more
dantrolene should be administered until all signs of MH have abated. There is no formal
recommendation as to the maximal dose of dantrolene that should be given. Recrudescence
is a serious condition with possibly fatal outcome. It is expected that administration of
dantrolene for at least 24 hours will decrease the frequency of recrudescence.
We chose to examine all cases in which dantrolene was administered, regardless of the
likelihood that MH was occurring in that case, because our goal was to describe potential
complications associated with administration of this drug. A limitation of this study is the
voluntary nature of reporting to this database. Another limitation of this study is incomplete
and possibly biased reporting on
AMRA
reports. Often the individual who reported the
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identification and initial treatment of an MH episode transferred the patient to the care of an
intensivist. This may have resulted in underreporting of the total dose of dantrolene given
and underreporting of the late complications of MH treatment.
To evaluate complications that may be associated with new formulations of dantrolene,
anesthesia providers should document in detail the anesthetics that they suspect are
complicated by MH by completing an
AMRA
report for suspected MH events and sending it
to the North American Malignant Hyperthermia Registry (www.mhreg.org). The data
supplied by such reports are necessary for improving our ability to diagnose and treat this
anesthetic-induced disease.
In summary, we report a 24% rate of complications associated with the administration of
dantrolene in 349 cases. The most common complications observed were muscle weakness,
phlebitis and gastrointestinal upset. In cases where serious underlying medical conditions
were also present, respiratory failure, pulmonary edema, and hyperkalemia were additionally
noted as complications. These severe complications were most likely due to the patient’s
underlying medical conditions rather than dantrolene administration itself. The likelihood of
a complication associated with dantrolene administration increased as the dose of dantrolene
increased, was variably affected by the type of surgery, and could be greatly increased by
fluid administration (full dataset) and decreased by administration of furosemide (reduced
dataset). When dantrolene is administered, clinicians should exercise vigilance for changes
in intravascular fluid volume and subsequent development of cardiorespiratory
complications.
Supplementary Material
Refer to Web version on PubMed Central for supplementary material.
Acknowledgments
We thank Douglas Landsittel, Ph.D. of the Center for Research on Health Care Data Center, Institute for Clinical
Research Education, Associate Professor of Medicine and of Clinical and Translational Science at the University of
Pittsburgh, Pittsburgh, PA who also contributed to the revision of this manuscript through consultation on
alternative statistical approaches. His effort was made possible by Grant Number 5UL1 RR024153-04 from the
National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH
Roadmap for Medical Research. However, the contents of this manuscript are solely the responsibility of the
authors and do not necessarily represent the official view of NCRR or NIH. We also thank Gregory C. Allen, MD,
FRCPC, MH Hotline consultant and director emeritus of the North American Malignant Hyperthermia Registry of
MHAUS and member of Olympia Anesthesia Associates in Olympia, Washington, for his helpful review of the
manuscript. We are grateful for the valuable time that many anesthesiologists and other health care providers have
spent submitting
AMRA
reports to the North American Malignant Hyperthermia Registry and Kristee Adams for
her contributions to the production of this manuscript.
Funding: North American Malignant Hyperthermia Registry of the Malignant Hyperthermia Association of the
United States, Pittsburgh, PA
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Figure 1.
depicts the number of cases in the full dataset with and without complications stratified by
dantrolene dose category. X axis is dantrolene dose category with I = 1 -20 mg, II = 21 -80
mg, III = 81-320 mg, IV = 321-1,280 mg, and V>1,280 mg. Y axis is number of cases.
Green shading indicates no dantrolene complications; yellow shading indicates dantrolene
complications.
Brandom et al. Page 12
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Figure 2.
depicts the number of cases in the full dataset with and without fluid administration and with
and without complications, stratified by dantrolene dose category. X axis is the dantrolene
dose category with I = 1 -20 mg, II = 21 -80 mg, III = 81-320 mg, IV = 321-1,280 mg, and
V>1,280 mg. Y axis is number of cases. Green shading indicates no dantrolene
complications; yellow shading indicates dantrolene complications.
Brandom et al. Page 13
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Figure 3.
depicts the number of cases in the reduced dataset with and without complications stratified
by dantrolene dose category. X axis is dantrolene dose category with I = 1 -20 mg, II = 21
-80 mg, III = 81-320 mg, IV = 321-1,280 mg, and V>1,280 mg. Y axis is number of cases.
Green shading indicates no dantrolene complications; yellow shading indicates dantrolene
complications.
Brandom et al. Page 14
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Figure 4.
depicts the number of cases in the reduced dataset with and without furosemide and with and
without complications, stratified by dantrolene dose category. X axis is the dantrolene dose
category with I = 1 -20 mg, II = 21 -80 mg, III = 81-320 mg, IV = 321-1,280 mg, and
V>1,280 mg. Y axis is number of cases. Green shading indicates no dantrolene
complications; yellow shading indicates dantrolene complications.
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Table 1
Subject and Event Characteristics
Full Dataset
Characteristic N Median 25% 75% Range
Age, yr 346 20.0 8.0 37.0 0 – 78
Weight, kg 368 68.0 24.3 85.7 3 – 159
CGS Score
*
368 48 33 60 0 – 88
Restricted
Dataset
Characteristic N Median 25% 75% Range
Age, yr 328 19.0 7.0 35.8 0 - 78
Weight, kg 349 66.4 23.7 84.1 3 - 159
CGS Score
*
349 48 33 58 0 - 88
*
The clinical grading scale (CGS) score is designed to translate to a malignant hyperthermia (MH) rank that estimates the qualitative likelihood that an episode of MH occurred, based on observed signs and
laboratory tests.33 CGS more than 34 indicates very likely MH. CGS greater than 49 indicates MH is almost certain. There were no significant differences between datasets for the listed characteristics.
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Table 2
Dantrolene Doses
Full Dataset
Dose Type N Median 25% 75% Range
Total Dose, mg 368 234.0 100.0 600.0 2.0 – 6,720
Total Dose, mg/kg 368 4.9 2.5 9.0 0.02 – 100
Initial Dose, mg/kg 364 2.4 1.7 2.7 0 – 15.0
Reduced
Dataset
Dose Type N Median 25% 75% Range
Total Dose, mg 349 222.0 94.5 600.0 2.0 – 6,720
Total Dose, mg/kg 349 4.7 2.5 8.7 0.02 - 100
Initial Dose, mg/kg 345 2.4 1.6 2.6 0 – 15.0
Dantrolene doses were reported in the
AMRA
(
a
dverse
m
etabolic/
m
usculoskeletal
r
eaction to
a
nesthesia) as initial dose and total dose. There were cases in which one of these two was not reported.
Therefore, the Total Dose was defined as the total dose when reported or the initial dose if no other dose was reported. This definition of total dose is the variable used in regression analysis. There was no
significant difference between the full and reduced datasets for any of these dantrolene doses.
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Table 3
Complication Frequency
Complication Type Full
Dataset
(n=368)
Number (%)
Reduced
Dataset
(n=349)
Number (%)
Any Complication 129 (35.1) 83 (23.8)
Muscle Weakness 80 (21.7) 51 (14.6)
Phlebitis 33 (9.0) 32 (9.2)
Gastrointestinal Upset 15 (4.1) 15 (4.3)
Respiratory Failure 14 (3.8) 0 (0)
Hyperkalemia 12 (3.3) 0 (0)
Excessive Secretions 3 (0.8) 3 (0.9)
Other Complications 30 (8.2)
*
13 (3.7)
**
*
Other complications for the full dataset included: pulmonary edema (N=6), difficulty mixing dantrolene or precipitate in the IV (N=5), pain on
injection (N=3), swollen extremity (N=2), concomitant decrease in cardiac output (N=2), prolonged mechanical ventilation (N=2), and
hypotension, decreased hearing for 24 hours, blurred vision, difficulty opening eyes, anxiety for several minutes after injection, dysphoria,
disorientation, somnolence, generalized weakness, increased alanine aminotransferase (ALT) on the second postoperative day, hyponatremia, each
noted once in the full dataset. Some subjects had more than one complication.
**
Other complications for the reduced dataset included: difficulty mixing dantrolene or precipitate in the IV (N=5), pain on injection (N=3) and
swollen extremity, decreased hearing for 24 hours, blurred vision, dysphoria, disorientation, somnolence, each noted once in the reduced dataset.
Some subjects had more than one complication.
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Table 4
Logistic Regressions: Outcome is the Risk of Any Complication Associated with Dantrolene
Full
Dataset
(N=368)
Variables Coefficients S.E. P Value Odds Ratio (95% CI)
Dose Factor
*
0.363 0.101 0.000 1.29 (1.12-1.48)
Fluid
Administration 0.893 0.289 0.002 2.44 (1.37-4.35)
Oral Surgery −1.341 0.581 0.021 0.26 (0.08-0.84)
Neurosurgery −1.760 0.647 0.006 0.17 (0.05-0.63)
Constant −3.142 0.599 0.000
Reduced
Dataset
(N=349)
Dose Factor
*
0.317 0.111 0.004 1.25 (1.07-
1.45)
Obstetrics/
Gynecology 1.906 0.608 0.002 6.72 (1.99-
22.7)
Furosemide −0.822 0.317 0.009 0.44 (0.23-
0.82)
Constant −2.766 0.614 0.000
*
Dose Factor is the natural log of the total dose of dantrolene or of the initial dose if a total dose was not reported.
The logistic regression for the full dataset describes a 29% increase in risk of any complication when the total dantrolene dose was doubled, a 144% increase in risk when fluid administration was part of
treatment, an 83% decrease in risk in the presence of neurosurgery and a 74% decrease in risk in the presence of oral surgery.
The logistic regression for the reduced dataset describes a 25% increase in risk of any complication when the total dantrolene dose was doubled, a 572% increase in risk in the presence of obstetric or
gynecologic surgery, a 56% decrease in risk if furosemide was given and no relationship with fluid administration or other types of surgery.
As is common in statistical analysis, some but not all of the assumptions of this technique are met by the data. The outcome variable, presence or absence of complications reported after dantrolene
administration, is binary, but it is a composite of all reported complications. The independent variables are not linear combinations of each other. Observations are independent because each case is
independent. There may be error in the measurement of independent variables. As described in Methods we used stepwise entry of variables into the regression to judge that no important variables were
omitted and no extraneous variables were included. We assume that the logit function is appropriate to describe the outcome variable. For all the above reasons we do not propose that these regressions are
sufficient to predict the occurrence of complications. Our goal is to use the available data to alert the clinician to conditions which have been associated with complications after administration of
dantrolene. For example, the logistic regression for the full model describes an 18.7% chance of any complication after administration of 100 mg of dantrolene in the absence of fluid administration,
neurosurgery or oral surgery. The dose of 100 mg dantrolene is the 1st quartile of the distribution of doses and 600 mg is the 3rd quartile. Increasing the dose to 600 mg is associated with 30.6% chance of
any complication and in the presence of fluid administration the chance of any complication increases to 51.8%. Similarly the logistic regression for the reduced model describes a 21.0% chance of any
complication after administration of 94.5 mg of dantrolene in the absence of furosemide or obstetric-gynecologic surgery. The dose of 94.5 mg dantrolene is the 1st quartile of the distribution of doses and
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600 mg is the 3rd quartile in the reduced dataset. Increasing the dose to 600 mg is associated with 32.3% chance of any complication and in the presence of furosemide the chance of any complication
decreases to 17.4%.
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Table 5
Number of Complications in Binary Variables of Interest in Both Models
Dataset Type Variable Any Complication No Complications
Full Dataset
Fluid Administration 109 161
No Fluid Load 20 78
Oral Surgery 4 18
None 125 221
Neurosurgery 3 20
None 126 219
Reduced Dataset
Obstetrics/Gynecology 8 5
None 75 261
Furosemide 19 87
None 64 179
This table presents the data that contributed to significant logistic regressions modeling for the risk of complications associated with dantrolene.
The total number in each of these 2 by 2 comparisons differs because the first three variables in Table 5 were significant in the full dataset model
and the last two in the reduced dataset model.
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Table 6
Correlations Matrix of Variables for the Full Dataset
Full Dataset Weight
(kg) Age
(years) Initial Dose
(mg) Total Dose
(mg) Total Dose
(mg/kg)
Weight (kg) Pearson Correlation 1.000 .678
**
.581
**
.470
**
.040
Sig (2-tailed) .000 .000 .000 .445
Age (Years) Pearson Correlation .678
**
1.000 .399
**
.298
**
.011
Sig (2-tailed) .000 .000 .000 .842
Initial Dose Pearson Correlation .581
**
.399
**
1.000 .484
**
.188
**
Sig (2-tailed) .000 .000 .000 .000
Total Dose Pearson Correlation .470
**
.298
**
.484
**
1.000 .706
**
Sig (2-tailed) .000 .000 .000 .000
Total Dose (mg/kg) Pearson Correlation .040 .011 .188
**
.706
**
1.000
Sig (2-tailed) .445 .842 .000 .000
**
Correlation is significant (sig) at the 0.01 level (2-tailed).
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Table 7
Correlations Matrix of Variables for the Reduced Dataset
Reduced Dataset Weight
(kg) Age
(years) Initial Dose
(mg) Total Dose
(mg) Total Dose
(mg/kg)
Weight (kg) Pearson Correlation 1.000 .685
**
.571
**
.453
**
.029
Sig (2-tailed) .000 .000 .000 .585
Age (Years) Pearson Correlation .685
**
1.000 .413
**
.298
**
.009
Sig (2-tailed) .000 .000 .000 .871
Initial Dose Pearson Correlation .571
**
.413
**
1.000 .480
**
.186
**
Sig (2-tailed) .000 .000 .000 .001
Total Dose Pearson Correlation .453
**
.298
**
.480
**
1.000 .707
**
Sig (2-tailed) .000 .000 .000 .000
Total Dose (mg/kg) Pearson Correlation .029 .009 .186
**
.707
**
1.000
Sig (2-tailed) .585 .871 .001 .000
**
Correlation is significant (sig) at the 0.01 level (2-tailed).
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... The patient was transported with the anesthesiology team by ambulance with ETCO2 and vital sign monitoring to the receiving dantrolene [7]. The mechanism is thought to be attributed to the insolubility of dantrolene and its alkaline pH. ...
... Another study suggested that dantrolene may cause skeletal weakness and result in a higher likelihood of thrombogenesis [8]; however, given the location of phlebitis in this patient, the latter mechanism seems less likely. Complications may be related to the total dantrolene dose administered [7]. Dantrolene should be administered through a large-bore IV or central access and sites should be assessed for evidence of phlebitis. ...
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... It is widely available, from generic formulations to more sophisticated preparations designed to reduce the number of vials needed for reconstitution of the drug. Brandom et al. demonstrated that the complications with dantrolene are rarely life-threatening but may include muscle weakness (14.6%), phlebitis (9.2%), and gastrointestinal upset (4.3%) [11]. The benefits of using dantrolene with our patient certainly outweighed the risks, resulting in a favorable outcome, but such prudent clinical decisions may have longlasting effects. ...
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Malignant hyperthermia is defined in the International Classification of Diseases as a progressive life‐threatening hyperthermic reaction occurring during general anaesthesia. Malignant hyperthermia has an underlying genetic basis, and genetically susceptible individuals are at risk of developing malignant hyperthermia if they are exposed to any of the potent inhalational anaesthetics or suxamethonium. It can also be described as a malignant hypermetabolic syndrome. There are no specific clinical features of malignant hyperthermia and the condition may prove fatal unless it is recognised in its early stages and treatment is promptly and aggressively implemented. The Association of Anaesthetists has previously produced crisis management guidelines intended to be displayed in all anaesthetic rooms as an aide memoire should a malignant hyperthermia reaction occur. The last iteration was produced in 2011 and since then there have been some developments requiring an update. In these guidelines we will provide background information that has been used in updating the crisis management recommendations but will also provide more detailed guidance on the clinical diagnosis of malignant hyperthermia. The scope of these guidelines is extended to include practical guidance for anaesthetists dealing with a case of suspected malignant hyperthermia once the acute reaction has been reversed. This includes information on care and monitoring during and after the event; appropriate equipment and resuscitative measures within the operating theatre and ICU; the importance of communication and teamwork; guidance on counselling of the patient and their family; and how to make a referral of the patient for confirmation of the diagnosis. We also review which patients presenting for surgery may be at increased risk of developing malignant hyperthermia under anaesthesia and what precautions should be taken during the peri‐operative management of the patients.
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Faced with a malignant hyperthermia crisis, the immediate access to sufficient dantrolene is essential to achieve the best possible outcome for the patient. However, malignant hyperthermia crises are rare, and there may be administrative pressures to limit the amount of dantrolene stocked or, in some countries, not to stock dantrolene at all. There are no published guidelines to support anaesthetic departments in their effort to ensure availability of sufficient dantrolene for the management of malignant hyperthermia crises. After a literature review that confirmed a lack of clinical trials to inform this guideline, we undertook a formal consensus development process, in which 25 members of the European Malignant Hyperthermia Group participated. The consensus process used a modified web-based Delphi exercise, in which participants rated the appropriateness of statements that covered the dosing regimen for dantrolene in a malignant hyperthermia crisis, the types of facility that should stock dantrolene, and the amount of dantrolene that should be stocked. The resulting guidelines are based on available evidence and the opinions of international malignant hyperthermia experts representing a large group of malignant hyperthermia laboratories from around the world. Key recommendations include: the dosing regimen of dantrolene should be based on actual body weight, dantrolene should be available wherever volatile anaesthetics or succinylcholine are used, and 36 vials of dantrolene should be immediately available with a further 24 vials available within 1 h.
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Introduction Cerebral vasoconstriction is associated with increased cytosolic Ca2+ concentration in vascular smooth muscle, presumably due to Ca2+ influx and Ca2+ release from intracellular stores. We tested the hypothesis that dantrolene (a blocker of Ca2+-induced Ca2+ release from the ryanodine receptor channel on the sarco-endoplasmic reticulum) would potentiate the action of nimodipine (a voltage-dependent L-type Ca2+ channel blocker, considered standard therapy for SAH) in inhibiting the vasoconstriction of isolated cerebral arteries. Method Sprague–Dawley rat basilar and femoral arteries were analyzed for ryanodine receptor expression by immunofluorescence and PCR. Vasoconstriction of basilar artery ex vivo was measured in a wire myograph while exposed to serotonin (5-HT) or endothelin-1 (ET-1) in the presence or absence of dantrolene (10–100 μM) and/or nimodipine (30 nM). Femoral artery was examined for comparison. Results Basilar and femoral arteries express only the ryanodine receptor 3 (RyR3) isoform. In both basilar and femoral arteries, dantrolene significantly inhibited the constriction to 5-HT, whereas it poorly affected the constriction to ET-1. The inhibitory effect of dantrolene on 5-HT was substantially increased by nimodipine, inducing a 10-fold increase in the 50% effective concentration of 5-HT and a 46% reduction in maximum basilar constriction. In femoral artery, dantrolene modestly affected constriction to phenylephrine and there was no interaction with nimodipine. Conclusion Dantrolene has synergistic effects with nimodipine against 5-HT-induced vasoconstriction in isolated cerebral arteries. Dantrolene–nimodipine interaction will require testing in a pathophysiological model but might provide treatment for reducing SAH-related vasospasm or other 5-HT-related vasospastic syndromes, such as Call-Fleming syndrome.
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The use of dantrolene in the treatment of hyperpyrexia related to MDMA (3,4-methylenedioxymethamphetamine) is controversial, with little data available to guide clinical decision-making. Although the treatment is recommended by several poison control centres, published data are primarily in the form of case reports and animal and in vitro experiments. We conducted a systematic review to investigate the published evidence regarding the safety and benefits of dantrolene for MDMA-related hyperpyrexia in humans. A systematic search of Embase and MEDLINE was conducted from the earliest possible date to November 2008. All human trials and case reports of MDMA related hyperpyrexia were considered. Data were abstracted systematically and characteristics including use of dantrolene, adverse reactions attributed to dantrolene, peak temperature, complications from MDMA-related hyperpyrexia and survival were recorded. Our search yielded 668 articles of which 53, reporting 71 cases of MDMA-induced hyperpyrexia, met our inclusion criteria. No clinical trials, randomized controlled trials, observational studies or meta-analyses were identified. Dantrolene was used in 26 cases. Patient characteristics were similar in the dantrolene and no dantrolene groups. The proportion of survivors was higher in the dantrolene group (21/26) than in the no dantrolene group (25/45). This difference was especially pronounced in those with extreme (≥ 42°C) and severe (≥ 40°C) fever, with a survival rate of 8 of 13 and 10 of 10, respectively, in the dantrolene group compared with 0 of 4 and 15 of 27 in the no dantrolene group. There were no reports of adverse events attributable to dantrolene with the exception of a possible association with an episode of transient hypoglycemia. Our systematic review suggests that dantrolene is safe for patients with MDMA-related hyperpyrexia. Dantrolene may also be associated with improved survival and reduced complications, especially in patients with extreme (≥ 42°C) or severe (≥ 40°C) hyperpyrexia, although this conclusion must be interpreted with caution given the risk of reporting or publication bias.
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Calcium plays a central role in neuronal function and injury. Dantrolene, an inhibitor of the ryanodine receptor, inhibits intracellular calcium release from the sarco-endoplasmic reticulum. We review the available data of dantrolene as a potential neuroprotective agent and briefly summarize its other pharmacologic effects that may have potential applications for patients in the neurointensive care unit (NICU). Areas with the need for continued research are identified.
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