ArticlePDF Available

Update on Dantrolene in the Treatment of Anesthetic Induced Malignant Hyperthermia

  • North American MH Registry of MHAUS
*Corresponding author email:
Symbiosis Group
Update on Dantrolene in the Treatment of Anesthetic
Induced Malignant Hyperthermia
Brandom BW*, Kang A, Sivak EL and Young MC
Department of Anesthesiology, Mercy Hospital UPMC, University of Pittsburgh Medical Center, USA
SOJ Anesthesiology and Pain Management
Open Access
Research Article
Adverse Metabolic/Muscular Reaction to Anesthesia Reports
(AMRAs) received after January 1, 2007 and before December 31,
2013 in the North American Malignant Hyperthermia Registry of
the Malignant Hyperthermia Association of the United States were
examined with the goal of describing any changes in the administration
of dantrolene, complications associated with dantrolene or with the
Malignant Hyperthermia (MH) episode itself that might contribute to
increased morbidity. Greater age of the patient, longer time from the
          
        
all found to be associated with increased risk of complications due
     
dantrolene from the previous report of AMRAs prior to 2007. Patients
in whom Pulmonary Edema (PE) was reported received about twice
those in whom PE was not reported.
Received: December 24, 2014; Accepted: April 10, 2015, Published: April 20, 2015
*Corresponding author: Brandom BW, Department of Anesthesiology, Mercy Hospital UPMC, North American MH Registry of MHAUS, University of
Pittsburgh Medical Center, Ermire Building (B) 8th floor, 1400 Locust St, Pittsburgh, PA, 15219, USA, Tel: 4122325679; E-mail: brandombw@anes.
than it had been previously [2]. Using reports of MH cases
Adverse Metabolic/Muscular Reaction to Anesthesia reports
(AMRAs) voluntarily submitted to the North American Malignant
Hyperthermia Registry (NAMHR) Visoiu et al. observed that
Anesthetics utilizing halothane and succinylcholine produced
 
or third hour of the anesthetic [2].
However, the MH deaths known to the NAMHR after 2006
suggest that the death rate from MH due to anesthetic exposure
has increased [10]. Therefore, AMRAs reporting anesthetic
induced MH occurring after January 1, 2007 and before
December 31, 2013, were examined. The goal of this review is
to describe the complications that were reported as a result of
the MH episode and to examine the hypothesis that the time to
details of the administration of dantrolene are associated with
increased morbidity following anesthetic induced MH episodes.
Complications associated with the administration of
dantrolene were described in a review of AMRAs reporting MH
events between 1987 and 2006 [9]. A secondary purpose of the
present review is to determine if the complications associated
with administration of dantrolene have changed in recent years.
       
in events that occurred in the US or Canada between January 1,
2007 and December 31, 2013, with at least one anesthetic drug
and dantrolene given at some point during the event (Figure 1).
Patient outcomes after the MH episode were documented in
the AMRA reports as checkboxes. These complications included:
cardiac dysfunction, change in consciousness level and/or coma,
disseminated intravascular coagulation, hepatic dysfunction,
pulmonary edema, and renal dysfunction. Patient survival was
documented as a separate checkbox option. For this study,
serious complications associated with the MH episode were
Acute Malignant Hyperthermia (MH) is a rare but potentially
fatal pharmacogenetic disorder that most often occurs after the
administration of volatile anesthetics and/or succinylcholine
[1,2]. Dantrolene reduces intracellular calcium in skeletal muscle
through inhibition of the Ryanodine Receptor (RYR1) and
for clinical use in 1979. The case-fatality rate of MH decreased
from 70% in 1970 [6] to 1.4% in 2008 [7]. Review of MH cases
through 2006 showed that earlier treatment with dantrolene is
associated with reduced morbidity and mortality in acute MH
episodes [8]. Since 2007 generic dantrolene has been sold in the
United States by two different companies.
         
      
      
of regional analgesia and new intravenous drugs has allowed
reduction of the concentration of any potent inhalation anesthetic.
Alternatives to succinylcholine are available. After 1997 MH
        
Page 2 of 6
Hyperthermia. SOJ Anesthesiol Pain Manag, 2(2): 1-6.
Update on Dantrolene in the Treatment of Anesthetic Induced Malignant Hyperthermia
© 2015 Brandom et al.
pared these intervals between the groups in
which serious complications including death were reported, to
the group without these complications.
Fluid loading, as part of the treatment of the MH episode, was
documented in the AMRA with a checkbox. There was also an
     
treatment of the MH episode. This volume was presented as ml/
Each 1 mg of dantrolene in either the Dantrium or Revonto
formulations of dantrolene is put into solution using 3 ml of
water. For the purpose of addressing the possible association
         
these 2 volumes were added together.
The complications attributed to the administration of
dantrolene during the MH episode are included in the AMRA
reports as checkboxes. These complications included: phlebitis,
excessive secretions, gastrointestinal upset, hyperkalemia,
muscle weakness, and respiratory failure. There was also an
option for the reporter to enter a free text record of other
The Clinical Grading Scale (CGS) was calculated for each case,
as an indicator of the severity of the MH event. The CGS has 6
each category, including rigidity, muscle necrosis, respiratory
acidosis, temperature increase, cardiac involvement and other
          
after dantrolene administration), points are assigned for each
SPSS 21 was used to produce descriptive statistics and
perform analyses. Medians with upper and lower quartiles
are presented in the text. For categorical variables, a Fisher’s
Exact test (FE) was used to assess the differences between the
groups and the Clopper-Pearson method was used to calculate
       
         
        
associated with risk of serious complications or death associated
with the MH episode. No p values were corrected for multiple
examined. 66% of cases occurred in males. Median weight was
          
nt MH was occurring.
Figure 1: Flow Chart of Study inclusion.
during the MH episode or later in the same hospitalization as the
MH episode was also considred to be a serious complication of
MH. The clinician who completes the AMRA records their opinion
regarding the nature of this adverse event with a check box. The
options include; adverse event not related to MH, possible MH,
the reporting clinician is not determined by the Clinical Grading
Scale score.
The time between the beginning of anesthetic administration
           
the time between recognitio       
Page 3 of 6
Hyperthermia. SOJ Anesthesiol Pain Manag, 2(2): 1-6.
Update on Dantrolene in the Treatment of Anesthetic Induced Malignant Hyperthermia
© 2015 Brandom et al.
MH episode
        
from 3 to 88. The median CGS was 48 (33, 60). There was no
       
            
dantrolene ((r=0.124; p=0.173, Pearson correlation). There
was a closer low correlation between CGS and time from the
beginning of anesthetic administration to administration of
dantrolene, (r=0.188; p=0.039, Pearson correlation). Thus when
the patient had received anesthesia for a longer time before the
administration of dantrolene, the CGS was higher.
MH episode complications
Serious complications or death associated with the MH
of the total cases. Death occurred in 7% (3-12%). Frequent
serious complications associated with the MH episode were:
cardiac dysfunction, change in level of consciousness, renal
dysfunction and pulmonary edema (Table 1).
The demographics and other characteristics of these cases
are presented in Table 2.
      
the MH episode included: compartment syndrome in three cases,
pleural effusion, severe cellulitis, refractory bronchospasm,
one case.
There were 112 cases with no serious complications or
          
   
complications, (p = 0.003 and 0.023
complications or death and the group that had no complications
related to the MH episode in age, weight and CGS (p < 0.001, p =
0.002, p = 0.001,
complications was older, weighed more and had a higher CGS
         
weight (mg/kg) there was no difference between these groups in
Most delayed administration of dantrolene
There were 14 cases in which administration of dantrolene
Change in consciousness 
Cardiac Dysfunction 11.8% (7.2-18.1%)
Pulmonary Edema 7.2% (3.7-12.6%)
Renal Dysfunction 8.6% (4.6-14.2%)
 4.6% (1.9-9.3%)
Hepatic Dysfunction 
Other 7.2% (3.7-12.6%)
Table 1:
Patients with serious complications or death associated with the MH episode
Number of Cases Median  Minimum Maximum
Age(yr) 39 41 30-61 6 84
 38 86  10 146
Dantrolene Dose(mg) 34 190  3 660
CGS 40  43-63 23 78
 37 126 60-189 0* 660
Min2 Dantrolene(min) 30 42 22-99 0* 
Patients with no complications associated with the MH episode
Number of Cases Median  Minimum Maximum
Age(yr) 109 24 9-47 0 90
 111 70 32-91 10 
Dantrolene Dose(mg) 107 160 60-220 7 436
CGS 112 43  3 88
 102 63 26-120 0* 600
Min2 Dantrolene(min) 93 26  0* 300
Table 2: Demographic and Outcomes.
CGS is calculated based on the physical sign, physiological parameters and clinic pathologic variables measured during the MH episode
Often data is missing. Therefore there is a bias in CGS to be lower than actual
Page 4 of 6
Hyperthermia. SOJ Anesthesiol Pain Manag, 2(2): 1-6.
Update on Dantrolene in the Treatment of Anesthetic Induced Malignant Hyperthermia
© 2015 Brandom et al.
dantrolene showed that these cases were separated from the rest
         
masseter muscle rigidity, generalized rigidity, hyperkalemia and
decreased level of consciousness Furthermore, in nine of these
      
not recognized until the patient was in the intensive care unit
       
ventilation was continued after leaving the OR, dantrolene was
     
between the risk of serious complications or death and both the
interval from the beginning of administration of the anesthetic
          
this regression (Table 3 and Figure 2). For the purpose of this
regression analysis, cases in which a zero time interval was
dosing of dantrolene was really begun in less than one minute
has to be reconstituted.
Fluid loading
Fluid loading was noted as part of the treatment of MH in 91 of
       
         
as a binary variable, (p = 0.46      
  
p = 0.20, F E).
complications in general (p = 0.012,       
           
   
solutions in 2 of these 31 and sterile water used to prepare the
dantrolene formulation. There was no difference in age, weight,
CGS, or initial dose of dantrolene between these 31 cases and the
other 121 cases (Table 4).
Dantrolene complications
Complications were reported with the administration
           
complications were reported the median age was 39 years in 60
older (p = 0.016
weight, initial dantrolene dose (mg/kg), or CGS between those
cases with or without complications reported with dantrolene
(p = 0.601, 0.976 and 0.369,    
frequently reported complications were muscle weakness and
phlebitis. Other reported complications of dantrolene, in order of
Variable Parameter Standard error Estimate
Age 0.041 0.012 0.001
 0.691 0.241 0.004
 0.618 0.233 0.008
Constant -7.824 1.693 0.000
Table 3:
Age is the age in years at the time of MH episode
administration of dantrolene
p associate with this model is < 0.00001, including the constant
Figure 2: Model of MH Risk. The ages and time selected for the graph
are values at the upper and lower quartile ranges for this data.
      
with dantrolene included: hyponatremia in 3 cases, ventilation
required for > 24 hours in 2, nausea in 2, and in one case each,
unable to give full dose due to hypotension, unable to give full
     
to mix dantrolene, generalized myalgia, mild pulmonary edema,
elevated liver enzymes and total bilirubin, diplopia, cellulitis, and
Previous analyses of similar data from the NAMHR found that
longer anesthetic exposures before dantrolene was administered
were associated with higher peak temperatures [10]. That
study examined AMRAs until the end of 2012 and addressed the
likelihood of dying from MH, but did not examine the interval of
for association with risk of serious complications from the MH
episode. The AMRAs were examined again for this study. An
earlier report
to 2007 noted the likelihood of any complication associated with
Page of 6
Hyperthermia. SOJ Anesthesiol Pain Manag, 2(2): 1-6.
Update on Dantrolene in the Treatment of Anesthetic Induced Malignant Hyperthermia
© 2015 Brandom et al.
the MH episode increased 1.61 times for every 30 minute increase
of dantrolene [8]. The model presented in the present report
         
increase; by 49% when patient age increases by 10 years, by
MH to administration of dantrolene doubles. The present model
predicts that the risk of complications increases 2.27 times when
MH of 87 min.
The current report goes further than previous studies
to identify separately the increase in risk of complications
   
sign and administration of dantrolene.
The anesthesia provider cannot alter the age and weight
of the patient. Alterations in anesthesia practice that might
reduce time between the beginning of anesthetic administration
           
examined, with the exception that recent data demonstrates that
core temperature monitoring
[10] offers the best opportunity
        
dantrolene can reduce the risk of complications further.
          
administration of dantrolene was greater than 100 minutes
          
signs were recognized, but MH was not diagnosed quickly
         
MH. Thus, there may have been a lower clinical suspicion of
MH at the beginning of these MH episodes. The presentation of
Median 25%-75% Minimum Maximum
Age(yr) 36  1 78
 78 49-90 10 
Dantrolene Dose(mg) 180 100-260 3 360
CGS 48 33-60  78
 37   88
Table 4:
 20.4% (14.3-27.7%)
Phlebitis 
Hyperkalemia 6.6% (3.2-11.8%)
Respiratory Failure 2.6% (0.7-6.6%)
 2.0% (0.4-4.7%)
Other 
Table 5:      
Care Unit changes in hemodynamic stability of a patient may be
attributed to post operative stress, emergence from anesthesia,
underlying life-threatening conditions or factors other than MH.
         
delayed MH reactions may raise less suspicion.
This report supports the conclusion that dantrolene should be
administered as soon as possible after the recognition of signs of
MH due to the potential for serious complications or fatalities with
       
and likely costs of treatment suggest that earlier administration
of dantrolene may decrease the overall cost of hospitalization.
As discussed, as the time to dantrolene administration increases,
there is a greater increase in the chance of serious complications
associated with the MH episode, including cardiac dysfunction,
        
       
associated with MH often require a longer recovery time and
costs of healthcare.
     
     
admission ($6667 without mechanical ventilation) and stabilized
by day three ($3496 without mechanical ventilation) [12]. Thus,
           
 
complications reported with administration of dantrolene from
2007 to 2013, than was reported previously [9]. The incidence of
each previously reported complication
was produced by two companies that make generic drugs. Data
          
difference between the earlier formulation of dantrolene and
         
Currently there is a new formulation of dantrolene which requires
the incidence of pulmonary edema associated with the treatment
of MH. As this new form of dantrolene is introduced into clinical
practice it will be important to collect data to compare the
         
and other health care providers who submitted AMRAs to the
NAMHR and the Malignant Hyperthermia Association of the
United States and the Department of Anesthesiology in the
University of Pittsburgh for their support of the NAMHR over
many years.
Page 6 of 6
Hyperthermia. SOJ Anesthesiol Pain Manag, 2(2): 1-6.
Update on Dantrolene in the Treatment of Anesthetic Induced Malignant Hyperthermia
© 2015 Brandom et al.
1. 
hyperthermia in Canada: Characteristics of index anesthetics in 129
malignant hyperthermia susceptible probands. Anesth Analg. 2014;
118(2): 381-7. doi: 10.1213/ANE.0b013e3182937d8b.
2. 
onset of malignant hyperthermia. Anesth Analg. 2014; 118(2): 388-
96. doi: 10.1213/ANE.0000000000000062.
3. 
Ryanodine Receptor Ca2+ Release Channels Molecular Mechanism
4. 
inhibits a component of store-operated calcium entry coupled to the
        
 Yarotskyy V, Protasi F, Dirksen RT. Accelerated activation of SOCE
current in myotubes from two mouse models of anesthetic- and heat-
6.       
7. 
arrests and deaths associated with malignant hyperthermia in North
America from 1987 to 2006: a report from the North American
Malignant Hyperthermia Registry of the Malignant Hyperthermia
Association of the United States. Anesthesiology. 2008; 108(4): 603-
8. 
presentation, treatment, and complications of malignant hyperthermia
doi: 10.1213/ANE.0b013e3181c6b9b2.
9.         
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. Anesth
10.          
Malignant hyperthermia deaths related to inadequate temperature
monitoring, 2007-2012: a report from the North American Malignant
Hyperthermia Registry of the Malignant Hyperthermia Association of
11. 
           
intensive care unit day: The contribution of mechanical ventilation.
... MH morbidity has been well studied, with complications seen in 35% of patients who have an MH crisis, 2 and the risk of MH-related complications increase 2.27 times (or 79%) when the time from the first MH sign and dantrolene administration increases from 10 to 40 min. 16 Costs associated with MH complications would likely require intensive care stays with ventilation and were estimated to be on average $75,000 per stay. 17,18 The cost associated with an increase in maternal morbidity was calculated by subtracting the MH mortality assuming no treatment from the incidence of MH (80,427/170,968 -0.33 = 0.14) and multiplying that number by the increase in morbidity costs (79% minus 35% times $75,000 = $33,147), which equaled $4,641. ...
Full-text available
Background: The Malignant Hyperthermia Association of the United States recommends that dantrolene be available for administration within 10 min. One approach to dantrolene availability is a malignant hyperthermia cart, stocked with dantrolene, other drugs, and supplies. However, this may not be of cost benefit for maternity units, where triggering agents are rarely used. Methods: The authors performed a cost-benefit analysis of maintaining a malignant hyperthermia cart versus a malignant hyperthermia cart readily available within the hospital versus an initial dantrolene dose of 250 mg, on every maternity unit in the United States. A decision-tree model was used to estimate the expected number of lives saved, and this benefit was compared against the expected costs of the policy. Results: We found that maintaining a malignant hyperthermia cart in every maternity unit in the United States would reduce morbidity and mortality costs by $3,304,641 per year nationally but would cost $5,927,040 annually. Sensitivity analyses showed that our results were largely driven by the extremely low incidence of general anesthesia. If cesarean delivery rates in the United States remained at 32% of all births, the general anesthetic rate would have to be greater than 11% to achieve cost benefit. The only cost-effective strategy is to keep a 250-mg dose of dantrolene on the unit for starting therapy. Conclusions: It is not of cost benefit to maintain a fully stocked malignant hyperthermia cart with a full supply of dantrolene within 10 min of maternity units. We recommend that hospitals institute alternative strategies (e.g., maintain a small supply of dantrolene on the maternity unit for starting treatment).
Full-text available
Background: AMRA (adverse metabolic or muscular reaction to anesthesia) reports submitted to The North American Malignant Hyperthermia Registry of the Malignant Hyperthermia Association of the United States from 1987 to 2006 revealed a 2.7% cardiac arrest and a 1.4% death rate for 291 malignant hyperthermia (MH) events. We analyzed 6 years of recent data to update MH cardiac arrest and death rates, summarized characteristics associated with cardiac arrest and death, and documented differences between early and recent cohorts of patients in the MH Registry. We also tested whether the available data supported the hypothesis that risk of dying from an episode of MH is increased in patients with inadequate temperature monitoring. Methods: We included U.S. or Canadian reports of adverse events after administration of at least 1 anesthetic drug, received between January 1, 2007, and December 31, 2012, with an MH clinical grading scale rank of "very likely MH" or "almost certain MH." We excluded reports that, after review, were judged to be due to pathologic conditions other than MH. We analyzed patient demographics, family and patient anesthetic history, anesthetic management including temperature monitoring, initial dantrolene dose, use of cardiopulmonary resuscitation, MH complications, survival, and reported molecular genetic DNA analysis of RYR1 and CACNA1S. A one-sided Cochran-Armitage test for proportions evaluated associations between mode of monitoring and mortality. We used Miettinen and Nurminen's method for assessing the relative risk of dying according to monitoring method. We used the P value of the slope to evaluate the relationship between duration of anesthetic exposure before dantrolene administration and peak temperature. We calculated the relative risk of death in this cohort compared with our previous cohort by using the Miettinen and Nurminen method adjusted for 4 comparisons. Results: Of 189 AMRA reports, 84 met our inclusion criteria. These included 7 (8.3%) cardiac arrests, no successful resuscitations, and 8 (9.5%) deaths. Of the 8 patients who died, 7 underwent elective surgeries considered low to intermediate risk. The average age of patients who died was 31.4 ± 16.9 years. Five were healthy preoperatively. Three of the 8 patients had unrevealed MH family history. Four of 8 anesthetics were performed in freestanding facilities. In those who died, 3 MH-causative RYR1 mutations and 3 RYR1 variants likely to have been pathogenic were found in the 6 patients in whom RYR1 was examined. Compared to core temperature monitoring, the relative risk of dying with no temperature monitoring was 13.8 (lower limit 2.1). Compared to core temperature monitoring, the relative risk of dying with skin temperature monitoring was 9.7 (1.5). Temperature monitoring mode best distinguished patients who lived from those who died. End-tidal CO2 was the worst physiologic measure to distinguish patients who lived from those who died. Longer anesthetic exposures before dantrolene were associated with higher peak temperatures (P = 0.00056). Compared with the early cohort, the recent cohort had a higher percentage of MH deaths (4/291 vs 8/84; relative risk = 6.9; 95% confidence interval, 1.7-28; P = 0.0043 after adjustment for 4 comparisons). Conclusions: Despite a thorough understanding of the management of MH and the availability of a specific antidote, the risk of dying from an MH episode remains unacceptably high. To increase the chance of successful MH treatment, the American Society of Anesthesiologists and Malignant Hyperthermia Association of the U.S. monitoring standards should be altered to require core temperature monitoring for all general anesthetics lasting 30 minutes or longer.
Full-text available
Store-operated calcium entry (SOCE) channels play an important role in Ca(2+) signaling. Recently, excessive SOCE was proposed to play a central role in the pathogenesis of malignant hyperthermia (MH), a pharmacogenic disorder of skeletal muscle. We tested this hypothesis by characterizing SOCE current (ISkCRAC) magnitude, voltage dependence, and rate of activation in myotubes derived from two mouse models of anesthetic- and heat-induced sudden death: 1) type 1 ryanodine receptor (RyR1) knock-in mice (Y524S/+) and 2) calsequestrin 1 and 2 double knock-out (dCasq-null) mice. ISkCRAC voltage dependence and magnitude at -80 mV were not significantly different in myotubes derived from wild type (WT), Y524S/+ and dCasq-null mice. However, the rate of ISkCRAC activation upon repetitive depolarization was significantly faster at room temperature in myotubes from Y524S/+ and dCasq-null mice. In addition, the maximum rate of ISkCRAC activation in dCasq-null myotubes was also faster than WT at more physiological temperatures (35-37°C). Azumolene (50 µM), a more water-soluble analog of dantrolene that is used to reverse MH crises, failed to alter ISkCRAC density or rate of activation. Together, these results indicate that while an increased rate of ISkCRAC activation is a common characteristic of myotubes derived from Y524S/+ and dCasq-null mice and that the protective effects of azumolene are not due to a direct inhibition of SOCE channels.
Full-text available
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.
Full-text available
We analyzed cases of malignant hyperthermia (MH) reported to the North American MH Registry for clinical characteristics, treatment, and complications. Our inclusion criteria were as follows: AMRA (adverse metabolic/musculoskeletal reaction to anesthesia) reports between January 1, 1987 and December 31, 2006; "very likely" or "almost certain" MH as ranked by the clinical grading scale; United States or Canadian location; and more than one anesthetic drug given. An exclusion criterion was pathology other than MH; for complication analysis, patients with unknown status or minor complications attributable to dantrolene were excluded. Wilcoxon rank sum and Pearson exact chi(2) tests were applied. A multivariable model of the risk of complications from MH was created through stepwise selection with fit judged by the Hosmer-Lemeshow statistic. Young males (74.8%) dominated in 286 episodes. A total of 6.5% had an MH family history; 77 of 152 patients with MH reported >or=2 prior unremarkable general anesthetics. In 10 cases, skin liquid crystal temperature did not trend. Frequent initial MH signs were hypercarbia, sinus tachycardia, or masseter spasm. In 63.5%, temperature abnormality (median maximum, 39.1 degrees C) was the first to third sign. Whereas 78.6% presented with both muscular abnormalities and respiratory acidosis, only 26.0% had metabolic acidosis. The median total dantrolene dose was 5.9 mg/kg (first quartile, 3.0 mg/kg; third quartile, 10.0 mg/kg), although 22 patients received no dantrolene and survived. A total of 53.9% received bicarbonate therapy. Complications not including recrudescence, cardiac arrest, or death occurred in 63 of 181 patients (34.8%) with MH. Twenty-one experienced hematologic and/or neurologic complications with a temperature <41.6 degrees C (human critical thermal maximum). The likelihood of any complication increased 2.9 times per 2 degrees C increase in maximum temperature and 1.6 times per 30-minute delay in dantrolene use. Elevated temperature may be an early MH sign. Although increased temperature occurs frequently, metabolic acidosis occurs one-third as often. Accurate temperature monitoring during general anesthetics and early dantrolene administration may decrease the 35% MH morbidity rate.
Full-text available
As an inhibitor of Ca(2+) release through ryanodine receptor (RYR) channels, the skeletal muscle relaxant dantrolene has proven to be both a valuable experimental probe of intracellular Ca(2+) signaling and a lifesaving treatment for the pharmacogenetic disorder malignant hyperthermia. However, the molecular basis and specificity of the actions of dantrolene on RYR channels have remained in question. Here we utilize [(3)H]ryanodine binding to further investigate the actions of dantrolene on the three mammalian RYR isoforms. The inhibition of the pig skeletal muscle RYR1 by dantrolene (10 microm) was associated with a 3-fold increase in the K(d) of [(3)H]ryanodine binding to sarcoplasmic reticulum (SR) vesicles such that dantrolene effectively reversed the 3-fold decrease in the K(d) for [(3)H]ryanodine binding resulting from the malignant hyperthermia RYR1 Arg(615) --> Cys mutation. Dantrolene inhibition of the RYR1 was dependent on the presence of the adenine nucleotide and calmodulin and reflected a selective decrease in the apparent affinity of RYR1 activation sites for Ca(2+) relative to Mg(2+). In contrast to the RYR1 isoform, the cardiac RYR2 isoform was unaffected by dantrolene, both in native cardiac SR vesicles and when heterologously expressed in HEK-293 cells. By comparison, the RYR3 isoform expressed in HEK-293 cells was significantly inhibited by dantrolene, and the extent of RYR3 inhibition was similar to that displayed by the RYR1 in native SR vesicles. Our results thus indicate that both the RYR1 and the RYR3, but not the RYR2, may be targets for dantrolene inhibition in vivo.
The time between the beginning of anesthetic administration and recognition of the first sign of malignant hyperthermia (MH) (MH onset time) could differ among anesthetic drugs. We examined the time of the first signs of suspected MH, anesthetic drugs administered, subject age, and year of event in Adverse Metabolic/Musculoskeletal Reaction to Anesthesia reports in the North American Malignant Hyperthermia Registry. Inclusion criteria were judgment by the reporting clinician that the event was possible or fulminant MH, documentation of the time when anesthetic administration began, and the time when the first MH sign was noted. Descriptive statistics, Kruskal-Wallis analysis, and nonparametric correlation were used to assess the difference in MH onset times under different conditions. Four hundred seventy-seven cases met inclusion criteria; 58.5% were possible MH and 41.5% fulminant MH. Inhaled anesthetic and succinylcholine were given in 53.9% of cases, inhaled anesthetic only in 41.7%, and succinylcholine without inhaled anesthetics in 2.9%. No causative anesthetic drugs were reported in 7 MH cases. In 394 patients exposed to only 1 of the 4 inhaled anesthetics, without regard for subject age, MH onset time was shorter in the presence of halothane than any of the other anesthetics and shorter after succinylcholine in all anesthetics. If succinylcholine was not given, MH onset was shorter during sevoflurane anesthesia than during desflurane or isoflurane. In 322 cases, 1 rather than multiple first signs of MH were reported with masseter spasm as the earliest MH sign. In 339 cases in which masseter spasm was not reported, there was no difference in MH onset time with or without succinylcholine. In 146 cases in which masseter spasm was not reported and succinylcholine was not given, MH onset was shorter during halothane anesthesia, than during exposure to desflurane, or isoflurane. MH onset time during sevoflurane was shorter than during desflurane or isoflurane. MH was reported later in the course of anesthesia after 1998, when halothane and succinylcholine were less often reported. MH occurred after succinylcholine administration in the absence of inhaled anesthetics. We could not separate an effect of age from that of other variables. The onset of MH has been observed later during desflurane and isoflurane anesthesia than during exposure to sevoflurane. Since 1998, MH signs have more often appeared later, in the second or third hour of anesthesia, than they did before 1998.
Background: Between 1992 and 2011, 373 Canadian individuals with adverse anesthetic reaction were referred to the Malignant Hyperthermia Unit in Toronto, Ontario, Canada for malignant hyperthermia (MH) diagnostic testing. We analyzed the epidemiologic characteristics of the index adverse anesthetics for those probands who were confirmed to be MH susceptible. Methods: One hundred twenty-nine proband survivors of adverse anesthetic reactions, whose MH susceptible status was confirmed by caffeine-halothane contracture testing were selected. Individuals were excluded if the index anesthetic record was not available for review. Data regarding demographics, clinical signs, laboratory findings, treatment, and complications were retrospectively compiled and analyzed. A Fisher exact test and χ test were applied to compare categorical variables. The Wilcoxon rank-sum test was applied with continuous variables. Results: Young males (61.2%) dominated among selected patients. Seventeen of 129 (13.2%) patients had prior unremarkable anesthesia. Anesthetic triggers were volatile-only (n = 58), succinylcholine-only (n = 20), or both volatile and succinylcholine (n = 51). Eight (6.2%) cases occurred in the postanesthetic care unit. There were no reactions after discharge from the postanesthetic care unit. The most frequent clinical signs were hyperthermia (66.7%), sinus tachycardia (62.0%), and hypercarbia (51.9%). Complications occurred in 20.1% of patients, the most common complication being renal dysfunction. When 20 or more minutes between the first adverse sign and dantrolene treatment elapsed, complication rates increased to ≥30%. Conclusions: This is the first Canadian study in 3 decades to report nationwide data on MH epidemiology. Features that differ from earlier reports include a 15.5% incidence of reactions triggered by succinylcholine alone and lower complication rates. In agreement with previously published studies, we confirmed in this independent dataset that increased complication rates were associated with an increased time interval between the first adverse clinical sign and dantrolene treatment. This underscores the need for early diagnosis and rapid dantrolene access and administration in anesthetizing locations using either succinylcholine or volatile anesthetic drugs.
A specific inherited muscle membrane disorder predisposes to a variety of clinical problems. The most common is malignant hyperthermia (MH), a dangerous hypermetabolic state after anaesthesia with suxamethonium and/or volatile halogenated anaesthetic agents. MH may also be triggered in susceptible individuals by severe exercise in hot conditions, infections, neuroleptic drugs, and overheating in infants. Inbred pigs have provided a helpful model, and experiments on these animals and in MH-susceptible patients have shown that the essential biochemical abnormality is an increase in calcium ions in the muscle cells. This knowledge has led to a specific muscle test to identify susceptibility to MH and to a specific treatment, dantrolene; and as a result the case-fatality rate in MH has fallen from 70% in the 1970s to 5% today. In pigs susceptibility to MH is caused by a single mutation in the ryanodine receptor (RYR) in skeletal muscle. In man the genetics is more complex and three clinical myopathies that predispose to MH have been defined. By far the most common is inherited as a mendelian dominant characteristic and at present mutations in the human RYR account for no more than 20% of susceptible families.
To quantify the mean daily cost of intensive care, identify key factors associated with increased cost, and determine the incremental cost of mechanical ventilation during a day in the intensive care unit. Retrospective cohort analysis using data from NDCHealth's Hospital Patient Level Database. A total of 253 geographically diverse U.S. hospitals. The study included 51,009 patients >/=18 yrs of age admitted to an intensive care unit between October 1, 2002, and December 31, 2002. None. Days of intensive care and mechanical ventilation were identified using billing data, and daily costs were calculated as the sum of daily charges multiplied by hospital-specific cost-to-charge ratios. Cost data are presented as mean (+/-sd). Incremental daily cost of mechanical ventilation was calculated using log-linear regression, adjusting for patient and hospital characteristics. Approximately 36% of identified patients were mechanically ventilated at some point during their intensive care unit stay. Mechanically ventilated patients were older (63.5 yrs vs. 61.7 yrs, p < .0001) and more likely to be male (56.1% vs. 51.8%, p < 0.0001), compared with patients who were not mechanically ventilated, and required mechanical ventilation for a mean duration of 5.6 days +/- 9.6. Mean intensive care unit cost and length of stay were 31,574 +/- 42,570 dollars and 14.4 days +/- 15.8 for patients requiring mechanical ventilation and 12,931 +/- 20,569 dollars and 8.5 days +/- 10.5 for those not requiring mechanical ventilation. Daily costs were greatest on intensive care unit day 1 (mechanical ventilation, 10,794 dollars; no mechanical ventilation, 6,667 dollars), decreased on day 2 (mechanical ventilation:, 4,796 dollars; no mechanical ventilation, 3,496 dollars), and became stable after day 3 (mechanical ventilation, 3,968 dollars; no mechanical ventilation, 3,184 dollars). Adjusting for patient and hospital characteristics, the mean incremental cost of mechanical ventilation in intensive care unit patients was 1,522 dollars per day (p < .001). Intensive care unit costs are highest during the first 2 days of admission, stabilizing at a lower level thereafter. Mechanical ventilation is associated with significantly higher daily costs for patients receiving treatment in the intensive care unit throughout their entire intensive care unit stay. Interventions that result in reduced intensive care unit length of stay and/or duration of mechanical ventilation could lead to substantial reductions in total inpatient cost.
The high costs of critical illness make economic outcomes important adjuncts to clinical outcomes in intensive care unit research. Costs are markedly different than other clinical outcomes, both in their measurement and their interpretation. Although not necessarily patient-centered, economic outcomes are important to society. Costs are also useful summary measures of less-meaningful surrogates such as organ failures and lengths of stay. Limitations of economic outcomes, however, are numerous. Accurate measurement of costs in the ICU requires a thorough consideration of both direct and indirect costs, an understanding of the fixed and variable components of critical care expenditures, and knowledge that reducing resource use saves only the marginal, versus average, cost of ICU resources. Costs must also be interpreted alongside measures of effectiveness using proper modeling techniques. Interpretation can vary based on choice of effectiveness measure, perspective of the analysis, and societal and cultural norms. When correctly measured and interpreted alongside measures of effectiveness, costs are a useful and important outcome in critical care research.