Update on Dantrolene in the Treatment of Anesthetic Induced Malignant Hyperthermia

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*Corresponding author email: brandombw@anes.upmc.edu
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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
Abstract
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.
upmc.edu
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.
Methods
       

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
Introduction
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
        

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Citation:
Hyperthermia. SOJ Anesthesiol Pain Manag, 2(2): 1-6.
Update on Dantrolene in the Treatment of Anesthetic Induced Malignant Hyperthermia
Copyright:
© 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/
kg.
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
complications.
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
comparisons.
Results
Demographics

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       


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Citation:
Hyperthermia. SOJ Anesthesiol Pain Manag, 2(2): 1-6.
Update on Dantrolene in the Treatment of Anesthetic Induced Malignant Hyperthermia
Copyright:
© 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
1
St
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 
1
St
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


recorded.

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Citation:
Hyperthermia. SOJ Anesthesiol Pain Manag, 2(2): 1-6.
Update on Dantrolene in the Treatment of Anesthetic Induced Malignant Hyperthermia
Copyright:
© 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

Discussion
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
Citation:
Hyperthermia. SOJ Anesthesiol Pain Manag, 2(2): 1-6.
Update on Dantrolene in the Treatment of Anesthetic Induced Malignant Hyperthermia
Copyright:
© 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 
1
st
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:      
intervals).
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.
11
     

     
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
formulations.
         

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.

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Citation:
Hyperthermia. SOJ Anesthesiol Pain Manag, 2(2): 1-6.
Update on Dantrolene in the Treatment of Anesthetic Induced Malignant Hyperthermia
Copyright:
© 2015 Brandom et al.
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presentation, treatment, and complications of malignant hyperthermia

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
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Malignant hyperthermia deaths related to inadequate temperature
monitoring, 2007-2012: a report from the North American Malignant
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
ANE.0000000000000421.
11. 

12.
           
intensive care unit day: The contribution of mechanical ventilation.
