Klaus Glahn, Thierry Girard, Anna Hellblom, Philip Hopkins, Stephan Johannsen, Henrik Rueffert, Marc Snoeck, Albert Urwyler and EMHG collaborators#

In 2010 the European Malignant Hyperthermia Group (EMHG) published a guideline for the recognition and management of a malignant hyperthermia (MH) crisis [1]. Although halothane is no longer available in many high income countries and the use of succinylcholine has diminished, MH can be triggered by any of the potent inhalation anaesthetics (sevoflurane, isoflurane, desflurane, methoxyflurane) [2]. MH remains an important cause of morbidity and mortality arising directly from anaesthesia [3], often occurring in young, healthy individuals. It is well established that early recognition of a suspected MH crisis and prompt intervention are the most important measures to secure patient survival.

As part of planned review of its guidelines, the Executive Committee of the EMHG instigated a review of the recognition and management of an MH crisis guideline in 2021. The guideline from 2010 consist primarily of two textboxes: Box 1 on recognizing MH and Box 2 on the treatment of an MH crisis, to create an easy overview of both symptoms and treatment options. It was decided to keep this format. The process of reviewing the guideline has included a literature search, a call for feedback on the previous guideline, a face-to-face discussion and an online modified Delphi consensus process. The final document was approved at the EMHG annual general assembly 2024.

Literature search

Our primary search of PubMed and Embase databases combined the following search terms: (i) ‘malignant hyperthermia’ (MeSH terms, keywords, and text words) published 2000 or later. Further searches combined the following search terms: (ii) ‘symptoms´ OR ‘signs’ AND ‘malignant hyperthermia’, and (iii) ‘management’ AND ‘malignant hyperthermia’ plus (iv)`treatment’ AND `malignant hyperthermia´. Again, the search was limited to publications from 2000 or later. The titles; abstracts; and, ultimately, the full texts were screened for relevance based on whether they contained information on (i) clinical features related to an MH episode, (ii) treatment of an MH episode; all types of articles were considered.

Feedback and face-to-face discussion

In addition to the literature search all members of the EMHG were asked to give feedback and provide proposals for a revised guideline on recognizing and treating an MH episode. It is important to note that the EMHG is no longer a geographically restricted group but includes members from many countries outside of Europe.

Possible changes and modifications to the existing guideline based on the literature search and the feedback from the EMHG members was presented and discussed at a face-to-face meeting of the Board of Directors of the EMHG in May 2022: the Board of Directors is made up of one representative from each MH Unit that conducts diagnostic testing for MH susceptibility using the EMHG protocol [3].

Recognition of an MH crisis

Regarding the recognition of an MH crisis, almost nothing new was revealed from the literature search, the call for feedback or the face-to-face discussion. Only the addition of serotonin syndrome, as a differential diagnosis, was added to the guideline.

Treatment of an MH crisis

No new treatment options were revealed in the literature search or the call for feedback. The dosing of dantrolene has been updated and aligned with the recommendations in the EMHG guideline on dantrolene availability [5] from 2020. However, the face-to-face meeting showed a large discrepancy in how the secondary, non-specific features of an MH reaction (e.g. hyperkalaemia, acidosis, arrhythmia) are treated in circumstances other than MH. Many participants expressed a wish to adapt the guideline to accommodate these differences and be more open for local adaptations, thus allowing anaesthesiologists to use local routines for treatment modalities in an MH crisis where the situation may already be stressful. It was therefore decided to focus in the new guideline on the secondary clinical features that need to be managed and less didactic on the specifics of their treatment. The need for local adaptation of the guideline is emphasised in the text: “guidelines for the treatment of an MH crisis adapted to local routines and conditions (incl. accessible equipment, medication, and relevant communication lines) should be in place and easily accessible together with dantrolene”.

Modified Delphi process

Those elements of the guideline that did not reach 100% agreement at the meeting were then taken forward to an online modified Delphi consensus process involving all anaesthesiologist members of the Board of Directors and Executive Committee (using methodology previously described [4]).

There were two Delphi rounds involving 18 respondents from 15 countries before stopping criteria were reached for all statements.

We used a web-based adaptation of the RAND/UCLA Appropriateness Method for generating consensus. This uses a 9-point scale (1=completely inappropriate; 9=completely appropriate) by which panel members rate the appropriateness of a series of statements. The level of agreement amongst the panel is expressed as the disagreement index (DI). The DI is based on the inter-percentile range (difference between the 66th and 33rd centile appropriateness scores) with a correction factor for asymmetry. When the 66th and 33rd centiles have the same value, DI=0, which is interpreted as full agreement. A DI <1 is used to indicate consensus or agreement. We planned a Delphi process of at least two rounds, thereafter using stopping criteria for each statement of DI <0.5, or if the DI failed to improve by more than 15% between rounds.

The statements for the first Delphi round were based on the discussion at the face-to-face meeting of the Board of directors and finalized through e-mail correspondence. The Delphi process was undertaken online using Google Forms. None of the statements was compulsory. In addition to rating each statement, the panel members had the opportunity to submit freehand comments on the statements. The panel members were given 3 weeks to respond to each round with an e-mail reminder after 2 weeks.

After each round, the panel members were sent their own scores along with the de-identified scores and comments of other panel members. They were also provided with the calculated median appropriateness score and DI for each statement along with freehand comments. For subsequent rounds, the wording of statements could be adjusted in response to freehand comments or a high DI. The subsequent round was conducted in a similar way to Round 1.

Table 1

Statements included in the final round of the Delphi process, their median appropriateness score, Disagreement index (DI), and if the statement reached consensus / agreement.

    
    NrStatementMedian	DI	Consensus	Agreement
    
    

        1
        The following action should be added to the immediate treatment actions as the last bullet:
     If available, activated charcoal filters should be placed in the inspiratory and the expiratory limb.
        
        9
        0,048
        Yes
        Yes
     

        2
        Regarding the treatment of hyperkalaemia, the following option should be mentioned in the guidelines:
      A combination of insulin and dextrose i.v.
    
    9
    0,048
    Yes
    Yes
 

            3
            Regarding the treatment of hyperkalaemia, the following option should be mentioned in the guidelines:   CaCl2 i.v. 
            
            8
        0,292
        Yes
        Yes
     

            4
            Regarding the treatment of hyperkalaemia, the following option should be mentioned in the guidelines:
    Beta 2 adrenergic agonists i.v./inhalation
    
    8,5
    0.364
    Yes
    Yes
    

            5
            Regarding the treatment of hyperkalaemia, the following option should be mentioned in the guidelines:    Dialysis/haemofiltration
            
            8
                0,190
                Yes
                Yes
            

                6
            Regarding the treatment of acidosis:
    Treat acidosis by ventilating to normocapnia
    
    9
    0.048
    Yes
    Yes

    7
            Regarding the treatment of acidosis:
    If pH < 7.2 give sodium bicarbonate or other buffer
    
    8
    0,194
    Yes
    Yes

    8
            Regarding the treatment of arrhythmias, the following option should be mentioned in the guidelines:    Amiodarone
            
            8,5
            0,190
            Yes
            Yes
        

            9
            Regarding the treatment of arrhythmias, the following option should be mentioned in the guidelines:     Lignocaine
            
            6,5
            0,55
            Yes
            Uncertain
        

            10
            Regarding the treatment of arrhythmias, the following option should be mentioned in the guidelines:      Magnesium
            
            7,5
            0,403
            Yes
            Yes
        

            11
            Regarding urinary output:
    Following the sentence “Depending on clinical situation urinary output may be stimulated using:” The following option should be mentioned     Crystalloids
    
    9
    0,132
    Yes
    Yes

    12
            Regarding urinary output:
    Following the sentence “Depending on clinical situation urinary output may be stimulated using:” The following option should be mentioned      Furosemide
    
    7
    0,364
    Yes
    Yes

    13
            Regarding urinary output: 
    Following the sentence “Depending on clinical situation urinary output may be stimulated using:” The following option should be mentioned:     Mannitol (note that each dantrolene ampoule contains 3 mg mannitol)
    
    6
    0,851
    Yes
    Uncertain
    

The guideline was then adapted to the results of the modified Delphi process and the complete revised guideline was given final approval by the Board of Directors of the EMHG as well as approval at the EMHG annual general assembly.

Prior to publication of the new guideline, it was realised that Dantrolen i.v. 20 mg, which has been authorised in the European Union since 1984 and been the only source of dantrolene sodium for the last 40 years in most countries, is now being challenged by new formulations of the drug. It was therefore decided by the Executive Committee of the EMHG to adapt the guideline to include the newer formulations of dantrolene sodium. Thus, the guideline now describes the dosing of dantrolene sodium in mg - independent of form, formulation or manufacturer.

Summary

This is a new and updated guideline from the EMHG on recognising and treating an MH crisis. The main changes from the previous guideline are:

Acknowledging that in a crisis situation it is important to stick with well known routines and treatment options, the revised guidelines are more open to different treatment modalities in the symptomatic treatment section.
Use of activated charcoal filters if available.
Management of hyperkalaemia only gives suggestions to treatment options
The dosing of dantrolene has been updated and aligned with the recommendations in the EMHG guideline on dantrolene availability [5]. The new guideline now accommodates other formulations of dantrolene sodium that are available on the market.

Box 1. Recognising an MH crisis

Early recognition of an impending MH crisis and its immediate treatment is essential for the patient’s survival. As the clinical signs associated with MH are not unique, anaesthetists must be able to recognise a pattern of signs to make a rapid diagnosis. Any patient may develop MH during or shortly after an anaesthetic where trigger agents are used—this can occur even in patients who have had uneventful general anaesthesia previously.

Trigger agents are

all volatile (inhalation) anaesthetic agents
succinylcholine

Clinical signs

Early signs

Metabolic

Inappropriately elevated CO2 production (raised end-tidal CO2 on capnography, tachypnoea if breathing spontaneously).
Increased O2 consumption.
Mixed metabolic and respiratory acidosis.
Profuse sweating and mottling of skin.

Cardiovascular

Inappropriate increase in heart rate.
Cardiac arrhythmias (especially ectopic ventricular beats and ventricular bigeminy).
Unstable arterial pressure.

Muscle

Masseter spasm if succinylcholine has been used.
Generalised muscle rigidity.

Later signs

Hyperkalaemia.
Rapid increase in core body temperature.
Grossly elevated blood creatine kinase (CK) levels.
Grossly elevated blood myoglobin levels.
Dark-coloured urine due to myoglobinuria.
Severe cardiac arrhythmias and cardiac arrest.
Disseminated intravascular coagulation.

Differential diagnosis

Insufficient anaesthesia, analgesia, or both.
Infection or septicaemia.
Insufficient ventilation or fresh gas flow.
Anaesthetic machine malfunction.
Anaphylactic reaction.
Phaeochromocytoma.
Thyroid crisis.
Cerebral ischaemia.
Neuromuscular disorders.
Elevated end-tidal CO2 due to laparoscopic surgery.
Ecstasy or other recreational drugs.
Malignant neuroleptic syndrome
Serotonin syndrome

Box 2: Treating an MH Crisis

Wherever trigger agents are used guidelines for the treatment of an MH crisis adapted to local routines and conditions (incl. accessible equipment, medication, and relevant communication lines) should always be in place and easily accessible together with dantrolene sodium.

Start treatment as soon as an MH crisis is suspected.
The clinical presentation of MH varies, and it is important to adapt treatment accordingly.

Immediate treatment

Stop all trigger agents.
Hyperventilate (use a minute volume 2–3 times normal) with 100% O2 at high flow.
Declare an emergency and call for help.
Change to non-trigger anaesthesia (TIVA, total intravenous anaesthesia).
Inform the surgeon and ask for termination/postponement of surgery.
Remove the vaporiser—do not waste time changing the circuit / anaesthetic machine.
If available activated charcoal filters should be placed in the inspiratory and expiratory limb.

Dantrolene sodium (e.g. Dantrolen® / Agilus® / Ryanodex®)

Give dantrolene sodium 2 – 2.5 mg kg-1 i.v.
The dose of dantrolene sodium should be based on the patient’s actual body weight up to a maximum of 300 mg per dose.
The initial dose of dantrolene sodium should be repeated every 10 min (or as often as possible if administration takes >10 min)
Dantrolene sodium infusions should be repeated until PaCO2 <6 data-preserve-html-node="true" kPa with normal minute ventilation and a decreasing core body temperature.
Obtain dantrolene sodium from other sources, for example, pharmacy/nearby hospitals – a total of 1,200 mg may be needed for the treatment of an adult patient.
The maximum total dose (10 mg kg-1) may need to be exceeded (If so reconsider differential diagnoses).

Monitoring and further actions

Continue routine anaesthetic monitoring (SaO2, ECG, NIBP, ETCO2).
Monitor core body temperature.
Establish good i.v. access with wide-bore cannulas.
Insert an arterial line and a urinary catheter. Consider inserting a central venous line.
Check arterial blood gases, K+, CK, myoglobin, and glucose frequently.
Check renal and hepatic function and coagulation.
Check for signs of compartment syndrome.
Monitor the patient for a minimum of 24 h (critical care or recovery unit). If signs of MH should reoccur, give further doses of 2-2.5 mg kg-1 dantrolene sodium every 10 min until the signs of MH regress once more.

Treatment of secondary features

Treat hyperthermia

2000–3000 ml of chilled (4-8 oC) crystalloids i.v.
Surface cooling or other cooling devices if available.
Stop cooling once temperature < 38.5°C

Treat hyperkalaemia For instance:

Combination of insulin and dextrose i.v.
CaCl2 i.v (use calcium gluconate if CaCl2 is unavailable)
Beta-2 adrenergic agonists i.v./nebulised
Dialysis

Treat acidosis

Ventilate to normocapnoea.
Give sodium bicarbonate (or other buffer) i.v. if pH < 7.2.

Treat arrhythmias

Amiodarone / magnesium
Beta adrenergic blockers (e.g. propranolol / metoprolol / esmolol) - if tachycardia persists.

Monitor urinary output closely

Depending on clinical situation urinary output may be stimulated using:

Crystalloids / Furosemide

Consult your local Malignant Hyperthermia Investigation Unit about the case. Patients suspected of being MH-susceptible should be referred to a designated MH-laboratory to confirm the diagnosis (www.emhg.org).

Footnote to Box 2: NIBP = non-invasive blood pressure; CK = creatine kinase

Conflict of interest:

None declared.

References

Glahn KPE, Ellis FR, Halsall PJ, et al. Recognizing and managing a malignant hyperthermia crisis: guidelines from the European Malignant Hyperthermia Group. Br J Anaesth 2010; 105: 417-20
Hopkins PM. Malignant hyperthermia – pharmacology of triggering. Br J Anaesth 2011; 107:48-56
Kaura V, Aboelsaod EM, Hopkins PM. Has malignant hyperthermia really disappeared with halothane? Comment on Br J Anaesth 2017; 119: i44-52. Br J Anaesth. 2018;121:980-1
Hopkins PM, Rüffert H, Snoeck MM, et al. European Malignant Hyperthermia Group guidelines for investigation of malignant hyperthermia susceptibility. Br J Anaesth. 2015;115:531-9
Rüffert H, Bastian B, Bendixen D, et al. Consensus guidelines on perioperative management of malignant hyperthermia suspected or susceptible patients from the European Malignant Hyperthermia Group. Br J Anaesth. 2021;126:120-30
Glahn KPE, Bendixen D, Girard T, et al. Availability of dantrolene for the management of malignant hyperthermia crises: European Malignant Hyperthermia Group guidelines. Br J Anaesth 2020;125:133-40

# EMHG collaborators:

O Bandschapp, Basel, Switzerland.
B Bastian, Leipzig, Germany.
D Bendixen, Copenhagen, Denmark
J Bilmen, Leeds, United Kingdom.
JC Brand, Pretoria, South Africa.
O Diaz-Cambronero, Valencia Spain.
R Gillies, Melbourne, Australia.
V Glauber, Tel -Aviv, Israel.
L Heytens, Antwerp, Belgium.
A Michalek-Sauberer Vienna, Austria.
A-F Dalmas, Lille, France.
T Bulger, Palmerston North, New Zealand.
HCA Silva, São Paulo, Brazil.
D Štěpánková, Brno, Czechia
V Tegazzin, Padua, Italy

Recommendations

Recommendations

Recognising and managing a malignant hyperthermia crisis (v2024)

European Malignant Hyperthermia Group

EMHG