Use of Penthrox (methoxyflurane)

Situation

The increasing and widespread use of Penthrox® (Methoxyflurane), makes it relevant for the European Malignant Hyperthermia Group to address the potential risk of malignant hyperthermia (MH) related to the use of this volatile anaesthetic agent. 

Background

Methoxyflurane is a volatile anaesthetic agent that was withdrawn from the anaesthetic pharmacopaedia in the 1970s dues to its adverse effects on renal function. However, during that time, it was found that methoxyflurane exhibited analgesic effects at lower doses which did not appear to cause the same adverse effects. It was also found that methoxyflurane could trigger an MH-reaction in MH-susceptible individuals.

Some years later, Methoxyflurane was relicensed as an inhalational analgesic agent known as Penthrox®. As such, it has enjoyed a recent resurgence and is currently used for the treatment of acute pain in the pre-hospital and emergency department/acute admission setting. It is currently licensed for analgesic use in Australia, Europe, New Zealand, and the United Kingdom.

Concerns have been raised that Penthrox® could trigger an MH reaction in susceptible individuals, either directly (patient use of Penthrox®) or indirectly through exposure of a susceptible individual in the vicinity of a Penthrox®-user.

Review of the literature demonstrates that in a 3 ml dose of pure methoxyflurane through the Penthrox® delivery system yields a standardised minimum alveolar concentration of 0.3 MAC-hours (Dayan A, 2016). For comparison, a dose of 2 MAC-hours is considered the upper safe limit of nephrotoxicity (Dayan A, 2016).

Dosing of Penthrox®.

The current dosing regimen for Penthrox®is no more than 2 doses (6ml) methoxyflurane in a day and no more than 5 doses in a 1 week. 6mls of methoxyflurane back-to-back, this could lead to a dose of around 0.6 MAC-hours, Current SOPs mandate the administering individual to ask the patient whether they have any history or family history of problems with general anaesthetics (especially MH) – as a screening question prior to administration.

The risk of exposure to an MH susceptible individual in close proximity to a patient using Penthrox®

The delivery system for Penthrox®, when assembled and used correctly, carries an exhaust port tightly connected to an activated charcoal (AC) filter, through which all the exhaled gas passes before being released into the environment. In the AC filter, most of the Methoxyflurane is adsorbed and removed from the exhaled air. Recent work by Frangos et al. (2020) demonstrates that in an emergency department environment (triage rooms with no significant ventilation systems), the median amount of Methoxyflurane exposure after an 8 hour shift was approximately 0.017 ppm (range 0.008 – 0.736 ppm). This is far below the accepted upper limit of exposure that is considered safe for an MH susceptible individual, which is currently 5 ppm.

Assessment

Currently, there are SOPs for Penthrox® use by the administering practitioner (background questions asked, equipment assembled correctly, delivery device used correctly and adhering to a maximum dose of no more than 2 x 3 ml within 24 hours etc.)

There are currently no recommendations for MH-susceptible individuals with regards to the use of Penthrox® in their (the individual’s) proximity.

EMHG view

The European Malignant Hyperthermia Group is aware of the use of the volatile anaesthetic agent methoxyflurane in low doses (marketed as Penthrox®) as an analgesic agent in both pre-hospital for pain relief and in-hospital for short painful procedures.

For Malignant Hyperthermia (MH) susceptible individuals who require analgesia, Penthrox® should be avoided as it carries a risk of triggering an MH episode. It is important to always ensure that the patient is not at an increased risk of MH susceptibility prior to the administration of Penthrox®. Alternative analgesia should be offered.

When assembled and used correctly (including the fitting of the activated charcoal filter), the exhaled air from the Penthrox®-device does not pose any risk to MH susceptible individuals who may be near to the patient. The expired levels of the agent are well below the minimum concentration threshold considered as the lower limit of exposure risk, (5 ppm).

References

Dayan A. Analgesic use of inhaled methoxyflurane: Evaluation of its potential nephrotoxicity. Human & Experimental Toxicology. 2016;35(1):91-100. doi:10.1177/0960327115578743)

Frangos J, Belbachir A, Dautheville S, Jung C, Herklotz K, Amon F, Dickerson S, Chomier B. Non-interventional study evaluating exposure to inhaled, low-dose methoxyflurane experienced by hospital emergency department personnel in France. BMJ Open. 2020 Feb 10;10(2):e034647. doi: 10.1136/bmjopen-2019-034647. PMID: 32047020; PMCID: PMC7045269.

C. Jephcott, J. Grummet, N. Nguyen and O. Spruyt:  A review of the safety and efficacy of inhaled methoxyflurane as an analgesic for outpatient procedures; BJA 120(5): 1040-1048 (2018)

Recognising and managing a malignant hyperthermia crisis (v2024)

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]).

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.

---

Nr	Statement	Median	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:

1. 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.

2. Use of activated charcoal filters if available.

3. Management of hyperkalaemia only gives suggestions to treatment options

4. 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

1. 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

2. Hopkins PM. Malignant hyperthermia – pharmacology of triggering. Br J Anaesth 2011; 107:48-56

3. 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

4. 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

5. 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

6. 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

Perioperative management of known or suspected MHS

We are pleased to announce publication of the EMHG guidance on perioperative management of malignant hyperthermia suspected or susceptible patients.

https://doi.org/10.1016/j.bja.2020.09.029

Dantrolene availability

The EMHG has published guidelines on the availability of dantrolene:

Availability of dantrolene for the management of malignant hyperthermia crises: European Malignant Hyperthermia Group guidelines. Br J Anaesth. 2020;125:133-140.

Occupational exposure to volatile anaesthetics

There is an international consensus that, providing standard  COSHH ( Control of substances hazardous to health) regulations are followed , MH susceptible individuals are not at risk of developing MH through occupational exposure in the operating theatre, post anaesthesia care unit or intensive care unit. We now recognise MH is a time weighted dose-dependent  phenomenon.  In other words in order for MH to be triggered the MH susceptible individual must be exposed to a certain quantity of anaesthetic. Triggering could therefore occur after a short period of exposure to a high concentration of triggering anaesthetic or a longer duration exposure to a lower concentration of anaesthetic. The dose required to trigger MH is considerably more than the exposure limits permitted by COSHH regulations. We also have the reassurance of knowing that theatre personnel with MH susceptibility have spent their whole careers without untoward events-many working in the days when scavenging or removal of the anaesthetic gases was not as good as it is currently.

It is theoretically possible that chronic exposure to relatively low anaesthetic concentrations could cause some instability of muscle membranes in an MH individual and this might be asymptomatic or produce muscle aches or cramps. This would likely be associated with a rise in the serum creatine kinase concentration.  It should be noted that some MH susceptible patients develop muscle aches and/or cramps associated with a rise in serum creatine kinase levels during the course of every day life.  Before an MH susceptible individual starts working in an operating theatre environment we advise that a series of baseline creatine kinase concentration measurements are made. This can be done by taking three such measurements over a one week period when the individual is undertaking similar activities in terms of physical exertion that they would otherwise be taking in the operating theatre environment. If there are subsequently any concerns about chronic exposure to anaesthetic gases, creatine kinase concentrations can be measured and compared to the baseline levels.

source: www.ukmhr.ac.uk/patients-relatives/faqs/

Management of MH crisis

The EMHG has published Recognition and management of a malignant hyperthermia crisis

In addition there is a free online MH registry for suspected MH events.

in-vitro contracture testing

In addition to the guideline for the investigation of MH susceptibility, there are the following recommendations:

• Ryanodine muscle contracture testing (optional test)

• 4-chloro-m-kresol bolus test

• Cryopreservation of muscle tissue