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Penthrox: a breath of PHEC air for the military?

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Penthrox for the military: Possilbly, but you need to understand what you are using
Les Gordon
Published on: 28 July 2020

Published on: 28 July 2020
Penthrox for the military: Possilbly, but you need to understand what you are using
- Les Gordon, Consultant Anaesthetist Royal Lancaster Infirmary
The article by Cohen and Wolstenholme provides a useful overview of Penthrox but is unfortunately incomplete.

Compared with modern anaesthetic agents, Penthrox is an unclean drug and would not get a product license if invented today. The high fat solubility means a tissue reservoir persists for ≈1 week. About 70% is biotransformed, and this continues after administration until the tissue reservoir is empty. Nephrotoxicity was not just “a concern” but actually happened; ≈20 people died [1].

It has only been possible to use Penthrox 5 million times safely because of essential pre-use checks to ensure no contraindications. It is worth remembering that methoxyflurane was used 10-12 million times before the nephrotoxic potential was established [1].

Penthrox produces nephrotoxic metabolites at all doses, but this only becomes clinically significant above a certain level. The claim that Penthrox use is not nephrotoxic is technically correct, however, the presence of other factors that can also induce renal injury will reduce the Penthrox safety net. Of relevance to military use, this includes crush injury, hypovolaemic shock and patients subsequently requiring nephrotoxic antibiotics. Other potential issues for military use: (1) Limit to ≈50min administration (two bottles); (2) Activated charcoal adsorber is only effective IF the patient exhales through it. The patient will continue to exhale small amounts of drug for hours after administration; (3) There i...
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The article by Cohen and Wolstenholme provides a useful overview of Penthrox but is unfortunately incomplete.

Compared with modern anaesthetic agents, Penthrox is an unclean drug and would not get a product license if invented today. The high fat solubility means a tissue reservoir persists for ≈1 week. About 70% is biotransformed, and this continues after administration until the tissue reservoir is empty. Nephrotoxicity was not just “a concern” but actually happened; ≈20 people died [1].

It has only been possible to use Penthrox 5 million times safely because of essential pre-use checks to ensure no contraindications. It is worth remembering that methoxyflurane was used 10-12 million times before the nephrotoxic potential was established [1].

Penthrox produces nephrotoxic metabolites at all doses, but this only becomes clinically significant above a certain level. The claim that Penthrox use is not nephrotoxic is technically correct, however, the presence of other factors that can also induce renal injury will reduce the Penthrox safety net. Of relevance to military use, this includes crush injury, hypovolaemic shock and patients subsequently requiring nephrotoxic antibiotics. Other potential issues for military use: (1) Limit to ≈50min administration (two bottles); (2) Activated charcoal adsorber is only effective IF the patient exhales through it. The patient will continue to exhale small amounts of drug for hours after administration; (3) There is no evidence that it is superior to other analgesics in current use. Its time profile differs from e.g. fentanyl lozenges, but not necessarily the quality of analgesia; (4) Any hangover from opioid can be easily reversed with naloxone. This is not possible with Penthrox; (5) Cardiovascular stability is not guaranteed, as suggested in the review, so the manufacturers have specifically made cardiovascular instability a contraindication.

Penthrox is metabolised to fluoride (and dichloroacetic acid, which may have a role in nephrotoxicity). Sevoflurane is metabolised to subtoxic levels of fluoride ion [1]. This may be enhanced by concurrent administration of enzyme-inducing drugs, as it is for Penthrox [2], including smoking [3], and related to duration of administration [3]. Sub-toxic fluoride levels of the two drugs could be additive, and it is this concern that led authorities to state that sevoflurane is contraindicated after Penthrox. The research to confirm or refute this has not yet been done.

The manufacturer has identified nine items to be checked before administering Penthrox. Other analgesics must therefore still be available for people who should not receive it. Conclusion: Penthrox can be another analgesic in the armamentarium, but it is not the answer on its own.

References
1. Mazze RI. Methoxyflurane revisited. Tale of an anesthetic from cradle to grave. Anesthesiology 2006; 105: 843-6
2. European Medicines Consortium. Penthrox 3mL inhalation vapour, liquid. Summary of Product Characteristics (Updated 14-Jan-2019. Galen Limited)
3. Cabibel C, Gerard L, Maiter D, Collin V, Hantson P. Complete nephrogenic diabetes insipidus after prolonged sevoflurane sedation: a case report of 3 cases. Anesth Analg Case Rep 2019; 12: 155-9
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Conflict of Interest:
None declared.
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