ANZCA Bulletin June 2012 - final.pdf - Australian and New Zealand ...

Methylene blue andserotonin reuptakeinhibitors – an updateMixing methylene blue and SRIstriggers severe toxicityAn informed understanding of serotonintoxicity with methylene blue has notchanged since my previous comment in2008 1 . The seriousness and accuracy ofthe previous warning has been borneout by subsequent international reportsof severe reactions and a few deaths. Forthose who wish to refresh their memoryabout methylene blue and serotonintoxicity there is a summary in my mostrecent review 2 , as well as updatedinformation on my website (Google“Gillman methylene blue”).The story of interactions betweenmonoamine oxidase inhibitors (MAOIs),which includes methylene blue, anddrugs that possess significant serotoninreuptake inhibitor (SRI) capacity, mostlyantidepressants, 3 has confused not onlythe profession, but also the regulatoryauthorities. For instance, various sourcesincorrectly warn against mirtazapine,nortriptyline, bupropion etc, which donot have any SRI action and pose no risk.That is confusing and may precipitateunnecessary disruption or reschedulingof operations.One particular aspect of the (usuallypostoperative) presentation of serotonintoxicity warrants attention. Anaesthesiaitself is not only an effective treatmentfor the central nervous system and corehyperthermia of serotonin toxicity,but also tends to modify and disguisesigns and symptoms in the immediatepostoperative period. Body temperaturetends not to be elevated for a few hourspostoperatively, but can then rapidlyrise. In one recent case such a patientdied of hyperthermia, despite energeticcooling efforts 4 . Monitoring of core tempis essential, and judicious use of 5-HT2Aantagonists to treat hyperthermia maysometimes be required as a life-savingmeasure.There is no firm evidence as to whichof the available 2A antagonist candidatesis best. The choice may depend on thehistory and condition of the patient, therequired speed of onset (sub-lingual, IMIor IV) and the experience of the doctor.The possibilities are cyproheptadine(PO only), chlorpromazine (IMI/IV),risperidone (IM), olanzapine (sublingual),droperidol (IMI/IV), but notziprasidone, because it has significantSRI potency). As a guide, all these drugswould be expected to produce significantblockade at the 5-HT2A receptor in “usualclinical” doses 5 .Evidence supports the propositionthat in Australia, in contrast to othercountries, we have been successful inavoiding the toxic drug interaction ofserotonin toxicity.No cases have been reported to theTherapeutic Goods Administration(personal communication, March 2012),and all inquiries to me about methyleneblue toxicity have been from Europeand USA. There have been none fromAustralia.I would like to think that it is at leastpartly because of the attention thatAustralian anaesthetists have given tothe evidence that has been presented.Congratulations are due not only tothe medical profession, but also tothe manufacturers of methylene bluein Australia (Phebra), who included aspecific warning about serotonin toxicityon my advice. In contrast, warnings fromnational agencies (US Food and DrugAdministration and the British Medicineand Healthcare Products Agency), and inthe package inserts, are either absent orimprecise.ConclusionsMixing methylene blue with serotoninreuptake inhibitors predictably andfrequently causes severe and potentiallyfatal serotonin toxicity: discontinuationof SRIs, with appropriate washout periodsbefore using intravenous methylene blue,is a high priority and should probablybe considered mandatory. The situationwith smaller doses of methylene blue viaother routes is uncertain. Oral absorbencyis good and proposed uses of methyleneblue, such as chromo-endoscopy, maygenerate blood levels sufficient to provokeserotonin toxicity 6 .Dr P Ken Gillman, MRC PsychDr Gillman is a retired clinicalpsychiatrist with a special interestin neuropharmacology.References1. Gillman, PK, Methylene Blue: A Risk forSerotonin Toxicity. ANZCA Bull, 2008.17: p. 36.2. Gillman, PK, CNS toxicity involvingmethylene blue: the exemplar forunderstanding and predicting druginteractions that precipitate serotonintoxicity. J Psychopharmacol (Oxf), 2011.25(3): p. 429-3.3. Gillman, PK, Monoamine oxidase inhibitors,opioid analgesics and serotonin toxicity.Br. J. Anaesth., 2005. 95: p. 434-441.4. Top, W, Gillman, PK, de Langen, C, andKooy, A, Fatal methylene blue associatedserotonin toxicity. 2012: p. [in preparation].5. Kapur, S, Zipursky, RB, Remington, G, Jones,C, et al., 5-HT2 and D2 receptor occupancyof olanzapine in schizophrenia: a PETinvestigation. Am J Psychiatry, 1998. 155:p. 921-928.6. Repici, A, Di Stefanob, AFD, Radicionib,MM, Jasc, V, et al., Methylene blue MMX®tablets for chromoendoscopy. Safetytolerability and bioavailability in healthyvolunteers. Contemporary Clinical Trials,2011. 33: p. 260–267.43