The emerging landscape of etomidate e-cigarettes use

Abstract

The emergence of etomidate, an imidazole-derived hypnotic agent indicated for anaesthetic induction [1], as an adulterant in electronic cigarettes (e-cigarettes) represents a critical public health concern. In Singapore, the emergence of e-cigarette pods laced with etomidate, also known as ‘Kpods’, have been increasingly detected [2, 3], against a backdrop of wider global concerns surrounding the illegal production and distribution of etomidate and analogues [4]. Unlike the precise dosing and supervised administration of etomidate in clinical settings, when inhaled through e-cigarettes, effects can be unpredictable and dangerous. Given this, the aim of this letter is to illustrate some of the acute psychiatric manifestation associated with the use of these e-cigarettes (through a review of the existing published case studies), and to highlight potential testing methods to detect for the presence of etomidate.

Etomidate is a positive allosteric modulator of the gamma-aminobutyric acid type A (GABA-A) receptor, enhancing inhibitory neurotransmission in the central nervous system [1, 5]. By inducing a rapid-onset hypnotic effect [5], etomidate leads to incoordination, drowsiness and confusion frequently reported in harmful use. At higher doses, seizures, impaired consciousness and a comatose state may occur. Although not fully understood, the harmful use of etomidate may trigger psychiatric symptoms through altering GABA-A receptor equilibrium, a disturbance linked to increased impulsivity in magnetic resonance spectroscopy studies [6]. Given this, it is unsurprising that case reports have documented severe psychiatric disturbances linked to etomidate-laced e-cigarettes including suicidal behaviour, agitation, aggression and mood lability [7, 8]. In addition, neurological effects including drowsiness, confusion, weakness, dizziness and falls [7-10] have been observed, along with tremors and involuntary movements [8, 9].

Aside from neuropsychiatric effects, there have been associations with medical comorbidities. Case reports have linked etomidate-laced e-cigarettes to adrenal insufficiency through inhibiting adrenal 11β-hydroxylase, an enzyme crucial for cortisol production [11]. Adrenal dysfunction may cause blood pressure changes, adrenal hyperplasia and hypokalemia—resulting in muscle weakness, hypokalemic paralysis, cardiac arrhythmias and potentially death [10]. It is, therefore, necessary for healthcare professionals to have a heightened index of suspicion when individuals present with the above physical or medical manifestations, especially in a context when e-cigarettes have been used, given the rising trend.

Detecting recent etomidate use is possible, but challenging and not routine. Standard immunoassays do not detect etomidate and its metabolites [12]. Currently, detection of etomidate and its primary metabolite, etomidate acid requires specific suspicion and testing in specialized laboratories using targeted liquid chromatography–tandem mass spectrometry analysis [1, 13]. Methods for rapid detection of etomidate in samples such as thermal desorption electrospray ionization coupling triple quadrupole mass spectrometry [14] and surface enhanced raman spectroscopy have also been described [15].

In summary, etomidate-adulterated e-cigarettes can cause serious neuropsychiatric effects and life-threatening adrenal suppression. There is an urgent need for point-of-care screening tools and clinical protocols to guide evaluation of suspected cases. Establishing a database on etomidate-related adverse events will consolidate knowledge and guide public health responses. Last, as e-cigarettes may increasingly be used as a conduit to deliver other prescription drugs, etomidate could be just the beginning of a broader trend requiring urgent attention.

Melvyn Weibin Zhang contributed the original idea for this manuscript. Chong Zheng Ng, Harith Hamood Said Al-Aamari and Melvyn Weibin Zhang performed the initial literature search. Chong Zheng Ng wrote up the first draft of the manuscript, which was further amended under the guidance of Melvyn Weibin Zhang and Lambert Tchern Kuang Low. All authors approved of the final manuscript.

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