CKY Ngai, CCA Fu

Abstract

There is a growing concern about the misuse of etomidate, a drug used to be a general anaesthetic agent, which is now being abused in the community through vaping via "space oil" electronic cigarettes. Beyond its immediate effects on the central nervous system, etomidate presents substantial risks due to its adrenal toxicity and the potential for long term impairments in cognitive and endocrine functions. The effects of inhaled etomidate is hypothesised to cause similar adrenal suppression. Here we investigate the endocrine risks of adrenal suppression in 13 adolescent aged patients who were found to have positive urine toxicology results for etomidate and its metabolites in a local centre in Hong Kong. Baseline blood tests and low dose short synacthen test (LDSST) were performed in patients with confirmed positive urine toxicology results. Three out of six patients were confirmed with adrenal insufficiency via LDSST. Out of 13 patients, four demonstrated elevated baseline ACTH levels as well as elevated 11-deoxycortisol, highlighting the potential toxicity of vaping etomidate, with findings suggest vaping "space oil" etomidate e-cigarettes can cause primary adrenal insufficiency. Protecting our younger generations, especially those from more complex social backgrounds, remain a clinician's collective responsibility that requires concerted efforts in education, intervention, and policy-making.

Introduction

Etomidate was first developed by an American pharmaceutical company in 1964. It is a controlled substance and a sedative that acts on the central nervous system. It has a rapid onset of action and a short recovery time, making it a short-acting non-barbiturate anaesthetic primarily administered intravenously by clinicians during intubation procedures. Due to its central nervous system depressant effects, physicians carefully monitor patients' medication usage to avoid concurrent use with sedatives.

There is increasing concern about the abuse of etomidate. Criminal groups have exploited its anaesthetic properties to create smokeable powders or e-liquids for use in e-cigarettes, turning it into a new type of drug. After inhalation, users may experience an inability to think or speak, loss of bodily control, twisting movements, and abnormal trembling. Commonly referred to as "space oil," the drug earned its nickname due to the hallucinations users experience, often described as a sensation of space travel. Milder cases may result in confusion and respiratory failure, while severe cases can pose life-threatening risks. Adolescents frequently encounter etomidate for the first time through peer influence, leading to a gradual increase in usage and frequency, ultimately resulting in profound physical and mental health problems. In Hong Kong, etomidate abusers reached an alarming 30.5% of all new reported drug abuses in young people aged 21 or below in 2024, with similar results observed in Mainland China.¹ These figures clearly illuminate the grave seriousness of etomidate e-cigarette abuse and underscore its perilous implications for society.

Moreover, adrenal toxicity has long been known as a side effect of etomidate, as it inhibits 11-beta-hydroxylase, causing decreased cortisol and aldosterone production, along with elevated precursors 11-deoxycorticosterone, 11-deoxycortisol, and 17-hydroxyprogesterone, therefore affecting the mineralocorticoid pathway.² Insufficient adrenal hormones can lead to symptoms such as dehydration, nausea, vomiting, loss of appetite, fever, chest, abdominal, or back pain, joint pain, fatigue, and hypoglycaemia. In severe cases, it may result in adrenal crises characterised by hypotension, shock, and life-threatening hypoglycaemia. Long-term misuse of etomidate can potentially cause damage to the brain and endocrine system.

Methods

This is a retrospective observational study reviewing the electronic medical records of patients admitted to Princess Margaret Hospital in Hong Kong from January 1 2024 to 31 December 2024. Patients aged 18 years or below at presentation with positive urine toxicology result for etomidate or its metabolites (propoxate, isopropoxate) were eligible for inclusion. Patients who were administered etomidate as part of their medical treatment, older than 18 years old, with underlying endocrinopathies or on steroid medications were excluded. Hypertension was defined as systolic blood pressure higher than 130 mmHg and diastolic blood pressure higher than 90 mmHg for children aged 13 and over. For children aged 13 and below, hypertension was defined as blood pressure at or over 95th centile for their age, height and sex. Low dose short synacthen test (LDSST) was utilised for testing adrenal insufficiency, with peak cortisol of 376 nmol/L and or below was defined as an inadequate response. Hypokalaemia was defined as serum potassium of less than 3.3 mmol/L.

Results

Demographics
Thirteen cases were included, aged between 11.2-17.9 years. Twelve cases were of the adolescent age range of 14.1-17.9 years old, except one case of an 11-year-old boy (Table 1). They all lived within the Kowloon West cluster of Hong Kong, where the majority were residing in Kwai Chung.

None of the patients had underlying physical illness requiring regular follow up. However, seven out of 13 had regular psychiatric follow up. Amongst them, five of them were on regular psychiatric medications, with the majority being antidepressants. Six patients had mood disorders (depression, dysthymia and anxiety); four with behavioural disorders (conduct disorder, attention deficit hyperactivity disorder and oppositional defiant disorder). Nine patients admitted to having a habit of smoking cigarettes, six of them have regularly consumed alcohol (Table 1).

Clinical Features
Eleven cases were admitted to paediatric ward, while one was admitted to orthopaedics for hand laceration due to alcohol intoxication, and another to gynaecology ward for teenage pregnancy (as a victim of sexual assault). Of the 13 cases, seven exhibited physical complaints consistent with acute intoxication, with the most prevalent being acute confusion, dizziness and unsteady gait. For two of the cases, the confusion was reported to be acute and transient, with abnormal behaviour noted by their carers. Both cases had no focal neurology and confusion was resolved upon admission without treatment. Four cases were initially admitted for mood problems, including low mood, deliberate self-harm and one case with suicidal attempt via drug overdose (Table 2). The youngest patient was an asymptomatic 11-year-old boy admitted for suspected child neglect with an incidental positive urine toxicology result.

On presentation, four of them had hypertension (patients 4, 7, 11 and 12) with a systolic blood pressure range 132-160 mmHg, diastolic blood pressure range 85-130 mmHg. Two patients (patients 4 and 12) with hypertension were later found to have markedly elevated 11-deoxycortisol, potentially indicating that their hypertension could be due to etomidate misuse. None exhibited signs of hyperandrogenism. One patient was managed in paediatric intensive care unit (ICU) owing to inhalation injury upon the fire accident related to e-cigarette vaping.

Toxicology Results
Nine of them admitted to regular vaping of etomidate . The use of 'space oil' via e-cigarettes ranged from one month to eight months, with the average time of vaping around two months before presentation to hospital. Half of them admitted to vaping 'space oil' via e-cigarettes daily. Urine toxicology screening was performed for all by liquid chromatography-tandem mass spectrometry. Propoxate, an analogue of etomidate was detected in five patients. Five of them were found to have co-administration of other drugs of abuse. The most common drug of co-abuse was cocaine (4 out of 7) and methamphetamine (2 out of 7) (Figure 1).

Figure 1 Urine toxicology results.

Biochemical Findings
All cases with positive toxicology results for etomidate or its metabolites (propoxate, isopropoxate), were offered blood tests to screen for adrenal activity. Morning cortisol was performed as a screening for adrenal insufficiency (AI) in eight patients, of which three were found to be below the normal range (range: 44-83; reference >133 nmol/L). Baseline ACTH levels were checked in seven patients, and were elevated in four cases (range: 28-55; reference 1.6-13.9 pmol/L). Two out of four patients screened had low morning cortisol with high ACTH, suggesting adrenal insufficiency. Random cortisol checked on patient 12 (who was intubated and admitted to the intensive care unit for burn injury) was 333 nmol/L, below the normal peak cortisol cut-off in Short Synacthen test (SST). Blood tests to test for adrenal function and LDSST were offered to all 13 patients with positive urine test, however only six were performed due to patient refusal and logistical constraints. For the six patients where LDSST was performed, AI was demonstrated in three patients (peak cortisol range: 74-238; reference >376 nmol/L. Renin and aldosterone were both undetectable in six of the patients. 11-deoxycortisol, the precursor hormone accumulated right above the inhibition of 11β-hydroxylase (range: 72.4-564; reference ≤4.3 nmol/L) and 17-OHP (range 8.7-11; reference <4 nmol/L) along the glucocorticoid pathway were found elevated in four out of six patients (Table 3), demonstrating evidence of enzyme activity being inhibited by etomidate. Mild hypokalaemia was observed in two patients (range: 2.9-3.2; reference 3.3-4.5 mmol/L).

Treatment and Outcomes
Three patients failed LDSST and were diagnosed with adrenal insufficiency. Hydrocortisone replacement therapy was initiated for all, however only one of the AI patients received treatment, as the other two refused to return despite repeated explanation of the severity of undetected and untreated adrenal insufficiency. Two patients who demonstrated low morning cortisol (patients 3 and 12) were continuously advised for further diagnostic workup with LDSST, however they declined to return. Furthermore, two patients (patients 1 and 10), who were admitted for teenage pregnancy and finger laceration respectively, were lost to follow up after being admitted to other specialty wards. Social welfare referral and substance misuse interventions were introduced for all our patients. Notably, one of them begun attending the substance abuse clinic, ran by the local psychiatric hospital for support. Seven of them were seen by the psychiatric team during the inpatient stay for their mental condition and substance misuse, with follow up on discharge.

Discussion

It is well documented that etomidate specifically and reversibly inhibits adrenal mitochondrial cytochrome P450 enzyme 11-β hydroxylase (CYP11B1) in a dose-dependent fashion.² The 11β-hydroxylase is an enzyme catalysing the conversion of 11-deoxycortisol to cortisol, 11-deoxycorticosterone (DOC) to corticosterone, and androstenedione to 11β-hydroxyandrostenedione in the adrenal cortex. Chronic misuse or abuse of etomidate results in inhibition of 11β-hydroxylase activity, leading to decreases in the synthesis of cortisol, corticosterone, and aldosterone. The reduction in cortisol level provides negative feedback to stimulate the release of adrenocorticotropic hormone. These therefore result in transient primary adrenal insufficiency. On the other hand, inhibition of CYP11B1 increases the concentration of DOC that activates the mineralocorticoid receptor, suppresses the renin-angiotensin system, and causes hypertension.³

The use of etomidate as a continuous infusion for sedation in the ICU has been linked to a heightened risk of mortality.⁴ A documented case involving prolonged intravenous etomidate infusion revealed the drug's direct and reversible suppressive effect on adrenal function. The patient exhibited a low basal serum cortisol level and an impaired response to ACTH stimulation during the infusion. Remarkably, within 24 hours of discontinuation, cortisol levels increased, ACTH levels decreased, and the patient's response to ACTH stimulation normalised.2 Recently there was a death report of an adult man who died from acute intoxication after oral ingestion of liquid containing etomidate, when the autopsy revealed a significant decrease in both adrenocorticotropic and cortisol levels in the deceased's blood.⁵ The first documented case of adrenocortical suppression caused by inhaled etomidate was reported by Lau et al, describing a 35-year-old woman with history of chronic e-cigarette use for three months.⁶ She presented with secondary amenorrhea, hypertension and pronounced clinical hyperandrogenism, with initial biochemical findings mimicking 11 β-hydroxylase deficiency (11 βOHD) that shares the same metabolic profile.6 Amongst our cohort, one patient (patient 4) with confirmed adrenal insufficiency had elevated 11-deoxycortisol and 17-OHP levels and their blood pressure was elevated during hospitalisation. This phenotype is compatible with 11 βOHD.⁷ Two patients (patients 12 and 13) demonstrated elevated 11-deoxycortisol level, suggesting 11 β-hydroxylase deficiency, but not severe enough to cause cortical insufficiency. Daily vaping was reported by all three patients with confirmed adrenal insufficiency, raising the possibility that cumulative toxic exposure may induce adrenal suppression. A recent local case report by Chung et al. demonstrates similar results of adrenal insufficiency with marked elevation in 11-deoxycortisol in adolescents who have misused etomidate via e-cigarettes.⁸ Confirmed cases of adrenal suppression should be treated with hydrocortisone replacement as the effects of adrenal suppression remains unknown. Follow up testing is advised to monitor adrenal recovery.

The issue of abuse or misuse of etomidate has been emerging in recent years.⁹ The long-term health consequences of commonly abused substances, including the neuropsychiatric effects of cannabis, cocaine, ketamine, and methamphetamine, ketamine-induced cystitis, and cocaine-related cardiovascular damage, are well documented.¹⁰ In contrast, the chronic effects of etomidate misuse remain uncertain. While its well-documented role in causing adrenal insufficiency is concerning, the insidious onset and subtle symptoms of this drug render it perilous. Coupled with etomidate's affordability, the influence of peers, and the fleeting euphoria it provides, these factors highlight the considerable societal risks associated with this emerging substance of abuse. It is well-established that adolescents with depression are more likely to engage in substance use as a means of coping with peer pressure and navigating interpersonal relationships.¹¹ In Hong Kong, the predominant motivations for drug abuse among adolescents reflect similar trends, with peer influence cited as the leading factor at 57.5%, followed closely by the desire to alleviate depression or stress at 41%.¹ Vaping, in particular, has been significantly associated with adolescents facing mental health challenges, including depression and suicidality. These findings resonate with the patterns observed in our cohort, underscoring the urgent need to address the intersection of mental health and substance use in this vulnerable population. Our cases highlight the critical importance of obtaining a thorough clinical history when evaluating adolescent patients. as these young individuals may conceal their substance use out of fear of repercussions.

Since February 2025, etomidate and its 2 analogues (propoxate, isopropoxate) have been added to the First Schedule of the DDO in Hong Kong.¹² By providing comprehensive anti-drug education, we can effectively mitigate the misuse of etomidate in e-cigarettes, thereby safeguarding the health and well-being of our youth.

One of the challenges we encountered in our study was the wide spectrum of presenting complaints, which delayed the timely recognition of etomidate misuse. This, in turn, contributed to a lag between initial presentation and endocrinological evaluation, potentially accounting for some inconsistencies observed in our hormonal results. Additionally, managing adolescents with etomidate misuse posed its own difficulties, particularly due to a high rate of loss to follow-up and incomplete investigations. This represents a limitation of the study, as it restricts our capacity for long-term data collection on etomidate misuse within this demographic. Therefore, it is essential for clinicians to remain vigilant and to act promptly in pursuing further evaluation should etomidate abuse be suspected.

As far as we are aware, this is the first documented retrospective observational study revealing adrenocortical suppression linked to chronic inhaled Etomidate abuse in the paediatric population. It is crucial for healthcare professionals to be vigilant in recognising cases of chronic etomidate misuse, identifying associated complications, and providing timely intervention and treatment.

Conclusion

The use of etomidate via electronic cigarettes is an emerging public health concern in our region. Clinicians must remain vigilant regarding the potential risks of adrenal insufficiency and hypokalaemia linked to etomidate misuse, particularly among adolescents who have a history of electronic cigarette use. Further research is essential to illuminate the pharmacokinetics of inhaled etomidate and to assess its long-term health implications. The fight against substance abuse presents a formidable challenge for healthcare professionals, lawmakers, and society at large. As paediatricians, it is our responsibility to ensure that efforts to address this critical issue among our most vulnerable populations are both effective and impactful.

Acknowledgement

We would like to acknowledge Dr. LM Wong for his support and guidance in this article.

Funding/Support

This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Declaration of Interest

All authors have disclosed no conflicts of interest.

Ethical Consideration

This above study has been approved by the HA Central Institutional Review Board (Central IRB).

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