Forensic Science International 233 (2013) 333–337
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Deaths from recreational use of propofol in Korea Eunyoung Han a, Sujin Jung b, Seungkyung Baeck b, Sangki Lee b, Heesun Chung c,* a
College of Pharmacy, Duksung Women’s University, 33, Samyangro 144-gil, Dobonggu, Seoul 132-714, Republic of Korea National Forensic Service, 331-1 Shinwol 7-dong, Yangcheongu, Seoul 158-707, Republic of Korea c Graduate School of Analytical Science and Technology, Chungnam National University, 99 Daehak-ro, Yuseong-Ku, Daejeon, 305-764, Republic of Korea b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 15 July 2013 Received in revised form 17 September 2013 Accepted 5 October 2013 Available online 14 October 2013
Propofol, a short-acting and sedative-hypnotic agent, induces and maintains anesthesia. Since it is known to produce mild euphoria and hallucinations, the recreational use of propofol has been a big issue in Korea. Furthermore, many deaths have occurred due to its abuse and misuse. In order to study the prevalence of abuse and deaths due to propofol, all autopsy cases conducted between 2005 and 2010 at the NFS (National Forensic Service, Korea) were monitored by checking its concentrations in the blood. Propofol was detected in 131 cases (0.88%) out of 14,673 autopsied cases within 6 years. Propofol alone was detected in 49 of 131 fatal cases, while the combination of drugs was detected with propofol in the remaining 82 cases. The concentrations of propofol from autopsied cases ranged from 0.05 to 8.83 mg/L (mean 1.66; median 0.9) and from 0.08 to 8.65 mg/L (mean 1.71; median 1.05) in the heart (n = 31) and the femoral blood (n = 32), respectively. The investigation of the ratio of heart to femoral blood and the difference between the concentrations in heart and femoral blood (n = 15) from the same body revealed the ratio from 0.45 to 3.66 (mean 1.53; median 1.40). The autopsy resulted in accidental death after self-administration in 16 autopsied cases among 131 autopsied cases. In 16 cases, their ages ranged from 17 to 56 and 75% of them were in their 20’s and 30’s and 75% were female. Half of them were medical personnel including 19% of doctors and 38% of nurses. The combination of drugs was detected in 6 cases. Fluoxetine was detected in three and vecuronium was detected in two along with propofol. The cause of death in 14 cases was drug intoxication, while that in 2 cases was hanging. Due to its prevalence, Korea has become the first country that regulates propofol as a psychotropic substance. ß 2013 Elsevier Ireland Ltd. All rights reserved.
Keywords: Propofol Recreational use Gas chromatography/mass spectrometry Validation
1. Introduction Propofol (2,6-diisopropylphenol) is a short-acting and sedativehypnotic agent that induces and maintains anesthesia [1,2]. Due to its rapid recovery and a faster onset of action, general physicians and surgeons prefer to use it instead of other anesthesia [3– 5,2,6,7]. However there are several side effects including low blood pressure, bradycardia, hypotension, cardiac arrhythmia, transient apnea, dystonia, and mild myoclonic movements [8–10]. Since its side effects contain euphoria, sexual hallucinations and disinhibition during recovery, people are inclined to use it for recreational purposes [11–14]. In fact, the recreational use of propofol has been a big issue in Korea. Because many plastic surgery clinics often use it, some female clients have become addicted due to undergoing
* Corresponding author. Tel.: +82 42 821 8540; fax: +82 42 821 8541. E-mail address: [email protected] (H. Chung). 0379-0738/$ – see front matter ß 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.forsciint.2013.10.008
frequent plastic surgeries. There is also an assumption that Korean entertainers abuse propofol because they believe the drug is good for stress and insomnia. In addition, some doctors in local clinics have sold propofol shots as packages grouped with massages under false pretenses. Now, the government could take measures against these practices by the law. Roussin et al. [11] reported evidence of the potential for abuse and dependence on propofol. Zacny et al. [15] concluded that propofol may be rewarding (reinforcing) in some individuals without a history of drug abuse. Wilson et al. [1] recommended that the U.S. Drug Enforcement Administration and other international agencies should consider regulating propofol as a controlled substance. Because its abuse had been prevalent among celebrities as well as housewives, the Korean government classified it as a psychotropic agent in 2011 and regulated its use. Korea has become the first country that regulates propofol as a psychotropic substance. Even though it has been controlled, its abuse continues. In 2013, three famous female celebrities were charged with its
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illegal use. According to a report by the prosecution, they took propofol between 95 to 185 times. But they claimed that they used it for medical purposes, not to help them sleep or for recreational use. However, because the safety margin of propofol is very narrow, deaths have occurred accidentally in many cases, just as it contributed to the death of pop star Michael Jackson. Propofol is especially highly abused by medical professionals including nurses, nurse’s aides and medical doctors [11,16–18]. In this study, in order to observe the prevalence of propofol abuse, all autopsy cases conducted between 2005 and 2010 at the NFS (National Forensic Service, Korea) were monitored by checking its concentration in the blood. Firstly, a method was validated and then applied to determine the concentration. In all cases, systematic screening was conducted to detect propofol as well as other drugs. Among propofol positive cases, the blood concentrations in the femoral and the heart blood were evaluated to study the postmortem redistribution (PR). The autopsy resulted in accidental death after self-administration in 16 autopsied cases among 131 autopsied cases. The occupation, age, gender, case study, and detection of other drugs were investigated to determine the causes of deaths. 2. Methods 2.1. Chemicals Propofol (2,6-diisopropylphenol), 99.8% purity, was obtained from Cerilliant (TX, USA). Thymol (2-isopropyl-5-methylphenol), 99.5% purity, disodium hydrogen phosphate and monosodium phosphate were purchased from Sigma-Aldrich (MO, USA). HPLC grade methanol, chloroform and ethyl acetate, sodium hydroxide and sodium sulfate were obtained from Merck (Darmstadt, Germany).
2.5. GC/MS system The GC–MS system consisted of a Hewlett Packard 7683 series injector, HP 6890 series GC system (Wilmington, DE, USA), and HP 5973 mass selective detector. The column used (Agilent Technologies, Foster, CA, USA) was a fused silica capillary column (HP-5 MS capillary column, 30.0 m 250 mm 0.25 mm). The injector was operated in the splitless mode, the injection volume was 1 mL, the injector temperature was 200 8C, the ionization energy was 70 eV and the transfer line temperature was 280 8C. Initial oven temperature was 50 8C, maintained for 1 min, increasing at 10 8C/min to 190 8C and increasing at 20 8C/min to 290 8C. GC/MS was operated in selected ion monitoring mode (SIM). The quantification of propofol was based on peak area ratios. The m/z and retention time of propofol and thymol (internal standard) were as follows: propofol, m/z 163, 178, 121, RT 11.82 min; thymol, m/z 135, 150, 91, RT 10.86 min (the underlined ions were used for quantitation). 2.6. Method validation The method was validated by establishing specificity, selectivity, limit of detection (LOD), limit of quantification (LOQ), linearity, intra- and inter-assay accuracy, precision and recovery. To evaluate selectivity, fifty-five frequently detected drugs including amitriptyline, benztropine, etc. were added to six drugfree whole blood samples at concentrations of 0.1 mg/L for checking the interference. The LOQ was evaluated in triplicate and defined as the concentration that met LOD criteria for which the signal-to-noise ratio was at least 10:1 and the measured concentration was within 20% of the target in three replicates. Nine calibration standards ranging in concentrations from 0.05 to 2 mg/L propofol were prepared using 1 mL of drug-free blood. Spiked drug-free blood samples (1 mL) containing low, medium and high concentrations of propofol (0.08, 0.2 and 0.8 mg/ L) were prepared in order to assess intra-assay (n = 6) accuracy and precision. The inter-assay (n = 18) accuracy and precision were also examined in series on five consecutive days. Recovery was determined at 0.08, 0.2 and 0.8 mg/L of propofol and peak area ratios of propofol to thymol were compared with those of methanolic standards.
3. Results 2.2. Standard and internal standard solutions and calibration standards Stock solutions (1 mg/mL) of propofol and internal standard, thymol, were prepared in methanol and stored at 20 8C. Standard solutions were made by further dilution of stock solutions with methanol. For calibration curves, drug-free whole blood samples obtained from the deceased (1 mL) were spiked with diluted standard solutions to give final concentrations of 0.05, 0.075, 0.1, 0.125, 0.15, 0.5, 1, 1.5 and 2 mg/L. 2.3. Sample collection After autopsy, blood samples were collected and analyzed. Post-mortem cardiac and femoral blood specimens were collected in 50 mL plastic tubes and stored at 4 8C until analysis. The average time between the arrival of the body at NFS and the sample collection was approximately 3 h. Every year over 2000 autopsies were performed at the headquarters of NFS and a total of 14,673 autopsied cases were studied. 2.4. Sample preparation One mL of whole blood sample (done in triplicate) was put into a 15-mL glass screw cap tube to which the following was added: 50 mL of thymol (10 mg/L) as an internal standard, 0.5 mL of 0.05 M phosphate buffer (pH 6.0) and 0.2 mL of 0.1 M sodium hydroxide. Then 5 mL of chloroform–ethylacetate (70:30, v/v) was added, and the analytes were extracted gently by mechanical shaking for 30 min at 50 rpm. After centrifugation, an aliquot of the organic layer (bottom) was transferred to a glass tube containing sodium sulfate to eliminate water and was evaporated to dryness under nitrogen for 15 min. The dried extract was reconstituted in 100 mL of methanol. One mL was injected into the capillary column of the GC–MS system.
3.1. Validation of the method Table 1 shows the results of the method validation for propofol in blood. For specificity and selectivity, all six whole blood samples were free of co-eluting peaks at the retention times of propofol and thymol. The 55 commonly encountered medicines, which were added at 0.1 mg/L, did not interfere with propofol quantitation (0.2 mg/L) resulting in accuracy of +4.28% and a precision of 6.65%. The LOD and LOQ of propofol using 1 mL of blood were 0.02 and 0.05 mg/L, respectively. The calibration curves for propofol were linear in the concentration range of 0.05–2 mg/L and R2 was 0.9931. The intra- (n = 6) and inter-assay (n = 18) inaccuracy and imprecision for propofol in whole blood were all less than 14.04% at three concentrations. The recoveries of medium and high concentration groups were high, but that of the low concentration group was low. Overall, recoveries ranged from 82% to 116%. 3.2. Prevalence of propofol abuse Among a total of 14,673 autopsies, propofol was detected in 131 cases. As shown in Fig. 1, it was detected in 5 cases in 2005, 21 in 2006, 18 in 2007, 21 in 2008, 33 in 2009 and 33 in 2010. Among them, there were cases in which the combination of other drugs
Table 1 Validation data of propofol in whole blood. Analyte (mg/L)
Accuracya (%bias) Intra-day (n = 6)
0.08 0.2 0.8 a
10.59 10.62 13.39
Precisionb (%CV) Inter-day (n = 18)
Intra-day (n = 6)
Inter-day (n = 18)
n=6
11.67 14.04 9.50
14.08 4.36 10.32
14.00 9.83 13.56
82 116 105
Calculated as [(mean calculated concentration nominal concentration)/nominal concentration] 100 (% bias). The coefficient of variation (% CV): SD/mean 100%. Limit of detection: 0.02 mg/L (using 1 mL of blood). * Limit of quantitation: 0.05 mg/L (using 1 mL of blood). b
*
Recovery (%)
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Fig. 1. The number of death cases in which propofol alone and combination with other drugs were detected.
was determined with propofol, 3 in 2005, 13 in 2006 and 2007, 12 in 2008, 23 in 2009 and 18 in 2010. The number of cases where propofol was alone detected was 2 in 2005, 8 in 2006, 5 in 2007, 9 in 2008, 10 in 2009 and 15 in 2010. After evaluating the frequency of propofol alone cases and cases of combination with other drugs, we found that propofol alone was detected in 49 of 131 fatal cases; drugs such as lidocaine (n = 53), atropine (n = 30) and chlorpheniramine (n = 18) were combined with propofol. Among 131 cases, 57% comprised of females, while males 43%. 23% were in their twenties, 22% in their forties and 21% in their thirties. 3.3. Quantitation of propofol in autopsied blood and PMR The quantitation of propofol in the blood was performed in 48 of 131 autopsied cases. Its concentrations ranged from 0.05 to 8.83 mg/L (mean 1.66; median 0.9) and from 0.08 to 8.65 mg/L (mean 1.71; median 1.05). In order to study PMR, propofol concentrations in the heart and the femoral blood (n = 15) from the same body were determined to evaluate the ratios of heart to femoral blood and PMR phenomena. Propofol concentrations ranged from 0.12 to 6.12 mg/L (mean 2.21; median 1.78) and from 0.08 to 6.87 mg/L (mean 1.84; median 1.27) in the heart and the femoral blood, respectively. In 12 of 15 cases, heart blood concentrations were higher than femoral blood concentrations (Fig. 2), but there was no statistically significant
difference between the heart and the femoral blood (p > 0.05) by a paired t-test. 3.4. Propofol abuse contributed 16 fatalities Among 131 fatal cases, propofol abuse contributed to 16 fatalities. The occupation, age, gender, case history, other drugs detected and causes of death of the 16 are shown in Table 2. The causes of deaths were determined based on the autopsy, toxicology results, and information in the police reports and other related documentation. Half of them were medical personnel including 19% of doctors, 38% of nurses. In the 16 deaths, their age ranged from 19 to 56 and about 70% were in their 20’s and 30’s and 75% were female. The blood concentrations of propofol in the cases ranged from 0.07 to 8.83 mg/L (mean 3.05; median 2.22) and from 0.3 to 6.56 mg/L (mean 2.27; median 1.41) in the heart (n = 10) and the femoral blood (n = 14), respectively. There was a big gap between blood concentrations. Propofol concentrations in case No. 5 and 6 were highest, whereas the blood concentration in case No. 4 was lowest among 16 fatalites. The cause of death in all cases was drug intoxication except for case Nos. 12 and 16 (hanging). The blood concentrations in 14 intoxication deaths were compared with the concentrations of propofol in other causes of death (hanging). The propofol concentrations in the femoral blood ranged from 0.07 to 6.56 mg/L (mean 2.39; median 1.41) and from 1.08 to 1.91 mg/L
Fig. 2. The heart and femoral blood concentrations and the ratios of heart to femoral blood concentrations for propofol in 15 autopsied cases. The difference between the concentrations in heart and femoral blood was investigated. The cases were arranged in order of concentration.
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Table 2 Case history and blood concentration of propofol related fatalities. The cause of death in all cases was drug intoxication except for case Nos. 12 and 16 (hanging). Case No.
Age
Sex
Occupation
Case history
Concentration (mg/L) Femoral blood
Heart blood
Other drugs detected
1
19
F
Student
Found dead at home. A syringe was found in the small vessel of her right calf.
1.52
2.28
2
27
F
Nurse
2.57
2.21
3
42
F
Nurse
3.84
6.12
–
4
27
F
Doctor
0.07
0.07
Vecuronium
5
29
F
Nurse
6.37
–
–
6
38
F
–
6.56
–
–
7
50
M
Doctor
1.22
1.61
Ethanol
8
30
M
Doctor
0.72
–
–
9
28
M
–
–
8.83
–
10
46
F
–
ND
–
–
11
56
F
–
Found with vital signs at a hospital dormitory. Butterfly-needle canalized into the vein of the forearm. She was given emergency treatment, died after 20 h. Several empty propofol ampoules were found in her locker. Found dead in her room. Beside the body, 2 empty propofol ampoules and 2 blood-stained syringes were found. She had 2 injection marks in her forearm. Found dead in her studio. A syringe filled with white liquid was observed in the small vessel of the bend of the arm. Beside the body, 1 empty syringe was found. Also, empty propofol ampoule and empty vecuronium ampoule were found in a dustbin. Found dead in hospital room. A needle canalized with infusion bag was observed in the forearm. Found dead in a hotel room, naked. Police couldn’t find any evidence. Found dead in endoscope room. Beside the body, 21 blood-stained syringes were found. He had 11 injection marks in his arm. Found dead in hospital room. A needle canalized with infusion bag was observed in the forearm. Beside the body, 2 empty syringes and 3 empty propofol ampoules were found. Found dead in his room. He had 1 injection mark at back of his hand. Beside the body, empty syringe and empty propofol ampoule were found. Found dead in her room. Beside the body, empty syringe was found. She had 1 injection mark at back of her hand. Died after self administration of propofol (propofol addict)
2.68
3.57
12 13
28 37
F M
– –
1.91 0.61
– 2.23
Ketamin, Diazepam, Fluoxetine, Lidocaine – –
14
33
F
Nurse
1.3
–
–
15 16
28 34
F F
Nurse Nurse
1.27 1.08
1.78 1.76
– Fluoxetine, Triazolam, Quetiapine, Clotiazepam, Alprazolam
Hanged herself. Injection marks on her arm. Found dead in the restroom. Lots of injection marks. Propofol ampoule was found at the scene. She had suffered from depression. Found dead after an intravenous injection. Died after injection of propofol which were stored in her house. Hanged herself after injection of propofol. Some hypnotic drugs were found at the scene.
(mean 1.50; median 1.50) in 14 intoxication deaths and other cases of death (hanging), respectively. Fluoxetine was detected in three cases and vecuronium was detected in two along with propofol among 16 fatalites. In case No. 4, vecuronium was detected in her brain tissue. It was concluded that she took both propofol and vecuronium, resulting in low level of propofol. In case No. 1, fluoxetine, diphenhydramine, chlorpheniramine were also detected in the blood. In case No. 11, a 56years-old woman was known as a propofol addict. Ketamine, diazepam, fluoxetine and lidocaine were detected in her blood. In case Nos. 14, 15 and 16, three nurses were found dead and fluoxetine, triazolam, quetiapine, clotiazepam and alprazolam were detected in case No. 16. 4. Discussion The results of the method validation for the analysis of propofol in blood such as specificity, selectivity, LOD, LOQ, intra- and interassay accuracy and precision, and recovery were satisfactory. Fig. 1 shows the deaths related with propofol had increased more than 6 times from 2005 to 2010. After evaluating the frequency of propofol alone cases and cases of combination with other drugs, we found that propofol alone was detected in 49 of 131 fatal cases; drugs such as lidocaine (n = 53), atropine (n = 30)
Fluoxetine, Diphenhydramine, Chlorpheniramine Thiopental Phentermine Vecuronium
and chlorpheniramine (n = 18) were combined with propofol. These are frequently combined with propofol because they are often used in emergency medical treatment. The various causes of deaths were identified in all cases including drug intoxication, drug abuse, car accident, murder, multiple injuries, suicide and etc. Roussin [16] identified lidocaine in the blood at a sub-therapeutic concentration with propofol in a reported paper. Kranioti [17] also reported that lidocaine does not alter the effects of propofol but reduces the pain from its intravenous administration in case of the mixture of lidocaine with propofol. Wilson et al. [1] found evidence to support propofol’s abuse potential from a pharmacological and experiential standpoint with multiple reports describing tolerance, dependence, withdrawal phenomena, abuse, and death from recreational use. The quantitation of propofol in the blood was performed in 48 of 131 autopsied cases. Its concentrations ranged from 0.05 to 8.83 mg/L (mean 1.66; median 0.9) and from 0.08 to 8.65 mg/L (mean 1.71; median 1.05). Molina [19] reported the therapeutic concentrations of propofol ranged from 0.78 to 15 mg/L and lethal concentrations ranged from 0.22 to 5.5 mg/L, indicating a wide range of therapeutic levels. However the reference blood level list of therapeutic and toxic substances showed different therapeutic concentrations for propofol from 2 to 4 mg/L [20]. Therapeutic concentration of propofol means the concentration that causes
E. Han et al. / Forensic Science International 233 (2013) 333–337
anesthesia. However, even a concentration that causes sleep and anesthesia in a ventilated and closely monitored subject in an operating room could cause death in someone who is not ventilated artificially. Chao et al. [21] reported that the propofol level in the blood of a man suspected of having fatally selfadministered an intravenous dose of 1600 mg of propofol was 2.5 mg/L. Kirby et al. [22] reported the first case of murder with propofol. A woman was found dead in her home from apparent propofol toxicity and her blood level of propofol was 4.3 mg/L. Drummer [23] described a suicide by self-administration of propofol in a female radiographer. The post-mortem femoral blood concentration of propofol was 0.22 mg/L. The scene suggested that a dose of 400 mg was used. Kranioti et al. [17] reached the conclusion that one person’s death was a consequence of propofol self-administration at therapeutic doses and found that the postmortem concentrations were all at therapeutic levels in previously reported cases. Roussin et al. [16] also reported deaths related to a recreational abuse in a therapeutic dose range. The toxic concentrations of propofol in non-intubated patients may be different from patients who were intubated and fully supported in the operating room or in the intensive care unit [17]. In order to study PMR, propofol concentrations in the heart and the femoral blood (n = 15) from the same body were determined to evaluate the ratios of heart to femoral blood and PMR phenomena. The ratios of heart to femoral blood concentrations ranged from 0.45 to 3.66 (mean 1.53; median 1.40). PMR involves several, complex mechanisms; therefore, it cannot be evaluated only by comparing propofol concentrations in the blood taken from peripheral and central sites. However, such a comparison may give an indication that PMR has occurred. Among 131 fatal cases, propofol abuse contributed to 16 fatalities. Half of them were medical personnel including 19% of doctors and 38% of nurses. Most of the victims work in the medical field. Hospital diversion from medical use is a primary access for doctors or nurses. More measures to avoid diversion for personal use in hospitals might be more effective. There are many papers which report the deaths of healthcare practitioners [11] such as anesthetic nurses [16,18], radiographers [23], and anesthesiologists [17]. In this study, propofol was also proved to be abused by healthcare professionals including nurses, nurse’s aide, anesthesiologist, plastic surgeon, general practitioner and so on. They were mostly found dead in their beds at home, in the nurse’s room or doctor’s room after self-administration. It is obvious that they were prone to abuse it, due to its easy availability. Most of them were found with needles and syringes on site and injection marks. There were syringes, medicine bottles, and Ringer’s solution at the scene. Although not fatal, there was a case where a young woman had not had any meals for 5 days, only IV injections of propofol, presumably to obtain the euphoric effect of propofol. All 16 cases were assumed to be accidental deaths after self-administration. The cause of death in 14 cases was drug intoxication except No. 12 and No. 16 where the cause of death was hanging. 5. Conclusions Propofol was detected in 131 (0.89%) out of 14,673 autopsied cased between 2005 and 2010. The method for the analysis of propofol in the blood was specific and sensitive. This validated method was applied to screen the whole blood collected from autopsied cases (n = 131). Among them propofol alone was detected in 49, while the combination of drugs was detected with propofol in the remaining 82 cases. Medical examiners concluded
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that propofol directly affected deaths in only 16 of the 131 autopsied cases. The concentrations of propofol from autopsied cases were measured in the heart and femoral blood and the investigation of the ratio of heart to femoral blood (n = 15) from the same body were performed. After investigating accidental deaths after self-administering (n = 16), we found that propofol was used more frequently in medical personnel women aged 20–30 years. The cause of death in 14 cases was drug intoxication, while that in 2 cases was hanging. Due to its prevalence, Korea has become the first country that regulates propofol as a psychotropic substance. Acknowledgements This research was supported by the Research & Development Program for new technology of Forensic Science by the Ministry of Public Administration and Security and the Duksung Women’s University Research Grants 2013 (3000001965). References [1] C. Wilson, P. Canning, E.M. Caravati, The abuse potential of propofol, Clin. Toxicol. (Phila) 48 (3) (2010) 165–170. [2] S.I. Bergmann, P. Ro¨sner, H.C. Ku¨hnau, M. Junge, A. Schmoldt, Death after excessive propofol abuse, Int. J. Legal Med. 114 (4–5) (2001) 248–251. [3] M.S. Langley, R.C. Heel, Propofol: a review of its pharmacodynamic and pharmacokinetic properties and use as an intravenous anaesthetic, Drugs 35 (1988) 334– 372. [4] B. Fulton, E.M. Sorkin, Propofol: an overview of its pharmacology and a review of its clinical efficacy in intensive care sedation, Drugs 50 (1995) 636–657. [5] D. Nancy, M.D. Perrier, M.D. Yvonne Baerga-Varela, M.J. Murray, Death related to propofol use in an adult patient, Crit. Care Med. 28 (2000) 3071–3074. [6] P.E. Marik, Propofol: therapeutic indications and side-effects, Curr. Pharm. Des. 10 (2004) 3639–3649. [7] P.E. Marik, Propofol: an immune-modulating agent, Pharmacotherapy 25 (5 Pt 2) (2005) 28S–33S. [8] B.K. Burow, M.E. Johnson, D.L. Packer, Metabolic acidosis associated with propofol in the absence of other causative factors, Anesthesiology 101 (1) (2004) 239–241. [9] J.C. Salengros, C.E. Velghe-Lenelle, R. Bollens, E. Engelman, L. Barvais, Lactic acidosis during propofol-remifentanil anesthesia in an adult, Anesthesiology 101 (1) (2004) 241–243. [10] B.M. Schramm, B.A. Orser, Dystonic reaction to propofol attenuated by benztropine (Cogentin), Anesth. Analg. 94 (2002) 1237–1240. [11] A. Roussin, J.L. Montastruc, M. Lapeyre-Mestre, Pharmacological and clinical evidences on the potential for abuse and dependence of propofol: a review of the literature, Fund. Clin. Pharmacol. 21 (5) (2007) 459–466. [12] S.C. Sweetman, Martindale The Complete Drug Reference, 34th ed., Pharmaceutical Press, London, 2005, pp. 1305–1307. [13] M.N.G. Dukes, J.K. Aronson, Z. Baudoin, General anaesthetics and anaestheticgases, in: M.N.G. Dukes, J.K. Aronson (Eds.), Meyler’s Side Effects of Drugs, 14th ed., Elsevier, Amsterdam, 2000, p. 330. [14] T.Y. Euliano, J.S. Gravenstein, A Brief Pharmacology Related to Anesthesia. Essential Anesthesia: From Science to Practice, Cambridge University Press, Florida, 2004p. 173. [15] J.P. Zacny, J.L. Lichtor, W. Thompson, J.L. Apfelbaum, Propofol at a subanesthetic dose may have abuse potential in healthy volunteers, Anesth. Analg. 77 (3) (1993) 544–552. [16] A. Roussin, M. Mirepoix, G. Lassabe, V. Dumestre-Toulet, V. Gardette, J.L. Montastruc, M.L. Mestre, Death related to a recreational abuse of propofol at therapeutic dose range, Br. J. Anaesth. 97 (2) (2006) 268. [17] E.F. Kranioti, A. Mavroforou, P. Mylonakis, M. Michalodimitrakis, Lethal self administration of propofol (Diprivan): a case report and review of the literature, Forensic Sci. Int. 167 (1) (2007) 56–58. [18] G. Klausz, K. Rona, I. Kristof, K. Toro, Evaluation of a fatal propofol intoxication due to self administration, J. Forensic Leg. Med. 16 (2009) 287–289. [19] D.K. Molina, Handbook of Forensic Toxicology for Medical Examiners, CRC press, FL, 2010. [20] Reference Blood Level List of Therapeutic and Toxic Substances, TIAFT, 2011 http://www.tiaft.org/toxic_values (accessed 12.10.11). [21] T.C. Chao, D.S.T. Lo, P.P.S. Chui, T.H. Koh, The first fatal 2,6-di-isopropylphenol (propofol) poisoning in Singapore: a case report, Forensic Sci. Int. 66 (1) (1994) 1– 7. [22] R.R. Kirby, J.M. Colaw, M.M. Douglas, Death from propofol: accident, suicide, or murder? Anesth. Analg. 108 (4) (2009) 1182–1184. [23] O.H. Drummer, A fatality due to propofol poisoning, J. Forensic Sci. 37 (4) (1992) 1186–1189.
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Deaths from recreational use of propofol in Korea Eunyoung Han a, Sujin Jung b, Seungkyung Baeck b, Sangki Lee b, Heesun Chung c,* a
College of Pharmacy, Duksung Women’s University, 33, Samyangro 144-gil, Dobonggu, Seoul 132-714, Republic of Korea National Forensic Service, 331-1 Shinwol 7-dong, Yangcheongu, Seoul 158-707, Republic of Korea c Graduate School of Analytical Science and Technology, Chungnam National University, 99 Daehak-ro, Yuseong-Ku, Daejeon, 305-764, Republic of Korea b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 15 July 2013 Received in revised form 17 September 2013 Accepted 5 October 2013 Available online 14 October 2013
Propofol, a short-acting and sedative-hypnotic agent, induces and maintains anesthesia. Since it is known to produce mild euphoria and hallucinations, the recreational use of propofol has been a big issue in Korea. Furthermore, many deaths have occurred due to its abuse and misuse. In order to study the prevalence of abuse and deaths due to propofol, all autopsy cases conducted between 2005 and 2010 at the NFS (National Forensic Service, Korea) were monitored by checking its concentrations in the blood. Propofol was detected in 131 cases (0.88%) out of 14,673 autopsied cases within 6 years. Propofol alone was detected in 49 of 131 fatal cases, while the combination of drugs was detected with propofol in the remaining 82 cases. The concentrations of propofol from autopsied cases ranged from 0.05 to 8.83 mg/L (mean 1.66; median 0.9) and from 0.08 to 8.65 mg/L (mean 1.71; median 1.05) in the heart (n = 31) and the femoral blood (n = 32), respectively. The investigation of the ratio of heart to femoral blood and the difference between the concentrations in heart and femoral blood (n = 15) from the same body revealed the ratio from 0.45 to 3.66 (mean 1.53; median 1.40). The autopsy resulted in accidental death after self-administration in 16 autopsied cases among 131 autopsied cases. In 16 cases, their ages ranged from 17 to 56 and 75% of them were in their 20’s and 30’s and 75% were female. Half of them were medical personnel including 19% of doctors and 38% of nurses. The combination of drugs was detected in 6 cases. Fluoxetine was detected in three and vecuronium was detected in two along with propofol. The cause of death in 14 cases was drug intoxication, while that in 2 cases was hanging. Due to its prevalence, Korea has become the first country that regulates propofol as a psychotropic substance. ß 2013 Elsevier Ireland Ltd. All rights reserved.
Keywords: Propofol Recreational use Gas chromatography/mass spectrometry Validation
1. Introduction Propofol (2,6-diisopropylphenol) is a short-acting and sedativehypnotic agent that induces and maintains anesthesia [1,2]. Due to its rapid recovery and a faster onset of action, general physicians and surgeons prefer to use it instead of other anesthesia [3– 5,2,6,7]. However there are several side effects including low blood pressure, bradycardia, hypotension, cardiac arrhythmia, transient apnea, dystonia, and mild myoclonic movements [8–10]. Since its side effects contain euphoria, sexual hallucinations and disinhibition during recovery, people are inclined to use it for recreational purposes [11–14]. In fact, the recreational use of propofol has been a big issue in Korea. Because many plastic surgery clinics often use it, some female clients have become addicted due to undergoing
* Corresponding author. Tel.: +82 42 821 8540; fax: +82 42 821 8541. E-mail address: [email protected] (H. Chung). 0379-0738/$ – see front matter ß 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.forsciint.2013.10.008
frequent plastic surgeries. There is also an assumption that Korean entertainers abuse propofol because they believe the drug is good for stress and insomnia. In addition, some doctors in local clinics have sold propofol shots as packages grouped with massages under false pretenses. Now, the government could take measures against these practices by the law. Roussin et al. [11] reported evidence of the potential for abuse and dependence on propofol. Zacny et al. [15] concluded that propofol may be rewarding (reinforcing) in some individuals without a history of drug abuse. Wilson et al. [1] recommended that the U.S. Drug Enforcement Administration and other international agencies should consider regulating propofol as a controlled substance. Because its abuse had been prevalent among celebrities as well as housewives, the Korean government classified it as a psychotropic agent in 2011 and regulated its use. Korea has become the first country that regulates propofol as a psychotropic substance. Even though it has been controlled, its abuse continues. In 2013, three famous female celebrities were charged with its
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illegal use. According to a report by the prosecution, they took propofol between 95 to 185 times. But they claimed that they used it for medical purposes, not to help them sleep or for recreational use. However, because the safety margin of propofol is very narrow, deaths have occurred accidentally in many cases, just as it contributed to the death of pop star Michael Jackson. Propofol is especially highly abused by medical professionals including nurses, nurse’s aides and medical doctors [11,16–18]. In this study, in order to observe the prevalence of propofol abuse, all autopsy cases conducted between 2005 and 2010 at the NFS (National Forensic Service, Korea) were monitored by checking its concentration in the blood. Firstly, a method was validated and then applied to determine the concentration. In all cases, systematic screening was conducted to detect propofol as well as other drugs. Among propofol positive cases, the blood concentrations in the femoral and the heart blood were evaluated to study the postmortem redistribution (PR). The autopsy resulted in accidental death after self-administration in 16 autopsied cases among 131 autopsied cases. The occupation, age, gender, case study, and detection of other drugs were investigated to determine the causes of deaths. 2. Methods 2.1. Chemicals Propofol (2,6-diisopropylphenol), 99.8% purity, was obtained from Cerilliant (TX, USA). Thymol (2-isopropyl-5-methylphenol), 99.5% purity, disodium hydrogen phosphate and monosodium phosphate were purchased from Sigma-Aldrich (MO, USA). HPLC grade methanol, chloroform and ethyl acetate, sodium hydroxide and sodium sulfate were obtained from Merck (Darmstadt, Germany).
2.5. GC/MS system The GC–MS system consisted of a Hewlett Packard 7683 series injector, HP 6890 series GC system (Wilmington, DE, USA), and HP 5973 mass selective detector. The column used (Agilent Technologies, Foster, CA, USA) was a fused silica capillary column (HP-5 MS capillary column, 30.0 m 250 mm 0.25 mm). The injector was operated in the splitless mode, the injection volume was 1 mL, the injector temperature was 200 8C, the ionization energy was 70 eV and the transfer line temperature was 280 8C. Initial oven temperature was 50 8C, maintained for 1 min, increasing at 10 8C/min to 190 8C and increasing at 20 8C/min to 290 8C. GC/MS was operated in selected ion monitoring mode (SIM). The quantification of propofol was based on peak area ratios. The m/z and retention time of propofol and thymol (internal standard) were as follows: propofol, m/z 163, 178, 121, RT 11.82 min; thymol, m/z 135, 150, 91, RT 10.86 min (the underlined ions were used for quantitation). 2.6. Method validation The method was validated by establishing specificity, selectivity, limit of detection (LOD), limit of quantification (LOQ), linearity, intra- and inter-assay accuracy, precision and recovery. To evaluate selectivity, fifty-five frequently detected drugs including amitriptyline, benztropine, etc. were added to six drugfree whole blood samples at concentrations of 0.1 mg/L for checking the interference. The LOQ was evaluated in triplicate and defined as the concentration that met LOD criteria for which the signal-to-noise ratio was at least 10:1 and the measured concentration was within 20% of the target in three replicates. Nine calibration standards ranging in concentrations from 0.05 to 2 mg/L propofol were prepared using 1 mL of drug-free blood. Spiked drug-free blood samples (1 mL) containing low, medium and high concentrations of propofol (0.08, 0.2 and 0.8 mg/ L) were prepared in order to assess intra-assay (n = 6) accuracy and precision. The inter-assay (n = 18) accuracy and precision were also examined in series on five consecutive days. Recovery was determined at 0.08, 0.2 and 0.8 mg/L of propofol and peak area ratios of propofol to thymol were compared with those of methanolic standards.
3. Results 2.2. Standard and internal standard solutions and calibration standards Stock solutions (1 mg/mL) of propofol and internal standard, thymol, were prepared in methanol and stored at 20 8C. Standard solutions were made by further dilution of stock solutions with methanol. For calibration curves, drug-free whole blood samples obtained from the deceased (1 mL) were spiked with diluted standard solutions to give final concentrations of 0.05, 0.075, 0.1, 0.125, 0.15, 0.5, 1, 1.5 and 2 mg/L. 2.3. Sample collection After autopsy, blood samples were collected and analyzed. Post-mortem cardiac and femoral blood specimens were collected in 50 mL plastic tubes and stored at 4 8C until analysis. The average time between the arrival of the body at NFS and the sample collection was approximately 3 h. Every year over 2000 autopsies were performed at the headquarters of NFS and a total of 14,673 autopsied cases were studied. 2.4. Sample preparation One mL of whole blood sample (done in triplicate) was put into a 15-mL glass screw cap tube to which the following was added: 50 mL of thymol (10 mg/L) as an internal standard, 0.5 mL of 0.05 M phosphate buffer (pH 6.0) and 0.2 mL of 0.1 M sodium hydroxide. Then 5 mL of chloroform–ethylacetate (70:30, v/v) was added, and the analytes were extracted gently by mechanical shaking for 30 min at 50 rpm. After centrifugation, an aliquot of the organic layer (bottom) was transferred to a glass tube containing sodium sulfate to eliminate water and was evaporated to dryness under nitrogen for 15 min. The dried extract was reconstituted in 100 mL of methanol. One mL was injected into the capillary column of the GC–MS system.
3.1. Validation of the method Table 1 shows the results of the method validation for propofol in blood. For specificity and selectivity, all six whole blood samples were free of co-eluting peaks at the retention times of propofol and thymol. The 55 commonly encountered medicines, which were added at 0.1 mg/L, did not interfere with propofol quantitation (0.2 mg/L) resulting in accuracy of +4.28% and a precision of 6.65%. The LOD and LOQ of propofol using 1 mL of blood were 0.02 and 0.05 mg/L, respectively. The calibration curves for propofol were linear in the concentration range of 0.05–2 mg/L and R2 was 0.9931. The intra- (n = 6) and inter-assay (n = 18) inaccuracy and imprecision for propofol in whole blood were all less than 14.04% at three concentrations. The recoveries of medium and high concentration groups were high, but that of the low concentration group was low. Overall, recoveries ranged from 82% to 116%. 3.2. Prevalence of propofol abuse Among a total of 14,673 autopsies, propofol was detected in 131 cases. As shown in Fig. 1, it was detected in 5 cases in 2005, 21 in 2006, 18 in 2007, 21 in 2008, 33 in 2009 and 33 in 2010. Among them, there were cases in which the combination of other drugs
Table 1 Validation data of propofol in whole blood. Analyte (mg/L)
Accuracya (%bias) Intra-day (n = 6)
0.08 0.2 0.8 a
10.59 10.62 13.39
Precisionb (%CV) Inter-day (n = 18)
Intra-day (n = 6)
Inter-day (n = 18)
n=6
11.67 14.04 9.50
14.08 4.36 10.32
14.00 9.83 13.56
82 116 105
Calculated as [(mean calculated concentration nominal concentration)/nominal concentration] 100 (% bias). The coefficient of variation (% CV): SD/mean 100%. Limit of detection: 0.02 mg/L (using 1 mL of blood). * Limit of quantitation: 0.05 mg/L (using 1 mL of blood). b
*
Recovery (%)
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Fig. 1. The number of death cases in which propofol alone and combination with other drugs were detected.
was determined with propofol, 3 in 2005, 13 in 2006 and 2007, 12 in 2008, 23 in 2009 and 18 in 2010. The number of cases where propofol was alone detected was 2 in 2005, 8 in 2006, 5 in 2007, 9 in 2008, 10 in 2009 and 15 in 2010. After evaluating the frequency of propofol alone cases and cases of combination with other drugs, we found that propofol alone was detected in 49 of 131 fatal cases; drugs such as lidocaine (n = 53), atropine (n = 30) and chlorpheniramine (n = 18) were combined with propofol. Among 131 cases, 57% comprised of females, while males 43%. 23% were in their twenties, 22% in their forties and 21% in their thirties. 3.3. Quantitation of propofol in autopsied blood and PMR The quantitation of propofol in the blood was performed in 48 of 131 autopsied cases. Its concentrations ranged from 0.05 to 8.83 mg/L (mean 1.66; median 0.9) and from 0.08 to 8.65 mg/L (mean 1.71; median 1.05). In order to study PMR, propofol concentrations in the heart and the femoral blood (n = 15) from the same body were determined to evaluate the ratios of heart to femoral blood and PMR phenomena. Propofol concentrations ranged from 0.12 to 6.12 mg/L (mean 2.21; median 1.78) and from 0.08 to 6.87 mg/L (mean 1.84; median 1.27) in the heart and the femoral blood, respectively. In 12 of 15 cases, heart blood concentrations were higher than femoral blood concentrations (Fig. 2), but there was no statistically significant
difference between the heart and the femoral blood (p > 0.05) by a paired t-test. 3.4. Propofol abuse contributed 16 fatalities Among 131 fatal cases, propofol abuse contributed to 16 fatalities. The occupation, age, gender, case history, other drugs detected and causes of death of the 16 are shown in Table 2. The causes of deaths were determined based on the autopsy, toxicology results, and information in the police reports and other related documentation. Half of them were medical personnel including 19% of doctors, 38% of nurses. In the 16 deaths, their age ranged from 19 to 56 and about 70% were in their 20’s and 30’s and 75% were female. The blood concentrations of propofol in the cases ranged from 0.07 to 8.83 mg/L (mean 3.05; median 2.22) and from 0.3 to 6.56 mg/L (mean 2.27; median 1.41) in the heart (n = 10) and the femoral blood (n = 14), respectively. There was a big gap between blood concentrations. Propofol concentrations in case No. 5 and 6 were highest, whereas the blood concentration in case No. 4 was lowest among 16 fatalites. The cause of death in all cases was drug intoxication except for case Nos. 12 and 16 (hanging). The blood concentrations in 14 intoxication deaths were compared with the concentrations of propofol in other causes of death (hanging). The propofol concentrations in the femoral blood ranged from 0.07 to 6.56 mg/L (mean 2.39; median 1.41) and from 1.08 to 1.91 mg/L
Fig. 2. The heart and femoral blood concentrations and the ratios of heart to femoral blood concentrations for propofol in 15 autopsied cases. The difference between the concentrations in heart and femoral blood was investigated. The cases were arranged in order of concentration.
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Table 2 Case history and blood concentration of propofol related fatalities. The cause of death in all cases was drug intoxication except for case Nos. 12 and 16 (hanging). Case No.
Age
Sex
Occupation
Case history
Concentration (mg/L) Femoral blood
Heart blood
Other drugs detected
1
19
F
Student
Found dead at home. A syringe was found in the small vessel of her right calf.
1.52
2.28
2
27
F
Nurse
2.57
2.21
3
42
F
Nurse
3.84
6.12
–
4
27
F
Doctor
0.07
0.07
Vecuronium
5
29
F
Nurse
6.37
–
–
6
38
F
–
6.56
–
–
7
50
M
Doctor
1.22
1.61
Ethanol
8
30
M
Doctor
0.72
–
–
9
28
M
–
–
8.83
–
10
46
F
–
ND
–
–
11
56
F
–
Found with vital signs at a hospital dormitory. Butterfly-needle canalized into the vein of the forearm. She was given emergency treatment, died after 20 h. Several empty propofol ampoules were found in her locker. Found dead in her room. Beside the body, 2 empty propofol ampoules and 2 blood-stained syringes were found. She had 2 injection marks in her forearm. Found dead in her studio. A syringe filled with white liquid was observed in the small vessel of the bend of the arm. Beside the body, 1 empty syringe was found. Also, empty propofol ampoule and empty vecuronium ampoule were found in a dustbin. Found dead in hospital room. A needle canalized with infusion bag was observed in the forearm. Found dead in a hotel room, naked. Police couldn’t find any evidence. Found dead in endoscope room. Beside the body, 21 blood-stained syringes were found. He had 11 injection marks in his arm. Found dead in hospital room. A needle canalized with infusion bag was observed in the forearm. Beside the body, 2 empty syringes and 3 empty propofol ampoules were found. Found dead in his room. He had 1 injection mark at back of his hand. Beside the body, empty syringe and empty propofol ampoule were found. Found dead in her room. Beside the body, empty syringe was found. She had 1 injection mark at back of her hand. Died after self administration of propofol (propofol addict)
2.68
3.57
12 13
28 37
F M
– –
1.91 0.61
– 2.23
Ketamin, Diazepam, Fluoxetine, Lidocaine – –
14
33
F
Nurse
1.3
–
–
15 16
28 34
F F
Nurse Nurse
1.27 1.08
1.78 1.76
– Fluoxetine, Triazolam, Quetiapine, Clotiazepam, Alprazolam
Hanged herself. Injection marks on her arm. Found dead in the restroom. Lots of injection marks. Propofol ampoule was found at the scene. She had suffered from depression. Found dead after an intravenous injection. Died after injection of propofol which were stored in her house. Hanged herself after injection of propofol. Some hypnotic drugs were found at the scene.
(mean 1.50; median 1.50) in 14 intoxication deaths and other cases of death (hanging), respectively. Fluoxetine was detected in three cases and vecuronium was detected in two along with propofol among 16 fatalites. In case No. 4, vecuronium was detected in her brain tissue. It was concluded that she took both propofol and vecuronium, resulting in low level of propofol. In case No. 1, fluoxetine, diphenhydramine, chlorpheniramine were also detected in the blood. In case No. 11, a 56years-old woman was known as a propofol addict. Ketamine, diazepam, fluoxetine and lidocaine were detected in her blood. In case Nos. 14, 15 and 16, three nurses were found dead and fluoxetine, triazolam, quetiapine, clotiazepam and alprazolam were detected in case No. 16. 4. Discussion The results of the method validation for the analysis of propofol in blood such as specificity, selectivity, LOD, LOQ, intra- and interassay accuracy and precision, and recovery were satisfactory. Fig. 1 shows the deaths related with propofol had increased more than 6 times from 2005 to 2010. After evaluating the frequency of propofol alone cases and cases of combination with other drugs, we found that propofol alone was detected in 49 of 131 fatal cases; drugs such as lidocaine (n = 53), atropine (n = 30)
Fluoxetine, Diphenhydramine, Chlorpheniramine Thiopental Phentermine Vecuronium
and chlorpheniramine (n = 18) were combined with propofol. These are frequently combined with propofol because they are often used in emergency medical treatment. The various causes of deaths were identified in all cases including drug intoxication, drug abuse, car accident, murder, multiple injuries, suicide and etc. Roussin [16] identified lidocaine in the blood at a sub-therapeutic concentration with propofol in a reported paper. Kranioti [17] also reported that lidocaine does not alter the effects of propofol but reduces the pain from its intravenous administration in case of the mixture of lidocaine with propofol. Wilson et al. [1] found evidence to support propofol’s abuse potential from a pharmacological and experiential standpoint with multiple reports describing tolerance, dependence, withdrawal phenomena, abuse, and death from recreational use. The quantitation of propofol in the blood was performed in 48 of 131 autopsied cases. Its concentrations ranged from 0.05 to 8.83 mg/L (mean 1.66; median 0.9) and from 0.08 to 8.65 mg/L (mean 1.71; median 1.05). Molina [19] reported the therapeutic concentrations of propofol ranged from 0.78 to 15 mg/L and lethal concentrations ranged from 0.22 to 5.5 mg/L, indicating a wide range of therapeutic levels. However the reference blood level list of therapeutic and toxic substances showed different therapeutic concentrations for propofol from 2 to 4 mg/L [20]. Therapeutic concentration of propofol means the concentration that causes
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anesthesia. However, even a concentration that causes sleep and anesthesia in a ventilated and closely monitored subject in an operating room could cause death in someone who is not ventilated artificially. Chao et al. [21] reported that the propofol level in the blood of a man suspected of having fatally selfadministered an intravenous dose of 1600 mg of propofol was 2.5 mg/L. Kirby et al. [22] reported the first case of murder with propofol. A woman was found dead in her home from apparent propofol toxicity and her blood level of propofol was 4.3 mg/L. Drummer [23] described a suicide by self-administration of propofol in a female radiographer. The post-mortem femoral blood concentration of propofol was 0.22 mg/L. The scene suggested that a dose of 400 mg was used. Kranioti et al. [17] reached the conclusion that one person’s death was a consequence of propofol self-administration at therapeutic doses and found that the postmortem concentrations were all at therapeutic levels in previously reported cases. Roussin et al. [16] also reported deaths related to a recreational abuse in a therapeutic dose range. The toxic concentrations of propofol in non-intubated patients may be different from patients who were intubated and fully supported in the operating room or in the intensive care unit [17]. In order to study PMR, propofol concentrations in the heart and the femoral blood (n = 15) from the same body were determined to evaluate the ratios of heart to femoral blood and PMR phenomena. The ratios of heart to femoral blood concentrations ranged from 0.45 to 3.66 (mean 1.53; median 1.40). PMR involves several, complex mechanisms; therefore, it cannot be evaluated only by comparing propofol concentrations in the blood taken from peripheral and central sites. However, such a comparison may give an indication that PMR has occurred. Among 131 fatal cases, propofol abuse contributed to 16 fatalities. Half of them were medical personnel including 19% of doctors and 38% of nurses. Most of the victims work in the medical field. Hospital diversion from medical use is a primary access for doctors or nurses. More measures to avoid diversion for personal use in hospitals might be more effective. There are many papers which report the deaths of healthcare practitioners [11] such as anesthetic nurses [16,18], radiographers [23], and anesthesiologists [17]. In this study, propofol was also proved to be abused by healthcare professionals including nurses, nurse’s aide, anesthesiologist, plastic surgeon, general practitioner and so on. They were mostly found dead in their beds at home, in the nurse’s room or doctor’s room after self-administration. It is obvious that they were prone to abuse it, due to its easy availability. Most of them were found with needles and syringes on site and injection marks. There were syringes, medicine bottles, and Ringer’s solution at the scene. Although not fatal, there was a case where a young woman had not had any meals for 5 days, only IV injections of propofol, presumably to obtain the euphoric effect of propofol. All 16 cases were assumed to be accidental deaths after self-administration. The cause of death in 14 cases was drug intoxication except No. 12 and No. 16 where the cause of death was hanging. 5. Conclusions Propofol was detected in 131 (0.89%) out of 14,673 autopsied cased between 2005 and 2010. The method for the analysis of propofol in the blood was specific and sensitive. This validated method was applied to screen the whole blood collected from autopsied cases (n = 131). Among them propofol alone was detected in 49, while the combination of drugs was detected with propofol in the remaining 82 cases. Medical examiners concluded
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that propofol directly affected deaths in only 16 of the 131 autopsied cases. The concentrations of propofol from autopsied cases were measured in the heart and femoral blood and the investigation of the ratio of heart to femoral blood (n = 15) from the same body were performed. After investigating accidental deaths after self-administering (n = 16), we found that propofol was used more frequently in medical personnel women aged 20–30 years. The cause of death in 14 cases was drug intoxication, while that in 2 cases was hanging. Due to its prevalence, Korea has become the first country that regulates propofol as a psychotropic substance. Acknowledgements This research was supported by the Research & Development Program for new technology of Forensic Science by the Ministry of Public Administration and Security and the Duksung Women’s University Research Grants 2013 (3000001965). References [1] C. Wilson, P. Canning, E.M. Caravati, The abuse potential of propofol, Clin. Toxicol. (Phila) 48 (3) (2010) 165–170. [2] S.I. Bergmann, P. Ro¨sner, H.C. Ku¨hnau, M. Junge, A. Schmoldt, Death after excessive propofol abuse, Int. J. Legal Med. 114 (4–5) (2001) 248–251. [3] M.S. Langley, R.C. Heel, Propofol: a review of its pharmacodynamic and pharmacokinetic properties and use as an intravenous anaesthetic, Drugs 35 (1988) 334– 372. [4] B. Fulton, E.M. Sorkin, Propofol: an overview of its pharmacology and a review of its clinical efficacy in intensive care sedation, Drugs 50 (1995) 636–657. [5] D. Nancy, M.D. Perrier, M.D. Yvonne Baerga-Varela, M.J. Murray, Death related to propofol use in an adult patient, Crit. Care Med. 28 (2000) 3071–3074. [6] P.E. Marik, Propofol: therapeutic indications and side-effects, Curr. Pharm. Des. 10 (2004) 3639–3649. [7] P.E. Marik, Propofol: an immune-modulating agent, Pharmacotherapy 25 (5 Pt 2) (2005) 28S–33S. [8] B.K. Burow, M.E. Johnson, D.L. Packer, Metabolic acidosis associated with propofol in the absence of other causative factors, Anesthesiology 101 (1) (2004) 239–241. [9] J.C. Salengros, C.E. Velghe-Lenelle, R. Bollens, E. Engelman, L. Barvais, Lactic acidosis during propofol-remifentanil anesthesia in an adult, Anesthesiology 101 (1) (2004) 241–243. [10] B.M. Schramm, B.A. Orser, Dystonic reaction to propofol attenuated by benztropine (Cogentin), Anesth. Analg. 94 (2002) 1237–1240. [11] A. Roussin, J.L. Montastruc, M. Lapeyre-Mestre, Pharmacological and clinical evidences on the potential for abuse and dependence of propofol: a review of the literature, Fund. Clin. Pharmacol. 21 (5) (2007) 459–466. [12] S.C. Sweetman, Martindale The Complete Drug Reference, 34th ed., Pharmaceutical Press, London, 2005, pp. 1305–1307. [13] M.N.G. Dukes, J.K. Aronson, Z. Baudoin, General anaesthetics and anaestheticgases, in: M.N.G. Dukes, J.K. Aronson (Eds.), Meyler’s Side Effects of Drugs, 14th ed., Elsevier, Amsterdam, 2000, p. 330. [14] T.Y. Euliano, J.S. Gravenstein, A Brief Pharmacology Related to Anesthesia. Essential Anesthesia: From Science to Practice, Cambridge University Press, Florida, 2004p. 173. [15] J.P. Zacny, J.L. Lichtor, W. Thompson, J.L. Apfelbaum, Propofol at a subanesthetic dose may have abuse potential in healthy volunteers, Anesth. Analg. 77 (3) (1993) 544–552. [16] A. Roussin, M. Mirepoix, G. Lassabe, V. Dumestre-Toulet, V. Gardette, J.L. Montastruc, M.L. Mestre, Death related to a recreational abuse of propofol at therapeutic dose range, Br. J. Anaesth. 97 (2) (2006) 268. [17] E.F. Kranioti, A. Mavroforou, P. Mylonakis, M. Michalodimitrakis, Lethal self administration of propofol (Diprivan): a case report and review of the literature, Forensic Sci. Int. 167 (1) (2007) 56–58. [18] G. Klausz, K. Rona, I. Kristof, K. Toro, Evaluation of a fatal propofol intoxication due to self administration, J. Forensic Leg. Med. 16 (2009) 287–289. [19] D.K. Molina, Handbook of Forensic Toxicology for Medical Examiners, CRC press, FL, 2010. [20] Reference Blood Level List of Therapeutic and Toxic Substances, TIAFT, 2011 http://www.tiaft.org/toxic_values (accessed 12.10.11). [21] T.C. Chao, D.S.T. Lo, P.P.S. Chui, T.H. Koh, The first fatal 2,6-di-isopropylphenol (propofol) poisoning in Singapore: a case report, Forensic Sci. Int. 66 (1) (1994) 1– 7. [22] R.R. Kirby, J.M. Colaw, M.M. Douglas, Death from propofol: accident, suicide, or murder? Anesth. Analg. 108 (4) (2009) 1182–1184. [23] O.H. Drummer, A fatality due to propofol poisoning, J. Forensic Sci. 37 (4) (1992) 1186–1189.
