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O36: Driving under the influence of cocaine or therapeutic administration of cocaine?
Thursday 12 June 2014 / Toxicologie Analytique & Clinique (2014) 26, S15-S24
O36
O37
Driving under the influence of cocaine or therapeutic administration of cocaine?
Unexpected benzodiazepine findings in three forensic toxicological cases
M. Augsburger, C. Widmer, J. Deglon, P. Mangin University center of legal medicine, Lausanne-Geneva, Geneva, Switzerland.
K. Maudens, L. Patteet, V. Coucke, H. Neels Toxicological centre university of Antwerp, Wilrijk, Belgium.
Introduction. – In forensic toxicology, cocaine is better known for its powerful stimulating effects of nervous system and its high potential for recreational abuse, than for his therapeutic use. However, cocaine is still use as a topical anesthetic and peripheral vasoconstrictor in surgeries of eye, ear, nose and throat. Last decade, an increase of the presence of cocaine and metabolites in blood samples of drivers suspected to drive under the influence of drugs (DUID) was observed in Switzerland (Augsburger et al., Forensic Sci Int 153 (2005) 11-15; Senna et al., Forensic Sci Int 198 (2010) 11-16). Observed blood concentration ranges of cocaine and benzoylecgonine were 10-925 g/L and 20-5200 g/L, respectively. Since 2005, zero-tolerance approach was introduced in the Swiss legislation for different substances, especially cocaine (analytical cutoff: 15 g/L). Thus, the interpretation often amounts to determine if the concentration is situated above or under the limit. However, it is important for the interpretation to take into account the context and to be critical with the obtained results, at the risk of ending in erroneous conclusions. Methods. – Systematical toxicological analyses were performed on blood and urine, if available, for 5 DUID cases, as already published (Augsburger et al., Forensic Sci Int 153 (2005)). Positive results were confirmed and drugs were quantified in biological samples by GCMS, GC-MS/MS or LC-MS/MS. Results. – Administration of cocaine after traffic accident was identified in five cases. All people were admitted to the emergency room because of severe trauma. Maxillofacial surgery was done shortly after admission to the emergency room, involving use of nasal application of cocaine (swab). For all cases, use of cocaine swab was not mentioned in the document filled by the police and by medical staff requested for blood and urine sampling. The information was obtained retrospectively after consultation of the medical records, without precise indication of the application time or dose. Case 1. A 83-year old man (pedestrian) was hit by a car. Blood (+11h after the accident): cocaine (16 g/L), benzoylecgonine (370 g/L). Urine: cocaine (1700 g/L), benzoylecgonine (560 g/L). Case 2. A 84-year old woman (pedestrian) was hit by a car. Blood (+1.5h after the accident): cocaine (230 g/L), benzoylecgonine (370 g/L). Urine was not available. Hair (+4 months after the accident): segment 1 (0-2 cm), cocaine not detected; segment 2 (2-4 cm), cocaine: <0.5 ng/mg. Case 3. A 66-year old man was involved in a car/car accident. He died 2 hours and 5 minutes after the crash. Blood (+1.5h after the accident): cocaine and metabolites not detected. Blood (+2h after the accident): cocaine (1750 g/L), benzoylecgonine (460 g/L). Blood (post-mortem): cocaine (370 g/L), benzoylecgonine (200 g/L). Urine (+1.5h after the accident): cocaine not detected. Case 4. A 57-year old woman on a motor scooter was hit by a car. She died 2 hours and 10 minutes after the crash. Blood (+0.5h after the accident): cocaine and metabolites not detected. Urine (post-mortem): cocaine (<20 g/L), benzoylecgonine (120 g/L). Case 5. A 30-year old man was involved in a car accident. Blood (+4h after the accident): cocaine (29 g/L), benzoylecgonine (< 20 g/L). Urine (+4h after the accident): cocaine and metabolites not detected. Ethanol (1,32 g/kg) and cannabinoids (THC (2,0 g/L), THCCOOH (38 g/L)) were also detected in blood. Conclusion. – To our knowledge, this is the first description of DUID cases involving therapeutic use of cocaine after an accident. These results indicate that even if a per se law is effective for prosecution case of DUID, a critical interpretation of the results is always needed, especially if a medical intervention occurs after an accident.
S21
Introduction. – Three forensic cases with unexpected benzodiazepines are described. Case A involved a 41-year old man who was hospitalized with a severe head injury and died after four days of intensive treatment. In the autopsy samples, desalkylflurazepam was detected. In the samples collected at hospital admission, nor desalkylflurazepam nor one of its possible orally taken parent compounds (flurazepam or ethylloflazepate) were present. In case B, the urine of a 22 year old woman who was believed to be the victim of a drug facilitated sexual assault (DFSA) was confirmed positive for the presence of diazepam. The victim claimed not to have used diazepam. Case C involved a 20-month old toddler who was administered to the hospital with signs of weakness and sedation after a stay with the grandmother. Besides the presence of lorazepam in the urine, GC-MS analysis indicated the presence of delorazepam, which would be suggestive for the intake of cloxazolam. Methods. – All cases have undergone the Systematic Toxicological Analysis (STA) in our lab, which consists of screening procedures (immunological screening on urine, screening by GC-MS without and with derivatization on enzymatically hydrolyzed urine and blood, screening by HPLC-PDA on blood) and targeted analyses (ethanol by headspace-GC-FID, GHB and “classic” drugs of abuse by GC-MS). The libraries used for identification are both commercial (Maurer/Pfleger/Weber 4th edition 2011, Rösner Designer Drugs 2013) and in-house built. Furthermore, most compounds identified by screening were quantified in blood using the most suitable inhouse technique (GC-MS, LC-MSMS or HPLC-PDA). Results. – In case A, no alcohol, pharmaceuticals or drugs of abuse were detected in the samples collected at hospital admission. In the hospital, the patient was administered atracurium, levetiracetam, lidocaine, midazolam, propofol, remifentanyl and thiopental. In the autopsy samples, all pharmaceuticals (mostly together with one or more metabolites) were detected by our STA, except for remifentanyl. Moreover, desalkylflurazepam, the metabolite of flurazepam and ethylloflazepate, was detected. This phenomenon could initially not be explained, since both pharmaceuticals are taken orally, and the patient became comatose soon after hospital admission. The presence of desalkylflurazepam could be explained by a recent paper of Vogt et al. (Drug Test. Analysis 2013, 5, 745-747) who unravelled that desalkylflurazepam is not a metabolite of midazolam, but an intermediate in the synthesis of midazolam which is sometimes still present in the formulation Dormicum®. In case B, laboratory analysis revealed the presence in urine of acetaminophen, aripiprazole, citalopram, diazepam, tetrazepam and valproic acid (most of them together with one or more of their metabolites). All parent compounds were also detected in blood, except for diazepam. The presence of diazepam in urine could be explained by the metabolism of tetrazepam and not by an (involuntary) consumption of diazepam itself. In case C, a positive benzodiazepine screening on urine was confirmed by the presence of lorazepam in urine. Only after injection of an acetylated extract in the GC-MS apparatus, a library hit for delorazepam appeared. Further chromatographic analysis revealed that this compound was not delorazepam (different retention time), but most probably a lorazepam (metabolite) artefact. Therefore, the possibility of administration of cloxazolam (which metabolizes quickly to delorazepam) could be ruled out. Conclusion. – In a forensic context, one has to take care in the interpretation of the origin of benzodiazepine findings. The presence of synthesis-intermediates in pharmaceutical formulations, minor metabolism pathways and GC-artefacts can significantly complicate elucidation of the events.
O36
O37
Driving under the influence of cocaine or therapeutic administration of cocaine?
Unexpected benzodiazepine findings in three forensic toxicological cases
M. Augsburger, C. Widmer, J. Deglon, P. Mangin University center of legal medicine, Lausanne-Geneva, Geneva, Switzerland.
K. Maudens, L. Patteet, V. Coucke, H. Neels Toxicological centre university of Antwerp, Wilrijk, Belgium.
Introduction. – In forensic toxicology, cocaine is better known for its powerful stimulating effects of nervous system and its high potential for recreational abuse, than for his therapeutic use. However, cocaine is still use as a topical anesthetic and peripheral vasoconstrictor in surgeries of eye, ear, nose and throat. Last decade, an increase of the presence of cocaine and metabolites in blood samples of drivers suspected to drive under the influence of drugs (DUID) was observed in Switzerland (Augsburger et al., Forensic Sci Int 153 (2005) 11-15; Senna et al., Forensic Sci Int 198 (2010) 11-16). Observed blood concentration ranges of cocaine and benzoylecgonine were 10-925 g/L and 20-5200 g/L, respectively. Since 2005, zero-tolerance approach was introduced in the Swiss legislation for different substances, especially cocaine (analytical cutoff: 15 g/L). Thus, the interpretation often amounts to determine if the concentration is situated above or under the limit. However, it is important for the interpretation to take into account the context and to be critical with the obtained results, at the risk of ending in erroneous conclusions. Methods. – Systematical toxicological analyses were performed on blood and urine, if available, for 5 DUID cases, as already published (Augsburger et al., Forensic Sci Int 153 (2005)). Positive results were confirmed and drugs were quantified in biological samples by GCMS, GC-MS/MS or LC-MS/MS. Results. – Administration of cocaine after traffic accident was identified in five cases. All people were admitted to the emergency room because of severe trauma. Maxillofacial surgery was done shortly after admission to the emergency room, involving use of nasal application of cocaine (swab). For all cases, use of cocaine swab was not mentioned in the document filled by the police and by medical staff requested for blood and urine sampling. The information was obtained retrospectively after consultation of the medical records, without precise indication of the application time or dose. Case 1. A 83-year old man (pedestrian) was hit by a car. Blood (+11h after the accident): cocaine (16 g/L), benzoylecgonine (370 g/L). Urine: cocaine (1700 g/L), benzoylecgonine (560 g/L). Case 2. A 84-year old woman (pedestrian) was hit by a car. Blood (+1.5h after the accident): cocaine (230 g/L), benzoylecgonine (370 g/L). Urine was not available. Hair (+4 months after the accident): segment 1 (0-2 cm), cocaine not detected; segment 2 (2-4 cm), cocaine: <0.5 ng/mg. Case 3. A 66-year old man was involved in a car/car accident. He died 2 hours and 5 minutes after the crash. Blood (+1.5h after the accident): cocaine and metabolites not detected. Blood (+2h after the accident): cocaine (1750 g/L), benzoylecgonine (460 g/L). Blood (post-mortem): cocaine (370 g/L), benzoylecgonine (200 g/L). Urine (+1.5h after the accident): cocaine not detected. Case 4. A 57-year old woman on a motor scooter was hit by a car. She died 2 hours and 10 minutes after the crash. Blood (+0.5h after the accident): cocaine and metabolites not detected. Urine (post-mortem): cocaine (<20 g/L), benzoylecgonine (120 g/L). Case 5. A 30-year old man was involved in a car accident. Blood (+4h after the accident): cocaine (29 g/L), benzoylecgonine (< 20 g/L). Urine (+4h after the accident): cocaine and metabolites not detected. Ethanol (1,32 g/kg) and cannabinoids (THC (2,0 g/L), THCCOOH (38 g/L)) were also detected in blood. Conclusion. – To our knowledge, this is the first description of DUID cases involving therapeutic use of cocaine after an accident. These results indicate that even if a per se law is effective for prosecution case of DUID, a critical interpretation of the results is always needed, especially if a medical intervention occurs after an accident.
S21
Introduction. – Three forensic cases with unexpected benzodiazepines are described. Case A involved a 41-year old man who was hospitalized with a severe head injury and died after four days of intensive treatment. In the autopsy samples, desalkylflurazepam was detected. In the samples collected at hospital admission, nor desalkylflurazepam nor one of its possible orally taken parent compounds (flurazepam or ethylloflazepate) were present. In case B, the urine of a 22 year old woman who was believed to be the victim of a drug facilitated sexual assault (DFSA) was confirmed positive for the presence of diazepam. The victim claimed not to have used diazepam. Case C involved a 20-month old toddler who was administered to the hospital with signs of weakness and sedation after a stay with the grandmother. Besides the presence of lorazepam in the urine, GC-MS analysis indicated the presence of delorazepam, which would be suggestive for the intake of cloxazolam. Methods. – All cases have undergone the Systematic Toxicological Analysis (STA) in our lab, which consists of screening procedures (immunological screening on urine, screening by GC-MS without and with derivatization on enzymatically hydrolyzed urine and blood, screening by HPLC-PDA on blood) and targeted analyses (ethanol by headspace-GC-FID, GHB and “classic” drugs of abuse by GC-MS). The libraries used for identification are both commercial (Maurer/Pfleger/Weber 4th edition 2011, Rösner Designer Drugs 2013) and in-house built. Furthermore, most compounds identified by screening were quantified in blood using the most suitable inhouse technique (GC-MS, LC-MSMS or HPLC-PDA). Results. – In case A, no alcohol, pharmaceuticals or drugs of abuse were detected in the samples collected at hospital admission. In the hospital, the patient was administered atracurium, levetiracetam, lidocaine, midazolam, propofol, remifentanyl and thiopental. In the autopsy samples, all pharmaceuticals (mostly together with one or more metabolites) were detected by our STA, except for remifentanyl. Moreover, desalkylflurazepam, the metabolite of flurazepam and ethylloflazepate, was detected. This phenomenon could initially not be explained, since both pharmaceuticals are taken orally, and the patient became comatose soon after hospital admission. The presence of desalkylflurazepam could be explained by a recent paper of Vogt et al. (Drug Test. Analysis 2013, 5, 745-747) who unravelled that desalkylflurazepam is not a metabolite of midazolam, but an intermediate in the synthesis of midazolam which is sometimes still present in the formulation Dormicum®. In case B, laboratory analysis revealed the presence in urine of acetaminophen, aripiprazole, citalopram, diazepam, tetrazepam and valproic acid (most of them together with one or more of their metabolites). All parent compounds were also detected in blood, except for diazepam. The presence of diazepam in urine could be explained by the metabolism of tetrazepam and not by an (involuntary) consumption of diazepam itself. In case C, a positive benzodiazepine screening on urine was confirmed by the presence of lorazepam in urine. Only after injection of an acetylated extract in the GC-MS apparatus, a library hit for delorazepam appeared. Further chromatographic analysis revealed that this compound was not delorazepam (different retention time), but most probably a lorazepam (metabolite) artefact. Therefore, the possibility of administration of cloxazolam (which metabolizes quickly to delorazepam) could be ruled out. Conclusion. – In a forensic context, one has to take care in the interpretation of the origin of benzodiazepine findings. The presence of synthesis-intermediates in pharmaceutical formulations, minor metabolism pathways and GC-artefacts can significantly complicate elucidation of the events.