Severe Delirium Linked to Exposure to Synthetic Cannabinoid
Severe Delirium Linked to Exposure to Synthetic Cannabinoid
On August 22, 2013, a hospital in Brunswick, Georgia called the Georgia Poison Center seeking management recommendations for 7 patients who presented simultaneously after smoking an SC-containing product at a party. The patients were not known to have any medical history, and all had been well previously on the day of presentation. On the evening of admission, all patients had been at the same party and smoked the same product. Glynn County (GA) police noted that this index cluster of 7 patients had been smoking a new shipment of "Crazy Clown," a synthetic incense made in Colorado and purchased from a smoke shop in Brunswick, GA. Emergency Medical Services (EMS) were called after 3 of the patients began behaving aggressively and transported all 7 patients to the emergency department (ED). The patients underwent laboratory evaluation with complete blood count, comprehensive metabolic panel, creatinine phosphokinase (CPK), coagulation profile, arterial or venous blood gas, and venous lactate.
Upon identifying the source of the implicated product smoked by the case patients, law enforcement personnel removed all Crazy Clown product from the smoke shop. Analysis of the product inventory by the Georgia Bureau of Investigation Crime Laboratory identified the novel pentyl indazole SC N-(1-amino-3,3-dimethyl-1-oxobutan-2-yl)-1-pentyl-1H-indazole-3-carboxamide (ADB-PINACA) in samples of Crazy Clown.
Case 1. Patient 1 was a 25-year-old male who was markedly agitated and combative upon EMS arrival. He required chemical sedation and intubation to control his extreme agitation. First documented vital signs were heart rate (HR), 130 beats per minute (bpm); blood pressure (BP), 142/56 mm Hg; respiratory rate (RR), 20 breaths per minute (mechanically ventilated); and oxygen saturation (SpO2), 100%. His initial laboratory results were significant for an anion gap 15 mEq/L, venous lactate 3.13 mmol/L, and CPK 920 IU/L. All other results were within normal limits. He was admitted to the intensive care unit (ICU) and continued to have intermittent tachycardia and hypertension until hospital day (HD) 3, when he was extubated. Although he was initially confused after extubation, his mental status rapidly improved, and the hospital discharged him in his baseline state of health on HD 5.
Case 2. Patient 2 was a 24-year-old male who also was confused and agitated upon initial EMS evaluation. He required sedation and intubation for management of violent behavior. Initial vital signs were HR 132 bpm, BP 128/88 mm Hg, RR 22/min (mechanically ventilated), SpO2 98%, and temperature, 98.9°F. His initial laboratory results were within normal limits, without acidosis or elevated CPK. Approximately 7 h after presentation, his vital signs had normalized. He was admitted only briefly to the ICU and was extubated 15 h after presentation. Once fully alert, this patient signed out against medical advice (AMA), declining further evaluation.
Case 3. Patient 3 was a 30-year-old male who was reported to be the most severely combative and aggressive of these 7 patients. EMS administered haloperidol and lorazepam and intubated him shortly thereafter. En route to the ED, he suffered a witnessed cardiac arrest and was resuscitated by paramedics. He had regained spontaneous circulation by the time he arrived in the ED. Vital signs upon arrival were HR 93 bpm, BP 118/69 mm Hg, RR 16/min (mechanically ventilated), SpO2 99%, and temperature 98.9°F. Initial electrocardiogram (ECG) showed an anterior ST-elevation myocardial infarction, for which he was promptly transferred to the cardiac catheterization suite. Cardiac catheterization demonstrated complete occlusion of the left anterior descending, and the patient underwent successful balloon angioplasty. He was admitted to the cardiac care unit and extubated uneventfully on HD 3. Once awake and alert, this patient reported that he had a medical history of familial hypercholesterolemia, as well as premature coronary artery disease and past cocaine use. He was discharged home on HD 5.
Case 4. Patient 4 was a 25-year-old female who was brought to the ED agitated, but alert and oriented. Her initial vital signs were HR 82 bpm, BP 117/61 mm Hg, RR 20/min, SpO2 96% on room air (RA), and temperature 99.5°F. She left the hospital AMA after her initial blood draw. She did not receive any other interventions before she left the ED, and after her departure her laboratory results were reported to be within normal limits.
Case 5. Patient 5 was a 22-year-old female who was brought to the ED agitated, but alert and oriented. Her initial vital signs were HR 78 bpm, BP 105/63 mm Hg, RR 16/min, SpO2 97% RA, and temperature 97.8°F. She elected to remain in the ED for initial evaluation and a period of observation. Her laboratory results and ECG were unremarkable, and she was discharged from the ED without requiring any therapeutic interventions.
Case 6. Patient 6 was a 21-year-old female who was brought to the ED alert and oriented, markedly anxious, but not aggressive. Initial vital signs were HR 112 bpm, BP 131/81 mm Hg, RR 14/min, SpO2 96% RA, and temperature 98.0°F. She left the hospital AMA before a full evaluation was completed.
Case 7. Patient 7 was a 16-year-old female who was mildly agitated and anxious upon arrival to the ED, but was alert and oriented. Initial vital signs were HR 100 bpm, BP 153/71 mm Hg, RR 14/min, SpO2 95% RA, and temperature 98.0°F. Her initial laboratory results and ECG were within normal limits. After receiving 1 L normal saline, her vital signs normalized and she was discharged from the ED in her baseline state of health.
Case 8. On September 3, 2013, the Georgia Poison Center received a call regarding a healthy 24-year-old male who presented with disorientation and delayed-onset seizures several days after smoking SCs sold under the brand names of Crazy Clown and "10X." He had purchased both substances from the same smoke shop in Brunswick, GA where the previously reported index cluster of 7 patients had obtained their product on August 22. One day after smoking 10X and Crazy Clown, the patient developed anorexia, nausea, and vomiting. Four days after smoking the products, the patient complained of difficulty concentrating and recalling short-term memory. Seven days after smoking the product, the patient had a generalized seizure for which he was evaluated in the ED, then rehydrated and released. The following day he appeared more disoriented and paranoid, according to his family.
Two days later, on September 3, he went to a different ED for evaluation; the poison center was consulted. His initial vital signs included an HR 85 bpm and BP 150/90 mm Hg. In the ED, he developed severe agitation, had a witnessed generalized seizure, and required intubation. Laboratory evaluation showed slight elevation of aspartate aminotransferase (AST) of 83 U/L and alanine aminotransferase (ALT) of 150 U/L, an elevated creatinine of 1.7 mg/dL, and elevated CPK of 500 U/L. His liver function tests peaked at AST 214 U/L and ALT 154 U/L. He had no further seizure activity and was extubated the following day. An electroencephalogram (EEG), magnetic resonance imaging (MRI) of the brain, and bedside neurologic examination were normal, and he was discharged home on HD 7 of this hospitalization. On the day of discharge, the patient had an episode of disorientation followed by an additional seizure that required readmission to the hospital. Repeat EEG and neurologic evaluation were again normal, and he was discharged the following day.
Case 9. On September 13, 2013, an emergency physician consulted the Georgia Poison Center about a 49-year-old, previously healthy, male Drug Enforcement Administration (DEA) agent who was exhibiting symptoms of SC intoxication. According to the agent, 2 days earlier, he and a partner were searching and manipulating packaged SC product during an unrelated seizure of drugs; the agent wore Latex gloves but no respiratory protection. The following morning, his wife observed that he was lethargic and forgetful. He complained of anxiety, difficulty sleeping, nausea and vomiting, and chest discomfort. His wife reported he was irritable and argumentative but not violent. Two days after exposure, he was evaluated at the ED and admitted overnight; his symptoms resolved with benzodiazepines and supportive care. Routine laboratory testing was normal, as were an MRI and a work-up for acute coronary syndrome. He consented to serial blood sampling for subsequent analysis for SCs.
To identify additional cases, the Georgia Department of Public Health (DPH) asked the Brunswick ED to report any other patients who reported use of SCs to the Coastal District (GA) Health Department for the period August 22 (index cluster of 7 patients) through September 9; Georgia DPH investigators then reviewed medical records of these patients.
At the time of presentation, the ED collected clinical samples from the 7 patients who were transported from the party in Brunswick on August 22. The poison center subsequently sent the samples to a reference laboratory for analysis to confirm SC exposure. The laboratory analyzed serum and plasma samples using liquid chromatography-quadrupole time-of-flight chromatography (LC-QTOF/MS, Agilent LC1260- QTOF/MS 6550; Agilent Technologies, Santa Clara, CA). A 250-μL aliquot of each sample was prepared for analysis by protein precipitation using 750 μL acetonitrile:methanol (95:5). A 2.5-μL aliquot of the resulting extract was injected into the LC-QTOF/MS for nontargeted MS scans. Compounds in each sample were separated using gradient elution chromatography in a C18 reverse-phase column (Agilent Poroshell, 2.1 × 100 mm, 3.0-μm particle size) at 50°C. Compounds eluting off the column were ionized by electrospray ionization in the positive and negative polarities in separate runs. Each MS analysis consists of two MS experiments: a TOF-MS experiment to detect all parent ions of compounds in each sample and an MS/MS scan to collect fragment ion data of parent ions exhibiting intensities > 5000 arbitrary units. The total ion chromatogram (TIC) obtained for each sample was then queried for the targeted analysis of 43 SCs and metabolites (retention times for these compounds are established through a validated method). No formula and retention time matches were found for any of these compounds. The TIC was then queried for formula matches using an expanded database of SCs and metabolites (115 compounds). Formula matches to ADB-PINACA or its N-pentanoic acid metabolite were detected in the samples. Confirmation and quantitation of both compounds were performed by isotope dilution method using reference standards that became available 6 weeks after potential matches to them were observed in the patients. Agilent MassHunter Qualitative and Quantitative Analysis analyzed data for each sample.
In addition to the Department for Health and Human Services (DHHS), DEA may temporarily schedule a substance under the following conditions: if it is not listed in any other schedule; if no exemption or approval is in effect for the drug; or if the Attorney General (or the delegated Deputy Administrator of the DEA) perceives an imminent threat to public safety. DEA is required to consider the following factors in its decision: the substance's history and current pattern of abuse; the scope, duration, and significance of abuse; and any risk to the public safety. DEA also considers available information regarding actual abuse, diversion from legitimate channels, and clandestine importation, manufacture, or distribution.
Before publishing a Final Order in the Federal Register, DEA is required to notify the Secretary of DHHS of the intention to temporarily place a substance into Schedule I of the Controlled Substances Act (CSA), as well as publish a Notice of Intent to temporarily schedule a substance. The Final Order may not be issued before the expiration of 30 days from the Notice of Intent to temporarily place a substance in Schedule I of the CSA. The Final Order temporarily scheduling a substance under the CSA is effective on the date of publication in the Federal Register and will remain in effect for a period of no less than 2 years, with a possible extension of 1 additional year.
Case Report
Initial Epidemiological and Law Enforcement Investigation
On August 22, 2013, a hospital in Brunswick, Georgia called the Georgia Poison Center seeking management recommendations for 7 patients who presented simultaneously after smoking an SC-containing product at a party. The patients were not known to have any medical history, and all had been well previously on the day of presentation. On the evening of admission, all patients had been at the same party and smoked the same product. Glynn County (GA) police noted that this index cluster of 7 patients had been smoking a new shipment of "Crazy Clown," a synthetic incense made in Colorado and purchased from a smoke shop in Brunswick, GA. Emergency Medical Services (EMS) were called after 3 of the patients began behaving aggressively and transported all 7 patients to the emergency department (ED). The patients underwent laboratory evaluation with complete blood count, comprehensive metabolic panel, creatinine phosphokinase (CPK), coagulation profile, arterial or venous blood gas, and venous lactate.
Upon identifying the source of the implicated product smoked by the case patients, law enforcement personnel removed all Crazy Clown product from the smoke shop. Analysis of the product inventory by the Georgia Bureau of Investigation Crime Laboratory identified the novel pentyl indazole SC N-(1-amino-3,3-dimethyl-1-oxobutan-2-yl)-1-pentyl-1H-indazole-3-carboxamide (ADB-PINACA) in samples of Crazy Clown.
Individual Case Descriptions
Case 1. Patient 1 was a 25-year-old male who was markedly agitated and combative upon EMS arrival. He required chemical sedation and intubation to control his extreme agitation. First documented vital signs were heart rate (HR), 130 beats per minute (bpm); blood pressure (BP), 142/56 mm Hg; respiratory rate (RR), 20 breaths per minute (mechanically ventilated); and oxygen saturation (SpO2), 100%. His initial laboratory results were significant for an anion gap 15 mEq/L, venous lactate 3.13 mmol/L, and CPK 920 IU/L. All other results were within normal limits. He was admitted to the intensive care unit (ICU) and continued to have intermittent tachycardia and hypertension until hospital day (HD) 3, when he was extubated. Although he was initially confused after extubation, his mental status rapidly improved, and the hospital discharged him in his baseline state of health on HD 5.
Case 2. Patient 2 was a 24-year-old male who also was confused and agitated upon initial EMS evaluation. He required sedation and intubation for management of violent behavior. Initial vital signs were HR 132 bpm, BP 128/88 mm Hg, RR 22/min (mechanically ventilated), SpO2 98%, and temperature, 98.9°F. His initial laboratory results were within normal limits, without acidosis or elevated CPK. Approximately 7 h after presentation, his vital signs had normalized. He was admitted only briefly to the ICU and was extubated 15 h after presentation. Once fully alert, this patient signed out against medical advice (AMA), declining further evaluation.
Case 3. Patient 3 was a 30-year-old male who was reported to be the most severely combative and aggressive of these 7 patients. EMS administered haloperidol and lorazepam and intubated him shortly thereafter. En route to the ED, he suffered a witnessed cardiac arrest and was resuscitated by paramedics. He had regained spontaneous circulation by the time he arrived in the ED. Vital signs upon arrival were HR 93 bpm, BP 118/69 mm Hg, RR 16/min (mechanically ventilated), SpO2 99%, and temperature 98.9°F. Initial electrocardiogram (ECG) showed an anterior ST-elevation myocardial infarction, for which he was promptly transferred to the cardiac catheterization suite. Cardiac catheterization demonstrated complete occlusion of the left anterior descending, and the patient underwent successful balloon angioplasty. He was admitted to the cardiac care unit and extubated uneventfully on HD 3. Once awake and alert, this patient reported that he had a medical history of familial hypercholesterolemia, as well as premature coronary artery disease and past cocaine use. He was discharged home on HD 5.
Case 4. Patient 4 was a 25-year-old female who was brought to the ED agitated, but alert and oriented. Her initial vital signs were HR 82 bpm, BP 117/61 mm Hg, RR 20/min, SpO2 96% on room air (RA), and temperature 99.5°F. She left the hospital AMA after her initial blood draw. She did not receive any other interventions before she left the ED, and after her departure her laboratory results were reported to be within normal limits.
Case 5. Patient 5 was a 22-year-old female who was brought to the ED agitated, but alert and oriented. Her initial vital signs were HR 78 bpm, BP 105/63 mm Hg, RR 16/min, SpO2 97% RA, and temperature 97.8°F. She elected to remain in the ED for initial evaluation and a period of observation. Her laboratory results and ECG were unremarkable, and she was discharged from the ED without requiring any therapeutic interventions.
Case 6. Patient 6 was a 21-year-old female who was brought to the ED alert and oriented, markedly anxious, but not aggressive. Initial vital signs were HR 112 bpm, BP 131/81 mm Hg, RR 14/min, SpO2 96% RA, and temperature 98.0°F. She left the hospital AMA before a full evaluation was completed.
Case 7. Patient 7 was a 16-year-old female who was mildly agitated and anxious upon arrival to the ED, but was alert and oriented. Initial vital signs were HR 100 bpm, BP 153/71 mm Hg, RR 14/min, SpO2 95% RA, and temperature 98.0°F. Her initial laboratory results and ECG were within normal limits. After receiving 1 L normal saline, her vital signs normalized and she was discharged from the ED in her baseline state of health.
Case 8. On September 3, 2013, the Georgia Poison Center received a call regarding a healthy 24-year-old male who presented with disorientation and delayed-onset seizures several days after smoking SCs sold under the brand names of Crazy Clown and "10X." He had purchased both substances from the same smoke shop in Brunswick, GA where the previously reported index cluster of 7 patients had obtained their product on August 22. One day after smoking 10X and Crazy Clown, the patient developed anorexia, nausea, and vomiting. Four days after smoking the products, the patient complained of difficulty concentrating and recalling short-term memory. Seven days after smoking the product, the patient had a generalized seizure for which he was evaluated in the ED, then rehydrated and released. The following day he appeared more disoriented and paranoid, according to his family.
Two days later, on September 3, he went to a different ED for evaluation; the poison center was consulted. His initial vital signs included an HR 85 bpm and BP 150/90 mm Hg. In the ED, he developed severe agitation, had a witnessed generalized seizure, and required intubation. Laboratory evaluation showed slight elevation of aspartate aminotransferase (AST) of 83 U/L and alanine aminotransferase (ALT) of 150 U/L, an elevated creatinine of 1.7 mg/dL, and elevated CPK of 500 U/L. His liver function tests peaked at AST 214 U/L and ALT 154 U/L. He had no further seizure activity and was extubated the following day. An electroencephalogram (EEG), magnetic resonance imaging (MRI) of the brain, and bedside neurologic examination were normal, and he was discharged home on HD 7 of this hospitalization. On the day of discharge, the patient had an episode of disorientation followed by an additional seizure that required readmission to the hospital. Repeat EEG and neurologic evaluation were again normal, and he was discharged the following day.
Case 9. On September 13, 2013, an emergency physician consulted the Georgia Poison Center about a 49-year-old, previously healthy, male Drug Enforcement Administration (DEA) agent who was exhibiting symptoms of SC intoxication. According to the agent, 2 days earlier, he and a partner were searching and manipulating packaged SC product during an unrelated seizure of drugs; the agent wore Latex gloves but no respiratory protection. The following morning, his wife observed that he was lethargic and forgetful. He complained of anxiety, difficulty sleeping, nausea and vomiting, and chest discomfort. His wife reported he was irritable and argumentative but not violent. Two days after exposure, he was evaluated at the ED and admitted overnight; his symptoms resolved with benzodiazepines and supportive care. Routine laboratory testing was normal, as were an MRI and a work-up for acute coronary syndrome. He consented to serial blood sampling for subsequent analysis for SCs.
Case Finding
To identify additional cases, the Georgia Department of Public Health (DPH) asked the Brunswick ED to report any other patients who reported use of SCs to the Coastal District (GA) Health Department for the period August 22 (index cluster of 7 patients) through September 9; Georgia DPH investigators then reviewed medical records of these patients.
Laboratory Analyses
At the time of presentation, the ED collected clinical samples from the 7 patients who were transported from the party in Brunswick on August 22. The poison center subsequently sent the samples to a reference laboratory for analysis to confirm SC exposure. The laboratory analyzed serum and plasma samples using liquid chromatography-quadrupole time-of-flight chromatography (LC-QTOF/MS, Agilent LC1260- QTOF/MS 6550; Agilent Technologies, Santa Clara, CA). A 250-μL aliquot of each sample was prepared for analysis by protein precipitation using 750 μL acetonitrile:methanol (95:5). A 2.5-μL aliquot of the resulting extract was injected into the LC-QTOF/MS for nontargeted MS scans. Compounds in each sample were separated using gradient elution chromatography in a C18 reverse-phase column (Agilent Poroshell, 2.1 × 100 mm, 3.0-μm particle size) at 50°C. Compounds eluting off the column were ionized by electrospray ionization in the positive and negative polarities in separate runs. Each MS analysis consists of two MS experiments: a TOF-MS experiment to detect all parent ions of compounds in each sample and an MS/MS scan to collect fragment ion data of parent ions exhibiting intensities > 5000 arbitrary units. The total ion chromatogram (TIC) obtained for each sample was then queried for the targeted analysis of 43 SCs and metabolites (retention times for these compounds are established through a validated method). No formula and retention time matches were found for any of these compounds. The TIC was then queried for formula matches using an expanded database of SCs and metabolites (115 compounds). Formula matches to ADB-PINACA or its N-pentanoic acid metabolite were detected in the samples. Confirmation and quantitation of both compounds were performed by isotope dilution method using reference standards that became available 6 weeks after potential matches to them were observed in the patients. Agilent MassHunter Qualitative and Quantitative Analysis analyzed data for each sample.
Process of DEA Emergency Scheduling
In addition to the Department for Health and Human Services (DHHS), DEA may temporarily schedule a substance under the following conditions: if it is not listed in any other schedule; if no exemption or approval is in effect for the drug; or if the Attorney General (or the delegated Deputy Administrator of the DEA) perceives an imminent threat to public safety. DEA is required to consider the following factors in its decision: the substance's history and current pattern of abuse; the scope, duration, and significance of abuse; and any risk to the public safety. DEA also considers available information regarding actual abuse, diversion from legitimate channels, and clandestine importation, manufacture, or distribution.
Before publishing a Final Order in the Federal Register, DEA is required to notify the Secretary of DHHS of the intention to temporarily place a substance into Schedule I of the Controlled Substances Act (CSA), as well as publish a Notice of Intent to temporarily schedule a substance. The Final Order may not be issued before the expiration of 30 days from the Notice of Intent to temporarily place a substance in Schedule I of the CSA. The Final Order temporarily scheduling a substance under the CSA is effective on the date of publication in the Federal Register and will remain in effect for a period of no less than 2 years, with a possible extension of 1 additional year.
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