Dose Estimation Utility in a Population Pharmacokinetic Analysis of Inhaled Δ9-Tetrahydrocannabinol Cannabis Market Products in Occasional and Daily Users.

BACKGROUND: Unusually high variability in blood Δ9-tetrahydrocannabinol (THC) concentrations have been observed in subjects inhaling similar cannabis products over similar time periods when consumption is ad libitum. This makes simple gravimetric dose estimation a poor predictor of THC exposure. Population pharmacokinetic analyses of blood THC concentration versus time data are routinely used to estimate pharmacokinetic parameters. The aim of this study was to estimate the inhaled dose of THC in occasional and daily users of high potency market cannabis. METHODS: Blood THC concentrations were measured for 135 minutes from 29 participants who either smoked high concentration flower or inhaled concentrates ad libitum during a 15-minute session. Frequent blood samples were obtained over the following 135 minutes. RESULTS: The estimated central and rapidly equilibrating volumes of distribution of a 3-compartment model were 19.9 ± 1.2 and 51.6 ± 4.7 L whereas the intercompartmental clearances were 1.65 ± 0.14 and 1.75 ± 0.10 L/min, respectively. Covariate-adjusted analysis revealed that the estimated inhaled THC dose was considerably less among occasional users compared with daily users. CONCLUSIONS: Three-compartment pharmacokinetics of THC did not differ among the 3 user groups, and the early phase (first 135 minutes postinception of inhalation) kinetics were similar to those previously described after smoking low potency cannabis products. Therefore, inhaled THC dose can be estimated from pharmacokinetic data and covariate-driven adjustments can be used to estimate THC doses, based on the participant cannabis usage pattern (occasional versus daily), improving the accuracy of THC exposure estimates compared with those derived from weighed THC content alone.

Association between secondhand marijuana smoke and respiratory infections in children.

BACKGROUND: Little is known about the effects of secondhand marijuana smoke on children. We aimed to determine caregiver marijuana use prevalence and evaluate any association between secondhand marijuana smoke, childhood emergency department (ED) or urgent care (UC) visitation, and several tobacco-related illnesses: otitis media, viral respiratory infections (VRIs), and asthma exacerbations. METHODS: This study was a cross-sectional, convenience sample survey of 1500 subjects presenting to a pediatric ED. The inclusion criteria were as follows: caregivers aged 21-85 years, English- or Spanish-speaking. The exclusion criteria were as follows: children who were critically ill, medically complex, over 11 years old, or using medical marijuana. RESULTS: Of 1500 caregivers, 158 (10.5%) reported smoking marijuana and 294 (19.6%) reported smoking tobacco. Using negative-binomial regression, we estimated rates of reported ED/UC visits and specific illnesses among children with marijuana exposure and those with tobacco exposure, compared to unexposed children. Caregivers who used marijuana reported an increased rate of VRIs in their children (1.31 episodes/year) compared to caregivers with no marijuana use (1.04 episodes/year) (p = 0.02). CONCLUSIONS: Our cohort did not report any difference with ED/UC visits, otitis media episodes, or asthma exacerbations, regardless of smoke exposure. However, caregivers of children with secondhand marijuana smoke exposure reported increased VRIs compared to children with no smoke exposure. IMPACT: Approximately 10% of caregivers in our study were regular users of marijuana. Prior studies have shown that secondhand tobacco smoke exposure is associated with negative health outcomes in children, including increased ED utilization and respiratory illnesses. Prior studies have shown primary marijuana use is linked to negative health outcomes in adults and adolescents, including increased ED utilization and respiratory illnesses. Our study reveals an association between secondhand marijuana smoke exposure and increased VRIs in children. Our study did not find an association between secondhand marijuana smoke exposure and increased ED or UC visitation in children.

Use of both Fab and F(ab')2 fragment antivenom in a pediatric patient for treatment of a North American Crotalidae envenomation.

Crotalidae envenomation has been managed successfully in emergency departments across the world with antivenom. Over the years, antivenom has evolved and newer agents have been studied with the possibility of eliminating maintenance antivenom therapy. Here we report a patient who had worsening platelet and fibrinogen concentrations, as well as complaints of swelling and pain at the site of a rattlesnake envenomation following an initial dose of F(ab')2AV (Crotalidae immune F(ab')2 (equine) [ANAVIP®]) Crotalidae antivenom. The patient was subsequently transferred to a tertiary children's hospital for a higher level of care and received FabAV (Crotalidae polyvalent immune Fab (ovine) [CroFab®]) Crotalidae antivenom. The details of this patient's treatment course highlight the possibility that patients who receive F(ab')2AV, may require additional antivenom treatment. Furthermore, it appears that based on our single patient experience, giving FabAV after F(ab')2AV is safe and effective.

Increased Testing and Health Care Costs for Pediatric Cannabis Exposures.

OBJECTIVES: This study aimed to evaluate the process of identifying marijuana exposure in a children's hospital emergency department and compare the cost of diagnostic testing and procedures. METHODS: A retrospective chart review was performed on patients 31 days to 20 years old with a positive marijuana toxicology screen result between November 2009 and December 2014. Primary outcomes included time to provider recognition of marijuana exposure, number of diagnostic tests and procedures performed, and length of hospital stay. Patients were analyzed based on time of exposure recognition (forthcoming compared with not forthcoming of marijuana exposure) and age (children <12 years compared with adolescents >12 years). RESULTS: There were 37 children and 38 adolescents included. Mean time to exposure recognition was 2.3 ± 4.3 hours in children compared with 0.4 ± 0.9 hours in adolescents (P = 0.02). Patients who were not forthcoming of marijuana exposure experienced more than twice as many diagnostic tests or procedures compared with children who were forthcoming of marijuana exposure (mean, 8.91 vs 4 tests, P < 0.0001) and more than a 4-fold higher cost of potentially avoidable diagnostic tests/procedures. Length of hospital stay was significantly longer in children (18.34 ± 2.39 hours) compared with adolescents (4.22 ± 0.52 hours; P ≤ 0.0001). Few parents or guardians were able to disclose characteristics of the marijuana product. CONCLUSION: Delay in recognition of marijuana exposure is associated with high resource utilization, unnecessary medical costs, and prolonged length of stay.

Pediatric Exposures Reported to the Toxicology Investigators Consortium, 2010-2015.

BACKGROUND AND OBJECTIVE: Poisoning is the leading cause of injury death in pediatric patients. Hospital and provider readiness, including pharmacy stocking, depends on reliable surveillance data describing local patterns of age-specific clinically significant exposures and the therapeutic modalities employed in their treatment. We aimed to characterize trends in clinically significant toxic exposures and their management. METHODS: We performed a retrospective review of patients 18 years or younger in the American College of Medical Toxicology's Toxicology Investigators Consortium (ToxIC) Registry, a self-reporting database completed by bedside consulting medical toxicologists. We reviewed cases from January 1, 2010, through December 31, 2015. In 2015, ToxIC included 101 health care facilities. Data collected included demographics, geographic region, encounter and exposure details, survival, and therapeutic modalities employed, including antidotes, antivenoms, gastric decontamination, enhanced elimination, hyperbaric oxygen therapy, and extracorporeal membrane oxygenation. RESULTS: From 2010 to 2015, 11,616 consults were recorded in ToxIC. Pediatric consultations increased from 934 (23.7%) in 2010 to 2425 (29.9%) in 2015 (P < 0.001). Exposures were most commonly reported in females (57.8%) and adolescents (59.4%). Intentional ingestions (55.5%) comprised the majority of cases. The most frequent agents of exposure were analgesics (21.0%). There were 38 deaths reported (0.9%). The antidote used most commonly was N-acetylcysteine (11.0%). Geographic variation was demonstrated in prevalence of envenomations and heavy metal exposures, their respective treatments, and overall use of decontamination. CONCLUSIONS: Toxicology consultations for pediatric exposures increased from 2010 to 2015. Understanding which pediatric exposures require toxicologist management, the therapies most frequently employed, and geographical patterns is paramount to facility-level planning, pharmacy stocking, and provider education.

Toxicity From Unintentional Pediatric Ingestion of a Performance-Enhancing Drug: A Case Report With Review of Clenbuterol Toxicity and Treatment.

BACKGROUND: Clenbuterol is a long-acting ß-adrenergic agonist that is not Food and Drug Administration-approved for use in the United States, but may be obtained without a prescription from various unregulated sellers. It has seen increasing use as a performance-enhancing drug for sports. Literature on pediatric toxicity and treatment is limited. CASE REPORT: We report a case of a 2-year-old female presenting after an exploratory ingestion of clenbuterol. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Use of performance-enhancing agents is increasing and physicians should be aware of the potential toxicity of intentional and unintentional ingestions of ß-adrenergic agonists. Patients may exhibit nausea, vomiting, tremor, tachycardia, and hypotension, along with laboratory abnormalities, including hyperglycemia, hypophosphatemia, hypokalemia, and hyperglycemia. Hypotension might not respond to adrenergic agents and may require administration of ß-adrenergic antagonists to maintain adequate perfusion.

Marijuana Misadventures in Children: Exploration of a Dose-Response Relationship and Summary of Clinical Effects and Outcomes.

OBJECTIVES: This study aimed to explore a dose-response relationship of delta-9-tetrahydrocannabinol (THC) in THC-naïve children after unintentional acute exposure and compare clinical outcomes with non-naïve children. METHODS: A retrospective review was performed on children aged 31 days to 20 years who presented to Children's Hospital Colorado for care related to acute THC toxicity. The children were divided into groups based on exposure: group 1 (THC naïve) and group 2 (THC non-naïve). RESULTS: A total of 38 children (age, 3.5 [3] years) met inclusion for group 1 and an equal number of children (age, 15.1 [3.9] years) met the criteria for comparison in group 2. Eight naïve patients had documentation of estimated THC dose ingested (mean [SD], 7.13 [5.8] mg/kg; range, 2.9-19.5 mg/kg). A direct relationship between estimated oral THC dose, level of medical intervention required, and hospital disposition was observed. Lethargy/somnolence was more common in the naïve group (84% vs. 26%, P < 0.0001) whereas problems in cognition, perception, and behavior were more common in the non-naïve group (4% vs 11%, P = 0.01). The duration of clinical effect and length of hospital stay were longer in the naïve group (19.3 vs 5.0 hours, P < 0.0001) and (0.73 vs 0.19 days, P < 0.0001) respectively. CONCLUSIONS: There seems to be a direct relationship between the estimated oral THC dose (mg/kg), hospital disposition, and level of medical intervention required. Symptoms and duration of effects after THC exposure varied based on the route of exposure, age of patient, and history of previous THC experience.

An Atmospheric Pressure Chemical Ionization MS/MS Assay Using Online Extraction for the Analysis of 11 Cannabinoids and Metabolites in Human Plasma and Urine.

BACKGROUND: Although, especially in the United States, there has been a recent surge of legalized cannabis for either recreational or medicinal purposes, surprisingly little is known about clinical dose-response relationships, pharmacodynamic and toxicodynamic effects of cannabinoids such as Δ9-tetrahydrocannabinol (THC). Even less is known about other active cannabinoids. METHODS: To address this knowledge gap, an online extraction, high-performance liquid chromatography coupled with tandem mass spectrometry method for simultaneous quantification of 11 cannabinoids and metabolites including THC, 11-hydroxy-Δ9-tetrahydrocannabinol, 11-nor-Δ9-tetrahydrocannabinol-9-carboxylic acid, 11-nor-Δ9-tetrahydrocannabinol-9-carboxylic acid glucuronide (THC-C-gluc), cannabinol, cannabidiol, cannabigerol, cannabidivarin, Δ9-tetrahydrocannabivarin (THCV), and 11-nor-9-carboxy-Δ9-tetrahydrocannabivarin (THCV-COOH) was developed and validated in human urine and plasma. RESULTS: In contrast to atmospheric pressure chemical ionization, electrospray ionization was associated with extensive ion suppression in plasma and urine samples. Thus, the atmospheric pressure chemical ionization assay was validated showing a lower limit of quantification ranging from 0.39 to 3.91 ng/mL depending on study compound and matrix. The upper limit of quantification was 400 ng/mL except for THC-C-gluc with an upper limit of quantification of 2000 ng/mL. The linearity was r > 0.99 for all analyzed calibration curves. Acceptance criteria for intrabatch and interbatch accuracy (85%-115%) and imprecision (<15%) were met for all compounds. In plasma, the only exceptions were THCV (75.3%-121.2% interbatch accuracy) and cannabidivarin (interbatch imprecision, 15.7%-17.2%). In urine, THCV did not meet predefined acceptance criteria for intrabatch accuracy. CONCLUSIONS: This assay allows for monitoring not only THC and its major metabolites but also major cannabinoids that are of interest for marijuana research and clinical practice.

Pediatric tea tree oil aspiration treated with surfactant in the emergency department.

Tea tree oil is an essential oil containing a mixture of aromatic hydrocarbons. We describe an 18-month-old male patient who ingested tea tree oil, developed central nervous system depression, respiratory distress, and received early emergency department treatment with surfactant. Early treatment of hydrocarbon pneumonitis with surfactant has not been previously described. Early administration of surfactant should be further evaluated for treatment of hydrocarbon aspiration.

Association of unintentional pediatric exposures with decriminalization of marijuana in the United States.

STUDY OBJECTIVE: We compare state trends in unintentional pediatric marijuana exposures, as measured by call volume to US poison centers, by state marijuana legislation status. METHODS: A retrospective review of the American Association of Poison Control Centers National Poison Data System was performed from January 1, 2005, to December 31, 2011. States were classified as nonlegal if they have not passed legislation, transitional if they enacted legislation between 2005 and 2011, and decriminalized if laws passed before 2005. Our hypotheses were that decriminalized and transitional states would experience a significant increase in call volume, with more symptomatic exposures and more health care admissions than nonlegal states. RESULTS: There were 985 unintentional marijuana exposures reported from 2005 through 2011 in children aged 9 years and younger: 496 in nonlegal states, 93 in transitional states, and 396 in decriminalized states. There was a slight male predominance, and the median age ranged from 1.5 to 2.0 years. Clinical effects varied, with neurologic effects the most frequent. More exposures in decriminalized states required health care evaluation and had moderate to major clinical effects and critical care admissions compared with exposures from nonlegal states. The call rate in nonlegal states to poison centers did not change from 2005 to 2011. The call rate in decriminalized states increased by 30.3% calls per year, and transitional states had a trend toward an increase of 11.5% per year. CONCLUSION: Although the number of pediatric exposures to marijuana reported to the National Poison Data System was low, the rate of exposure increased from 2005 to 2011 in states that had passed marijuana legislation.

Toxic Tetrahydrocannabinol (THC) Dose in Pediatric Cannabis Edible Ingestions.

OBJECTIVE: The study characterizes cannabis toxicity in relation to tetrahydrocannabinol (THC) dose in pediatric edible cannabis ingestions. METHODS: This is a retrospective review of children aged <6 years presenting with edible cannabis ingestions of known THC dose within a pediatric hospital network (January 1, 2015-October 25, 2022). Cannabis toxicity was characterized as severe if patients exhibited severe cardiovascular (bradycardia, tachycardia/hypotension requiring vasopressors or intravenous fluids, other dysrhythmias), respiratory (respiratory failure, apnea, requiring oxygen supplementation), or neurologic (seizure, myoclonus, unresponsiveness, responsiveness to painful stimulation only, requiring intubation or sedation) effects. Cannabis toxicity was characterized as prolonged if patients required >6 hours to reach baseline. The relationship between THC dose and severe and prolonged toxicity was explored using multivariable logistic regression and receiver operator characteristic curve analyses. RESULTS: Eighty patients met inclusion. The median age was 2.9 years. The median THC ingestion was 2.1 mg/kg. Severe and prolonged toxicity was present in 46% and 74%, respectively. THC dose was a significant predictor of severe (adjusted odds ratio 2.9, 95% confidence interval: 1.8-4.7) and prolonged toxicity (adjusted odds ratio 3.2, 95% confidence interval: 1.6-6.5), whereas age and sex were not. Area under the curve was 92.9% for severe and 87.3% for prolonged toxicity. THC ingestions of ≥1.7 mg/kg can predict severe (sensitivity 97.3%) and prolonged toxicity (sensitivity 75.4%). CONCLUSIONS: The THC dose of edible cannabis correlates to the degree of toxicity in children <6 years old. The threshold of 1.7 mg/kg of THC may guide medical management and preventive regulations.

APCDs can Provide Important Insights for Surveilling the Opioid Epidemic, With Caveats.

State-level all-payer claims databases (APCDs) are a possible new public health surveillance tool, but their reliability is unclear. We compared Colorado's APCD with other state-level databases for use in monitoring the opioid epidemic (Colorado Hospital Association and Colorado's Prescription Drug Monitoring Program database for 2010-2017), using descriptive analyses comparing quarterly counts/rates of opioid-involved inpatient and emergency department visits and counts/rates of 30-day opioid fills between databases. Utilization is lower in the Colorado APCD than the other databases for all outcomes but trends are parallel and consistent between databases. State APCDs hold promise for researchers, but they may be better suited to individual-level analyses or comparisons of providers than for surveillance of public health trends related to addiction.

tRNA synthetase counteracts c-Myc to develop functional vasculature.

Recent studies suggested an essential role for seryl-tRNA synthetase (SerRS) in vascular development. This role is specific to SerRS among all tRNA synthetases and is independent of its well-known aminoacylation function in protein synthesis. A unique nucleus-directing domain, added at the invertebrate-to-vertebrate transition, confers this novel non-translational activity of SerRS. Previous studies showed that SerRS, in some unknown way, controls VEGFA expression to prevent vascular over-expansion. Using in vitro, cell and animal experiments, we show here that SerRS intervenes by antagonizing c-Myc, the major transcription factor promoting VEGFA expression, through a tandem mechanism. First, by direct head-to-head competition, nuclear-localized SerRS blocks c-Myc from binding to the VEGFA promoter. Second, DNA-bound SerRS recruits the SIRT2 histone deacetylase to erase prior c-Myc-promoted histone acetylation. Thus, vertebrate SerRS and c-Myc is a pair of 'Yin-Yang' transcriptional regulator for proper development of a functional vasculature. Our results also discover an anti-angiogenic activity for SIRT2.DOI: http://dx.doi.org/10.7554/eLife.02349.001.

The pharmacologic and clinical effects of medical cannabis.

Cannabis, or marijuana, has been used for medicinal purposes for many years. Several types of cannabinoid medicines are available in the United States and Canada. Dronabinol (schedule III), nabilone (schedule II), and nabiximols (not U.S. Food and Drug Administration approved) are cannabis-derived pharmaceuticals. Medical cannabis or medical marijuana, a leafy plant cultivated for the production of its leaves and flowering tops, is a schedule I drug, but patients obtain it through cannabis dispensaries and statewide programs. The effect that cannabinoid compounds have on the cannabinoid receptors (CB(1) and CB(2) ) found in the brain can create varying pharmacologic responses based on formulation and patient characteristics. The cannabinoid Δ(9) -tetrahydrocannabinol has been determined to have the primary psychoactive effects; the effects of several other key cannabinoid compounds have yet to be fully elucidated. Dronabinol and nabilone are indicated for the treatment of nausea and vomiting associated with cancer chemotherapy and of anorexia associated with weight loss in patients with acquired immune deficiency syndrome. However, pain and muscle spasms are the most common reasons that medical cannabis is being recommended. Studies of medical cannabis show significant improvement in various types of pain and muscle spasticity. Reported adverse effects are typically not serious, with the most common being dizziness. Safety concerns regarding cannabis include the increased risk of developing schizophrenia with adolescent use, impairments in memory and cognition, accidental pediatric ingestions, and lack of safety packaging for medical cannabis formulations. This article will describe the pharmacology of cannabis, effects of various dosage formulations, therapeutics benefits and risks of cannabis for pain and muscle spasm, and safety concerns of medical cannabis use.

Severe poisoning after accidental pediatric ingestion of glycol ethers.

Human glycol ether poisonings are sparsely reported in the medical literature. We describe a healthy 22-month-old boy who accidentally drank up to 330 mL of brake fluid containing a 75% bleed of various glycol ethers (5%-50% polyethylene glycol monomethyl ether, 15%-40% triethylene glycol monoethyl ether, 1%-30% triethylene glycol monomethyl ether, 1%-25% triethylene glycol monobutyl ether, 1%-20% polyethylene glycol, monobutyl ether, 1%-20% triethylene glycol, and <10% of other glycol ethers). Within 4 hours, he became somnolent and developed a persistent metabolic acidosis. Thirty minutes later, he received 1 dose of fomepizole. Neither progression nor improvement in clinical or metabolic status was noted after the fomepizole. He received hemodialysis for 3 hours ∼8 hours after ingestion, and his symptoms resolved resulting in an uneventfully recovery.

Hepatic failure despite early acetylcysteine following large acetaminophen-diphenhydramine overdose.

We describe the case of a patient with massive acetaminophen-diphenhydramine overdose and a 4-hour serum acetaminophen concentration of 653 µg/mL. The patient was treated with acetylcysteine 5 hours after ingestion. Because of a persistently elevated serum acetaminophen level of 413 µg/mL 45 hours after ingestion, a medical toxicologist recommended that the patient be treated with a second bolus of acetylcysteine (150 mg/kg followed by 12.5 mg/kg per hour for 4 hours, then 6.25 mg/kg per hour). On hospital day 3, she developed hepatic failure despite early treatment. Her transaminase levels and hepatic synthetic function began to improve on hospital day 6, and acetylcysteine was discontinued on hospital day 10. In cases of massive acetaminophen overdose, standard acetylcysteine dosing may not be adequate. We suggest that elevated serum acetaminophen concentrations at the end of a standard 20-hour acetylcysteine infusion should be discussed with the local poison center.