Naloxone dosing in the era of ultra-potent opioid overdoses: a systematic review.

OBJECTIVES: Evaluate the relationship between naloxone dose (initial and cumulative) and opioid toxicity reversal and adverse events in undifferentiated and presumed fentanyl/ultra-potent opioid overdoses. METHODS: We searched Embase, MEDLINE, Cochrane Central Register of Controlled Trials, DARE, CINAHL, Science Citation Index, reference lists, toxicology websites, and conference proceedings (1972 to 2018). We included interventional, observational, and case studies/series reporting on naloxone dose and opioid toxicity reversal or adverse events in people >12 years old. RESULTS: A total of 174 studies (110 case reports/series, 57 observational, 7 interventional) with 26,660 subjects (median age 35 years; 74% male). Heterogeneity precluded meta-analysis. Where reported, we abstracted naloxone dose and proportion of patients with toxicity reversal. Among patients with presumed exposure to fentanyl/ultra-potent opioids, 56.9% (617/1,085) responded to an initial naloxone dose ≤0.4 mg compared with 80.2% (170/212) of heroin users, and 30.4% (7/23) responded to an initial naloxone dose >0.4 mg compared with 59.1% (1,434/2,428) of heroin users. Among patients who responded, median cumulative naloxone doses were higher for presumed fentanyl/ultra-potent opioids than heroin overdoses in North America, both before 2015 (fentanyl/ultra-potent opioids: 1.8 mg [interquartile interval {IQI}, 1.0, 4.0]; heroin: 0.8 mg [IQI, 0.4, 0.8]) and after 2015 (fentanyl/ultra-potent opioids: 3.4 mg [IQI, 3.0, 4.1]); heroin: 2 mg [IQI, 1.4, 2.0]). Where adverse events were reported, 11% (490/4,414) of subjects experienced withdrawal. Variable reporting, heterogeneity and poor-quality studies limit conclusions. CONCLUSIONS: Practitioners have used higher initial doses, and in some cases higher cumulative naloxone doses to reverse toxicity due to presumed fentanyl/ultra-potent opioid exposure compared with other opioids. High-quality comparative naloxone dosing studies assessing effectiveness and safety are needed.

Minor Injury Crashes: Prevalence of Driver-Related Risk Factors and Outcome.

BACKGROUND: The majority of crashes cause "minor" injuries (i.e., treated and released from the emergency department [ED]). Minor injury crashes are poorly studied. OBJECTIVES: This study aims to determine the prevalence of driver-related risk factors and subsequent outcome in drivers involved in minor crashes. METHODS: We interviewed a convenience sample of injured drivers, aged over 17 years, who were treated and released from the ED. Follow-up interviews were conducted 6 months after the crash. RESULTS: We approached 123 injured drivers; baseline interviews were completed in 69 and follow-up interviews in 45. Prior to the index crash, 1.4% of drivers drank alcohol, 1.4% used illicit drugs, and 7.2% used sedating prescription medications. Nine drivers (13%) were distracted. In this sample, 5.8% met criteria for being aggressive drivers, 7.2% were risky drivers, and 11.6% drove while experiencing negative emotions. At 6-month follow-up, many drivers were still having health problems, 53.3% were not fully recovered, 46.7% had not returned to usual activities, and 28.9% were off work. Of the 42 participants who resumed driving, 16.7% had a near miss and 4.8% had another crash. Nine (21.4%) reported drinking and driving, and 9.5% reported driving after cannabis use. Cell phone use (16.7%) and use of other electronics while driving (23.8%) were also common. CONCLUSIONS: Driver-related risk factors are common in drivers involved in minor injury crashes, and drivers persist in taking risks after being involved in a crash. Despite their name, minor injury crashes are often associated with slow recovery and prolonged absenteeism from work.

Comparison of Rates of Coronary Angiography and Combined Testing Procedures in Patients Seen in the Emergency Room With Chest Pain (But No Objective Acute Coronary Syndrome Findings) Having Coronary Computed Tomography Versus Exercise Stress Testing.

Coronary computed tomography angiography (CCTA) appears comparable to standard care, including exercise stress testing (EST), in diagnosing acute coronary syndrome in emergency department (ED) patients with chest pain but may increase downstream testing. The objective of this study was to investigate rates of post-CCTA versus post-EST testing for (1) invasive angiography and (2) all combined cardiac testing. This was a retrospective cohort study performed at 2 urban Canadian EDs involving patients aged up to 65 years with chest pain but no objective ACS findings that were evaluated with CCTA or EST at the physician's discretion. The primary outcome was the proportion of patients who had 30-day invasive angiography in each group; secondary outcomes included all subsequent 30-day cardiac testing, including nuclear medicine scanning. From July 1, 2012, to June 30, 2014, we collected 1,700 patients: 521 CCTA and 1,179 EST. Demographics and risk factors were similar in both cohorts. In the following 30 days, 30 CCTA (5.8%) and 297 EST (25.2%) patients underwent any type of additional cardiac testing (difference 19.4%, 95% CI 16.0 to 22.6), whereas 12 CCTA (2.3%) and 20 EST patients (1.7%) underwent angiography (difference 0.6%, 95% CI -0.8% to 2.6%). No patients in either group died or had a myocardial infarction within 30 days. For ED patients with chest pain who underwent brief observation, CCTA and EST had similar 30-day angiography rates, but CCTA patients underwent significantly less overall cardiac investigations.

Maternal rat serum concentrations of dimethadione do not explain intra-litter differences in the incidence of dimethadione-induced birth defects, including novel findings in foetal lung.

To investigate mechanisms of chemical-induced congenital heart defects (CHD) we have developed a rat model using dimethadione (DMO), the N-demethylated metabolite of the anticonvulsant, trimethadione (TMD). Dosing pregnant rats with 300mg/kg DMO every 12h from the evening of gestational day (GD) 8 until the morning of GD 11 (six total doses) produces a mean 74% incidence of CHD with inter litter variability ranging from 40 to 100%. The goal of this study was to determine if the variability in maternal serum concentrations of DMO on GD 14, a surrogate marker for total exposure, was related to the inter-litter differences in teratogenic outcomes. To test this hypothesis, pregnant rats were dosed as described above and serum levels of DMO assessed on GD 14. On GD 21, foetuses were collected by caesarean section, assessed for a number endpoints and the outcomes were correlated with the GD 14 serum concentrations of DMO. DMO exposure was associated with decreased foetal body weight, increased incidence of sternal defects and CHD, but these endpoints were not meaningfully correlated with maternal concentrations of DMO. Novel findings were decreased viability as measured one-hour following caesarean section, and delayed alveolar maturation. The major conclusions from these studies were first, that serum DMO concentrations on GD 14 did not predict teratogenicity, and second, delayed lung development may contribute to the decreased survival of foetuses at the time of caesarean section.

In utero dimethadione exposure causes postnatal disruption in cardiac structure and function in the rat.

In utero exposure of rat embryos to dimethadione (DMO), the N-demethylated teratogenic metabolite of the anticonvulsant trimethadione, induces a high incidence of cardiac heart defects including ventricular septal defects (VSDs). The same exposure regimen also leads to in utero cardiac functional deficits, including bradycardia, dysrhythmia, and a reduction in cardiac output (CO) and ejection fraction that persist until parturition (10 days after the final dose). Despite a high rate of spontaneous postnatal VSD closure, we hypothesize that functional sequelae will persist into adulthood. Pregnant Sprague Dawley rats were administered six 300 mg/kg doses of DMO, one every 12 h in mid-pregnancy beginning on the evening of gestation day 8. Postnatal cardiac function was assessed in control (CTL) and DMO-exposed offspring using radiotelemetry and ultrasound at 3 and 11 months of age, respectively. Adult rats exposed to DMO in utero had an increased incidence of arrhythmia, elevated blood pressure and CO, greater left ventricular volume and elevated locomotor activity versus CTL. The mean arterial pressure of DMO-exposed rats was more sensitive to changes in dietary salt load compared with CTL. Importantly, most treated rats had functional deficits in the absence of a persistent structural defect. It was concluded that in utero DMO exposure causes cardiovascular deficits that persist into postnatal life in the rat, despite absence of visible structural anomalies. We speculate this is not unique to DMO, suggesting possible health implications for infants with unrecognized gestational chemical exposures.

Noninvasive high-resolution ultrasound reveals structural and functional deficits in dimethadione-exposed fetal rat hearts in utero.

BACKGROUND: We previously showed dimethadione (DMO), the N-demethylated metabolite of the anticonvulsant trimethadione, induces ventricular septation defects (VSD) and other heart anomalies in rat (Weston et al., 2011). Because of the relationship between cardiac structure and function, we hypothesized that DMO-induced structural defects of the heart are associated with in utero functional deficits. To test the hypothesis, the goals were (1) define the parameters for ultrasound in the rat conceptus, and; (2) use ultrasound to identify structural and functional deficits following DMO treatment. METHODS: Different ultrasound modes (B-mode, M-mode, and Pulse-wave Doppler) using four high-resolution ultrasound transducer heads of varying frequency (25-40 MHz) were tested on gestational day (GD) 14, 15, 16, 17, and 21. Having identified the optimal conditions, pregnant Sprague-Dawley rats were administered six 300 mg/kg doses of DMO every 12 hr beginning at 19:00 hr on GD 8 to generate conceptuses with a high incidence of VSD. RESULTS: The three ultrasound modalities were used to identify VSD and several novel and rare structural heart anomalies (cardiac effusions and bifurcated septum) in live rat fetuses. DMO-treated hearts had an array of functional deficits including a decrease in mean heart rate, ejection fraction, and cardiac output and increased incidence of bradycardia and dysrhythmia. CONCLUSIONS: The ultrasound biomicroscope is an effective tool for the real-time characterization of the structure and function of embryo/fetal rat hearts. DMO causes significant deficits to in utero heart function for up to ten days (GD 21) following its final administration, suggesting long-term or possible permanent changes cardiac function.