Effects of acute cannabis inhalation on reaction time, decision-making, and memory using a tablet-based application.

BACKGROUND: Acute cannabis use has been demonstrated to slow reaction time and affect decision-making and short-term memory. These effects may have utility in identifying impairment associated with recent use. However, these effects have not been widely investigated among individuals with a pattern of daily use, who may have acquired tolerance. The purpose of this study was to examine the impact of tolerance to cannabis on the acute effects as measured by reaction time, decision-making (gap acceptance), and short-term memory. METHODS: Participants (ages 25-45) completed a tablet-based (iPad) test battery before and approximately 60 min after smoking cannabis flower. The change in performance from before to after cannabis use was compared across three groups of cannabis users: (1) occasional use (n = 23); (2) daily use (n = 31); or (3) no current use (n = 32). Participants in the occasional and daily use group self-administered ad libitum, by smoking or vaping, self-supplied cannabis flower with a high concentration of total THC (15-30%). RESULTS: The occasional use group exhibited decrements in reaction time (slowed) and short-term memory (replicated fewer shapes) from before to after cannabis use, as compared to the no-use group. In the gap acceptance task, daily use participants took more time to complete the task post-smoking cannabis as compared to those with no use or occasional use; however, the level of accuracy did not significantly change. CONCLUSIONS: The findings are consistent with acquired tolerance to certain acute psychomotor effects with daily cannabis use. The finding from the gap acceptance task which showed a decline in speed but not accuracy may indicate a prioritization of accuracy over response time. Cognitive and psychomotor assessments may have utility for identifying impairment associated with recent cannabis use.

Accuracy and replicability of identifying eyelid tremor as an indicator of recent cannabis smoking.

INTRODUCTION: Cannabis intoxication may increase the risk of motor vehicle crashes. However, reliable methods of assessing cannabis intoxication are limited. The presence of eyelid tremors is among the signs of cannabis use identified under the Drug Evaluation and Classification Program of the International Association of Chiefs of Police. Our objectives were to assess the accuracy and replicability of identifying eyelid tremor as an indicator of recent cannabis smoking using a blinded, controlled study design. METHODS: Adult subjects (N = 103) were recruited into three groups based on their cannabis use history: daily, occasional, and no current cannabis use. Participants' closed eyelids were video recorded for 30 seconds by infrared videography goggles before and at a mean ± standard deviation time of 71.4 ± 4.6 minutes after the onset of a 15-minute interval of ad libitum cannabis flower smoking or vaping. Three observers with expertise in neuro-ophthalmology and medical toxicology were trained on exemplar videos of eyelids to reach a consensus on how to grade eyelid tremor. Without knowledge of subjects' cannabis use history or time point (pre- or post-smoking), observers reviewed each video for eyelid tremor graded as absent, slight, moderate, or severe. During subsequent data analysis, this score was further dichotomized as a consensus score of absent (absent/slight) or present (moderate/severe). RESULTS: Kappa and intraclass correlation coefficient statistics demonstrated moderate agreement among the coders, which ranged from 0.44-0.45 and 0.58-0.61, respectively. There was no significant association between recent cannabis use and the observers' consensus assessment that eyelid tremor was present, and cannabis users were less likely to have tremors (odds ratio: 0.75; 95 percent confidence interval: 0.25, 2.40). The assessment of eyelid tremor as an indicator of recent cannabis smoking had a sensitivity of 0.86, specificity of 0.18, and accuracy of 0.64. DISCUSSION: Eyelid tremor has fair sensitivity but poor specificity and accuracy for identification of recent cannabis use. Inter-rater reliability for assessment of eyelid tremor was moderate for the presence and degree of tremor. The weak association between recent cannabis use and eyelid tremor does not support its utility in identifying recent cannabis use. LIMITATIONS: Videos were recorded at only one time point after cannabis use. Adherence to abstinence could not be strictly supervised. Due to regulatory restrictions, we were unable to control the cannabis product used or administer a fixed Δ9-tetrahydrocannabinol dose. Participants were predominately non-Hispanic and White. CONCLUSIONS: In a cohort of participants with a range of cannabis use histories, acute cannabis smoking was not associated with the presence of eyelid tremor, regardless of cannabis use history, at 70 minutes post-smoking. Additional research is needed to identify the presence of eyelid tremor accurately, determine the relationship between cannabis dose and timeline in relation to last cannabis use to eyelid tremor, and determine how it should be, if at all, utilized for cannabis Drug Recognition Evaluator examinations.

Vagal sparing gastrectomy: A systematic review and meta-analysis.

Radical gastrectomy is associated with significant functional complications. In appropriate patients may be amenable to less invasive resection aimed at preserving the vagal trunks. The aim of this systematic review and meta-analysis is to assess the functional consequences and oncological safety of vagal sparing gastrectomy (VSG) compared to conventional non-vagal sparing gastrectomy (CG). A systematic review of four databases was undertaken for studies published between 1/11990 and 15/122021, comparing patients who underwent VSG to CG. We meta-analysed the following outcomes: operative time, blood loss, nodal yield, days to flatus, body weight changes, as well as the incidence of post-operative cholelithiasis, diarrhoea, delayed gastric emptying, and dumping syndrome. Thirty studies were included in the meta-analysis with a selection of studies qualitatively analysed. VSG was associated with a lower rate of cholelithiasis (OR 0.25, 95% CI 0.15-0.41, p<0.010) and early dumping syndrome (OR 0.42, 95% CI 0.21 - 0.86; p=0.02), less blood loss (MD -51 ml, 95% CI -89.11 to -12.81 ml, p=0.009), less long term weight loss (MD 2.03%, 95% CI 0.31-3.76%, p=0.02) and a faster time to flatus (MD -0.42 days, 95% CI -0.48 - 0.36, p<0.001). There was no significant difference in nodal harvest, overall survival, and all other endpoints. VSG significantly reduces the incidence of post-operative cholelithiasis and dumping syndrome, decreases weight loss and facilitates an earlier return of gut motility. Although technically more challenging, VSG should be considered for prophylactic surgery.

Circulating extracellular choline acetyltransferase regulates inflammation.

BACKGROUND: Choline acetyltransferase (ChAT) is required for the biosynthesis of acetylcholine, the molecular mediator that inhibits cytokine production in the cholinergic anti-inflammatory pathway of the vagus nerve inflammatory reflex. Abundant work has established the biology of cytoplasmic ChAT in neurons, but much less is known about the potential presence and function of ChAT in the extracellular milieu. OBJECTIVES: We evaluated the hypothesis that extracellular ChAT activity responds to inflammation and serves to inhibit cytokine release and attenuate inflammation. METHODS: After developing novel methods for quantification of ChAT activity in plasma, we determined whether ChAT activity changes in response to inflammatory challenges. RESULTS: Active ChAT circulates within the plasma compartment of mice and responds to immunological perturbations. Following the administration of bacterial endotoxin, plasma ChAT activity increases for 12-48 h, a time period that coincides with declining tumor necrosis factor (TNF) levels. Further, a direct activation of the cholinergic anti-inflammatory pathway by vagus nerve stimulation significantly increases plasma ChAT activity, whereas the administration of bioactive recombinant ChAT (r-ChAT) inhibits endotoxin-stimulated TNF production and anti-ChAT antibodies exacerbate endotoxin-induced TNF levels, results of which suggest that ChAT activity regulates endogenous TNF production. Administration of r-ChAT significantly attenuates pro-inflammatory cytokine production and disease activity in the dextran sodium sulfate preclinical model of inflammatory bowel disease. Finally, plasma ChAT levels are also elevated in humans with sepsis, with the highest levels observed in a patient who succumbed to infection. CONCLUSION: As a group, these results support further investigation of ChAT as a counter-regulator of inflammation and potential therapeutic agent.

Galantamine ameliorates experimental pancreatitis.

BACKGROUND: Acute pancreatitis is a common and serious inflammatory condition currently lacking disease modifying therapy. The cholinergic anti-inflammatory pathway (CAP) is a potent protective anti-inflammatory response activated by vagus nerve-dependent α7 nicotinic acetylcholine receptor (α7nAChR) signaling using splenic CD4+ T cells as an intermediate. Activating the CAP ameliorates experimental acute pancreatitis. Galantamine is an acetylcholinesterase inhibitor (AChEI) which amplifies the CAP via modulation of central muscarinic ACh receptors (mAChRs). However, as mAChRs also activate pancreatitis, it is currently unknown whether galantamine would be beneficial in acute pancreatitis. METHODS: The effect of galantamine (1-6 mg/kg-body weight) on caerulein-induced acute pancreatitis was evaluated in mice. Two hours following 6 hourly doses of caerulein (50 µg/kg-body weight), organ and serum analyses were performed with accompanying pancreatic histology. Experiments utilizing vagotomy, gene knock out (KO) technology and the use of nAChR antagonists were also performed. RESULTS: Galantamine attenuated pancreatic histologic injury which was mirrored by a reduction in serum amylase and pancreatic inflammatory cytokines and an increase the anti-inflammatory cytokine IL-10 in the serum. These beneficial effects were not altered by bilateral subdiaphragmatic vagotomy, KO of either choline acetyltransferase+ T cells or α7nAChR, or administration of the nAChR ganglionic blocker mecamylamine or the more selective α7nAChR antagonist methyllycaconitine. CONCLUSION: Galantamine improves acute pancreatitis via a mechanism which does not involve previously established physiological and molecular components of the CAP. As galantamine is an approved drug in widespread clinical use with an excellent safety record, our findings are of interest for further evaluating the potential benefits of this drug in patients with acute pancreatitis.

Health Effects of High-Concentration Cannabis Products: Scoping Review and Evidence Map.

Background. The concentration of pharmacologically active tetrahydrocannabinol (THC) in cannabis products has been increasing over the past decade. Concerns about potential harmful health effects of using these increasingly higher-concentration products have led some states to consider regulation of cannabis product THC concentration. We conducted a scoping review of health effects of high-concentration cannabis products to inform policy on whether the THC concentrations of cannabis product should be regulated or limited. Objectives. We conducted a scoping review to (1) identify and describe human studies that explore the relationship of high-concentration cannabis products with any health outcomes in the literature and (2) create an interactive evidence map of the included studies to facilitate further analyses. Search Methods. An experienced medical information specialist designed a comprehensive search strategy of 7 electronic databases. Selection Criteria. We included human studies of any epidemiological design with no restrictions by age, sex, health status, country, or outcome measured that reported THC concentration or included a known high-concentration cannabis product. Data Collection and Analysis. We imported search results into Distiller SR, and trained coders conducted artificial intelligence‒assisted screening. We developed, piloted, and revised data abstraction forms. One person performed data abstraction, and a senior reviewer verified a subset. We provide a tabular description of study characteristics, including exposures and outcomes measured, for each included study. We interrogated the evidence map published in Tableau to answer specific questions and provide the results as text and visual displays. Main Results. We included 452 studies in the scoping review and evidence map. There was incomplete reporting of exposure characteristics including THC concentration, duration and frequency of use, and products used. The evidence map shows considerable heterogeneity among studies in exposures, outcomes, and populations studied. A limited number of reports provided data that would facilitate further quantitative synthesis of the results across studies. Conclusions. This scoping review and evidence map support strong conclusions concerning the utility of the literature for characterizing risks and benefits of the current cannabis marketplace and the research approaches followed in the studies identified. Relevance of the studies to today's products is limited. Public Health Implications. High-quality evidence to address the policy question of whether the THC concentration of cannabis products should be regulated is scarce. The publicly available interactive evidence map is a timely resource for other entities concerned with burgeoning access to high-concentration cannabis. (Am J Public Health. 2023;113(12):1332-1342. https://doi.org/10.2105/AJPH.2023.307414).

2023 American Heart Association focused update on the management of patients with cardiac arrest or life-threatening toxicity due to poisoning: an update to the American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care

In this focused update, the American Heart Association provides updated guidance for resuscitation of patients with cardiac arrest, respiratory arrest, and refractory shock due to poisoning. Based on structured evidence reviews, guidelines are provided for the treatment of critical poisoning from benzodiazepines, ß-adrenergic receptor antagonists (also known as ß-blockers), L-type calcium channel antagonists (commonly called calcium channel blockers), cocaine, cyanide, digoxin and related cardiac glycosides, local anesthetics, methemoglobinemia, opioids, organophosphates and carbamates, sodium channel antagonists (also called sodium channel blockers), and sympathomimetics. Recommendations are also provided for the use of venoarterial extracorporeal membrane oxygenation. These guidelines discuss the role of atropine, benzodiazepines, calcium, digoxin-specific immune antibody fragments, electrical pacing, flumazenil, glucagon, hemodialysis, hydroxocobalamin, hyperbaric oxygen, insulin, intravenous lipid emulsion, lidocaine, methylene blue, naloxone, pralidoxime, sodium bicarbonate, sodium nitrite, sodium thiosulfate, vasodilators, and vasopressors for the management of specific critical poisonings.

2023 American Heart Association Focused Update on the Management of Patients With Cardiac Arrest or Life-Threatening Toxicity Due to Poisoning: An Update to the American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care.

In this focused update, the American Heart Association provides updated guidance for resuscitation of patients with cardiac arrest, respiratory arrest, and refractory shock due to poisoning. Based on structured evidence reviews, guidelines are provided for the treatment of critical poisoning from benzodiazepines, ß-adrenergic receptor antagonists (also known as ß-blockers), L-type calcium channel antagonists (commonly called calcium channel blockers), cocaine, cyanide, digoxin and related cardiac glycosides, local anesthetics, methemoglobinemia, opioids, organophosphates and carbamates, sodium channel antagonists (also called sodium channel blockers), and sympathomimetics. Recommendations are also provided for the use of venoarterial extracorporeal membrane oxygenation. These guidelines discuss the role of atropine, benzodiazepines, calcium, digoxin-specific immune antibody fragments, electrical pacing, flumazenil, glucagon, hemodialysis, hydroxocobalamin, hyperbaric oxygen, insulin, intravenous lipid emulsion, lidocaine, methylene blue, naloxone, pralidoxime, sodium bicarbonate, sodium nitrite, sodium thiosulfate, vasodilators, and vasopressors for the management of specific critical poisonings.

A randomized trial of continuous glucose monitoring to improve post-transplant glycemic control.

INTRODUCTION: This study examines whether the use of inpatient Continuous Glucose Monitors provides improved glycemic control over finger-stick glucose monitoring post-transplant. METHODS: This is a single-site, prospective randomized controlled trial of 40 patients receiving conventional finger-stick glucose monitoring or continuous monitoring using the Medtronic Guardian Sensor 3 during the first 5 days post-transplant. Included patients were adult renal transplant recipients with a diagnosis of diabetes. Assessed endpoints included post-transplant daily median glucose level, hyperglycemic (≥180 mg/dL) and hypoglycemic (≤80 mg/dL) episodes, number of post-transplant bacterial infections and length of stay. RESULTS: Groups were well matched in demographic variables. Median daily glucose was significantly lower in the intervention group. There were also significantly less episodes of hyperglycemia on postoperative days 2, 3, 4, and 5. There were no differences in the incidences of hypoglycemia, postoperative bacterial infections, or length of stay. CONCLUSION: In this randomized study, the use of a continuous glucose monitor to guide post-transplant glucose management significantly lowered the incidence of hyperglycemic episodes and median glucose levels through the first 5 days post-transplant without increasing the number of hypoglycemic episodes. The use of these devices can be considered in the immediate post-renal transplant setting.

Impact of Recreational Cannabis Legalization on Opioid Prescribing and Opioid-Related Hospital Visits in Colorado: an Observational Study.

BACKGROUND: Cannabis may be a substitute for opioids but previous studies have found conflicting results when using data from more recent years. Most studies have examined the relationship using state-level data, missing important sub-state variation in cannabis access. OBJECTIVE: To examine cannabis legalization on opioid use at the county level, using Colorado as a case study. Colorado allowed recreational cannabis stores in January 2014. Local communities could decide whether to allow dispensaries, creating variation in the level of exposure to cannabis outlets. DESIGN: Observational, quasi-experimental design exploiting county-level variation in allowance of recreational dispensaries. SUBJECTS: Colorado residents MEASURES: We use licensing information from the Colorado Department of Revenue to measure county-level exposure to cannabis outlets. We use the state's Prescription Drug Monitoring Program (2013-2018) to construct opioid-prescribing measures of number of 30-day fills and total morphine equivalents, both per county resident per quarter. We construct outcomes of opioid-related inpatient visits (2011-2018) and emergency department visits (2013-2018) with Colorado Hospital Association data. We use linear models in a differences-in-differences framework that accounts for the varying exposure to medical and recreational cannabis over time. There are 2048 county-quarter observations used in the analysis. RESULTS: We find mixed evidence of cannabis exposure on opioid-related outcomes at the county level. We find increasing exposure to recreational cannabis is associated with a statistically significant decrease in number of 30-day fills (coefficient: -117.6, p-value<0.01) and inpatient visits (coefficient: -0.8, p-value: 0.03), but not total MME nor ED visits. Counties with no medical exposure prior to recreational legalization experience greater reductions in the number of 30-day fills and MME than counties with prior medical exposure (p=0.02 for both). CONCLUSIONS: Our mixed findings suggest that further increases in cannabis beyond medical access may not always reduce opioid prescribing or opioid-related hospital visits at a population level.

Blood cannabinoid molar metabolite ratios are superior to blood THC as an indicator of recent cannabis smoking.

INTRODUCTION: Cannabis use is a growing concern in transportation and workplace incidents. Because Δ9-tetrahydrocannabinol is detectable after acute psychoactive effects have resolved, it has limitations as an indicator of recent usage or potential impairment. METHODS: In an observational study of driving and psychomotor performance, we measured whole blood Δ9-tetrahydrocannabinol plus its metabolites 11-hydroxy-Δ9-tetrahydrocannabinol and 11-nor-9-carboxy-Δ9-tetrahydrocannabinol by liquid chromatography with tandem mass spectrometry at baseline and 30 min after starting a 15-minute interval of smoking cannabis in 24 occasional and 32 daily cannabis smokers. We calculated two blood cannabinoid molar metabolite ratios: 1) [Δ9-tetrahydrocannabinol] to [11-nor-9-carboxy-Δ9-tetrahydrocannabinol] and 2) ([Δ9-tetrahydrocannabinol] + [11-hydroxy-Δ9-tetrahydrocannabinol]) to [11-nor-9-carboxy-Δ9-tetrahydrocannabinol]. We compared these to blood [Δ9-tetrahydrocannabinol] alone as indicators of recent cannabis smoking. RESULTS: Median Δ9-tetrahydrocannabinol concentrations increased from 0 ( 0.38). By comparison, a cut-point for Δ9-tetrahydrocannabinol of 5.3 µg/L yielded 88% specificity, 73% sensitivity, and 80% accuracy. CONCLUSIONS: In occasional and daily users, the blood cannabinoid molar metabolite ratios were superior to whole blood Δ9-tetrahydrocannabinol as indicators of recent cannabis smoking. We recommend measurement and reporting of Δ9-tetrahydrocannabinol, 11-hydroxy-Δ9-tetrahydrocannabinol, and 11-nor-9-carboxy-Δ9-tetrahydrocannabinol, and their molar metabolite ratios in forensic and safety investigations.

Early Follow-Up after Arteriovenous Fistula Creation is Associated with Improved Access-Related Outcomes.

BACKGROUND: Up to 60% of arteriovenous fistulas (AVF) require intervention to assist maturation, which prolongs the time until it can be used for hemodialysis (HD). Current guidelines recommend early postoperative AVF examination to detect and address immaturity to decrease time to maturation. This study evaluates how the timing of postoperative follow-up to assess AVF maturity affects patients' outcomes. METHODS: All patients who underwent AVF creation between 2017 and 2021 in an academic medical center were retrospectively reviewed, excluding patients lost to follow-up or not on HD. Outcomes were compared between patients that had delayed follow-up to assess AVF maturity, >8 weeks post surgery, versus early follow-up, <8 weeks post-surgery. AVF evaluation for maturity consisted of physical examination and duplex ultrasound. Primary endpoints were time to first cannulation (interval from AVF creation to first successful cannulation) and time to catheter-free dialysis (interval from AVF creation to central venous catheter removal). RESULTS: A total of 400 patients were identified: 111 in the delayed follow-up group and 289 in the early follow-up group. The median time to follow-up was 78 days (interquartile range [IQR], 66-125) in the delayed follow-up group versus 39 days (IQR, 36-47) in the early follow-up group, (P < 0.0001). The maturation rate was 87% in the delayed follow-up group versus 81% in the early follow-up group, (P = 0.1) and both groups had similar rates of interventions to assist maturation (66% vs. 57%, P = 0.2). The early follow-up group had a significantly shorter median time to first cannulation (50 vs. 88 days; P < 0.0001) and shorter time to catheter-free HD (75 vs. 118 days; P <0.0001). At 4 months after AVF creation, the incidence of first cannulation was 74% in the early follow-up group versus 63% in the delayed follow-up group (P = 0.001). Similarly, the incidence of catheter-free dialysis was 65% in the early follow-up group versus 50% in the delayed follow-up group at 4 months postoperatively, (P = 0.036). CONCLUSIONS: Early postoperative follow-up for evaluation of fistula maturation is associated with reduced time to first successful cannulation of AVF for HD and reduced time to catheter-free dialysis.

The minor cannabinoid cannabigerol (CBG) is a highly specific blood biomarker of recent cannabis smoking.

INTRODUCTION: The determination of recent cannabis use is of forensic interest in the investigation of automotive crashes, workplace incidents and other mishaps. Because Δ9-tetrahydrocannabinol may persist in blood after psychoactive effects of intoxication resolve, particularly in regular users, short-lived minor cannabinoids such as cannabigerol have merited examination as adjunct indicators of recent cannabis inhalation. METHODS: As part of an observational cohort study, whole blood cannabinoids including cannabigerol were measured in whole blood by liquid chromatography with tandem mass spectrometry at baseline, and 30 minutes after initiation of a 15-minute supervised interval of ad libitum cannabis smoking in occasional (1-2 days/week over the past 30 days) (n = 24) and daily cannabis smokers (n = 32). Per protocol, subjects self-reported abstention from inhaling cannabis (>8 h) or ingesting cannabis (>12 h) prior to baseline measurement. RESULTS: At baseline, none of the occasional users had detectable cannabigerol (limit of detection = 0.2 µg/L), whereas cannabigerol was detectable post-smoking in 7 of 24 (29%). Among daily cannabis users, 2 of 32 (6%) had detectable cannabigerol at baseline, increasing to 21 of 32 (66%) post-smoking. The odds ratio for recent cannabis smoking associated with a detectable cannabigerol was 27 (95% confidence interval: 6.6, 110.3). In this mixed cohort of occasional and daily cannabis users, receiver operator characteristic curve analysis indicated that whole blood cannabigerol concentration of ≥ 0.2 µg/L had 96% specificity, 50% sensitivity, and 73% accuracy for identifying a 15-minute interval of ad libitum cannabis smoking initiated 30 minutes earlier. Post smoking blood Δ9-tetrahydrocannabinol (median = 5.6 µg/L in occasional users, 21.3 µg/L in daily users) was significantly correlated with post-smoking cannabigerol (P < 0.0001). CONCLUSION: Whole blood cannabigerol may have forensic utility as a highly specific albeit insensitive biomarker of recent cannabis smoking.

Comparison of Two-Bag Versus Three-Bag N-Acetylcysteine Regimens for Pediatric Acetaminophen Toxicity.

BACKGROUND: Acetaminophen overdose is a leading cause of liver failure, and a leading cause of pediatric poisoning requiring hospital admission. The antidote, N-acetylcysteine (NAC), is traditionally administered as a three-bag intravenous infusion. Despite its efficacy, NAC is associated with high incidence of nonallergic anaphylactoid reactions (NAARs). Adult evidence demonstrates that alternative dosing regimens decrease NAARs and medication errors (MEs). OBJECTIVES: To compare NAARs and MEs associated with two- versus three-bag NAC for acetaminophen overdose in a pediatric population. METHODS: This is a retrospective observational cohort study comparing pediatric patients who received three- versus two-bag NAC for acetaminophen toxicity. The primary outcome was incidence of NAARs. Secondary outcomes were rates of MEs and relevant hospital outcomes (length of stay [LOS], intensive care unit (ICU) admission, liver transplant, death). RESULTS: Two hundred forty-three patients met inclusion criteria (median age of 15 years): 150 (62%) three-bag NAC and 93 (38%) two-bag NAC. There was no difference in overall NAARs (p = 0.54). Fewer cutaneous NAARs were observed in the two-bag group, three-bag: 15 (10%), two-bag: 2 (2%), p = 0.02. MEs were significantly decreased with the two-bag regimen, three-bag: 59 (39%), two-bag: 21 (23%), p = 0.01. No statistical differences were observed in LOS, ICU admissions, transplant, or death. CONCLUSION AND RELEVANCE: A significant decrease in cutaneous NAARs and MEs was observed in pediatric patients by combining the first two bags of the traditional three-bag NAC regimen. In pediatric populations, a two-bag NAC regimen for acetaminophen overdose may improve medication tolerance and safety.

High-frequency electrical stimulation attenuates neuronal release of inflammatory mediators and ameliorates neuropathic pain.

BACKGROUND: Neuroinflammation is an important driver of acute and chronic pain states. Therefore, targeting molecular mediators of neuroinflammation may present an opportunity for developing novel pain therapies. In preclinical models of neuroinflammatory pain, calcitonin gene-related peptide (CGRP), substance P and high mobility group box 1 protein (HMGB1) are molecules synthesized and released by sensory neurons which activate inflammation and pain. High-frequency electrical nerve stimulation (HFES) has achieved clinical success as an analgesic modality, but the underlying mechanism is unknown. Here, we reasoned that HFES inhibits neuroinflammatory mediator release by sensory neurons to reduce pain. METHODS: Utilizing in vitro and in vivo assays, we assessed the modulating effects of HFES on neuroinflammatory mediator release by activated sensory neurons. Dorsal root ganglia (DRG) neurons harvested from wildtype or transgenic mice expressing channelrhodopsin-2 (ChR2) were cultured on micro-electrode arrays, and effect of HFES on optogenetic- or capsaicin-induced neuroinflammatory mediator release was determined. Additionally, the effects of HFES on local neuroinflammatory mediator release and hyperalgesia was assessed in vivo using optogenetic paw stimulation and the neuropathic pain model of chronic constriction injury (CCI) of the sciatic nerve. RESULTS: Light- or capsaicin-evoked neuroinflammatory mediator release from cultured transgenic DRG sensory neurons was significantly reduced by concurrent HFES (10 kHz). In agreement with these findings, elevated levels of neuroinflammatory mediators were detected in the affected paw following optogenetic stimulation or CCI and were significantly attenuated using HFES (20.6 kHz for 10 min) delivered once daily for 3 days. CONCLUSION: These studies reveal a previously unidentified mechanism for the pain-modulating effect of HFES in the setting of acute and chronic nerve injury. The results support the mechanistic insight that HFES may reset sensory neurons into a less pro-inflammatory state via inhibiting the release of neuroinflammatory mediators resulting in reduced inflammation and pain.