Management of acetaminophen poisoning in the US and Canada: A consensus statement

IMPORTANCE: The US and Canada currently have no formal published nationwide guidelines for specialists in poison information or emergency departments for the management of acetaminophen poisoning, resulting in significant variability in management. OBJECTIVE: To develop consensus guidelines for the management of acetaminophen poisoning in the US and Canada. EVIDENCE REVIEW: Four clinical toxicology societies (America\u27s Poison Centers, American Academy of Clinical Toxicology, American College of Medical Toxicology, and Canadian Association of Poison Control Centers) selected participants (n = 21). Led by a nonvoting chairperson using a modified Delphi method, the panel created a decision framework and determined the appropriate clinical management of a patient with acetaminophen poisoning. Unique to this effort was the collection of guidelines from most poison centers in addition to systematic collection and review of the medical literature. Comments from review by external organizations were incorporated before the guideline was finalized. The project began in March 2021 and ended in March 2023. FINDINGS: The search retrieved 84 guidelines and 278 publications. The panel developed guidelines for emergency department management of single or repeated ingestion of acetaminophen. In addition, the panel addressed extended-release formulation, high-risk ingestion, coingestion of anticholinergics or opioids, age younger than 6 years, pregnancy, weight greater than 100 kg, and intravenous acetaminophen use. Differences from current US practice include defining acute ingestion as an ingestion presentation from 4 to 24 hours after overdose was initiated. A revised form of the Rumack-Matthew nomogram was developed. The term massive ingestion was replaced with the term high-risk ingestion and denoted by a specific nomogram line. Other recommendations include specific criteria for emergency department triage, laboratory evaluation and monitoring parameters, defining the role of gastrointestinal decontamination, detailed management of acetylcysteine treatment, associated adverse effects, and stopping criteria for acetylcysteine treatment, as well as criteria for consultation with a clinical toxicologist. Finally, specific treatment considerations, including acetylcysteine dosing, fomepizole administration, and considerations for extracorporeal elimination and transplant evaluation, were addressed. CONCLUSIONS AND RELEVANCE: This qualitative study provides a consensus statement on consistent evidence-based recommendations for medical, pharmacy, and nursing education and practice to optimize care of patients with acetaminophen poisoning

TRPV4 and KCa functionally couple as osmosensors in the PVN

BACKGROUND AND PURPOSE: Transient receptor potential vanilloid type 4 (TRPV4) and calcium-activated potassium channels (KCa ) mediate osmosensing in many tissues. Both TRPV4 and KCa channels are found in the paraventricular nucleus (PVN) of the hypothalamus, an area critical for sympathetic control of cardiovascular and renal function. Here, we have investigated whether TRPV4 channels functionally couple to KCa channels to mediate osmosensing in PVN parvocellular neurones and have characterized, pharmacologically, the subtype of KCa channel involved. EXPERIMENTAL APPROACH: We investigated osmosensing roles for TRPV4 and KCa channels in parvocellular PVN neurones using cell-attached and whole-cell electrophysiology in mouse brain slices and rat isolated PVN neurons. Intracellular Ca(2+) was recorded using Fura-2AM. The system was modelled in the NEURON simulation environment. KEY RESULTS: Hypotonic saline reduced action current frequency in hypothalamic slices; a response mimicked by TRPV4 channel agonists 4αPDD (1 μM) and GSK1016790A (100 nM), and blocked by inhibitors of either TRPV4 channels (RN1734 (5 μM) and HC067047 (300 nM) or the low-conductance calcium-activated potassium (SK) channel (UCL-1684 30 nM); iberiotoxin and TRAM-34 had no effect. Our model was compatible with coupling between TRPV4 and KCa channels, predicting the presence of positive and negative feedback loops. These predictions were verified using isolated PVN neurons. Both hypotonic challenge and 4αPDD increased intracellular Ca(2+) and UCL-1684 reduced the action of hypotonic challenge. CONCLUSIONS AND IMPLICATIONS: There was functional coupling between TRPV4 and SK channels in parvocellular neurones. This mechanism contributes to osmosensing in the PVN and may provide a novel pharmacological target for the cardiovascular or renal systems

A cross-sectional study of tampering in Xtampza ER, an abuse-deterrent formulation of an extended-release opioid, in a treatment center population

BACKGROUND AND OBJECTIVE: While the current landscape of opioid use disorder (OUD) is complicated by the increase in use of non-prescription opioids, prescription opioids continue to be frequently used in non-medical ways. In response to this abuse, pharmaceutical companies have developed abuse deterrent formulations (ADFs) for extended-release (ER) opioids. To test the effectiveness of Xtampza ER ADF (oxycodone myristate) at reducing tampering, its rate of tampering in a treatment-center population was compared to immediate release (IR) single entity (SE) oxycodone, other ER oxycodone opioids, and ER oxymorphone. METHODS: Data were collected between the third quarter of 2018 and the third quarter of 2021 from individuals entering nationally distributed opioid treatment programs. To determine odds of tampering with Xtampza ER compared to each comparator, a logistic model was fit with a random intercept allowing for multiple drugs in each subject. Within-subject correlation was assumed to have a compound symmetric relationship. RESULTS: Overlap among the categories of drug tampering was high. Logistic regression analyses found that oxycodone myristate had lower odds of tampering when compared to both IR SE oxycodone (OR = 0.23 [95% CI 0.11, 0.50], p = 0.0002) and ER oxymorphone (OR = 0.30 [95% CI 0.14, 0.67], p = 0.0038). Oxycodone myristate was not significantly different from other ER oxycodone opioids (OR = 0.5 [95% CI 0.24, 1.03], p = 0.0612). These findings did not change when the estimates were adjusted for age and sex. CONCLUSIONS: Drugs employing ADF technology may reduce the likelihood of tampering when compared to non-ADF formulations in a treatment-center population, which represents an opportunity for intervention in OUD among those still requiring pain management

Overuse of non-prescription analgesics by dental clinic patients

<p>Abstract</p> <p>Background</p> <p>Many patients present to dental clinics for treatment of painful conditions. Prior to seeking treatment, many of these patients will self-medicate with non-prescription analgesics (NPA), and some will unintentionally overdose on these products. The objective of this study is to describe the use of NPA among dental patients.</p> <p>Methods</p> <p>All adult patients presenting to an urban dental clinic during a two-week period in January and February of 2001 were approached to participate in this research project. Trained research assistants using a standardized questionnaire interviewed patients. Patient demographics and the NPA usage over the 3 days preceding the office visit were recorded. We defined a supra-therapeutic dose as any dose greater than the total recommended daily dose stated on package labeling.</p> <p>Results</p> <p>We approached 194 patients and 127 participated. The mean age of participants was 35.5 years, 52% were male. Analgesic use preceding the visit was reported by 99 of 127 patients, and most (81/99) used a NPA exclusively. Fifty-four percent of NPA users were taking more than one NPA. NPA users reported using ibuprofen (37%), acetaminophen (27%), acetaminophen/aspirin combination product (8%), naproxen (8%), and aspirin (4%). Sixteen patients reported supra-therapeutic use of one or more NPA (some ingested multiple products): ibuprofen (14), acetaminophen (3), and naproxen (5).</p> <p>Conclusion</p> <p>NPA use was common in patients presenting to a dental clinic. A significant minority of patients reported excessive dosing of NPA. Ibuprofen was the most frequently misused product, followed by naproxen and acetaminophen. Though mostly aware of the potential toxicity of NPA, many patients used supra-therapeutic dosages.</p

Deep-Channel uses deep neural networks to detect single-molecule events from patch-clamp data

Single-molecule research techniques such as patch-clamp electrophysiology deliver unique biological insight by capturing the movement of individual proteins in real time, unobscured by whole-cell ensemble averaging. The critical first step in analysis is event detection, so called “idealisation”, where noisy raw data are turned into discrete records of protein movement. To date there have been practical limitations in patch-clamp data idealisation; high quality idealisation is typically laborious and becomes infeasible and subjective with complex biological data containing many distinct native single-ion channel proteins gating simultaneously. Here, we show a deep learning model based on convolutional neural networks and long short-term memory architecture can automatically idealise complex single molecule activity more accurately and faster than traditional methods. There are no parameters to set; baseline, channel amplitude or numbers of channels for example. We believe this approach could revolutionise the unsupervised automatic detection of single-molecule transition events in the future

The Role of the Membrane Potential in Chondrocyte Volume Regulation

Many cell types have significant negative resting membrane potentials (RMPs) resulting from the activity of potassium-selective and chloride-selective ion channels. In excitable cells, such as neurones, rapid changes in membrane permeability underlie the generation of action potentials. Chondrocytes have less negative RMPs and the role of the RMP is not clear. Here we examine the basis of the chondrocyte RMP and possible physiological benefits. We demonstrate that maintenance of the chondrocyte RMP involves gadolinium-sensitive cation channels. Pharmacological inhibition of these channels causes the RMP to become more negative (100 µM gadolinium: ΔVm = −30 ± 4 mV). Analysis of the gadolinium-sensitive conductance reveals a high permeability to calcium ions (PCa/PNa ≈80) with little selectivity between monovalent ions; similar to that reported elsewhere for TRPV5. Detection of TRPV5 by PCR and immunohistochemistry and the sensitivity of the RMP to the TRPV5 inhibitor econazole (ΔVm = −18 ± 3 mV) suggests that the RMP may be, in part, controlled by TRPV5. We investigated the physiological advantage of the relatively positive RMP using a mathematical model in which membrane stretch activates potassium channels allowing potassium efflux to oppose osmotic water uptake. At very negative RMP potassium efflux is negligible, but at more positive RMP it is sufficient to limit volume increase. In support of our model, cells clamped at −80 mV and challenged with a reduced osmotic potential swelled approximately twice as much as cells at +10 mV. The positive RMP may be a protective adaptation that allows chondrocytes to respond to the dramatic osmotic changes, with minimal changes in cell volume. J. Cell. Physiol. 226: 2979–2986, 2011. © 2011 Wiley-Liss, Inc

Managing for change: October 11, 1989

Bi-weekly newsletter of University Hospital's Change Project, provided to managers at the hospital

Using Poison Center Exposure Calls to Predict Methadone Poisoning Deaths

PurposeThere are more drug overdose deaths in the Untied States than motor vehicle fatalities. Yet the US vital statistics reporting system is of limited value because the data are delayed by four years. Poison centers report data within an hour of the event, but previous studies suggested a small proportion of poisoning deaths are reported to poison centers (PC). In an era of improved electronic surveillance capabilities, exposure calls to PCs may be an alternate indicator of trends in overdose mortality.MethodsWe used PC call counts for methadone that were reported to the Researched Abuse, Diversion and Addiction-Related Surveillance (RADARS®) System in 2006 and 2007. US death certificate data were used to identify deaths due to methadone. Linear regression was used to quantify the relationship of deaths and poison center calls.ResultsCompared to decedents, poison center callers tended to be younger, more often female, at home and less likely to require medical attention. A strong association was found with PC calls and methadone mortality (b = 0.88, se = 0.42, t = 9.5, df = 1, p<0.0001, R2 = 0.77). These findings were robust to large changes in a sensitivity analysis assessing the impact of underreporting of methadone overdose deaths.ConclusionsOur results suggest that calls to poison centers for methadone are correlated with poisoning mortality as identified on death certificates. Calls received by poison centers may be used for timely surveillance of mortality due to methadone. In the midst of the prescription opioid overdose epidemic, electronic surveillance tools that report in real-time are powerful public health tools

“True fan = watch match”? In Search of the ‘Authentic’ Soccer Fan.

Academics have created typologies to divide association football (soccer) fans into categories based upon the assumed ‘authenticity’ of their fandom practices. One of the main requirements of ‘authentic’ fandom has been assumed to be match attendance. The goal of this paper was to critically assess this assumption through considering how fans themselves talk about the significance of match attendance as evidence of ‘authentic’ fandom. In light of the fact that the voices of English non-league fans on the ‘authenticity’ debate have so far been overshadowed by the overbearing focus of much previous research on the upper echelons of English soccer, an e-survey was conducted with 151 members of an online community of fans of English Northern League (NL) clubs (a semi-professional / amateur league based in North East England). Findings revealed that opinion was divided on the constituents of ‘authentic’ fandom and match attendance was not deemed to be the core evidence of support for a club by 42% of the sample. Elias (1978) suggested that dichotomous thinking hinders sociological understanding and it is concluded that fan typologies are not sufficient for assessing the ‘authenticity’ of fan activities