Introduction: Copperhead snakes account for approximately half of treated snakebites in the US, and bites can result in significant swelling, bruising and pain. While other pit vipers, such as rattlesnakes, frequently cause coagulopathy demonstrated by standard coagulation tests including international normalized ratio (INR), partial thromboplastin time (PTT), platelet count, and fibrinogen, copperheads do not appear to do so. Functional coagulation tests, such as rotational thromboelastometry (ROTEM®) and thromboelastography (TEG®) illustrate the clotting process and may detect coagulation defects that were not evident on standard tests.Methods: We reviewed a series of patients presenting with copperhead envenomation and compared coagulation parameters between those receiving standard coagulation tests and those receiving standard tests and ROTEM or TEG.Results: Sixteen adults and children presented with copperhead snakebites, and four received ROTEM or TEG. None of the sixteen patients had abnormalities in PT, INR, PTT, platelets, or fibrinogen, and only one patient had an elevated D-dimer test. All four patients receiving ROTEM or TEG had normal values for ROTEM/TEG parameters and for standard coagulation tests.Conclusion: This corroborates previous research indicating that copperhead bites generally do not produce clinically significant coagulopathy. The role of thromboelastometry or thromboelastography in North American crotalid bites warrants further study.

BACKGROUND:Paracetamol (acetaminophen) remains a leading cause of poisoning in Europe, North America, and Australia. For over four decades, acetylcysteine has been the antidote of choice. However, despite the use of acetylcysteine, some patients who ingest very large doses of paracetamol or who reach hospital late in the course of their poisoning, develop acute liver failure. Some will develop metabolic acidosis indicating mitochondrial toxicity.OBJECTIVE:We review the experimental and clinical data reported with the use of cimetidine, fomepizole, and calmangafodipir in the treatment of paracetamol toxicity to determine if these treatments alone or in combination with acetylcysteine might be of benefit.METHODS:We searched Ovid Medline 1946-2020, Embase 1947-2020, Scopus 2004-2020, Cochrane Databases of Systematic Reviews (CDSR), Cochrane Central Register of Controlled Trials (CENTRAL), and clinicaltrials.gov 1997-2020 for records including the concepts of paracetamol poisoning and cimetidine, fomepizole, calmangafodipir, and acetylcysteine. We included basic science studies in animals and all available study types in humans. We reviewed the reference lists of included articles to search for references missed in the original search. We registered the protocol in PROSPERO.RESULTS:We completed all search strategies on 20 August 2019, 27 January 2020, and 15 June 2020. These produced 6,826 citations. We identified and deleted 2,843 duplicate resulting in a total of 3,856 unique citations. After applying inclusion and exclusion criteria, 89 studies remained. The largest numbers of studies described the past use of cimetidine, and the more recent use of fomepizole.Cimetidine: There is good animal evidence that cimetidine blocks CYP 2E1 with the potential to inhibit the toxic metabolism of paracetamol. Early case reports were inconclusive regarding the benefit to humans in paracetamol poisoning. Two comparative trials found no benefit of cimetidine in paracetamol poisoning, but few patients had severe poisoning.Fomepizole: There is good animal evidence that fomepizole blocks CYP 2E1 with the potential to inhibit the toxic metabolism of paracetamol. There are no comparative trials of fomepizole for acute paracetamol poisoning. Case reports are inconclusive due to multiple other interventions including the use of acetylcysteine in all cases. The benefit of fomepizole as adjunct treatment has not been demonstrated.Calmangafodipir: Calmangafodipir, a drug mimicking superoxide dismutase, has emerged as a potential treatment for severe paracetamol toxicity because the formation of superoxide free radicals appears to explain part of the mitochondrial toxicity of extremely large paracetamol overdoses. Calmangafodipir has reached Phase I/II trial of safety in humans with acute paracetamol overdose. Planning for a Phase III study of efficacy is currently underway.CONCLUSIONS:The vast majority of patients with acute paracetamol overdose enjoy excellent outcomes with acetylcysteine alone. Although cimetidine and fomepizole inhibit CYP 2E1 in animals, there is insufficient evidence to recommend their use either as a primary treatment or adjunct therapy in paracetamol poisoning. Calmangafodipir remains investigational.

Key points The uterine artery (UA) markedly vasodilates during pregnancy to direct blood flow to the developing fetus. Inadequate UA vasodilatation leads to intrauterine growth restriction and fetal death. The large‐conductance voltage‐ and Ca2+‐activated K+ (BKCa) channel promotes UA vasodilatation during pregnancy. We report that BKCa channel activation increases the UA diameter at late pregnancy stages in mice. Additionally, a BKCa channel auxiliary subunit, γ1, participates in this process by increasing channel activation and inducing UA vasodilatation at late pregnancy stages. Our results highlight the importance of the BKCa channel and its γ1‐subunit for UA functional changes during pregnancy. AbstractInsufficient vasodilatation of the uterine artery (UA) during pregnancy leads to poor utero‐placental perfusion, contributing to intrauterine growth restriction and fetal loss. Activity of the large‐conductance Ca2+‐activated K+ (BKCa) channel increases in the UA during pregnancy, and its inhibition reduces uterine blood flow, highlighting a role of this channel in UA adaptation to pregnancy. The auxiliary γ1‐subunit increases BKCa activation in vascular smooth muscle, but its role in pregnancy‐associated UA remodelling is unknown. We explored whether the BKCa and its γ1‐subunit contribute to UA remodelling during pregnancy. Doppler imaging revealed that, compared to UAs from wild‐type (WT) mice, UAs from BKCa knockout (BKCa−/−) mice had lower resistance at pregnancy day 14 (P14) but not at P18. Lumen diameters were twofold larger in pressurized UAs from P18 WT mice than in those from non‐pregnant mice, but this difference was not seen in UAs from BKCa−/− mice. UAs from pregnant WT mice constricted 20–50% in response to the BKCa blocker iberiotoxin (IbTX), whereas UAs from non‐pregnant WT mice only constricted 15%. Patch‐clamp analysis of WT UA smooth muscle cells confirmed that BKCa activity increased over pregnancy, showing three distinct voltage sensitivities. The γ1‐subunit transcript increased 7‐ to 10‐fold during pregnancy. Furthermore, γ1‐subunit knockdown reduced IbTX sensitivity in UAs from pregnant mice, whereas γ1‐subunit overexpression increased IbTX sensitivity in UAs from non‐pregnant mice. Finally, at P18, γ1‐knockout (γ1−/−) mice had smaller UA diameters than WT mice, and IbTX‐mediated vasoconstriction was prevented in UAs from γ1−/− mice. Our results suggest that the γ1‐subunit increases BKCa activation in UAs during pregnancy.