Role of potassium and calcium channels in sevoflurane-mediated vasodilation in the foeto-placental circulation

<p>Abstract</p> <p>Background</p> <p>Sevoflurane has been demonstrated to vasodilate the foeto-placental vasculature. We aimed to determine the contribution of modulation of potassium and calcium channel function to the vasodilatory effect of sevoflurane in isolated human chorionic plate arterial rings.</p> <p>Methods</p> <p>Quadruplicate <it>ex vivo </it>human chorionic plate arterial rings were used in all studies. <b><it>Series 1 and 2 </it></b>examined the role of the K⁺channel in sevoflurane-mediated vasodilation. Separate experiments examined whether tetraethylammonium, which blocks large conductance calcium activated K⁺(K_Ca++) channels (<b><it>Series 1A+B</it></b>) or glibenclamide, which blocks the ATP sensitive K⁺(K_ATP) channel (<b><it>Series 2</it></b>), modulated sevoflurane-mediated vasodilation. <b><it>Series 3 – 5 </it></b>examined the role of the Ca⁺⁺channel in sevoflurane induced vasodilation. Separate experiments examined whether verapamil, which blocks the sarcolemmal voltage-operated Ca⁺⁺channel (<b><it>Series 3</it></b>), SK&F 96365 an inhibitor of sarcolemmal voltage-independent Ca⁺⁺channels (<b><it>Series 4A+B</it></b>), or ryanodine an inhibitor of the sarcoplasmic reticulum Ca⁺⁺channel (<b><it>Series 5A+B</it></b>), modulated sevoflurane-mediated vasodilation.</p> <p>Results</p> <p>Sevoflurane produced dose dependent vasodilatation of chorionic plate arterial rings in all studies. Prior blockade of the K_Ca++and K_ATPchannels augmented the vasodilator effects of sevoflurane. Furthermore, exposure of rings to sevoflurane in advance of TEA occluded the effects of TEA. Taken together, these findings suggest that sevoflurane blocks K⁺channels. Blockade of the voltage-operated Ca⁺⁺channels inhibited the vasodilator effects of sevoflurane. In contrast, blockade of the voltage-independent and sarcoplasmic reticulum Ca⁺⁺channels did not alter sevoflurane vasodilation.</p> <p>Conclusion</p> <p>Sevoflurane appears to block chorionic arterial K_Ca++and K_ATPchannels. Sevoflurane also blocks voltage-operated calcium channels, and exerts a net vasodilatory effect in the <it>in vitro </it>foeto-placental circulation.</p

Maternal positions and mobility during first stage labour

Background: It is more common for women in both high- and low-income countries giving birth in health facilities, to labour in bed. There is no evidence that this is associated with any advantage for women or babies, although it may be more convenient for staff. Observational studies have suggested that if women lie on their backs during labour this may have adverse effects on uterine contractions and impede progress in labour, and in some women reduce placental blood flow. Objectives: To assess the effects of encouraging women to assume different upright positions (including walking, sitting, standing and kneeling) versus recumbent positions (supine, semi-recumbent and lateral) for women in the first stage of labour on duration of labour, type of birth and other important outcomes for mothers and babies. Search methods: We searched the Cochrane Pregnancy and Childbirth Group’s Trials Register (31 January 2013). Selection criteria Randomised and quasi-randomised trials comparing women randomised to upright versus recumbent positions in the first stage of labour. Data collection and analysis: We used methods described in the Cochrane Handbook for Systematic Reviews of Interventions for carrying out data collection, assessing study quality and analysing results. Two review authors independently evaluated methodological quality and extracted data for each study. We sought additional information from trial authors as required. We used random-effects analysis for comparisons in which high heterogeneity was present. We reported results using the average risk ratio (RR) for categorical data and mean difference (MD) for continuous data. Main results: Results should be interpreted with caution as the methodological quality of the 25 included trials (5218 women) was variable. For Comparison 1: Upright and recumbent positions versus recumbent positions and bed care, the first stage of labour was approximately one hour and 22 minutes shorter for women randomised to upright as opposed to recumbent positions (average MD -1.36, 95% confidence interval (CI) -2.22 to -0.51; 15 studies, 2503 women; random-effects, T2 = 2.39, Chi2 = 203.55, df = 14, (P < 0.00001), I2 = 93%). Women who were upright were also less likely to have caesarean section (RR 0.71, 95% CI 0.54 to 0.94; 14 studies, 2682 women) and less likely to have an epidural (RR 0.81, 95% CI 0.66 to 0.99, nine studies, 2107 women; random-effects, T2 = 0.02, I2 = 61%). Babies of mothers who were upright were less likely to be admitted to the neonatal intensive care unit, however this was based on one trial (RR 0.20, 95% CI 0.04 to 0.89, one study, 200 women). There were no significant differences between groups for other outcomes including duration of the second stage of labour, or other outcomes related to the well being of mothers and babies. For Comparison 2: Upright and recumbent positions versus recumbent positions and bed care (with epidural: all women), there were no significant differences between groups for outcomes including duration of the second stage of labour, or other outcomes related to the well being of mothers and babies. Authors' conclusions: There is clear and important evidence that walking and upright positions in the first stage of labour reduces the duration of labour, the risk of caesarean birth, the need for epidural, and does not seem to be associated with increased intervention or negative effects on mothers' and babies' well being. Given the great heterogeneity and high performance bias of study situations, better quality trials are still required to confirm with any confidence the true risks and benefits of upright and mobile positions compared with recumbent positions for all women. Based on the current findings, we recommend that women in low-risk labour should be informed of the benefits of upright positions, and encouraged and assisted to assume whatever positions they choose

Effect of early tranexamic acid administration on mortality, hysterectomy, and other morbidities in women with post-partum haemorrhage (WOMAN): an international, randomised, double-blind, placebo-controlled trial

Background Post-partum haemorrhage is the leading cause of maternal death worldwide. Early administration of tranexamic acid reduces deaths due to bleeding in trauma patients. We aimed to assess the effects of early administration of tranexamic acid on death, hysterectomy, and other relevant outcomes in women with post-partum haemorrhage. Methods In this randomised, double-blind, placebo-controlled trial, we recruited women aged 16 years and older with a clinical diagnosis of post-partum haemorrhage after a vaginal birth or caesarean section from 193 hospitals in 21 countries. We randomly assigned women to receive either 1 g intravenous tranexamic acid or matching placebo in addition to usual care. If bleeding continued after 30 min, or stopped and restarted within 24 h of the first dose, a second dose of 1 g of tranexamic acid or placebo could be given. Patients were assigned by selection of a numbered treatment pack from a box containing eight numbered packs that were identical apart from the pack number. Participants, care givers, and those assessing outcomes were masked to allocation. We originally planned to enrol 15 000 women with a composite primary endpoint of death from all-causes or hysterectomy within 42 days of giving birth. However, during the trial it became apparent that the decision to conduct a hysterectomy was often made at the same time as randomisation. Although tranexamic acid could influence the risk of death in these cases, it could not affect the risk of hysterectomy. We therefore increased the sample size from 15 000 to 20 000 women in order to estimate the effect of tranexamic acid on the risk of death from post-partum haemorrhage. All analyses were done on an intention-to-treat basis. This trial is registered with ISRCTN76912190 (Dec 8, 2008); ClinicalTrials.gov, number NCT00872469; and PACTR201007000192283. Findings Between March, 2010, and April, 2016, 20 060 women were enrolled and randomly assigned to receive tranexamic acid (n=10 051) or placebo (n=10 009), of whom 10 036 and 9985, respectively, were included in the analysis. Death due to bleeding was significantly reduced in women given tranexamic acid (155 [1·5%] of 10 036 patients vs 191 [1·9%] of 9985 in the placebo group, risk ratio [RR] 0·81, 95% CI 0·65–1·00; p=0·045), especially in women given treatment within 3 h of giving birth (89 [1·2%] in the tranexamic acid group vs 127 [1·7%] in the placebo group, RR 0·69, 95% CI 0·52–0·91; p=0·008). All other causes of death did not differ significantly by group. Hysterectomy was not reduced with tranexamic acid (358 [3·6%] patients in the tranexamic acid group vs 351 [3·5%] in the placebo group, RR 1·02, 95% CI 0·88–1·07; p=0·84). The composite primary endpoint of death from all causes or hysterectomy was not reduced with tranexamic acid (534 [5·3%] deaths or hysterectomies in the tranexamic acid group vs 546 [5·5%] in the placebo group, RR 0·97, 95% CI 0·87-1·09; p=0·65). Adverse events (including thromboembolic events) did not differ significantly in the tranexamic acid versus placebo group. Interpretation Tranexamic acid reduces death due to bleeding in women with post-partum haemorrhage with no adverse effects. When used as a treatment for postpartum haemorrhage, tranexamic acid should be given as soon as possible after bleeding onset. Funding London School of Hygiene & Tropical Medicine, Pfizer, UK Department of Health, Wellcome Trust, and Bill & Melinda Gates Foundation

Clinico biological data to create a pharmacokinetics/pharmacodynamic model of tranexamic acid during hemorrhagic cesarean section

Au cours de la césarienne hémorragique, les données cliniques et biologiques ont été recueillies par l’étude TRACES, multicentrique randomisée dose-effet double aveugle versus placebo. L’impact de deux doses (TA1: dose-standard 1g et TA½: dose-faible0,5g) d’acide tranéxamique (TA), un antifibrinolytique, a été mesuré et comparé au groupe placebo. L’étude pilote a permis, à partir de 9 patientes recevant TA 0,5, 1 ou2g et 57 points, d’établir une modèle préliminaire pharmacocinétique bicompartimentalà double élimination de premier ordre à partir du compartiment central. De ce résultat,on émet l’hypothèse que TA administré en début d’HPP pourrait être éliminé dans leflux hémorragique. Le modèle est amélioré par la covariable poids-idéal/dose. De cerésultat on émet l’hypothèse que la dose devrait être adaptée au poids.L’étude TRACES multicentrique menée de 2015 à 2019 dans 8 centres a inclus 175patientes présentant une HPP initiale de plus de 800mL. Il existe un effet-dose sur lesaignement additionnel significativement inférieur dans le groupe TA1 (n=57) comparéau groupe TA½ (n=58) (134mL [CI 95% 50 to 419] versus 300mL [CI 95% 68 to 630]respectivement (p=0.042)). Il n’est pas montré de différence significative entre chacun des groupes et le placebo (n=60) concernant le saignement total, l’anémie, le besoin transfusionnel ou les paramètres de bien-être maternel. La faible dose TA 0,5g apparait moins active qu’une dose standard de 1g pour inhiber l’hyperfibrinolyse marquée in vivo par l’élévation des D-dimères, des complexes plasmine-antiplasmine et ex-vivo par le potentiel de génération de plasmine (réduction du pic, raccourcissement du délai du pic et de l’intervalle entre les pics de plasmine et pic de thrombine). Ces résultats ouvrent la voie à la modélisation pharmacocinétique et pharmacodynamique de l’acide tranéxamique au cours de l’hémorragie du postpartum active.Postpartum Hemorrhage (PPH) is the leading cause of maternal mortality and morbidity worldwide. Tranexamic acid (TA), an antifibrinolytic drug, is a part of patient blood management in obstetrics. In a multicenter dose-ranging double blind placebo controlled trial TRACES, TA (TA1: dose-standard 1g et TA½: dose-faible 0,5g) impact on clinical and biological course was measured and compared to placebo.Out of the pilot stud, (9 patients and 57 points), a bicompartimental PK model with a double first elimination was created. This model is improved by the covaraible ideal weight/dose. Because of the difference with TA prophylactic use in non-hemorrhagic model, the hypothesis of a drug leakage in the hemorrhagic flow may be suggested.TRACES trial performed in 8 French centers from 2015 to 2019 included 175 patients experiencing a PPH > de 800mL. TA impact on additionnal blood loss reduction was greater in the TA1 group (n=57) compared to TA½ group (n=58) (134mL [CI 95% 50 to 419] versus 300mL [CI 95% 68 to 630] respectively (p=0.042)). TA did not reduce total blood loss nor anemia nor transfusion need nor invasive procedure rate nor maternal well-being compared to placebo (n=60). TA low-dose was less efficient than TA standard-dose to inhibit hyperfibrinolysis , marked in vivo by D-dimers and plasmin-antiplasmin complexes, and ex-vivo by the plasmin generation potential (peak, time to peak, inerval between the peaks). TA did not affect thrombin generation potential nor fibrinogen course.Pharmacokinetics and pharmacodynamic model are now waited to confirm these data and optimize the use of TA in PPH