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

Hyperoxemia and excess oxygen use in early acute respiratory distress syndrome: insights from the LUNG SAFE study

Contains fulltext : 218568.pdf (publisher's version ) (Open Access)BACKGROUND: Concerns exist regarding the prevalence and impact of unnecessary oxygen use in patients with acute respiratory distress syndrome (ARDS). We examined this issue in patients with ARDS enrolled in the Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE (LUNG SAFE) study. METHODS: In this secondary analysis of the LUNG SAFE study, we wished to determine the prevalence and the outcomes associated with hyperoxemia on day 1, sustained hyperoxemia, and excessive oxygen use in patients with early ARDS. Patients who fulfilled criteria of ARDS on day 1 and day 2 of acute hypoxemic respiratory failure were categorized based on the presence of hyperoxemia (PaO2 > 100 mmHg) on day 1, sustained (i.e., present on day 1 and day 2) hyperoxemia, or excessive oxygen use (FIO2 >/= 0.60 during hyperoxemia). RESULTS: Of 2005 patients that met the inclusion criteria, 131 (6.5%) were hypoxemic (PaO2 < 55 mmHg), 607 (30%) had hyperoxemia on day 1, and 250 (12%) had sustained hyperoxemia. Excess FIO2 use occurred in 400 (66%) out of 607 patients with hyperoxemia. Excess FIO2 use decreased from day 1 to day 2 of ARDS, with most hyperoxemic patients on day 2 receiving relatively low FIO2. Multivariate analyses found no independent relationship between day 1 hyperoxemia, sustained hyperoxemia, or excess FIO2 use and adverse clinical outcomes. Mortality was 42% in patients with excess FIO2 use, compared to 39% in a propensity-matched sample of normoxemic (PaO2 55-100 mmHg) patients (P = 0.47). CONCLUSIONS: Hyperoxemia and excess oxygen use are both prevalent in early ARDS but are most often non-sustained. No relationship was found between hyperoxemia or excessive oxygen use and patient outcome in this cohort. TRIAL REGISTRATION: LUNG-SAFE is registered with ClinicalTrials.gov, NCT02010073

Individual and combined effects of chemical and mechanical power on postoperative pulmonary complications: a secondary analysis of the REPEAT study

Introduction: Intra-operative supplemental oxygen and mechanical ventilation expose the lungs to potentially injurious energy. This can be quantified as 'chemical power' and 'mechanical power', respectively. In this study, we sought to determine if intra-operative chemical and mechanical power, individually and/or in combination, are associated with postoperative pulmonary complications. Methods: Using an individual patient data analysis of three randomised clinical trials of intra-operative ventilation, we summarised intra-operative chemical and mechanical power using time-weighted averages. We evaluated the association between intra-operative chemical and mechanical power and a collapsed composite of postoperative pulmonary complications using multivariable logistic regression to estimate the odds ratios related to the effect of 1 J.min-1 increase in chemical or mechanical power with adjustment for demographic and intra-operative characteristics. We also included an interaction term to assess for potential synergistic effects of chemical and mechanical power on postoperative pulmonary complications. Results: Of 3837 patients recruited to three individual trials, 2492 with full datasets were included in the analysis. Intra-operative time-weighted average (SD) chemical power was 10.2 (3.9) J.min-1 and mechanical power was 10.5 (4.4) J.min-1. An increase of 1 J.min-1 in chemical power was associated with 8% higher odds of postoperative pulmonary complications (OR 1.08, 95%CI 1.05-1.10, p &lt; 0.001), while the same increase in mechanical power raised odds by 5% (OR 1.05, 95%CI 1.02-1.08, p = 0.003). We did not find evidence of a significant interaction between chemical and mechanical power (p = 0.40), suggestive of an additive rather than synergistic effect on postoperative pulmonary complications. Discussion: Both chemical and mechanical power are independently associated with postoperative pulmonary complications. Further work is required to determine causality

Nurses' perceptions of aids and obstacles to the provision of optimal end of life care in ICU

Contains fulltext : 172380.pdf (publisher's version ) (Open Access

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Neurological manifestations of COVID-19 in adults and children

Different neurological manifestations of coronavirus disease 2019 (COVID-19) in adults and children and their impact have not been well characterized. We aimed to determine the prevalence of neurological manifestations and in-hospital complications among hospitalized COVID-19 patients and ascertain differences between adults and children. We conducted a prospective multicentre observational study using the International Severe Acute Respiratory and emerging Infection Consortium (ISARIC) cohort across 1507 sites worldwide from 30 January 2020 to 25 May 2021. Analyses of neurological manifestations and neurological complications considered unadjusted prevalence estimates for predefined patient subgroups, and adjusted estimates as a function of patient age and time of hospitalization using generalized linear models. Overall, 161 239 patients (158 267 adults; 2972 children) hospitalized with COVID-19 and assessed for neurological manifestations and complications were included. In adults and children, the most frequent neurological manifestations at admission were fatigue (adults: 37.4%; children: 20.4%), altered consciousness (20.9%; 6.8%), myalgia (16.9%; 7.6%), dysgeusia (7.4%; 1.9%), anosmia (6.0%; 2.2%) and seizure (1.1%; 5.2%). In adults, the most frequent in-hospital neurological complications were stroke (1.5%), seizure (1%) and CNS infection (0.2%). Each occurred more frequently in intensive care unit (ICU) than in non-ICU patients. In children, seizure was the only neurological complication to occur more frequently in ICU versus non-ICU (7.1% versus 2.3%, P &lt; 0.001). Stroke prevalence increased with increasing age, while CNS infection and seizure steadily decreased with age. There was a dramatic decrease in stroke over time during the pandemic. Hypertension, chronic neurological disease and the use of extracorporeal membrane oxygenation were associated with increased risk of stroke. Altered consciousness was associated with CNS infection, seizure and stroke. All in-hospital neurological complications were associated with increased odds of death. The likelihood of death rose with increasing age, especially after 25 years of age. In conclusion, adults and children have different neurological manifestations and in-hospital complications associated with COVID-19. Stroke risk increased with increasing age, while CNS infection and seizure risk decreased with age