The purpose of this study was to investigate the effect of preexisting atrial fibrillation on early and midterm clinical outcome in patients undergoing coronary surgery.
All elective patients ...undergoing coronary artery bypass grafting surgery between April 1996 and September 2002 were investigated. Patients were grouped according to their preoperative cardiac rhythm: sinus rhythm (SR) or preexisting atrial fibrillation (AF). In-hospital clinical outcomes and 5-year patient survival and cardiac-related event-free survival were compared using regression methods to adjust for differences between the groups. In all, 5,092 patients were identified, 175 (3.4%) with a history of preexisting AF. These patients were older (median, 64 versus 68 years) and had higher Parsonnet scores (median, 4 versus 8) than the SR group. Previous myocardial infarction, cerebrovascular accident, hypertension, diabetes mellitus, renal impairment, peripheral vascular disease, ejection fraction less than 50%, previous surgery, congestive heart failure, and use of angiotensin-converting enzyme inhibitors were also more common in the AF group.
There were 60 in-hospital deaths (1.2%), with no difference between the two groups (odds ratio 1.02, 95% CI: 0.35 to 2.94). Atrial fibrillation patients were more likely to need intraoperative inotropes (p = 0.044), postoperative intra-aortic balloon pump (p = 0.038), and were less likely to be discharged within 6 days (p = 0.017). The risk of death in the 5 years after surgery was higher in the AF group (relative risk 1.49, 95% CI: 1.06 to 2.08, p = 0.020). In the AF group, 109 (62.2%) patients were cardioverted spontaneously by surgery, but only 69 (39.4%) remained in SR until discharge. Longer-term rhythm follow-up data were available for 48 of these 69 patients, and only 36 remained in SR at a median follow-up of 1,483 days (interquartile range, 1,120 to 2,209). Spontaneous conversion to SR after surgery did not confer a midterm survival benefit (p = 0.91).
Preexisting AF in patients undergoing coronary artery bypass graft surgery is not associated with increased in-hospital mortality and major morbidity; however, it is a risk factor for reduced 5-year survival. Spontaneous cardioversion to SR during surgery is transient in the majority of patients and is not associated with midterm survival benefit.
In chronic central serous chorioretinopathy (CSCR), fluid accumulates in the subretinal space. CSCR is a common visually disabling condition that develops in individuals up to 60 years of age, and ...there is no definitive treatment. Previous research suggests the mineralocorticoid receptor antagonist, eplerenone, is effective for treating CSCR; however, this drug is not licensed for the treatment of patients with CSCR. We aimed to evaluate whether eplerenone was superior to placebo in terms of improving visual acuity in patients with chronic CSCR.
This randomised, double-blind, parallel-group, multicentre placebo-controlled trial was done at 22 hospitals in the UK. Participants were eligible if they were aged 18–60 years and had had treatment-naive CSCR for 4 months or more. Patients were randomly assigned (1:1) to either the eplerenone or the placebo group by a trial statistician through a password-protected system online. Allocation was stratified by best-corrected visual acuity (BCVA) and hospital. Patients were given either oral eplerenone (25 mg/day for 1 week, increasing to 50 mg/day for up to 12 months) plus usual care or placebo plus usual care for up to 12 months. All participants, care teams, outcome assessors, pharmacists, and members of the trial management group were masked to the treatment allocation. The primary outcome was BCVA, measured as letters read, at 12 months. All outcomes apart from safety were analysed on a modified intention-to-treat basis (participants who withdrew consent without contributing a post-randomisation BCVA measurement were excluded from the primary analysis population and from most secondary analysis populations). The trial is registered with ISRCTN, ISRCTN92746680, and is completed.
Between Jan 11, 2017, and Feb 22, 2018, we enrolled and randomly assigned 114 patients to receive either eplerenone (n=57) or placebo (n=57). Three participants in the placebo group withdrew consent without contributing a post-randomisation BCVA measurement and were excluded from the primary outcome analysis population. All patients from the eplerenone group and 54 patients from the placebo group were included in the primary outcome. Modelled mean BCVA at 12 months was 79·5 letters (SD 4·5) in the placebo group and 80·4 letters (4·6) in the eplerenone group, with an adjusted estimated mean difference of 1·73 letters (95% CI −1·12 to 4·57; p=0·24) at 12 months. Hyperkalaemia occurred in eight (14%) patients in each group. No serious adverse events were reported in the eplerenone group and three unrelated serious adverse events were reported in the placebo group (myocardial infarction anticipated, diverticulitis unanticipated, and metabolic surgery unanticipated).
Eplerenone was not superior to placebo for improving BCVA in people with chronic CSCR after 12 months of treatment. Ophthalmologists who currently prescribe eplerenone for CSCR should discontinue this practice.
Efficacy and Mechanism Evaluation Programme, and National Institute for Health Research and Social Care.
Traumatic brain injury is a leading cause of death and disability worldwide. Interventions that mitigate secondary brain injury have the potential to improve outcomes for patients and reduce the ...impact on communities and society. Increased circulating catecholamines are associated with worse outcomes and there are supportive animal data and indications in human studies of benefit from beta-blockade after severe traumatic brain injury. Here, we present the protocol for a dose-finding study using esmolol in adults commenced within 24 h of severe traumatic brain injury. Esmolol has practical advantages and theoretical benefits as a neuroprotective agent in this setting, but these must be balanced against the known risk of secondary injury from hypotension. The aim of this study is to determine a dose schedule for esmolol, using the continual reassessment method, that combines a clinically significant reduction in heart rate as a surrogate for catecholamine drive with maintenance of cerebral perfusion pressure. The maximum tolerated dosing schedule for esmolol can then be tested for patient benefit in subsequent randomized controlled trials.
Trial registration
ISRCTN, ISRCTN11038397, registered retrospectively 07/01/2021
https://www.isrctn.com/ISRCTN11038397
Abstract Background Targeted beta-blockade after severe traumatic brain injury may reduce secondary brain injury by attenuating the sympathoadrenal response. The potential role and optimal dosage for ...esmolol, a selective, short-acting, titratable beta-1 beta-blocker, as a safe, putative early therapy after major traumatic brain injury has not been assessed. Methods We conducted a single-center, open-label dose-finding study using an adaptive model-based design. Adults (18 years or older) with severe traumatic brain injury and intracranial pressure monitoring received esmolol within 24 h of injury to reduce their heart rate by 15% from baseline of the preceding 4 h while ensuring cerebral perfusion pressure was maintained above 60 mm Hg. In cohorts of three, the starting dosage and dosage increments were escalated according to a prespecified plan in the absence of dose-limiting toxicity. Dose-limiting toxicity was defined as failure to maintain cerebral perfusion pressure, triggering cessation of esmolol infusion. The primary outcome was the maximum tolerated dosage schedule of esmolol, defined as that associated with less than 10% probability of dose-limiting toxicity. Secondary outcomes include 6-month mortality and 6-month extended Glasgow Outcome Scale score. Results Sixteen patients (6 37.5% female patients; mean age 36 years standard deviation 13 years) with a median Glasgow Coma Scale score of 6.5 (interquartile range 5–7) received esmolol. The optimal starting dosage of esmolol was 10 μg/kg/min, with increments every 30 min of 5 μg/kg/min, as it was the highest dosage with less than 10% estimated probability of dose-limiting toxicity (7%). All-cause mortality was 12.5% at 6 months (corresponding to a standardized mortality ratio of 0.63). One dose-limiting toxicity event and no serious adverse hemodynamic effects were seen. Conclusions Esmolol administration, titrated to a heart rate reduction of 15%, is feasible within 24 h of severe traumatic brain injury. The probability of dose-limiting toxicity requiring withdrawal of esmolol when using the optimized schedule is low. Trial registrationI SRCTN, ISRCTN11038397, registered retrospectively January 7, 2021 ( https://www.isrctn.com/ISRCTN11038397 ).
The ComFluCOV trial randomized 679 participants to receive an age-appropriate influenza vaccine, or placebo, alongside their second COVID-19 vaccine. Concomitant administration was shown to be safe, ...and to preserve systemic immune responses to both vaccines. Here we report on a secondary outcome of the trial investigating SARS-CoV-2-specific mucosal antibody responses. Anti-spike IgG and IgA levels in saliva were measured with in-house ELISAs. Concomitant administration of an influenza vaccine did not affect salivary anti-spike IgG positivity rates to Pfizer/BioNTech BNT162b2 (99.1 cf. 95.6%), or AstraZeneca ChAdOx1 (67.8% cf. 64.9%), at 3-weeks post-vaccination relative to placebo. Furthermore, saliva IgG positively correlated with serum titres highlighting the potential utility of saliva for assessing differences in immunogenicity in future vaccine studies. Mucosal IgA was not detected in response to either COVID-19 vaccine, reinforcing the need for novel vaccines capable of inducing sterilising immunity or otherwise reducing transmission. The trial is registered as ISRCTN 14391248.
To compare normothermic (35°C-36°C) versus hypothermic (28°C) cardiopulmonary bypass (CPB) in paediatric patients undergoing open heart surgery to test the hypothesis that normothermic CPB perfusion ...maintains the functional integrity of major organ systems leading to faster recovery.
Two single-centre, randomised controlled trials (known as
and
, respectively) were carried out to compare the effectiveness and acceptability of normothermic versus hypothermic CPB in children with congenital heart disease undergoing open heart surgery. In both studies, the co-primary clinical outcomes were duration of inotropic support, intubation time and postoperative hospital stay.
In total, 200 participants were recruited; 59 to the
study and 141 to the
study. 98 patients received normothermic CPB and 102 patients received hypothermic CPB. There were no significant differences between the treatment groups for any of the co-primary outcomes: inotrope duration HR=1.01, 95% CI (0.72 to 1.41); intubation time HR=1.14, 95% CI (0.86 to 1.51); postoperative hospital stay HR=1.06, 95% CI (0.80 to 1.40). Differences favouring normothermia were found in urea nitrogen at 2 days geometric mean ratio (GMR)=0.86 95% CI (0.77 to 0.97); serum creatinine at 3 days GMR=0.89, 95% CI (0.81 to 0.98); urinary albumin at 48 hours GMR=0.32, 95% CI (0.14 to 0.74) and neutrophil gelatinase-associated lipocalin at 4 hours GMR=0.47, 95% CI (0.22 to 1.02), but not at other postoperative time points.
Normothermic CPB is as safe and effective as hypothermic CPB and can be routinely adopted as a perfusion strategy in low-risk infants and children undergoing open heart surgery.
ISRCTN93129502.
Pleural biopsy is the gold standard for diagnosis of pleural malignancy but a significant proportion will have an inconclusive biopsy despite ongoing clinical suspicion of malignancy. We investigated ...whether positron emission tomography-computed tomography (PET-CT) targeted pleural biopsy is superior to standard CT-guided pleural biopsy following an initial non-diagnostic biopsy.
The TARGET trial was a multicentre, parallel group randomised trial. Patients with a previous inconclusive pleural biopsy but an ongoing suspicion of pleural malignancy were randomised (1:1) to receive either CT-guided biopsy (standard care) or PET-CT followed by a targeted CT biopsy (intervention). The primary outcome was pleural malignancy correctly identified from the trial biopsy.
Between September 2015 and September 2018, 59 participants were randomised from eight UK hospital sites: 29 to CT-only followed by targeted biopsy and 30 to PET-CT followed by targeted biopsy. The proportion of pleural malignancy correctly identified was similar between the groups (risk ratio 1.03 (95% CI 0.83-1.29); p=0.77). The sensitivity of the trial biopsy to identify pleural malignancy was 79% (95% CI 54-94%) in the CT-only group
81% (95% CI 54-96%) in the PET-CT group.
The results do not support the practice of PET-CT to guide pleural biopsies in patients with a previous non-diagnostic biopsy. The diagnostic sensitivity in the CT-only group was higher than anticipated and supports the practice of repeating a CT-guided biopsy following an inconclusive result if clinical suspicion of malignancy persists.
Inhibition of SK channel function is being pursued in animal models as a possible therapeutic approach to treat atrial fibrillation (AF). However, the pharmacology of SK channels in human atria is ...unclear. SK channel function is inhibited by both apamin and UCL1684, with the former discriminating between SK channel subtypes. In this proof-of-principle study, the effects of apamin and UCL1684 on right atrial myocytes freshly isolated from patients in sinus rhythm undergoing elective cardiac surgery were investigated. Outward current evoked from voltage clamped human atrial myocytes was reduced by these two inhibitors of SK channel function. In contrast, membrane current underlying the atrial action potential was affected significantly only by UCL1684 and not by apamin. This pharmacology mirrors that observed in mouse atria, suggesting that mammalian atria possess two populations of SK channels, with only one population contributing to the action potential waveform. Immuno-visualization of the subcellular localization of SK2 and SK3 subunits showed a high degree of colocalization, consistent with the formation of heteromeric SK2/SK3 channels. These data reveal that human atrial myocytes express two SK channel subtypes, one exhibiting an unusual pharmacology. These channels contribute to the atrial action potential waveform and might be a target for novel therapeutic approaches to treat supraventricular arrhythmic conditions such as atrial fibrillation.
•Small conductance calcium-activated potassium (SK) channel activity of unusual pharmacology regulate atrial action potentials.•SK channels are inhibited by the toxin apamin and the small organic molecule inhibitor UCL1684.•Only apamin-insensitive, UCL1684-sensitive SK channels contribute to the human atrial action potential.•Immunovisualization of SK2 and 3 subunits shows colocalization that is suggestive of heteromeric channel formation.•Human atrial myocytes express an apamin-insensitive SK channel, proposed to be a therapeutic treatment of atrial fibrillation.
Background
The success of coronary artery bypass grafting surgery (CABG) is dependent on long‐term graft patency, which is negatively related to early wall thickening. Avoiding high‐pressure ...distension testing for leaks and preserving the surrounding pedicle of fat and adventitia during vein harvesting may reduce wall thickening.
Methods
A single‐centre, factorial randomized controlled trial was carried out to compare the impact of testing for leaks under high versus low pressure and harvesting the vein with versus without the pedicle in patients undergoing CABG. The primary outcomes were graft wall thickness, as indicator of medial‐intimal hyperplasia, and lumen diameter assessed using intravascular ultrasound after 12 months.
Results
Ninety‐six eligible participants were recruited. With conventional harvest, low‐pressure testing tended to yield a thinner vessel wall compared with high‐pressure (mean difference MD; low minus high −0.059 mm, 95% confidence interval (CI) −0.12, +0.0039, p = .066). With high pressure testing, veins harvested with the pedicle fat tended to have a thinner vessel wall than those harvested conventionally (MD pedicle minus conventional −0.057 mm, 95% CI: −0.12, +0.0037, p = .066, test for interaction p = .07). Lumen diameter was similar across groups (harvest comparison p = .81; pressure comparison p = .24). Low‐pressure testing was associated with fewer hospital admissions in the 12 months following surgery (p = .0008). Harvesting the vein with the pedicle fat was associated with more complications during the index admission (p = .0041).
Conclusions
Conventional saphenous vein graft preparation with low‐pressure distension and harvesting the vein with a surrounding pedicle yielded similar graft wall thickness after 12 months, but low pressure was associated with fewer adverse events.
Chronic central serous chorioretinopathy (CSCR) is poorly understood. Fluid accumulates in the subretinal space and retinal pigment epitheliopathy and neurosensory atrophy may develop. Permanent ...vision loss occurs in approximately one third of cases. There are no effective treatments for CSCR. Recent studies have shown the mineralocorticoid receptor antagonist, eplerenone, to be effective in resolving subretinal fluid and improving visual acuity. This trial aims to compare the safety and efficacy of eplerenone in patients with CSCR in a double-masked randomised placebo-controlled trial.
Patients are randomised 1:1 to receive eplerenone with usual care or placebo with usual care for 12 months; 25 mg per day for 1 week, then 50 mg per day up to 12 months (unless discontinued for safety or resolution of CSCR). Key eligibility criteria are: age 18-60 years, one eye with CSCR for ≥4 months duration, best-corrected visual acuity (BCVA) >53 and <86 letters and no previous treatment. The primary outcome is BCVA at 12 months. Secondary outcomes include resolution of subretinal fluid, development of macular atrophy, subfoveal choroidal thickness, changes in low luminance visual acuity, health-related quality of life and safety.
Recruitment is complete but was slower than expected. We maintained the eligibility criteria to ensure participants had 'true' CSCR and recruited additional centres. Effective distribution of the investigational medicinal product (IMP) was achieved by implementing a database to manage ordering and accountability of IMP packs. The results will provide adequately powered evidence to inform clinical decisions about using eplerenone to treat patients with CSCR.
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