Elevated ferritin, mediated by IL-18 is associated with systemic inflammation and mortality in acute respiratory distress syndrome (ARDS).

BACKGROUND: Inflammatory subphenotypes have been identified in acute respiratory distress syndrome (ARDS). Hyperferritinaemia in sepsis is associated with hyperinflammation, worse clinical outcomes, and may predict benefit with immunomodulation. Our aim was to determine if raised ferritin identified a subphenotype in patients with ARDS. METHODS: Baseline plasma ferritin concentrations were measured in patients with ARDS from two randomised controlled trials of simvastatin (Hydroxymethylglutaryl-CoA Reductase Inhibition with Simvastatin in Acute Lung Injury to Reduce Pulmonary Dysfunction-2 (HARP-2); discovery cohort, UK) and neuromuscular blockade (ROSE; validation cohort, USA). Results were analysed using a logistic regression model with restricted cubic splines, to determine the ferritin threshold associated with 28-day mortality. RESULTS: Ferritin was measured in 511 patients from HARP-2 (95% of patients enrolled) and 847 patients (84% of patients enrolled) from ROSE. Ferritin was consistently associated with 28-day mortality in both studies and following a meta-analysis, a log-fold increase in ferritin was associated with an OR 1.71 (95% CI 1.01 to 2.90) for 28-day mortality. Patients with ferritin >1380 ng/mL (HARP-2 28%, ROSE 24%) had a significantly higher 28-day mortality and fewer ventilator-free days in both studies. Mediation analysis, including confounders (acute physiology and chronic health evaluation-II score and ARDS aetiology) demonstrated a statistically significant contribution of interleukin (IL)-18 as an intermediate pathway between ferritin and mortality. CONCLUSIONS: Ferritin is a clinically useful biomarker in ARDS and is associated with worse patient outcomes. These results provide support for prospective interventional trials of immunomodulatory agents targeting IL-18 in this hyperferritinaemic subgroup of patients with ARDS.

Sex-based differences in short- and longer-term diet-induced metabolic heart disease.

Sex-based differences in the development of obesity-induced cardiometabolic dysfunction are well documented, however, the specific mechanisms are not completely understood. Obesity has been linked to dysregulation of the epitranscriptome, but the role of N6-methyladenosine (m6A) RNA methylation has not been investigated in relation to the sex differences during obesity-induced cardiac dysfunction. In the current study, male and female C57BL/6J mice were subjected to short- and long-term high-fat/high-sucrose (HFHS) diet to induce obesogenic stress. Cardiac echocardiography showed males developed systolic and diastolic dysfunction after 4 mo of diet, but females maintained normal cardiac function despite both sexes being metabolically dysfunctional. Cardiac m6A machinery gene expression was differentially regulated by duration of HFHS diet in male, but not female mice, and left ventricular ejection fraction correlated with RNA machinery gene levels in a sex- and age-dependent manner. RNA-sequencing of cardiac transcriptome revealed that females, but not males may undergo protective cardiac remodeling early in the course of obesogenic stress. Taken together, our study demonstrates for the first time that cardiac RNA methylation machinery genes are regulated early during obesogenic stress in a sex-dependent manner and may play a role in the sex differences observed in cardiometabolic dysfunction.NEW & NOTEWORTHY Sex differences in obesity-associated cardiomyopathy are well documented but incompletely understood. We show for the first time that RNA methylation machinery genes may be regulated in response to obesogenic diet in a sex- and age-dependent manner and levels may correspond to cardiac systolic function. Our cardiac RNA-seq analysis suggests female, but not male mice may be protected from cardiac dysfunction by a protective cardiac remodeling response early during obesogenic stress.

Restoring microvascular circulation with diagnostic ultrasound and contrast agent: Rationale and Design of the REDUCE trial.

OBJECTIVES: This study aims to evaluate the efficacy and cost-effectiveness of sonothrombolysis delivered pre and post primary percutaneous coronary intervention (pPCI) on infarct size assessed by cardiac MRI, in patients presenting with STEMI, when compared against sham procedure. BACKGROUND: More than a half of patients with successful pPCI have significant microvascular obstruction and residual infarction. Sonothrombolysis is a therapeutic use of ultrasound with contrast enhancement that may improve microcirculation and infarct size. The benefits and real time physiological effects of sonothrombolysis in a multicentre setting are unclear. METHODS: The REDUCE (Restoring microvascular circulation with diagnostic ultrasound and contrast agent) trial is a prospective, multicentre, patient and outcome blinded, sham-controlled trial. Patients presenting with STEMI will be randomized to one of two treatment arms, to receive either sonothrombolysis treatment or sham echocardiography before and after pPCI. This tailored design is based on preliminary pilot data from our centre, showing that sonothrombolysis can be safely delivered, without prolonging door to balloon time. Our primary endpoint will be infarct size assessed on day 4±2 on Cardiac Magnetic Resonance (CMR). Patients will be followed up for six months post pPCI to assess secondary endpoints. Sample size calculations indicate we will need 150 patients recruited in total. CONCLUSIONS: This multicentre trial will test whether sonothrombolysis delivered pre and post primary PCI can improve patient outcomes and is cost-effective, when compared with sham ultrasound delivered with primary PCI. The results from this trial may provide evidence for the utilization of sonothrombolysis as an adjunct therapy to pPCI to improve cardiovascular outcomes in STEMI. ANZ Clinical Trial Registration number: ACTRN 12620000807954.

Acute hypoxaemic respiratory failure after treatment with lower tidal volume ventilation facilitated by extracorporeal carbon dioxide removal: long-term outcomes from the REST randomised trial.

INTRODUCTION: Lower tidal volume ventilation, facilitated by veno-venous extracorporeal carbon dioxide removal (vv-ECCO2R), does not improve 90-day mortality in patients with acute hypoxaemic respiratory failure (AHRF). The aim of this analysis was to evaluate the effect of this therapeutic strategy on long-term outcomes. METHODS: This was a prespecified analysis of the REST trial, a UK-wide multicentre randomised clinical trial that compared lower tidal volume ventilation, facilitated by vv-ECCO2R (intervention), with standard care in the treatment of patients with moderate-to-severe AHRF. Mortality to 2 years was assessed, while respiratory function, post-traumatic stress disorder, cognitive function and health-related quality of life were evaluated in survivors at 1 year using standardised questionnaires. RESULTS: Of 412 patients enrolled into the REST trial, 391 (95%) had 2-year mortality outcome data available. There was no difference in the time to death between intervention and standard care (HR 1.08 (0.81, 1.44); log-rank test p=0.61). 161 patients alive at 1 year provided at least one questionnaire response. There was no difference in respiratory function, post-traumatic stress disorder, cognitive dysfunction or health-related quality of life between patients allocated to intervention or standard care. CONCLUSION: Lower-tidal volume ventilation facilitated by vv-ECCO2R does not affect 1-year mortality in patients with moderate-to-severe AHRF. Of the patients who provided questionnaire responses, there was no treatment effect on long-term respiratory function, post-traumatic stress disorder, cognitive dysfunction or health-related quality of life. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier: NCT02654327.

Aortic valve replacement rates in Australia from 2004 to 2019.

BACKGROUND: Several surgical and percutaneous treatments are available for patients with aortic valve disease. AIM: To establish whether trends in aortic valve replacements (AVR) in Australia reflect recent evidence. METHODS: Using the Australian Institute of Health and Welfare data, this study calculated all AVR and balloon aortic valvuloplasty (BAV) procedures conducted in all Australian hospitals from 2004 to 2019. Linear regression analysis was performed to determine whether age-adjusted rates had changed over the study period. RESULTS: There were 80 883 AVR performed. Of these, 66% were men and 64% were aged >70 years. Absolute rates of AVR increased from 3631 to 7277 with a significant 22% age-adjusted rise seen (1.9% increase per year (+0.26 per 100 000 per year; 95% confidence interval 0.19-0.34); P < 0.001). This trend was more pronounced in men than women and in those aged >80 years (+0.23 per 100 000 per year; P < 0.001). Proportion of mechanical AVR implanted fell from 38.4% to 8.6% (P < 0.001). A total of 2683 transcatheter aortic valve implantation (TAVI) procedures was performed in 2019, representing a 52% annual increase from 2014. BAV increased from 66 procedures in 2004 to 862 in 2019. CONCLUSION: Rates of AVR have increased significantly over the past 16 years, particularly in the elderly. Despite international guideline recommendations, fewer mechanical AVR are being used in younger cohorts. The uptake in TAVI rates might reflect evidence that suggests it is a safe alternative, at least in the medium term. BAV has also seen a resurgence during this time period.

Mind The Gap, Aboriginal and Torres Strait Islander Cardiovascular Health: A Narrative Review.

Australia's First Nations Peoples, Aboriginal and Torres Strait Islanders, have reduced life expectancy compared to the wider community. Cardiovascular diseases, mainly driven by ischaemic heart disease, are the leading contributors to this disparity. Despite over a third of First Nations Peoples living in New South Wales, the bulk of the peer-reviewed literature is from Central Australia and Far North Queensland. Regardless of the site of publication, First Nations Peoples are significantly younger at disease onset and have higher rates of comorbidities, in turn driving adverse health events. On top of this, very few First Nations Peoples specific cardiovascular interventions or programs have been shown to improve outcomes. The traditional biomedical model of care is less efficacious and non-traditional models of communication such as clinical yarning may benefit both clinicians and patients. The key purpose of this review is to highlight the deficiencies of our knowledge of cardiovascular burden of disease for First Nations Peoples; and to serve as a catalyst for more dedicated research. We need to have relationships with communities and concentrate on community improvement and partnerships. By involving First Nations Peoples researchers in collaboration with local communities in all levels of health care design and intervention will improve outcomes.

Rehabilitation Support via Postcard (RSVP): A Randomised Controlled Trial of a Postcard to Promote Uptake of Cardiac Rehabilitation.

PURPOSE: The aim was to increase cardiac rehabilitation (CR) uptake using a novel intervention, Rehabilitation Support Via Postcard (RSVP), among patients with acute myocardial infarction discharged from two major hospitals in Hunter New England Local Health District (HNELHD), New South Wales, Australia. METHODS: The RSVP trial was evaluated using a two-armed randomised controlled trial design. Participants (N=430) were recruited from the two main hospitals in HNELHD, and enrolled and randomised to either the intervention (n=216) or control (n=214) group over a six-month period. All participants received usual care; however, the intervention group received postcards promoting CR attendance between January and July 2020. The postcard was ostensibly written as an invitation from the patient's admitting medical officer to promote timely and early uptake of CR. The primary outcome was CR attendance at outpatient HNELHD CR services in the 30-days post-discharge. RESULTS: Fifty-four percent (54%) of participants who received RSVP attended CR, compared to 46% in the control group; however this difference was not statistically significant (odds ratio [OR]=1.4, 95% confidence interval [CI]=0.9-2.0, p=0.11). Exploratory post-hoc analysis among four sub-groups (i.e., Indigeneity, gender, age and rurality), found that the intervention significantly increased attendance in males (OR=1.6, 95%CI=1.0-2.6, p=0.03) but had no significant impact on attendance for other sub-groups. CONCLUSIONS: While not statistically significant, postcards increased overall CR attendance by 8%. This strategy may be useful to increase attendance, particularly in men. Alternative strategies are necessary to increase CR uptake among women, Indigenous people, older people and people from regional and remote locations.

The importance of anaesthesia in atrial fibrillation ablation: Comparing conscious sedation with general anaesthesia.

BACKGROUND: General anaesthesia (GA) for atrial fibrillation (AF) ablation is often preferred over conscious sedation (CS) to minimize patient discomfort and reduce the risk of map disruption from patient movement but may pose an additional risk to some patients with significant comorbidity or poor cardiac function. METHODS: We extracted data for 300 patients who underwent AF ablation between the years 2017 and 2019 and compared the outcomes of AF ablation with CS and GA. RESULTS: Compared to the GA group, patients were younger in the CS group (63 versus 66 years, p = 0.02), had less persistent AF (34% versus 46%, p = 0.048) and the left atrial dimension was smaller (41 versus 45 mm, p = 0.01). More patients had cryoballoon ablation (CBA) than radiofrequency (RFA) ablation in the CS than the GA group (88% CB with CS and 56% RF with GA, p < 0.01), frequency of ASA score 3-4 (higher anaesthetic risk) was less for CS than for GA (45% versus 75%, p < 0.01), and procedural duration was shorter for patients who had CS (110 versus 139 min, p < 0.001). Of the patients receiving CS, 127/182 (70%) were planned for same day discharge (SDD) and this occurred in 120 (94%) of those patients. There were no significant differences in complication rates between the groups (5.1% in GA and 6% in CS, p = 0.8). AF type was the only significant predictor of freedom from AF recurrence on multivariate analysis (HR 0.33, 0.13-0.82, p = 0.018). CONCLUSION: In this study, the use of CS compared with GA for AF ablation was associated with similar outcomes and complication rates.

Baseline plasma IL-18 may predict simvastatin treatment response in patients with ARDS: a secondary analysis of the HARP-2 randomised clinical trial.

BACKGROUND: Interleukin (IL)-18 is a marker of inflammasome activation, and high baseline plasma IL-18 is associated with increased mortality in patients with sepsis-induced ARDS. The aim of this analysis was to determine if simvastatin was associated with benefit in patients with ARDS and high plasma IL-18. METHODS: In this secondary analysis of the HARP-2 study, we compared 28-day mortality and response to simvastatin according to baseline plasma IL-18 using cox proportional hazards analysis. Separately, monocyte-derived macrophages from healthy volunteers were pre-incubated with simvastatin or rosuvastatin before stimulation with ATP and LPS, and the effect on secreted IL-18 and IL-1ß compared. RESULTS: 511 patients from HARP-2 had available data. High baseline plasma IL-18 (≥ 800 pg/ml) was associated with increased 28-day mortality (high IL-18 30.6% vs. low IL-18 17.5%; HR 1.89 [95% CI 1.30-2.73]; p = 0.001). Allocation to simvastatin in patients with high baseline plasma IL-18 was associated with a lower probability of 28-day mortality compared with placebo (24.0% vs 36.8%; p = 0.01). Finally, simvastatin, but not rosuvastatin, reduced stimulated macrophage secretion of IL-18 and IL-1ß. CONCLUSION: In patients with high baseline plasma IL-18, simvastatin is associated with a higher probability of survival, and this effect may be due to reduced inflammasome activation. These data suggest that baseline plasma IL-18 may allow a personalised treatment approach by identifying patients with ARDS who could benefit from simvastatin therapy.

A State-of-the-Art Review: The Percutaneous Treatment of Highly Calcified Lesions.

Coronary artery calcification is prevalent in coronary heart disease with its progression being predictive of future adverse cardiac events. Its presence is considered to be a marker of interventional procedural complexity. Several adjunctive percutaneous coronary intervention tools, such as modifying balloons, atherectomy devices and intravascular lithotripsy, now exist to successfully treat calcified lesions. In this state-of-the-art review, a step-wise progression of strategies is described to modify coronary plaque, from well-recognised techniques to techniques that should only be considered when standard manoeuvres have proven unsuccessful. Technology has advanced greatly over the past few decades and we discuss how future technologies might shape percutaneous intervention.

Considerations for the Bioengineering of Advanced Cardiac In Vitro Models of Myocardial Infarction.

Despite the latest advances in cardiovascular biology and medicine, myocardial infarction (MI) remains one of the major causes of deaths worldwide. While reperfusion of the myocardium is critical to limit the ischemic damage typical of a MI event, it causes detrimental morphological and functional changes known as "reperfusion injury." This complex scenario is poorly represented in currently available models of ischemia/reperfusion injury, leading to a poor translation of findings from the bench to the bedside. However, more recent bioengineered in vitro models of the human heart represent more clinically relevant tools to prevent and treat MI in patients. These include 3D cultures of cardiac cells, the use of patient-derived stem cells, and 3D bioprinting technology. This review aims at highlighting the major features typical of a heart attack while comparing current in vitro, ex vivo, and in vivo models. This information has the potential to further guide in developing novel advanced in vitro cardiac models of ischemia/reperfusion injury. It may pave the way for the generation of advanced pathophysiological cardiac models with the potential to develop personalized therapies.

Oro-mucosal midazolam maleate: Use and effectiveness in adults with epilepsy in the UK.

BACKGROUND: Oro-mucosal midazolam maleate (OMM) with suitable training to family and carers is being increasingly recognized as the treatment of choice to mitigate the development of status epilepticus in non-hospital community settings. There are no studies to describe the use, effectiveness, and suitable dosing of OMM in adults with epilepsy in community settings. PURPOSE: To describe the use, effectiveness, and dosing of OMM in the emergency treatment of epileptic seizures in community settings. METHODS: A retrospective observational study (2016-17) design was used with participant recruitment from four UK NHS secondary care outpatient clinics providing epilepsy management. Study sample was of adult people with epilepsy (PWE) having had a recent seizure requiring OMM. Data on patient demographics, patient care plans, details of a recent seizure requiring emergency medication, and dose of OMM were collected from medical records. RESULTS: Study data from 146 PWE were included. The mean age of PWE was 41.0 years (SD 15.2) and mean weight was 64.8Kg (SD 18.2). Fifty-three percent of PWE were recorded as having intellectual disability. The most frequently used concomitant medications were lamotrigine (43%). The majority of seizures occurred at people's homes (n = 92, 63%). OMM was most often administered by family/professional care-givers (n = 75, 48.4%). Generalized (tonic/clonic) seizures were recorded in most people (n = 106, 72.6%). The most common initial dose of OMM was 10 mg (n = 124, 84.9%). The mean time to seizure cessation after administration of this initial dose was 5.5 minutes (SD = 4.5, Median 5.0, IQR 2.1-5.0). Only a minority of seizures led to ambulance callouts (n = 18, 12.3%) or hospital admissions (n = 13, 9%). CONCLUSION: This is the first observational study describing the use and effectiveness of OMM in adults in community settings. Minimal hospital admissions were reported in this cohort and the treatment was effective in ending seizures in adults in community settings.

Natural history and prognostic implications of left ventricular end-diastolic pressure in reperfused ST-segment elevation myocardial infarction: an analysis of the thrombolysis in myocardial infarction (TIMI) II randomized controlled trial.

BACKGROUND: The aim of the current study is to assess the natural history and prognostic value of elevated left ventricular end-diastolic pressure (LVEDP) in patients with ST-segment elevation myocardial infarction (STEMI) after reperfusion with thrombolysis; we utilize data from the Thrombolysis in Myocardial Infarction (TIMI) II study. METHODS: A total of 3339 patients were randomized to either an invasive (n = 1681) or a conservative (n = 1658) strategy in the TIMI II study following thrombolysis. To make the current cohort as relevant as possible to modern pharmaco-invasively managed cohorts, patients in the invasive arm with TIMI flow grade ≥ 2 (N = 1201) at initial catheterization are included in the analysis. Of these, 259 patients had a second catheterization prior to hospital discharge, and these were used to define the natural history of LVEDP in reperfused STEMI. RESULTS: The median LVEDP for the whole cohort was 18 mmHg (IQR: 12-23). Patients were divided into quartiles by LVEDP measured during the first cardiac catheterization. During a median follow up of 3 (IQR: 2.1-3.2) years, quartile 4 (highest LVEDP) had the highest incidence of mortality and heart failure admissions. In the cohort with paired catheterization data, the LVEDP dropped slightly from 18 mmHg (1QR: 12-22) to 15 mmHg (IQR: 10-20) (p = 0.01) from the first to the pre-hospital discharge catheterization. CONCLUSIONS: LVEDP remains largely stable during hospitalisation post-STEMI. Elevated LVEDP is a predictor of death and heart failure hospitalization in STEMI patients undergoing successful thrombolysis.

Combined Mesenchymal Stromal Cell Therapy and Extracorporeal Membrane Oxygenation in Acute Respiratory Distress Syndrome. A Randomized Controlled Trial in Sheep.

Rationale: Mesenchymal stromal cell (MSC) therapy is a promising intervention for acute respiratory distress syndrome (ARDS), although trials to date have not investigated its use alongside extracorporeal membrane oxygenation (ECMO). Recent preclinical studies have suggested that combining these interventions may attenuate the efficacy of ECMO.Objectives: To determine the safety and efficacy of MSC therapy in a model of ARDS and ECMO.Methods: ARDS was induced in 14 sheep, after which they were established on venovenous ECMO. Subsequently, they received either endobronchial induced pluripotent stem cell-derived human MSCs (hMSCs) (n = 7) or cell-free carrier vehicle (vehicle control; n = 7). During ECMO, a low Vt ventilation strategy was employed in addition to protocolized hemodynamic support. Animals were monitored and supported for 24 hours. Lung tissue, bronchoalveolar fluid, and plasma were analyzed, in addition to continuous respiratory and hemodynamic monitoring.Measurements and Main Results: The administration of hMSCs did not improve oxygenation (PaO2/FiO2 mean difference = -146 mm Hg; P = 0.076) or pulmonary function. However, histological evidence of lung injury (lung injury score mean difference = -0.07; P = 0.04) and BAL IL-8 were reduced. In addition, hMSC-treated animals had a significantly lower cumulative requirement for vasopressor. Despite endobronchial administration, animals treated with hMSCs had a significant elevation in transmembrane oxygenator pressure gradients. This was accompanied by more pulmonary artery thromboses and adherent hMSCs found on explanted oxygenator fibers.Conclusions: Endobronchial hMSC therapy in an ovine model of ARDS and ECMO can impair membrane oxygenator function and does not improve oxygenation. These data do not recommend the safe use of hMSCs during venovenous ECMO.

Impact of fast-food outlet density on incidence of myocardial infarction in the Hunter region.

BACKGROUND: There is an established association between fast-food consumption and metabolic diseases. Some studies also suggest that calorie-dense food promotes a proinflammatory response, which is itself linked with myocardial infarction (MI). Whether increased fast-food availability is a risk factor for MI remains unknown. AIM: To investigate the role of fast-food outlet density (FFD) as a novel environmental risk factor for MI in the Hunter region, New South Wales (NSW). METHODS: We conducted a retrospective cohort study using a database of all MI events between 1996 and 2013, extracted from the Hunter Cardiac and Stroke Outcomes unit. FFD was calculated for each local government area (LGA) of the Hunter region, allowing for a comparative analysis. Stratification by fast-food outlet data and LGA resulted in a total of 3070 cases. Weighted linear regression was used to investigate the role of FFD on incidence of MI in regional and rural Australia. RESULTS: FFD was positively correlated with rates of MI, remaining consistent in both single and multivariate predictor models adjusting for age, obesity, hyperlipidaemia, hypertension, smoking status, diabetes and socioeconomic status (P < 0.001). An increase of one fast-food outlet corresponded with four additional cases of MI per 100 000 people per year (4.07, 95% confidence interval, 3.86-4.28). CONCLUSIONS: FFD was positively associated with incidence of MI in both rural and metropolitan areas of NSW. This relationship remained consistent after multivariate adjustment for standard cardiovascular risk factors, highlighting the importance of an individual's food environment as a potential contributor towards their health.

Hyperoxaemia and hypoxaemia are associated with harm in patients with ARDS.

BACKGROUND: Oxygen therapy is routinely administered to mechanically ventilated patients. However, there remains uncertainty about the optimal oxygen titration target in patients with the acute respiratory distress syndrome (ARDS). METHODS: Prospectively identified adult patients meeting the Berlin definition of ARDS between 1st January 2014 and 13th December 2016 were analyzed. Oxygen exposure variables were collected at 6-hourly intervals. The primary exposure was the average time-weighted partial pressure of arterial oxygen (PaO2) calculated over a maximum of 7 days from meeting ARDS criteria. The primary outcome was ICU mortality. Univariable and multivariable logistic regression analyses were performed to assess the impact of exposure variables on clinical outcomes. Results are presented as odds ratio [95% confidence interval]. RESULTS: 202 patients were included in the final analysis. Overall ICU mortality was 31%. The average time-weighted PaO2 during the first 7 days of ARDS was similar between non-survivors and survivors (11.3 kPa [10.2, 12.5] (84.8 mmHg [76.5, 93.8]) vs. 11.9 kPa [10.9, 12.6] (89.3 mmHg [81.8, 94.5]); p = 0.08). In univariable and multivariable analysis, average time-weighted PaO2 demonstrated a U-shaped relationship with ICU mortality. There was a similar relationship identified with hospital mortality. CONCLUSIONS: In patients with ARDS, the predicted probability of both ICU and hospital mortality was lowest when the average time-weighted PaO2 was between 12.5 and 14 kPa (93.8-105.0 mmHg), suggesting this is a reasonable oxygenation target for clinicians to aim for.

Effect of Lower Tidal Volume Ventilation Facilitated by Extracorporeal Carbon Dioxide Removal vs Standard Care Ventilation on 90-Day Mortality in Patients With Acute Hypoxemic Respiratory Failure: The REST Randomized Clinical Trial.

Importance: In patients who require mechanical ventilation for acute hypoxemic respiratory failure, further reduction in tidal volumes, compared with conventional low tidal volume ventilation, may improve outcomes. Objective: To determine whether lower tidal volume mechanical ventilation using extracorporeal carbon dioxide removal improves outcomes in patients with acute hypoxemic respiratory failure. Design, Setting, and Participants: This multicenter, randomized, allocation-concealed, open-label, pragmatic clinical trial enrolled 412 adult patients receiving mechanical ventilation for acute hypoxemic respiratory failure, of a planned sample size of 1120, between May 2016 and December 2019 from 51 intensive care units in the UK. Follow-up ended on March 11, 2020. Interventions: Participants were randomized to receive lower tidal volume ventilation facilitated by extracorporeal carbon dioxide removal for at least 48 hours (n = 202) or standard care with conventional low tidal volume ventilation (n = 210). Main Outcomes and Measures: The primary outcome was all-cause mortality 90 days after randomization. Prespecified secondary outcomes included ventilator-free days at day 28 and adverse event rates. Results: Among 412 patients who were randomized (mean age, 59 years; 143 [35%] women), 405 (98%) completed the trial. The trial was stopped early because of futility and feasibility following recommendations from the data monitoring and ethics committee. The 90-day mortality rate was 41.5% in the lower tidal volume ventilation with extracorporeal carbon dioxide removal group vs 39.5% in the standard care group (risk ratio, 1.05 [95% CI, 0.83-1.33]; difference, 2.0% [95% CI, -7.6% to 11.5%]; P = .68). There were significantly fewer mean ventilator-free days in the extracorporeal carbon dioxide removal group compared with the standard care group (7.1 [95% CI, 5.9-8.3] vs 9.2 [95% CI, 7.9-10.4] days; mean difference, -2.1 [95% CI, -3.8 to -0.3]; P = .02). Serious adverse events were reported for 62 patients (31%) in the extracorporeal carbon dioxide removal group and 18 (9%) in the standard care group, including intracranial hemorrhage in 9 patients (4.5%) vs 0 (0%) and bleeding at other sites in 6 (3.0%) vs 1 (0.5%) in the extracorporeal carbon dioxide removal group vs the control group. Overall, 21 patients experienced 22 serious adverse events related to the study device. Conclusions and Relevance: Among patients with acute hypoxemic respiratory failure, the use of extracorporeal carbon dioxide removal to facilitate lower tidal volume mechanical ventilation, compared with conventional low tidal volume mechanical ventilation, did not significantly reduce 90-day mortality. However, due to early termination, the study may have been underpowered to detect a clinically important difference. Trial Registration: ClinicalTrials.gov Identifier: NCT02654327.

Effect of Outcome Measures on the Apparent Efficacy of Ablation for Atrial Fibrillation: Why "Success" is an Inappropriate Term.

INTRODUCTION: Different endpoint criteria, different durations of follow-up and the completeness of follow-up can dramatically affect the perceived benefits of atrial fibrillation (AF) ablation. METHODS: We defined three endpoints for recurrence of AF post ablation in a cohort of 200 patients with symptomatic AF, refractory to antiarrhythmic drugs (AADs). A 'Strict Endpoint' where patients were considered to have a recurrence with any symptomatic or documented recurrence for ≥30 seconds with no blanking period, and off their AADs, a 'Liberal Endpoint' where only documented recurrences after the blanking period, either on or off AADs were counted, and a 'Patient-defined Outcome endpoint' which was the same as the Liberal endpoint but allowed for up to two recurrences and one repeat ablation or DCCV during follow-up. We also surveyed 50 patients on the waiting list for an AF ablation and asked them key questions regarding what they would consider to be a successful result for them. RESULTS: Freedom from recurrence of atrial tachyarrhythmias (AT) at 5 years was 62% for the Strict Endpoint, 73% for the Liberal Endpoint, and 80% for the Patient-defined Outcome endpoint (p<0.001). Of the 50 patients surveyed awaiting AF ablation, 70% said they would still consider the procedure a success if it required one repeat ablation or one DCCV (p=0.004), and 76% would be accepting of one or two recurrences during follow-up (p<0.001). CONCLUSION: In this study, the majority of patients still considered AF ablation a successful treatment if they had up to two recurrences of AF, one repeat procedure or one DCCV. Furthermore, a 'Patient-defined' definition of success lead to significantly different results in this AF ablation cohort when compared to conventionally used/guideline directed measures of success.

Impact of Delay in Surgery on Outcome in Patients Undergoing Cardiac Revascularisation Surgery.

BACKGROUND: Diagnosis of critical coronary artery disease, including after acute coronary syndrome presentation (ACS), represents an important indication for early coronary artery bypass graft (CABG) surgery. The study aims to investigate the influence of time from diagnosis to CABG on outcomes and document barriers to early revascularisation. METHODS: All patients 18 years and older with an acute presentation due to ACS or critical coronary artery disease who were considered to require urgent inpatient cardiac surgery between January 2016-February 2019 were included in the study. The primary endpoints were 30-day all-cause mortality or readmission, 1-year all-cause mortality, all-cause readmission. The secondary endpoint was the rate of complications while waiting for surgery. The time duration between diagnostic coronary angiography and surgery was considered as the time interval. RESULTS: Of 266 eligible patients, 251 underwent surgical revascularisation with 15 (6%) not undergoing surgery due to preoperative complications (n=12) or due to perceived prohibitively high surgical risk (n=3). The majority (85%) were male (mean age 67 years), 37% of patients had diabetes and 71% had hypertension. Non-ST elevation myocardial infarction was documented in 51% of the patients. The median time between diagnosis and inpatient CABG was 7 days (IQR 5-11). Thirty-five per cent (35%) of patients experienced complications while awaiting surgery. Of the 266 patients, 140 patients (53% - cohort 1) underwent surgery within 7 days. The cohort 1 rate of complications was lower than in cohort 2 (surgery after 7 days) (24 vs 47%, p<0.001). Moreover, 1-year mortality was less in cohort 1 (2 vs 8%, p=0.029). CONCLUSION: In patients requiring urgent inpatient CABG, delay for more than 7 days is associated with a higher rate of in-hospital complications and worse 30 day and 12-month outcomes.

Contemporary trends in stroke complicating cardiac catheterisation.

BACKGROUND: Stroke remains an important complication of diagnostic cardiac catheterisation and percutaneous coronary intervention and is associated with high rates of in-hospital mortality. AIMS: To evaluate the incidence of stroke over a 10-year period and assess the long-term influence of stroke following cardiac catheterisation and PCI on functional outcomes, based on modified Rankin score and mortality. METHODS: The study was performed using a case-control design in a single tertiary referral centre. Patients were identified by correlating those patients undergoing cardiac catheterisation between October 2006 and December 2016 with patients who underwent neuroimaging within 7 days to identify possible cases of suspected stroke or transient ischaemic attack. RESULTS: A total of 21 510 patients underwent cardiac catheterisation during the study period. Sixty (0.28%) patients experienced stroke or transient ischaemic attack. Compared to control patients, those who did experience cerebral ischaemic events were older (70.5 vs 64 years; P < 0.001), with higher rates of atrial fibrillation, hypertension and diabetes mellitus. Stroke complicating cardiac catheterisation was associated with an increased risk of readmission, with a significantly higher hazard of readmission for stroke noted. Despite minimal functional impairment based on modified Rankin score, stroke was associated with a significant risk of early and cumulative mortality. Stroke incidence remained stable over the study period despite changes in procedural practice. CONCLUSIONS: The incidence and functional severity of stroke remains low despite evolving procedural practice with a stable incidence over time despite changes in procedural practice; however, post-procedural stroke confirms an increased mortality hazard.