Routine gastric residual volume measurement to guide enteral feeding in mechanically ventilated infants and children : the GASTRIC feasibility study

Background The routine measurement of gastric residual volume to guide the initiation and delivery of enteral feeding, is widespread in paediatric intensive care and neonatal units, but has little underlying evidence to support it. Objective(s) To answer the question: Is it feasible to conduct a trial of not measuring gastric residual volume on clinical outcomes in mechanically ventilated infants and children in the UK? Design A mixed methods study involving five linked work packages in two parallel arms, neonatal units and paediatric intensive care units. 1. A survey of units to establish current UK practice. 2. qualitative interviews with healthcare professionals and caregivers of children admitted to either setting. 3. A modified two-round e-Delphi survey to investigate health care professionals’ opinions on trial design issues and to obtain consensus on outcomes. 4. National databases were examined to determine the potential eligible populations. 5. Two consensus meetings, of health care professionals and parents to review the data and agreed consensus on outcomes that had not reached consensus in the e-Delphi. Participants and setting Parents of children with experience of ventilation and tube feeding in both neonatal units and in paediatric intensive care units, and health care professionals working in neonatal units and paediatric intensive care units. Results Baseline surveys showed the practice of gastric residual volume measurement was very common: 96% PICUs and 65% in neonatal units. Ninety percent of parents both from neonatal units and paediatric intensive care units supported a future trial, whilst highlighting concerns around possible delays in detecting complications. Health care professionals also indicated a trial was feasible, with 84% of staff willing to participate in a trial. Concerns expressed by junior nurses about the intervention arm of not measuring gastric residual volumes were addressed by developing a simple flowchart and education package. The trial design survey and e-Delphi study gained consensus on trial 12 PICU and 9 neonatal unit outcome measures and identified acceptable inclusion and exclusion criteria. Given the differences in physiology, disease processes, environments, staffing and outcomes of interest, two different trials are required in the two settings. Database analyses subsequently showed trials were feasible in both settings in terms of patient numbers. Of 16222 children who met the inclusion criteria in PICU 12 629 stayed > 3 days. In neonatal units, 15 375 neonates <32 weeks age. Finally, the two consensus meetings demonstrated ‘buy in’ from the wider UK neonatal communities and paediatric intensive care units and enabled us to discuss and vote on the outcomes that did not achieve consensus in the e-Delphi study. Conclusions and future work Two separate UK trials (one in neonatal units and one in paediatric intensive care units) are feasible to conduct, but they cannot be combined due to differences in outcome measures and treatment protocols, reflecting the distinctness of the two specialties

Non-invasive ventilation for the management of children with bronchiolitis (NOVEMBR): a feasibility study and core outcome set development protocol

Background: Bronchiolitis is an acute lower respiratory infection which predominantly affects young children. Treatment for bronchiolitis is limited to supportive therapy. Nasal oxygen therapy is part of routine care, and delivery now incorporates varying levels of non-invasive continuous positive airway pressure and/or high-flow nasal cannula oxygen therapy. Despite wide clinical use, there remains a lack of evidence on the comparative effectiveness and safety of these interventions. Furthermore, research in this field is hampered by the use of multiple outcome measures in current clinical trials. Methods/design: This mixed methods study includes a systematic review of outcome measures, telephone interviews with parents, focus group workshops and a Delphi survey with healthcare professionals and parents. These methods will be used to identify and prioritise outcomes for inclusion in a core outcome set and to explore issues pertinent to the design of a future randomised controlled trial comparing different modes of oxygen therapy for bronchiolitis. UK hospitals will also be contacted and asked to complete a survey to provide an overview of current practice to enable assessment of capability and capacity to run a future clinical trial. Discussion: This study will facilitate the design of a future clinical trial of non-invasive ventilation in children with bronchiolitis which is acceptable to important stakeholders. Furthermore, core outcome set development will improve standardisation, measurement and reporting of clinically important outcomes in bronchiolitis. Trial registration: ISRCTN Registry, ISRCTN75766048. Registered on 18 December 2017. This study was retrospectively registered in the ISRCTN Registry and on the Core Outcome Measures in Effectiveness Trials (COMET) Initiative database (15 September 2017)

Antiplatelet therapy with aspirin, clopidogrel, and dipyridamole versus clopidogrel alone or aspirin and dipyridamole in patients with acute cerebral ischaemia (TARDIS): a randomised, open-label, phase 3 superiority trial

Background: Intensive antiplatelet therapy with three agents might be more effective than guideline treatment for preventing recurrent events in patients with acute cerebral ischaemia. We aimed to compare the safety and efficacy of intensive antiplatelet therapy (combined aspirin, clopidogrel, and dipyridamole) with that of guideline-based antiplatelet therapy. Methods: We did an international, prospective, randomised, open-label, blinded-endpoint trial in adult participants with ischaemic stroke or transient ischaemic attack (TIA) within 48 h of onset. Participants were assigned in a 1:1 ratio using computer randomisation to receive loading doses and then 30 days of intensive antiplatelet therapy (combined aspirin 75 mg, clopidogrel 75 mg, and dipyridamole 200 mg twice daily) or guideline-based therapy (comprising either clopidogrel alone or combined aspirin and dipyridamole). Randomisation was stratified by country and index event, and minimised with prognostic baseline factors, medication use, time to randomisation, stroke-related factors, and thrombolysis. The ordinal primary outcome was the combined incidence and severity of any recurrent stroke (ischaemic or haemorrhagic; assessed using the modified Rankin Scale) or TIA within 90 days, as assessed by central telephone follow-up with masking to treatment assignment, and analysed by intention to treat. This trial is registered with the ISRCTN registry, number ISRCTN47823388. Findings: 3096 participants (1556 in the intensive antiplatelet therapy group, 1540 in the guideline antiplatelet therapy group) were recruited from 106 hospitals in four countries between April 7, 2009, and March 18, 2016. The trial was stopped early on the recommendation of the data monitoring committee. The incidence and severity of recurrent stroke or TIA did not differ between intensive and guideline therapy (93 [6%] participants vs 105 [7%]; adjusted common odds ratio [cOR] 0·90, 95% CI 0·67–1·20, p=0·47). By contrast, intensive antiplatelet therapy was associated with more, and more severe, bleeding (adjusted cOR 2·54, 95% CI 2·05–3·16, p<0·0001). Interpretation: Among patients with recent cerebral ischaemia, intensive antiplatelet therapy did not reduce the incidence and severity of recurrent stroke or TIA, but did significantly increase the risk of major bleeding. Triple antiplatelet therapy should not be used in routine clinical practice

Antiplatelet therapy with aspirin, clopidogrel, and dipyridamole versus clopidogrel alone or aspirin and dipyridamole in patients with acute cerebral ischaemia (TARDIS): a randomised, open-label, phase 3 superiority trial

Background: Intensive antiplatelet therapy with three agents might be more effective than guideline treatment for preventing recurrent events in patients with acute cerebral ischaemia. We aimed to compare the safety and efficacy of intensive antiplatelet therapy (combined aspirin, clopidogrel, and dipyridamole) with that of guideline-based antiplatelet therapy.Methods: We did an international, prospective, randomised, open-label, blinded-endpoint trial in adult participants with ischaemic stroke or transient ischaemic attack (TIA) within 48 h of onset. Participants were assigned in a 1:1 ratio using computer randomisation to receive loading doses and then 30 days of intensive antiplatelet therapy (combined aspirin 75 mg, clopidogrel 75 mg, and dipyridamole 200 mg twice daily) or guideline-based therapy (comprising either clopidogrel alone or combined aspirin and dipyridamole). Randomisation was stratified by country and index event, and minimised with prognostic baseline factors, medication use, time to randomisation, stroke-related factors, and thrombolysis. The ordinal primary outcome was the combined incidence and severity of any recurrent stroke (ischaemic or haemorrhagic; assessed using the modified Rankin Scale) or TIA within 90 days, as assessed by central telephone follow-up with masking to treatment assignment, and analysed by intention to treat. This trial is registered with the ISRCTN registry, number ISRCTN47823388.Findings: 3096 participants (1556 in the intensive antiplatelet therapy group, 1540 in the guideline antiplatelet therapy group) were recruited from 106 hospitals in four countries between April 7, 2009, and March 18, 2016. The trial was stopped early on the recommendation of the data monitoring committee. The incidence and severity of recurrent stroke or TIA did not differ between intensive and guideline therapy (93 [6%] participants vs 105 [7%]; adjusted common odds ratio [cOR] 0·90, 95% CI 0·67–1·20, p=0·47). By contrast, intensive antiplatelet therapy was associated with more, and more severe, bleeding (adjusted cOR 2·54, 95% CI 2·05–3·16,

Gastric residual volume measurement inU.K. PICUs: a survey of practice*

Objectives: Despite little evidence, the practice of routine measurementof gastric residual volume to guide both the initiation anddelivery of enteral feeding in PICUs is widespread internationally.In light of increased scrutiny of the evidence surrounding thispractice, and as part of a trial feasibility study, we aimed to determineenteral feeding and gastric residual volume measurementpractices in U.K. PICUs.Design: An online survey to 27 U.K. PICUs.Setting: U.K. PICUs.Subjects: A clinical nurse, senior doctor, and dietician were invitedto collaboratively complete one survey per PICU and send a copy oftheir unit guidelines on enteral feeding and gastric residual volume.Interventions: None.Measurement and Main Results: Twenty-four of 27 units (89%)approached completed the survey. Twenty-three units (95.8%;23/24) had written feeding guidelines, and 19 units (19/23;83%) sent their guidelines for review. More units fed continuously(15/24; 62%) than intermittently (9/24; 37%) via the gastric routeas their primary feeding method. All but one PICU routinely measuredgastric residual volume, regardless of the method of feeding.Eighteen units had an agreed definition of feed tolerance, and allthese included gastric residual volume. Gastric residual volumethresholds for feed tolerance were either volume based (mL/kgbody weight) (11/21; 52%) or a percentage of the volume offeed administered (6/21; 29%). Yet only a third of units providedguidance about the technique of gastric residual volume measurement.Conclusions: Routine gastric residual volume measurement is partof standard practice in U.K. PICUs, with little guidance providedabout the technique which may impact the accuracy of gastricresidual volume. All PICUs that defined feed tolerance includedgastric residual volume in the definition. This is important to knowwhen proposing a standard practice arm of any future trial of no routine gastric residual volume measurement in critically ill children

Pirfenidone in heart failure with preserved ejection fraction—rationale and design of the PIROUETTE trial

Background The PIROUETTE (PIRfenidOne in patients with heart failUre and preserved lEfT venTricular Ejection fraction) trial is designed to evaluate the efficacy and safety of the anti-fibrotic pirfenidone in patients with chronic heart failure and preserved ejection fraction (HFpEF) and myocardial fibrosis. HFpEF is a diverse syndrome associated with substantial morbidity and mortality. Myocardial fibrosis is a key pathophysiological mechanism of HFpEF and myocardial fibrotic burden is strongly and independently associated with adverse outcome. Pirfenidone is an oral anti-fibrotic agent, without haemodynamic effect, that leads to regression of myocardial fibrosis in preclinical models. It has proven clinical effectiveness in pulmonary fibrosis. Methods The PIROUETTE trial is a randomised, double-blind, placebo-controlled phase II trial evaluating the efficacy and safety of 52 weeks of treatment with pirfenidone in patients with chronic HFpEF (symptoms and signs of heart failure, left ventricular ejection fraction ≥ 45%, elevated natriuretic peptides [BNP ≥ 100 pg/ml or NT-proBNP ≥ 300 pg/ml; or BNP ≥ 300 pg/ml or NT-proBNP ≥ 900 pg/ml if in atrial fibrillation]) and myocardial fibrosis (extracellular matrix (ECM) volume ≥ 27% measured using cardiovascular magnetic resonance). The primary outcome measure is change in myocardial ECM volume. A sub-study will investigate the relationship between myocardial fibrosis and myocardial energetics, and the impact of pirfenidone, using 31phosphorus magnetic resonance spectroscopy. Discussion PIROUETTE will determine whether pirfenidone is superior to placebo in relation to regression of myocardial fibrosis and improvement in myocardial energetics in patients with HFpEF and myocardial fibrosis (NCT02932566). Clinical Trial Registration clinicaltrials.gov (NCT02932566) https://clinicaltrials.gov/ct2/show/NCT02932566</p

Pirfenidone in heart failure with preserved ejection fraction—rationale and design of the PIROUETTE trial

Background The PIROUETTE (PIRfenidOne in patients with heart failUre and preserved lEfT venTricular Ejection fraction) trial is designed to evaluate the efficacy and safety of the anti-fibrotic pirfenidone in patients with chronic heart failure and preserved ejection fraction (HFpEF) and myocardial fibrosis. HFpEF is a diverse syndrome associated with substantial morbidity and mortality. Myocardial fibrosis is a key pathophysiological mechanism of HFpEF and myocardial fibrotic burden is strongly and independently associated with adverse outcome. Pirfenidone is an oral anti-fibrotic agent, without haemodynamic effect, that leads to regression of myocardial fibrosis in preclinical models. It has proven clinical effectiveness in pulmonary fibrosis. Methods The PIROUETTE trial is a randomised, double-blind, placebo-controlled phase II trial evaluating the efficacy and safety of 52 weeks of treatment with pirfenidone in patients with chronic HFpEF (symptoms and signs of heart failure, left ventricular ejection fraction ≥ 45%, elevated natriuretic peptides [BNP ≥ 100 pg/ml or NT-proBNP ≥ 300 pg/ml; or BNP ≥ 300 pg/ml or NT-proBNP ≥ 900 pg/ml if in atrial fibrillation]) and myocardial fibrosis (extracellular matrix (ECM) volume ≥ 27% measured using cardiovascular magnetic resonance). The primary outcome measure is change in myocardial ECM volume. A sub-study will investigate the relationship between myocardial fibrosis and myocardial energetics, and the impact of pirfenidone, using 31phosphorus magnetic resonance spectroscopy. Discussion PIROUETTE will determine whether pirfenidone is superior to placebo in relation to regression of myocardial fibrosis and improvement in myocardial energetics in patients with HFpEF and myocardial fibrosis (NCT02932566). Clinical Trial Registration clinicaltrials.gov (NCT02932566) https://clinicaltrials.gov/ct2/show/NCT02932566</p

Pirfenidone in heart failure with preserved ejection fraction: a randomized phase 2 trial.

From PubMed via Jisc Publications RouterHistory: received 2020-12-24, accepted 2021-06-25Publication status: ppublishFunder: DH | National Institute for Health Research (NIHR); Grant(s): CS-2015-15-003In heart failure with preserved ejection fraction (HFpEF), the occurrence of myocardial fibrosis is associated with adverse outcome. Whether pirfenidone, an oral antifibrotic agent without hemodynamic effect, is efficacious and safe for the treatment of HFpEF is unknown. In this double-blind, phase 2 trial ( NCT02932566 ), we enrolled patients with heart failure, an ejection fraction of 45% or higher and elevated levels of natriuretic peptides. Eligible patients underwent cardiovascular magnetic resonance and those with evidence of myocardial fibrosis, defined as a myocardial extracellular volume of 27% or greater, were randomly assigned to receive pirfenidone or placebo for 52 weeks. Forty-seven patients were randomized to each of the pirfenidone and placebo groups. The primary outcome was change in myocardial extracellular volume, from baseline to 52 weeks. In comparison to placebo, pirfenidone reduced myocardial extracellular volume (between-group difference, -1.21%; 95% confidence interval, -2.12 to -0.31; P = 0.009), meeting the predefined primary outcome. Twelve patients (26%) in the pirfenidone group and 14 patients (30%) in the placebo group experienced one or more serious adverse events. The most common adverse events in the pirfenidone group were nausea, insomnia and rash. In conclusion, among patients with HFpEF and myocardial fibrosis, administration of pirfenidone for 52 weeks reduced myocardial fibrosis. The favorable effects of pirfenidone in patients with HFpEF will need to be confirmed in future trials. [Abstract copyright: © 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.