Cost-effectiveness of oral ondansetron for children with acute gastroenteritis in primary care:a randomised controlled trial

BackgroundAcute gastroenteritis is a common childhood condition with substantial medical and indirect costs, mostly because of referral, hospitalisation, and parental absence from work.AimTo determine the cost-effectiveness of adding oral ondansetron to care as usual (CAU) for children with acute gastroenteritis presenting to out-of-hours primary care (OOH-PC).Design and settingA pragmatic randomised controlled trial from December 2015 to January 2018, at three OOH-PC centres in the north of the Netherlands (Groningen, Zwolle, and Assen) with a follow-up of 7 days.MethodChildren were recruited at the OOH-PC and parents kept a parental diary. Inclusion criteria were: aged 6 months-6 years; diagnosis of acute gastroenteritis; at least four reported episodes of vomiting 24 hours before presentation, at least one of which was in the 4 hours before presentation; and written informed consent from both parents. Children were randomly allocated at a 1:1 ratio to either CAU (oral rehydration therapy) or CAU plus one dose of 0.1 mg/kg oral ondansetron.ResultsIn total, 194 children were included for randomisation. One dose of oral ondansetron decreased the proportion of children who continued vomiting within the first 4 hours from 42.9% to 19.5%, (a decrease of 54.5%), with an odds ratio of 0.4 (95% confidence interval [CI] = 0.2 to 0.7; number needed to treat: four). Total mean costs in the ondansetron group were 31.2% lower ((sic)488 [420] pound versus (sic)709 [610]) pound, and the total incremental mean costs for an additional child free of vomiting in the first 4 hours was -(sic)9 (8) pound (95% CI = -(sic)41 [35] pound to (sic)3 [3]) pound.ConclusionA single oral dose of ondansetron for children with acute gastroenteritis, given in OOH-PC settings, is both clinically beneficial and cost-effective.</p

Recommendations for clinical research in children presenting to primary care out-of-hours services

BACKGROUND: Research in primary care is essential, but recruiting children in this setting can be complex and may cause selection bias. Challenges surrounding informed consent, particularly in an acute clinical setting, can undermine feasibility. The off-protocol use of an intervention nearing implementation has become common in pragmatic randomized controlled trials (RCTs) set in primary care. AIM: To describe how the informed consent procedure affects study inclusion and to assess how off-protocol medication prescribing affects participant selection in a paediatric RCT. DESIGN: A pragmatic RCT evaluating the cost-effectiveness of oral ondansetron in children diagnosed with acute gastroenteritis in primary care out-of-hours services and a parallel cohort study. METHOD: Consecutive children aged 6 months to 6 years attending primary care out-of-hours services with acute gastroenteritis were evaluated to assess the feasibility of obtaining informed consent, the off-protocol use of ondansetron, and other inclusion/exclusion criteria. RESULTS: The RCTs feasibility was reduced by the informed consent procedure because 39.0% (325/834) of children were accompanied by only one parent. General practitioners prescribed ondansetron off-protocol to 34 children (4.1%), whereof 19 children were eligible for the RCT. RCT-eligible children included in the parallel cohort had fewer risk factors for dehydration than children in the RCT despite similar dehydration assessments by general practitioners. CONCLUSION: The informed consent procedure and off-protocol use of study medication affect the inclusion rate but had little effect on selection. A parallel cohort study alongside the RCT can help evaluate selection bias, and a pilot study can reveal potential barriers to inclusion

Oral ondansetron for paediatric gastroenteritis in primary care:a randomised controlled trial

BACKGROUND: Acute gastroenteritis (AGE) affects almost all children aged ≤5 years. In secondary care, ondansetron was found to be effective at reducing vomiting. AIM: To determine the effectiveness of adding oral ondansetron to care as usual (CAU) to treat vomiting in children with AGE attending out-ofhours primary care (OOH-PC). DESIGN AND SETTING: A pragmatic randomised controlled trial at three OOH-PC centres in the north of the Netherlands (Groningen, Zwolle, and Assen), with a follow-up of 7 days. METHOD: Children were included if they were: aged 6 months–6 years; AGE diagnosed by a GP; ≥4 reported episodes of vomiting in the 24 hours before presentation; ≥1 reported episode of vomiting in the 4 hours before presentation; and written informed consent from both parents. Children were randomly allocated to either the control group or the intervention group. The control group received CAU, namely oral rehydration therapy. The intervention group received CAU plus one dose of oral ondansetron (0.1 mg/kg). RESULTS: In total, 194 children were included for randomisation. One dose of oral ondansetron decreased the proportion of children who continued vomiting within 4 hours from 42.9% to 19.5%, with an odds ratio of 0.37 (95% confidence interval [CI] = 0.20 to 0.72, number needed to treat: four). Ondansetron also decreased the number of vomiting episodes within 4 hours (incidence rate ratio 0.51 [95% CI = 0.29 to 0.88]) and improved overall parental satisfaction with treatment (P = 0.027). CONCLUSION: Children with AGE and increased risk of dehydration due to vomiting could be treated with ondansetron in primary care to stop vomiting more quickly and increase parental satisfaction with treatment. These results could be used to improve the quality and efficacy of general practice medicine

Brown adipose tissue activity after a high-calorie meal in humans.

BACKGROUND: Studies in rodents have shown that brown adipose tissue (BAT) is activated on food intake, thereby reducing metabolic efficiency. OBJECTIVE: The current study investigated whether a single high-calorie, carbohydrate-rich meal activates BAT in lean human adults. DESIGN: BAT activity was studied in 11 lean adult men [age: 23.6 +/- 2.1 y; body mass index (BMI; in kg/m2): 22.4 +/- 2.1] after consumption of a high-calorie, carbohydrate-rich meal (1622 +/- 222 kcal; 78% carbohydrate, 12% P, 10% F). BAT activity during 2 h of mild cold exposure served as a positive control experiment. BAT activity was assessed by [18F]fluorodeoxyglucose (FDG)-positron emission tomography-computed tomography. Energy expenditure was measured by indirect calorimetry. RESULTS: Postprandial [18F]FDG uptake was significantly higher in BAT [1.65 +/- 0.99 mean standard uptake value (SUVmean)] than in subcutaneous (0.35 +/- 0.15 SUVmean; P < 0.05) and visceral (0.49 +/- 0.24 SUVmean; P < 0.05) white adipose tissue and liver (0.95 +/- 0.28 SUVmean; P < 0.05). Postprandial BAT activity was lower than cold-induced BAT activity (7.19 +/- 2.09 SUVmean). However, postprandial BAT activity may have been underestimated because of high postprandial [18F]FDG uptake in skeletal muscle compared with cold (1.36 +/- 0.31 compared with 0.59 +/- 0.07 SUVmean, P < 0.05), which reduces [18F]FDG bioavailability for BAT and other tissues. No direct relation was found between BAT and diet-induced thermogenesis (DIT). CONCLUSIONS: Glucose uptake in BAT increases after a meal in humans, which indicates a role for BAT in reducing metabolic efficiency. However, the quantitative contribution of BAT to DIT relative to other tissues, such as skeletal muscle, remains to be investigated. This trial was registered at www.controlled-trials.com as ISRCTN21413505

A Randomized Trial of Intravenous Alteplase before Endovascular Treatment for Stroke

The value of administering intravenous alteplase before endovascular treatment (EVT) for acute ischemic stroke has not been studied extensively, particularly in non-Asian populations. METHODS We performed an open-label, multicenter, randomized trial in Europe involving patients with stroke who presented directly to a hospital that was capable of providing EVT and who were eligible for intravenous alteplase and EVT. Patients were randomly assigned in a 1:1 ratio to receive EVT alone or intravenous alteplase followed by EVT (the standard of care). The primary end point was functional outcome on the modified Rankin scale (range, 0 [no disability] to 6 [death]) at 90 days. We assessed the superiority of EVT alone over alteplase plus EVT, as well as noninferiority by a margin of 0.8 for the lower boundary of the 95% confidence interval for the odds ratio of the two trial groups. Death from any cause and symptomatic intracerebral hemorrhage were the main safety end points. RESULTS The analysis included 539 patients. The median score on the modified Rankin scale at 90 days was 3 (interquartile range, 2 to 5) with EVT alone and 2 (interquartile range, 2 to 5) with alteplase plus EVT. The adjusted common odds ratio was 0.84 (95% confidence interval [CI], 0.62 to 1.15; P=0.28), which showed neither superiority nor noninferiority of EVT alone. Mortality was 20.5% with EVT alone and 15.8% with alteplase plus EVT (adjusted odds ratio, 1.39; 95% CI, 0.84 to 2.30). Symptomatic intracerebral hemorrhage occurred in 5.9% and 5.3% of the patients in the respective groups (adjusted odds ratio, 1.30; 95% CI, 0.60 to 2.81). CONCLUSIONS In a randomized trial involving European patients, EVT alone was neither superior nor noninferior to intravenous alteplase followed by EVT with regard to disability outcome at 90 days after stroke. The incidence of symptomatic intracerebral hemorrhage was similar in the two groups

Safety and efficacy of aspirin, unfractionated heparin, both, or neither during endovascular stroke treatment (MR CLEAN-MED):an open-label, multicentre, randomised controlled trial

Background: Aspirin and unfractionated heparin are often used during endovascular stroke treatment to improve reperfusion and outcomes. However, the effects and risks of anti-thrombotics for this indication are unknown. We therefore aimed to assess the safety and efficacy of intravenous aspirin, unfractionated heparin, both, or neither started during endovascular treatment in patients with ischaemic stroke. Methods: We did an open-label, multicentre, randomised controlled trial with a 2 × 3 factorial design in 15 centres in the Netherlands. We enrolled adult patients (ie, ≥18 years) with ischaemic stroke due to an intracranial large-vessel occlusion in the anterior circulation in whom endovascular treatment could be initiated within 6 h of symptom onset. Eligible patients had a score of 2 or more on the National Institutes of Health Stroke Scale, and a CT or MRI ruling out intracranial haemorrhage. Randomisation was done using a web-based procedure with permuted blocks and stratified by centre. Patients were randomly assigned (1:1) to receive either periprocedural intravenous aspirin (300 mg bolus) or no aspirin, and randomly assigned (1:1:1) to receive moderate-dose unfractionated heparin (5000 IU bolus followed by 1250 IU/h for 6 h), low-dose unfractionated heparin (5000 IU bolus followed by 500 IU/h for 6 h), or no unfractionated heparin. The primary outcome was the score on the modified Rankin Scale at 90 days. Symptomatic intracranial haemorrhage was the main safety outcome. Analyses were based on intention to treat, and treatment effects were expressed as odds ratios (ORs) or common ORs, with adjustment for baseline prognostic factors. This trial is registered with the International Standard Randomised Controlled Trial Number, ISRCTN76741621. Findings: Between Jan 22, 2018, and Jan 27, 2021, we randomly assigned 663 patients; of whom, 628 (95%) provided deferred consent or died before consent could be asked and were included in the modified intention-to-treat population. On Feb 4, 2021, after unblinding and analysis of the data, the trial steering committee permanently stopped patient recruitment and the trial was stopped for safety concerns. The risk of symptomatic intracranial haemorrhage was higher in patients allocated to receive aspirin than in those not receiving aspirin (43 [14%] of 310 vs 23 [7%] of 318; adjusted OR 1·95 [95% CI 1·13–3·35]) as well as in patients allocated to receive unfractionated heparin than in those not receiving unfractionated heparin (44 [13%] of 332 vs 22 [7%] of 296; 1·98 [1·14–3·46]). Both aspirin (adjusted common OR 0·91 [95% CI 0·69–1·21]) and unfractionated heparin (0·81 [0·61–1·08]) led to a non-significant shift towards worse modified Rankin Scale scores. Interpretation: Periprocedural intravenous aspirin and unfractionated heparin during endovascular stroke treatment are both associated with an increased risk of symptomatic intracranial haemorrhage without evidence for a beneficial effect on functional outcome. Funding: The Collaboration for New Treatments of Acute Stroke consortium, the Brain Foundation Netherlands, the Ministry of Economic Affairs, Stryker, Medtronic, Cerenovus, and the Dutch Heart Foundation.</p

Referral rates for children with acute gastroenteritis: a retrospective cohort study

BackgroundHospital admission rates are increasing for children with acute gastroenteritis. However, it is unknown whether this increase is accompanied by an increase in referral rates from GPs due to increased workloads in primary care out-of-hours (OOH) services.AimTo assess trends in referral rates from primary care OOH services to specialist emergency care for children presenting with acute gastroenteritis.Design &amp; settingThis retrospective cohort study covered a period from September 2007–September 2014. Children aged 6 months to 6 years presenting with acute gastroenteritis to a primary care OOH service were included.MethodPseudonymised data were obtained, and children were analysed overall and by age category. Χ2 trend tests were used to assess rates of acute gastroenteritis, referrals, face-to-face contacts, and oral rehydration therapy (ORT) prescriptions.ResultsThe data included 12 455 children (6517 boys), with a median age of 20.2 months (interquartile range [IQR] 11.6 to 36.0 months). Over 7 years, incidence rates of acute gastroenteritis decreased significantly, and face-to-face contact rates increased significantly (both, P&lt;0.01). However, there was no significant trend for referral rates (P = 0.87) or prescription rates for ORT (P = 0.82). Subgroup analyses produced comparable results, although there was an increase in face-to-face contact rates for the older children.ConclusionIncidence rates for childhood acute gastroenteritis presenting in OOH services decreased and referral rates did not increase significantly. These findings may be useful as a reference for the impact of new interventions for childhood acute gastroenteritis.</jats:sec

Referral rates for children with acute gastroenteritis: a retrospective cohort study

BACKGROUND: Hospital admission rates are increasing for children with acute gastroenteritis. However, it is unknown whether this increase is accompanied by an increase in referral rates from GPs due to increased workloads in primary care out-of-hours (OOH) services. AIM: To assess trends in referral rates from primary care OOH services to specialist emergency care for children presenting with acute gastroenteritis. DESIGN & SETTING: This retrospective cohort study covered a period from September 2007-September 2014. Children aged 6 months to 6 years presenting with acute gastroenteritis to a primary care OOH service were included. METHOD: Pseudonymised data were obtained, and children were analysed overall and by age category. Χ2 trend tests were used to assess rates of acute gastroenteritis, referrals, face-to-face contacts, and oral rehydration therapy (ORT) prescriptions. RESULTS: The data included 12 455 children (6517 boys), with a median age of 20.2 months (interquartile range [IQR] 11.6 to 36.0 months). Over 7 years, incidence rates of acute gastroenteritis decreased significantly, and face-to-face contact rates increased significantly (both, P<0.01). However, there was no significant trend for referral rates (P = 0.87) or prescription rates for ORT (P = 0.82). Subgroup analyses produced comparable results, although there was an increase in face-to-face contact rates for the older children. CONCLUSION: Incidence rates for childhood acute gastroenteritis presenting in OOH services decreased and referral rates did not increase significantly. These findings may be useful as a reference for the impact of new interventions for childhood acute gastroenteritis

Cost-effectiveness of oral ondansetron for children with acute gastroenteritis in primary care: a randomised controlled trial

BackgroundAcute gastroenteritis is a common childhood condition with substantial medical and indirect costs, mostly because of referral, hospitalisation, and parental absence from work.AimTo determine the cost-effectiveness of adding oral ondansetron to care as usual (CAU) for children with acute gastroenteritis presenting to out-of-hours primary care (OOH-PC).Design and settingA pragmatic randomised controlled trial from December 2015 to January 2018, at three OOHPC centres in the north of the Netherlands (Groningen, Zwolle, and Assen) with a follow-up of 7 days.MethodChildren were recruited at the OOH-PC and parents kept a parental diary. Inclusion criteria were: aged 6 months–6 years; diagnosis of acute gastroenteritis; at least four reported episodes of vomiting 24 hours before presentation, at least one of which was in the 4 hours before presentation; and written informed consent from both parents. Children were randomly allocated at a 1:1 ratio to either CAU (oral rehydration therapy) or CAU plus one dose of 0.1 mg/kg oral ondansetron.ResultsIn total, 194 children were included for randomisation. One dose of oral ondansetron decreased the proportion of children who continued vomiting within the first 4 hours from 42.9% to 19.5%, (a decrease of 54.5%), with an odds ratio of 0.4 (95% confidence interval [CI] = 0.2 to 0.7; number needed to treat: four). Total mean costs in the ondansetron group were 31.2% lower (€488 [£420] versus €709 [£610]), and the total incremental mean costs for an additional child free of vomiting in the first 4 hours was −€9 (£8) (95% CI = −€41 [£35] to €3 [£3]).ConclusionA single oral dose of ondansetron for children with acute gastroenteritis, given in OOH-PC settings, is both clinically beneficial and cost-effective.</jats:sec