Prehospital continuous positive airway pressure for acute respiratory failure: the ACUTE feasibility RCT.

BACKGROUND: Acute respiratory failure is a life-threatening emergency. Standard prehospital management involves controlled oxygen therapy. Continuous positive airway pressure is a potentially beneficial alternative treatment; however, it is uncertain whether or not this treatment could improve outcomes in NHS ambulance services. OBJECTIVES: To assess the feasibility of a large-scale pragmatic trial and to update an existing economic model to determine cost-effectiveness and the value of further research. DESIGN: (1) An open-label, individual patient randomised controlled external pilot trial. (2) Cost-effectiveness and value-of-information analyses, updating an existing economic model. (3) Ancillary substudies, comprising an acute respiratory failure incidence study, an acute respiratory failure diagnostic agreement study, clinicians perceptions of a continuous positive airway pressure mixed-methods study and an investigation of allocation concealment. SETTING: Four West Midlands Ambulance Service hubs, recruiting between August 2017 and July 2018. PARTICIPANTS: Adults with respiratory distress and peripheral oxygen saturations below the British Thoracic Society's target levels were included. Patients with limited potential to benefit from, or with contraindications to, continuous positive airway pressure were excluded. INTERVENTIONS: Prehospital continuous positive airway pressure (O-Two system, O-Two Medical Technologies Inc., Brampton, ON, Canada) was compared with standard oxygen therapy, titrated to the British Thoracic Society's peripheral oxygen saturation targets. Interventions were provided in identical sealed boxes. MAIN OUTCOME MEASURES: Feasibility objectives estimated the incidence of eligible patients, the proportion recruited and allocated to treatment appropriately, adherence to allocated treatment, and retention and data completeness. The primary clinical end point was 30-day mortality. RESULTS: Seventy-seven patients were enrolled (target 120 patients), including seven patients with a diagnosis for which continuous positive airway pressure could be ineffective or harmful. Continuous positive airway pressure was fully delivered to 74% of participants (target 75%). There were no major protocol violations/non-compliances. Full data were available for all key outcomes (target ≥ 90%). Thirty-day mortality was 27.3%. Of the 21 deceased participants, 14 (68%) either did not have a respiratory condition or had ceiling-of-treatment decision implemented that excluded hospital non-invasive ventilation and critical care. The base-case economic evaluation indicated that standard oxygen therapy was probably cost-effective (incremental cost-effectiveness ratio £5685 per quality-adjusted life-year), but there was considerable uncertainty (population expected value of perfect information of £16.5M). Expected value of partial perfect information analyses indicated that effectiveness of prehospital continuous positive airway pressure was the only important variable. The incidence rate of acute respiratory failure was 17.4 (95% confidence interval 16.3 to 18.5) per 100,000 persons per year. There was moderate agreement between the primary prehospital and final hospital diagnoses (Gwet's AC1 coefficient 0.56, 95% confidence interval 0.43 to 0.69). Lack of hospital awareness of the Ambulance continuous positive airway pressure (CPAP): Use, Treatment Effect and economics (ACUTE) trial, limited time to complete trial training and a desire to provide continuous positive airway pressure treatment were highlighted as key challenges by participating clinicians. LIMITATIONS: During week 10 of recruitment, the continuous positive airway pressure arm equipment boxes developed a 'rattle'. After repackaging and redistribution, no further concerns were noted. A total of 41.4% of ambulance service clinicians not participating in the ACUTE trial indicated a difference between the control and the intervention arm trial boxes (115/278); of these clinician 70.4% correctly identified box contents. CONCLUSIONS: Recruitment rate was below target and feasibility was not demonstrated. The economic evaluation results suggested that a definitive trial could represent value for money. However, limited compliance with continuous positive airway pressure and difficulty in identifying patients who could benefit from continuous positive airway pressure indicate that prehospital continuous positive airway pressure is unlikely to materially reduce mortality. FUTURE WORK: A definitive clinical effectiveness trial of continuous positive airway pressure in the NHS is not recommended. TRIAL REGISTRATION: Current Controlled Trials ISRCTN12048261. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 7. See the NIHR Journals Library website for further project information.

Acute respiratory failure is a life-threatening medical emergency. It occurs when heart or lung disease suddenly develops, or deteriorates, and leads to the patient being unable to maintain oxygen levels in their blood. Continuous positive airway pressure is a potentially useful treatment that could be used by paramedics. It involves delivering oxygen under increased pressure through a tight-fitting face mask. However, it is uncertain whether or not it could work effectively in NHS ambulance services, or if it represents value for money. The Ambulance continuous positive airway pressure (CPAP): Use, Treatment Effect and economics (ACUTE) trial investigated whether or not it is possible and worthwhile to undertake a full-scale study comparing continuous positive airway pressure with normal paramedic treatment. Paramedics identified adults with acute respiratory failure when attending 999 emergency calls. Half were randomly assigned to receive continuous positive airway pressure, whereas the other half were treated normally. Patients were then followed up to see what happened to them. Fewer patients than expected were entered into the trial, but paramedics were able to provide treatment with continuous positive airway pressure, and most patients were successfully followed up. It therefore seems possible to do a full-scale trial. A cost-effectiveness model also showed that it is uncertain whether or not continuous positive airway pressure represents value for money for the NHS, so further research might be worthwhile, if continuous positive airway pressure is thought to be effective. However, examination of patients recruited to the trial uncovered important doubts about whether or not continuous positive airway pressure would help them. One-quarter of patients were not able to tolerate the tight continuous positive airway pressure mask. Some of the patients had conditions that are not usually treated by continuous positive airway pressure, or had severe underlying disease that could not be helped by this treatment. Others had collapsed lungs that could have been made worse by continuous positive airway pressure. This means that, although a full-scale trial may be possible, it is difficult to see how continuous positive airway pressure could save enough lives to make a trial worthwhile.

Cost-effectiveness of out-of-hospital continuous positive airway pressure for acute respiratory failure: decision analytic modelling using data from a feasibility trial.

BACKGROUND: Standard prehospital management for Acute respiratory failure (ARF) involves controlled oxygen therapy. Continuous positive airway pressure (CPAP) is a potentially beneficial alternative treatment, however, it is uncertain whether this could improve outcomes and provide value for money. This study aimed to evaluate the cost-effectiveness of prehospital CPAP in ARF. METHODS: A cost-utility economic evaluation was performed using a probabilistic decision tree model synthesising available evidence. The model consisted of a hypothetical cohort of patients in a representative ambulance service with undifferentiated ARF, receiving standard oxygen therapy or prehospital CPAP. Costs and quality adjusted life years (QALYs) were estimated using methods recommended by NICE. RESULTS: In the base case analysis, using CPAP effectiveness estimates form the ACUTE trial, the mean expected costs of standard care and prehospital CPAP were £15,201 and £14,850 respectively and the corresponding mean expected QALYs were 1.190 and 1.128, respectively. The mean ICER estimated as standard oxygen therapy compared to prehospital CPAP was £5685 per QALY which indicated that standard oxygen therapy strategy was likely to be cost-effective at a threshold of £20,000 per QALY (67% probability). The scenario analysis, using effectiveness estimates from an updated meta-analysis, suggested that prehospital CPAP was more effective (mean incremental QALYs of 0.157), but also more expensive (mean incremental costs of £1522), than standard care. The mean ICER, estimated as prehospital CPAP compared to standard care, was £9712 per QALY. At the £20,000 per QALY prehospital CPAP was highly likely to be the most cost-effective strategy (94%). CONCLUSIONS: Cost-effectiveness of prehospital CPAP depends upon the estimate of effectiveness. When based on a small pragmatic feasibility trial, standard oxygen therapy is cost-effective. When based on meta-analysis of heterogeneous trials, CPAP is cost-effective. Value of information analyses support commissioning of a large pragmatic effectiveness trial, providing feasibility and plausibility conditions are met.

The diagnostic accuracy of pre-hospital assessment of acute respiratory failure.

INTRODUCTION: Acute respiratory failure (ARF) is a common medical emergency. Pre-hospital management includes controlled oxygen therapy, supplemented by specific management options directed at the underlying disease. The aim of the current study was to characterise the accuracy of paramedic diagnostic assessment in acute respiratory failure. METHODS: A nested diagnostic accuracy and agreement study comparing pre-hospital clinical impression to the final hospital discharge diagnosis was conducted as part of the ACUTE (Ambulance CPAP: Use, Treatment effect and Economics) trial. Adults with suspected ARF were recruited from the UK West Midlands Ambulance Service. The pre-hospital clinical impression of the recruiting ambulance service clinician was prospectively recorded and compared to the final hospital diagnosis at 30 days. Agreement between pre-hospital and hospital diagnostic assessments was evaluated using raw agreement and Gwets AC1 coefficient. RESULTS: 77 participants were included. Chronic obstructive pulmonary disease (32.9%) and lower respiratory tract infection (32.9%) were the most frequently suspected primary pre-hospital diagnoses for ARF, with secondary contributory conditions recorded in 36 patients (46.8%). There was moderate agreement between the primary pre-hospital and hospital diagnoses, with raw agreement of 58.5% and a Gwets AC1 coefficient of 0.56 (95% CI 0.43 to 0.69). In five cases, a non-respiratory final diagnosis was present, including: myocardial infarction, ruptured abdominal aortic aneurysm, liver failure and sepsis. CONCLUSIONS: Pre-hospital assessment of ARF is challenging, with limited accuracy compared to the final hospital diagnosis. A syndromic approach, providing general supportive care, rather than a specifically disease-orientated treatment strategy, is likely to be most appropriate for the pre-hospital environment.

The ACUTE (Ambulance CPAP: Use, Treatment effect and economics) feasibility study: a pilot randomised controlled trial of prehospital CPAP for acute respiratory failure.

BACKGROUND: Acute respiratory failure (ARF) is a common and life-threatening medical emergency. Standard prehospital management involves controlled oxygen therapy and disease-specific ancillary treatments. Continuous positive airway pressure (CPAP) is a potentially beneficial alternative treatment that could be delivered by emergency medical services. However, it is uncertain whether this treatment could work effectively in United Kingdom National Health Service (NHS) ambulance services and if it represents value for money. METHODS: An individual patient randomised controlled external pilot trial will be conducted comparing prehospital CPAP to standard oxygen therapy for ARF. Adults presenting to ambulance service clinicians will be eligible if they have respiratory distress with peripheral oxygen saturation below British Thoracic Society (BTS) target levels, despite titrated supplemental oxygen. Enrolled patients will be allocated (1:1 simple randomisation) to prehospital CPAP (O_two system) or standard oxygen therapy using identical sealed boxes. Feasibility outcomes will include incidence of recruited eligible patients, number of erroneously recruited patients and proportion of cases adhering to allocation schedule and treatment, followed up at 30 days and with complete data collection. Effectiveness outcomes will comprise survival at 30 days (definitive trial primary end point), endotracheal intubation, admission to critical care, length of hospital stay, visual analogue scale (VAS) dyspnoea score, EQ-5D-5L and health care resource use at 30 days. The cost-effectiveness of CPAP, and of conducting a definitive trial, will be evaluated by updating an existing economic model. The trial aims to recruit 120 patients over 12 months from four regional ambulance hubs within the West Midlands Ambulance Service (WMAS). This sample size will allow estimation of feasibility outcomes with a precision of < 5%. Feasibility and effectiveness outcomes will be reported descriptively for the whole trial population, and each trial arm, together with their 95% confidence intervals. DISCUSSION: This study will determine if it is feasible, acceptable and cost-effective to undertake a full-scale trial comparing CPAP and standard oxygen treatment, delivered by ambulance service clinicians for ARF. This will inform NHS practice and prevent inappropriate prehospital CPAP adoption on the basis of limited evidence and at a potentially substantial cost. TRIAL REGISTRATION: ISRCTN12048261. Registered on 30 August 2017. http://www.isrctn.com/ISRCTN12048261.

The free healthcare initiative in Sierra Leone: Evaluating a health system reform, 2010-2015.

This article presents the findings of a theory-based evaluation of the Sierra Leone Free Health Care Initiative (FHCI), using mixed methods. Analytical approaches included time-series analysis of national survey data to examine mortality and morbidity trends, as well as modelling of impact using the Lives Saved Tool and expenditure trend analysis. We find that the FHCI responded to a clear need in Sierra Leone, was well designed to bring about needed changes in the health system to deliver services to the target beneficiaries, and did indeed bring funds and momentum to produce important systemic reforms. However, its ambition was also a risk, and weaknesses in implementation have been evident in a number of core areas, such as drugs supply. We conclude that the FHCI was one important factor contributing to improvements in coverage and equity of coverage of essential services for mothers and children. Modelled cost-effectiveness is high-in the region of US$ 420 to US$ 444 per life year saved. The findings suggest that even-or perhaps especially-in a weak health system, a reform-like fee removal, if tackled in a systematic way, can bring about important health system gains that benefit vulnerable groups in particular.

"They Shouldn't Be Coming to the ED, Should They?": A Descriptive Service Evaluation of Why Patients With Palliative Care Needs Present to the Emergency Department.

BACKGROUND: Patients with palliative care needs frequently attend the emergency department (ED). There is no international agreement on which patients are best cared for in the ED, compared to the primary care setting or direct admission to the hospital. This article presents the quantitative phase of a mixed-methods service evaluation, exploring the reasons why patients with palliative care needs present to the ED. METHODS: This is a single-center, observational study including all patients under the care of a specialist palliative care team who presented to the ED over a 10-week period. Demographic and clinical data were collected from electronic health records. RESULTS: A total of 105 patients made 112 presentations to the ED. The 2 most common presenting complaints were shortness of breath (35%) and pain (28%). Eighty-three percent of presentations required care in the ED according to a priori defined criteria. They either underwent urgent investigation or received immediate interventions that could not be delivered in another setting, were referred by a health-care professional, or were admitted. CONCLUSIONS: Findings challenge the misconception that patients known to a palliative care team should be cared for outside the ED. The importance and necessity of the ED for patients in their last years of life has been highlighted, specifically in terms of managing acute, unpredictable crises. Future service provision should not be based solely on a patient's presenting complaint. Further qualitative research exploring patient perspective is required in order to explore the decision-making process that leads patients with palliative care needs to the ED.

Safety and feasibility of sublingual microcirculation assessment in the emergency department for civilian and military patients with traumatic haemorrhagic shock: a prospective cohort study.

OBJECTIVES: Sublingual microcirculatory monitoring for traumatic haemorrhagic shock (THS) may predict clinical outcomes better than traditional blood pressure and cardiac output, but is not usually performed until the patient reaches the intensive care unit (ICU), missing earlier data of potential importance. This pilot study assessed for the first time the feasibility and safety of sublingual video-microscopy for THS in the emergency department (ED), and whether it yields useable data for analysis. SETTING: A safety and feasibility assessment was undertaken as part of the prospective observational MICROSHOCK study; sublingual video-microscopy was performed at the UK-led Role 3 medical facility at Camp Bastion, Afghanistan, and in the ED in 3 UK Major Trauma Centres. PARTICIPANTS: There were 15 casualties (2 military, 13 civilian) who presented with traumatic haemorrhagic shock with a median injury severity score of 26. The median age was 41; the majority (n=12) were male. The most common injury mechanism was road traffic accident. PRIMARY AND SECONDARY OUTCOME MEASURES: Safety and feasibility were the primary outcomes, as measured by lack of adverse events or clinical interruptions, and successful acquisition and storage of data. The secondary outcome was the quality of acquired video clips according to validated criteria, in order to determine whether useful data could be obtained in this emergency context. RESULTS: Video-microscopy was successfully performed and stored for analysis for all patients, yielding 161 video clips. There were no adverse events or episodes where clinical management was affected or interrupted. There were 104 (64.6%) video clips from 14 patients of sufficient quality for analysis. CONCLUSIONS: Early sublingual microcirculatory monitoring in the ED for patients with THS is safe and feasible, even in a deployed military setting, and yields videos of satisfactory quality in a high proportion of cases. Further investigations of early microcirculatory behaviour in this context are warranted. TRIAL REGISTRATION NUMBER: NCT02111109.

The assessment of circulating volume using inferior vena cava collapse index and carotid Doppler velocity time integral in healthy volunteers: a pilot study.

BACKGROUND: Assessment of circulating volume and the requirement for fluid replacement are fundamental to resuscitation but remain largely empirical. Passive leg raise (PLR) may determine fluid responders while avoiding potential fluid overload. We hypothesised that inferior vena cava collapse index (IVCCI) and carotid artery blood flow would change predictably in response to PLR, potentially providing a non-invasive tool to assess circulating volume and identifying fluid responsive patients. METHODS: We conducted a prospective proof of concept pilot study on fasted healthy volunteers. One operator measured IVC diameter during quiet respiration and sniff, and carotid artery flow. Stroke volume (SV) was also measured using suprasternal Doppler. Our primary endpoint was change in IVCCI after PLR. We also studied changes in IVCCI after "sniff", and correlation between carotid artery flow and SV. RESULTS: Passive leg raise was associated with significant reduction in the mean inferior vena cava collapsibility index from 0.24 to 0.17 (p < 0.01). Mean stroke volume increased from 56.0 to 69.2 mL (p < 0.01). There was no significant change in common carotid artery blood flow. Changes in physiology consequent upon passive leg raise normalised rapidly. DISCUSSION: Passive leg raise is associated with a decrease of IVCCI and increase in stroke volume. However, the wide range of values observed suggests that factors other than circulating volume predominate in determining the proportion of collapse with respiration. CONCLUSION: In contrast to other studies, we did not find that carotid blood flow increased with passive leg raise. Rapid normalisation of post-PLR physiology may account for this.

Academic-industrial partnerships in drug discovery in the age of genomics.

Many US FDA-approved drugs have been developed through productive interactions between the biotechnology industry and academia. Technological breakthroughs in genomics, in particular large-scale sequencing of human genomes, is creating new opportunities to understand the biology of disease and to identify high-value targets relevant to a broad range of disorders. However, the scale of the work required to appropriately analyze large genomic and clinical data sets is challenging industry to develop a broader view of what areas of work constitute precompetitive research.

Is the case-mix of patients who self-present to ED similar to general practice and other acute-care facilities?

OBJECTIVE: To benchmark walk-in presentations to emergency departments (ED) with those presenting to other local acute healthcare facilities. SETTING: A large teaching hospital with an annual ED census of 140, 000 adult patients and surrounding associated acute healthcare providers. METHODS: A random sample of 384 patients who self-presented to the ED was obtained. Benchmarking data were drawn from two general practices; the Tower Hamlets Community Services walk-in centre (co-located on-site with the ED) and the GP-run out-of-hours service. RESULTS: The case-mix presenting to the ED was characterised by a higher proportion of injuries and chest pain, but fewer simple infections and non-traumatic musculoskeletal conditions as compared to other acute care facilities in our region. CONCLUSIONS: Patients with injuries and possible cardiac chest pain were more likely to attend the ED, and those with infection or musculoskeletal problems less likely, as compared with other acute healthcare facilities. The population presenting to the ED is distinct from that presenting to general practice, out-of-hours clinics, or walk-in centres.

Clinical and cost effectiveness of switching asthma patients from fluticasone-salmeterol to extra-fine particle beclometasone-formoterol: a retrospective matched observational study of real-world patients.

BACKGROUND: Efficacy trials suggest that extra-fine particle beclometasone dipropionate-formoterol (efBDP-FOR) is comparable to fluticasone propionate-salmeterol (FP-SAL) in preventing asthma exacerbations at a clinically equivalent dosage. However, switching from FP-SAL to efBDP-FOR has not been evaluated in real-world asthma patients. AIMS: The REACH (Real-world Effectiveness in Asthma therapy of Combination inHalers) study investigated the clinical and cost effectiveness of switching typical asthma patients from FP-SAL to efBDP-FOR. METHODS: A retrospective matched (1:3) observational study of 1,528 asthma patients aged 18-80 years from clinical practice databases was performed. Patients remaining on FP-SAL (n=1,146) were compared with those switched to efBDP-FOR at an equivalent or lower inhaled corticosteroid (ICS) dosage (n=382). Clinical and economic outcomes were compared between groups for the year before and after the switch. Non-inferiority (at least equivalence) of efBDP-FOR was tested against FP-SAL by comparing exacerbation rates during the outcome year. RESULTS: efBDP-FOR was non-inferior to FP-SAL (adjusted exacerbation rate ratio 1.01 (95% CI 0.74 to 1.37)). Switching to efBDP-FOR resulted in significantly better (p<0.05) odds of achieving overall asthma control (no asthma-related hospitalisations, bronchial infections, or acute oral steroids; salbutamol ≤200µg/day) and lower daily short-acting ß2-agonist usage at a lower daily ICS dosage (mean -130µg/day FP equivalents; p<0.001). It also reduced mean asthma-related healthcare costs by £93.63/patient/year (p<0.001). CONCLUSIONS: Asthma patients may be switched from FP-SAL to efBDP-FOR at an equivalent or lower ICS dosage with no reduction in clinical effectiveness but a significant reduction in cost.

Cricoid pressure and laryngeal manipulation in 402 pre-hospital emergency anaesthetics: essential safety measure or a hindrance to rapid safe intubation?

OBJECTIVES: This is the first study to look at the effects of cricoid pressure/laryngeal manipulation on the laryngeal view and intubation success in the emergency or pre-hospital environment. Cricoid pressure is applied in the hope of reducing the incidence of aspiration. However the technique has never been evaluated in a randomized trial and may adversely affect laryngeal view. In order to improve intubating conditions cricoid pressure may be released and the larynx manipulated into a more favourable position. METHODS: We carried out a prospective observational study to evaluate the effects of cricoid pressure and laryngeal manipulation on laryngeal view in our physician led pre-hospital trauma service. RESULTS: 402 patients were included over a 16-month period. We intubated 98.8% patients on the first or second attempt. In 61 intubations (in 55 patients, 13.6%) the larynx required manipulation to facilitate intubation. In 22 intubations cricoid pressure was removed with the laryngeal view improving in 50%. Bimanual laryngeal manipulation was used in 25 intubations and the larynx better visualised in 60% of these. Backwards upwards rightwards pressure was applied to the larynx in 14 intubations and the laryngeal view improved in 64%. Two patients regurgitated when cricoid pressure was released. Both had prolonged periods of bag valve mask ventilation and difficult intubations. DISCUSSION: The results suggest that cricoid pressure should be removed if the laryngeal view obtained is not sufficient to allow immediate intubation. Further manipulation of the larynx is likely to improve the chances of successful tracheal tube placement.