Fluid resuscitation in emergency patients with sepsis and hypotension (ARISE Fluids)

The question of fluid volume in resuscitation has been identified as the top priority in sepsis research by emergency physicians in the United Kingdom, Australia and New Zealand. Guidelines and sepsis pathways recommend an initial intravenous (IV) fluid bolus of 30ml/kg isotonic crystalloid for patients with sepsis and hypotension. However, there is a lack of evidence from clinical trials to support this strategy. Both observational data as well as randomised studies suggest there may be harm associated with injudicious use of fluids in sepsis. Since there is equipoise regarding a more liberal or restricted fluid volume resuscitation as first line treatment for sepsis-related hypotension, we conducted the pilot multicentre REstricted Fluid REsuscitation in Sepsis-associated Hypotension (REFRESH) trial comparing a restricted fluid protocol with early initiation of vasopressor support against standard guideline care.

The data from REFRESH will inform feasibility of a large, multicentre phase III study. However, further ground work is essential for the optimal design of a Phase III trial that will provide valuable information on feasibility (road test recruitment rate and screening processes) as well as refinement of the protocol (sample size estimation, processes of care, prevalence of the population of interest, real world clinical practice regarding fluid use).

In this ARISE Fluids study, we aim to provide more insight into current practice by conducting a bi-national multi-site prospective observational study of fluid administration in (suspected) sepsis and hypotension in the Emergency Departments of Australia and New Zealand hospitals. Sites have been selected on the basis of having expressed interest in participating in a phase III trial.

REstricted Fluid REsuscitation in Sepsis-related Hypotension (REFRESH)

The REFRESH study is a multicentre, open-label, randomised, phase II clinical feasibility trial. This is the first randomised trial examining fluid volume for initial resuscitation in septic shock in an industrialised country. A pragmatic, open-label design will establish the feasibility of undertaking a large, international, multicentre trial with sufficient power to assess clinical outcomes. The embedded biomarker study aims to provide mechanistic plausibility for a larger trial by defining the effects of fluid volume on markers of systemic inflammation and the vascular endothelium.

Participants will be patients presenting to the emergency departments of Australian metropolitan hospitals with suspected sepsis and a systolic blood pressure of < 100 mmHg, persisting after a 1000-ml fluid bolus with isotonic crystalloid. Participants will be randomised to either a second 1000-ml fluid bolus (standard care) or maintenance rate fluid only, with the early commencement of a vasopressor infusion to maintain a mean arterial pressure of > 65 mmHg, if required (restricted fluid). All will receive further protocolised fluid boluses (500 ml or 250 ml, respectively), if required during the 6-h study period. The primary outcome measure is total volume administered in the first 6 h. Secondary outcomes include fluid volume at 24 h, organ support 'free days' to day 28, 90-day mortality, and a range of feasibility and process-of-care measures. Participants will also undergo serial measurement, over the first 24 h, of biomarkers of inflammation, endothelial cell activation and glycocalyx degradation for comparison between the groups.

A randomised controlled trial of interventional versus conservative treatment of primary spontaneous pneumothorax

Primary spontaneous pneumothorax (PSP) is defined as a collapsed lung with air in the pleural cavity that occurs in the absence of clinically apparent underlying lung disease. PSP is a significant global health problem affecting adolescents and young adults. Throughout the 20th century the treatment of PSP was predominantly bed rest, with invasive treatment reserved for severely symptomatic episodes. A study in 1966 suggested that managing large and small PSP in the community was safe. Despite this, rates of intervention have steadily increased over the decades. The reasons for this are unclear and this approach has recently been questioned in the scientific literature. Preliminary data suggests that a conservative approach to management may allow faster healing and reduce the risk of recurrence from around 25 per cent to 5 per cent in the first year. Conservative management is also likely to reduce the risks of prolonged admission due to persistent leak from approximately 30 per cent to less than 10 per cent and of other complications related to interventional management. Clinicians are, however, unlikely to change a practice entrenched for decades and re-enforced by current international guidelines without robust evidence.

This study will significantly increase our understanding of Primary spontaneous pneumothorax and its optimal management. If allowing the lung to remain collapsed initially results in improved healing of the pleural defect and lower recurrence rates then this study will contribute to improve outcomes and a reduction in the morbidity associated with current treatment.