Role of Active Deresuscitation After Resuscitation-2 (RADAR-2) – a pilot randomised controlled trial of conservative fluid administration and deresuscitation in critical illness: study protocol

Role of Active Deresuscitation After Resuscitation-2 (RADAR-2) – a pilot randomised controlled trial of conservative fluid administration and deresuscitation in critical illness: study protocol

Jonathan A Silversides1,2, John C Marshall3,4, Andrew J Ferguson2, Bronagh Blackwood1, and Daniel F McAuley1

1Wellcome-Wolfson Institute for Experimental Medicine, Queen’s University Belfast, 97 Lisburn Road, Belfast, BT9 7BL
2Critical Care Unit, Belfast Health and Social Care Trust, Belfast City Hospital, Lisburn Road, Belfast BT9 7AB
3Interdepartmental Division of Critical Care, University of Toronto, 585 university Avenue, Toronto, Ontario, M5G 2N2, Canada
4Department of Critical Care Medicine, St. Michael’s Hospital, 30 Bond Street, Toronto, Ontario, M5B 1W8, Canada

Email: jon.silversides@belfasttrust.hscni.net

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AbstractFull-TextReference ListSupplementary MaterialCitationQR code

Background: Intravenous fluid administration is a common intervention in critically ill patients. However, this frequently contributes to a positive fluid balance, which is consistently associated with
adverse outcomes including mortality. A conservative or deresuscitative (use of diuretics or renal replacement therapies to remove accumulated fluid) approach to fluid management in critical illness may be beneficial but evidence is limited.

Methods/Design: Role of Active Deresuscitation After Resuscitation-2 (RADAR-2) is an open-label pilot randomised controlled trial of conservative fluid administration and deresuscitation compared with usual care. Mechanically ventilated patients in an adult intensive care unit expected to need critical care beyond the next calendar day and who do not meet any exclusion criteria  will be randomised between 24 and 48 hours from intensive care admission. The intervention comprises discontinuation of maintenance intravenous fluids, concentration of intravenous drugs,  and a titrated regimen of furosemide, indapamide and spironolactone commenced if fluid balance is greater than 2 litres positive from intensive care admission or there is clinical evidence of oedema in more than one anatomical site. The primary feasibility outcome is fluid balance between groups over the 24 hour period of study day 2. Secondary outcomes are categorised as feasibility (e.g. cumulative fluid balance, incidence of protocol violations); safety (incidence of adverse events); and clinical efficacy (e.g. change in sequential organ failure assessment scores,  mortality). Exploratory mechanistic studies will evaluate cardiac function, cerebral and muscle oximetry and biomarkers of endothelial injury and systemic inflammation.

Discussion: RADAR-2 is a pilot randomised controlled trial comparing a multimodal conservative fluid strategy with usual care in a broad cohort of critically ill patients and will inform future large-scale multicentre comparative effectiveness studies.

Keywords: Fluid therapy; Water-electrolyte balance; Furosemide; Diuretics; Critical illness; Clinical trial; Deresuscitation; Renal replacement therapy; Spironolactone; Indapamide; Fluid restriction

Trial Registration: NCT03512392

Funding: The study is funded by The Health & Social Care Research & Development Division of the Public Health Agency, Northern Ireland; National Institute of Academic Anaesthesia Earnest Leach Research Fund; and a British Journal of Anaesthesia/Royal College of Anaesthetists Project Grant.

Background information

Although intravenous fluid administration is an almost universally applied therapy in critical care, much is unknown about how to maximise benefits and minimise harms. The majority of critically ill patients exhibit alterations in cardiovascular homeostasis, characterised by an exaggerated release of pro-inflammatory cytokines, endothelial injury and capillary leak. Initial fluid resuscitation to improve cardiac output, and thus to optimise oxygen delivery to tissues, is standard care in the management of haemodynamically unstable critically ill patients. Fluid intake is also derived from ‘maintenance’ fluids, drug diluents, and nutritional intake. In critical illness, excretion of fluid is often impaired as a result of endocrine and renal factors, leading to a positive sodium and water balance over time. There has been increasing recognition of the potential harms of excess extravascular fluid and therefore of the need to balance potential benefits and harms when administering intravenous fluid.

There is a strong and consistent association between fluid accumulation in critical illness and poor outcomes, particularly mortality, in observational cohort studies of critically ill patients. This association has now been demonstrated in both adults and children with acute respiratory distress syndrome (ARDS),, sepsis,, acute kidney injury (AKI),, and other sub-populations. The major limitation with all of these studies, however, is the potential for residual confounding, with more severely ill patients receiving more fluid.

We recently undertook a systematic review and meta-analysis of randomised trials in which a conservative approach to fluid administration or active deresuscitation was compared to either a liberal approach or standard care11. In the 11 randomised trials (2051 patients) included in this meta-analysis, there was a non-significant reduction in mortality with conservative or deresuscitative fluid strategies compared to liberal strategies or usual care (relative risk (RR) 0.92, 95% Confidence Interval (CI) 0.82 to 1.02). There was a significant reduction in intensive care unit (ICU) length of stay (mean difference (MD)-1.88 days, 95% CI -0.12 to -3.64) and an increase in ventilator free days (MD 1.82 days, 95% CI 0.53 to 3.10) with conservative or deresuscitative strategies compared to a liberal strategy or standard care.

The major safety considerations relate to the potential for hypovolaemia, leading to haemodynamic instability and/or worsened perfusion of kidneys and other end organs, and to the metabolic side effect profile of diuretic drugs. In studies of conservative or deresuscitative fluid strategies, haemodynamic stability was similar between intervention and control arms,,,, and in our systematic review, we found no difference in the incidence of acute kidney injury between conservative or deresuscitative strategies and usual care.

Side effects of diuretics include electrolyte abnormalities and metabolic alkalosis. In the largest trial of conservative fluid management to date, a conservative fluid management strategy which utilised loop diuretics resulted in higher rates of hypernatraemia, hypokalaemia, and metabolic alkalosis14 than a liberal fluid strategy.

In a post-hoc secondary analysis of a small cohort of 122 survivors from the Fluids And Catheter Treatment Trial which compared conservative and liberal fluid strategies in patients with ARDS, Mikkelsen and colleagues identified conservative fluid management as an independent risk factor for long-term cognitive impairment. In a randomised trial of patients with ARDS in which extravascular lung water index was used to guide a conservative fluid strategy compared with usual care, however, Wang et al found more favourable cognitive function scores with conservative fluid. The impact of fluid strategy on cognitive outcomes, therefore, remains uncertain.

Current practice regarding fluid strategy in the postresuscitation phase of critical illness is highly variable. In a 400-patient observational study of fluid management in 10 ICUs in the United Kingdom and Canada, we found considerable intersite variation in fluid administration, diuretic use, and fluid balance. Similarly, in a survey of over 500 intensive care clinicians in the UK and Europe, we found wide variation in reported practice regarding fluid strategy in a range of clinical scenarios. (unpublished data). The results of our systematic review, observational study, and survey of practice indicate there is uncertainty regarding the optimal fluid strategy for critically ill patients.

We hypothesise that in critically ill patients, following the initial resuscitation period, a fluid strategy comprising conservative fluid administration and active deresuscitation reduces net fluid balance, is safe and improves clinical outcomes.

Design

Study aims

The aims of the study are (1) to determine the feasibility, safety and clinical outcomes of conservative fluid administration and deresuscitation compared with usual care in critically ill patients following initial resuscitation; and (2) to explore the biological effects of conservative fluid administration and deresuscitation.

Study design

This will be a randomised, open-label, allocation concealed, pilot trial of conservative fluid administration and deresuscitation compared with usual care in adult patients who are critically ill following initial resuscitation. The study design conforms to SPIRIT guidelines for the reporting of clinical trial protocols (http://www.spirit-statement.org/), and the Spirit 2013 checklist for this protocol can be found in the Supplementary Material.

Study setting

Participants will be recruited from adult general ICUs.

Study participants

Participants in the trial will be eligible if receiving invasive mechanical ventilation, are between 24 and 48 hours of ICU admission at the time of randomisation, and the treating intensive care doctor expects treatment in an ICU to be required beyond the next calendar day. Exclusion criteria are as follows:

  • age < 16 years;
  • weight < 40 kg;
  • known pregnancy;
  • expectation of death within 72 hours;
  • refusal of consent;
  • inability to measure fluid balance;
  • inability of the personal consultee to understand written or verbal information where no interpreter is available (a personal consultee is someone who knows the patient in a personal capacity, and is able to advise the researcher about that patient’s likely wishes and feelings in relation to the project and whether they should participate in the study);
  • active treatment for diabetic ketoacidosis, hyperosmolar hyperglycaemic state, non-traumatic subarachnoid haemorrhage, acute cardiac failure, cardiogenic shock, end-stage renal failure, or active diabetes insipidus.

Study procedures (see Table 1)

Patients will be prospectively screened daily. All patients meeting inclusion criteria will be entered into a screening log, and reasons for non-recruitment recorded. It is anticipated that the incapacitating nature of the condition will almost invariably preclude obtaining prospective informed consent from participants. In this situation, advice will be sought from a personal consultee as to their views on the wishes and feelings of the patient if they had capacity. Patients will be informed of their participation in the trial once they regain capacity and asked for consent to continue to participate in the trial.

Subjects will be randomised in a 1:1 ratio using blocks of variable size and randomisation will be stratified by study site. Online randomisation software (www.sealedenvelope.com) will be used. Blinding of participants, caregivers and investigators will not be undertaken for short-term outcomes in the 28-day study period. Investigators undertaking assessment of long-term follow up of cognitive function and biomarker assays will be blinded to group assignment.

Intervention

On study day 1 (from randomisation until 07:00 the following day), maintenance intravenous fluids will be discontinued and all prescribed medications will be given in minimum volumes according to standard guidelines. The clinical team responsible for the patient will be asked to administer intravenous fluids only where there is suspected blood or other overt fluid loss, to treat electrolyte abnormalities, or where alternative therapies for cardiovascular instability are deemed to have failed or to be contraindicated.

On study days 2-4, fluid restriction will be continued as above and there will be an assessment of eligibility for deresuscitation each day. Criteria for deresuscitation are:

  1. the presence of oedema in > 1 site i.e. arms, legs, flanks, abdominal wall, lungs (PaO2/FiO2 ratio < 40 kPa (300 mm Hg) and chest radiograph consistent with pulmonary oedema), or
  2. cumulative fluid balance from ICU admission > 2000 ml.

Contra-indications to deresuscitation are:

  1. noradrenaline (or adrenaline) dose > 0.2 mcg/kg/min,
  2. more than 1 vasopressor agent in use,
  3. uncorrected hypokalaemia (< 3.0 mmol/L),
  4. uncorrected hyponatraemia (< 130 mmol/L), or
  5. uncorrected hypernatraemia (> 150 mmol/L).

If deresuscitation criteria are met, the intervention will comprise administration of indapamide 5 mg enterally 24-hourly, spironolactone 100 mg enterally 24-hourly, 0.5 mg/kg furosemide (rounded to nearest 10 mg, maximum 40 mg) intravenously as a single dose, and an intravenous infusion of furosemide. The infusion will be titrated within the range 2.5 to 20 mg/hour to target a negative fluid balance of 1000 to 3000 ml/day (42-125 ml/hour) (Figure 1). For patients on renal replacement therapy (RRT), diuretics will not be administered and ultrafiltration will be used to target a daily negative fluid balance of 2000 ml (83 ml/hour).

The study treatment regimen will be continued until one of the following criteria is met:

  1. beginning of study day 5 (maximum treatment period),
  2. discharge from critical care,
  3. death or discontinuation of active treatment,
  4. request for withdrawal from the trial by patient or their personal consultee,
  5. decision by the attending clinician on safety grounds, or
  6. occurrence of a treatment-related serious adverse event

Comparator

Patients in the comparator group will receive usual care with respect to fluid management at the discretion of the responsible clinical team.

Outcome measures

The primary endpoint is the fluid balance (ml) during the 24- hour period up to the beginning of study day 3. Secondary clinical outcomes are shown in Table 2.

Further exploratory work

We will explore the relationship of cerebral oximetry measurements with cognitive outcomes, adjusting for fluid status and group assignment. We will further explore the relationship between vital signs and measurements of cerebral and tissue oximetry.

Ethical considerations

The trial has been approved by the Northern Ireland Research Ethics Committee B (17/NI/0192). The study will be conducted in accordance with the ethical principles which have their origin in the Declaration of Helsinki. All data will be stored securely in a pseudo-anonymised fashion.

Adverse event reporting

Data on adverse events and serious adverse events will be collected during follow-up. The occurrence of a treatment-related serious adverse event will trigger withdrawal of the patient from the study. A Data Monitoring Committee (DMC) will be appointed which will be independent of the study team and sponsor, and will comprise an Intensive Care consultant, a clinician with experience in undertaking clinical trials, and a statistician. The DMC will meet 6-monthly for the duration of the trial, and will function primarily as a check for safety, reviewing adverse events. Any issues pertaining to safety will be reported to the Chief Investigator who will be responsible for informing the sponsor.

Sample size

Based on data from our recently completed observational study, we anticipate a fluid balance in the 24 hours up to day 3 of 494 +/- 1512 ml in the usual care group. A sample size of 174 subjects (87 in each group) will have 90% power at a two-tailed significance level of 0.05 to detect a difference in fluid balance of 750 ml over 24 hours. We have allowed for a drop-out rate of 3% and the study will therefore require a total of 180 patients (90 in each group).

Statistical analysis

The study will be analysed on an intention to treat basis. A p value of < 0.05 will be considered as significant. A single final analysis is planned at the end of the trial. We will undertake subgroup analyses for patients with, and without, ARDS (Berlin criteria); sepsis; patients with traumatic brain injury; and patients with hypo- and hyper-inflammatory phenotypes.

The primary outcome of day 3 fluid balance and other fluid balance variables will be formally compared between groups using an independent samples Student’s t-test, since the treatment must affect fluid balance in order to justify a clinical outcomes trial. Other feasibility outcomes assess various aspects related to the feasibility of completing a large-scale clinical outcomes study and will be reported descriptively.

For safety, efficacy and exploratory outcomes, continuous variables will be analysed using independent t-tests or non-parametric alternatives. Categorical variables will be analysed using Chi-square tests (or Fisher’s Exact tests). Time to event variables will be analysed using survival analysis technique and the Kaplan-Meier method will be used to estimate median survival time and 95% CI. Equality of survival curves will be tested using log rank tests. A Cox proportional hazard model will be used if proportional hazards assumptions hold. Repeated measures ANOVA will be used to analyse serial measures over time for continuous variables. Scatterplots will be used to assess the relationship between biological markers, physiological and clinical outcomes. If a linear relationship exists, Pearson’s correlation coefficient or non-parametric alternative will be used to estimate the strength of the relationship.

A full statistical analysis plan is available as a supplementary appendix to this manuscript.

Trial status

To date, 45 patients have been randomised in 3 sites, in keeping with the planned recruitment rate. We anticipate completion of the trial in Autumn 2019.

Discussion

Although fluid management is an integral aspect of intensive care management of the critically ill, considerable uncertainty remains as to the indications, benefits and harms associated with fluid administration and deresuscitation. Despite the large body of observational evidence demonstrating harm associated with fluid overload, RADAR-2 is the first randomised trial of an integrated conservative fluid administration and active deresuscitation intervention to be performed in a broad cohort of critically ill patients. This study is primarily a feasibility trial, with a view to undertaking a large multicentre randomised trial in the future, but also affords the opportunity to explore physiological and biochemical aspects of fluid management.

Our study has a number of limitations. Caregivers and researchers will not be blinded to group assignment, due to the limited likelihood of successful blinding given diuretics have the signature physiological effect of inducing diuresis, as well as the manufacturing cost of a suitable placebo. The open-label nature of the study also risks the Hawthorne effect, and indeed it is possible that clinical practice is already changing towards a more conservative approach to fluids, given recent attention in the literature to the harms of fluid overload. In addition, protocolising fluid and diuretic therapy is challenging, when the response to both is highly patient-dependent. For these reasons, it is important to test the feasibility of the proposed intervention in the current trial prior to embarking on a large multi-centre randomised trial powered for clinical outcomes.

Declaration of interests

The investigators confirm that they have no competing interests.

Dissemination of results

The results of this trial will be published in a peer-reviewed journal and may be presented at medical conferences. No professional writers will be involved. Criteria for authorship will be those set out by the International Committee of Medical Journal Editors (http://icmje.org/).

Role of funders and sponsor

Neither the funders nor the sponsor have any responsibility for study design, data collection or analysis, interpretation or publication.

References

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  2. Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016.  Intensive Care Medicine. 2017;43(3):304–377. https://doi.org/10.1007/s00134-017-4683-6.
  3. Hjortrup PB, Delaney A. Fluid management in the ICU: has the tide turned? Intensive Care Medicine. 2016;43(2):237–239. https://doi.org/10.1007/s00134-016-4605-z.
  4. Sakr Y, Vincent JL, Reinhart K, Groeneveld J, Michalopoulos A, Sprung CL, et al. High Tidal Volume and Positive Fluid Balance Are Associated With Worse Outcome in Acute Lung Injury. Chest. 2005;128(5):3098–3108. https://doi.org/10.1378/chest.128.5.3098.
  5. Rosenberg AL, Dechert RE, Park PK, Bartlett RH. Review of A Large Clinical Series: Association of Cumulative Fluid Balance on Outcome in Acute Lung Injury: A Retrospective Review of the ARDSnet Tidal Volume Study Cohort. Journal of Intensive Care Medicine. 2008;24(1):35– 46. https://doi.org/10.1177/0885066608329850.
  6. Acheampong A, Vincent JL. A positive fluid balance is an independent prognostic factor in patients with sepsis. Critical Care. 2015;19(1). https://doi.org/10.1186/s13054-015-0970-1.
  7. Boyd JH, Forbes J, Nakada T, Walley KR, Russell JA. Fluid resuscitation in septic shock: A positive fluid balance and elevated central venous pressure are associated with increased mortality. Critical Care Medicine. 2011;39(2):259– 265. https://doi.org/10.1097/ccm.0b013e3181feeb15.
  8. Payen D, de Pont ACJM, Sakr Y, Spies C, Reinhart K, Vincent JL. A positive fluid balance is associated with a worse outcome in patients with acute renal failure. Critical Care. 2008;12(3):R74. https://doi.org/10.1186/cc6916.
  9. Vaara ST, Korhonen AM, Kaukonen KM, Nisula S, Inkinen O, Hoppu S, et al. Fluid overload is associated with an increased risk for 90-day mortality in critically ill patients with renal replacement therapy: data from the prospective FINNAKI study. Critical Care. 2012;16(5):R197. https://doi.org/10.1186/cc11682.
  10. Silversides JA, Pinto R, Kuint R, Wald R, Hladunewich MA, Lapinsky SE, et al. Fluid balance, intradialytic hypotension, and outcomes in critically ill patients undergoing renal replacement therapy: a cohort study. Critical Care. 2014;18(6). https://doi.org/10.1186/s13054-014-0624-8.
  11. Silversides JA, Major E, Ferguson AJ, Mann EE, McAuley DF, Marshall JC, et al. Conservative fluid management or deresuscitation for patients with sepsis or acute respiratory distress syndrome following the resuscitation phase of critical illness: a systematic review and metaanalysis. Intensive Care Medicine. 2017;43(2):155–170. https://doi.org/10.1007/s00134-016-4573-3.
  12. Martin GS, Mangialardi RJ, Wheeler AP, Dupont W, Morris JA, Bernard GR. Albumin and furosemide therapy in hypoproteinemic patients with acute lung injury. Critical Care Medicine. 2002 Oct;30(10):2175–2182.
  13. Martin GS, Moss M, Wheeler AP, Mealer M, Morris JA, Bernard GR. A randomized, controlled trial of furosemide with or without albumin in hypoproteinemic patients with acute lung injury. Critical Care Medicine. 2005;33(8):1681– 1687. https://doi.org/10.1097/01.ccm.0000171539.47006.02.
  14. National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network. Comparison of Two Fluid-Management Strategies in Acute Lung Injury. New England Journal of Medicine. 2006;354(24):2564–2575. https://doi.org/10.1056/nejmoa062200.
  15. Hjortrup PB, Haase N, Wetterslev J, Lange T, Bundgaard H, Rasmussen BS, et al. Effects of fluid restriction on measures of circulatory efficacy in adults with septic shock. Acta Anaesthesiologica Scandinavica. 2017;61(4):390–398. https://doi.org/10.1111/aas.12862.
  16. Mikkelsen ME, Christie JD, Lanken PN, Biester RC, Thompson BT, Bellamy SL, et al. The Adult Respiratory Distress Syndrome Cognitive Outcomes Study. American Journal of Respiratory and Critical Care Medicine. 2012;185(12):1307–1315. https://doi.org/10.1164/rccm.201111-2025oc.
  17. Wang L, Long X, Lv M. Effect of different liquid management strategies on the prognosis of acute respiratory distress syndrome. Journal of the Dalian Medical University. 2014;36:140–143.
  18. Silversides JA, Fitzgerald E, Manickavasagam US, Lapinsky SE, Nisenbaum R, Hemmings N, et al. Deresuscitation of Patients With Iatrogenic Fluid Overload Is Associated With Reduced Mortality in Critical Illness. Critical Care Medicine. 2018;46(10):1600–1607. https://doi.org/10.1097/CCM.0000000000003276.
  19. The ARDS Definition Task Force. Acute respiratory distress syndrome: The berlin definition. JAMA. 2012;307(23):2526–2533. https://doi.org/10.1001/jama.2012.5669.
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  21. Famous KR, Delucchi K, Ware LB, Kangelaris KN, Liu KD, Thompson BT, et al. ARDS Subphenotypes Respond Differently to Randomized Fluid Management Strategy. American Journal of Respiratory and Critical Care Medicine. 2016;195:331–338. https://doi.org/10.1164/rccm.201603-0645OC.

Additional file 1: Spirit 2013 checklist

Additional file 2: Information sheet and consultee declaration

Additional file 3: RADAR-2 SAP

Cite this article as follows:

Silversides JA, Marshall JC, Ferguson AJ, Blackwood B, McAuley DF. Role of Active Deresuscitation After Resuscitation-2 (RADAR-2) – a pilot randomised controlled trial of conservative fluid administration and deresuscitation in critical illness: study protocol. Critical Care Horizons 2018: 9-15.

ASpirin as a Treatment for Acute Respiratory Distress Syndrome – a multi-centre, randomised, double-blind, placebo-controlled trial (STAR): study protocol

ASpirin as a Treatment for Acute Respiratory Distress Syndrome – a multi-centre, randomised, double-blind, placebo-controlled trial (STAR): study protocol

Philip Toner1, Cecilia O’Kane1, James McNamee2, Rejina Verghis1,3, and Daniel F McAuley1,2

1Wellcome-Wolfson Institute for Experimental Medicine, Queen’s University Belfast, 97 Lisburn Road, Belfast, BT9 7BL
2Regional Intensive Care Unit, Royal Victoria Hospital, Belfast Health and Social Care Trust, Grosvenor Road, Belfast, BT12 6BA
3Northern Ireland Clinical Trials Unit, 1st floor Elliott Dynes Building, Royal Hospitals, Grosvenor Road, Belfast, BT12 6BA

Email: ptoner09@qub.ac.uk

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Background: Acute respiratory distress syndrome (ARDS) remains a common cause of significant morbidity and mortality in the critically ill, for which there is currently no pharmacological treatment. There is in vivo, in vitro, observational and phase I evidence suggesting aspirin may be of benefit in this condition. The aim of the STAR trial (aSpirin as a Treatment for Acute Respiratory Distress Syndrome) is to test the hypothesis that aspirin 75 mg is both safe and effective in improving important surrogate outcomes in patients with ARDS.

Methods/Design: STAR is a randomised, double-blind, allocation-concealed, placebo-controlled, multi-centred phase II trial. Patients diagnosed with ARDS, as per the Berlin Definition, will be randomised in a 1:1 ratio to receive enteral aspirin 75 mg or placebo for a maximum of 14 days. Randomisation is stratified by vasopressor requirement. The primary endpoint is to evaluate the efficacy of aspirin to improve oxygenation index at day 7. A total of 60 patients will be recruited from intensive care units (ICUs) across Northern Ireland. Plasma, bronchoalveolar lavage (BAL) and urine samples will be obtained to further investigate mechanisms by which aspirin might improve clinical outcomes in these patients.

Keywords: Aspirin; acute respiratory distress syndrome, oxygenation index

Trial Registration: NCT02326350

Funding:  The study is funded by the Health & Social Care Research & Development Division of the Public Health Agency, Northern Ireland.

Background information

Acute respiratory distress syndrome (ARDS) is defined by the Berlin Definition as an acute onset of hypoxia (PaO2/FiO2 < 40 kPa), in the presence of a positive end-expiratory pressure (PEEP) > 5 cmH2O and with bilateral radiological opacities not solely explained by cardiac dysfunction. Despite advances in treatment,,, mortality remains relatively high at 35-40%, with significant post morbid functional impairment and reduction in quality of life,. The high mortality and long-term consequences, coupled with the high financial burden, make the treatment of ARDS a healthcare priority. Multiple drugs have been investigated as potential treatments, most recently simvastatin, but as yet there is no effective pharmacological treatment

The rationale for aspirin as a treatment for ARDS

The use of aspirin as a treatment for ARDS is a novel approach. There are various pathways in which aspirin could attenuate the pathophysiology in ARDS. Firstly, through the inhibition of cyclooxygenase enzymes (COX), aspirin can prevent platelet activation. Platelets play a significant role in the development of sepsis and ARDS, especially as the lungs are a major site of platelet maturation and subsequent reservoirs. Once activated, platelets degranulate and release a pro-inflammatory cocktail promoting further platelet degranulation and aggregation, leucocyte recruitment and oedema formation. Furthermore, platelet and neutrophil aggregation is essential for the formation of neutrophil extracellular traps (NETs), which, in excess, can directly damage the lung architecture, thus escalating the inflammatory and thrombotic processes,. In an ARDS murine model, platelet depletion resulted in reduced neutrophil migration, less oedema formation and improved outcomes15.

Secondly, aspirin can downregulate the production of proinflammatory cytokines through the inhibition of NFκB, subsequently reducing leucocyte recruitment. Thirdly, aspirin promotes nitric oxide (NO) production, resulting in decreased leucocyte migration, oedema formation and microthrombi, all of which are important features in ARDS. Finally, aspirin promotes resolution via the production of lipoxins (aspirin triggered lipoxin [ATL]), a feature absent in ARDS.

Both aspirin and ATL administration reduce pulmonary inflammation and improve outcomes in murine models of ARDS,. Observational studies have shown a benefit to prior aspirin use in those admitted to ICU with ARDS or sepsis13,. In a local single centre retrospective study, aspirin was associated with reduced mortality in ARDS, with an odds ratio 0.42 (95% confidence interval, 0.18 – 0.96). Aspirin also significantly reduced bronchoalveolar lavage (BAL) neutrophil count, not only in an ex vivo lung perfusion (EVLP) lipopolysaccharide (LPS)-induced inflammation model of ARDS, but also in a healthy volunteer model of ARDS-induced by inhaled LPS. These animal models, observational studies, and human models support the hypothesis that aspirin may have a role in the treatment of ARDS.

Aspirin has recently been investigated as a preventive agent for ARDS in high-risk patients presenting to the emergency department. However, it did not significantly reduce the incidence of ARDS at day 7. On closer review, the study was underpowered, thus limiting the impact of this result.

The aim of the STAR trial is to test the hypothesis that aspirin 75 mg, when administered enterally, is both safe and effective in improving important surrogate outcomes in patients diagnosed with ARDS.

Methods/design

STAR is a randomised, double-blind, allocation-concealed, multi-centre, placebo-controlled phase II trial to determine if aspirin is safe and whether it improves important surrogate clinical outcomes in adult patients with ARDS. The trial is sponsored by the Belfast Health and Social Care Trust (BHSCT). The protocol was reviewed and approved by the Office for Research Ethics Committees Northern Ireland (ORECNI) (14/NI/1093) and by the Medicines and Health Care Products Regulatory Authority (MHRA). STAR is registered with ISRCTN (NCT02326350) and with the European Union Drug Regulation Authorities Clinical Trials Database (2014-002564-32). The trial will be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and will be carried out in accordance with the principles of the International Conference on Harmonisation Good Clinical Practice (ICH-GCP) guidelines (https://ichgcp.net/). STAR is coordinated through the Northern Ireland Clinical Trials Unit (NICTU) and has been adopted on to the Clinical Research Portfolio supported by the Northern Ireland Clinical Research Network (NICRN) for Critical Care.

In PICO terms:
Population: adult patients with ARDS
Intervention: aspirin 75 mg
Comparator: placebo
Outcome: safety and physiological indices of efficacy

Figure 1. Trial Schematic

Outcome Measures

As this is a phase II clinical study, several surrogate outcomes will be evaluated.

The primary endpoint is oxygenation index (OI) at day 7. OI is a physiological index of the severity of ARDS, which measures both impaired oxygenation and the amount of mechanical ventilation delivered. and independently predicts mortality in patients with ARDS. Day 7 was chosen as this time interval will minimise the competing effects of death and extubation, while allowing a sufficient time interval for a biological effect to occur. OI is calculated as (mean airway pressure (cmH2O) x FiO2 x 100) ÷ PaO2 (kPa).

The secondary outcomes are:

  1. OI at days 4 and 14
  2. Physiological indices of ARDS, as measured by respiratory compliance (Crs) and P/F ratio on days 4, 7 and 14
  3. Change in sequential organ failure assessment (SOFA) score from baseline to day 4, 7 and 14
  4. Safety and tolerability, as assessed by the occurrence of suspected unexpected serious adverse reactions (SUSARs)

Duration of ventilation, ventilation-free-days at day 28, mortality at both day 28 and 90, as well as length of ICU stay will also be recorded. These important clinical outcomes are not included as outcome measures as the study is not adequately powered to assess them.

Safety

The frequency with which the following events occur will be reported to the Data, Monitoring and Ethical Committee (DMEC):

  1. fall in haemoglobin below 70 g/l
  2. incidence of acute kidney injury
  3. all adverse events (AEs), including serious adverse events (SAEs) and occurrences of suspected unexpected serious adverse events (SUSARs)

Safety monitoring blood tests including full blood count (FBC), urea and electrolytes (U&E), coagulation profile, liver function tests (LFTs) and clinical assessment is undertaken on a daily basis for 14 days. All AEs are reported up to 28 days from completion of study drug.

Biological mechanisms

An exploratory study will provide insight into the mechanism by which aspirin may be an effective treatment in ARDS. Blood, BAL and urine will be taken on days 0 and 4, with further blood and urine samples taken on days 7 and 14 while patients continue to receive the study drug. Samples will be analysed for biological markers of pulmonary and systemic inflammation, as well as pulmonary and systemic epithelial and endothelial function. Furthermore, we will measure several lipid inflammatory mediators in addition to assessing the pharmacokinetics and pharmacodynamics of aspirin in the critically ill.

It may not be possible to collect all samples from all patients at all time points. If samples are not collected, this will not be recorded as a protocol violation.

Eligibility criteria

Inclusion

Patients are screened on a daily basis to determine if they fulfil the following inclusion criteria:

  1. receiving invasive mechanical ventilation
  2. ARDS as defined by the Berlin Definition1
    • onset within 1 week of an identified insult
    • within the same 24 hour time period
      • hypoxic respiratory failure (PaO2/FiO2 ratio < 40 kPa on PEEP > 5 cmH20)
      • bilateral infiltrates on chest radiograph consistent with pulmonary oedema not explained by another pulmonary pathology
      • no evidence of heart failure or volume overload

Exclusion

Patients fulfilling any of the criteria below will be excluded from the trial:

  1. greater than 72 hours from the onset of ARDS
  2. age < 16 years
  3. patient is known to be pregnant
  4. participation in a clinical trial of an investigational medicinal product within 30 days
  5. current treatment with aspirin or within the past 4 weeks
  6. platelet count < 50 x 109/l
  7. haemophilia or other haemorrhagic disorder or concurrent therapeutic anticoagulant therapy
  8. history of aspirin-sensitive asthma or nasal polyps associated with asthma
  9. active or history of recurrent peptic ulcer and/or gastric or intestinal haemorrhage, or other kinds of bleeding, such as cerebrovascular haemorrhage
  10. traumatic brain injury
  11. active gout
  12. currently receiving methotrexate
  13. severe chronic liver disease with Child-Pugh score > 12
  14. known hypersensitivity or previous adverse reaction to salicylic acid compounds or prostaglandin synthetase inhibitors
  15. physician decision that aspirin is required for proven indication
  16. contraindication to enteral drug administration, e.g. patients with mechanical bowel obstruction
  17. treatment withdrawal imminent within 24 hours
  18. consent declined.

Power and sample size

The primary outcome measure will be the difference in OI between the aspirin and placebo treated groups at day 7. Based on data from a recently completed clinical trial in ARDS, the mean (standard deviation; SD) OI at day 7 in patients with ARDS is 62 (51) cmH2O/kPa. A sample size of 56 subjects (28 in each group) will have 80% power, at a two-tailed significance level of 0.05, to detect a clinically significant difference of 39 cmH2O/kPa in OI between groups. In a previous phase II study of similar size, we found that an intervention can demonstrate a change in OI of a similar magnitude confirming a treatment effect of this size can be achieved29. Although we anticipate few withdrawals or loss to follow-up, we have allowed for this in the sample size calculation. In our previous single centre study of simvastatin in ARDS, there were no withdrawals. In a multi-centre UK study of pulmonary artery catheters in ICU patients (PACMan), no patients were lost to follow up, and only 3% withdrew consent after recovering competency. Therefore, a drop-out rate of 5% has been estimated and the study will require a total of 60 patients (30 in each group).

Trial conduct

Consent

Informed consent will be obtained before conducting any trial specific procedures. Due to the incapacitating nature of the condition, the patients typically lack the capacity to give consent. In this situation, informed consent will be sought from a Personal Legal Representative (Per LR) or Professional Legal Representative (Pro LR), in keeping with requirements from the EU clinical trails directive. Once they regain capacity, patients will be informed of their participation in the trial, have the trial explained to them, and consent to continue in the trial will be sought. Where consent to continue is not obtained, consent from the legal representative will remain valid. Similar consent mechanisms have been used successfully in other critical care trials10,29,30.

Randomisation and study drug design

Victoria Pharmaceuticals will prepare the drug packs. Aspirin 75 mg and the placebo will have an identical appearance. All trial drugs will be packaged identically and identified by a unique pack number.

After informed consent, the researcher will contact the clinical trials pharmacist who will allocate the next sequential number as per the randomisation schedule, maintaining blinding. Randomisation will be stratified by vasopressor use and subjects will be randomised in a 1:1 ratio using blocks of variable size. The researcher will then register the recruited patient with the CTU.

Study drug administration

Subjects will be randomised to receive aspirin 75 mg capsule or a placebo capsule enterally for up to 14 days. The first dose of the study drug will ideally be administered within 4 hours of  randomisation and subsequent doses will be as close to 10 am as possible starting on the following calendar day. The clinical staff administering the drug will not be involved in any of the study specific assessments.

 

Post randomisation withdrawals and exclusions

Patients may withdraw, or be withdrawn by their representative, from the trial at any time without prejudice. Consent will be requested to use the data collected to that point. If a patient, or their representative, requests termination of the trial drug during the treatment period, the drug will be stopped but the patient will continue to be followed-up as part of the trial, unless they also explicitly request withdrawal from follow-up.

Study drug termination criteria

The study drug will be continued until one of the following is met:

  1. 14 days after randomisation (maximum treatment period)
  2. study drug related adverse event
  3. critical care discharge
  4. death or discontinuation of active treatment
  5. request from Per LR or Pro LR to withdraw the patient from the study
  6. decision by the attending clinician on safety grounds
  7. clinical indication for treatment with aspirin e.g. myocardial infarction.

Study drug compliance

Any omission of the study drug will be recorded in the case report form (CRF) to monitor compliance.

Clinical management of patients in the trial

All patients will receive standard management with regards to nutrition, antibiotic policy, fluid management and weaning. It is recommended patients will be managed using a standardised mechanical ventilation protocol aiming for tidal volumes of 6 ml/kg predicted body weight2. Rescue therapies, such as extra-corporeal membrane oxygenation, can be used according to local policy.

Study procedures for unblinding

As STAR is a randomised, placebo-controlled, double-blind trial, the research staff, treating clinical staff, and patients, will be blinded as to which arm of the study the patient is allocated. All trial drugs have identical appearance and are only identified by a unique pack number. The investigator or treating physician may unblind a participant’s treatment assignment in the case of an emergency, when knowledge of the study treatment is essential for the appropriate clinical management or welfare of the subject. Emergency unblinding will be performed by telephone contact with the pharmacy in the BHSCT. The date and reason for unblinding will be recorded in the CRF.

Data collection

All data for an individual patient will be collected by the research team and recorded in the CRF. The majority of the data will be obtained from the patient’s hospital record. Data will be collected from the time the patient is considered for entry into the trial through to their discharge from hospital and recorded on a secure, backed up custom database. Data censorship will occur after 90 days post randomisation.

Adverse event reporting

As STAR is recruiting in a population that is already in a life-threatening situation, it is expected that many of the patients will experience AEs. Events that are suspected in this population (i.e. events in keeping with the underlying condition) will not be reported as AEs. The adverse effects as listed in the summary of product characteristics (SmPC) for aspirin will be used as the reference safety information. AEs that occur between trial entry and up to 28 days after completion of the study drug will be reported. SAEs and SUSARs will be reported within 24 hours of becoming aware of their occurrence and the sponsor will inform the regulatory authorities as per the regulatory requirements.

End of trial

The trial will end when 60 patients have been recruited and completed 90-day follow-up. The trial will be stopped prematurely if mandated by the Ethics Committee, MHRA, or the sponsor e.g. following recommendations from the DMEC.

Statistical analysis plan

A full statistical analysis plan is available in the STAR Supplementary Data.

Trial oversight

The Chief Investigator will have overall responsibility for the conduct of the study. The Trial Management Group will have responsibility for the daily running of the trial. An independent DMEC will monitor the safety of the participants through regular review of AEs, deaths and any other data as requested by the DMEC. They will report any issues pertaining to safety to the Chief Investigator. It will be the responsibility of the Chief Investigator to inform the sponsor who will take appropriate action to halt the trial if concerns exist about patient safety.

Trial status

The trial has been successfully initiated and as of August 2018 46 patients have been successfully enrolled. There has been one major amendment to the protocol design and eligibility criteria, which has been approved by the MHRA and local ethics committee. That amendment was to extend from a single site to a multi-centre trial to ensure adequate recruitment and to adjust the absolute platelet exclusion count from 100 x109/l to 50 x109/l.

Author’s contributions

DFM and CO’K conceived the study. All authors made a substantial contribution to the protocol development. All authors have read and approved the manuscript.

Acknowledgements

The study is funded by the Health & Social Care Research & Development Division of the Public Health Agency, Northern Ireland. The authors thank the Data Monitoring and Ethics Committee:

  • Dr P Glover (Chair – Consultant, Belfast Health and Social Care Trust)
  • P McKeown (Consultant/Professor, Belfast Health and Social Care Trust/Queen’s University Belfast), and
  • M Clarke (Professor, Queen’s University Belfast).

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Additional file 1: Statistical analysis plan: STAR_Supplementary_Data

Cite this article as follows:

Toner P, O’Kane C, McNamee J, Verghis R, McAuley DF. ASpirin as a Treatment for Acute Respiratory Distress Syndrome – a multi-centre, randomised, double-blind, placebo-controlled trial (STAR): study protocol. Critical Care Horizons 2018: 1-7.