Overview

The aim of our study is to answer if dexamethasone treatment in patients with ARDS can save lives, reduce the need for extended ICU care, improve longer term patient quality of life and find the best value for the public and health services.
Every year about 120,000 adults who are admitted to Intensive Care Units (ICUs) require a machine, called a ventilator, to help them breathe. In patients who need ventilation, about 1 in 4 have a life-threatening condition with severe breathing difficulties called acute respiratory distress syndrome (ARDS). Unfortunately, around 40% of patients with ARDS die within 60 days of developing this condition.
Breathing difficulties in ARDS happen because the lungs fill with fluid because of inflammation, which is part of the body’s response to the conditions causing ARDS.
Over the last 30-years, various drug treatments have been tested to reduce the inflammation in ARDS, with limited success. At present, there are no drugs that cure ARDS. However, in 2020, a small research study (the DEXA-ARDS trial) in Spain looked at dexamethasone as a treatment for ARDS. Dexamethasone is a well-known steroid, which is a cheap anti-inflammation drug, that is already widely used to treat other illnesses. The result of DEXA-ARDS trial showed that it may help patients survive ARDS.
These results from Spain are encouraging but to help us know how effective dexamethasone is, we need to test it in a much bigger group of patients who come into the NHS with ARDS. We are planning to conduct a large clinical trial across the UK.

Inclusion criteria

(a) Provision of informed consent

(b) Aged 16 years or older

(d) Receiving respiratory support via invasive mechanical ventilation or non-invasive ventilatory support (non-invasive ventilatory support includes mask or helmet) or high flow nasal cannula (HFNC) >30L/min

(e) Within 72 hours of diagnosis of ARDS with moderate to severe hypoxaemia defined as i) ii) iii) a known acute clinical insult or new or worsening respiratory dysfunction (Note: this includes new deterioration at any time-point during the ICU stay), and opacities on chest imaging not fully explained by effusions, lobar/lung collapse/atelectasis, or nodules, and respiratory failure not fully explained by cardiac failure or fluid overload, and iv) assessment of hypoxaemia done with either PaO2/FiO2 ratio <26.7 kPa from arterial blood gases, or SpO2/FiO2 <235 with SaO2<97%

Additional Notes

Patients who change from mild hypoxaemia to moderate or severe hypoxaemia are eligible.
For this trial, patients with unilateral opacities are eligible, as they would meet the definition of acute hypoxemic respiratory failure, and often have biological changes similar to ARDS. Furthermore, it is well recognised that there are differences in interpretation of chest radiography between observers (low inter observer agreement, validity, and reliability), what may appear to be a unilateral infiltrate on chest radiograph can seem bilateral infiltrates in a CT scan; and in mechanically ventilated patients radiological infiltrates can be masked in portable chest radiographs for numerous reasons.
We will include patients requiring other immunosuppressive drugs, provided there exists clinician equipoise for randomising such a patient.

Exclusion criteria

a) ARDS due to microbiologically confirmed SARS-Co-V2 infection (COVID-19 ARDS)

(b) Major upper gastrointestinal bleeding during current hospital admission, defined as requiring endoscopy and transfusion for two or more units of packed red blood cells. This exclusion criterion will exclude patients with contraindications to the glucocorticoids on the grounds of safety.

(c) High dose glucocorticoids are required for a separate proven clinical indication at the time of randomisation as withholding treatments that have been deemed clinically effective, would be unethical. Note: Low dose glucocorticoid treatments for clinical indications (defined as maximum daily dose of 200mg hydrocortisone or equivalent other steroids) is not an exclusion criterion.

(d) Known hypersensitivity to dexamethasone.

(e) Infections that are not being effectively treated as determined by the treating medical team. Note: Once infections are considered as effectively treated by the treating medical team, they are eligible for the trial.

(f) Planned intensive care treatment withdrawal within next 24 hours as determined by the treating medical team

(g) Patients who are known to be pregnant

(h) Previous enrolment in the GuARDS trial.

Additional Notes

Exclusion criterion (a) will exclude patients with COVID-19 who should be receiving glucocorticoids as part of their standard of care. There may be occasions where the reporting of COVID-19 status may be delayed and or proven clinical indications may become apparent few days after randomisation. This is likely to be a small proportion of patients. In this scenario, we will analyse on the intention to treat principles and provide additional sensitivity analyses, as appropriate.

Exclusion criterion (c): In patients receiving low dose (defined as maximum daily dose of 200mg hydrocortisone or equivalent other glucocorticoids) for clinical indications, the decision to continue this low dose glucocorticoids post randomisation in the usual care arm, and in the intervention arm will be at the discretion of the treating physicians.

Exclusion criterion (g) will exclude patients who are pregnant, as administering glucocorticoids in the first trimester of pregnancy increases the risk of cleft palate in the foetus, and in the third trimester of pregnancy, glucocorticoids are part of usual care for facilitating lung maturation in the foetus. Pregnancy tests are carried out on female patients on admission either to the emergency department, or to the hospital or when they are admitted to the ICU. This means that pregnant patients will be identified, and excluded appropriately. The SPC states that drug may pass to breast milk but no additional data is available. Lactation is not considered as an exclusion criterion as breastfeeding is highly unlikely in patients with moderate to severe ARDS in the ICU setting.

Co-enrolment agreements are in place for: ABBRUPT, ABC Post-ICU, AWAKE-PRONE (domain trial part of CoReCCT), Cardiac patients’ and their families’ perceptions of recovery after critical illness, FLO-ELA, GenOMICC, GUT-BIOME, HITEC, INFINIT, iRehab, MARCH, MEC-ROX, NOTE-AF, PQIP, PROTECT Airways (domain trial part of CoReCCT), RELEASE (domain trial part of CoReCCT), SHORTER, SOS, Threshold for Platelets (T4P), UK-ROX, VitDalize UK

Co-enrolment agreements are in progress for: MOSAICC, SepTIC, REMAP-CAP, PANTHER, ARDS Neut, SINFONIA, SPICE IV, RECOVERY, ASPECT, Voriconazole PK, EMErALD, UKAR, Cognishine, TRAITS

Other Information

GuARDS_Summary.pdf

Guards_Protocol_v2.0.pdf