What are the genes that cause some people to be susceptible to life-threatening infection, or death from critical illness?

Inclusion Criteria

1. Are deemed, in the view of the treating physician, to require continuous cardiovascular or respiratory monitoring or invasive mechanical ventilation,
2. AND provide appropriate consent or assent,
3. AND have one of the following illnesses:

• Bacterial/viral/fungal pneumonia
• Respiratory distress from atypical cause (vaping, inhalational injury etc)
• Sepsis
• Non-infective pro-inflammatory state (e.g. burns, pancreatitis, check point inhibitor therapy)

Exclusion Criteria

There are no specific exclusion criteria

To determine the clinical effectiveness of dexamethasone in patients with ARDS with moderate to severe hypoxaemia (referred to as patients with moderate to severe ARDS) on the primary outcome of 60-day mortality

Inclusion Criteria

1. Provision of informed consent
2. Aged 16 years or older
3. Admitted to intensive care unit or high dependency unit (ICU)
4. Receiving respiratory support via invasive mechanical ventilation or non-invasive ventilatory support (NIV or High flow O2 >30L/min)
5. Within 72 hours of diagnosis of ARDS with moderate to severe hypoxaemia defined as:
   • 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
   • Assessment of hypoxaemia done with either PaO2/FiO2 ratio <26.7 kPa from arterial blood gases, or SpO2/FiO2 <235 with SaO2<97%

 Exclusion Criteria

1. ARDS due to microbiologically confirmed SARS-Co-V2 infection (COVID-19 ARDS)
2. Major upper gastrointestinal bleeding during current hospital admission, defined as requiring endoscopy and transfusion for two or more units of packed red blood cells.
3. 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.
4. Known hypersensitivity to dexamethasone
5. Infections that are not being effectively treated as determined by the treating medical team.
6. Planned intensive care treatment withdrawal within next 24 hours as determined by the treating medical team
7. Patients who are known to be pregnant
8. Previous enrolment in the GuARDS trial

Study Objective

To define best practice in the use of anti-epileptic drugs for patients following a traumatic brain injury. 

The MAST-PROPHYLAXIS trial has been designed to assess the clinical effectiveness of a short course of phenytoin or levetiracetam, used as seizure prophylaxis.

The MAST-DURATION trial has been designed to determine the clinical effectiveness of a short course versus a longer course of AEDs in the prevention of further seizures.

Inclusion Criteria

MAST-PROPHYLAXIS:

1. Patients aged ≥10 years, with TBI managed in an NSU without an acute symptomatic seizure
2. Patient or Legal Representative is willing and able to provide informed consent or in the absence of a legal representative, an Independent Healthcare Professional provides authorisation for patient randomisation within 48 hours of admittance.

MAST-DURATION:

1. Patients aged ≥10 years with TBI managed in an NSU who have started on an phenytoin or levetiracetam due to an acute symptomatic seizure during acute hospitalisation
2. Patient or Legal Representative is willing and able to provide informed consent or in the absence of a legal representative, an Independent Healthcare Professional provides authorisation for patient enrolment

Exclusion Criteria

MAST-PROPHYLAXIS:

The presence of any of the following will preclude patient inclusion:

1. Post-traumatic seizures
2. Unsurvivable injury
3. Previous history of epilepsy
4. Patients who are taking an AED pre-TBI
5. Pregnancy or breastfeeding
6. Any known hypersensitivity to study drugs (or hydantoins or pyrrolidone derivatives) or any of its excipients
7. Time interval from the time of admission to NSU to randomisation exceeds 48 hours

MAST-DURATION:

The presence of any of the following will preclude patient inclusion:

1. Unsurvivable injury
2. Previous history of epilepsy
3. Patients who are taking an AED pre-TBI
4. Patient who has been clinically prescribed an AED to treat PTS (other than phenytoin or levetiracetam since current admission
5. Any known hypersensitivity to study drug selected or any of its excipients
6. For phenytoin: known hypersensitivity to other hydantoins
7. For levetiracetam: known hypersensitivity to other pyrrolidone derivative

Trial to assess the clinical effectiveness and cost-effectiveness of:

1. Rapid PCR-based microbiological diagnostics combined with procalcitonin (in the Diagnostic trial)
2. Conservative fluid therapy with an active fluid de-resuscitation strategy (in the Fluids trial)
3. GM-CSF, using an enrichment strategy to both identify patients at higher risk of mortality (prognostic enrichment) and who are more likely to respond to treatment (predictive enrichment) (in the GM-CSF trial).

Inclusion Criteria

1. Adults (≥16 years of age) admitted to ICU due to suspected sepsis and expected to stay for at least two calendar days (i.e. expected to still to be in ICU the day after tomorrow).
2. Receiving intravenous antibiotics for suspected sepsis
3. According to local clinical judgement, patient has received adequate initial early fluid resuscitation

The following inclusion are for GM-CSF trial only (can be after initial trial entry):

1. Intubated and mechanically ventilated and expected to continue for another 24 hours
2. Or requiring two organ support (i.e. vasopressors or renal replacement therapy)
3. An absolute lymphocyte count < 1.2 x109 /L on two consecutive calendar days at least 12 hours apart, with no values >1.2 x10^9 /L in between

Exclusion Criteria

1. More than 24 hours since ICU admission (this does NOT apply for trial 3, GM-CSF).
2. Previously admitted to ICU due to sepsis on this hospital admission
3. Not expected to survive 90 days, due to pre-existing chronic (end-stage) disease
4. Not expected to survive initial resuscitation (24 hours)
5. Neutropaenia (<0.5 neutrophils x109 /L) due to chemotherapy/malignancy (but not due to sepsis)
6. A source of infection that will require a prolonged course of antibiotics, for greater than 21 days.
7. Diabetic ketoacidosis (DKA) or hyperglycaemic hyperosmolar state (HHS)
8. Within 21 days of a spontaneous subarachnoid haemorrhage
9. Diabetes Insipidus
10. Weight <40Kg

The following additional exclusion criteria relate to GM-CSF trial only:

1. More than 120 hours since ICU admission
2. Already receiving G-CSF or GM-CSF
3. A total white blood cell count >50 x10^9 /L
4. Allergy or previous adverse reaction to GM-CSF
5. Known to be pregnant or breastfeeding
6. Known recent (required treatment within the last 5 years) haematological malignancy
7. Solid organ or bone marrow transplantation
8. Patient weight >125kg
9. Known anaphylaxis to GM-CSF or yeast-derived products

The primary hypothesis is that hypertonic saline is more effective than mannitol in the management of raised ICP after severe TBI through improving clinical outcomes and cost-effectiveness.

Inclusion Criteria

1. Age 16 years or over
2. Admission to ICU following traumatic brain injury
3. ICP > 20mmHg for more than 5 minutes despite stage 1 procedures
4. <10 days from initial head injury
5. Abnormal CT scan consistent with traumatic brain injury

Exclusion Criteria

1. Devastating brain injury with withdrawal of treatment anticipated in the next 24 hours
2. Pregnancy
3. Severe hypernatraemia (Na > 155 mmol/L)
4. 2 or more prior doses of hyperosmolar therapy given on ICU

To demonstrate that platelet transfusion in critically ill patients has net clinical and monetary benefit only below certain thresholds where any gain of preventing bleeding exceeds harm from exacerbating inflammatory and/or infective processes.

Inclusion criteria

1. Adult (aged 18 years or older)
2. Accepted for admission or admitted to a participating critical care unit
3. Platelet count <50 x 10⁹/L
4. Planned to undergo a specified* low bleeding risk invasive procedure OR platelet transfusion being considered for an other procedure**

*Low risk Procedures

1. Vascular catheter insertion and removal (central venous – including vascular access for renal replacement therapy)
2. Paracentesis/superficial abdominal fluid collection drainage
3. Pleural aspiration

**Other procedures

1. Arterial catheter line insertion
2. Pleural drain
3. Interventional radiology (as defined by Society of Interventional Radiology guidelines)
4. Bronchoscopy with or without lavage
5. Wound dressing changes
6. Surgical procedures where the clinical team agree risk of bleeding is low, e.g. re-look laparotomy, or wound closure

 Exclusion criteria

1. Ongoing major haemorrhage requiring blood products and/or surgical/radiological intervention
2. Intercranial haemorrhage within prior 72 hours
3. Contra-indication to platelet transfusion (such as thrombotic microangiopathies; heparin-induced thrombocytopaenia; immune thrombocytopaenia; congenital platelet function defects)
4. Acute promyelocytic leukaemia (APML)
5. Known advance decision refusing blood/blood component transfusions (e.g. Jehovah’s Witnesses)
6. Death perceived as imminent or admission for palliation
7. Previously randomised into T4P
8. Fulfilled all the inclusion criteria and none of the other exclusion criteria ≥72 hours

Study Objectives

1. Compare the consequences of early versus late VTE prophylaxis administration on functional neurological outcome (assessed using the Glasgow Outcome Score Extended) and quality of life using the EQ-5D-5L
2. Compare all-cause mortality between the two arms
3. Compare intracranial haemorrhage progression and all serious adverse events between the two arms
4. Undertake a detailed economic evaluation

Inclusion Criteria

1. Adult patients (≥16 years of age)
2. Acute TBI (defined as acute traumatic changes on CT brain, either in isolation or in the context of polytrauma)
3. Patients admitted to hospital within 72 hours of injury

 Exclusion Criteria

1. Patients with recent Venous Thromboembolism (VTE) - within 3 months before TBI
2. Known hypersensitivity to any VTE prophylaxis agents to be used in this trial
3. Patients not expected to live beyond 72 hours
4. Time interval from injury to randomisation exceeding 72 hours
5. Participation in the same study within last 12 months
6. Current use of anticoagulation for an alternative indication, with a clinical decision to continue
7. Acute bleeding deemed serious enough that the treating clinical team lack equipoise for the study question
8. Progression of early traumatic intracranial haemorrhage or unstable neurological condition, such that the treating clinical team lack equipoise for the study questions