PRophylaxis Against Early VENTilator-associated Infections in Acute Brain Injury

This research is about whether treatment with a commonly used antibiotic can prevent infections in airway and lungs and improves the chance of surviving, if it is given soon after patients commence mechanical ventilation when they have been admitted to hospital with an acute severe brain injury. An acute severe brain injury can occur as a result of a stroke, a traumatic injury or due to lack of oxygen to the brain that happens as a result of a cardiac arrest. Patients who are unconscious after an acute severe brain injury often need assistance to breath adequately, and this assistance is given by a breathing tube, connected to a mechanical ventilator. This treatment is an emergency medical treatment. The breathing tube is inserted into the patients' airway by either their mouth or neck. For patients who need assistance with their breathing from a mechanical ventilator, infections in the airways and lungs, known as pneumonia, are a common complication. Everyone naturally has bacteria in their mouth, esophagus and stomach. Clinicians think that during the process of inserting the breathing tube, small amounts of these bacteria can be introduced into the airways and lung when people are unconscious following an acute severe brain injury, or during the process of placing the breathing tube into the airways. These bacteria are now in a place they aren't meant to be and can cause an infections in the airways and lungs known as pneumonia. The purpose of this research is to see if giving one dose of a common antibiotic can prevent patients developing pneumonia, which is associated with having a breathing tube inserted and being on a ventilator, improving the chance of recovery following the acute severe brain injury and ultimately improving the chance of surviving. When patients have a known infection, current guidelines are to treat them with antibiotics. Antibiotics work to kill the bacteria causing the infection. When a patient has an infection in their lungs, they often need to stay on the mechanical ventilator for longer. While current practice is to give patients with a proven infection in their airways and lungs (pneumonia) antibiotics, it is unknown if giving an antibiotic to patients to prevent these infections before they show signs of pneumonia may lead to better outcomes.

Key Concepts * Lower respiratory tract infections are a common complication in invasively mechanically ventilated ICU patients. * Micro-aspiration before or during endotracheal intubation may contaminate the tracheobronchial tree and lungs with bacteria that can subsequently cause a lower respiratory tract infection. * Patients with a depressed level of consciousness are at particular risk of developing such infections. * In patients who have been hospitalised for fewer than 3-4 days, common community-acquired bacteria including S. aureus, and H. influenzae are the pathogens isolated most frequently from the lower respiratory tract. * Several small, single centre pilot RCTs, have suggested that prophylactic antibiotics might be effective at preventing lower respiratory tract infections in invasively mechanically ventilated ICU patients with acute neurological conditions. * In a multicentre placebo-controlled randomised clinical trial (RCT) prophylactic antibiotics significantly reduced early ventilator-associated pneumonia (VAP) compared to placebo in patients who were mechanically ventilated and treated with targeted temperature management after an out of hospital cardiac arrest. * In another recent RCT (PROPHY-VAP), trial participants allocated to receive a single dose of 2g of ceftriaxone within 12 hours of endotracheal intubation, who were comatose and expected to require at least 48 h of invasive mechanical ventilation in the ICU, had a significantly lower rate of VAP than trial participants allocated to placebo. * These RCTs were not adequately powered to determine the effect of antibiotic prophylaxis on patient-important outcomes. However, in the PROPHY-VAP trial a total of 32 of 161 participants (20%) allocated to prophylactic ceftriaxone had died and a total of 46 of 157 (30%) allocated to placebo had died (hazard ratio, 0.66 (95%CI, 0.42-1.04); P=0.074). * Lower respiratory tract infections that occur within the first week of hospitalisation potentially have major consequences for ICU patients with acute neurological conditions. * Such infections occur at a time when critically ill patients with acute neurological conditions are at risk of secondary brain injury. These infections can cause fevers, hypoxaemia, hypercapnia, and elevated intracranial pressure, all of which may potentially contribute to secondary brain injury. * Patients with impaired airway reflexes due to neurological injuries may have difficulty managing respiratory secretions. The sputum burden associated with a lower respiratory tract infection may prolong the duration of invasive mechanical ventilation in brain-injured patients putting them at risk of unfavourable outcomes. Lower respiratory tract infections in this setting may also increase the risk of patients requiring a tracheostomy. * Overall, it is highly plausible that antibiotic prophylaxis around the time of intubation in ICU patients who have acute neurological injuries and conditions may prevent early lowe trial.show_full_description

Inclusion Criteria: 1. ≥ 18 years of age 2. Receiving invasive mechanical ventilation 3. The requirement for mechanical ventilation is because of an acute brain injury due to intracranial haemorrhage, ischaemic stroke, cerebral venous sinus thrombosis, subarachnoid haemorrhage, suspected hypoxic ischaemic encephalopathy post cardiac arrest, or traumatic brain injury. 4. Admitted to an ICU or is anticipated to be admitted to an ICU Exclusion Criteria: 1. Endotracheal intubation was more than 12 hours ago 2. Hospital admission was more than 72 hours ago 3. Anticipated inability to deliver trial intervention within 90 minutes of randomisation 4. Documented use of antibiotic therapy in the week prior to hospitalisation 5. Currently receiving antibiotic therapy, or intention to prescribe antibiotic therapy, excluding cephazolin for peri-operative prophylaxis 6. Any contraindication to receiving ceftriaxone 7. Known or suspected pregnancy 8. Death within 90 days is deemed inevitable due to the current illness or intercurrent medical conditions 9. Previously enrolled in the PREVENT-NEURO trial.