PRophylaxis Against Early VENTilator-associated Infections to Reduce Mortality in Mechanically Ventilated Intensive Care Unit (ICU) Patients With Acute Brain Injuries: a Phase 3 Randomised, Double Blind, Parallel Group, Placebo-controlled Two-side Superiority Trial

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 lower respiratory tract infections and might, thereby, mitigate secondary brain injury, and reduce mortality.

Background and rationale Respiratory tract infections are common in ventilated adults with acute neurological conditions Ventilator associated pneumonia or VAP, defined as an infection of the lung parenchyma occurring >48 hours after endotracheal intubation, is common in patients in the ICU receiving invasive mechanical ventilation. A diagnosis of VAP requires a new lung infiltrate evident on chest radiograph plus clinical evidence that the infiltrate has an infectious origin. Such evidence can include new onset of fever, purulent sputum, and/or leukocytosis. Although pneumonia complicating intubation can occur before 48 hours have elapsed, chemical pneumonitis due to aspiration is a common cause of radiological pulmonary infiltrates in this period and does not necessarily progress to pneumonia. While micro-aspiration does not always result in infection, organisms that colonise the upper airway are frequently subsequently grown from tracheobronchial secretions. Moreover, micro-aspiration of mouth organisms around the time of intubation may be a common cause of lower respiratory tract infection in patients who are mechanically ventilated. When lower respiratory tract infections develop within the first 3-4 days of hospitalisation, common community-acquired pathogens including S. aureus, and H. influenzae are the most frequently isolated from tracheobronchial secretions.

Patients with a diminished level of consciousness, including those with traumatic brain injury and other acute neurological conditions, appear to be at particular risk of developing VAP. In such patients, impairment of airway reflexes for a period of time prior to securing the airway may be responsible for the heightened risk of VAP compared with other ICU patients. The daily risk of developing VAP appears to be greatest in the early period after intubation. This comparatively higher daily risk of developing early, as opposed to late VAP, may reflect the particular role of the introduction of bacteria into the lower respiratory tract around the time of intubation.

Even among patients who do not develop pulmonary infiltrates, and thus do not fulfil the definition of VAP, purulent deep respiratory secretions developing in association with fever are common in invasively mechanically ventilated patients. While the role antibiotic treatment in patients who do not fulfil the criteria for VAP is uncertain, patients with these clinical findings are often treated with antibiotics and, frequently, no non-respiratory source of infection is apparent. It is plausible that even in the absence of an infection fulfilling the formal definition of VAP, a lower respiratory tract infection occurring in a mechanically ventilated patient may be clinically consequential.