PRophylaxis Against Early VENTilator-associated Infections in Acute Brain Injury

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.

Consequences for ventilated adults with neurological conditions and respiratory infections.

It has been estimated that the attributable mortality of VAP is approximately 13%, reflecting both the natural history of the disease as well as the effectiveness of therapies including antimicrobials and advanced organ support. While it is rare to encounter patients in clinical practice where death clearly occurs as a direct consequence of an ICU-acquired lower respiratory tract infection, such infections appear to be associated with prolongation of invasive mechanical ventilation by an average of ≈7 days, ICU length of stay by ≈8 days, and hospitalisation by ≈12 days.

In neurologically injured patients who are invasively mechanically ventilated in the ICU, early lower respiratory tract infections can have major specific clinical consequences. Neurologically injured patients with lower respiratory tract infections may develop sputum plugging which impairs ventilation leading to pathological elevations of intracranial pressure. These elevations in intracranial pressure, particularly when coupled with hypoxaemia, may contribute to secondary brain injury. Such infections can also cause fevers, which may also contribute to secondary brain injury. For neurologically injured patients, it is plausible that lower respiratory tract infections developing when patients are at high risk of secondary brain injury, adversely affect survival and long-term functional recovery. The sputum burden associated with a lower respiratory tract infection may be particularly likely to prolong invasive mechanical ventilation in brain-injured patients because such patients often have impaired airway reflexes. Prolonged ventilation itself may put patients at risk of unfavourable outcomes and may also result in more patients requiring tracheostomy to facilitate respiratory weaning.

Preliminary data suggest that prophylactic antibiotics may be effective Several RCTs have been conducted evaluating the role of prophylactic intravenous antibiotics in the prevention of VAP in patients with acute severe neurological injury.

In a single centre open-label prospective RCT in mechanically ventilated patients with head injury, stroke, or following surgery for space-occupying lesions, two doses of 1.5g of cefuroxime administered 12 hours apart significantly reduced microbiologically confirmed pneumonia, 70% of which occurred within the first four days following intubation. A total of 12 of 50 (24%) participants and 25 of 50 (50%) allocated to antibiotic prophylaxis and control respectively developed pneumonia (P=0.007).

In another single open-label RCT in comatose mechanically ventilated patients with traumatic, surgical or medical brain injury, 3g of intravenous ampicillin-sulbactam given every 6h for 3 days following intubation significantly reduced the occurrence of pneumonia in the first four days of mechanical ventilation compared to usual treatment. A total of 4 of 19 (21.0%) and 11 of 19 (57.9%) participants allocated to antibiotic prophylaxis and control respectively developed early VAP (Relative risk, 0.36 (95% CI, 0.14-0.94); P=0.02).

Two RCTs have been conducted in comatose post-cardiac arrest patients. In the first, 60 patients were enrolled in a single centre. This trial focussed on the effect of 1.2g of intravenous amoxicillin + clavulanic acid given every 8 h on the systemic inflammatory response (estimated based on the white cell count, C reactive protein, procalcitonin, and CD 64 concentrations from day 1 to 7). While some minor differences in inflammatory response markers between groups were evident, the clinical importance of these was unclear. However, consistent with the earlier studies a mini-bronchoalveolar lavage specimen taken on day 3 was positive in 2 of 27 (7%) and 10 of 24 (42%) participants in the prophylactic antibiotic and control groups respectively (P\<0.01).

The second RCT, is the Antibiotherapy during Therapeutic Hypothermia to prevent Infectious Complications (ANTHARTIC) trial. Published in the New England Journal of Medicine, this trial demonstrated that, among patients who were mechanically ventilated and treated with targeted temperature management following out of hospital cardiac arrest, 1.2g of amoxicillin + clavulanic acid 8 hourly for two days significantly reduced early VAP compared to placebo. A total of 19 of 99 (19%) and 32 of 95 (35%) of participants in the prophylactic antibiotic and placebo groups developed early VAP (HR 0.53; 95% CI, 0.31-0.92; P=0.03). Mortality rates were similar by treatment group and no deaths considered attributable to VAP occurred. While neurological outcomes at six months and one year were also similar by treatment group, the ANTHARTIC trial lacked power to confirm or refute an effect of antibiotic prophylaxis on such outcomes.

Finally, in the Prophylactic Antibiotics for VAP trial (PROPHY-VAP), 2g of prophylactic intravenous ceftriaxone in patients with acute brain injuries requiring mechanical ventilation in the ICU significantly reduced early VAP compared to placebo. A total of 23 of 162 allocated to ceftriaxone (14%) and 51 or 157 allocated to placebo (32%) developed early ventilated pneumonia (hazard ratio 0·60; 95% CI 0·38-0·95; p=0·03). A total of 32 of 161 in the ceftriaxone (20%) and 46 of 157 in the placebo group (30%) died by day 60 (hazard ratio 0·66; 95% CI 0·42-1·04; p=0·07).

The effect of antibiotics on prevention of lower respiratory tract infections that do not fulfil formal criteria for diagnosis of VAP has not been studied. While data from existing RCTs suggesting antibiotic prophylaxis reduces VAP are promising, further research focusing on patient-important outcomes is needed before this treatment strategy can be implemented in clinical practice.

Evidence to support the choice of antibiotic agent The data presented above provide a compelling case to support further research to assess the potential for prophylactic antibiotics to prevent early ventilator associated infection and improve patient centred outcomes. It is important to note that guidelines for

• Functional outcome [Срок оценки: Measured 180 days post randomisation]