Acute brain injuries (ABIs) include acute ischemic stroke, subarachnoid hemorrhage (SAH), intracerebral hemorrhage (ICH), status epilepticus and hypoxic ischemic encephalopathy (HIE), meningitis, and encephalitis, among others. First, let’s dive a little deeper into pneumonia and the need for mechanical ventilation in ABI before we discuss two topics: the use of prophylactic antibiotics in ABI to prevent pneumonia and how to extubate patients with ABI successfully.
Pneumonia and mechanical ventilation
Pneumonia in ABI can be characterized based on the timing from the primary neurological injury—early (within 72 hours) vs late (beyond 72 hours) pneumonia. This has implications for the potential organisms and etiologies and guides selection of empiric antibiotics. Patients who are critically ill with ABI may need to be intubated for airway protection given a high risk of aspiration; may have diminished cough and gag reflexes due to their underlying brain injuries; or may develop acute hypoxic and/or hypercarbic respiratory failure, neurogenic pulmonary edema, or ARDS as a complication of their underlying brain injury or due to the expected trajectory of their underlying neurological injury.
Patients with ABI are at a higher risk of developing pneumonia due to mechanical reasons, systemic immunological effects of the underlying brain injury, and need for prolonged mechanical ventilation—for example, due to secondary neurological injuries such as cerebral edema, raised intracranial pressure, or seizures.1 Respiratory failure and pneumonia remain among the highest causes of morbidity and mortality in this patient population. Hence, studies that have investigated the role of prophylactic antibiotics in this patient population could potentially change our management.
The use of prophylactic antibiotics
A recent systematic review published in the journal CHEST® that included seven randomized controlled trials (RCTs) recruiting N = 27,319 patients attempts to provide us with relevant clinical guidance regarding the use of prophylactic antibiotics before or after 48 hours from the primary neurological injury for a short course (24 to 72 hours).2 Only two of the seven trials included in this review were multicenter French trials. While the organisms that cause early vs late pneumonia in patients with ABI may vary depending on the time of onset and guide empiric antibiotic coverage, most of the studies that were included in this review included antibiotics such as cefuroxime, ampicillin-sulbactam, piperacillin-tazobactam, or ceftriaxone. The authors had three a priori subgroup analyses: 1) patients with HIE would benefit less than patients with other brain injuries; 2) patients who received prophylactic antibiotics for more than 48 hours would benefit more than those who received antibiotics for less than 48 hours; and 3) patients who had antibiotics within 12 hours of being on mechanical ventilation would benefit the most. The pooled analysis showed that prophylactic antibiotics could potentially reduce ventilator-associated pneumonia (VAP) (ARR, 380 cases/1,000 vs 211 cases/1,000; RR, 0.56 [0.35-0.91]) but may not affect mortality, duration of mechanical ventilation, ICU length of stay, or functional outcomes.
It is important to acknowledge the heterogeneity in the definitions of VAP used in these trials. It is difficult to diagnose VAP in ABI as patients can have fevers due to other causes such as central fevers or thromboembolism; they could also have chest infiltrates due to aspiration pneumonitis, pulmonary edema, atelectasis, pneumonia, or a combination of these factors. They may end up receiving antibiotics for other reasons such as perioperative antibiotic prophylaxis. Hence, these trials may end up underestimating the incidence of VAP.
Given the risk of high-resistance organisms by increasing exposure to antibiotics or the risk of Clostridium difficile (C. diff) colitis, the decision to administer antibiotic prophylaxis needs to be weighed against the risks. In my practice, I am planning to weigh the risk-benefit ratio of administering prophylactic antibiotics to patients with ABI. I’ll assess the risk of C. diff colitis, history of prior colonization or infections with multidrug resistant organisms, and exposure to any perioperative antibiotics before administering prophylactic antibiotics to these patients. Given that the largest trial, the PROPHY-VAP: Prevention of Early Ventilation Acquired Pneumonia (VAP) in Brain Injured Patients by a Single Dose of Ceftriaxone (PROPHY-VAP) study, had 319 patients with ABI and their protocol was a single dose of ceftriaxone within 12 hours of endotracheal intubation, I think that might be the best evidence-based protocol we have.3 In my neurosciences ICU, we are currently in the process of launching a quality improvement project to improve our documentation of VAP and implement a new protocol for VAP prevention, including our current VAP bundle (with chlorhexidine mouthwash and frequent chest physiotherapy) and a single dose of ceftriaxone.
How to extubate patients with ABI
The European Society of Intensive Care Medicine recommendations for mechanical ventilation in patients with ABI provide some guidance on the decision to extubate patients with ABI while highlighting the paucity of literature.4 The decision to extubate patients with ABI depends on the anticipated trajectory of the underlying primary and secondary neurological injuries, level of consciousness, and airway protective reflexes. Strategies for successful extubation in ABI have not been well studied, which prompted the international ENIO (Extubation strategies in Neuro-Intensive care unit patients and associations with Outcomes) collaboration.5 This observational study included N = 1,512 patients from 73 ICUs in 18 countries—50% were patients with traumatic brain injuries (TBIs), and a third were patients with ICH. Extubation failure within five days of extubation occurred in 20% of patients, and 20% of patients underwent tracheostomy at day 9 (IQR, 5-15 days). The ENIO study included patients with ABI but excluded patients with postcardiac arrest HIE, patients intubated for acute neuromuscular respiratory failure, or patients who underwent withdrawal of life-sustaining therapies within 24 hours, among others.
The primary objective was to develop a validated extubation score in ABI. Extubation failure was defined as the need for reintubation by day 5. The authors split the data to create a training set (2/3) and a validation set (1/3). The ideal score had 20 variables but could not realistically be used clinically, so a simplified model with seven predictors was created; these included TBI, vigorous cough, gag reflex, swallowing attempts, endotracheal suctioning ≤ 2 times per hour, a Glasgow Coma Scale motor score of 6, and body temperature the day of extubation. However, the AUC of the score was 0.79 CI95 (0.71-0.86) in the training cohort and 0.65 CI95 (0.53-0.76) in the validation cohort. The most common causes of extubation failure included respiratory failure in more than half the patients, neurological cause in 40% of patients, and airway failure in about 40% of patients. Interestingly, the incidence of pneumonia, ICU length of stay, prolonged duration of mechanical ventilation, and mortality were similar in patients with direct tracheostomy and those who suffered from extubation failure.
The Early Tracheostomy in Ventilated Stroke Patients 2 (SETPOINT-2) study, an RCT comparing early vs delayed tracheostomy in ABI, showed that patients in the delayed tracheostomy group needed fewer tracheostomies.6 Our ability to predict extubation success and the need for tracheostomy is limited in patients with ABI.
The NEUROlogically-impaired Extubation Timing Trial could not be completed due to the outbreak of the COVID-19 pandemic, but the authors performed an emulation by creating a pseudopopulation weighted from a retrospective cohort to understand extubation success after prompt extubation following a spontaneous breathing trial (SBT).7 It was an interesting approach, but the only thing I learned from this study was that younger patients with seizures or TBI and less severe neurological injuries could benefit from an earlier trial of extubation. This study, however, had several limitations and lacked many variables that the ENIO study deemed to be helpful.
Hence, in my practice, I combine objective and subjective data to determine which patients with ABI will benefit from a trial of extubation and how to optimize their clinical status similar to patients without brain injuries, including volume status, quality and frequency of secretions, ability to tolerate SBT with a positive end-expiratory pressure of ≤ 7 cm of H2O, anticipated trajectory of the underlying neurological and systemic illnesses, and airway protective reflexes—essentially, some of the variables included in the simplified ENIO score. My default approach also includes extubating these patients to high-flow nasal cannula despite lack of data to support clear benefit in this patient population, and I have found it helpful to extrapolate data to support this practice from studies in patients without brain injuries. It is important to note that uncertainty in predicting extubation success has led to widespread practice variation, and more studies are needed for us to understand the correct strategies to maximize extubation success in ABI.
Transfusion thresholds
In patients who are critically ill, anemia could be seen due to a variety of reasons, including inflammation-associated bone marrow suppression, phlebotomies, acute blood loss, hemodilution due to IV fluids, reduced lifespan of RBCs, etc. Anemia has been associated with worsened outcomes in patients with ABI.8 The TRansfusion strategies in Acute brain INjured patients (TRAIN) trial was a pragmatic RCT conducted in 72 ICUs from 22 countries evaluating two transfusion thresholds: hemoglobin (Hb) ≥ 9 g/dL vs Hb ≥ 7 g/dL in ABI.9 The study included patients with ICH, SAH, and TBI randomized to receive a transfusion triggered by Hb < 9 g/dL (N = 408) or a restrictive transfusion triggered by Hb < 7 g/dL (N = 442) over a 28-day period. The primary outcome was unfavorable neurological outcome as measure by the Glasgow Outcome Scale-Extended-E. At six months, 246 patients (62.6%) in the liberal strategy group had an unfavorable neurological outcome compared with 300 patients (72.6%) in the restrictive strategy group (absolute difference, -10.0% [95% CI, -16.5% to -3.6%]; adjusted RR, 0.86 [95% CI, 0.79-0.94]; P = .002).
Of note, in the recently published HEMOglobin Transfusion Threshold in Traumatic Brain Injury OptimizatioN: The HEMOTION Trial (HEMOTION), a liberal transfusion strategy (Hb ≥ 10 g/dL) was associated with a nonsignificant 5.4% absolute reduction (95% CI, -2.9% to 13.7%) in the risk of unfavorable neurological outcomes at six months in patients with TBI compared with a restrictive strategy.10 The improvement in neurological outcomes could be due to better cerebral tissue oxygenation or lesser ischemic events. However, this would need to be counterbalanced against the risk of volume overload, increasing duration of mechanical ventilation, transfusion-related acute lung injury, transfusion-associated circulatory overload, etc.
In my clinical practice, if there are no contraindications such as underlying heart failure (heart failure with reduced ejection fraction or heart failure with preserved ejection fraction), end-stage renal disease, volume overload, etc, then I might aim for a higher Hb goal in the acute phase—for example, the first week or two—to potentially improve neurological outcomes.
This article was originally published in the Winter 2025 issue of CHEST Physician.
References
1. Hu PJ, Pittet JF, Kerby JD, Bosarge PL, Wagener BM. Acute brain trauma, lung injury, and pneumonia: more than just altered mental status and decreased airway protection. Am J Physiol Lung Cell Mol Physiol. 2017;313(1):L1–15. doi:10.1152/ajplung.00485.2016
2. Hadley-Brown K, Hailstone L, Devane R, et al. Prophylactic antibiotics in adults with acute brain injury who are invasively ventilated in the ICU: a systematic review and meta-analysis. Chest. 2025;167(4):1079-1089. doi:10.1016/j.chest.2024.10.031
3. Dahyot-Fizelier C, Lasocki S, Kerforne T, et al; PROPHY-VAP Study Group and the ATLANREA Study Group. Ceftriaxone to prevent early ventilator-associated pneumonia in patients with acute brain injury: a multicentre, randomised, double-blind, placebo-controlled, assessor-masked superiority trial. Lancet Respir Med. 2024;12(5):375-385. doi:10.1016/S2213-2600(23)00471-X
4. Robba C, Poole D, McNett M, et al. Mechanical ventilation in patients with acute brain injury: recommendations of the European Society of Intensive Care Medicine consensus. Intensive Care Med. 2020;46(12):2397-2410. doi:10.1007/s00134-020-06283-0
5. Cinotti R, Mijangos JC, Pelosi P, et al; ENIO Study Group, the PROtective VENTilation network, the European Society of Intensive Care Medicine, the Colegio Mexicano de Medicina Critica, the Atlanréa group and the Société Française d’Anesthésie-Réanimation–SFAR research network. Extubation in neurocritical care patients: the ENIO international prospective study. Intensive Care Med. 2022;48(11):1539-1550. doi:10.1007/s00134-022-06825-8
6. Bösel J, Niesen WD, Salih F, et al; SETPOINT2 and the IGNITE Study Groups. Effect of early vs standard approach to tracheostomy on functional outcome at 6 months among patients with severe stroke receiving mechanical ventilation: the SETPOINT2 randomized clinical trial. JAMA. 2022;327(19):1899-1909. doi:10.1001/jama.2022.4798
7. Angriman F, Amaral ACKB, Fan E, et al. Timing of extubation in adult patients with acute brain injury. Am J Respir Crit Care Med. 2025;211(3):339-346. doi:10.1164/rccm.202408-1553OC
8. Lelubre C, Bouzat P, Crippa IA, Taccone FS. Anemia management after acute brain injury. Crit Care. 2016;20(1):152. doi:10.1186/s13054-016-1321-6
9. Taccone FS, Rynkowski CB, Møller K, et al; TRAIN Study Group. Restrictive vs liberal transfusion strategy in patients with acute brain injury: the TRAIN randomized clinical trial. JAMA. 2024;332(19):1623-1633. doi:10.1001/jama.2024.20424
10. Turgeon AF, Fergusson DA, Clayton L, et al; HEMOTION Trial Investigators on behalf of the Canadian Critical Care Trials Group, the Canadian Perioperative Anesthesia Clinical Trials Group, and the Canadian Traumatic Brain Injury Research Consortium Liberal or restrictive transfusion strategy in patients with traumatic brain injury. N Engl J Med. 2024;391(8):722-735. doi:10.1056/NEJMoa2404360
