In the Literature

https://youtu.be/s8NAlZO5MOA?si=Wp8hfOsy6mGPeAEg Welcome to the emDOCs Videocast – please subscribe to our YouTube channel. These videos will cover post summaries, takehomes on clinical condition, and EBM/guideline literature updates. Today we focus on acute brain injury, including the effects of hypotension, antibiotics in mechanically ventilated patients, transfusion thresholds, and ventilation strategies. Article #1: Lee JW, Wang W, Rezk A, et al. Hypotension and Adverse Outcomes in Moderate to Severe Traumatic Brain Injury: A Systematic Review and Meta-Analysis. JAMA Netw Open. 2024 Nov 4;7(11):e2444465. Clinical Question:  In patients with moderate to severe TBI, is hypotension associated with adverse outcomes? Design:  Systematic review and meta-analysis. Included RCTs and cohort studies evaluating patients > 10 years with moderate to severe TBI and hypotension. Excluded studies with mild TBI.  Outcomes: Hypotension with death and/or vegetative state within 6 months and incidence of hypotension Results: 51 studies with 384,329 patients. Overall hypotension incidence 18% (95% CI, 12%-26%) (P < .001;I2 = 99.84%). Significant increase in mortality in patients with hypotension and moderate to severe TBI (crude OR, 3.82; 95% CI, 3.04-4.81;P < .001; I2 = 96.98%; adjusted OR, 2.22; 95% CI, 1.96-2.51; P < .001; I2 = 92.21%). Considerations:  No reported data on vegetative state, and lack of uniformity of reported data. Limited data on duration of hypotension and management of hypotension. High heterogeneity in mortality outcome data, reducing generalizability and applicability. The Bottom Line: Hypotension in patients with moderate to severe TBI is associated with higher mortality. Article #2: 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 May;12(5):375-385. Background: Ventilator-associated pneumonia (VAP), or infection-related ventilator-associated complication (IVAC),  is a nosocomial pneumonia occurring on day 3 of mechanical ventilation that was preceded by 2 days of stable or decreasing ventilator requirements. Overall incidence is 5-40%, but in patients with TBI, the risk may reach 60%. Clinical Question:  In adults with severe brain injury who require invasive mechanical ventilation (IMV), does an early, single dose of ceftriaxone compared with placebo reduce early VAP? Design:  Multicenter, double-blind, placebo-controlled RCT; conducted at nine ICUs at 8 French hospitals. Included adults with GCS < 12, within 12 hr of intubation and within 48 hr of hospitalization, expected IMV duration > 48 hr. Brain injury: defined as head trauma, stroke, subarachnoid hemorrhage Patients randomized to single dose of ceftriaxone 2 g IV versus placebo. All patients underwent standard VAP-preventative measures: Hand washing before any care, Head of bed elevation at 30 degrees mounted every 4 hours, Preferential use of heat and humidity exchange filters, changed only when soiled, Monitoring of cuff pressure of tracheal tube every 8 hours to maintain pressure between 25-30 cm H20, Tracheal aspiration using sterile equipment, and only when required, Mouth care every 8 hours at minimum, No systemic changes of the respirator circuits, Preferential oral insertion of feeding tubes, Starting enteral feeding as soon as possible, Blood glucose monitoring every 4 hours, Ulcer prophylaxis, Extubation as soon as possible.   Outcomes: Primary: Development of early VAP (2ndto 7th day of mechanical ventilation) VAP confirmed by 2-3 intensivist committee based on clinical, radiological, microbiological criteria outlined by American Thoracic Society (ATS) Clinical criteria: temperature ≥38°C or <36°C, white blood cell count >12,000/mm3 or <4000/mm3, purulent tracheal aspirates Radiological criteria: new or changed chest X-ray infiltrate Micro criteria: positive respiratory cultures Secondary: At ICU discharge or day 28 (whichever came first) Development of late VAP (>7 days after intubation) Organism identified with development of VAP Number ventilator-free days Number antibiotic-free days Development of ventilator-associated events (VAE) Comparison to global number of VAE Time from inclusion to first spontaneous breathing trial Number patients with ESBL-producing Enterobacteriaceae Neuro outcomes: mRS and GCS Mortality Safety At day 60: Number ICU-free days Number hospital-free days Neuro outcomes:  mRS and GCS Mortality   Results: Included 319 patients; 162 ceftriaxone vs. 157 placebo Primary outcome: early VAP 14% vs. 32% (HR 0.60; 95% CI 0.38-0.95) Secondary outcomes at day 28: Lower VAP risk, fewer median vent days, improved mRS, lower mortality Secondary outcomes at day 60: More median ICU/hospital free days, no difference in neuro/mortality Considerations:  Study was multicenter, randomized, blinded. Used intention to treat analysis. Groups were well balanced. Authors used standardized VAP definition and prevention measures. Primary outcome controversial, as the detection/diagnosis of VAP is inaccurate. Limited generalizability. Definition of VAP is controversial, as diagnosis is inaccurate. VAP prevention measures not monitored. Limited generalizability. Secondary outcomes hypothesis generating. The Bottom Line: A single dose of ceftriaxone likely reduces VAP in intubated patients with severe brain injury. Article #3: 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 Nov 19;332(19):1623-1633. Clinical Question:  In patients with acute brain injury who are intubated and mechanically ventilated, does ventilation with lower VT and higher PEEP versus conventional ventilation improve clinical outcomes? Design:  Multicenter, open-label RCT. Included adults with TBI who were mechanically ventilated. Outcomes: Primary: Unfavorable neurologic outcome 180 days based on Glasgow Outcome Scale extended. Secondary: 28-day mortality, organ failure, ICU LOS, adverse events, cerebral ischemia Results: 806 patients; 393 liberal, 413 restrictive Primary outcome unfavorable neurologic outcome: liberal 62.6% vs. restrictive 72.6% (aRR 0.86; 95% CI 0.78-0.95). Secondary outcome: No difference in 28-day mortality, organ failure, ICU LOS, but fewer cerebral ischemic events in liberal 8.8% vs. 13.5% (RR 0.65; 95% CI 0.44-0.97). Considerations:  Study was multicenter, randomized. Blinded outcome assessors, but ICU staff not blinded. Groups were well balanced. Slow enrollment, requiring two sample size adjustments. Most patients enrolled at hospital/ICU day 3; unknown if patients received transfusion prior to enrollment. Broad range of neurocritical illnesses included, and serum hemoglobin is a nonspecific surrogate for cerebral oxygenation. Limited generalizability. Definition of VAP is controversial, as diagnosis is inaccurate. The Bottom Line: In patients with acute brain injury and anemia, hemoglobin transfusion threshold of 9 g/dL may reduce unfavorable neurologic outcomes at 180 days. Further randomized data needed.   Article #4: Mascia L, Fanelli V, Mistretta