Traumatic Brain Injury — Part 2: Initial Management & Resuscitation

Airway management and RSI in TBI, oxygenation and ventilation targets, blood pressure management, seizure prophylaxis, coagulopathy reversal, TXA (CRASH-3), and cerebral herniation emergency management.

guidelinesMar 2026guidelines

1. Airway Management in TBI

1.1 Indications for Endotracheal Intubation

Definitive airway management with endotracheal intubation is one of the most critical early interventions in TBI. Indications include.1 2

IndicationRationale
GCS ≤ 8Inability to protect airway; universal threshold for intubation in severe TBI
Declining GCS (drop of ≥ 2 points)Indicates clinical deterioration and impending airway compromise
Loss of protective airway reflexesAspiration risk
Hypoxemia refractory to supplemental oxygenPaO2 < 60 mmHg or SpO2 < 90%
Hypercarbia (PaCO2 > 45 mmHg)Increased ICP from cerebral vasodilation
Combative patient requiring sedation for imaging/transportSafety and diagnostic necessity
Bilateral mandibular fractures or massive facial traumaStructural airway compromise
Anticipated clinical course (prolonged transport, need for emergent surgery)Proactive airway management

Critical Warning: Avoid nasal intubation in patients with suspected basilar skull fracture (raccoon eyes, Battle sign, CSF rhinorrhea/otorrhea, hemotympanum) due to the risk of intracranial tube passage through a disrupted cribriform plate. Oral intubation with in-line cervical spine stabilization is the preferred route.2

1.2 Rapid Sequence Intubation (RSI) in TBI

RSI is the method of choice for emergency intubation in TBI patients. The goals are to achieve rapid, controlled intubation while minimizing ICP elevations and maintaining cerebral perfusion pressure.3

Pre-Intubation Preparation

StepAction
Preoxygenation100% O2 via NRB mask or BVM with PEEP valve for ≥ 3 minutes (or 8 vital capacity breaths). Target SpO2 ≥ 95% before attempt
PositionHead of bed elevated 20–30° if no spinal precautions; in-line cervical stabilization (remove anterior collar, maintain manual stabilization)
EquipmentPrepare two laryngoscopes (video preferred), bougie, surgical airway kit
Hemodynamic optimizationEnsure IV access; prepare push-dose vasopressor (phenylephrine 100 mcg/mL or epinephrine 10 mcg/mL) for post-intubation hypotension

RSI Medications for TBI

PhaseMedicationDoseNotes
PretreatmentFentanyl1–3 mcg/kg IV over 30–60 secBlunts sympathetic response to laryngoscopy; optional; avoid in hypotension
Lidocaine1.5 mg/kg IVTraditionally used to blunt ICP rise; evidence for benefit is weak; optional
InductionKetamine1–2 mg/kg IVNow preferred in TBI. Previously avoided due to theoretical ICP concerns, but multiple studies demonstrate hemodynamic stability without clinically significant ICP elevation. Neuroprotective NMDA antagonism. Ideal for hemodynamically unstable patients.4
Etomidate0.3 mg/kg IVHemodynamically neutral. Risk of adrenal suppression with single dose is debated. Does not lower ICP
Propofol1–2 mg/kg IVLowers ICP but causes significant hypotension — avoid in hypotensive patients
Midazolam0.1–0.3 mg/kg IVSlower onset; less predictable; generally not first-line for RSI
ParalyticSuccinylcholine1.5 mg/kg IVOnset 45–60 sec; duration 6–10 min. Theoretical ICP rise from fasciculations is clinically insignificant. Avoid if hyperkalemia risk (delayed presentation > 72h with denervation injury)
Rocuronium1.2 mg/kg IVOnset 45–60 sec; duration 45–70 min. Preferred by many due to absence of hyperkalemia risk and can be reversed with sugammadex (16 mg/kg)

Key Evidence on Ketamine in TBI: A systematic review and meta-analysis demonstrated that ketamine does not increase ICP and may actually reduce ICP in mechanically ventilated patients with TBI. Multiple trauma society guidelines now list ketamine as an acceptable induction agent for TBI, including for prehospital RSI.4

1.3 Post-Intubation Management

ParameterTargetRationale
SpO2≥ 94%Avoid hypoxemia (associated with doubled mortality in severe TBI)
PaCO235–40 mmHg (normocapnia)Hyperventilation causes cerebral vasoconstriction → ischemia; only use brief hyperventilation as a bridge for herniation
ETCO235–40 mmHgCorrelate with ABG early; ETCO2 may underestimate PaCO2 by 3–8 mmHg
Head positionHOB 30°, midlinePromotes venous drainage; avoid neck flexion, tight cervical collars, and internal jugular central lines on the ipsilateral side
SedationPropofol or midazolam + fentanylPrevent coughing/bucking on ETT which raises ICP

2. Oxygenation and Ventilation

2.1 Oxygenation Targets

Both hypoxemia and extreme hyperoxia are harmful after TBI.5

ParameterTargetEvidence Level
SpO2≥ 90% (preferably ≥ 94%)Level III recommendation. Even a single episode of SpO2 < 90% is associated with significantly worse outcomes
PaO2≥ 60 mmHg (preferably 80–120 mmHg)Level III recommendation
Avoid extreme hyperoxiaPaO2 > 300 mmHg may worsen oxidative stressEmerging evidence; aim for normoxia once stabilized

2.2 Ventilation Targets

ParameterTargetRationale
PaCO235–40 mmHg (normocapnia)Hyperventilation (PaCO2 < 35) causes cerebral vasoconstriction, reduces cerebral blood flow, and may cause ischemia
Tidal volume6–8 mL/kg IBWLung-protective ventilation; TBI patients at high risk for ARDS
PEEP5–8 cmH2O (up to 12 if needed for oxygenation)PEEP > 15 may impair cerebral venous drainage; monitor ICP if high PEEP required
Respiratory rateAdjust to achieve target PaCO2Typically 14–18 breaths/min

Critical Warning — Prophylactic Hyperventilation: Prolonged prophylactic hyperventilation (PaCO2 ≤ 25 mmHg) is contraindicated in the first 24 hours after severe TBI and should be avoided throughout the acute phase. This is a Level IIB recommendation from the fourth edition of the severe TBI management guidelines. Brief, controlled hyperventilation (PaCO2 30–35 mmHg) is reserved ONLY as a temporizing measure for acute herniation.5


3. Blood Pressure Management and Cerebral Perfusion

3.1 Avoiding Hypotension — The Single Most Important Systemic Factor

Hypotension (SBP < 90 mmHg) is the most powerful modifiable predictor of poor outcome in TBI. A single episode of hypotension doubles mortality in severe TBI.5 6

RecommendationTargetEvidence Level
Avoid SBP < 90 mmHgMinimum SBP ≥ 90 mmHg at all timesLevel III
SBP ≥ 100 mmHg for patients age 50–69Optimal threshold based on IMPACT/BTF analysisLevel III
SBP ≥ 110 mmHg for patients age 15–49 or > 70Higher threshold may improve outcomesLevel III
MAP target≥ 80 mmHg (to maintain CPP 60–70 once ICP monitored)Level II

3.2 Cerebral Autoregulation

In the uninjured brain, cerebral blood flow (CBF) remains constant across a MAP range of approximately 50–150 mmHg through autoregulatory mechanisms. In TBI, autoregulation is frequently impaired, making CBF directly pressure-dependent. This means.6

  • Hypotension → direct reduction in CBF → cerebral ischemia → secondary injury
  • Hypertension → may worsen cerebral edema and hemorrhage expansion in regions with disrupted blood-brain barrier

3.3 Fluid Resuscitation

RecommendationDetail
First-line fluidIsotonic crystalloid (0.9% NaCl or lactated Ringer’s)
Avoid hypotonic fluidsD5W, 0.45% NaCl, and other hypotonic solutions worsen cerebral edema
Avoid albuminThe SAFE trial demonstrated increased mortality with albumin resuscitation in TBI patients (RR 1.63 at 24 months)7
Blood productsTransfuse PRBCs for Hgb < 7 g/dL; consider higher threshold (< 10) in patients with brain tissue hypoxia
VasopressorsNorepinephrine is the first-line vasopressor for TBI patients with hypotension refractory to volume resuscitation. Phenylephrine is an alternative. Avoid vasopressin as first-line (reduces CBF)

SAFE Trial Evidence: The Saline vs. Albumin Fluid Evaluation (SAFE) study demonstrated that 4% albumin resuscitation in TBI patients was associated with significantly higher mortality compared to 0.9% saline (33.2% vs. 20.4%; RR 1.63; 95% CI 1.17–2.26). Albumin should NOT be used for resuscitation in TBI patients.7


4. Seizure Prophylaxis

4.1 Risk Factors for Post-Traumatic Seizures

Post-traumatic seizures (PTS) are classified by timing.8 9

ClassificationTimingClinical Significance
Immediate< 24 hoursEarly PTS; prophylaxis effective
EarlyWithin 7 daysEarly PTS; prophylaxis effective
Late> 7 daysPost-traumatic epilepsy; prophylaxis NOT effective for prevention

Risk Factors for Early Post-Traumatic Seizures:

Risk Factor
GCS ≤ 10
Cortical contusion
Depressed skull fracture
Subdural hematoma
Epidural hematoma
Intracerebral hematoma
Penetrating brain injury
Seizure within 24 hours of injury
Chronic alcohol use

4.2 Seizure Prophylaxis Recommendations

RecommendationDetailEvidence
Prophylaxis indicated forSevere TBI (GCS ≤ 8) to prevent early PTS (within 7 days)Level IIA
Duration7 days from injury; do NOT continue beyond 7 days for prophylaxis aloneLevel IIA — Prophylaxis does not prevent late PTS or post-traumatic epilepsy8
Preferred agentLevetiracetam (Keppra) 500–1000 mg IV/PO q12h (20 mg/kg load, then 500–1000 mg q12h)Comparable efficacy to phenytoin with more favorable side effect profile; no need for drug level monitoring9
Alternative agentPhenytoin (Dilantin) 20 mg/kg IV loading dose (max rate 50 mg/min), then 100 mg IV/PO q8hLevel IIA; historically the standard. Requires drug level monitoring (target total 10–20 mcg/mL, free 1–2 mcg/mL). Risk of hypotension with rapid IV loading
NOT recommendedValproic acid for seizure prophylaxis in severe TBILevel III — Trend toward higher mortality in CRASH trial subgroup
Prophylaxis NOT indicated forMild TBI (GCS 14–15) with normal CTInsufficient evidence of benefit

4.3 Levetiracetam vs. Phenytoin

FeatureLevetiracetamPhenytoin
Efficacy for early PTSEquivalentStandard reference
Drug level monitoringNot requiredRequired (narrow therapeutic index)
Drug interactionsMinimalExtensive (CYP450 inducer)
Adverse effectsSomnolence, irritabilityHypotension (IV loading), cardiac arrhythmia, Stevens-Johnson syndrome, purple glove syndrome
CostHigher (though now generic)Lower
HepatotoxicityRarePossible
IV-to-PO conversion1:11:1 (approximately)

4.4 Treatment of Active Post-Traumatic Seizures

LineAgentDose
First-lineLorazepam0.1 mg/kg IV (max 4 mg per dose, may repeat x1)
Midazolam (if no IV access)0.2 mg/kg IM (max 10 mg) or 0.2 mg/kg intranasal
Second-lineLevetiracetam60 mg/kg IV (max 4500 mg) over 15 min
Fosphenytoin20 mg PE/kg IV (max rate 150 mg PE/min)
Valproic acid40 mg/kg IV (max 3000 mg) over 10 min
Third-line (status epilepticus)Continuous infusion: midazolam, propofol, or pentobarbitalPer status epilepticus protocol; continuous EEG monitoring required

5. Coagulopathy in TBI

5.1 Trauma-Induced Coagulopathy (TIC) in TBI

TBI is uniquely associated with coagulopathy even in the absence of significant extracranial hemorrhage. The injured brain releases tissue factor and phospholipids that activate the extrinsic coagulation cascade, leading to a consumptive coagulopathy and hyperfibrinolysis. Up to 60% of patients with severe isolated TBI develop coagulopathy, which is an independent predictor of hemorrhage progression and poor outcome.10

Laboratory Markers:

TestThreshold of ConcernAction
INR> 1.4Correct with FFP, PCC, or vitamin K
PTT> 35 secCorrect with FFP
Platelet count< 100,000/μLTransfuse platelets (goal > 100,000 in TBI)
Fibrinogen< 200 mg/dLCryoprecipitate (10 units) or fibrinogen concentrate
Thromboelastography (TEG/ROTEM)Abnormal parametersGoal-directed component therapy

5.2 Anticoagulant Reversal Protocols

Warfarin Reversal

AgentDoseOnsetNotes
4-Factor PCC (Kcentra)INR 2–4: 25 units/kg; INR 4–6: 35 units/kg; INR > 6: 50 units/kg (max 5000 units)10–15 minutesFirst-line agent. Fastest correction. Fixed-dose protocols (1500 units for all INR levels) are also used at some centers11
Vitamin K (phytonadione)10 mg IV over 10–20 min4–6 hours for full effectAlways administer WITH PCC; PCC effect is temporary (6–8 hours) and vitamin K ensures sustained correction
FFP10–15 mL/kg30–60 minutes (includes thaw time)Second-line if PCC unavailable. Volume overload risk. Incomplete correction

Target: INR ≤ 1.4 within 60 minutes of presentation.

DOAC Reversal

DOACReversal AgentDoseNotes
Dabigatran (Pradaxa)Idarucizumab (Praxbind)5 g IV (two 2.5 g vials)Specific reversal agent; onset within minutes. If unavailable, use aPCC (FEIBA) 50 units/kg12
Rivaroxaban, Apixaban, Edoxaban (Factor Xa inhibitors)Andexanet alfa (Andexxa)Low-dose: 400 mg bolus → 4 mg/min x 120 min; High-dose: 800 mg bolus → 8 mg/min x 120 minExpensive; limited availability. High dose for rivaroxaban > 10 mg or apixaban > 5 mg taken within 8 hours13
Rivaroxaban, Apixaban, Edoxaban (if andexanet unavailable)4-Factor PCC50 units/kg IVOff-label but widely used. Reasonable alternative
All DOACsActivated charcoal50 g POOnly if DOAC ingested within 2–4 hours

Antiplatelet Reversal

ScenarioRecommendationEvidence
Aspirin or clopidogrel with ICHPlatelet transfusion is NOT routinely recommendedThe PATCH trial demonstrated that platelet transfusion in patients on antiplatelet agents with ICH was associated with WORSE outcomes (OR for death or dependence 2.05; 95% CI 1.18–3.56)14
Aspirin with active surgical bleedingConsider platelet transfusion or desmopressin (DDAVP) 0.3 mcg/kg IVDDAVP may improve platelet function; limited evidence in TBI specifically
Dual antiplatelet therapy with expanding ICHCase-by-case basis; consider DDAVP 0.3 mcg/kgNo high-quality evidence to guide management

5.3 Tranexamic Acid (TXA) in TBI — CRASH-3 Trial

The CRASH-3 trial was a landmark international RCT (12,737 patients, 175 hospitals, 29 countries) evaluating TXA in acute TBI.15

CRASH-3 Protocol:

  • Loading dose: 1 g IV over 10 minutes
  • Maintenance dose: 1 g IV over 8 hours
  • Within 3 hours of injury

Key Results:

FindingDetail
Primary outcome (head injury–related death)Overall: OR 0.94 (95% CI 0.86–1.04) — not statistically significant for entire cohort
Mild-to-moderate TBI (GCS 9–15)Significant benefit: RR 0.78 (95% CI 0.64–0.95). Head injury-related death reduced
Severe TBI (GCS 3–8)No significant benefit
Time-dependent effectBenefit strongest when administered within 3 hours of injury; no benefit after 3 hours
SafetyNo increase in thrombotic events (PE, DVT, stroke, MI)
Patients with GCS 3 and bilateral unreactive pupilsExcluded from primary analysis (very high mortality regardless of treatment)

Clinical Recommendation for TXA in TBI:

Patient GroupRecommendation
GCS 9–15, intracranial hemorrhage on CT, within 3 hoursAdminister TXA 1 g IV bolus + 1 g over 8 hours
GCS 3–8 with reactive pupils, within 3 hoursConsider TXA (potential benefit, not statistically proven)
GCS 3 with bilateral fixed pupilsTXA unlikely to benefit
> 3 hours from injuryDo NOT administer TXA
Isolated extracranial hemorrhageUse per CRASH-2 protocol (different indication)

6. Cerebral Herniation — Recognition and Emergency Management

6.1 Herniation Syndromes

SyndromeMechanismClinical Features
Uncal (transtentorial)Temporal lobe herniates through tentorial notch, compressing CN III and cerebral peduncleIpsilateral pupil dilation (CN III compression) → contralateral hemiparesis (cerebral peduncle compression) → progressive obtundation. Kernohan notch phenomenon: ipsilateral hemiparesis from contralateral peduncle compression against opposite tentorial edge (false localizing sign)
Central (descending transtentorial)Bilateral downward herniation through tentorial notchBilateral small reactive pupils → bilateral fixed midpoint pupils → bilateral fixed dilated pupils. Progressive rostral-to-caudal deterioration. Cushing response (hypertension, bradycardia, irregular respirations)
Tonsillar (cerebellar)Cerebellar tonsils herniate through foramen magnum, compressing medullaSudden respiratory arrest, cardiovascular collapse. May present with neck stiffness, head tilt. Often rapidly fatal
SubfalcineCingulate gyrus herniates under falx cerebriContralateral leg weakness (ACA compression); may progress to ACA infarction. Often clinically subtle
Upward (ascending transtentorial)Posterior fossa mass pushes cerebellum upward through tentorial notchRapidly deteriorating consciousness, Parinaud syndrome (impaired upgaze), bilateral small pupils

6.2 Cushing Response (Cushing Triad)

The classic triad of elevated ICP and impending herniation.16

ComponentMechanism
Systemic hypertension (often severe, SBP > 200)Brainstem reflex to maintain CPP against rising ICP
Bradycardia (often < 60 bpm)Baroreceptor-mediated vagal response to hypertension
Irregular respirations (Cheyne-Stokes, ataxic, apnea)Brainstem compression affecting respiratory centers

Clinical Pearl: The full Cushing triad is a late and ominous sign. Hypertension alone may be the earliest component. Do not wait for the complete triad to initiate emergency treatment. Any new pupillary asymmetry > 1 mm or loss of pupillary reactivity in a TBI patient should be treated as herniation until proven otherwise.16

6.3 Emergency Management of Suspected Herniation

The following interventions are temporizing measures to buy time for definitive treatment (surgery or ICP-directed therapy). They should be initiated immediately upon clinical suspicion of herniation — do NOT wait for imaging confirmation.5 17

InterventionDetailsOnset
Hyperosmolar bolus — 23.4% hypertonic saline30 mL IV bolus over 10–20 min via central line (can use peripheral for emergency if central line not available; risk of phlebitis)Minutes
Hyperosmolar bolus — 3% hypertonic saline250 mL (5 mL/kg in children) IV bolus over 10–20 min via peripheral or central lineMinutes
Hyperosmolar bolus — Mannitol1 g/kg IV bolus (20% solution) over 15–20 min. Example: 70 kg patient = 350 mL of 20% mannitol15–30 min
Brief hyperventilationTarget PaCO2 30–35 mmHg (temporary bridge only — not sustained therapy). Use ETCO2 to guideSeconds to minutes
Elevate HOB to 30°Promotes venous drainageImmediate
Ensure midline head positionAvoid rotation/flexion that impedes jugular venous drainageImmediate
Ensure adequate MAPMaintain SBP > 100–110 mmHgOngoing
Neurosurgical consultationSTAT for decompressive surgery evaluationImmediate

Key Distinction: Hypertonic saline is generally preferred over mannitol for acute herniation because: (1) it does not cause hypotension (mannitol is an osmotic diuretic), (2) it may be more effective at reducing ICP, and (3) it provides volume expansion rather than volume depletion.17


7. Temperature Management in Acute TBI

7.1 Fever Prevention

Fever (core temperature > 38°C / 100.4°F) is common after TBI and is associated with worse outcomes. Each degree of temperature elevation above 37°C is associated with increased ICP and worsened cerebral metabolism.18

RecommendationDetail
TargetNormothermia (36–37.5°C / 96.8–99.5°F)
PharmacologicAcetaminophen 650–1000 mg q6h (PO/PR/IV), ibuprofen 400–600 mg q6h if not contraindicated
Surface coolingCooling blankets, ice packs to groin and axillae
Intravascular coolingArctic Sun, Thermogard — if refractory to surface cooling
Avoid shiveringBuspirone 30 mg q8h, meperidine 25 mg IV PRN, skin counterwarming, magnesium sulfate 2–4 g IV

7.2 Prophylactic Hypothermia

See Part 3 (Tier 3 ICP management) for detailed discussion of therapeutic hypothermia, including the Eurotherm3235 trial evidence.


8. Glucose Management

Hyperglycemia (> 180 mg/dL) is associated with worse outcomes after TBI, while hypoglycemia (< 70 mg/dL) is directly harmful to the injured brain. Tight glycemic control (80–110 mg/dL) is NOT recommended due to increased risk of hypoglycemia and cerebral energy crisis (demonstrated by cerebral microdialysis studies).19

ParameterTarget
Blood glucose100–180 mg/dL
AvoidGlucose > 200 mg/dL (treat with insulin infusion)
AvoidGlucose < 70 mg/dL (associated with cerebral energy crisis)
MonitoringEvery 1–4 hours depending on insulin requirements

9. Venous Thromboembolism Prophylaxis

TBI patients are at very high risk for VTE (DVT and PE) due to immobility, inflammation, and coagulopathy. The challenge is balancing VTE prevention against the risk of hemorrhage progression.20

RecommendationDetail
Mechanical prophylaxisIntermittent pneumatic compression devices (IPCDs) — start on admission for ALL TBI patients
Pharmacologic prophylaxisLow-molecular-weight heparin (enoxaparin 40 mg SQ daily) or unfractionated heparin (5000 units SQ q8–12h)
Timing of pharmacologic prophylaxisStart 24–72 hours after injury if repeat CT shows stable hemorrhage. Earlier initiation (24 hours) appears safe for most patients with stable imaging.20
Higher-risk patientsThose with large contusions, expanding hemorrhage, or post-craniotomy — delay pharmacologic prophylaxis until 48–72 hours with confirmed CT stability
ContraindicationActive intracranial hemorrhage expansion on serial imaging

10. Nutrition

Early nutrition is associated with improved outcomes in severe TBI.5

RecommendationDetailEvidence Level
Start enteral nutritionWithin 24–72 hours of admissionLevel IIA
Caloric goalAchieve full caloric replacement by Day 5 at the latest, preferably Day 7Level IIB
RouteEnteral preferred over parenteralLevel IIA
Protein target1.5–2 g/kg/day (TBI patients are hypermetabolic)Expert recommendation
Gastric vs. post-pyloricStart gastric; advance to post-pyloric if gastric intolerance

11. Steroids — CONTRAINDICATED

Corticosteroids (methylprednisolone, dexamethasone) are contraindicated in moderate-to-severe TBI. This is one of the highest-level evidence recommendations in TBI management.21

CRASH Trial Evidence: The CRASH trial (MRC CRASH, 10,008 patients) demonstrated that high-dose methylprednisolone (2 g loading dose followed by 0.4 g/hour for 48 hours) significantly increased 14-day mortality (21.1% vs. 17.9%; RR 1.18; 95% CI 1.09–1.27) and 6-month mortality. This represents a Level I recommendation AGAINST steroid use in TBI.21


12. Initial Disposition and Transfer Decisions

12.1 Disposition by TBI Severity

SeverityDisposition
Mild TBI (GCS 15), normal CT, no risk factorsMay be discharged from ED after observation period (4–6 hours) with reliable companion and clear return precautions
Mild TBI (GCS 14–15), abnormal CTAdmit to monitored setting; serial neurologic exams q1–2h; repeat CT if clinical deterioration
Mild TBI (GCS 15), on anticoagulantsAdmit for observation, repeat CT at 6–24 hours
Moderate TBI (GCS 9–12)ICU or step-down admission; serial neurologic exams; neurosurgical consultation
Severe TBI (GCS ≤ 8)ICU admission; ICP monitoring if indicated; neurosurgical consultation

12.2 Transfer Criteria to Trauma Center / Neurosurgical Center

Criterion
GCS ≤ 13 at any time after injury
Deteriorating neurological examination
Intracranial hemorrhage requiring potential neurosurgical intervention
Open or depressed skull fracture
Signs of basilar skull fracture
Penetrating head injury
Two or more proximal long bone fractures or pelvic fracture (polytrauma)
Need for ICP monitoring not available at the transferring facility


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  10. Harhangi BS, Kompanje EJ, Leebeek FW, Maas AI. “Coagulation disorders after traumatic brain injury.” Acta Neurochir (Wien). 2008;150(2):165-175. DOI: 10.1007/s00701-007-1475-8 ↩︎

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  13. Connolly SJ, Crowther M, Eikelboom JW, et al. “Full study report of andexanet alfa for bleeding associated with factor Xa inhibitors.” N Engl J Med. 2019;380(14):1326-1335. DOI: 10.1056/NEJMoa1814051 ↩︎

  14. Baharoglu MI, Cordonnier C, Salman RA-S, et al. “Platelet transfusion versus standard care after acute stroke due to spontaneous cerebral haemorrhage associated with antiplatelet therapy (PATCH): a randomised, open-label, phase 3 trial.” Lancet. 2016;387(10038):2605-2613. DOI: 10.1016/S0140-6736(16)30392-0 ↩︎

  15. CRASH-3 Trial Collaborators. “Effects of tranexamic acid on death, disability, vascular occlusive events and other morbidities in patients with acute traumatic brain injury (CRASH-3): a randomised, placebo-controlled trial.” Lancet. 2019;394(10210):1713-1723. DOI: 10.1016/S0140-6736(19)32233-0 ↩︎

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  19. Vespa P, McArthur DL, Stein N, et al. “Tight glycemic control increases metabolic distress in traumatic brain injury: a randomized controlled within-subjects trial.” Crit Care Med. 2012;40(6):1923-1929. DOI: 10.1097/CCM.0b013e31824e0fcc ↩︎

  20. Abdel-Aziz H, Dunham CM, Malik RJ, Hileman BM. “Timing for deep vein thrombosis chemoprophylaxis in traumatic brain injury: an evidence-based review.” Crit Care. 2015;19:96. DOI: 10.1186/s13054-015-0814-z ↩︎ ↩︎

  21. CRASH Trial Collaborators. “Final results of MRC CRASH, a randomised placebo-controlled trial of intravenous corticosteroid in adults with head injury — outcomes at 6 months.” Lancet. 2005;365(9475):1957-1959. DOI: 10.1016/S0140-6736(05)66552-X ↩︎ ↩︎