The usual distinction between primary and secondary brain injury remains useful, provided it is not interpreted too literally. Primary injury is the mechanical damage occurring at impact: skull deformation, direct tissue disruption, vascular tearing, contusion, hematoma formation, and axonal strain from rotational acceleration. Secondary injury is the evolving physiologic and biochemical amplification that follows. But secondary injury begins within seconds, not hours. Mechanical membrane deformation produces potassium efflux, sodium and calcium influx, glutamate release, ATP-dependent pump activation, and an enormous increase in energy demand at precisely the time that regional blood flow and oxygen delivery may be impaired. Mitochondria become dysfunctional, reactive oxygen species accumulate, the blood–brain barrier becomes permeable, microvascular thrombosis develops, inflammatory cells are recruited, and cytotoxic and vasogenic edema evolve. Some tissue is destroyed immediately, some is structurally intact but metabolically vulnerable, and some is injured because the circulation we provide afterward is inadequate.

This is why “severe TBI” should never be treated as a single disease. A temporal epidural hematoma compressing an otherwise relatively preserved brain is not physiologically equivalent to an acute subdural hematoma with extensive underlying cortical injury. Neither resembles diffuse axonal injury, bifrontal contusions, traumatic subarachnoid hemorrhage with vasomotor dysfunction, diffuse cerebral swelling, or a posterior-fossa hematoma obstructing the fourth ventricle. Each may produce the same Glasgow Coma Scale score and eventually the same ICP, but the appropriate definitive treatment and recovery potential can be radically different.

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The Glasgow Coma Scale therefore establishes a common language rather than a complete diagnosis. After initial resuscitation, GCS 13 to 15 is conventionally mild, 9 to 12 moderate, and 3 to 8 severe. The phrase “after resuscitation” is essential. Hypoxemia, shock, hypoglycemia, intoxication, sedatives, paralytics, facial trauma, aphasia, and spinal cord injury can all lower the score without reflecting the severity of primary cerebral injury. Document the individual eye, verbal, and motor components rather than only the total. Record whether the examination preceded intubation, which drugs were administered, the time of the last paralytic, whether hypotension or hypoxemia was present, and whether the response was symmetric. A motor score that falls from localizing to extension is more actionable than a total GCS that changes from seven to six without explanation.

Pupils deserve similar discipline. Size, symmetry, direct and consensual reactivity, and any ocular trauma must be documented serially. A unilateral enlarging pupil in a deteriorating patient is a herniation emergency until proved otherwise, but pharmacologic dilation, direct globe trauma, preexisting anisocoria, and third-nerve injury can confound it. Bilateral nonreactive pupils are ominous but do not remove the obligation to correct hypoxia, hypotension, hypothermia, drug effects, and surgically reversible mass lesions. The pupil examination is a physiologic alarm, not by itself a declaration of futility.

A GCS of eight or less is a strong reason to secure the airway, but it is not the only consideration and should not be treated as an autonomous rule. The relevant questions are whether the patient can maintain oxygenation and ventilation, protect the airway, tolerate transport and imaging, and undergo the anticipated interventions safely. The danger is that an intubation intended to protect the brain can instead produce apnea-associated hypoxemia and induction-associated hypotension. Preoxygenate aggressively, resuscitate before induction when time permits, maintain cervical-spine precautions without obstructing venous return, and have a vasopressor prepared rather than waiting for the pressure to collapse. Etomidate or ketamine may be reasonable when hemodynamic reserve is limited. Ketamine is not contraindicated simply because intracranial pressure may be elevated. Propofol is useful in a well-resuscitated patient but can be disastrous when sympathetic tone is maintaining blood pressure. Paralysis improves intubating conditions but abolishes the motor examination, and it must immediately be followed by adequate analgesia and sedation.

Once the airway is secured, target normoxemia rather than merely avoiding cyanosis. Brief use of a high inspired oxygen concentration for preoxygenation and procedural safety is appropriate, but prolonged extreme hyperoxia has no established neuroprotective role. A practical early goal is an oxygen saturation of at least 94% with subsequent titration of the inspired oxygen concentration and confirmation by arterial blood gas. A normal systemic saturation also does not prove adequate cerebral oxygen delivery. Delivery depends on cerebral blood flow multiplied by arterial oxygen content, and arterial oxygen content is determined predominantly by hemoglobin-bound oxygen rather than dissolved PaO₂. A patient can therefore have a PaO₂ of 150 mm Hg and still have inadequate cerebral oxygen delivery because of anemia, low cardiac output, regional hypoperfusion, diffusion limitation, or microvascular failure.

Ventilation must be controlled just as carefully. Hypercapnia causes cerebral vasodilation, increases cerebral blood volume, and may worsen intracranial hypertension. Hypocapnia lowers ICP by constricting cerebral arterioles but simultaneously reduces cerebral blood flow. In the first hours after severe TBI, when flow may already be reduced, prophylactic hyperventilation can transform vulnerable tissue into ischemic tissue. Target an initial PaCO₂ around 35 to 40 mm Hg, using continuous capnography but checking an arterial blood gas because the end-tidal-to-arterial gradient may be large in shock, pulmonary contusion, or high dead-space states. Hyperventilation to an end-tidal CO₂ around 30 to 35 mm Hg is a rescue bridge for active herniation while osmotherapy and definitive surgical treatment are being mobilized. It is not a destination. Prolonged PaCO₂ of 25 mm Hg or lower is specifically discouraged by the current Brain Trauma Foundation severe-TBI guideline.

The hemodynamic objective is equally simple conceptually and difficult operationally: do not let the injured brain become ischemic because the systemic circulation failed. The formal Brain Trauma Foundation floors remain an SBP of at least 100 mm Hg for patients 50 to 69 years old and at least 110 mm Hg for patients 15 to 49 or older than 70, although these are low-certainty population thresholds rather than patient-specific optima. A chronically hypertensive patient may require more pressure, and once ICP is known the more relevant target becomes CPP, generally 60 to 70 mm Hg. An SBP of 110 should be understood as a floor to avoid, not as proof that cerebral perfusion is adequate.

This creates a real conflict in patients with simultaneous hemorrhagic shock. Permissive hypotension may reduce bleeding in selected trauma patients without brain injury, but it is not an acceptable default when severe TBI is present. The solution is not unlimited crystalloid or indiscriminate vasoconstriction. It is rapid hemorrhage control, balanced blood-product resuscitation when indicated, correction of hypocalcemia and hypothermia, and judicious norepinephrine to shorten hypotension while circulating volume and hemostasis are restored. A vasopressor is an adjunct to resuscitation, not a substitute for blood in a bleeding patient.

For nonhemorrhagic volume replacement, use an isotonic crystalloid and avoid free water, dextrose-containing maintenance solutions, and other hypotonic fluids during the vulnerable period. Four-percent albumin should generally be avoided in acute TBI because the SAFE-TBI analysis found higher mortality with albumin than saline. (SAFE-TBI study) Hypertonic saline is valuable when treating intracranial hypertension or herniation, but that does not make routine hypertonic resuscitation neuroprotective. A large randomized prehospital trial found that a single bolus of 7.5% saline, with or without dextran, did not improve six-month neurologic outcome compared with normal saline in presumed severe TBI without hemorrhagic shock. (JAMA hypertonic-resuscitation trial) This is another recurring lesson: an intervention can transiently improve pressure physiology without improving functional outcome when applied indiscriminately.

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Anemia adds a newer layer to this oxygen-delivery problem. The 2024 HEMOTION trial randomized 742 patients with moderate or severe TBI and anemia to liberal or restrictive transfusion strategies. Unfavorable six-month outcome occurred in 68.4% with the liberal strategy and 73.5% with the restrictive strategy, an adjusted absolute difference of 5.4 percentage points whose confidence interval crossed zero; the prespecified primary analysis therefore did not establish superiority of the liberal strategy. (HEMOTION trial) Later in 2024, TRAIN randomized 850 patients with TBI, subarachnoid hemorrhage, or intracerebral hemorrhage and hemoglobin below 9 g/dL. A transfusion trigger of 9 rather than 7 g/dL reduced its broader definition of unfavorable outcome from 72.6% to 62.6% and reduced recorded cerebral ischemic events. (TRAIN trial)

While circulation and ventilation are being stabilized, the next task is to identify a lesion requiring immediate source control. Obtain noncontrast head CT without avoidable delay, but do not image the head in isolation from the trauma. Cervical-spine imaging, chest and abdominal evaluation, and hemorrhage assessment remain essential because extracranial injury commonly produces the secondary insults that damage the brain. CTA of the head and neck is indicated when the mechanism, fracture pattern, cervical injury, neurologic deficit, or other screening criteria raise concern for blunt cerebrovascular injury. CT venography should be considered when a skull fracture crosses a major dural sinus or when otherwise unexplained edema, hemorrhage, or intracranial hypertension suggests traumatic venous sinus thrombosis.

Read the CT as a physiologic map rather than a list of hemorrhages. Ask which compartment is expanding, whether the basal cisterns remain open, whether the ventricles are compressed or obstructed, whether there is midline shift, whether the lesion is temporal or posterior fossa, and whether the radiographic abnormality explains the examination. An epidural hematoma is usually lentiform and commonly related to arterial injury, but the textbook lucid interval is neither necessary nor reassuring. An acute subdural hematoma is crescentic and often accompanies substantial underlying cortical and axonal injury. Frontal and temporal contusions may be initially unimpressive and then blossom because damaged microvessels continue to bleed into injured tissue. Traumatic subarachnoid and intraventricular blood may impair CSF circulation. Diffuse swelling may erase the cisterns without producing a dominant mass lesion.

Diffuse axonal injury deserves particular caution. Rotational strain injures axons and small vessels at the gray–white junction, corpus callosum, and, in more severe cases, the dorsolateral brainstem. The admission CT can be nearly normal despite profound coma. Punctate hemorrhages may be visible, but MRI susceptibility, diffusion, and FLAIR sequences are substantially more sensitive. MRI can clarify the injury pattern after stabilization, but it should not delay resuscitation, monitoring, or treatment of an evolving surgical lesion. Conversely, the discovery of brainstem microhemorrhages does not by itself determine the eventual functional outcome.

Traumatic hemorrhage is also dynamic. Repeat CT immediately for any neurologic deterioration, new pupillary abnormality, unexplained ICP increase, or new coagulopathy. In a high-risk lesion being observed nonoperatively, many centers obtain scheduled repeat imaging within roughly four to six hours, but that interval is not biologically magical and should be individualized. A stable scan does not guarantee future stability, particularly with contusions, coagulopathy, or ongoing systemic shock.

At the same time, identify and reverse coagulopathy. Obtain platelet count, PT/INR, fibrinogen, type and crossmatch, and, when available and interpretable, viscoelastic testing. Determine the exact antithrombotic, dose, renal function, and time last taken. Warfarin-associated hemorrhage requires rapid factor replacement plus intravenous vitamin K; heparin requires protamine; dabigatran and factor Xa inhibitors require agent-specific reversal according to local protocol and availability. Do not let a known clinically significant anticoagulant exposure sit untreated while waiting for every assay to return. Antiplatelet exposure is less straightforward: empiric platelet transfusion for every nonsurgical TBI patient is not supported by strong evidence, whereas platelet therapy or desmopressin may be considered when urgent neurosurgery or demonstrable platelet dysfunction changes the risk–benefit balance.

Tranexamic acid occupies a narrow but important time-dependent role. In CRASH-3, treatment within three hours did not significantly reduce the primary outcome across the entire cohort, but it reduced head-injury death in the prespecified mild-to-moderate subgroup, with no benefit demonstrated in severe TBI. The physiologic explanation is coherent: an antifibrinolytic can limit ongoing bleeding while salvageable tissue remains, but it cannot reverse tissue already destroyed by the impact. Early TXA is therefore reasonable in appropriately selected bleeding TBI or broader major trauma protocols, especially within three hours, but it is not a treatment for cerebral edema, not a substitute for anticoagulant reversal, and not a substitute for evacuation of a mass lesion. (CRASH-3 trial)

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After operative lesions and systemic threats are addressed, the general intracranial principles from the preceding module return. Elevate the head when hemodynamically tolerated, maintain neutral neck alignment, remove or refit anything obstructing jugular drainage once cervical stability permits, provide analgesia and sedation, avoid fever and hyponatremia, and prevent coughing, ventilator dyssynchrony, shivering, and seizures. Do not induce routine hypernatremia in a patient without intracranial hypertension, and do not confuse prophylactic hypothermia with fever prevention. Prophylactic hypothermia has not improved outcome and can worsen coagulopathy, infection risk, electrolyte disturbance, and hemodynamic instability. Controlled normothermia remains the objective.

For a salvageable patient with severe TBI after resuscitation and an abnormal CT showing hematoma, contusion, swelling, herniation, or compressed cisterns, ICP monitoring remains standard practice despite imperfect trial evidence. The historical indication for severe TBI with a normal CT requires at least two of age over 40, motor posturing, or an episode of SBP below 90, although these criteria are based on limited older evidence. An EVD is especially useful when ventricular access is feasible because it both measures pressure and drains CSF; a parenchymal monitor may be faster or technically easier in compressed ventricles. Treat sustained ICP above approximately 22 mm Hg, but integrate the waveform, examination, imaging, CPP, and multimodality data rather than treating every brief excursion. Target CPP roughly 60 to 70 mm Hg and avoid indiscriminate escalation above 70 when autoregulation is unknown because excessive fluids and vasopressors can produce pulmonary and systemic harm. (Brain Trauma Foundation severe-TBI guideline)

Early antiseizure prophylaxis is another area in which routine practice is stronger than the evidence. Cortical contusions, subdural hematoma, depressed skull fracture, penetrating injury, early clinical seizure, and severe depressed consciousness increase early-seizure risk. However, the 2024 Neurocritical Care Society guideline concluded that either prophylaxis or no prophylaxis may be used in hospitalized adults with moderate or severe TBI. If prophylaxis is chosen, it weakly suggests levetiracetam over phenytoin or fosphenytoin and a duration of no more than seven days; all of these recommendations rest on low or very low certainty. Prophylaxis reduces neither late post-traumatic epilepsy nor established seizures, and a patient with clinical or electrographic seizures has moved from prophylaxis into treatment. (NCS seizure-prophylaxis guideline) Continuous EEG is appropriate when coma is out of proportion to imaging, awakening is delayed, paroxysmal movements occur, or unexplained ICP and metabolic crises raise concern for occult seizures.