Secondary brain injury and neuroprotective measures

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Secondary brain injury is an indirect injury caused by physiological changes that are triggered by an acute CNS insult (e.g., traumatic brain injury, stroke, cerebral hypoxia secondary to cardiac arrest) and/or the management of the primary insult. Unlike primary brain injury, which refers to the direct, immediate, and potentially irreversible neuronal damage from an acute CNS insult, secondary brain injury is preventable or can be minimized with the early administration of neuroprotective measures. Neuroprotective measures involve the early and aggressive control of factors that are implicated in the etiology of secondary brain injury. Such measures include optimization of oxygenation, ventilation, blood pressure, blood sugar, body temperature, intracranial pressure, and electrolyte levels. In addition, seizure prophylaxis and treatment, nutritional support, and patient positioning are important aspects of neuroprotective measures.

• Secondary brain injury: indirect brain injury that results from physiological changes triggered by acute CNS insults and/or treatment measures for acute CNS insults that affect ICP, oxygenation, blood pressure, etc.
• Neuroprotective measures: measures to prevent and/or minimize secondary brain injury in the immediate management of patients who have sustained an acute CNS insult

An acute CNS insult can trigger any of the following, resulting in secondary brain injury. ^[2][3][4]

• Disruption of physiological (homeostatic) measures
  • Blood-brain barrier disruption, cerebral vasodilation, neuronal depolarization and release of excitatory neurotransmitters → cerebral edema → ↑ ICP
  • Mitochondrial dysfunction → impaired cerebral metabolism → neuronal cell death
  • Stress-induced hyperglycemia → endothelial dysfunction of the cerebral blood vessels → cerebral vasoconstriction or vasodilation → cerebral hypoxia or cerebral hyperemia
  • Loss of cerebral autoregulation of cerebral blood flow→ increased risk of brain injury secondary to critical care measures
  • Injury to hypothalamus and/or pituitary → neurogenic fever and central diabetes insipidus
• Initiation of reparative responses: activation of the inflammatory cascade → hyperthermia and hyperglycemia

Secondary brain injury is preventable. Neuroprotective measures to prevent or minimize secondary brain injury should be initiated as early as possible in all patients with acute CNS insults.

Avoid hypoxia, hyperoxia, hypocapnia, and hypercapnia in patients with acute CNS insult. ^[3]

Control of PaO₂ (oxygenation) ^[3]

• Goals
  • Avoid hypoxia to prevent hypoxic brain injury, especially in patients with impaired cerebral autoregulation.
  • Avoid prolonged hyperoxia as it can cause or worsen cerebral vasoconstriction and cerebral ischemia. ^[5]
• Target: Normoxia or mild hyperoxia
  • Target PaO₂: > 60 mm Hg ^[4]
  • Target SpO₂: > 92–94% ^[6][7][8]
• Measures to achieve target oxygenation
  • Avoid hypotension: See ''Blood pressure and cerebral perfusion pressure''.
  • Oxygen therapy
    • Administer supplemental oxygen only if SpO₂ is < 94% ^[9]
    • Use the lowest FiO₂ possible to maintain normoxia
  • Airway management: if necessary, intubate (rapid sequence intubation) according to local hospital protocols ^[8][10]
    • Carefully consider intubation induction agents: Ketamine usually preferred if no signs of ↑ ICP ^[8][10]
    • Patients with signs of ↑ ICP: See intubation of patients with increased ICP. ^[6]
    • See improving oxygenation in mechanically ventilated patients for further details.

Hypoxia and hyperoxia can worsen neurological outcome and should be avoided.

Routine use of supplemental oxygen in nonhypoxic patients is of no clinical benefit in the prevention of secondary brain injury. ^[9]

Control of PaCO₂ (ventilation)

• Goals
  • Aim for normocapnia as both hypercapnia and hypocapnia can worsen secondary brain injury.
    • Hypercapnia (due to hypoventilation) → cerebral vasodilation → cerebral edema, ↑ ICP, and intracerebral steal phenomenon ^[11][12]
    • Hypocapnia (due to hyperventilation) → cerebral vasoconstriction → ↓ CBF → ↑ risk of ischemia to uninjured brain tissue ^[11]
  • Consider limited hypocapnia as a temporizing measure for acute uncontrolled ↑ ICP or cerebral herniation syndrome. ^[8]
    • Short-term hypocapnia → temporary ↓ CBF → temporary ↓ ICP
    • Long-term hypocapnia → ↓ CBF → ↑ cerebral ischemia
• Target PaCO₂: 35–45 mmHg ^[3][13]
• Measures to achieve target ventilation ^[3]
  • No signs of ↑ ICP: Maintain normoventilation (prophylactic hyperventilation is discouraged).
  • Signs of ↑ ICP or signs of cerebral herniation syndromes present: Consider short-term (< 30 minutes) hyperventilation to attain mild hypocapnia (PaCO₂30–35 mm Hg). ^[6][8][13]
    • See ventilation strategy for elevated ICP for suggested initial ventilator settings.
    • See ICP management for details.

Hypercapnia (including permissive hypercapnia) and long-term hypocapnia worsen neurological outcome in patients with acute CNS insults and should be avoided. ^[3]

Hypocapnia should only be used as a temporizing measure for patients with signs of cerebral herniation syndromes while simultaneously initiating definitive management for ↑ ICP. ^[8][13]

Monitoring

• Continuous pulse oximetry
• Continuous capnography/capnometry
• Intermittent ABG analysis: Consider arterial line placement.
• See also “Monitoring in mechanical ventilation.”

Goals

• Blood pressure control after acute CNS insult is complex and the optimal treatment goals are yet to be established.
• The main aim is to maintain cerebral perfusion pressure (CPP) between 60–70 mm Hg by maintaining mean arterial pressure (MAP) between 65–100 mm Hg ^[3][4][14]
• In patients with ↑ ICP, maintain blood pressure so that CPP remains between 60–80 mm Hg. ^[15][16]
• Avoid MAP < 65 mm Hg to minimize the risk of underperfusion and secondary ischemic injury to the brain. ^[3][17]

Avoid hypovolemia and hypervolemia when resuscitating a patient with an acute CNS insult. Hypovolemia decreases cerebral perfusion, worsens cerebral ischemia, and may potentiate thromboses in the injured tissue. Hypervolemia worsens cerebral edema. ^[6]

Hypotensive patients

Hypotension should be avoided in all patients with depressed consciousness as it decreases CBF, thus worsening neurological outcomes and increasing the mortality risk. ^[3][18][19]

• Target: SBP > 90 mm Hg or mean arterial pressure (MAP) > 65–80 mm Hg ^[3][4][20]
• Treatment ^[3]
  • IV fluid resuscitation: isotonic saline typically preferred ^{[6][21][22][23]}
  • Vasopressor therapy: phenylephrine preferred in patients with TBI and vasodilatory shock ^[8][23][24]
  • Identify and treat the underlying cause (see “Shock”).

Hypertensive patients

The SBP threshold at which to administer antihypertensives and target SBP differ according to the etiology of the acute CNS insult. ^[16][25][26]

Ischemic stroke

• See “Blood pressure management” in treatment of ischemic stroke.

Intracranial hemorrhage (including TBI)

• Target SBP: 140–180 mm Hg ^[16][27][28]
• Timing: Initiate treatment as soon as possible in patients with SBP > 180 mm Hg ^{[15][19][25][26]}
• Commonly used antihypertensive agents ^[19][25]
  • Nicardipine ^[16][27]
  • Labetalol
  • Sodium nitroprusside

Monitoring

• Monitor blood pressure frequently (5–10 minutes) or continuously.
• Consider placing an arterial line in patients receiving vasopressors. ^[12]
• Calculate and monitor CPP in patients with severe TBI (CPP = MAP-ICP). ^[20][29]
• Perform intravascular volume monitoring, echocardiography and cardiac output assessment in hemodynamically unstable patients.

Blood glucose should be checked at presentation and serially monitored. Strict blood glucose control is recommended as hypoglycemia or hyperglycemia worsen the neurological outcome after an acute CNS insult.

• Target blood sugar: normoglycemia
  • In nontraumatic acute CNS insult: 140–180 mg/dL ^[9]
  • In traumatic brain injury: 80–180 mg/dL ^[3][30]
• Treatment
  • Hypoglycemic patients (blood glucose < 60 mg/dL): See treatment of hypoglycemia. ^[6][9]
  • Hyperglycemic patients (blood glucose > 180 mg/dL): See management of hyperglycemia in critically ill patients. ^[3][6]

Avoid dextrose-containing solutions in the resuscitation of nonhypoglycemic patients with an acute CNS insult. ^[6]

• Seizure prophylaxis ^[3][9]
  • Prophylactic administration of anticonvulsants is not routinely recommended. ^[9]
  • Seizure prophylaxis for the first 7 days after injury is recommended in patients with severe traumatic brain injury. ^[4][20][31]
  • Consider seizure prophylaxis in patients with spontaneous ICH or SAH at high risk for seizures. ^[32][33]
• Seizure treatment: Seizures detected clinically or on EEG should be managed with anticonvulsants
• Suggested anticonvulsants ^[31][34][35]
  • Levetiracetam ^[32][36]
  • Phenytoin

Because seizures may be clinically inapparent in comatose patients or those on neuromuscular blockers, continuous EEG monitoring is recommended in this group of patients.

Sodium disorders and hypokalemia are the most common electrolyte abnormalities seen after an acute CNS insult. Provide electrolyte repletion as needed for electrolyte deficiencies. ^[37][38]

Disorders of sodium balance ^[39]

• General considerations
  • Identify and treat the underlying cause.
  • Sodium disturbances are often self-limiting in patients with brain injury.
• Hyponatremia ^[39]
  • Acutely symptomatic patients: prompt treatment with gradual correction (see “Treatment” in hyponatremia and SIADH)
  • Asymptomatic patients: Supportive treatment strategy is usually appropriate.
• Hypernatremia ^[40]
  • Severe elevation (> 160 mEq/L): gradual correction (see “Treatment” section in hypernatremia)
  • Mild–moderate elevation (up to 160 mEq/L): consider gradual correction

Symptomatic hypernatremia should be corrected gradually to minimize the risk of cerebral and pulmonary edema. Symptomatic hyponatremia should be corrected gradually to minimize the risk of central pontine myelinolysis. ^[39]

Disorders of potassium balance

• Hypokalemia: See “Potassium repletion” ”Treatment” section in hypokalemia and repletion regimens of hypokalemia.
• Hyperkalemia: See “Treatment” section in hyperkalemia.

Neurogenic fever (central hyperthermia) ^[41][42]

• Definition: Noninfectious fever after an acute CNS insult is likely caused by injury to the hypothalamic thermoregulation centers.
• Epidemiology: seen in up to 37% of patients with TBI; may also occur after stroke or neurosurgical intervention
• Implication: associated with worse neurological outcomes and increased mortality
• Management: targeted temperature management

In patients with acute CNS insults, fever should be aggressively treated as it is associated with a poor neurological outcome and increased risk of mortality.

Targeted temperature management (TTM)

• Definition: controlled maintenance of a target body temperature aimed to prevent secondary brain injury after an acute CNS insult
• Target body temperature: differs according to the inciting event
  • Indications for controlled normothermia (36–37.8°C/96.8–100°F) ^[22]
    • TBI ^[3][43]
    • Hemorrhagic stroke
    • Ischemic stroke ^{[9][44][45][46]}
    • Neurogenic fever
  • Indication for moderate therapeutic hypothermia (33°C/91.4°F): postarrest hypoxic ischemic encephalopathy ^[47][48]
• Measures to achieve TTM ^[49]
  • Physical/surface cooling: may be local (e.g., head cooling with a cooling helmet) or general (e.g., with cooling blankets/pads) ^[50]
  • Endovascular cooling (e.g., rapid IV infusion with cold normal saline) ^[3]
  • Pharmacological hypothermia (for therapeutic hypothermia): hypothermia-inducing drugs (e.g., cannabinoids, opioids) ^[44][49][51]
  • Antipyretics (e.g., acetaminophen ) ^[9][52]
• Monitoring: Continuous/hourly monitoring of temperature is recommended.
• Optimal duration of TTM: unclear ^[44][51]
• Complications of therapeutic hypothermia ^[44]
  • Bradycardia, hypotension, arrhythmias
  • Immunosuppression and increased risk of infection
  • Coagulopathy
  • Altered serum electrolyte and blood glucose levels

Intracranial pressure (ICP)

• Target: Maintain ICP below 20–22 mm Hg ^[3][4][20]
• Treatment: See ICP management.
• Monitoring: ICP is not routinely monitored, but patients should be observed for signs of raised ICP.

Patient positioning

• Patients without features of raised ICP or hypoxia: supine position with no elevation of the head ^[9]
• Patients with features of raised ICP or those at risk of aspiration or airway obstruction: head end elevation to 30º ^[6]

Transfusion

• Red cell transfusion: Transfuse packed red cells if Hb ≤ 7 g/dL (restrictive threshold) ^[8][53][54]
• Platelet transfusion in intracranial bleeding
  • Spontaneous intracerebral hemorrhage (ICH): Platelet transfusion is not recommended in patients with ICH who are on antiplatelet therapy ^[55]
  • TBI: There is currently no clear recommendation for/against platelet transfusion in patients with TBI and concurrent thrombocytopenia, platelet dysfunction, or antiplatelet therapy. ^[3][4][54]
  • Consider platelet transfusion if platelet count is less than 80–100,000/mm³ in patients planned for neurosurgery or invasive procedures. ^[56]

Nutrition ^[57][58]

• Neurological insult typically leads to a hypermetabolic state. ^[59]
• Early (ideally within 24 hours) nutritional support (enteral and parenteral) improves neurological outcomes compared to delayed nutritional support.
• Enteral nutrition is preferred if possible; patients with low GCS or dysphagia may require a nasogastric or nasojejunal tube.

• Identify and treat hypoxia.
• Maintain normocapnia (consider short-term hypocapnia in patients with signs of ↑ICP or cerebral herniation syndromes).
• Blood pressure management
• Normoglycemia
• Consider seizure prophylaxis and/or seizure management (if appropriate)
• Identify and treat electrolyte abnormalities.
• Identify and treat hyperthermia.
• ICP management.
• Patient positioning
• Support nutritional needs.