The Role of Neuroprotective Interventions in Traumatic Brain Injury

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The Role of Neuroprotective Interventions in Traumatic Brain Injury


David M. Panczykowski and David O. Okonkwo


BACKGROUND


Definitions


A.   Primary (1°) Injury: Neuronal death or dysfunction as a consequence of initial impact.


B.   Secondary (2°) Injury: Progressive ischemic, inflammatory, and cytotoxic processes initiated or potentiated by systemic and/or intracranial insults.


      1.   Systemic insults: Hypoxia, hypotension, hyperthermia, hyperglycemia


      2.   Intracranial insults: Intracranial hypertension, cerebral edema, mass lesion, cerebral vasospasm


C.   Neuroprotective Intervention: Treatment initiated prior to and/or at the onset of 2° injury with the aim of minimizing its intensity or immediate effects.


General Principles


A.   Prophylaxis and early treatment of secondary insults may mitigate 2° injury and improve outcome following TBI. Secondary insults such as hypoxemia, hypotension, hypercarbia, hyperthermia, electrolyte disturbances, increased intracranial pressure, and seizures potentiate 2° injury through ongoing ischemic, inflammatory, and cytotoxic cascades. In turn, these potentiate a vicious circle of further metabolic compromise, oxidative stress, inflammation, vascular dysfunction, apoptosis, and neuroregeneration.


B.   Vast research has been conducted delineating the cascade of factors responsible for 2° injury following TBI, with a subsequent focus on a host of potential agents directed at ameliorating these insults. Putative therapeutic targets to counteract 2° insults in TBI can be categorized by the core pathophysiologic processes from which they are derived:


      1.   Neuronal, axonal, and astroglial damage


            a.   N-methyl-D-aspartic acid (NMDA) and a-amino-3-hydroxy-methyl-4-isoxazolyl-propionic acid (AMPA) receptor antagonists—suppresion of the excitotoxic response that follows TBI


            b.   Cyclosporine A analogues and caspase inhibitors—target mitochondrial dysfunction and its interplay with apoptosis


            c.   Prostacyclin—produces vasodilation, also inhibits leukocyte adhesion and platelet aggregation theoretically decreasing secondary ischemia


      2.   Astrogliosis and neuroinflamation


            a.   Progesterone—down-regulates synthesis of proinflammatory cytokines, while decreasing immune cell migration and proliferation


            b.   Recombinant human IL-1 receptor antagonist—reduces the secretion of proinflamatory cytokines while increasing the release of anti-inflammatory mediators


      3.   Disrupted integrity of the blood–brain barrier.


            a.   Mesenchymal stem cells—mediate the repair of the blood–brain barrier in addition to providing immunomodulation


C.   Despite promising experimental results all phase III randomized clinical trials evaluating neuroprotection via pharmacological interventions have failed to show an improvement in outcome following TBI.


D.   Various reasons have been postulated for the lack of successful translation of preclinical studies into human clinical trials:


      1.   Complexity and poor understanding of the pathophysiologic mechanisms at play in TBI


      2.   Heterogeneity of the condition and population


      3.   Flaws in trial design and outcome assessment


E.   Given the plurality of mechanisms responsible for cellular injury, it remains unlikely that any single-agent treatment can address all aspects of TBI pathophysiology.


F.   The only widely accepted neuroprotective strategies at present target systemic and intracranial insults readily amenable to common therapeutic interventions (e.g., hypoxemia, hypotension, hyperthermia, and hyperglycemia).


HYPOXEMIA


Guiding Principles


A.   The brain accounts for 20% of the body’s oxygen consumption. Blood oxygen content exceeds the brain’s utilization by only a factor of 2 or 3, leaving the brain vulnerable to small changes in oxygen supply.


B.   Primary injury stresses the tenuous balance between supply and demand, making the brain more susceptible to secondary ischemic insults.


C.   The detrimental effect of secondary ischemic damage is well documented; both depth and duration of hypoxemia are significantly associated with increased morbidity and mortality.


D.   Cerebral oxygen delivery is a function of cerebral blood flow (CBF) and arterial oxygen content.


Diagnosis and Treatment


A.   Although no treatment threshold exists per se, studies have found severe morbidity and mortality to be associated with PaO2 less than 60 mmHg and O2 saturation less than 90% [1]. Hyperventilation, except as a brief temporizing maneuver in the setting of elevated intracranial pressure (ICP), should be avoided [2].


B.   Multiple therapies directed at increasing oxygen delivery and utilization have been investigated (e.g., normo- and hyperbaric hyperoxia, brain oxygen tension (PbO2) directed therapy), but have produced only equivocal results [3].


      1.   Direct measures of the cerebral metabolic rate of oxygen consumption (CMRO2) have shown no increase in brain O2 utilization with normobaric hyperoxia. Hyperbaric treatment has been shown to increase CMRO2; however, a clear clinical benefit has yet to be demonstrated.


      2.   Although studies have shown poor outcome with hypoxic brain oxygen tension (PbO2 less than 15 mmHg), no randomized controlled trial currently exists proving PbO2 monitoring to be beneficial [4].


C.   Potential toxicity of hyperoxia:


      1.   Prolonged high fraction of inspired oxygen (FiO2) has been associated with injury to the lens of the eye, lungs, heart, brain, and gastrointestinal tract, and may also lead to cerebral vasoconstriction.


      2.   High positive end expiratory pressure (PEEP greater than 15–20 mmHg) should be avoided; PEEP is transmitted through lungs to thoracic vessels leading to cerebral venous congestion and increased ICP [5].


D.   The potential risks in combination with no clear benefit should preclude the use of hyperoxia until RCTs demonstrate a clear advantage.


E.   Goals of ventilator management should be sufficient oxygen delivery to avoid hypoxemia or brain hypoxia, while also avoiding ventilation-induced lung injury and acute respiratory distress syndrome. Specifically, this employs protective ventilation using low tidal volumes (Vt, 6–8 mL/kg), plateau pressure less than 30 cm H2O, and adequate PEEP levels [5]. A goal of eucapneic ventilation (PaCO2 35–40 mmHg) is especially important in those suffering intracranial hypertension [6].


HYPOTENSION


Guiding Principles


A.   Hypotension is one of the most powerful predictors of outcome—a relationship that is independent of Glasgow Coma Scale score (GCS), age, or intracranial lesion. Cerebral ischemia may occur in the acute postinjury phase in as many as 35% of patients independent of systemic hypotension [1].


B.   The critical threshold for CBF, below which irreversible tissue damage occurs, can shift following TBI to 15 mL/100 g/minute, versus 5 to 8.5 mL/100 g/minute in healthy brain tissue [7].


C.   Major influences on CBF include adequate blood pressure, flow-metabolism coupling, PaCO2, and cerebral autoregulation; dysfunction in any or all post-TBI puts patients at risk for hyperemia and/or ischemia.


      1.   The relationship of CBF to blood pressure and vascular resistance is demonstrated by the equation CBF = CPP/CVR; where cerebral perfusion pressure (CPP) is the difference between mean arterial pressure (MAP) and ICP is divided by cerebrovascular resistance (CVR).


D.   Changes in CBF following TBI generally occur in three phases:


      1.   Hypoperfusion and ischemia: 6–12 hours postinjury


      2.   Hyperemia and concomitant ICP increases: 24–48 hours


      3.   Vasospasm with decreased perfusion: greater than 72 hours


E.   Posttraumatic cerebral vasospasm is pathologic narrowing of intracranial blood vessels with or without resultant ischemia that is precipitated by blood in the subarachnoid space and direct vascular injury by impact or stretch [8].


      1.   Occurs in 10% to 30% of severe TBI patients, with 4% to 16% experiencing referable neurologic deficits.


      2.   Begins 1 to 3 days postinjury and follows a more abbreviated course than vasospasm secondary to aneurysmal subarachnoid hemorrhage (SAH).


      3.   The risk of developing vasospasm is associated with greater volumes of blood in subarachnoid as well as blast-induced neurotrauma.


Diagnosis and Treatment


A.   MAP or CPP can be used as surrogates for estimating CBF with goal thresholds being an MAP greater than 60 and CPP values of 50 to 70 mmHg. Indiscriminate maintenance of CPP greater than 70 mmHg has been associated with increased ICP, acute respiratory distress syndrome (ARDS), and mortality.


B.   Transcranial Doppler (TCD) ultrasonography is routinely employed as an indirect assessment of cerebral perfusion and vasoreactivity, as well as for cerebral vasospasm surveillance following TBI.


C.   CT perfusion studies provide quantitative information regarding CBF, mean transit time (MTT) or time to peak (TTP), and cerebral blood volume (CBV).


D.   Therapies to treat symptomatic posttraumatic vasospasm include intra-arterial calcium channel blockers and balloon angioplasty [8].


HYPERTHERMIA


Guiding Principles


A.   Hyperthermia in the acute postinjury phase is associated with longer ICU stay and worsened neurologic outcome [9].


B.   Temperature surges occur in up to 67% of TBI patients within the first 72 hours after admission, and may result from multiple causes (hypothalamic disruption, inflammation, medications, surgery, etc.).


Diagnosis and Treatment


A.   Core temperature should be monitored (preferably by brain temperature probe or rectal thermometer) and temperature spikes ≥38°C should be avoided and aggressively treated [10].


B.   Inconsistent research results preclude recommendation of hypothermia as a standard of care intervention in TBI [11].


C.   In addition to the common methods of identifying causative factors accompanying fever (e.g., infection), one should also consider central causes of temperature dysregulation.


D.   Antipyretics, extra-corporeal cooling, gastric lavage, and intravascular cooling catheters have all been investigated as means to prophylactically control temperature in TBI patients. Intravascular cooling catheters have shown the most consistency in induced normothermia, without increases in rates of infection, antibiotic, or sedation usage [10,12].


HYPOCAPNIA


Guiding Principles


A.   Hypocapnia (PaCO2 ~30–35 mmHg) is generally caused by intended or accidental hyperventilation (e.g., with therapeutic hyperventilation in managing increased ICP) [1].


B.   The ability of hyperventilation (and hypocapnia) to reduce CBV is achieved at a disproportionate cost to CBF, which may be especially harmful in the first 24 hours postinjury [6].


C.   The effects of hypocapnia on vascular smooth muscle are pH mediated; cerebral and renal buffering returns pH to normal within 4 to 6 hours eliminating this effect and precluding the use of sustained hypocapnia. Additionally, this buffering leads to pH-overshoot and subsequent rebound hyperemia/increased ICP.


Diagnosis and Treatment


A.   Prophylactic hyperventilation should not be used, as it has been associated with worsened ICP control and poor neurologic outcome [1,12].


B.   Brief (e.g., 20 minutes) moderate hyperventilation for ICP reduction should be undertaken cautiously and only until a pathology-specific intervention can be instituted.


HYPERGLYCEMIA


Guiding Principles


A.   The massive stress response following TBI results in elevated circulating catecholamine levels with subsequent increases in serum glucose.


B.   Hyperglycemia, which leads to intracellular acidosis, is associated with the development of reactive oxygen species, especially during the acute ischemic phase of TBI, exacerbating 2° brain injury.


C.   Admission and early postoperative hyperglycemia (serum glucose ≥200 mg/dL) has been associated with worse neurologic and mortality outcomes [13].


Diagnosis and Treatment


A.   A target serum glucose greater than 180 to 200 mg/dL decreases episodes of hyperglycemia and has been associated with decreased mortality [13].


B.   Note that intensive insulin therapy (target glucose 80–110 mg/dL) results in an increased risk of hypoglycemic episodes without conferring mortality benefits. Conservative treatment of glucose levels greater than 180 mg/dL is generally accepted as striking the best balance.


POSTTRAUMATIC SEIZURES


Guiding Principles


A.   Posttraumatic seizures (PTS) may occur in 20% to 25% of all patients suffering TBI and the incidence ratio of PTS for mild, moderate, and severe TBI has been shown to be 1.5, 2.9, and 17, respectively [14]. PTS can be classified by time of onset: immediate (first few hours), early (occurring during first week), and late (greater than 1-week postinsult).


B.   Late posttraumatic epilepsy is associated with severity and type of injury (subdural and intracerebral hemorrhage, skull fractures, neurologic dysfunction) [15]; biochemical and structural alterations have been the main pathophysiologic mechanisms proposed.


Diagnosis and Treatment


Studies to date have not addressed effects of PTS on secondary injury. However, early prophylactic treatment with antiepileptic drugs (AEDs) (i.e., for the 1st week postinjury) has been shown to decrease the relative risk of early PTS; although this is without a concordant decrease in development of late seizures (i.e., posttraumatic epilepsy), morbidity, or mortality [16].


May 29, 2017 | Posted by in PSYCHIATRY | Comments Off on The Role of Neuroprotective Interventions in Traumatic Brain Injury

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