Bradley A. Boucher and G. Christopher Wood
KEY CONCEPTS
Cerebral ischemia is the key pathophysiologic event triggering secondary neuronal injury following severe traumatic brain injury (TBI). Intracellular accumulation of calcium is postulated to be a central pathophysiologic process in amplifying and perpetuating secondary neuronal injury via inhibition of cellular respiration and enzyme activation.
Guidelines for the Management of Severe Brain Injury, published by the Brain Trauma Foundation (BTF)/American Association of Neurological Surgeons (AANS), serve as the foundation on which clinical decisions in managing adult neurotrauma patients are based; comparable guidelines for infants, children, and adolescents have also been published.
Correcting and preventing early hypotension (systolic blood pressure less than 90 mm Hg) and hypoxemia (PaO2 less than 60 mm Hg [8.0 kPa]) are primary goals during the initial resuscitative and intensive care of severe TBI patients.
Nonpharmacologic treatment in the management of intracranial hypertension includes raising the head of the bed 30°, short-term mild hyperventilation (PaCO2 30 to 35 mm Hg [4.0 to 4.7 kPa]), ventricular drainage if a ventriculostomy is present, and decompressive surgery.
The principal monitoring parameter for severe TBI patients within the intensive care environment is intracranial pressure (ICP). Cerebral perfusion pressure (CPP) is also a critical monitoring parameter and should be maintained between 50 and 70 mm Hg (6.7 and 9.3 kPa) (greater than 40 mm Hg [5.3 kPa] in pediatric patients) through the use of fluids, vasopressors, and/or ICP normalization therapy.
Nonspecific pharmacologic treatment in the management of intracranial hypertension should include analgesics, sedatives, antipyretics, and paralytics under selected circumstances
Specific pharmacologic treatment in the management of intracranial hypertension includes mannitol, hypertonic saline, furosemide, and high-dose pentobarbital. Neither routine use of corticosteroids nor aggressive hyperventilation (i.e., PaCO2 less than 25 mm Hg [3.3 kPa]) should be used in the management of intracranial hypertension
Use of phenytoin for the prophylaxis of posttraumatic seizures usually should be discontinued after 7 days if no seizures are observed.
Numerous investigational strategies (e.g., calcium antagonists, glutamate antagonists, antioxidants, free-radical scavengers, and progesterone) targeted at interrupting the pathophysiologic cascade of events occurring following severe TBI have been employed, but no proven therapeutic benefits have been identified.
Traumatic brain injury (TBI) is currently the leading cause of death and disability among children and young adults in the industrialized world.1 A focus on TBI prevention, and improved acute care and rehabilitation must remain national priorities. This chapter summarizes TBI epidemiology and pathophysiology, and highlights the major guidelines and systematic reviews of the literature pertaining to the management of severe TBI patients.
EPIDEMIOLOGY
It is estimated that approximately 1.7 million persons sustain a TBI each year in the United States.2 Among these individuals, 275,000 require hospital admission and 52,000 die annually.2 Importantly, over 3.1 million Americans currently live with disabilities as a result of their TBI, highlighting the enormous physical and emotional toll of this health care problem.3 The economic effects of acute neurotrauma are also enormous, with estimates of spending on TBI patients requiring hospitalization of $60 billion in the United States in 2000.4 Economic costs to society from lost productivity are also massive, especially considering the young age of many TBI patients.5 Falls are the leading cause of TBI (35.2%) while motor vehicle accidents result in the greatest number of TBI-related hospitalizations and deaths overall.2Death rates from TBI are highest in patients 75 years of age or older.2
PRIMARY AND SECONDARY BRAIN INJURY PATHOPHYSIOLOGY
The neurologic sequelae of brain trauma can occur instantaneously as a consequence of the primary injury or can result from secondary injuries that follow within minutes, hours, or days.1 Primary injury involves the external transfer of kinetic energy to various structural components of the brain (e.g., neurons, nerve synapses, glial cells, axons, and cerebral blood vessels). The biomechanical forces responsible for primary brain injury can be classified broadly as contact (e.g., blunt-object blow, penetrating-missile injuries) and acceleration/deceleration (e.g., instantaneous brain movements following motor vehicle accidents).1 Contact forces commonly result in skull fractures, brain contusions, and/or hemorrhages. Primary injuries are categorized further as focal (e.g., contusions, hematomas) or diffuse.5 The latter usually are associated with shearing or stretch forces, which primarily affect axons within the brain (i.e., diffuse axonal injury).6 The type of primary injury (i.e., focal vs. diffuse) is a major factor as to which of the secondary injury mechanisms discussed below will predominate following a TBI; however, many patients, especially those involved in high-speed accidents, sustain both types of injury.7
A complex sequence of pathophysiologic events precipitated by primary brain injury may seriously disrupt the normal CNS balance between oxygen supply and demand.7 Hypotension during the early posttraumatic period is a major contributor to this imbalance and a primary determinant of outcome.1,6 The end result of this imbalance may be cerebral ischemia, the key pathophysiologic event triggering secondary injury.7,8 Figure 42-1 is a simplified schematic of the processes that constitute secondary brain injury and their various interrelationships. The brain is particularly susceptible to ischemia because of its normally high resting energy requirement and its limited capacity to store oxygen, glucose, and adenosine triphosphate (ATP).8 Vasospasm also can occur in approximately one-fourth to one-third of TBI patients.6 These phenomena can result in imbalances in cerebral oxygen delivery (CDO2) and consumption (CMRO2), processes that are closely autoregulated under normal circumstances. Factors that can diminish cerebral oxygen supply following brain injury include cerebral edema, expanding mass lesions (e.g., epidural, subdural, and intracerebral hematomas), cerebral vasospasm, and loss of vasoregulatory control. Vasogenic cerebral edema can develop as a consequence of cerebral capillary endothelial damage and disruption of the blood–brain barrier.7,8 Cytotoxic cerebral edema is a consequence of loss of cell wall integrity that accompanies ischemia or hypoxia.8 With cytotoxic and vasogenic edema comes expansion of the intracellular and extracellular fluid spaces, respectively. Elevated intracranial pressure (ICP) is the most detrimental consequence of cerebral edema formation and occurs as the brain tissue volume increases within the nondistensible skull. A significant increase in ICP may further compromise cerebral blood flow (CBF) and extend cytotoxic edema. Hence an increase in ICP can be self-perpetuating unless this cycle is reversed. Hypoxemia can further exacerbate local decreases in cerebral oxygen supply following acute respiratory failure and systemic hypotension. Metabolic demand also can increase following neurotrauma secondary to seizures, agitation, and temperature elevation.8 Brain tissue affected by focal ischemia can have a dense core surrounded by a marginally viable region.8 If adequate CBF is restored, the affected tissue may recover; however, sustained ischemia can result in further loss of cellular integrity and eventual cell death.
FIGURE 42-1 Schematic illustration of the cascade of biochemical events proposed to occur following severe neurotrauma (secondary brain injury). (Ca, calcium; CNS, central nervous system; K, potassium; Mg, magnesium; Na, sodium; Cl, chloride; PMN, polymorphonucleocyte; PG, prostaglandin.)
The two distinctive end points along the spectrum of secondary neuronal injury are: (a) cellular necrosis characterized by membrane cell lysis, edema, and inflammation, and (b) apoptosis that leads to cell shrinkage and cell membrane dissolution.7,8 Apoptosis, which is also known as programmed cell death, requires a cascade of intracellular events for completion of cell death.7 The loss of ionic homeostasis is postulated to be a key event in fostering secondary brain injury following cerebral ischemia. Cellular influx of sodium, chloride, magnesium, and water with a corresponding efflux of potassium secondary to cytotoxic edema and Na+-K+-ATPase pump dysfunction.7,8 An influx of calcium into the presynaptic terminal ends of damaged neurons is mediated by N-type voltage-sensitive calcium channels. This influx is postulated to stimulate excessive release of the excitatory amines glutamate and aspartate from the affected neurons. These amines then accumulate in the neuronal synaptic cleft in the presence of cellular energy failure.8 The result is ongoing stimulation of postsynaptic cells, which can result in an extension of neurotoxicity and cell death. Influx of calcium and additional sodium is stimulated by activation of ionophore receptors including the N-methyl-D-aspartate (NMDA) receptor.7,8 Calcium influx and its intracellular accumulation initiate a number of events that amplify and perpetuate secondary neuronal injury. High intracellular concentrations of calcium result in mitochondrial dysfunction, which further inhibits cellular respiration, a process already affected by ischemic and/or hypoxic insults.7 A second major deleterious effect of calcium is to stimulate activation of autodestructive enzymes, including phospholipases, endonucleases, and proteases, such as the caspase family of enzymes.7,8 The effect of phospholipase A2 stimulation includes formation of several arachidonic acid metabolites derived from membrane lipids: thromboxane A2, prostaglandins, and leukotrienes.7,8 The subsequent effects of these metabolites are lipid peroxidation and the formation of reactive oxygen species.1,7,8 Data suggest that this event occurs very early after injury (e.g., before hospitalization), which may limit the effectiveness of exogenously administered antioxidants.
Cell-mediated injury involving inflammatory mediators (e.g., proinflammatory cytokines) and nitric oxide activation is yet another possible mechanism involved in secondary neuronal injury.7 Among the cell lines implicated are polymorphonuclear neutrophils, platelets, endothelial cells, and macrophages. Noteworthy is that limited data suggest that activation of some inflammatory mediators may actually be beneficial such that the relative balance of the mediators versus absolute concentrations may be the most significant pathophysiologic factor following TBI. Stimulation of platelet aggregation, vasodilation, and vasoconstriction also may occur.
CLINICAL PRESENTATION
The Glasgow Coma Scale (GCS) is the most widely used system to grade the arousal and functional capacity of the cerebral cortex.6 The GCS defines the level of consciousness according to eye opening, motor response, and verbal response Table 42-1). A GCS score of 15 corresponds to a normal neurologic examination. A GCS score of 3 to 8, 9 to 12, and 13 to 15 is consistent with severe, moderate, and mild or minor brain injury, respectively.6 The possibility of ethanol or drug intoxication, hypotension, hypoxia, postictal state, or hypothermia altering the neurologic examination always should be considered. Because opiates, sedatives, and neuromuscular blockers affect the neurologic examination, they should not be administered until the initial examination is complete if at all possible. Simple, rapidly attainable clinical variables that are predictive of survival include patient age, presence of hypotension, increased ICP, elevated GCS score (especially the motor score), pupillary reactivity, and findings on a computed tomographic (CT) scan of the head that include the presence and size of a hematoma, subarachnoid hemorrhage, midline shift, and compression of the ventricular cisterns.9
TABLE 42-1 Glasgow Coma Scale
CLINICAL PRESENTATION Acute Brain Injury
General
• Level of consciousness on admission ranges from awake and alert to completely unresponsive (i.e., GCS 15 to 3, respectively)
Symptoms
• Posttraumatic amnesia (e.g., greater than 1 hour), increasing dizziness, a moderate-to-severe headache, nausea/vomiting, limb weakness, or paresthesia may indicate more severe injury
Signs
• CSF otorrhea or rhinorrhea and seizures may indicate more severe injury
• A rapid deterioration in mental status strongly suggests the presence of an expanding lesion within the skull
• Severe TBI may be accompanied by significant alterations or instability in vital signs, including abnormal breathing patterns (e.g., apnea, Cheyne–Stokes respiration, tachypnea), hypertension, or bradycardia
Laboratory Tests
• ABGs indicating hypoxia (i.e., decreased Pao2) or hypercapnia (i.e., increased PaCO2) may indicate compromised ventilation
• A positive blood ethanol concentration and/or positive urine drug screen indicates that drug intoxication may be affecting the patient’s mental status in addition to the TBI
• Electrolyte disturbances can cause alterations in mental status, and their effects may interfere with assessment of neurological status relative to brain lesion
Other Diagnostic Tests
• CT of the head is an important diagnostic tool for detecting the presence of mass lesions
GCS, Glasgow Coma Scale; CSF, cerebrospinal fluid; TBI, traumatic brain injury; ABG, arterial blood gas; PaO2, partial pressure of arterial blood oxygen; PaCO2, partial pressure of arterial blood carbon dioxide; CT, computed tomography
GENERAL TRAUMATIC BRAIN INJURY TREATMENT PRINCIPLES
In July 1995, the Brain Trauma Foundation (BTF) published an extensive document entitled Guidelines for the Management of Severe Brain Injury as a joint initiative with the Guidelines Committee of the American Association of Neurological Surgeons (AANS) and the Joint Section on Neurotrauma and Critical Care of the AANS and the Congress of Neurological Surgeons, with subsequent revision in 2000.10 A third revision was released in 2007.11 This landmark publication constitutes the most widely accepted series of evidence-based standards, guidelines, and options for the care of severe TBI patients. Recommendations are reported as Level I (standards), Level II (guidelines), or Level III (options) based on the corresponding classes of evidence. As important are the data documenting that compliance with the BTF/AANS guidelines can result in improved outcomes relative to mortality rate, functional outcome scores, length of hospitalization, and cost.12 Since then, guidelines addressing prehospital TBI management,13 surgical management,14 and management of penetrating brain injury have been published. Furthermore, TBI management guidelines for infants, children, and adolescents have been developed.15 The recommendations emanating from these published guidelines on TBI management and various published systematic reviews will be highlighted throughout the remaining portion of this chapter. Until further clinical studies become available, recommendations from the published guidelines should serve as the foundation on which all clinical decisions in managing severe TBI are based. Nonetheless, it should be noted that the majority of the guidelines are based on Class II evidence (primarily prospective clinical trials) and Class III evidence (primarily retrospective clinical trials). Few Class I evidence studies (i.e., prospective, randomized, controlled trials) are available for treatment of TBI. The pharmacologic management of TBI is summarized in Table 42-2. Recommendations provided in this chapter pertain to adults and children unless specifically noted to the contrary
TABLE 42-2 Pharmacologic Management of Traumatic Brain Injury
Desired Outcomes
The overall goal in TBI management is not only reduction in morbidity and mortality, but also optimization of long-term functional outcome for these patients. This requires careful attention to the following short-term therapeutic goals: (a) establishment of an adequate airway and maintenance of ventilation and circulation during the initial period of resuscitation and evaluation, (b) maintenance of balance between CDO2 and CMRO2, (c) prevention or attenuation of secondary neuronal injury, and (d) prevention and/or treatment of associated medical complications.
Initial Resuscitation
The first priority in the unconscious patient is the establishment of an airway, which ensures adequate oxygenation and prevents aspiration.6 
Thereafter, restoration of circulating blood volume and maintenance of systolic arterial pressure (SBP) greater than 90 mm Hg are of utmost importance.1,11 In pediatric patients, the SBP goal should be greater than 70 mm Hg + (2 × age in years).15 Correcting and preventing early hypotension (SBP less than 90 mm Hg) and hypoxia (PaO2 less than 60 mm Hg [8.0 kPa]) are essential because these two factors are among the most powerful predictors of outcome.9,11Isotonic saline (0.9% normal saline) and lactated Ringer’s solution have been traditionally used as initial resuscitation fluids of choice in TBI patients.10 However, some clinicians believe that hypertonic saline (e.g., 3% or 7.5% saline) is beneficial in the resuscitation of TBI patients. Clinical studies have yielded equivocal results relative to superiority over isotonic solutions.1,16 Regardless, no clear consensus exists as to the optimal initial resuscitation fluid. While albumin therapy may be considered as an alternative to crystalloid fluid resuscitation, a retrospective analysis of 460 TBI patients revealed an increase in mortality (33.2%) compared with those patients receiving 0.9% normal saline.17 Vasopressors and inotropic agents may be needed to maintain an adequate mean arterial pressure (MAP) if hypotension persists after adequate restoration of intravascular volume. Figure 42-2 is an algorithm summarizing treatment priorities in the initial management of acute TBI.
FIGURE 42-2 Algorithm for the acute management of the TBI patient. (GCS, Glasgow coma scale; BP, blood pressure; ABG, arterial blood gas; CBC, complete blood count; EtOH Cp, ethanol plasma concentration; SBP, systolic blood pressure; NS, normal saline; PRBC, packed red blood cells; Hct, hematocrit; PaCO2, partial pressure of arterial blood carbon dioxide; ICP, intracranial pressure; CT, computed tomography; OR, operating room; ICU, intensive care unit; CPP, cerebral perfusion pressure; CSF, cerebral spinal fluid.) (Adapted with permission from Wood CG, Boucher BA. Management of Acute Traumatic Brain Injury. In: Richardson M, Chant C, Chessman KH, et al., eds. Pharmacotherapy Self-Assessment Program, 7th ed. Neurology and Psychiatry. Lenexa, KS: American College of Clinical Pharmacy, 2012:143, Figure 1-1.)
Postresuscitative Care
Following successful resuscitation, priorities shift toward diagnostic evaluation of intracranial and extracranial injuries and emergent surgical intervention as needed. In many patients, evacuation of intracranial hematomas (i.e., epidural, subdural, and intracerebral hematomas) is essential to control ICP and improve outcome. Elevation of depressed skull fractures and debridement of penetrating wound tracts are other important emergent surgical procedures in TBI patients. 
Decompressive craniectomies (i.e., removal of variable amount of skull bone) with or without temporal or frontal lobectomy may be considered in patients with increases in ICP refractory to more conservative measures.1 The beneficial effects of routine decompressive surgery in adult TBI patients to date are controversial.18 However, a recent pivotal randomized trial, while demonstrating acute effectiveness in ICP control using decompressive craniectomy, also found worse long-term outcomes compared with controls. This latter study calls into question the routine use of decompressive craniectomy in patients with refractory ICP.19 Continuous ICP monitoring (e.g., intraventricular catheter, intraparenchymal fiberoptic catheter) is indicated in salvageable patients with a GCS score of 3 to 8 after resuscitation with an abnormal admission CT scan. In addition, continuous ICP monitoring is indicated in high-risk severe TBI patients with a normal CT scan and two of the following criteria: age older than 40 years, motor posturing, or SBP less than 90 mm Hg.11 Intraventricular catheters have a therapeutic advantage over the alternatives but are associated with a higher complication rate and can be difficult to place in the setting of the swollen brain. Specifically, cerebrospinal fluid (CSF) can be drained using this device as a means to lower ICP.1 Continuous ICP monitoring is the only means to objectively evaluate the success of therapies used to decrease ICP. Once the ICP exceeds 20 to 25 mm Hg (2.7 to 3.3 kPa), therapy should be initiated to decrease ICP below 20 mm Hg (2.7 kPa).11,15 While used extensively in TBI patients and advocated within consensus guidelines, the need for a prospective, randomized, controlled trial to further define its value has been suggested.20,21 Jugular venous oxygen saturation (Sjvo2) monitoring is advocated by some practitioners for detection of global cerebral hypoxia (i.e., adequacy of CBF relative to CMRo2), although it is technically difficult to achieve consistent results.8Hence its role remains confined predominantly to use in academic centers and for research.8 The use of brain tissue oxygen monitoring may prove to be a superior alternative to Sjvo2 to measuring oxygen diffusion in TBI patients.8,22 Cerebral microdialysis is yet another technique that has been used successfully as a research tool to measure the cerebral extracellular chemistry of TBI patients.8 Biochemical markers (e.g., S-100 protein) have been suggested as having utility relative to monitoring TBI patients.23 However, no clear role has yet to be defined for such markers, especially since there may be incongruence between serum and brain concentrations of proteins such as S-100.24 Neuron-specific enolase is another substance that may have potential utility as a biomarker based on the positive association between neuron-specific enolase CSF concentrations and cerebral hypoperfusion.25
Another important monitoring parameter for severe TBI patients within the intensive care environment is the cerebral perfusion pressure (CPP). The CPP is the difference between MAP and ICP (i.e., CPP = MAP – ICP). Maintenance of an acceptable CPP has been postulated to be critical in reducing cerebral ischemia and secondary injury. The BTF/AANS guidelines recommend maintaining a range of CPP between 50 and 70 mm Hg (6.7 and 9.3 kPa) and specifically indicate avoiding CPP values less than 50 mm Hg (6.7 kPa).11 Current guidelines also recommend that aggressive attempts to maintain CPP greater than 70 mm Hg (9.3 kPa) in adults should be avoided because of the risk of the acute respiratory distress syndrome.11 In children, the recommended CPP goal is greater than 40 mm Hg (5.3 kPa).15Despite being commonly used, the optimal approach to CPP management continues to be debated.26
The goal CPP can be achieved by increasing MAP through the use of fluids and/or vasopressors or by lowering elevated ICP. The goal of volume expansion should be euvolemia as well as avoidance of a hypoosmolar state and negative fluid balance.15 If the hematocrit is below 30% (0.30), transfusion of packed red blood cells (PRBCs) is indicated.1 However, recent evidence cautions against the liberal use of blood in TBI and other critically ill patients secondary to worse outcomes associated with their use.27 Volume status should be targeted to a central venous pressure of 7 to 12 cm H2O if invasive monitoring is employed.1 After achievement of euvolemia, the patient’s head should be elevated at 30° to promote venous drainage and decrease ICP. If restoration of the intravascular volume is inadequate in elevating MAP to an acceptable level, hypertension should be induced using vasopressors or inotropic support. The drugs employed most commonly to induce hypertension are dopamine, phenylephrine, and norepinephrine.1 Patients should be monitored for renal dysfunction, lactic acidosis, and signs of peripheral ischemia when these agents are used, especially in large doses.
TREATMENT OF INTRACRANIAL HYPERTENSION
General Pharmacologic Strategies
The use of analgesics and sedatives has an important primary role in the management of intracranial hypertension (see Table 42-3 and Fig. 42-3).28 This is related directly to the association of pain, agitation, excessive muscle movement, and resisting mechanical ventilation with transient increases in ICP. Paralytics are a secondary option in refractory patients. Nonetheless, there is no strong evidence that one agent is superior to another relative to affecting outcome in patients with severe TBI based on a recent systematic review of randomized clinical trials.29 Effects on ICP, CPP, and MAP are variable.29Morphine sulfate is the most commonly used analgesic and sedative in this setting.11,30 Noteworthy is that bolus doses of opiates may increase ICP by increasing CBF.30 However, while continuous infusions of fentanyl and sufentanil are gaining in popularity, their use also may be associated with mild elevations in ICP.11,30 Propofol has become the sedative of choice in TBI patients among many clinicians because of its ease of titration, rapidly reversible effects on discontinuation, and possible neuroprotective effects.11 Although it is used for sedation in infants and children who are mechanically ventilated in the intensive care unit (ICU) setting, the FDA requires that the manufacturer labeling contains specific information that propofol is not approved for sedation of pediatric patients admitted to an ICU. One of the biggest safety concerns with the use of propofol is the propofol infusion syndrome (PIS) characterized by hyperkalemia, hepatomegaly, lipemia, metabolic acidosis, myocardial failure, rhabdomyolysis, renal failure, and death in some cases.11,31 While initially reported in children, PIS can also occur in adults. Doses greater than 5 mg/kg/h and infusion exceeding 48 hours should be used with extreme caution.11Triglyceride concentrations also should be monitored in patients receiving prolonged propofol infusions and/or high dosages of propofol considering its lipid emulsion formulation and the potential for inducing hypertriglyceridemia under these conditions. Alternative sedatives include etomidate (particularly useful in rapid-induction anesthesia), intermittent low-dose pentobarbital, and short-acting benzodiazepines (e.g., midazolam), especially if there is a reasonable suspicion of alcohol withdrawal as the underlying etiology of the agitation. The potential for these agents to decrease MAP and CPP must be monitored closely. Additionally, the cumulative sedative effects of longer-acting drugs, especially benzodiazepines, must be taken into account. The use of any sedative agent also must be weighed against its potential to obscure the neurologic examination of the patient. Interference with the neurologic examination is also a problem with paralytic agents.
TABLE 42-3 Drug Dosing and Monitoring in TBI Patients
FIGURE 42-3 Algorithm for the management of increased ICP. aTreatment thresholds: ICP 20 to 29 mm Hg (2.7 to 3.9 kPa) for >15 minutes; ICP 30 to 39 mm Hg (4.0 to 5.2 kPa) for >2 minutes; ICP ≥ 40 mm Hg (≥5.3 kPa) for >1 minute. Note: Transient increases may occur following respiratory procedures (e.g., suctioning, chest physiotherapy, bronchoscopy, and intubation). bHold if serum osmolality >320 mOsm/kg (320 mmol/kg). cPartial pentobarbital loading dose (mg) = (30 mg/L – measured Cp) (1 L/kg × wt(kg)) (pentobarbital concentration in μmol/L must first be divided by 4.439 to convert to mg/L). (Cp, plasma concentration; CT, computed tomography; OR, operating room; ICP, intracranial pressure; ICU, intensive care unit; T, temperature; CSF, cerebral spinal fluid; EEG, electroencephalogram; RR, respiratory rate; PaCO2, partial pressure of arterial blood carbon dioxide.) (Adapted with permission from Wood CG, Boucher BA. Management of Acute Traumatic Brain Injury. In: Richardson M, Chant C, Chessman KH, et al., eds. Pharmacotherapy Self-Assessment Program, 7th ed. Neurology and Psychiatry. Lenexa, KS: American College of Clinical Pharmacy, 2012:144, Figure 1-2.)
Hyperventilation
The practice of prolonged aggressive hyperventilation (PaCO2 less than 25 mm Hg [3.3 kPa]) to decrease ICP is no longer recommended.11 Hyperventilation acutely decreases systemic and cerebral PaCO2. The resulting hypocapnia, in turn, induces cerebral vasoconstriction, thereby decreasing CBF and cerebral blood volume (CBV).8 For decades, it was a widely held belief that a reduction in CBV and any accompanying decrease in ICP were beneficial. Nonetheless, a comprehensive literature review concluded that there are no data demonstrating improved outcomes using this therapeutic intervention.32Hyperventilation should be avoided during the first 24 hours following acute TBI when CBF is often critically reduced according to the most current BTF/AANS guidelines.11 
Hyperventilation for brief periods with a goal of 30 to 35 mm Hg (4.0 to 4.7 kPa) nonetheless may be considered as a temporary maneuver in the setting of refractory intracranial hypertension or in the initial management of patients with signs of cerebral herniation.11,15 If hyperventilation is performed, the use of SjvO2 or cerebral tissue oxygen perfusion monitoring is recommended.11
Hypothermia
Therapeutic hypothermia has been an attractive strategy for attempting to minimize secondary brain injury after TBI for decades. The mechanism underlying a protective effect of hypothermia is likely multifactorial, although a reduction in CMRO2 is offered most frequently as the basis of any therapeutic benefits. Early TBI studies suggested promise for therapeutic hypothermia. In addition, some other patient populations with brain ischemia (e.g., cardiac arrest patients) have improved outcomes with hypothermia. Unfortunately, data from recent clinical trials of prophylactic therapeutic hypothermia in TBI patients have not shown improved outcomes. The first of two large randomized clinical trials of therapeutic hypothermia in 392 patients with nonpenetrating TBI using a targeted temperature of 33°C (91°F) revealed no improvement in outcome compared with the normothermic group.11 In addition, more hypotension was observed in the therapeutic hypothermia group. The second major multicenter study focused on early cooling (i.e., less than or equal to 2.5 hours) to 35°C (95°F), then 48 hours at 33°C (91°F) followed by gradual rewarming.33 The control group was treated under normothermia conditions. This study was discontinued after enrollment of 108 patients because of futility with poorer outcomes including death observed in the hypothermic group. Based on the clinical evidence to date, prophylactic therapeutic hypothermia is not recommended as a routine neuroprotective strategy in patients with TBI.34–36 Nevertheless, a recent report emanating from five critical care societies would not recommend for or against therapeutic hypothermia (i.e., “targeted temperature management”) based on available data.37 Noteworthy is that a large, multicenter study of hypothermia for ICP reduction in TBI patients (Eurotherm3235Trial) is currently underway that may provide additional insights on the use of this therapeutic intervention.38 Potential side effects of therapeutic hypothermia include coagulation disturbances, infectious complications, and cardiac arrhythmias.35 An increase in ICP also may occur secondary to hypothermia-associated shivering that can be prevented with neuromuscular blocking agents. Therapeutic hypothermia can have effects on the pharmacokinetics of drugs that should also be considered. Specifically, cardiac output decreases by 7% for every 1°C (1.8°F) decrease in core body temperature.39
Clinical Controversy…
Hypertonic saline is an attractive alternative to mannitol for the treatment of increased ICP. While data supporting its effectiveness and superiority over mannitol are lacking, many centers use hypertonic saline in TBI management. Selection of an osmotic agent should take into account factors such as the patient’s intravascular volume, renal function, serum electrolytes, and acid/base status.
Osmotic Agents
Although a number of osmotic diuretics (e.g., urea, glycerol) can be used to decrease ICP, mannitol is unquestionably the most widely employed.1,11 Despite the common practice of administering mannitol to patients with suspected or actual increases in ICP following brain injury, no clinical trial comparing its effects against placebo have been performed.30,40 The mechanisms responsible for mannitol’s beneficial effects likely relate to (a) an immediate plasma-expanding effect that reduces blood viscosity and increases CBF and (b) establishment of an osmotic concentration gradient across an intact blood–brain barrier that decreases ICP as water diffuses from the brain into the intravascular compartment.11 Recommended doses of mannitol typically range from 0.25 to 1 g/kg IV every 4 hours.11 However, a recent study demonstrating that higher mannitol doses (1.4 g/kg) may be more effective than 0.7 g/kg calls into question this dosing recommendation.41 Increased ICP is reduced within minutes following mannitol administration, and the duration of action ranges from 90 minutes to 6 hours depending on the dose and the clinical conditions that are present.11 In order to maximize benefit and minimize adverse events, it was previously recommended that mannitol be administered as a bolus and not as a continuous infusion in this setting.1,10 However, more recent analyses conclude that there is no demonstrable benefit using one administration approach over the other.11
Several adverse effects are associated with mannitol. In addition to hypotension resulting from its diuretic effect, a reversible acute renal dysfunction may occur in patients with previously normal renal function after long-term, large-dose administration, especially if the serum osmolality and serum sodium exceed 320 mOsm/kg (320 mmol/kg) and 160 meq/L (160 mmol/L), respectively.1 Hence monitoring and maintaining the serum osmolality and sodium, and replacing urinary fluid losses are important to minimize this adverse event. Mannitol should be avoided in patients with renal failure.15 Acute exacerbation of underlying congestive heart failure and pulmonary edema also may occur following rapid intravascular volume expansion. Furosemide is recommended as an alternative diuretic for lowering ICP in these latter patient groups.
While hypertonic saline solutions have been advocated by some as a resuscitative fluid following TBI as previously mentioned, solutions ranging from concentrations of 3% to 23.4% have also been used to acutely lower increased ICP.16 Not only do hypertonic saline solutions create an osmotic gradient in favor of reducing cerebral edema, but evidence suggests that they may also have beneficial vasoregulatory, immunologic, and neurochemical effects as well. Plasma expansion may also lead to an increase in CBF. It is noteworthy, however, that the 2007 BTF guidelines do not recommend hypertonic saline due to a lack of supporting evidence.42 Nonetheless, a crossover study of 20% mannitol versus 7.5% hypertonic saline and 6% dextan-70 in nine TBI patients with ICP greater than 20 mm Hg (greater than 2.7 kPa) demonstrated a significantly greater decrease in ICP and a longer duration of effect following the hypertonic saline infusions.43 A recent meta-analysis also suggested that hypertonic saline may be modestly more effective than mannitol.44 In contrast, two recent studies of equimolar doses of mannitol versus 7.45% and 15% hypertonic saline, respectively, revealed similar effects between the regimens in TBI patients.45,46 If used, serum sodium concentrations should not be allowed to increase by more than 12 mEq/L (12 mmol/L) in a 24-hour period (0.5 mEq/L [0.5 mmol/L] per hour) to avoid neurologic adverse events. Furthermore, hypertonic saline should not be used if the serum sodium concentration exceeds 155 to 160 mEq/L (155 to 160 mmol/L).
Barbiturates
High-dose barbiturate therapy (i.e., barbiturate coma) has been used for decades in the management of increased ICP despite a lack of evidence documenting beneficial effects on patient morbidity and mortality.47 Nonetheless, based largely on beneficial outcomes observed in a randomized clinical trial published in 1988, BTF/AANS and pediatric guidelines recommend that high-dose barbiturate therapy be considered in hemodynamically stable severe TBI patients refractory to maximal medical ICP-lowering therapy and decompressive surgery.11,15 A recent study indicated survival at a discharge of 40% and good functional outcomes in 68% of survivors at 1 year in this TBI patient subset receiving high-dose barbiturate therapy.48 Prophylactic use of barbiturates is not advocated in light of insufficient evidence supporting this practice and the potential for adverse events (e.g., hypotension).11,15,47 Several mechanisms responsible for the cerebral protective effects of barbiturates have been proposed. These include (a) lowering the regional CMRO2 with a coupled reduction in CBF to these areas, (b) inhibition of lipid peroxidation, and (c) alteration of cerebral vascular tone.1,28 Prior to inducing a barbiturate coma, the severe TBI patient must be mechanically ventilated with continuous monitoring of arterial blood pressure, electrocardiogram (ECG), and ICP. Pentobarbital is the most commonly used barbiturate for this indication, although thiopental also has been used. Pentobarbital should be administered as an IV loading infusion totaling 25 mg/kg (i.e., 10 mg/kg over 30 minutes and then 5 mg/kg per hour for 3 hours), followed by a maintenance infusion of 1 to 2 mg/kg per hour.1,11 If the systolic blood pressure falls during the loading or maintenance infusions, the rate should be slowed temporarily and blood pressure support initiated. The goal of a barbiturate coma is to maintain ICP and CPP at the previously discussed target thresholds in addition to achieving a pentobarbital steady-state concentration of between 30 and 40 mg/L (133 and 178 μmol/L) (despite poor correlation between serum concentrations and outcome) and EEG burst suppression.11 Initiation of barbiturate therapy withdrawal can occur when ICP has been controlled satisfactorily for 24 to 48 hours. Barbiturates should be tapered over 24 to 72 hours to prevent ICP spikes.
Side effects associated with high-dose barbiturate therapy involve primarily the cardiovascular system. Hypotension caused by peripheral vasodilation may occur, necessitating decreasing the barbiturate dose or the administration of fluids and vasopressors to maintain blood pressure. A systematic review of the literature suggested that one of every four patients receiving barbiturate therapy will develop hypotension.47 GI effects of barbiturates include decreased GI muscular tone and decreased amplitude of contraction. On emergence from coma, there may be a period of GI hypermotility. Care should be taken to avoid extravasation of pentobarbital and thiopental solutions because severe tissue damage may occur. Barbiturates should be administered by continuous infusion through a central line dedicated for this purpose. The potential for barbiturates to induce the hepatic drug metabolism of concurrent medications should be also considered. Lastly, the potential for prolonged interference with the neurologic examination of TBI patients must be considered prior to the initiation of high-dose barbiturate therapy.
Corticosteroids
Although corticosteroids are effective in preventing or reducing cerebral edema in patients with nontraumatic conditions producing vasogenic edema, studies in TBI patients have not demonstrated the ability of corticosteroids to lower ICP or improve outcome.11,49 Specifically, use of corticosteroids following TBI has been associated with increased mortality and complications, including GI bleeding, glucose intolerance, electrolyte abnormalities, and infection. The largest investigation to date was known as the corticosteroid randomization after significant head injury (CRASH) study.50 In this study, 10,008 patients with a GCS score less than or equal to 14 were randomized to receive a 48-hour continuous infusion of methylprednisolone or placebo. Results of this study indicated a higher risk of death within 2 weeks of enrollment (relative risk 1.18) in those patients receiving corticosteroids compared with patients receiving placebo (P <0.001).50 Based on this and several other major randomized trials, the BTF/AANS adult and pediatric guidelines recommend that high-dose corticosteroids not be used in patients with moderate to severe TBI.11,15
Clinical Controversy…
The role of levetiracetam in the treatment of TBI patients is uncertain. It continues to gain in popularity for the prevention of seizures despite the lack of data supporting its use for this indication.
TREATMENT AND PROPHYLAXIS OF COMPLICATIONS
Posttraumatic Seizures
It is generally agreed that patients who have experienced one or more seizures following a moderate-to-severe TBI should receive anticonvulsant therapy to avoid increases in CMRO2 that occur with the onset of subsequent seizures and to prevent the development of (sometimes subclinical) status epilepticus with associated increase in mortality. Initial therapy in these persons should consist of incremental IV doses of diazepam (5 to 40 mg adults, 0.1 to 0.5 mg/kg infants and children) or lorazepam (2 to 8 mg adults, 0.03 to 0.1 mg/kg infants and children) to terminate any active seizure activity followed by IV phenytoin to prevent seizure recurrence. Phenytoin dosing regimens for adults and pediatric patients include an IV loading dose of 15 to 20 and 10 to 15 mg/kg, respectively, followed by a maintenance dose of 5 mg/kg per day. Alternatively, fosphenytoin, a water-soluble phosphate ester of phenytoin, can be administered IV or intramuscularly using the same doses, specified as phenytoin equivalents (PE). The merits of preventive anticonvulsant therapy in patients who have not had a seizure postinjury historically have been more controversial. Risk factors for early posttraumatic seizures (less than 7 days after injury) include a GCS score of less than 10, a cortical contusion, a depressed skull fracture, a subdural hematoma, an epidural hematoma, an intracerebral hematoma, a penetrating head wound, or a seizure within the first 24 hours of injury.11 In a landmark randomized, placebo-controlled study, the incidence of early posttraumatic seizures in patients receiving placebo was 14.2% compared with 3.6% in patients receiving phenytoin (P <0.05) without a significant increase in drug-related side effects.51 
A systematic review of the literature corroborated these findings, estimating an improved pooled relative risk for early seizure prevention of 0.34 (95% confidence interval [CI]: 0.21 to 0.54) in patients receiving anticonvulsants.52 Thus, it is recommended that phenytoin (or alternatively carbamazepine) should be used to prevent seizures in TBI patients at high risk for the first 7 days after injury.11,15,51 Valproate therapy is not recommended based on a trend for higher mortality in a study comparing valproate-treated patients with those receiving phenytoin short-term therapy.51 Levetiracetam is a potentially attractive option53; however, the drug should be used cautiously because is not approved as monotherapy for seizures, and effectiveness in patients with TBI has not been studied in a large randomized clinical trial. Furthermore, the cost-effectiveness of levetiracetam versus phenytoin favors phenytoin.54,55 A high-quality, randomized, clinical trial demonstrating superiority is needed before levetiracetam displaces phenytoin as the drug of choice following TBI. Nonetheless, if used in TBI patients, the potential for increased levetiracetam systemic clearance should be considered in dosing this agent.56 The benefits of prophylactic anticonvulsants beyond 7 days have not been demonstrated, and thus their use for this indication is not recommended.11 Unfortunately, despite reducing the incidence of early seizures following brain injury, no beneficial effects have been documented for anticonvulsants on patient mortality or long-term disability.11,51 This is particularly disconcerting considering that the long-term risk of epilepsy after TBI has been documented up to 10 years or longer based on the results of a recent population-based cohort study.57
Clinical Controversy…
Prevention of deep venous thrombosis is of major importance in TBI patients. However, controversy remains relative to how early to initiate systemic anticoagulants in TBI patients with CT evidence of intracranial hemorrhage. Currently, the best available data suggest that pharmacologic prophylaxis can be started after a follow-up CT scan shows no worsening of the intracranial hemorrhage in patients who have stable ICP control and who did not have a severe hemorrhage on admission.
Supportive Care
While normalizing ICP and maintaining an adequate CPP are the highest priorities in preventing secondary injury following severe TBI, attention also must be given to preventing and/or treating systemic and extracranial complications.11 One such complication is systemic hypertension. While several antihypertensives can be used, nicardipine is commonly used in TBI patients because of its effectiveness and lack of adverse effects on brain tissue oxygenation.58 Fluid and electrolyte management is another important area of focus in the critically ill TBI patient.16 Common electrolyte disturbances in TBI patients that should be monitored and treated aggressively include hyponatremia, hypomagnesemia, hypokalemia, and hypophosphatemia. Aggressive nutritional support of the TBI patient is another important therapeutic consideration. Evidence suggests that early feeding of TBI patients (i.e., by 7 days) may be associated with a trend toward better outcomes in terms of survival and disability.11,59 Early enteral nutrition, in particular, within 48 hours is associated with better survival and better outcome at one month postinjury based on a recent retrospective study of severe TBI patients compared with matched controls who did not receive early enteral nutrition.60 Hyperglycemia (glucose greater than or equal to 160 mg/dL [8.9 mmol/L]) is also common in patients with TBI and is associated with worse outcomes.61 Nevertheless, intensive insulin therapy versus conventional glucose control should not be used since it is associated with adverse effects on brain glucose metabolism62 and poor outcomes.63 Infectious complications commonly encountered in severe TBI patients include nosocomial pneumonia, sepsis, urinary tract infections, and meningitis.1 Treatment of these potentially devastating infections should be aggressive, with careful attention being paid to antibiotic blood–brain barrier penetration for intracranial infections. Hyperthermia also should be avoided in TBI patients because patients with elevated temperatures have poorer outcomes than normothermic patients.1,64 Hence aggressive maintenance of a core temperature of less than 37.5°C (99.5°F) using acetaminophen, nonsteroidal antiinflammatory drugs (NSAIDs), and cooling blankets is indicated for patients following severe TBI. Other important therapeutic interventions include acute gastritis prophylaxis, and prevention of decubiti and contractures. Prevention of thromboembolic events is also extremely important supportive care in TBI patients since the incidence of a deep venous thrombosis is higher in TBI patients compared with patients without brain injury.1,65This can be accomplished with the use of graduated compression stockings or intermittent pneumatic compression devices initially. Thereafter, the decision to start systemic therapy (e.g., low-molecular weight heparin) depends on multiple factors. Generally, patients who had relatively minor bleeding on the initial CT scan and good ICP control can have pharmacological prophylaxis started immediately or shortly (1 to 3 days) after a follow-up CT scan shows no worsening of bleeding. Prophylaxis is continued until they are ambulatory.11,66,67However, systemic anticoagulation must be used with caution in patients with more severe intracerebral hemorrhage, or in patients who may need to undergo craniotomy early in their course. Monitoring for a coagulopathy is important in any severe TBI patient, since the incidence is high (greater than 30%), and coagulopathy is associated with a significantly longer ICU length of stay and an almost 10-fold increase in mortality based on data from a recent study.68 Reversal of coagulopathy with recombinant factor VIIa in critically ill trauma patients with TBI is gaining in popularity among some practitioners despite lacking an approved indication or large clinical trials demonstrating its safety and efficacy in TBI patients.69,70 Tranexamic acid is a more inexpensive hemostatic alternative to recombinant factor VIIa. However, more data are needed to determine the role of this agent in TBI patients before it is used routinely.71
Clinical Pathways/Guideline Implementation
Use of clinical pathways and formal TBI management guidelines have been demonstrated to improve TBI patient outcomes and reduce institutional resource utilization.72,73 A cost–benefit analysis revealed that adoption of the BTF guidelines resulted in an increase of more than 3,600 adult severe TBI patients surviving at least 1 day from the more than 23,000 patients with severe TBI admitted annually to U.S. hospitals. Furthermore, patients having a good outcome based on their Glasgow Outcome Scale (GOS) increased from 35% to 66% with an overall estimated annual cost savings exceeding $4 billion.74 Few practitioners would dispute the overall importance of integrating current evidence-based management guidelines into clinical practice as a means to optimize care and improve the functional outcome of TBI patients.
Investigational Therapy
The steady decrease in morbidity and mortality following severe neurotrauma over the last 30 years can be attributed largely to expeditious and aggressive management of events resulting in secondary injury (i.e., ischemia, hypoxia, increased ICP) using conventional treatment strategies. Numerous neuroprotective agents targeting specific pathophysiologic processes that are theorized to occur following severe TBI have been investigated over the last decade in an attempt to further enhance the prospects for a meaningful recovery. Prominent among these strategies have been attempts to modulate calcium influx through the administration of calcium antagonists75,76 and glutamate antagonists including magnesium,75,77–80 and the use of antioxidants/free radical scavengers.75 Inhibitors of inflammatory mediators also are under consideration as neuroprotective agents.81,82 Unfortunately, none of these agents to date has demonstrated a significant reduction in morbidity or mortality following severe TBI in phase III clinical trials. Noteworthy is that a Phase II pilot study demonstrated a decrease in mortality in 100 TBI patients randomized to receive a three-day infusion of progesterone compared with placebo.83 A follow-up independently conducted, double-blinded clinical trial of progesterone in 159 TBI patients also improved outcome at 6 months postinjury.84 Two Phase III trials of this promising pharmacologic strategy are currently underway85 consistent with clinical data revealing a pooled relative risk for mortality for progesterone in TBI patients of 0.61 (95% CI 0.40 to 0.93).86 Another recent prospective clinical trial comparing the erythropoiesis-stimulating agent (ESA), darbepoetin alfa, in severe TBI patients also demonstrated significantly improved survival in those receiving the darbepoetin compared with matched patients not receiving an ESA.87 In light of such positive clinical trial results, the search is likely to continue for neuroprotective agents that eventually may improve the long-term outcome in severe TBI patients.88 Other agents that have may have beneficial effects in TBI based on limited clinical or epidemiologic data include 3-hydroxy-3-methylglutaryl (HMG) coenzyme A reductase inhibitors85,89 and β-blockers.90,91 However, neither drug class has been studied in a published prospective, randomized, clinical trial in TBI patients. Miscellaneous agents being considered as viable neuroprotective agents based on experimental TBI studies including calpain inhibitors, inhibitors of caspases (enzymes involved in apoptosis), and the immunosuppressant, cyclosporine.85
Other Treatment Strategies
The concept of administering commercially available CNS-active agents for nonapproved indications in TBI patients should presently be considered investigative therapy. One example is the use of CNS stimulants in the management and rehabilitation of TBI patients. A comprehensive review of the use of methylphenidate relative to improving cognition following TBI was recently conducted. It was the opinion of the author that the literature does provide a degree of support for improvements in memory, attention, concentration, and mental processing in this patient subset, although results and study designs were highly variable for those investigations included in the analysis.92 Another example is the use of Parkinson’s disease medications (e.g., amantadine, bromocriptine, carbidopa/levodopa) in severe TBI patients in an attempt to enhance dopamine release and inhibit reuptake within the injured region of the brain. The results of a multicenter, prospective, double-blind, randomized, placebo controlled trial of amantadine, which was conducted in nonpenetrating TBI patients, were recently published.93 Patients were enrolled 4 to 16 weeks after their TBI. The amantadine-treated patients had a significantly faster recovery and favorable rehabilitation outcomes compared with placebo. Unfortunately, the two groups became indistinguishable relative to neurologic improvement following taper of amantadine. Regardless, this agent holds excellent promise in TBI patients during the postinjury rehabilitation period. Cholinergic agents such as donepezil have also undergone limited investigation in TBI patients.94,95Antidepressants represent yet another class of agents that has been studied in TBI patients.94 While intuitively appealing, use of psychostimulants to improve cognitive outcomes in TBI patients should be done cautiously with perhaps the lone exception of amantadine until large, well-controlled studies demonstrating beneficial effects are available. Additionally, the timing of administration of these drugs is controversial; the potential for cardiovascular side effects in the face of uncertain benefit would suggest that these drugs should be reserved for the postacute phase of treatment (i.e., weeks to months postinjury).
EVALUATION OF THERAPEUTIC OUTCOMES
The process for evaluation of therapeutic outcomes is summarized in Table 42-4. Patients with severe TBI require ICU monitoring initially with the goals of maintaining or reestablishing neurologic and systemic homeostasis as well as readily detecting any neurologic deterioration. This requires frequent evaluation of the patient’s neurologic status (e.g., GCS) and measurement of vital signs, urine output, and arterial oxygen saturation (as well as ICP in patients with an ICP monitor in place). Furthermore, careful attention must be paid to the potential for development of a variety of electrolyte, mineral, and acid–base disturbances; coagulopathies; and infections by obtaining various laboratory tests on a daily basis initially. The intensity of monitoring will be a function of the relative degree of neurologic and hemodynamic stability of the patient in the hours and days following the neurologic insult. Lastly, radiologic tests (e.g., CT scans) are essential not only for the initial diagnostic evaluation of TBI patients but also as means to evaluate the etiology for any subsequent neurologic deterioration.
TABLE 42-4 Evaluation of Therapeutic Outcomes
PERSONALIZED PHARMACOTHERAPY
There are several opportunities for personalized pharmacotherapy in severe TBI patients. The most common general pharmacokinetic challenge is that TBI patients have a larger volume of distribution and more rapid hepatic clearance of drugs than most other patient populations.96 These pharmacokinetic changes often make the optimizing of phenytoin and, less commonly, pentobarbital concentrations very difficult. As such, recommendations for phenytoin and pentobarbital dosing are weight based, and in the case of phenytoin, usually higher than the 300 mg/day dose is commonly seen in ambulatory patients. Pharmacodynamically, there can be wide interpatient variability in the efficacy of pharmacologic and nonpharmacologic interventions for ICP control. For some patients, there is a high degree of trial and error to find the best combination of interventions that are effective and not contraindicated by other factors. Lastly, the decision to start pharmacologic deep venous thrombosis prophylaxis may also be highly personalized depending on CT findings, neurologic progress, ICP control, and the possible need for surgery
ABBREVIATIONS
ACKNOWLEDGMENTS
The authors would like to acknowledge Shelly D. Timmons, MD, PhD, FACS, for her contributions to previous editions of this chapter.
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