Acute Management of Brain Injury Patient PDF

Acute Management of the Brain Injury Patient Bradley A. Boucher and G. Christopher Wood KEY CONCEPTS 1 Cerebral ischemia is the key pathophysiologic event that triggers secondary neuronal injury following severe traumatic...

Acute Management of the Brain Injury Patient Bradley A. Boucher and G. Christopher Wood KEY CONCEPTS 1 Cerebral ischemia is the key pathophysiologic event that triggers secondary neuronal injury following severe traumatic Chapter 77 intracranial pressure (ICP). Cerebral perfusion pressure (CPP) is also a critical monitoring parameter and should be brain injury (TBI). Intracellular calcium accumulation is maintained between 60 and 70 mm Hg (8.0 and 9.3 kPa) postulated to be a central pathophysiologic process in (greater than 40 and 50 mm Hg [5.3 and 6.7 kPa] in pediatric amplifying and perpetuating secondary neuronal injury via patients) through the use of fluids, vasopressors, and/or ICP inhibition of cellular respiration and enzyme activation. normalization therapy. 2 Guidelines for the Management of Severe Brain Injury, 4th 6 Nonspecific pharmacologic management of intracranial edition, published by the Brain Trauma Foundation (BTF)/ hypertension should include analgesics, sedatives, and American Association of Neurological Surgeons (AANS), antipyretics; paralytics may be advantageous under serves as the foundation on which clinical decisions selected circumstances. in managing adult neurotrauma patients are based; Specific pharmacologic management of intracranial 7 comparable guidelines for infants, children, and adolescents hypertension includes mannitol, hypertonic saline, have also been published. furosemide, and high-dose pentobarbital. Neither routine 3 Correcting and preventing early hypotension (systolic blood use of corticosteroids nor aggressive hyperventilation (ie, pressure [SBP] less than 100-110 mm Hg depending on PaCO2 less than 25 mm Hg [3.3 kPa]) should be used in the age) with an SBP goal of 120 to 140 mm Hg and reversal of management of intracranial hypertension. hypoxemia are primary goals during the initial resuscitative Numerous investigational strategies targeted at limiting 8 and intensive care of patients with severe TBI. injury and/or stimulating axonal repair following severe 4 Nonpharmacologic management of intracranial hypertension TBI have been employed; however, no proven therapeutic includes raising the head of the bed 30°, and ventricular benefits have been identified. drainage if an extraventricular drain (EVD) is present. Use of phenytoin (alternatively levetiracetam) for the 9 5 The principal monitoring parameter for patients with severe prophylaxis of posttraumatic seizures generally should be TBI within the intensive care environment is increased discontinued after 7 days if no seizures are observed. BEYOND THE BOOK epidemiology and pathophysiology, and highlights the major guide- lines and systematic literature reviews pertaining to the severe TBI Watch the video entitled “Overview of Traumatic Brain Injury management. (TBI)” (https://www.youtube.com/watch?v=T0WBMM7WKL4) presented by Dr. Christopher Wolf and moderated by Brent EPIDEMIOLOGY Ghan at the University of Missouri School of the Health Professions. This 7.5-minute video provides a general Approximately 2.87 million persons sustain a TBI each year in the overview of human brain anatomy and physiology and a United States equating to one occurring nearly every 11 seconds.1 Among these individuals, over 288,000 require hospital admis- succinct introduction to the more detailed pathophysiology sion, and over 56,000 die annually.1 Importantly, an estimated outlined in the chapter and a context for understanding TBI 5.3 million Americans live with disabilities resulting from their pharmacologic and nonpharmacologic management. This TBI, highlighting the enormous physical and emotional toll of this includes TBI pathophysiology including cerebral contusions, healthcare problem.2 The economic effects of acute neurotrauma diffuse axonal injury, secondary brain injury, in addition to TBI are also enormous, with estimates of direct and indirect spending recovery. on patients requiring hospitalization reaching $76.5 billion in the United States in 2010.2 Economic costs to society from lost pro- ductivity are also massive, especially considering the young age of many patients with TBI.2 Falls are the leading cause of uninten- tional TBI (48%), while TBI-related hospitalizations and deaths INTRODUCTION vary based on age.1,2 For example, death rates from TBI after a fall TBI is one of the leading causes of death and disability in the United are highest in patients aged 65 years or older while motor vehi- States.1 A focus on TBI prevention, improved acute care, and reha- cle crashes are the leading cause of death in persons aged 15 to bilitation remain national priorities. This chapter summarizes TBI 34 years and adults over 75 years.1 921 CH77.indd 921 06-12-2022 14:20:50  922 PRIMARY AND SECONDARY BRAIN because of its normally high resting energy requirement and its lim- ited capacity to store oxygen, glucose, and adenosine triphosphate INJURY PATHOPHYSIOLOGY (ATP). These phenomena can result in imbalances in cerebral oxygen delivery (CDO2) and cerebral metabolic rate of oxygen consumption The neurologic sequelae of brain trauma can occur instantaneously (CMRO2), processes that are closely autoregulated under normal cir- as a consequence of the primary injury or can result from second- cumstances.5 Factors that can diminish cerebral oxygen supply fol- ary injuries that follow within minutes, hours, or days after the ini- lowing brain injury include cerebral edema, expanding mass lesions SECTION     Neurologic Disorders tial injury.3 Primary injury involves the external transfer of kinetic (eg, epidural, subdural, and intracerebral hematomas), cerebral energy to various structural components of the brain (eg, neurons, vasospasm, and loss of vasoregulatory control. Vasogenic cerebral nerve synapses, glial cells, axons, and cerebral blood vessels). The edema can develop as a consequence of cerebral capillary endothe- biomechanical forces responsible for primary brain injury can be lial damage and disruption of the blood–brain barrier.6 Cytotoxic classified broadly as contact (eg, blunt-object blow, penetrating-­ cerebral edema is a consequence of loss of cell wall integrity that missile injuries) and acceleration/deceleration (eg, instantaneous 8 brain movements following motor vehicle accidents).3 Contact accompanies ischemia or hypoxia with accumulation of lactic acid secondary to anaerobic metabolism.7 With cytotoxic and vasogenic forces to the head commonly result in skull fractures, brain contu- edema comes expansion of the intracellular and extracellular fluid sions, and/or hemorrhages. Primary brain injuries are categorized spaces, respectively. Increased intracranial pressure (ICP) is the further as focal (eg, contusions, hematomas) or diffuse,3,4 with the most detrimental consequence of cerebral edema formation, which latter usually being associated with shearing or stretch forces, which occurs as the brain tissue volume increases within the nondistensible primarily affect axons within the brain (ie, diffuse axonal injury).4 skull. A significant ICP increase may further compromise cerebral The type of primary injury (ie, focal vs diffuse) is a major factor as to blood flow (CBF) and extend cytotoxic edema. Hence, increased ICP which of the secondary injury mechanisms discussed below will pre- can be self-perpetuating unless reversed. Hypoxemia can further dominate following a TBI; however, many patients, especially those exacerbate local decreases in cerebral oxygen supply following acute involved in high-speed accidents, sustain both types of injury.3,4 respiratory failure and systemic hypotension. Metabolic demand 1 A complex sequence of pathophysiologic events precipi- also can increase following neurotrauma secondary to seizures, agi- tated by primary brain injury may seriously disrupt the normal tation, and temperature elevation. central nervous system (CNS) balance between oxygen supply and Two distinctive end points along the spectrum of second- demand resulting in a metabolic crisis.5,6 Hypotension during the ary neuronal injury are: (a) energy-independent cellular necrosis early posttraumatic period is a major contributor to this imbalance characterized by membrane cell lysis, edema, and inflammation, and a primary determinant of outcome. The end result of this imbal- and (b) energy-independent apoptosis leading to cell shrinkage ance is cerebral ischemia, the key pathophysiologic event trigger- and cell membrane dissolution.7 Apoptosis, which is also known as ing secondary injury.5 Figure 77-1 is a simplified schematic of the programmed cell death, requires a cascade of intracellular events processes that constitute secondary brain injury and their various for cell death completion with ionic homeostasis loss being postu- interrelationships. The brain is particularly susceptible to ischemia lated as a key event in fostering secondary brain injury following Severe brain injury Ischemia ↓ Aerobic metabolism Mitochondrial ↑ Presynaptic cellular Ca Ion pump failure CNS acidosis dysfunction ↑ Excitatory amines ↓ Cellular K, Mg Vasodilation ↑ Postsynaptic cellular Ca ↑ Cellular Na, Cl Cerebral edema Stimulation of phospholipase A2 5-Lipooxygenase Cyclooxygenase ↑ Arachidonic acid PGI2 Leukotrienes ↑ PGH2, PGG2 (Prostacyclin) PMN influx ↑ Free radicals Vasodilation ↑ Thromboxane A2 Lipid peroxidation Platelet aggregation, Cellular injury vasoconstriction FIGURE 77-1 Schematic illustration of the cascade of biochemical events proposed to occur following severe neurotrauma (secondary brain injury). (Ca, calcium; Cl, chloride; CNS, central nervous system; K, potassium; Mg, magnesium; Na, sodium; PMN, polymorphonucleocyte; PGH2, prostaglandin H2; PGG2, prostaglandin PGG2; PGI2, prostaglandin PGI2.) CH77.indd 922 06-12-2022 14:20:52  923 cerebral ischemia.7 In this process, cellular influx of sodium, chlo- of platelet aggregation, vasodilation, and vasoconstriction also ride, magnesium, and water occurs with a corresponding efflux may occur.5 of potassium secondary to cytotoxic edema and Na+-K+-ATPase The Glasgow Coma Scale (GCS) was designed nearly 50 years ago pump dysfunction. Calcium influx into the presynaptic terminal and is still the most widely used system to grade the arousal and func- ends of damaged neurons is mediated by N-type voltage-sensitive tional capacity of the cerebral cortex,3 as it defines the level of conscious- calcium channels and is postulated to stimulate excessive release ness according to eye opening, motor response, and verbal response CHAPTER        Acute Management of the Brain Injury Patient of the excitatory amines glutamate and aspartate from the affected (Table 77-1). A GCS score of 15 corresponds to a normal neurologic neurons. These amines then accumulate in the neuronal synaptic cleft in the presence of cellular energy failure, resulting in ongo- ing stimulation of postsynaptic cells, which extend neurotoxic- ity and cell death. The influx of calcium and additional sodium is stimulated by activation of ionophore receptors including the TABLE 77-1 Glasgow Coma Scale N-methyl-D-aspartate (NMDA) receptor.7 Calcium influx and its Response Score 77 intracellular accumulation initiate a number of events that amplify Eyes and perpetuate secondary neuronal injury as well as mitochondrial dysfunction, which further inhibits cellular respiration, a process Open spontaneously 4 To verbal command 3 already affected by ischemic and/or hypoxic insults.5,7 A second To pain 2 major deleterious effect of calcium is activation of autodestructive No response 1 enzymes, including phospholipases, endonucleases, and proteases, Best motor response such as the caspase family of enzymes.7 The effect of phospholi- To verbal command 6 pase A2 stimulation includes formation of several arachidonic acid Obeys metabolites derived from membrane lipids (eg, thromboxane A2, To painful stimulus (pressure to nailbeds) prostaglandins, and leukotrienes) that facilitate lipid peroxida- Localizes pain 5 tion and reactive oxygen species formation.5,7 This event occurs Flexion, withdrawal 4 early after injury (eg, before hospitalization), which may limit Flexion, abnormal (decorticate rigidity) 3 Extension (decerebrate rigidity) 2 the effectiveness of exogenously administered antioxidants. Cell- No response 1 mediated injury involving inflammatory mediators (eg, proinflam- Best verbal response matory cytokines) and nitric oxide activation is another possible (Arouse patient with painful stimulus if necessary) mechanism involved in secondary neuronal injury,6,7 implicating Oriented and converses 5 polymorphonuclear neutrophils, platelets, endothelial cells, and Disoriented and converses 4 macrophages. However, activation of some inflammatory media- Inappropriate words 3 Incomprehensible sounds 2 tors may actually be beneficial, such that the relative balance of No response 1 the mediators rather than absolute concentrations may be the most Total 3-15 significant pathophysiologic factor following TBI. Stimulation CLINICAL PRESENTATION ACUTE BRAIN INJURY General Laboratory Tests Level of consciousness on admission ranges from Arterial blood gases (ABGs) indicating hypoxia (ie, completely unresponsive to awake and alert (ie, decreased PaO2) or hypercapnia (ie, increased PaCO2) Glasgow Coma Scale 3-15 [Table 77-1]). may indicate compromised ventilation. Blood ethanol concentration and/or urine toxicology Symptoms results indicates that substance intoxication may be Posttraumatic amnesia (eg, greater than 1 hour), affecting the patient’s mental status in addition to increasing dizziness, a moderate-to-severe headache, the TBI. nausea/vomiting, limb weakness, or paresthesia may Electrolyte disturbances can cause alterations in indicate more severe injury. mental status, and their effects may interfere with assessment of the patient’s neurological status. Signs Cerebrospinal fluid (CSF) otorrhea or rhinorrhea, Other Diagnostic Tests seizures, or unequal or unreactive pupils may indicate CT scan of the head is an important diagnostic more severe injury. tool for detecting the presence of mass lesions A rapid deterioration in mental status strongly and structural signs of edema (eg, midline shift, suggests the presence of an expanding lesion within compressed ventricles). the skull. Severe TBI may be accompanied by significant alterations or instability in vital signs, including abnormal breathing patterns (eg, apnea, Cheyne– Stokes respiration, tachypnea), hypertension, or bradycardia. CH77.indd 923 06-12-2022 14:20:52  924 examination based on eye, motor, and verbal responses. Scores from TABLE 77-2 Pharmacologic Management of TBI 3 to 8 correspond to severe brain injury, while scores from 9 to 12 and Hyperosmolar therapy 13 to 15 is consistent with moderate, and mild or minor brain injury, Mannitol effectiveness in lowering ICP is uncertain (no recommendation respectively.3 Always consider the impact of ethanol or substance intoxi- level due to insufficient evidence). cation, hypotension, hypoxia, postictal state, hypoglycemia, electrolyte Hypertonic saline effectiveness in lowering ICP is uncertain (no imbalances, or hypothermia on altering the neurologic examination recommendation level due to insufficient evidence). Deep venous thrombosis prophylaxis when administering this scale. Opiates, sedatives, and neuromuscular SECTION     Neurologic Disorders LMWH or low-dose unfractionated heparin may be used in combination blockers should not be administered until the initial examination is with mechanical prophylaxis. However, there is an increased risk of complete, if at all possible, as they affect the neurologic examination. expansion of intracranial hemorrhage (Recommendation level III). Simple, rapidly attainable clinical variables that are predictive of poor Anesthetics, analgesics, and sedatives outcomes include extremes of age, presence of hypotension, hypoxia Prophylactic administration of barbiturates to reduce burst suppression ECG is not recommended (Recommendation level II B). and/or coagulopathy, increased ICP, decreased GCS score (especially High-dose barbiturate administration is recommended to control 8 the motor score), and pupillary changes.8 elevated ICP refractory to maximum standard medical and surgical treatment in adults. Hemodynamic stability is essential before and after barbiturate therapy (Recommendation level II B). TREATMENT Propofol is recommended for the control of ICP, but not for improvement in mortality or 6-month outcomes. High-dose propofol can produce significant morbidity (Recommendation level II B). Desired Outcomes Antiseizure prophylaxis Prophylactic use of phenytoin or valproate is not recommended for The overall goal in TBI management is reduction in morbidity and preventing late PTS (occurring later than 7 days) (Recommendation mortality, and optimization of long-term functional outcome for level II A). Phenytoin is recommended to decrease the incidence of early PTS (within patients. This requires careful attention to the following short-term 7 days of injury) (Recommendation level II A). therapeutic goals: (a) establishment of an adequate airway and main- Levetiracetam cannot be recommended over phenytoin regarding tenance of ventilation and circulation during the initial period of efficacy in preventing early PTS and toxicity. (No recommendation resuscitation and evaluation, (b) maintenance of balance between based on insufficient evidence.) CDO2 and CMRO2, (c) prevention or attenuation of secondary Corticosteroids The use of steroids is not recommended for improving outcome or neuronal injury, and (d) prevention and/or treatment of associated reducing ICP in patients with TBI. In patients with moderate or severe medical complications. TBI, high-dose methylprednisolone is associated with increased mortality and is contraindicated (Recommendation level I). General Approach to Treatment ECG, electrocardiogram; LMWH, low-molecular-weight heparin; PTS, posttraumatic 2 The Brain Trauma Foundation (BTF) has developed an exten- seizures; TBI, traumatic brain injury. Level I: Recommendation based on a high- quality body of evidence. Level II A: Recommendation based on a moderate-level sive document entitled Guidelines for the Management of Severe quality of evidence. Level II B: Recommendation based on a low-quality body of Brain Injury as a joint initiative with the Guidelines Committee of evidence (direct evidence but overall low quality). Level III: Recommendation based the American Association of Neurological Surgeons (AANS), the on a low-quality body of evidence. Joint Section on Neurotrauma and Critical Care of the AANS, and Data from Reference 9. the Congress of Neurological Surgeons.9 This document presently constitutes the most widely accepted evidence-based standards, guidelines, and options for the care of patients with severe TBI in the an admission SBP outside this range is associated with increased United States.10 Recommendations are reported as Level I (high qual- mortality.15 More specifically correcting and preventing early hypo- ity of evidence), Level II (moderate quality of evidence), or Level III tension (goal SBP >100 mm Hg for patients ages 50 to 69 years or (low quality of evidence). Data show that compliance with the BTF/ >110 mm Hg for patients ages 15 to 49 or over 70 years) is critical AANS guidelines results in improved patient outcomes relative to as it is among the most powerful predictors of outcome.9 Isotonic mortality, functional outcome scores, length of hospitalization, and saline (0.9% normal saline) and lactated Ringer’s solution have been cost. Additionally, guidelines addressing prehospital TBI manage- traditionally used as initial resuscitation fluids of choice in patients ment11 and surgical management12 have also been published, as have with TBI. While some clinicians believe that hypertonic saline TBI management guidelines for infants, children, and adolescents.13 (eg, 3% or 7.5% saline) is beneficial in this situation, clinical stud- The recommendations emanating from the published BTF/AANS ies yield equivocal results relative to their superiority over isotonic guidelines on TBI management and various published systematic solutions.16 Regardless, no clear consensus exists as to the optimal reviews will be highlighted throughout the remaining portion of this initial resuscitation fluid. Furthermore, the volume of crystalloids chapter. Recommendations from the BTF/AANS guidelines should administered requires careful monitoring considering there are data serve as the foundation on which all clinical decisions in manag- associating lower volumes with improved survival.17 While colloids ing severe TBI are based. Nonetheless, it should be noted that the may be considered an alternative to crystolloid therapy, strong rec- majority of the guidelines are based on Class II evidence (primar- ommendation against their use was made within a consensus state- ily prospective clinical trials) and Class III evidence (primarily ment regarding fluid therapy in neurointensive care patients.18 retrospective clinical trials) as few Class I evidence studies (ie, pro- Vasopressors and inotropic agents may be needed to maintain an spective, randomized, controlled trials) are available for treatment adequate mean arterial pressure (MAP) if hypotension persists after of TBI. The pharmacologic management of TBI is summarized in adequate restoration of intravascular volume. Nonpharmacologic Table 77-2. Recommendations provided in this chapter pertain to management of intracranial hypertension includes raising the head adults and children unless specifically noted to the contrary. of the bed 30°, and ventricular drainage if an extraventricular drain (EVD) is present. Figure 77-2 is an algorithm summarizing treat- Pharmacologic Therapy ment priorities in the initial management of acute TBI. Initial Resuscitation 3 4 The first priority in the unconscious patient is airway estab- Postresuscitative Care lishment that facilitates adequate oxygenation and prevents aspi- Following successful resuscitation, priorities shift toward diagnos- ration.14 Thereafter, restoration and maintenance of systolic blood tic evaluation of intracranial and extracranial injuries, and emer- pressure (SBP) between 120 and 140 mm Hg is desired since having gent surgical intervention as needed. In many patients, evacuation CH77.indd 924 06-12-2022 14:20:54  925 1 Severe brain injury patient (GCS 2.9 kPa)? Go to ICP algorithm (Fig. 58–3) No Go to 11 FIGURE 77-2 Algorithm for the acute management of the patient with a TBI. (BP, blood pressure; CBC, complete blood count; CPP, cerebral perfusion pressure; CT, computed tomography; EtOH Cp, ethanol plasma concentration; Hct, hematocrit; ICU, intensive care unit; NS, normal saline; OR, operating room; PaCO2, partial pressure of arterial blood carbon dioxide; PRBC, packed red blood cells.) (Reprinted, with permission, from Management of Acute Traumatic Brain. 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.) CH77.indd 925 06-12-2022 14:20:54  926 fluid therapy with a goal of euvolemia, and starting early enteral nutrition SECTION     Neurologic Disorders Plan* Unless contraindicated, initiate appropriate supportive care measures for the issues outlined above in the Assess section (Fig. 77-2) Nonpharmacologic management of increased ICP with 8 first-line options (eg, raise head of the bed 30°, open extraventricular drain if ICP is greater than 22 mm Hg [2.9 kPa, if present]) (Fig. 77-2) Pharmacologic management of increased ICP with first- line agents (eg, short-acting sedation and analgesia, and hyperosmolar agents [hypertonic saline, mannitol]) (Fig. 77-3 and Table 77-2) Avoid low CPP with IV fluid therapy, possible administration of blood products, or vasopressors (eg, norepinephrine, phenylephrine, dopamine) if SBP is less than 100 mm Hg Patient Care Process for Acute Management Treat hyperthermia, if present, using antipyretic agents and/ or cooling blankets of the Brain Injury Patient If ICP is uncontrolled after optimizing first-line options for ICP control, move to second-line options (eg, pentobarbital, The image shows the five fundamental steps included in neuromuscular blocking agents, hyperventilation) The Pharmacist’s Care Process endorsed by the Joint (Table 77-3) Commission for Pharmacy Practitioners (2014). The tagline of this process reads collaborate, communicate, and document. The five fundamental steps listed here are collect, assess, plan, Implement* implement, and follow-up: monitor and evaluate. All these Work with the medical team on mutually agreeable and steps are listed in a circular block diagram. patient-centered implementation of treatments where some differences in opinion and practice may exist (eg, Collect initial choice of sedatives, antiseizure medications, or hyperosmolar agents) GCS (Table 77-1), vital signs, physical exam and head Work with the medical team and nursing staff to implement computed tomography (CT) scan findings, ABGs, ICP and an understanding of treatment goals (ie, ICP and CPP), as CPP (if available), laboratory data (see “Clinical Presentation” well as clear priorities in treatment selection and escalation section) among the many options for treating elevated ICP Prior and current medications, including alcohol and illicit substances Follow-up: Monitor and Evaluate Monitor ICP and CPP, especially response to therapies for Assess elevated ICP to determine which modalities work best in Consistency between with the GCS/physical exam and each patient (Fig. 77-3) injuries on head CT scan (ie, could there be other reasons for Other routine monitoring includes GCS, fluid/electrolyte the neurologic deficit such as intoxication) status, ABGs, and vital signs (Table 77-4) ICP (goal less than 22 mm Hg [2.9 kPa]) and CPP (goal 60-70 Medication-specific monitoring includes issues such as: mm Hg [8.0-9.3 kPa]) (Fig. 77-2) hypotension from sedatives/opiates, hypertriglyceridemia or Need for general ICU supportive care including: mechanical PRIS from propofol, risk of bleeding/worsening intracranial ventilation/appropriate oxygenation, stress ulcer hemorrhage from VTE prophylaxis agents, antiseizure prophylaxis, and sedation/analgesia medication adverse events such as rash, acute kidney injury For VTE prophylaxis, it is important to determine if from mannitol, or hypernatremia/hyperchloremia from pharmacologic prophylaxis is contraindicated due to hypertonic saline (Table 77-3) intracranial bleeding Discontinue seizure prophylaxis after 7 days if no seizures Need for other supportive care measures more specific to occur in the hospital (Table 77-2) TBI including: spine immobilization, seizure prophylaxis, avoiding fever and excessive hyperglycemia, appropriate Collaborate with patient, caregivers, and other healthcare professionals. * of intracranial hematomas (ie, epidural, subdural, and intracere- Decompressive craniectomies (ie, removal of a variable amount bral hematomas) is essential to control ICP and improve outcome. of skull bone) with or without temporal or frontal lobectomy may Elevation of depressed skull fractures and debridement of penetrat- be considered in patients with increases in ICP refractory to more ing wound tracts are other important emergent surgical procedures. conservative measures.5 In the largest randomized study to date, CH77.indd 926 06-12-2022 14:20:55  927 patients with TBI and refractory elevated ICPs undergoing decom- monitoring is employed. After euvolemia is achieved, the patient’s pressive craniectomy had significantly improved survival but higher head should also be elevated by 30° to promote venous drainage rates of vegetative state and disability compared with medical ther- and decrease ICP.9 If intravascular volume restoration is inadequate apy.19 Thus, decompressive surgery’s role in adult patients with TBI in elevating MAP to an acceptable level, hypertension should be and refractory ICP remains controversial in light of these quality of induced using vasopressors (eg, norepinephrine, phenylephrine, life data outcomes. dopamine)9 and patients should be monitored for renal dysfunction, CHAPTER        Acute Management of the Brain Injury Patient Continuous ICP monitoring (eg, EVD and/or intraparenchy- lactic acidosis, and signs of peripheral ischemia when they are used, mal fiberoptic catheter) has been the mainstay of ICP monitoring and especially in large doses. treatment for decades in patients with severe TBI. Extraventricular drains have a therapeutic advantage over the alternatives but are Anesthetics, Analgesics, and Sedatives associated with higher complication rates and can be difficult to 6 Analgesics and sedatives have an important primary role in the place in the setting of the swollen brain. Specifically, while CSF can management of intracranial hypertension (Fig. 77-3 and Table 77-3) be drained using this device as a means to lower ICP, the most recent that are directly related to the association of pain, agitation, excessive 77 BTF/AANS guidelines have softened the indications for ICP moni- muscle movement, and resisting mechanical ventilation with tran- toring based on data suggesting that invasive monitoring may lack sient increases in ICP. Paralytics are a secondary option in refrac- superiority over clinical/radiologic monitoring; challenging the tra- tory patients or during stimulatory procedures in patients with ditional paradigm.9,20 If continuous ICP monitoring is employed, the elevated ICP.28 There is no strong evidence that one agent is superior goal should be to treat any ICP values above 22 mm Hg (2.9 kPa) to another in affecting patient outcomes with severe TBI29 as their since values above this level are associated with increased mortality.9 effects on ICP, CPP, and MAP are variable.29 Morphine sulfate is the Yet another approach to ICP monitoring or no ICP monitoring most commonly used analgesic and sedative in this setting9,29 and is multimodality neuromonitoring (MMM).21 This practice involves bolus doses of opiates may increase ICP by increasing CBF.29 While using advanced technologies such as cerebral microdialysis, CBF, continuous infusions of fentanyl and sufentanil are gaining in popu- brain tissue oxygenation, electroencephalography (EEG), near-infra- larity, their use also may be associated with mild elevations in ICP.9,29 red spectroscopy, pressure reactivity, and/or transcranial doppler Propofol has become the sedative of choice in the treatment of (TCD) monitoring in combination. Although this practice assesses a patients with TBI among many clinicians because of its ease of titra- wide array of cerebral metabolic, oxygen, and cerebrovascular mea- tion, rapidly reversible effects on discontinuation, and possible neu- surements, MMM use is limited to institutions that are equipped to roprotective effects.9 Although it is used for sedation in infants and perform such measurements and have individuals capable of utiliz- children who are mechanically ventilated in the intensive care unit ing these data to guide expeditious therapy.22 Furthermore, each of (ICU) setting, the Food and Drug Administration (FDA) requires the MMM techniques either alone or in combination with conven- that the manufacturer labeling contains specific information that tional ICP monitoring has limitations and/or potential risks. As such, it is not approved for sedation of pediatric patients admitted to BTF/AANS guidelines only recommend considering jugular venous an ICU. Propofol’s biggest safety concerns is the propofol infusion oxygen saturation monitoring as a potential advanced monitoring syndrome (PRIS) characterized by hyperkalemia, hepatomegaly, modality to improve outcome in patients with TBI.9 Biochemical lipemia, metabolic acidosis, myocardial failure, rhabdomyolysis, markers (eg, S-100 calcium-binding protein B, neuron-specific eno- renal failure, and death in some cases.30 While initially reported lase, glial fibrillary acid protein, serum substance P23) may also have in children, PRIS can also occur in adults; therefore, doses greater utility in diagnosing and monitoring patients with TBI. However, than 5 mg/kg/hr and infusions exceeding 48 hours should be used their role has yet to be defined as each have assorted limitations.24 with extreme caution.30 Triglyceride concentrations also should be 5 Another important monitoring parameter within the inten- monitored in patients receiving prolonged propofol infusions and/ sive care environment is the cerebral perfusion pressure (CPP), or high dosages considering its lipid emulsion formulation and the which is the difference between MAP and ICP (ie, CPP = MAP – potential for inducing hypertriglyceridemia under these conditions. ICP). Maintenance of an acceptable CPP is postulated to be critical Furthermore, evidence of neurotoxicity from animal studies has in reducing cerebral ischemia and secondary injury. The BTF/AANS raised concerns regarding use of this sedative in patients with TBI.30 guidelines recommend maintaining a CPP range between 60 and Alternative sedatives include short-acting benzodiazepines (eg, 70 mm Hg (8.0 and 9.3 kPa).9 It is also recommended that aggressive midazolam), especially if there is a reasonable suspicion of alcohol attempts to maintain CPP greater than 70 mm Hg (9.3 kPa) in adults withdrawal as the underlying etiology of the agitation,31 and inter- should be avoided due to the risk of the acute respiratory distress mittent low-dose pentobarbital, ketamine,32 dexmedetomidine,33,34 syndrome. In children, the recommended CPP goal is between 40 or etomidate (particularly useful in rapid-induction anesthesia). and 50 mm Hg (5.3 and 6.7 kPa). While using a fixed target range The potential for these agents to decrease MAP and CPP must be is the most common approach for monitoring CPP, the concept of monitored closely.29,30,33 Additionally, the cumulative sedative effects individualizing the CPP target range to restore cerebral vasoreactiv- of longer-acting medications, especially benzodiazepines, must be ity has been advocated.23,25 taken into account. The use of any sedative or paralytic agent also In order to achieve the goal CPP, the MAP may need to be must be weighed against its potential to obscure the neurologic increased either through the use of fluids and/or vasopressors, and/ examination of the patient. or by lowering elevated ICP. In general the goal of volume expansion 7 High-dose barbiturate therapy (ie, barbiturate coma) has should be euvolemia to avoid a hypoosmolar state and negative fluid been used for decades in the management of increased ICP despite balance.26 If the hemoglobin is below 7 g/dL (70 g/L; 4.34 mmol/L), a lack of evidence documenting beneficial effects on patient mor- transfusion of packed red blood cells (PRBCs) is indicated. Liberal bidity and mortality.34 Nonetheless, BTF/AANS and pediatric guide- transfusions should be avoided since using a target goal of 10 g/ lines recommend that high-dose barbiturate therapy be considered dL (100 g/L; 6.21 mmol/L) is associated with a higher incidence in hemodynamically stable patients with severe TBI refractory to of thromboembolic events without neurologic outcome improve- maximal medical ICP-lowering therapy and decompressive sur- ment based on a randomized trial.27 More data are needed before gery.9,13 Prophylactic use of barbiturates is not advocated in light these findings can be applied to all patients with TBI. Furthermore, of insufficient evidence supporting this practice and the potential erythropoietin use was not associated with an improved neurologic for adverse events (eg, hypotension).9,13,34 The mechanism respon- outcome in the same trial.27 Volume status should be targeted to a sible for the cerebral protective effects of barbiturates is generally central venous pressure of 7 to 12 cm H2O (0.7-1.2 kPa) if invasive attributed to suppression of cerebral metabolism, thereby cerebral CH77.indd 927 06-12-2022 14:20:55  928 Patient with ICP >22 mm Hga (>2.9 kPa) SECTION     Neurologic Disorders 1 Administerb mannitol (0.25 g/kg IV every 2-4 hours) or hypertonic saline Open ventriculostomy (if present) for ICP >22 mm Hg (>2.9 kPa) Consider sedation with propofol (alternative: midazolam) ± short acting opiate 8 2 Yes 3 Go to 4 after return to Surgery indicated? Transport to OR ICU No 4 Yes 5 Is ICP >22 mm Hg Administer sedation as in box 1 (>2.9 kPa)a (especially if agitated) No 6 Optimize first line therapies: Continuous ICP and vital signs monitoring 7 Yes If ICP continues >22 mm Hg Monitor neurologic status Is ICP >22 mm Hg (>2.9 kPa) go to 8 If T >37.5°C (99.5°F), administer acetaminophen, (>2.9 kPa)a If ICP 2.9 kPa) Go to 1 Pentobarbital 25 mg/kg IV, then 1 mg/kg/hr, Cp in 24 hours. over last 24 hoursb Obtain EEG. Consider short-term hyperventilation to No PaCO 2 30–35 mm Hg (4.0–4.7 kPa). Consider short acting neuromuscular blocker if sedation is maximized. 16 Consider furosemide if not hypovolemic Remove ICP monitor Supportive care 9 10 11 12 Yes Yes Yes Is ICP >22 mm Hga Is pentobarbital Is ICP >22 mm Hg Reevaluate all (>2.9 kPa) Cp >30 mg/L (>133 µmol/L)? (>2.9 kPa)?a medical and surgical options No No No 13 14 Go to 15 Wean pentobarbital Partial pentobarbital over 24 hours loading dose based on Cpc Increase pentobarbital 1 mg/kg/hr (max dose 3 mg/kg/hr) Go to 6 Go to 9 FIGURE 77-3 Algorithm for the management of increased ICP. (Cp, plasma concentration; EEG, electroencephalogram; ICU, intensive care unit; OR, operating room; PaCO2, partial pressure of arterial blood carbon dioxide.) (Reprinted, with permission, from Management of acute trauma. 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.) metabolic demands and CBV.34 Prior to inducing a barbiturate coma, and CPP at the previously discussed target thresholds, as well as EEG the patient with severe TBI must be mechanically ventilated with burst suppression.9,34 Although there is a poor correlation between continuous monitoring of arterial blood pressure, electrocardio- serum pentobarbital serum concentrations and outcomes, the goal is gram (ECG), and ICP. Pentobarbital is the most commonly used to achieve steady-state concentrations between 30 and 40 mg/L (133 barbiturate for this indication, although thiopental also has been and 178 µmol/L).34 Initiation of barbiturate therapy withdrawal can used. Pentobarbital should be administered as an IV loading infu- occur when ICP has been controlled satisfactorily for 24 to 48 hours sion totaling 25 mg/kg (ie, 10 mg/kg over 30 minutes and then 5 and should be tapered over 24 to 72 hours to prevent ICP spikes. mg/kg/hr for 3 hours), followed by a maintenance infusion of 1 to Adverse events associated with high-dose barbiturate therapy 2 mg/kg/hr.9,34 If the SBP falls during the loading or maintenance involve primarily the cardiovascular system. Hypotension caused infusions, the rate should be slowed temporarily and blood pressure by peripheral vasodilation may occur in one of every four patients, support initiated. The goal of a barbiturate coma is to maintain ICP necessitating decreasing the barbiturate dose or the administration of CH77.indd 928 06-12-2022 14:20:56  929 TABLE 77-3 Medication Dosing and Monitoring in Patients with TBI Medication (Brand Name) Adverse Medication Reactions Monitoring Parameters Dosage Comments Levetiracetam (Keppra) CNS changes Seizures, SCr 500-1,000 mg IV Q12 Caution in patients with renal hr (during first 14 dysfunction days) If used for active seizures: increase to 1,000 mg every 12 hours after CHAPTER        Acute Management of the Brain Injury Patient 14 days, then to 1,500 mg every 12 hours after 28 days Mannitol (Generic) Hypotension, renal ICP, CPP, BP, serum 0.25-1 g/kg IV every Avoid in patients with renal failure dysfunction, hyperosmolality osmolality, Na, UO, SCr 2-4 hours or CHF Pentobarbital (Nembutal) Hypotension, GI hypomotility, ICP, CPP, BP, EEG, GI 10 mg/kg IV over 30 Administer via central line. General induction of hepatic function minutes, then 5 dose range for infusion is medication metabolism mg/kg over 1-3 mg/kg/hr 3 hours, then 77 1 mg/kg/hr Phenytoin (Dilantin) Hypotension, dysrhythmias, Seizures, BP, ECG, 15-20 mg/kg IV over Administer 6 mg/kg/ day) to achieve therapeutic concentrations Propofol (Diprivan) Hypotension, hyperkalemia, ICP, CPP, BP, SCr, K, arterial General range: 0.5-3 Avoid doses greater than 5 mg/kg/hr metabolic, acidosis, pH, triglycerides, lactate mg/kg/hr titrated or prolonged infusions; not rhabdomyolysis, renal to desired effect approved for use in children failure, hepatomegaly, lipemia BP, blood pressure; CHF, congestive heart failure; GI, gastrointestinal; K, potassium; Na, sodium; SCr, serum creatinine; UO, urine output. fluids and vasopressors to maintain blood pressure.34 Gastrointestinal Hypothermia (GI) effects of barbiturates include decreased GI muscular tone and Therapeutic hypothermia has been an attractive strategy for attempt- decreased amplitude of contraction; however, on emergence from ing to minimize secondary brain injury after TBI for decades. The coma, there may be a period of GI hypermotility. Care should be mechanism underlying its protective effect is likely multifactorial, taken to avoid extravasation of barbiturate solutions because severe although a reduction in CMRO2 is most frequently cited as the basis of tissue damage may occur. Therefore, barbiturates should be admin- any therapeutic benefits. Although early studies suggested its benefit istered by continuous infusion through a central line dedicated for for patients with TBI, as well as other patient populations with this purpose. The potential for barbiturates to induce the hepatic brain ischemia (eg, cardiac arrest patients), large clinical trials data medication metabolism of concurrent medications should be also of prophylactic hypothermia have not demonstrated improved out- considered. Lastly, the potential for prolonged interference with the comes, but rather may in fact indicate poorer outcomes.9,36-39 Its neurologic examination of patients with TBI must be considered potential adverse effects include coagulation disturbances, infectious prior to the initiation of high-dose barbiturate therapy. complications, and cardiac arrhythmias. Thus, prophylactic thera- peutic hypothermia is not recommended as a routine neuroprotec- Corticosteroids tive strategy,9 except for perhaps patients with TBI with refractory 7 Although corticosteroids are effective in preventing or reducing ICP elevations. However, its use in this case is also unclear at best.40 cerebral edema in patients with nontraumatic conditions that pro- duce vasogenic edema, studies in patients with TBI have not demon- strated their ability to lower ICP or improve outcomes.9,13 Specifically, Osmotic Agents corticosteroid use following TBI has been associated with increased 7 Although a number of osmotic diuretics (eg, urea, glycerol) can mortality and complications including GI bleeding, glucose intol- be used to decrease ICP, mannitol is the most widely employed.9,41 erance, electrolyte abnormalities, and infection. The largest inves- Despite the common practice of administering mannitol to patients tigation to date, known as the Corticosteroid Randomization After with suspected or actual increases in ICP following brain injury, Significant Head Injury (CRASH) study, indicated a higher risk clinical trials comparing its effects against placebo have not been of death within 2 weeks of enrollment (relative risk 1.18) in those performed.42 Based on this lack of evidence, the BTF/AANS guide- receiving corticosteroids compared with those receiving placebo.35 lines removed the previous recommendation regarding mannitol’s Based on this and several other major randomized trials, the BTF/ effectiveness for control of increased ICP.9 AANS adult and pediatric guidelines recommend not to use high- Mannitol’s beneficial effects likely relate to (a) an immedi- dose corticosteroids in patients with moderate-to-severe TBI.9,13 ate plasma-expanding effect that reduces blood viscosity and increases CBF, and (b) establishment of an osmotic concentration Hyperventilation gradient across an intact blood–brain barrier that decreases ICP as 7 The practice of prolonged aggressive hyperventilation (PaCO2 water diffuses from the brain into the intravascular compartment.9 less than 25 mm Hg [3.3 kPa]) to decrease ICP is no longer recom- Recommended doses typically range from 0.25 to 1 g/kg IV every mended8 as this practice is not associated with improved outcomes. 2 to 4 hours with higher doses being used in emergency situations As such, BTF/AANS has removed this intervention as a temporizing and the lower dose for a maintenance regimen.43 Increased ICP is measure in managing patients with TBI with elevated ICP from their reduced within minutes following mannitol administration with guidelines.9 a maximum effect within 20 to 60 minutes.43 To maximize benefit CH77.indd 929 06-12-2022 14:20:56  930 and minimize adverse events, it has been suggested that mannitol β-blockers.53 While two meta-analysis of β-blockers use in patients be administered as a bolus and not as a continuous infusion in this with TBI demonstrated mortality benefits,54,55 their usage was asso- setting. ciated with increased infection rates, ICU length of stay, and overall Several adverse effects are associated with mannitol.43 In hospitalization days.55 Thus, evaluation of the benefit to risk ratio for addition to hypotension resulting from its diuretic effect, a revers- this medication class will require additional prospective, random- ible acute renal dysfunction may occur in patients with previously ized, clinical trials in patients with TBI. Miscellaneous agents and normal renal function after long-term, large-dose administration. therapies being considered as viable neuroprotective agents based on SECTION     Neurologic Disorders Patients particularly susceptible are those with advanced age and clinical and/or experimental TBI studies include growth hormone, preexisting renal dysfunction which is based on data in patients with cyclosporine, nitric oxide synthase inhibitor, minocycline, hyper- intracranial hemorrhage.44 As such, mannitol should be avoided in baric oxygen, and CNS bone marrow stromal cell transplantation.53 patients with acute kidney injury or chronic kidney diseases. Acute Others have proposed that stimulation of axonal repair processes exacerbation of underlying congestive heart failure and pulmonary versus limiting injury may be the most fruitful neuroprotective path- 8 edema also may occur following rapid intravascular volume expan- way for future investigations.47 sion and furosemide is recommended as an alternative diuretic for The concept of administering commercially available CNS- lowering ICP in these latter patient groups. active agents for nonapproved indications in patients with TBI While hypertonic saline solutions have been advocated by should presently be considered investigational. Examples include some as a resuscitative fluid following TBI, solutions ranging from the use of CNS stimulants in the management and rehabilitation concentrations of 3% to 20% have also been used to acutely lower of patients with TBI as data supporting this approach are equivo- increased ICP.43 Doses range from approximately 150 mL of 3% cal.47 Another example is the use of Parkinson’s disease medications saline solution to 75 mL of 7.5% saline solution to 30 mL of 23.4% (eg, amantadine, bromocriptine, carbidopa/levodopa) in patients saline solution boluses.43 Saline concentrations greater than 3% with severe TBI in an attempt to enhance dopamine release and should be administered via a central venous catheter.43 Not only do inhibit reuptake within the injured region of the brain.56 While intui- hypertonic saline solutions create an osmotic gradient in favor of tively appealing, use of psychoactive agents to improve CNS sequa- reducing cerebral edema, but they may also have beneficial vasoreg- lae should be administered cautiously since large, well-controlled ulatory, immunologic, and neurochemical effects as well.45 Plasma studies with a wide array of agents are lacking. Additionally, the tim- expansion may also lead to an increase in CBF. However, the 2016 ing for administration of these medications is controversial and the BTF guidelines do not recommend hypertonic saline due to a lack potential for cardiovascular adverse effects in the face of uncertain of supporting evidence9 consistent with a systematic review which benefit would suggest that these medications should be reserved for found no mortality benefit or beneficial effect on ICP compared the postacute phase of treatment (ie, weeks to months postinjury). with other ICP-lowering agents.45 In most of these studies, the goal Acknowledging the complexities surrounding acute TBI, a of therapy was to treat an elevated ICP; however, for some the goal broad-based, multidisciplinary approach is undoubtedly needed was to increase the serum sodium regardless of ICP. If used in this before breakthrough therapies are identified for this multifaceted, way, hypertonic saline should target serum sodium concentration catastrophic condition. Examples of these types of initiatives include less than 160 mEq/L (mmol/L) since additional benefit is unlikely at the International Mission on Prognosis and Clinical Trial Design higher concentrations.43 (IMPACT) study group,58 and the BRAIN Initiative—Brain Research Through Advancing Neurotechnologies, which is a Presidential and Investigational Therapy National Institutes of Health focused program aimed at revolution- 8 The steady decrease in morbidity and mortality following severe izing understanding of the human brain launched in 2014.59 neurotrauma over the past several decades can be attributed largely to the use of conventional treatment strategies to expeditiously and Treatment and Prophylaxis aggressively manage events resulting in secondary injury (ie, isch- of Complications emia, hypoxia, increased ICP). Numerous neuroprotective agents In addition to specific management of TBI problems such as intra- targeting specific pathophysiologic processes that are theorized to cranial hypertension, the potential for secondary complications occur following severe TBI have been investigated over the past must also be considered as a wide variety of complications occur three decades in an attempt to further enhance the prospects for a in more than 20% of patients with TBI and are associated with meaningful recovery. Prominent among these strategies have been increased mortality and length of stay.60 Development and imple- attempts to modulate calcium influx through the administration of mentation of clinical pathways for consistency of care, and clinical calcium antagonists,46 glutamate antagonists including magnesium, investigation of neuroprotective agents are important in advancing and the use of antioxidants/free radical scavengers.47,48 Inhibitors TBI treatment in the future. of inflammatory mediators have also been considered as potential neuroprotective agents.48 Unfortunately, none of these agents to date has demonstrated a significant reduction in morbidity or mortality Posttraumatic Seizures following severe TBI in clinical trials. There was immense enthu- 9 It is generally agreed that adult patients who experience one or siasm for progesterone as a neuroprotective agent based on two more seizures following a moderate-to-severe TBI should receive moderately sized clinical studies that demonstrated improved out- antiseizure medication therapy to avoid increases in CMRO2 that come following acute TBI.49 However, two subsequent large ran- occur with the onset of subsequent seizures and to prevent the devel- domized, placebo controlled, prospective trials of progesterone in opment of (sometimes subclinical) status epilepticus associated with patients with acute TBI were halted early due to lack of functional increased mortality.9 Initial therapy should consist of incremental outcomes improvement.50,51 In contrast, interest continues to exist IV doses of diazepam (5-40 mg adults, 0.1-0.5 mg/kg infants and for the pleiotropic cytokine, erythropoietin, as a neuroprotective children) or lorazepam (2-8 mg adults, 0.03-0.1 mg/kg infants and agent independent of its ability to increase hemoglobin concentra- children) to terminate any active seizure activity, followed by IV tions47 despite data indicating equivocal results relative to improve- phenytoin to prevent seizure recurrence. Phenytoin dosing regi- ment in neurologic outcomes and survival benefits.52 Other agents mens for adults and pediatric patients include an IV loading dose that may have beneficial effects in TBI based on limited clinical or of 15 to 20 mg/kg and 10 to 15 mg/kg, respectively, followed by a epidemiologic data include 3-Hydroxy-3-methylglutaryl-coenzyme maintenance dose of 5 mg/kg/day divided into two or three daily A (HMG-CoA) reductase inhibitors and sympatholytics such as doses. Alternatively, fosphenytoin, a water-soluble phosphate ester CH77.indd 930 06-12-2022 14:20:56  931 of phenytoin, can be administered IV or intramuscularly using the Hyperthermia should also be avoided in patients with TBI same doses, specified as phenytoin equivalents (PE). The merits of because patients with elevated temperatures have poorer outcomes preventive antiseizure medication therapy in patients who have not than normothermic patients.71 Hence, aggressive maintenance of a had a seizure postinjury historically is controversial. Risk factors for core temperature of less than 37.5°C (99.5°F) using acetaminophen, early posttraumatic seizures (less than 7 days after injury) include nonsteroidal anti-inflammatory drugs (NSAIDs), and cooling blan- a GCS score of less than 10, a cortical contusion, a depressed skull kets is indicated for patients following severe TBI. CHAPTER        Acute Management of the Brain Injury Patient fracture, a subdural hematoma, an epidural hematoma, an intrace- Other important therapeutic interventions include acute gas- rebral hematoma, a penetrating head wound, or a seizure within tritis prophylaxis, and prevention of decubiti and contractures. the first 24 hours of injury.9 In a landmark randomized, placebo- Prevention of thromboembolic events is extremely important in the controlled study, the incidence of early posttraumatic seizures in supportive care in TBI patients since they are high risk of developing patients receiving placebo was 14.2% compared with 3.6% in patients this complication.72 This can be accomplished with the use of inter- receiving phenytoin without a significant increase in medication- mittent pneumatic compression devices (preferred) or graduated related adverse events.61 Thus, phenytoin should be used to prevent compression stockings initially. Thereafter, the decision to start sys- 77 seizures in adult and pediatric patients with TBI for the first 7 days temic therapy (eg, low-molecular-weight heparin or unfractionated after injury9,13 despite newer data suggesting that phenytoin may not heparin) depends on multiple factors. A noteworthy study revealed decrease early posttraumatic seizures and may diminish functional better survival and lower thromboembolic complications in patients outcome after blunt TBI,62 which is fueling debate challenging this with TBI receiving LMWH compared with those receiving unfrac- longstanding practice.63 Valproate therapy is not recommended for tionated heparin.73 Generally, patients who had relatively minor patients with TBI, based on a trend for higher mortality compared bleeding or no bleeding on the initial CT scan and good ICP control to short-term phenytoin therapy.61 Levetiracetam is a potentially can have pharmacological prophylaxis started within 24 to 48 hours attractive option; however, it should be used cautiously as large ran- postinjury.74,75 Patients at moderate-to-high risk of intracranial domized clinical trials of its use has not been conducted in patients hemorrhage postinjury can safely receive pharmacologic prophy- with TBI. Nevertheless, two meta-analyses found no difference in laxis within the first 72 hours postinjury without a corresponding the rate of early posttraumatic seizures between levetiracetam and increase in intracranial hemorrhage compared with patients receiv- phenytoin,64,65 and levetiracetam may have a superior safety profile ing prophylaxis greater than 72 hours after their TBI.75 Regardless of based on one of these evaluations.65 In a survey of nearly 70 neu- initiation time, prophylaxis is continued until patients are ambula- rotrauma centers in Europe, levetiracetam has become the antisei- tory. Systemic anticoagulation must be used with caution in patients zure medication of choice over phenytoin in patients with TBI.66 If with more severe intracerebral hemorrhage, or in patients who may used in TBI patients, the potential for increased levetiracetam sys- need to undergo craniotomy early in their course.9 Monitoring for temic clearance should be considered when dosing this agent.67 The a coagulopathy is important as the incidence is greater than 30%, benefits of prophylactic antiseizure medications beyond 7 days have and coagulopathy is associated with a significantly longer ICU not been demonstrated, and thus their use for this indication is not length of stay and an almost 10-fold increase in mortality.75 A low recommended.9,13 Unfortunately, despite reducing the incidence of platelet count was the strongest predictor of intracranial bleeding early seizures following brain injury, no beneficial effects have been progression compared with other coagulation tests in patients with documented for antiseizure medications on patient mortality or