Posttraumatic ischemia

The early studies of cerebral blood flow (CBF) in pediatric TBI focused on the role of hyperemia in secondary brain swelling. ^, However, Adelson and colleagues assessed CBF in 30 infants and children after severe TBI. Early posttraumatic hypoperfusion was commonly observed, and a global CBF less than 20 mL/100 g per minute was associated with a poor outcome. After the initial 24 hours, CBF often recovered, in some cases to high levels. However, delayed increases in CBF were not associated with poor outcome. This seminal finding shifted the emphasis toward the recognition and possible treatment of hypoperfusion early after TBI to avert secondary damage.

Numerous mechanisms may contribute to early posttraumatic hypoperfusion, including (1) direct vascular disruption; (2) an attenuated vasodilatory response to nitric oxide (NO), cyclic guanosine monophosphate, cyclic adenosine monophosphate, or prostanoids; (3) loss of endothelial NO production and elaboration of endothelin-1; and (4) production of other vasoconstrictors. ^{, ,} Contemporary models suggest an important role of pericytes at the capillary level in the cerebral microcirculation. Early after injury, increases in metabolic demands result from uptake of glutamate, producing an increased risk from ischemic damage. Vavilala and coworkers identified an important factor that could increase the importance of ischemic brain injury in infants and young children. They reported that no difference exists in the lower limit of blood pressure autoregulation of CBF in children younger than versus older than 2 years. This finding led them to conclude that the autoregulatory reserve (i.e., the difference between baseline mean arterial pressure [MAP] of the blood and the lower limit of autoregulation) is smaller in infants than in older children or adults; even modest MAP reductions may exacerbate ischemia in infants.

Excitotoxicity

Excitotoxicity is the process by which glutamate and other excitatory amino acids cause neuronal damage. Glutamate is the most abundant neurotransmitter in the brain, but exposure to toxic levels produces neuronal death by multiple mechanisms. Sodium-dependent neuronal swelling quickly occurs, followed by delayed, calcium-dependent degeneration. These effects are mediated through both ionophore-linked receptors, labeled according to specific agonists (N-methyl- d -aspartate [NMDA], kainite, and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) and receptors linked to second messenger systems (i.e., metabotropic receptors). Activation of these receptors leads to calcium accumulation via receptor-gated or voltage-gated channels or through the release of intracellular stores. Progress in NMDA receptor (NMDAR)-mediated neurotransmission has revealed greater complexity than previously appreciated—and may better inform therapy. NMDARs consist of heterodimeric glutamate receptor (GluR) subunits, including GluN1, GluN2A, and GluN2B. In adults, GluN2A-containing NMDARs are enriched in the synapse (synaptic NMDARs), whereas GluN2B-containing NMDARs are enriched at extrasynaptic sites (extrasynaptic NMDARs). During early development, GluN2B will predominate the synapse. The localization of NMDARs is believed to regulate activation of receptor-mediated cell death versus survival pathways. Activation of synaptic NMDARs is neuroprotective. They increase nuclear calcium, activate CREB, BDNF, protein kinase B (AKT), phosphorylated-JACOB (pJACOB), and upregulated antioxidants. In contrast, activation of extrasynaptic NMDARs by glutamate spillover or potentially malfunctioning astrocytes after injury has the opposite effect. Extrasynaptic NMDARs increase cytoplasmic calcium; inhibit CREB, AKT, p-JACOB, BDNF, and active calpain; stimulate death-associated protein kinase; and activate autophagy. Thus, the extrasynaptic NMDARs may mediate neuronal death. In addition, glutamate toxicity may be catastrophic to the infant brain, which expresses higher levels of numerous types of NMDAR subunits than in the adult. Pathologic increases in intracellular calcium concentration can also trigger other processes that can lead to cell death, such as activation of constitutive NO synthase, leading to NO production, peroxynitrite formation, and resultant deoxyribonucleic acid (DNA) damage and poly(ADP[adenosine diphosphate]-ribose) polymerase activation. This, in turn, exacerbates adenosine triphosphate (ATP) depletion, metabolic failure, and necrotic cell death. Finally, evidence supports a role for the nonreceptor-mediated effects of high concentrations of glutamate in producing neuronal death. Oxidative stress from intracellular glutathione depletion appears to play an important role.

Glutamate levels are markedly increased in cerebrospinal fluid (CSF) from children with severe TBI and correlate with both poor outcome and AHT as an injury mechanism. Antiexcitotoxic therapies improve outcome after experimental TBI; pretreatment with NMDA antagonists (e.g., MK-801) attenuate behavioral deficits. ^, Other therapies that modify glutamate-NMDA receptor interaction and improve outcome after experimental TBI are magnesium, glycine site antagonists, hypothermia, and pentobarbital. Despite this benefit, clinical trials with antiexcitotoxic therapies have been unsuccessful in adults, perhaps because of adverse effects of these drugs, delayed treatment, a relative reduction in NMDAR subunit targets, or the antiexcitotoxic effects of many current therapies (barbiturates, hypothermia, and sedatives). Developing neurons are more susceptible to excitotoxic injury than are mature cells; concerns have been raised about use of NMDA antagonists in infants because these drugs may induce apoptotic neurodegeneration. Investigating candidate NMDA receptor subunits targeted to produce antiexcitotoxic effects without triggering apoptosis is a key area for future research in pediatric TBI. One agent that is seeing increased clinical use that has antiexcitotoxic properties is levetiracetam. Several preclinical reports support its use and indicate that it is more neuroprotective than other anticonvulsants, such as phenytoin. ^{, ,} The new TBI guidelines support the use of either levetiracetam or fos-phenytoin at a level III of evidence. However, an RCT testing levetiracetam in severe TBI has not been carried out in children, although a phase II study in children has been carried out and reported safety.

Delayed neuronal death cascades

Cells that die after TBI can be categorized on a morphologic continuum ranging from necrosis to apoptosis. ^, Apoptosis is a morphologic description of cell death defined by cell shrinkage and nuclear condensation, internucleosomal DNA fragmentation, and formation of apoptotic bodies. In contrast, cells that die of necrosis display cellular and nuclear swelling with dissolution of membranes. Because apoptosis requires a cascade of intracellular events for completion of cell death, programmed cell death has also been used to describe it. In TBI, distinguishing morphologic apoptotic from necrotic cell death may be difficult, and some cells have mixed phenotypes. In mature tissues, programmed cell death requires initiation via either intracellular or extracellular signals ( Fig. 118.2 ). Intracellular signaling is initiated in mitochondria, triggered by disturbances in cellular homeostasis such as ATP depletion, oxidative stress, or calcium fluxes. Mitochondrial dysfunction leads to egress of cytochrome C into the cytosol. Oxidation of the mitochondrial lipid cardiolipin may play a central role in cytochrome C release. Cytochrome C release can be blocked by antiapoptotic members of the Bcl-2 family (e.g., Bcl-2, Bcl-xL, Bcl-w, and Mcl-1) and promoted by proapoptotic members of the Bcl-2 family (e.g., Bax, Bcl-xS, Bad, and Bid). Cytochrome C activates the initiator cysteine protease caspase-9. Caspase-9 then activates the effector cysteine protease caspase-3, which cleaves cytoskeletal proteins, DNA repair proteins, and activators of endonucleases. Intrinsic signaling of apoptosis can also proceed via mitochondrial release of apoptosis-inducing factor, a caspase-independent apoptotic process mediated by poly(ADP-ribose) polymerases and posttranslational poly-ADP-ribosylation (PAR) of proteins. As such, this apoptotic pathway is sometimes referred to as parthanosis .

Programmed apoptotic and regulated necrotic cell death cascades involved in delayed neuronal death after severe traumatic brain injury. AIF , Apoptosis-inducing factor; APAF , apoptotic protease-activating factor; ASC , caspase activity and recruitment domain; Atg , autophagy-related; CAD , caspase-activated deoxyribonuclease; CD95 , cluster of differentiation 95; CL , cardiolipin; Cyto C , cytochrome C; DNA , deoxyribonucleic acid; EndoG , endonuclease G; Fe , iron containing; GSH , glutathione; iCAD , inhibitor of CAD; IL , interleukin; LOX , lipoxygenase; MLKL , mixed lineage kinase domain-like; mTOR , mammalian target of rapamycin; NLRP , NOD-like receptor family, pyrin domain; O , oxidized; P , phosphorylated; PARP , poly(ADP-ribose) polymerase; PI3K , phosphoinositide 3-kinase; PKB , protein kinase B; RIPK , receptor-interacting protein kinase; t , truncated; TNF , tumor necrosis factor.

Extracellular signaling of apoptosis occurs via the tumor necrosis factor (TNF) superfamily of cell surface death receptors, which includes TNFR-1 and Fas/Apo1/CD95. Receptor-ligand binding of tumor necrosis factor receptor 1 (TNFR-1)–TNF-α or Fas-FasL promotes formation of a trimeric complex of TNF- or Fas-associated death domains. These ultimately lead to caspase-3 activation, in which the mitochondrial and cell death receptor pathways converge (see Fig. 118.2 ). Both the intrinsic and extrinsic pathways may contribute to cell death after severe pediatric TBI. CSF levels of the antiapoptotic protein Bcl-2 in pediatric patients after TBI were increased about fourfold in patients with TBI versus controls. Similarly, CSF levels of sFas receptor and sFas ligand are increased in patients with TBI versus controls. Apoptosis may be an important therapeutic target for new therapies in infants with severe TBI. Current therapies likely attenuate both necrotic and apoptotic injury cascades.

Several additional cell death cascades have been shown to play a role in the evolution of neuronal death after TBI in preclinical models, including pyroptosis, necroptosis, autophagy, and ferroptosis. Pyroptosis is an inflammasome-mediated cell death pathway linked to caspase-1 activation, interleukin-1β (IL-1β) production, and mitochondrial pore formation, whereas necroptosis represents TNF-triggered, receptor-interaction protein kinases (RIPKs) and pseudokinase mixed-lineage kinase domain-like (MLKL)-mediated programmed necrosis. Autophagy involves phagocytosis of mitochondria and organelles in the setting of cellular injury—which may contribute to neuronal death or have beneficial properties. ^, Ferroptosis, an iron-dependent form of regulated necrosis, may also play a role. Ferroptosis results from the accumulation of 15 lipoxygenase-derived products of lipid peroxidation. This mechanism was recently shown to play a prominent role after experimental TBI. All of these processes could represent targets for future trials (see Fig. 118.1 ). Neuronal death after TBI may also result from disconnection, with subsequent Wallerian degeneration of otherwise lethally injured axons. This is discussed further in the section on axonal injury.

The currently available data strongly suggest that early after injury, severe TBI produces a state of hypoperfusion and loss of blood flow autoregulation, with simultaneous increased metabolic demands from excitotoxicity. This is a state of enhanced vulnerability to secondary insults (hypotension and hypoxemia). These processes are intimately linked with the evolution of neuronal death.

Cerebral swelling

After the initial minutes to hours of posttraumatic hypoperfusion and hypermetabolism, metabolic depression occurs. The cerebral metabolic rate of oxygen (CMRO ₂ ) decreases to about one-third of normal and is maintained at that level for the duration of the coma unless perturbed by second insults, such as seizures or spreading depression. The etiology of this state remains to be defined; however, contributions from reduced synaptic activity and mitochondrial failure may be important. Sustained increases in glycolysis are reported in some cases, possibly related to seizure activity or sustained increases in glutamate levels. Cerebral swelling develops and generally peaks between 24 and 72 hours after injury, although sustained increases in intracranial pressure (ICP) for 1 week or longer occasionally are observed.

Cerebral blood volume

Several mechanisms may contribute to intracranial hypertension after severe pediatric TBI (see Fig. 118.1 ). Brain swelling and accompanying intracranial hypertension contribute to secondary damage in two ways. Intracranial hypertension can compromise cerebral perfusion, leading to secondary ischemia. It can also produce the devastating consequences of deformation through herniation syndromes. Bruce and colleagues described the phenomenon of “malignant posttraumatic cerebral swelling” in children. CBF was measured in six children; hyperemia was believed to be the major culprit. Muizelaar and coworkers, in a series of 32 children, suggested similar findings. However, Sharples and associates suggested that hyperemia was uncommon after severe TBI in children; rather, reduced CMRO ₂ was associated with poor outcome. Suzuki measured CBF in 80 normal children. He showed an age dependence of CBF, with high values in children ages 2 to 9 years, levels previously defined as posttraumatic hyperemia. Nevertheless, in some patients with TBI, after resolution of the aforementioned early posttraumatic hypoperfusion, CBF may increase to levels greater than metabolic demands, producing a state of relative hyperemia.

Bergsneider and coworkers posed the alternative hypothesis of hyperglycolysis to explain the increases in CBF in patients with severe TBI whose CBF is uncoupled from CMRO ₂ . Cerebral glutamate uptake is coupled to glucose utilization by glycolysis in astrocytes. Studies suggest two other potential contributors to increased glycolysis after TBI even in the absence of low CBF: mitochondrial failure and nitration and inactivation of pyruvate dehydrogenase, an enzyme critical to oxidative metabolism. Thus, in injured brain regions with reduced CMRO ₂ , increases in CBF may be coupled to local increases in glucose utilization even in the absence of ischemia.

Local or global increases in glycolysis occur in adults with severe TBI. The prevalence or importance of secondary hyperemia or hyperglycolysis in pediatric TBI remains to be determined. It may occur in select cases, but secondary increases in CBF probably are not the major contributor to raised ICP. Increases in CBF were not associated with raised ICP in adults, and hyperemia was not associated with poor outcome in children. The contribution of hyperemia (increased cerebral blood volume [CBV]) to the development of raised ICP has been studied in adults with TBI. Increased CBV was seen in only a small number of patients. These studies suggest that the importance of posttraumatic hyperemia was likely overstated and that edema, rather than hyperemia, may be the predominant contributor to brain swelling after TBI. Loss of blood pressure autoregulation of CBF may also play a role in some patients by contributing to the development of intracranial hypertension. Studies using a pressure reactivity index (PRx) approach to assess the status of autoregulation at the bedside have shed additional light on this possibility. In some patients, this tool may help define an optimal cerebral perfusion pressure (CPP), which may need to be individually targeted. ^, Recently, a potentially more robust version of the PRx, called a wavelet PRx , has been suggested to be able to provide a more reliable optimal CPP assessment—although further study is needed.

Edema

Both cytotoxic and vasogenic edema may play important roles in cerebral swelling ( Fig. 118.3 ). However, the traditional concept of cytotoxic and vasogenic edema has evolved. There are multiple mechanisms for edema formation in the injured brain. First, vasogenic edema may form in the extracellular space as a result of blood-brain barrier (BBB) disruption. Second, cellular swelling can be produced in two ways. Astrocyte swelling can occur as part of the homeostatic uptake of substances such as glutamate. Glutamate uptake is coupled to glucose utilization via a sodium/potassium adenosine triphosphatase, with sodium and water accumulation in astrocytes. Swelling of both neurons and other cells in the neuropil can result from ischemia- or trauma-induced ionic pump failure. Finally, osmolar swelling may contribute to edema formation in the extracellular space, particularly in contusions. Osmolar swelling is dependent on an intact BBB or an alternative solute barrier. Cellular swelling may be of greatest importance. Using a model of diffuse TBI in rats, Barzo and coworkers applied diffusion-weighted magnetic resonance imaging (MRI) to localize the increase in brain water. A decrease in the apparent diffuse coefficient after injury suggested cellular swelling rather than vasogenic edema in the development of raised ICP. Katayama and associates also suggested that the role of the BBB in the development of posttraumatic edema may have been overstated, even in the setting of cerebral contusion. They posed that as macromolecules are degraded within injured brain regions, the osmolar load in the contused tissue increases. As the BBB reconstitutes (or as other osmolar barriers form), a large osmolar driving force for local accumulation of water develops, resulting in the marked swelling so often seen in and around cerebral contusions. Thus, in either diffuse injury or focal contusion, BBB permeability may play a limited role in the development of cerebral swelling. If these results can be generalized, then hypertonic saline solution or mannitol would represent optimal therapies, particularly outside of the immediate postinjury time period. However, a role for BBB permeability in cases of severe TBI should not be dismissed. Polderman and colleagues reported that prolonged use (>48 hours) of mannitol (a large molecule that does not cross the intact BBB) was associated with its progressive accumulation in CSF in adults with severe TBI and, in some cases, a reverse osmotic gradient was even established. This suggests that breaching of the BBB is important and that prolonged use of osmolar therapy might, in some patients, produce rebound intracranial hypertension. Studies of the extent of BBB injury versus the contribution of cellular swelling to intracranial hypertension in pediatric TBI are needed.

Schematic of three classic cascades leading to cerebral edema. Top left , Cellular swelling is predominantly seen in astrocytes and is stimulated by potassium, acidosis, glutamate, arachidonic acid (AA), and other factors. This key pathway is less representative of a toxic process and more consistent with a homeostatic or mediator-driven process. Neuronal swelling from pump leak probably is less important. Bottom , Osmolar swelling from contusion necrosis. In the hours after injury, reconstitution of the blood brain barrier (BBB) or development of an osmolar barrier around a contusion sets the stage for marked local swelling as macromolecules in the contusion break down, increasing local osmolality. Water moves in via aquaporin channels. Top right , Vasogenic edema results from protein and water accumulation across the damaged BBB, which is formed by tight junctions (astrocyte foot processes). Direct vascular disruption by trauma, reactive oxygen species such as hydroxyl radical (OH), superoxide anion (O ₂ ^– ), and peroxynitrite (ONOO), metalloproteases (MP), kinins, leukotrienes (LT), cytokines, and other mediators contribute to BBB damage. TNF , tumor necrosis factor.

There have been several exciting new developments in our understanding of brain edema based on new pathways that may represent therapeutic targets ( Fig. 118.4 ). ^{, ,} This includes sulfonylurea receptor 1 (Sur-1)–regulated cation channels, which can be targeted by the drug glyburide ^{, ,} ; aquaporin-4 channels, which can be blocked either with direct channel blockers or via inhibition of their upregulation, which may be linked to high-mobility group box 1 (HMGB-1) release or Toll-receptor activation ; and the use of novel resuscitation agents to reduce fluid requirements. These are promising developments that are already generating clinical trials in adults (glyburide [RP-1127] for TBI; NCT01454154) and stroke.

Contemporary view of molecular participants in the development of cerebral edema after traumatic brain injury (TBI). On the left, neuronal necrosis results in release of the high-mobility group box 1 protein (HMGB-1), which binds to Toll-like receptor-4 (TLR-4) on microglia, leading to interleukin-6 (IL-6) production and upregulation of AQP-4 water channels, as suggested by Laird and colleagues. On the right, upregulation of sulfonylurea receptor-1 (SUR-1) leads to ion channel opening and water accumulation. ^{, ,}

Axonal injury

Traumatic axonal injury (TAI) encompasses the spectrum from mild to severe TBI. ^, The extent and distribution of TAI depend on injury severity and category (focal vs. diffuse). Its incidence and nature appear to be age independent, but its consequences may be greater in children. The effects of TAI in children during a period of developmental axonal connectivity remain unknown but likely are considerable. Clinical data on TAI after pediatric TBI are limited. However, strongly supporting the role for TAI in pediatric TBI, after publication of the guidelines, Berger and colleagues reported that serum levels of myelin basic protein are markedly increased in infants and children after either accidental TBI or AHT—in contrast to hypoxic-ischemic encephalopathy. Large increases in CSF levels of myelin basic protein were also reported after severe TBI in children. In children affected by AHT, TAI may be highly prevalent. The classic view suggested that TAI occurs because immediate physical shearing with frank axonal tears occurs. However, experimental studies suggest that TAI occurs by a delayed process termed secondary axotomy, which results from either calcium accumulation or altered axoplasmic flow with accumulation of proteins such as amyloid precursor protein (APP; Fig. 118.5 ). What remains to be determined is how much of TAI results from a reversible evolution of damage to axons versus Wallerian degeneration of disconnected axons. The former but not the latter would be amenable to treatment. There are as many, if not more, unmyelinated than myelinated axons that are injured after TBI. New preclinical studies have revealed potential utility of phospho-neurofilament-heavy protein as a prognostic and pharmacodynamic response serum biomarker of TAI. Also, laboratory studies suggest that hypothermia, calpain antagonists, and cyclosporine A can attenuate TAI, but clinical data are lacking.

Secondary injury cascade after traumatic brain injury (TBI) relevant specifically to traumatic axonal injury. Rather than direct axonal disruption from trauma, shearing forces set into motion several processes, including mitochondrial permeability transition pore opening and resultant mitochondrial failure and calpain-mediated proteolysis of microtubules, both of which lead to failure of axoplasmic transport and accumulation of proteins such as amyloid precursor protein. In addition, direct axolemmal poration may occur.

Rapid-sequence induction and intubation

Tracheal intubation, although lifesaving, is a noxious stimulus. Rapid-sequence induction and intubation secures the airway of an unprepared patient, who is at risk for aspiration of gastric contents, in an immediate and safe manner. It eliminates resistance to direct laryngoscopy and the counterproductive normal responses to the placement of a foreign body into the trachea. Rapid-sequence induction is documented to be a safer technique than either nasotracheal intubation or orotracheal intubation without neuromuscular blockade. ^{, ,}

In the pediatric patient with TBI, a cerebroprotective rapid-sequence induction strategy should be used. The sequence involves preparation, preoxygenation, sedation, neuromuscular blockade, and orotracheal intubation. Pharmacologic adjuncts are used to prevent morbidity associated with hypotension, hypoxemia, intracranial hypertension, and gastric aspiration. The neurologic and hemodynamic status of the patient directs the choice of adjunctive pharmacologic strategy.

For a victim in cardiac arrest, cardiopulmonary resuscitation should begin immediately, accompanied by direct orotracheal intubation. No pharmacologic adjuncts are necessary to secure the airway. For a hemodynamically unstable patient, the combination of fentanyl, lidocaine, and rocuronium bromide is the first choice ( Table 118.2 ). At Pittsburgh Children’s Hospital either etomidate or fentanyl, in combination with lidocaine, is used for rapid-sequence intubation. Etomidate use is accompanied by concerns with adrenal suppression. Fentanyl, in combination with lidocaine, reduces the catecholamine surge associated with direct laryngoscopy. Either of these sequences of drugs can be used in hemodynamically stable patients, for whom a rapidly acting benzodiazepine (midazolam) can be added. Historically, thiopental was an excellent agent for rapid-sequence induction in hemodynamically stable patients, but its availability has been curtailed related to its use in lethal injections in the United States. Alternatively, similar CNS effects can be achieved with propofol if there is no concern for hemodynamic compromise.

Circulatory stabilization

Assessment of circulatory function after trauma involves the rapid determination of heart rate, blood pressure, central and peripheral pulse quality, capillary refill, and cerebral perfusion. Posttraumatic hypoperfusion must be assumed to be hypovolemic (i.e., hemorrhagic) in nature, but it also may have a secondary component of myocardial depression resulting from cardiac contusion. However, cardiac contusion is less common in children than in adults. In patients with severe TBI, fluid therapy for hypovolemic shock entails rapid replacement of intravascular volume. The current recommendation is 20 mL/kg isotonic crystalloid (0.9% NaCl solution) given as soon as vascular access is obtained. Hypotonic fluid should not be used in the resuscitation of a patient with a brain injury. Subsequent doses of fluid should be isotonic crystalloid or packed red blood cells titrated based on serial assessment of blood pressure, perfusion, and hematocrit. Although concerns exist regarding the relative hypotonicity of lactated Ringer solution, evidence from studies in laboratory animals supports the safety of the use of lactated Ringer solution in patients with TBI. However, some controversy remains based on recent studies in adults. Fisher and colleagues reported the successful use of 3% saline solution as a maintenance fluid in children with TBI. Titration of 3% saline solution as an infusion to prevent development of intracranial hypertension is an acceptable first-tier strategy. Unfortunately, hypertonic saline, albumin, or other colloids have all failed to show efficacy in TBI resuscitation. Albumin use in acute ICU fluid management in adult TBI patients was associated with increased mortality, and National Institutes of Health (NIH)-funded trials in adults involving hypertonic saline (7.5%) with or without 6% dextran-70 were halted because of futility. ^, Details of the approach to osmotherapy are discussed later in this chapter.

Herniation

The need to simultaneously address airway control, cardiovascular assessment and stabilization, treatment of extracerebral insults (hemorrhage and multiple trauma), and initial trauma survey in the field and emergency department makes acute management challenging. Although mass lesions are less common in children than in adults, they still occur in about 30% of children with severe TBI. Some of these patients, particularly those with rapidly expanding mass lesions (e.g., epidural hematoma), can present with signs and symptoms of herniation (i.e., pupillary dilation, systemic hypertension, bradycardia, and extensor posturing). Because the devastating complications of herniation can sometimes be successfully prevented or treated in the initial minutes of their progression, the importance of aggressively and presumptively treating signs and symptoms of herniation, which is a medical emergency, cannot be overemphasized until these signs and symptoms are proved not to represent herniation. ^,

There has been an evidence-based move away from prophylactic application of aggressive hyperventilation to manage severe TBI. However, it is important to recognize that temporary use of hyperventilation with an F io ₂ of 1.0 is a therapy that can be immediately applied and can be lifesaving in the setting of impending herniation until other therapies can be instituted. The new pediatric TBI algorithm also now provides a “herniation pathway” to address this topic. Hyperventilation on an F io ₂ of 1.0 should be accompanied by emergent administration of mannitol (0.5–1.0 g/kg) or hypertonic saline (3%, 1–3 mL/kg, up to a maximum dose of 250 mL, or 23.4% 0.5 mL/kg up to a maximum dose of 30 mL). If a ventriculostomy is in place, it should be emergently opened to continuous drainage. Appropriate analgesia and sedation should also be ensured. This approach is outlined in Fig. 118.6 . One must recognize that factors other than a focal mass lesion may lead to herniation and that these situations may arise more commonly in children than in adults. Diffuse swelling is more common in children than in adults and, in this setting, inadvertent hypercarbia or hypoxemia, iatrogenic excessive fluid administration, or status epilepticus after TBI can precipitate herniation. Although discussed in this chapter in the context of acute therapy, herniation can occur at any time in the PICU course, and this approach to treatment also applies (see Fig. 118.6 ).

Transition from the emergency department to the pediatric intensive care unit: Computed tomographic scan and intracranial pressure monitoring

The transition of patients with severe TBI from the emergency department to the PICU includes computed tomographic (CT) evaluation of the head (and other anatomic regions, when clinically indicated) followed by placement of an ICP monitor, transport to the operating suite for surgical intervention, or both. In the initial resuscitation, sedation must be carefully titrated to the challenging goals of stability, analgesia, and anxiolysis during transport and scanning while facilitating rapid emergence for clinical assessment (as indicated) until a decision is made regarding surgery or ICP monitoring. Because the early period after injury generally reflects a state of increased vulnerability of the brain to second insults because of the brain’s increased metabolic demands and compromised perfusion, providing adequate sedation and maintaining stable hemodynamics are important. An end-tidal carbon dioxide (CO ₂ ) monitor also should be considered to avoid iatrogenic hyperventilation or hypoventilation. Clinical trials supporting definitive recommendations are not available. Nevertheless, the risks of intrahospital transport are well described. Thus, when possible, a provider capable of serial neurocritical care assessment and management should accompany the infant or child on transport to the scanner to direct care because serial assessment to titrate therapy is needed.

Computed tomography

Since becoming commercially available in 1973, CT has been of enormous benefit to neurointensive care. Examples of classic findings in severe pediatric TBI are shown in Fig. 118.7 . Standard CT classification in adults with severe TBI is done most commonly with the Marshall classification ( Table 118.3 ). A similar system specifically for pediatric TBI has not yet been developed, although several reviews characterize the spectrum of injury in infants and children as defined by CT. ^, Ewing-Cobbs and colleagues compared acute CT findings in infants and children with AHT and accidental injuries. Subdural interhemispheric and convexity hemorrhages and preexisting lesions were two to three times more common in the AHT group. Epidural hematomas were more common in accidental TBI.

Axial cranial computed tomography images of important lesions in pediatric traumatic brain injury. (A) Acute epidural hematoma, (B) penetrating brain injury resulting from a gunshot wound (with bullet fragments), and (C) abusive head trauma (shaken baby syndrome) with acute right subdural hematoma extending over most of the right hemisphere, right-side alterations of gray-white differentiation, and decreased cerebrospinal fluid spaces.

Timing of repeat cranial CT scans has been investigated in children. Routine reimaging at 24 or 48 hours after injury is not supported by the literature and a decision to reimage should be based on changes in ICP or clinical examination.

Studies in adults and children indicate that CT scans are not without limitations and must be used as only one, albeit important, piece of information. After severe TBI, in about 15% of adults with a normal CT scan, clinically significant intracranial hypertension develops. This position is supported by the new pediatric severe TBI guidelines, which state that a normal head CT scan does not exclude the possibility of raised ICP. Finally, patients with normal initial head CT scans who also have hypotension or abnormal posturing have the same propensity for the development of intracranial hypertension as do their counterparts with an abnormal scan.

Magnetic resonance imaging

MRI may have future applications salient to acute management in pediatric TBI. The use of diffusion-weighted MRI to study cerebral edema, the use of novel MRI methods to assess CBF, and new methods such as susceptibility-weighted, diffusion tensor and high-definition fiber tract ( Fig. 118.8 ) imaging to assess white matter damage increasingly are being applied. ^, The potential ability to couple these techniques with MR spectroscopy and functional MRI is beginning to yield unprecedented advances in our understanding of the brain’s response to injury. However, MRI suites in most institutions are remote from the emergency department and PICU, introducing the risk of transport. Hardware incompatibilities (e.g., ventilators and intravenous pumps) and long data acquisition times (relative to CT) still limit the utility of this important tool.

Comparison of conventional T1-weighted imaging (A–C), diffusion tensor imaging fractional anisotropy maps (D–F), and state-of-the-art high-definition fiber tract (HDFT) imaging (G–I) of a healthy volunteer (A, D, G) and a traumatic brain injury patient at 4 months (B, E, H) and 10 months (C, F, I) after injury. HDFT demonstrates the progression of loss of white matter tracts with remarkable anatomic clarity.

(From Shin SS, Verstynen T, Pathak S, et al. High-definition fiber tracking for assessment of neurological deficit in a case of traumatic brain injury: finding, visualizing, and interpreting small sites of damage. J Neurosurg . 2012;116:1062–1069).

Intracranial pressure monitoring

Unfortunately, clinical signs—such as pupillary size, light response, and papilledema—fail as early indicators of intracranial hypertension. Although the most reliable clinical signs are those associated with herniation, the introduction of ICP monitoring devices has allowed detection of intracranial hypertension well before herniation develops, allowing us to target the impact of raised ICP on perfusion and possibly other mechanisms. ^, In the pediatric guidelines, ICP monitoring was suggested as appropriate in children with an abnormal admission head CT scan and initial GCS score between 3 and 8. Also, ICP monitoring was suggested to be appropriate in adults with severe TBI and a normal head CT scan if the clinical course was complicated by hypotension or posturing. This modality is essential to implementation of a physiologically guided approach to manage CPP in severe TBI.

ICP monitoring has not been studied in an RCT in children to establish its efficacy in altering outcome after severe TBI. Forsyth and coworkers examined the United Kingdom multicenter database of more than 500 cases of pediatric TBI and reported that both ICP greater than 20 mm Hg and lack of ICP monitoring were independently associated with death before discharge. Given that raised ICP correlates with poor outcome, there is a strong rationale for identifying and treating this problem. ^, As discussed in the section on CT, although CT is useful to identify patients at high risk for the development of raised ICP (e.g., those with mass lesions), the finding of a “normal” cranial CT scan does not rule out the potential for raised ICP. ^, Despite this evidence, ICP monitoring in children with TBI, particularly in infants, is still not rigorously performed in clinical practice. Surprisingly in 2005, only 33% of infants and young toddlers (<2 years) with severe TBI underwent ICP monitoring in the state of North Carolina. Bennett et al. examined two national databases to assess the impact of ICP monitoring on outcome in children with severe TBI. Using propensity matching in approximately 3000 children, no evidence of benefit was seen. However, limitations of this approach make it difficult to draw firm conclusions. It was also remarkable that, in this study, only about one-third of the pediatric patients with severe TBI received ICP monitoring given that treatment protocols are not available to manage severe pediatric TBI in this setting. Therapies in the absence of monitoring are undoubtedly based on studies in children for whom ICP monitoring guided therapy. Consideration of risk versus benefit for ICP monitoring should guide the clinical decision in cases in which the complication rate is high, such as in patients with coagulopathy.

Two studies in adult TBI merit discussion. Supporting ICP monitoring, Gerber et al. reported on the results of a study on all cases of TBI in the state of New York. Between 2001 and 2009, mortality decreased from 23% to 13%, with a concurrent increase in guidelines-based ICP monitoring from 56% to 75%. In contrast, Chesnut and colleagues found no differences in outcome in a study of 324 patients in Latin America randomized to treatment led by either ICP-directed care or a protocol in which treatment was based on imaging and clinical examination. A consensus-based interpretation of that study suggested that the results of the trial should not be generalized and that it should not change practice of those currently using ICP monitoring. Additional investigation of ICP monitoring was recommended.

Currently, ICP monitoring by ventricular catheter is considered the most accurate, low-cost, reliable method. The ventricular catheter also affords a therapeutic option—CSF drainage. Other acceptable methods include parenchymal fiberoptic and microtransducer systems; subarachnoid, subdural, and epidural monitors of any type are less reliable. The type of monitor (ventricular catheter or fiberoptic pressure transducer) used is dependent on the local preference of the neurosurgical staff.

The location of the patient in the hospital when the monitor is placed varies among centers and includes the emergency department/trauma bay, operating room, or PICU. Despite the flurry of activity that often surrounds the stabilization of a critically injured child with severe TBI, it is important to provide adequate anesthesia during placement of the monitor to prevent pain-induced spikes in ICP or herniation. Monitoring and treatment of ICP are considered essential to contemporary management.

Advanced monitoring techniques

Monitoring cerebral blood flow

Several techniques for assessing CBF, autoregulation of CBF, or metabolism can provide additional insight into the occurrence of cerebral ischemia or other metabolic derangements during management and can help guide therapy. However, information on the use of these techniques and their impact on outcome in infants and children with severe TBI remains limited. Often, these methods are used only in clinical research or specialized trauma centers with particular experience in pediatric neurointensive care.

Clinically available techniques for measuring CBF after severe TBI in children include (1) transcranial Doppler (TCD) and (2) arterial spin-label MRI (ASL-MRI). ^{, ,}

TCD is gaining acceptance in pediatric neurocritical care because it is noninvasive and readily repeated at the bedside. ^, It can serve as an early warning monitor of the development of an unfavorable trend in cerebral perfusion. It can also assess autoregulation, identify vasospasm, and contribute to prognostic information. ^, TCD measures velocity rather than flow and usually is applied to assess middle cerebral artery distribution. However, the inability of TCD to acquire regional data limits its use in titrating care. Some have suggested that TCD also can identify the presence of raised ICP, but results have been conflicting. ^,

ASL-MRI has been used for decades in preclinical investigations in TBI and is now used routinely in advanced neurocritical care in some centers. ^, However, its use to assess CBF in pediatric TBI is only beginning to emerge. It is not a monitoring tool given its need for MRI. However, it provides quantitative maps of CBF at a single point in time and can be used for dynamic studies such as assessment of CO ₂ reactivity or pressure autoregulation. Its use is likely to increase as faster MRI techniques are developed. Unfortunately, the stable xenon CT method that was used in a number of seminal studies of pediatric TBI ( Fig. 118.9 ) is not available for routine clinical use. ^,

Time course of CBF measured by Xe-enhanced computed tomography (CT) images in a 2-month-old infant after severe traumatic brain injury from a motor vehicle accident. Standard CT images (upper row) and Xe-enhanced cerebral blood flow (CBF) maps (lower row) are shown from studies performed on admission (A) and at 2 days (B) and 5 days (C) after injury. Flow is severely reduced (black) on admission. Some recovery of CBF is seen at 2 days and 5 days after injury. CBF ranges from lowest (darkest image) to highest (brightest image) .

Brady and associates have generated interest in continuous monitoring of blood pressure autoregulation of CBF with use of a PRx that is calculated as a linear correlation between ICP and blood pressure. With use of this noninvasive adjunct to ICP monitoring, intact autoregulation was shown to be associated with survival in 21 children with severe TBI. This method also may contribute to better definition of optimal CPP. However, it fails to provide regional assessments—and, as the consistency of its bedside performance is unclear, it remains a research tool at this time.

Monitoring cerebral metabolism

Jugular venous saturation has been used to monitor cerebral oxygen delivery in adults, but limited data on the use of this technique in children are available. ^, Studies in adults suggest that therapies such as barbiturates and hyperventilation can be titrated according to jugular venous saturation. ^, Desaturations below the threshold value of 50% are associated with mortality in adults. However, jugular venous desaturation below this level was rarely the sole indication that urgent intervention was needed, and false desaturations occurred. Nevertheless, this tool can assist in clinical decision-making, but some have questioned its ability to monitor regional effects. Thus, it has not been commonly used in pediatric TBI.

Several other modes to monitor cerebral metabolic rate may be helpful. Near-infrared spectroscopy has been used to track the oxidative state of cytochromes in the brain. Near-infrared spectroscopy has been used to assess cerebral metabolic status in hypoxemic-ischemic neonates and is beginning to be used in pediatric TBI. Although its role remains unclear, it may prove valuable as a trend monitor. Limitations with topographic resolution and the dominance of the superficial brain tissue in generating the signal are concerns.

Monitoring partial pressure of oxygen in brain tissue (PbtO ₂ ) with a microelectrode implanted in the parenchyma has now been given a level III recommendation in the severe pediatric TBI guidelines. ^, Maintaining a threshold value greater than 10 mm Hg is recommended, although thresholds anywhere from 10 to 30 mm Hg have been recommended in various studies. Stiefel and colleagues reported on the use of PbtO ₂ monitoring in children and suggested a threshold of 20 mm Hg. Stippler and associates reported experience with PbtO ₂ monitoring in a series of children and found that a PbtO ₂ of 30 mm Hg was associated with the highest sensitivity/specificity for favorable 6-month neurologic outcome. We routinely use PbtO ₂ in children with TBI, targeting a threshold of 20 mm Hg. Therapy is first targeted to optimize ICP and CPP. However, in some cases, PbtO ₂ is less than 20 mm Hg despite control of ICP, and it is necessary to evaluate other potential factors that might be affecting brain oxygenation. This could include inadvertent hyperventilation or a decline in partial pressure of arterial oxygen (Pa o ₂ ) due to lung disease; if so, these issues should be addressed. If there is no extracerebral complication affecting PbtO ₂ , interventions such as increasing F io ₂ or raising partial pressure of arterial carbon dioxide (Pa co ₂ ) or MAP/CPP to improve CBF may increase PbtO ₂ . The limitations of PbtO ₂ are its invasiveness and provision of only focal data. Suggestions to integrate PbtO ₂ monitoring and ICP/CPP-guided therapy are provided in the severe TBI algorithm. In adults, PbtO ₂ measurement has been coupled to cerebral microdialysis to provide metabolic data (i.e., glutamate levels). ^,

Finally, positron emission tomography (PET) has been used in adults with severe TBI ( Fig. 118.10 ). Although limited by long acquisition times and the risk of intrahospital transport of critically ill patients, the metabolic maps generated provide much insight, particularly into cerebral glucose utilization after TBI. Diringer and coworkers used PET to provide insight into the effect of hyperventilation on CMRO ₂ in adults with severe TBI (see the section on hyperventilation). Both PET and advanced MRI, along with magnetic resonance spectroscopy, can provide insight into regional brain disturbances and the effect of therapy.

Computed tomography (CT) image (left) of an acute subdural hematoma with mass effect that was treated with surgical evacuation. F-fluorodeoxyglucose positron emission tomographic (FDG-PET) map (center) obtained 5 days after surgery shows marked local increases in cerebral glucose utilization in the brain regions underlying the hematoma. Stable Xe-enhanced CT cerebral blood flow (CBF) map (right) also obtained 5 days after surgery shows increased CBF in the same region, indicating that the increase in glucose utilization is not the result of hypoperfusion. This phenomenon, termed hyperglycolysis , likely represents increased glucose utilization by astrocytes coupled to glutamate uptake. This highlights the complex regional metabolic demands of the traumatically injured brain.

(From Bergsneider M, Hovda DA, Shalmon E, et al. Cerebral hyperglycolysis following severe traumatic brain injury in humans: a positron emission tomography study. J Neurosurg . 1997;86:241–251.)

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