1378 SECTION XII Pediatric Critical Care Environmental Injury and Trauma and nuclear condensation, internucleosomal DNA fragmenta tion, and formation of apoptotic bodies 47 In contrast, cells that die[.]
1378 S E C T I O N X I I Pediatric Critical Care: Environmental Injury and Trauma and nuclear condensation, internucleosomal DNA fragmentation, and formation of apoptotic bodies.47 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,48 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.49 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.50 Trophic factors 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).51 Cytochrome C activates the initiator cysteine protease caspase-9.52 Caspase-9 then activates the effector cysteine protease caspase-3, which cleaves cytoskeletal proteins, DNA repair proteins, and activators of endonucleases.53 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.54 Extracellular signaling of apoptosis occurs via the tumor necrosis factor (TNF) superfamily of cell surface death receptors, which System Xccystine/glutamate antiporter CD95L (FasL) PI3K-I Autophagy TNF PKB P mTOR Beclin1 P e tBID BID Inflammation APAF1 BAX Caspase-9 Caspase-8 Caspase-12 AIF poly-ADP ribose Caspase-3 Large-scale DNA fragmentation p53 iC “Pyroptosis” ASC NLRP IL-1β IL-18 Caspase-1 “Inflammasome” Pro-caspase-3 Calpain Apoptosis DNA damage PARP-1 Lysosome Ca2+ AD CAD Nucleus MLKL Cyto “Apoptosome” c Endo G P O CL “Parthanosis” Proteolysis of structural proteins Endoplasmic reticulum Internucleosomal DNA fragmentation • Fig 118.2 Programmed Damageassociated molecular patterns ag Cyto c RIPK3 m ONOOEndo G AIF Proteolysis of structural proteins P Oxidative stress Mitochondria PARP RIPK1 Lipid peroxidation da Cathepsins LOX15 Fe ue • O2– “Necroptosis” ss H2O2 Pro-caspase-8 Fe LOX12 Ti CL BAD Calcineurin Pre-autophagasomal membrane Lysosome GSH “Ferroptosis” P BCLW Atg complexes BCLxL BCL2 BAX BAD PI3K-III 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, caspaseactivated 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, receptorinteracting protein kinase; t, truncated; TNF, tumor necrosis factor CHAPTER 118 Traumatic Brain Injury includes TNFR-1 and Fas/Apo1/CD95.55 Receptor-ligand binding of tumor necrosis factor receptor (TNFR-1)–TNF-a 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.56 Similarly, CSF levels of sFas receptor and sFas ligand are increased in patients with TBI versus controls.57 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-1b (IL-1b) production, and mitochondrial pore formation,58 whereas necroptosis represents TNF-triggered, receptor-interaction protein kinases (RIPKs) and pseudokinase mixed-lineage kinase domain-like (MLKL)-mediated programmed necrosis.54 Autophagy involves phagocytosis of mitochondria and organelles in the setting of cellular injury—which may contribute to neuronal death or have beneficial properties.59,60 Ferroptosis, an iron-dependent form of regulated necrosis, may also play a role.61 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.62 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 (CMRO2) decreases to about one-third of normal63 and is maintained at that level for the duration of the coma unless perturbed by second insults, such as seizures or spreading depression.64 The etiology of this state remains to be defined; however, contributions from reduced synaptic activity and mitochondrial failure may be important.65 Sustained increases in glycolysis are reported in some cases, possibly related to seizure activity or sustained increases in glutamate levels.29 Cerebral swelling develops and generally peaks between 24 and 72 hours after injury, although sustained increases in intracranial pressure (ICP) for 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 1379 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 colleagues24 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,66 in a series of 32 children, suggested similar findings However, Sharples and associates67 suggested that hyperemia was uncommon after severe TBI in children; rather, reduced CMRO2 was associated with poor outcome Suzuki68 measured CBF in 80 normal children He showed an age dependence of CBF, with high values in children ages to 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.21 Bergsneider and coworkers30 posed the alternative hypothesis of hyperglycolysis to explain the increases in CBF in patients with severe TBI whose CBF is uncoupled from CMRO2 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 failure65 and nitration and inactivation of pyruvate dehydrogenase, an enzyme critical to oxidative metabolism.69 Thus, in injured brain regions with reduced CMRO2, 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.30 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,70 and hyperemia was not associated with poor outcome in children.25 The contribution of hyperemia (increased cerebral blood volume [CBV]) to the development of raised ICP has been studied in adults with TBI.70 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.71 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.72,73 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.74 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 1380 S E C T I O N X I I Pediatric Critical Care: Environmental Injury and Trauma Astrocyte K+, AA, H+, glutamate H2O + Na Plasma protein • OH O2- H2O + Na H2O H2O Na+ H2O • OONO MP Plasma protein LT Neuron H2O H 2O TNFα H2O Kinin H2O H2O H2O H2O H2O Contusion necrosis H2O • Fig 118.3 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 (O2–), and peroxynitrite (ONOO), metalloproteases (MP), kinins, leukotrienes (LT), cytokines, and other mediators contribute to BBB damage TNF, tumor necrosis factor 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 coworkers75 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 associates76 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 colleagues77 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 CHAPTER 118 Traumatic Brain Injury 1381 TBI New pathways and potential therapies targeting brain edema Necrosis Sur-1 Neurons Neurons Sur-1 Astrocytes HMGB-1 Vascular endothelium TLR-4 Sur-1 Microglia IL-6 IL-6 IL-6 H2O Neuronal swelling Astrocytes Vasogenic edema AQP-4 AQP-4 AQP-4 AQP-4 AQP-4 Astrocyte swelling • Fig 118.4 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 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.83 On the right, upregulation of sulfonylurea receptor-1 (SUR-1) leads to ion channel opening and water accumulation.78,79,81 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).36,78,79 This includes sulfonylurea receptor (Sur-1)–regulated cation channels, which can be targeted by the drug glyburide8–10,80,81; aquaporin-4 channels, which can be blocked either with direct channel blockers or via inhibition of their upregulation,82 which may be linked to high-mobility group box (HMGB-1) release or Toll-receptor activation83; and the use of novel resuscitation agents to reduce fluid requirements.84 These are promising developments that are already generating clinical trials in adults (glyburide [RP-1127] for TBI; NCT01454154) and stroke.85 Axonal Injury Traumatic axonal injury (TAI) encompasses the spectrum from mild to severe TBI.86,87 The extent and distribution of TAI depend on injury severity and category (focal vs diffuse) Its incidence and nature appear to be age independent,88 but its consequences may be greater in children.89 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 colleagues90 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.91 In children affected by AHT, TAI may be highly prevalent.92 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).93 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.94 New preclinical studies have revealed potential utility of phospho-neurofilamentheavy protein as a prognostic and pharmacodynamic response serum biomarker of TAI.95 Also, laboratory studies suggest that hypothermia, calpain antagonists, and cyclosporine A can attenuate TAI, but clinical data are lacking History The special case of AHT contributes to increased importance of the history in pediatric TBI.96 In severe AHT, a history that is incompatible with the observed injury is common.97 Occult 1382 S E C T I O N X I I Pediatric Critical Care: Environmental Injury and Trauma Severe TBI Axolemma poration Permeability transition pore opening Ca2+ Ca2+ Calpain mediated microtubule proteolysis & polymerization 2+ Ca2+ Ca Axonal dysfunction, failure, or loss • Fig 118.5 Secondary injury cascade after traumatic brain injury (TBI) relevant specifically to traumatic axonal injury.93 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 presentations of AHT can be important because they may be recognized as cases of severe TBI late in their treatment course.98 In this setting, brain edema already may have evolved to lifethreatening levels, and other superimposed secondary insults (e.g., seizures and apnea) may complicate management and worsen outcome Signs and Symptoms The GCS score99 (Table 118.1), first described in 1974, remains a valuable tool for grading and communicating severity of neurologic injury after TBI, although limitations remain with pediatric use Its verbal and motor components have been modified to assess infants.100 The motor score has become the most important component A rapid mini-neuroassessment that allows evaluation of the patient’s level of consciousness, pupillary size and light response, the fundi, extraocular movements, response of extremities to pain, deep tendon reflexes, and brainstem reflexes should all be part of the initial evaluation.101 Until proved otherwise, an altered level of consciousness, pupillary dysfunction, and lateralizing extremity weakness in an infant or child should raise suspicion of a mass lesion that may require surgery.102 These signs of impending herniation require an immediate response, as outlined in Fig 118.6 The approach to herniation has also now been addressed in the most recent pediatric TBI algorithm.4 Initial Resuscitation The identification and correction of airway obstruction, inadequate ventilation, and shock take priority over a detailed neurologic assessment.103 Thus, the first step in managing a patient with TBI is complete, rapid physiologic resuscitation.3,4 Raised ICP and cerebral herniation are the major complications Brainspecific interventions in the absence of signs of herniation or other neurologic deterioration currently are not recommended Mannitol may be counterproductive to manage malignant intracranial hypertension during initial resuscitative efforts, and some have suggested that immediate post-TBI use of either osmolar agents or colloids could cause leakage into the injured brain, contributing to the development of a reverse osmolar gradient and delayed swelling.104,105 Studies have consistently shown that increased morbidity and mortality are associated with the secondary insults of hypotension and hypoxemia.106 The increased use of tracheal intubation and ventilation reduced hypoxemia and increased favorable outcomes.107 Although the basis for this improvement may be multifactorial, early correction of hypoxemia and hypovolemia must be the initial objective However, specific recommendations for intubation at the scene are complex and likely influenced by the expertise of caregivers in the field and by the transport distance, among other factors.108 ... about one-third of normal63 and is maintained at that level for the duration of the coma unless perturbed by second insults, such as seizures or spreading depression.64 The etiology of this state... 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... 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