Pearls
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Cardiac arrest in pediatric patients is predominantly due to asphyxia. This is in contrast to adults, for whom, despite an increase in asphyxial cardiac arrest related to the opioid epidemic, cardiac arrhythmia remains a major cause.
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Important developmental differences between pediatric and adult patients include ongoing synaptogenesis, lower cerebral blood flow in neonates and higher cerebral blood flow in toddlers and children compared with adults, neurotransmitter receptor maturation, and higher energy expenditure.
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At present, there is no clinically proven brain-targeted therapy for hypoxic-ischemic encephalopathy. It is likely that targeted therapies, spanning prehospital interventions, intensive care, and rehabilitation, will be required to mitigate hypoxic-ischemic encephalopathy in infants and children after cardiac arrest.
Hypoxic-ischemic encephalopathy (HIE) in children surviving cardiac arrest is a significant public health problem that confers a lifelong burden on patients and families. Despite the lack of new targeted therapies for HIE, outcomes for some children after in-hospital pediatric cardiac arrest are improving, which is likely multifactorial. Beginning in 2002, clinical trials of targeted temperature management (TTM) for neuroprotection in adults and neonates showed promise for therapeutic hypothermia compared with uncontrolled normothermia. More recent trials showed no difference between hypothermia at 33°C compared with 36°C in adults and a nonsignificant trend between hypothermia and normothermia in children. Even the optimal supportive care and monitoring to minimize secondary organ injury and maximize recovery after cardiac arrest are controversial. Thus, a proven effective treatment protocol that reliably prevents HIE and improves neurologic recovery after cardiac arrest in infants and children remains elusive. These trials did, however, spur a resurgence in quality improvement and research aimed in improving survival following cardiac arrest, which is positively impacting outcomes.
A key question is whether more advanced monitoring of the brain with titration of supportive care, at least in part, to brain-related pathophysiologic derangements will improve outcomes. This question arises from the pathobiological complexity of cerebral injury and the limitations to monitoring key metabolic and physiologic parameters in the brain. This question is beginning to be addressed in both preclinical and clinical investigations via brain tissue oxygen monitoring and intracerebral microdialysis. , Clinical stumbling blocks in the history of brain resuscitation have also slowed our understanding of HIE after cardiac arrest. Historically, this entity was largely ignored as a specific disease process. Brain resuscitation was dealt with as a single therapeutic paradigm regardless of the etiology. This resulted in the unproven application of results from studies of traumatic brain injury (TBI), stroke, Reye syndrome, and cerebral protection to patients sustaining cardiac arrest. Second, within cardiac arrest, etiologies and patient-relevant biologic factors are lumped together. Factors influencing neurologic damage and recovery are clearly different depending on the cause (asphyxia, arrhythmia, hemorrhage, trauma, sepsis, and others), age, comorbidities, genetic factors, interval between arrest and return of spontaneous circulation (ROSC), and effectiveness of cardiopulmonary resuscitation (CPR).
This chapter reviews the epidemiology, outcomes, and pathobiology of HIE with emphasis on cellular mechanisms, pathophysiology, and histopathology. Differences between the most prevalent etiologies of cardiac arrest in children (asphyxia versus cardiac arrhythmia) are examined, and an appraisal of traditional and novel therapies is presented. Finally, any discussion of HIE in children is complicated not only by the specific mode of arrest in children but also by the unique nature of these young patients. The child’s brain is still developing, adding another layer of variability in terms of age-specific pathologic and reparative mechanisms, potential for therapies to afford benefit, evaluation of therapeutic effectiveness, and neurologic outcome. Therefore the effect of the host’s immaturity on the pathobiology of HIE is also discussed.
Epidemiology
In the United States, cardiac arrest occurs in 8 to 20 per 100,000 children per year in the out-of-hospital setting and in 1 of every 1000 pediatric hospital admissions, resulting in roughly two to three times as many in-hospital as out-of-hospital cases. Males have an increased frequency of cardiac arrest (60% vs. 40% for females), but there are no sex differences in mortality. More than half of children with out-of-hospital, and nearly all children with in-hospital, cardiac arrest have underlying comorbidities. ,
Asphyxia is the most frequent cause of cardiac arrests and the principal cause of HIE in children. , In asphyxial arrest, asystole, bradycardia, or pulseless electrical activity (PEA) is preceded and precipitated by a period of hypoxemic or anoxic perfusion. Studies now define the cascade of events that ultimately leads to no flow during asphyxia, revealing specific cardiovascular phases and remarkable brain-heart interactions. Hypoxia most commonly results from submersion accidents, airway obstruction, pulmonary aspiration, severe asthma or pneumonia, inhalation injury, drug ingestion, or apnea syndromes. , , In ventricular fibrillation (VF)–induced cardiac arrest, respiration ceases shortly after loss of perfusion pressure. VF also occurs in children, but at an estimated incidence of <10% of pediatric victims of cardiac arrest overall.
Nearly all in-hospital events are witnessed, with bystander CPR performed by healthcare personnel. Less than one-third of out-of-hospital events are witnessed, with 30% to 50% of those children receiving bystander CPR; this distinction influences outcome. , The largest proportion of unwitnessed out-of-hospital cardiac arrest occurs in infants (86%), the age group with the worst outcomes.
Mechanisms of hypoxic-ischemic brain injury
Cerebral neurons in culture can tolerate hours of extreme hypoxia. Although it takes about 160 minutes of exposure to an anoxic gas mixture for oxygen tension in the culture medium to reach 1 mm Hg, cortical neurons tolerate 1 to 3 additional hours with little histologic change ( eFig. 65.1 ). If 1 mmol/L sodium cyanide is used to simulate immediate anoxia, hippocampal neurons become swollen and vacuolated within 20 to 60 minutes and begin to disintegrate in 4 hours. Similarly, even 1 hour of complete global brain ischemia in monkeys is followed by electrophysiologic recovery of many neurons and significant recovery of some aspects of brain metabolism, such as protein synthesis. Although the time limit for consistently normal outcome after normothermic cardiac arrest is unknown, it is certainly closer to 5 to 10 minutes than 1 to 3 hours. Restoration of integrated brain function—that is, neurologic recovery—differs markedly from physiologic or metabolic cellular recovery. The functional specificity and interactions of neurons and glia in the brain make patchy areas of cell death potentially devastating. This is evident in the neuropathology of dogs in persistent coma 1 week after a 10- to 15-minute cardiac arrest in which only scattered, regional neuronal death is evident. Cardiac arrest is unique from other forms of focal brain ischemia and nonischemic brain injury in that survival requires reperfusion. Therefore, reperfusion injury is a mandatory part of the postischemic recovery period and likely contributes to the unique phenotype of HIE.
Energy failure
The brain depends on large amounts of energy substrate (glucose and lactate) and oxygen because of its tremendous metabolic demands and paltry energy stores. Interruption of cerebral blood flow (CBF) results in loss of consciousness and electroencephalographic silence within seconds. Within 5 to 7 minutes, energy failure occurs, accompanied by disturbances of ion homeostasis in neurons and glial cells. Rapid depletion of brain high-energy phosphates has been demonstrated after neonatal hypoxia-ischemia using phosphorus magnetic resonance spectroscopy (MRS). Influx of sodium and water and efflux of potassium occur because the cells cannot maintain their energy-dependent electrochemical gradients. When the extracellular potassium concentration reaches 10 to 15 mmol/L, voltage-gated channels open and extracellular calcium influx occurs. As mitochondrial bioenergetics are profoundly disturbed after cardiac arrest, the inability to replenish energy substrates exacerbates energy failure.
If CBF remains inadequate and energy failure persists, calcium-mediated events such as phospholipase and protease activation can lead to irreversible injury and neuronal cell death. Cerebral acidosis deepens during this time. If CBF is restored, recovery of basal cellular metabolism (adenosine triphosphate [ATP] levels, protein synthesis, oxygen consumption) and pH occurs. This has been shown in brain tissue samples and intact brain measurements after global ischemic insults that result in a persistent minimally conscious state. Though the recovery of aerobic metabolism is essential for good outcome, it is not sufficient. Despite global metabolic recovery, certain neurons progress to cell death. After restitution of CBF and oxidative metabolism, cells may die via immediate necrosis (complete energy failure), programmed cell death (apoptosis, autophagic stress, or regulated necrosis), or a spectrum of these processes (see also Chapter 83 ). Brain MRS demonstrates early (during ischemia) and late (48 hours after reperfusion) depletion of high-energy phosphorous compounds and a corresponding lactate peak occurring in the face of normal vital signs, serum glucose, and arterial oxygen saturation after experimental hypoxia-ischemia. ,
Selective vulnerability
Certain neurons—such as those in the CA 1 region of the hippocampus; basal ganglia; cerebral cortical layers III and V; portions of the amygdaloid nucleus; the cerebellar Purkinje cells; and, in infants, periventricular white matter regions and some brainstem nuclei—are known to be especially vulnerable to global hypoxia-ischemia and reperfusion. , Five minutes of complete global brain ischemia produces cell death in these regions starting at 48 and 72 hours, without apparent histologic damage in other brain areas.
While transient calcium accumulation occurs in all cells during ischemia, secondary irreversible accumulation occurs many hours later in the selectively vulnerable zones. It is hypothesized that ischemic and early postischemic calcium accumulation leads to a complex sequence of derangements in cellular metabolism, such as protease activation and oxygen-derived free radical formation. Calcium accumulation may also depress mitochondrial respiration. These conditions, in concert with excessive release of excitatory neurotransmitters (glutamate, glycine, aspartate) lead to excitotoxicity and cell death. In neuronal culture, calcium influx accompanies cell death in the presence of anoxia or supraphysiologic levels of excitatory amino acids such as glutamate, , and CA 1 cells are the most sensitive to glutamate-mediated injury. Finally, delayed energy depletion, mitochondrial dysfunction, and infarction occur in concert but are regionally distinct, suggesting that metabolic characteristics of brain regions affect recovery from ischemia.
Of particular interest is that these intrinsically vulnerable cells do not have a unique vascular distribution. They represent neither vascular watersheds nor hypoperfused zones during reperfusion. Death of these neurons after a threshold ischemic insult occurs in a delayed fashion following reperfusion. Thus, it may be preventable by treatment, at least in part.
Cell death mechanisms
Cell death can occur by multiple distinct pathways—for example, necrosis, apoptosis, or autophagy. However, overlap and combination exist. A number of additional neuronal death pathways—including necroptosis, pyroptosis, and ferroptosis—have been identified, although their contribution to brain injury after cardiac arrest remains to be defined. , Nevertheless, in any given brain region irrespective of the neuronal death pathway that is activated, a highly complex series of events occurs during the arrest and after ROSC. A theoretic scheme of the mechanisms involved is provided in Fig. 65.2 , a scheme that remains remarkably contemporary despite being conceptualized in the 1990s by Bellamy, Safar, and others.
), although this pathway is of questionable importance in neurons ( X, xanthine; UA, uric acid). Excitatory amino acid neurotransmitters (EAA), particularly glutamate and aspartate, increase in extracellular fluid. Increased [EAA] e activates N -methyl- d -aspartate (NMDA) and non-NMDA receptors (R), thereby increasing calcium and sodium influx and mobilizing stores of [Ca 2++ ] i. Increased extracellular potassium activates EAA receptors by membrane depolarization. Glycolysis during hypoxia results in anaerobic metabolism and lactic acidosis until all glucose is used (in the brain, during anoxia after <20 minutes). This lactic acidosis, plus inability to wash out CO 2 , results in mixed tissue acidosis that adversely influences neuronal viability. The net effect of acidosis on the cascades during and after ischemia is not clear. Mild acidosis may actually attenuate NMDA-mediated [Ca 2++ ] i accumulation. Without reoxygenation, cells progress via first reversible, later irreversible structural damage, to necrosis at specific rates for different cell types. During reperfusion and reoxygenation (right) , lactate and molecular breakdown products can create osmotic edema and rupture of organelles and mitochondria. Recovery of [ATP] and [Pcr] and of the ionic membrane pump may be hampered by hypoperfusion as a result of vasospasm, cell sludging, adhesion of neutrophils (granulocytes) (N), and capillary compression by swollen astrocytes, which also help to protect neurons by absorbing extracellular potassium. Capillary (blood-brain barrier [BBB]) leakage results in interstitial (vasogenic) edema. Increased concentrations of at least four oxyradical species that break down membranes and proteins, worsen the microcirculation, and possibly also damage the nucleus may be formed: Superoxide anion (O 
) leading to hydroxyl radical (•OH) (via the iron-catalyzed Fe +++ →Fe ++ , Haber-Weiss/Fenton reaction); free lipid radicals (FLR) and peroxynitrite (OONO − -). O 
may be formed from several sources: (1) directly from eicosanoid metabolism; (2) by the previously described XO system; (3) via quinone-mediated reactions within and outside the electron transport chain (from mitochondria [M]); and (4) by activation of NADPH-oxidase in accumulated neutrophils in the microvasculature or after diapedesis into tissue. Increased O 
leads to increased hydrogen peroxide (H 2 O 2 ) production as a result of intracellular action of superoxide dismutase (SOD). [H 2 O 2 ] is controlled by intracellular catalase. Increased O 
further leads to increased •OH, because of conversion of H 2 O 2 to •OH via the Haber-Weiss/Fenton reaction, with iron liberated from mitochondria. This reaction is promoted by acidosis. •OH and OONO − damage cellular lipids, proteins, and nucleic acids. Also, AA is metabolized by the cyclooxygenase pathways to prostaglandins (PGs), including thromboxane A 2 , or by the lipoxygenase pathway to produce leukotrienes (LTs), and by the cytochrome P-450 pathway. These products can act as neurotransmitters and signal transducers in neuronal and glial cells and can activate thrombotic and inflammatory pathways in the microcirculation. Inflammatory reactions after ischemia have been shown to occur in extracerebral organs, focal brain ischemia, or brain trauma. To date, they have not been demonstrated after temporary complete global brain ischemia. Neuronal injury can signal interleukin-1 and other cytokines to be produced and trigger endogenous activation of microglia, with additional injury ( QA, quinolinic acid). In addition, tissue or endothelial injury—particularly associated with necrosis—can signal the endothelium to produce adhesion molecules (intercellular [ICAM], e-selectin [e-sel], p-selectin [p-sel]), cytokines, chemokines, and other mediators, triggering local involvement of systemic inflammatory cells in an interaction between blood and damaged tissue. Reoxygenation restores [ATP] through oxidative phosphorylation, which may result in massive uptake of [Ca 2++ ] i into mitochondria, which are swollen from increased osmolality. Thus, mitochondria loaded with bound [Ca 2++ ] may self-destruct by rupturing and releasing additional free radicals. Increased [Ca 2++ ] i by itself and by triggering free radical reactions may result in lipid peroxidation, leaky membranes, and cell death. Neuronal damage can be caused, in part, by increased EAA (excitotoxicity). During reperfusion, [Ca 2++ ] i and increased EAAs normalize. Their contribution to ultimate death of neurons is more likely through the cascades that they have triggered during ischemia. During ischemia and subsequent reperfusion, loading of cells and calcium maldistribution in cells are believed to be the key trigger common to the development of cell death. This calcium loading signals a wide variety of pathologic processes. Proteases, lipases, and nucleases are activated, which may contribute to activation of genes or gene products (i.e., caspases [ Casp ] or P53 ) critical to the development of programmed cell death (PCD, i.e., apoptosis, autophagy, or regulated necrosis), or inactivation of genes or gene products normally inhibiting this process. Activation of nNOS by calcium can lead to production of nitric oxide (NO), which can combine with superoxide to generate peroxynitrite (OONO − ). OONO − and •OH both can lead to DNA injury and PCD or protein and membrane peroxidation and necrosis, respectively. Nerve growth factor (NGF) nuclear immediate early response genes (IERG) such as heat shock protein, free radical scavengers (FRSs), adenosine, and other endogenous defenses (ED) may modulate the damage.See ExpertConsult.com and Chapter 83 for additional details.
Neuronal death pathophysiology
Necrosis, which is characterized by denaturing and coagulation of cellular proteins, is the basic pattern of pathologic cell death that results from a progressive reduction in the cellular content of ATP. Necrosis involves progressive derangements in energy and substrate metabolism that are followed by a series of morphologic alterations, including swelling of cells and organelles, subsurface cellular blebbing, amorphous deposits in mitochondria, condensation of nuclear chromatin, and, finally, breaks in plasma and organellar membranes. Although necrotic cell death was traditionally felt to be entirely irreversible, studies showing that some degree of necrotic cell death responds to treatment after hypoxia-ischemia implicate regulated or programmed necrosis, also termed necroptosis. ,
Cell death after hypoxic-ischemic insults can also occur by apoptosis. Development of apoptosis usually requires new protein synthesis and the activation of endonucleases. Two distinct types of characteristic cleavage of deoxyribonucleic acid (DNA) have been described. The most well-described, caspase-dependent apoptosis, involves cleavage by caspase-activated deoxyribonuclease at linkage regions between nucleosomes to form fragments of double-stranded DNA. This produces a pattern of DNA cleavage observed on Southern blot analysis, termed DNA laddering . In contrast, caspase-independent apoptosis results in large-scale DNA fragmentation induced by the mitochondrial flavoprotein apoptosis-inducing factor (AIF). , Selective vulnerable cell death in brain regions such as the CA 1 region of the hippocampus after transient global brain ischemia appears to occur by apoptosis. Thalamic-delayed neuronal death was caused by Fas-mediated apoptosis in a model of neonatal hypoxia-ischemia and durable electrophysiologic disturbances are observed in thalami after asphyxia cardiac arrest in juvenile rats. Li and colleagues reported that apoptosis in the postischemic brain is not limited to scattered neuronal death in what have been traditionally deemed to be selectively vulnerable regions, but it is seen even in penumbral regions around evolving cerebral infarcts (see eFig. 65.1 ). Finally, the proportion of apoptosis in the developing brain after ischemia appears to be sex dependent, as females but not males respond to antiapoptotic agents after neonatal hypoxia-ischemia. Cultures of embryonic neurons from male versus female rats exhibit differential vulnerability to various stresses, underscoring the concept of sexual dimorphism in the development of brain injury though observational studies fail to identify sex as a predictor of outcome following pediatric cardiac arrest.
Autophagy is a homeostatic process that recycles cell resources during periods of nutrient stress. Autophagy is upregulated after experimental brain ischemia, , which can be considered profound nutrient stress. Studies show that blocking autophagy after hypoxia-ischemia can be protective or detrimental. , , As such, autophagy’s role after acute brain injury is controversial, and it may depend on the stage of brain development and sex of the patient, animal, or cell. , Mouse pups lacking Atg7 (a necessary component for autophagy) or rat pups treated with an inhibitor of autophagy (3-methyladenine) are protected from focal hypoxia-ischemia. , Knockdown of Atg7 using small interfering ribonucleic acid (siRNA) was shown to reduce autophagy and Purkinje neuron death in juvenile rats after asphyxia cardiac arrest, with the beneficial effects more prominent in female versus male rat pups.
The proportion of neuronal death that occurs via apoptosis, necrosis, autophagy, or other pathways after cerebral ischemia remains undetermined. , Although neurons may appear histologically normal in the days after reperfusion, electron microscopy reveals changes present within 6 hours. Moreover, it remains possible that treatments inhibiting apoptosis, for example, may simply convert cell death to necrosis or autophagy, or another pathway. , Although speculative, it is possible that after cardiac arrest and resuscitation, a continuum exists in neurons from recovery to necrosis that depends on the duration of the insult, the local milieu, and the given brain region.
Reperfusion injury
Reoxygenation and reperfusion are essential to recovery of any organ after ischemia. Experimental evidence suggests, however, that certain aspects of reperfusion result in tissue injury. , Reperfusion injury is a complex series of interactions between parenchyma and microcirculatory elements resulting in detrimental effects that negate some fraction of the benefits of reperfusion. The magnitude of reperfusion injury varies with the organ in question; the duration and type of hypoxic-ischemic insult; and the timing, duration, and magnitude of reperfusion. ,
In the case of cardiac arrest, ischemia and reperfusion are global events. In the brain, early reperfusion (5–15 minutes) after asphyxia results in significant hyperemia. , In many organs and in the brain after focal insults, progressive microcirculatory failure is thought to be an important aspect of reperfusion injury. Four key mechanisms hypothesized to be important to reperfusion injury in the brain are (1) excitotoxicity and calcium accumulation, (2) protease activation, (3) oxygen radical formation, and (4) membrane phospholipid hydrolysis and mediator formation.
See ExpertConsult.com for additional details.
Anoxia, ischemia, reperfusion pathophysiology
Excitotoxicity and calcium accumulation
Glutamate and aspartate are the major excitatory amino acid neurotransmitters in the mammalian central nervous system (CNS), but both also have neurotoxic properties. Pioneering studies by Rothman demonstrated in vitro that hypoxia-induced neuronal death is mediated by synaptic activity. Inhibition of synaptic glutamate release or blockade of glutamate receptors prevented hypoxia-induced neuronal injury. Glutamate is the major neurotransmitter in the selectively vulnerable zones and accumulates extracellularly at supraphysiologic levels in these regions after hypoxic or ischemic insults. In other regions asphyxia induces significant increases in dopamine, serotonin, norepinephrine, and γ-aminobutyric acid, which are larger than the increases in glutamate in relative, though not absolute, concentrations.
Glutamate is released at the presynaptic terminal in response to neuronal stimulation and acts by binding to postsynaptic dendritic receptors. Two main classes of excitatory neurotransmitter receptors have been identified. One class consists of the ligand-gated ion channels (“ionotropic” receptors) and includes N -methyl- D -aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) or quisqualate, and kainate receptor subtypes. Toxicity caused by NMDA receptor (NMDAR) activation is usually rapid, whereas AMPA or kainate receptor–mediated cell death is somewhat slower to develop. Activation of synaptic NMDARs is neuroprotective whereas activation of extrasynaptic NMDARs by glutamate spillover in ischemia has the opposite effect. The other class of excitatory neurotransmitter receptors includes the metabotropic receptors, which are coupled with G proteins and modulate intracellular second messengers such as calcium, cyclic nucleotides, and inositol triphosphate. When activated, the ionotropic glutamate receptors open sodium channels and may also initiate membrane depolarization and spreading depression. With ionotropic receptor activation, rapid excitatory amino acid–mediated calcium accumulation occurs. In the face of ischemia, this calcium accumulation is exacerbated by cellular energy failure, which disables the sodium-potassium adenosine triphosphatase (Na + /K + -ATPase) membrane pump and results in further calcium accumulation. Calcium influx causes death of neurons in culture under anoxic conditions or in the presence of glutamate. The intracellular accumulation of calcium (1) activates proteases, lipases, and endonucleases, resulting in the breakdown of membrane phospholipids; (2) activates neuronal nitric oxide synthase (nNOS), resulting in nitric oxide (NO) production and, in the presence of superoxide, peroxynitrite formation; (3) damages mitochondria; (4) disrupts nucleic acid sequences; and (5) ultimately mediates cell death via necrosis, programmed necrosis, apoptosis, or autophagy (see Fig. 65.2 ). The disturbance of the finely regulated intracellular calcium homeostasis is now recognized as a possible final common pathway of neuronal death. , , , Studies suggest that approaches targeting calcium-calmodulin–dependent protein kinase II may have promise in protecting against neuronal death.
Protease activation
Protease activation, resulting from increases in intracellular calcium, plays a central role in mediating both necrosis and apoptosis. Both calpains and caspases are activated in the brain after cardiac arrest and contribute to injury. Calpains are calcium-dependent cytosolic cysteine proteases with a homeostatic role in cell cycle regulation and signal transduction, which mediate proteolysis of cytoskeletal proteins and activation of protein kinase C and phospholipases, resulting in necrosis. Calpains also proteolyze the sodium/calcium exchanger in neurons during excitotoxicity, creating a positive feedback loop that worsens extrasynaptic NMDA excitotoxicity. The caspase family of cysteine proteases may have a more prominent role in the developing versus mature mammalian brain. , After unilateral hypoxic-ischemic brain injury, neonatal rats had increased cytochrome C release and caspase-3 activation versus juvenile and adult rats. Regulation of apoptotic machinery also appears to be sex dependent after neonatal hypoxic-ischemic brain injury. Comparatively, female rats had more caspase-mediated apoptosis, whereas male rats had more caspase-independent, AIF-mediated apoptosis.
Oxygen radical formation
Toxic oxygen radical species produced during postischemic reperfusion have been implicated as important contributors to reperfusion injury and delayed cell death. The primary species of interest include superoxide anion, hydrogen peroxide, hydroxyl radical, and the reactive nitrogen species peroxynitrite. Very high, pathologic levels of free radical generation occur in the brain early in reperfusion, with resolution within the first hour.
A major source of reactive oxygen species upon reperfusion after cardiac arrest is the mitochondrion. , , Superoxide generation early in reperfusion is driven by reverse electron transport from complex II to complex I as accumulated succinate is metabolized. Mitochondrial oxidative stress after cardiac arrest and TBI results in oxidation of the unique mitochondrial lipid cardiolipin by cytochrome C in the inner mitochondrial membrane. , Inhibition of cardiolipin oxidation using a mitochondrial-targeted nitroxide improved outcome in a preclinical model of pediatric asphyxial cardiac arrest.
Other potential sources of reperfusion reactive oxygen species include (1) nicotinamide adenine dinucleotide phosphate (NADPH) oxidase isoforms (Nox1, Nox2, and Nox4) ; (2) the cyclooxygenase, lipoxygenase, and cytochrome P-450 pathways, in which metabolism of arachidonic acid may produce superoxide anion as an enzymatic by-product , ; (3) the xanthine oxidase (XO) , pathway, though the importance of XO-mediated free radical generation in humans remains unclear , ; (4) autoxidation of circulating catecholamines or of neurotransmitter catecholamines may represent another potential source of oxygen radicals; (5) delocalized iron, normally transported in the blood tightly bound to transferrin and stored inside the cell bound to ferritin , ; and (6) NO increases via NMDAR stimulation and subsequent calcium-mediated activation of nNOS. NO in the presence of superoxide produces peroxynitrite. However, NO can also serve as a potent antioxidant, and beneficial effects of local release of NO and nitrosylation reactions may underlie promising effects of new therapies, such as nitrite therapy or remote ischemic postconditioning. Free radicals have also been associated directly with an increase release of excitatory amino acids and vice versa. ,
The brain contains a high concentration of polyunsaturated fatty acids—especially arachidonic acid that, on exposure to oxygen radicals, results in autocatalytic lipid peroxidation. Cerebrospinal fluid has low concentrations of iron-binding proteins; therefore, iron released from injured neurons or glia is likely to contribute to these peroxidation reactions. Lipid peroxides accumulate in the selectively vulnerable zones during reperfusion after transient forebrain ischemia. , These peroxides only accumulate following reperfusion.
Oxidative damage impacts brain proteins after reperfusion. Pyruvate dehydrogenase, a key mitochondrial matrix enzyme that converts pyruvate into acetyl-coenzyme A, undergoes oxidative protein modification after ischemia that impairs enzyme activity, possibly contributing to neuronal cell death ; oxidative damage to DNA could also play a role. Developmental and sex differences exist in terms of the degree of oxidative stress and amount and function of antioxidant enzymes after brain injury. In mice, glutathione and catalase activity in the brain are higher in adult female versus male mice; discrepancies become more exaggerated with age. Furthermore, neurons from male rats have less capacity to replenish glutathione levels after cytotoxic stress in vitro and in vivo after asphyxial cardiac arrest.
Membrane phospholipid hydrolysis and mediator formation
Membrane phospholipids modulate signaling cascades, affecting the development, differentiation, function, and repair of the CNS, functions that become dysregulated with ischemia and oxidative stress. Free fatty acids (FFAs) are released from neuronal membranes during ischemia; the amount of FFA released is proportional to the duration of ischemia. FFA release continues to change in proportion to duration of ischemia after the completion of energy failure. The FFAs released then have potential detrimental effects during the postischemic period by multiple mechanisms: (1) arachidonic acid metabolism via the cyclooxygenase pathway may contribute to oxygen radical production during reperfusion ; (2) FFAs and diacylglycerol directly increase membrane fluidity, inhibit ATPases, increase neurotransmitter release, and uncouple oxidative phosphorylation; (3) enzymatic oxidation of arachidonic acid during reperfusion by cyclooxygenase, lipoxygenase, or cytochrome P-450 produces a large number of bioactive lipids, including prostaglandins, thromboxanes, leukotrienes, and hydroxyl-fatty acids, many of which mediate detrimental effects (see Fig. 65.2 ); and (4) release of lipid mediators from oxidized cardiolipin by phospholipase A 2 γ. Studies suggest that the cytochrome P-450 metabolite 20-hydroxyeicosatetraenoic acid may play a role in producing cortical vasoconstriction after cardiac arrest, and inhibitors of the responsible enzyme are being investigated as a possible therapy for cardiac arrest. This pathway also appears to play a role in the development of brain edema after cardiac arrest.
Endogenous defenses
Several endogenous neuroprotectants are produced, induced, or activated after ischemia, and their postulated or proven functions improve cell (specifically neuronal) survival in in vivo and in vitro models. The heat shock proteins (HSPs) are induced after ischemia and TBI. Simon and colleagues showed that after global ischemia, the 72 kDa HSP72 is temporally expressed in a pattern that mirrors the pattern of selective vulnerability in the model, seen first in the CA 1 region of the hippocampus, followed by CA 3 , cortex, and thalamus, and, finally, in the dentate granule cells. HSP72 is also induced in both gray and white matter of piglets following mild and severe hypoxia. The HSPs have generated major interest as potential neuroprotectants because their prior induction by a sublethal stress can afford protection from subsequent injury. Transient, subthreshold whole-body hyperthermia reduces subsequent ischemic brain injury in both adult and neonatal rats. Furthermore, exogenous HSP72 reduces glutamate toxicity in neuronal cell cultures. Importantly, overexpression of HSP72 reduces ischemic damage and apoptosis after experimental stroke and global ischemia in vivo.
Another potential mechanism for endogenous neuroprotection is the upregulation of genes that inhibit apoptosis and augment neurogenesis. The mammalian gene Bcl-2 , a proto-oncogene, can block apoptosis and perhaps necrosis as well. The Bcl-2 gene is expressed in neurons surviving both focal and global ischemia , and is reduced in degenerating neurons after cardiac arrest in rats. Viral transfection of Bcl-2 reduces infarction after focal ischemia, and upregulation of Bcl-2 via ceramide administered 30 minutes after hypoxia-ischemia reduced the number of cells with DNA damage in the immature rat brain. Forced overexpression of the BCL-2 family member BCL-XL also reduces tissue damage after focal cerebral ischemia in adult rats. After TBI in infants and children, cerebrospinal fluid levels of BCL-2 are increased in patients who survive compared with those who die. Finally, BCL-2 overexpression promotes neurogenesis in adult mice with and without ischemic injury.
Adenosine is an endogenous biochemical mediator that may serve a protective role after cerebral ischemia, particularly early after injury. It may be produced from ATP breakdown or via the more recently discovered 2,3 cyclic adenosine monophosphate adenosine pathway that has been shown to exist in the brain. Adenosine is increased in brain tissue after experimental ischemia and in response to hypoxia, hypotension, and hypoglycemia. When bound to A2 receptors, adenosine is a potent cerebrovasodilator and inhibits platelet activation and neutrophil function. Bound to A1 receptors, adenosine reduces neuronal metabolism and excitatory amino acid release and stabilizes postsynaptic membranes. Thus, the beneficial effects of adenosine after cerebral ischemia include improved regional CBF, reduced local oxygen demand, attenuation of both excitotoxicity and calcium accumulation, and antiinflammatory and rheologic effects. Finally, adenosine agonists have been shown to improve survival of selectively vulnerable neurons after ischemia in many studies (reviewed in Rudolphi and coworkers ).
Clinical pathophysiology
Cerebral blood flow and metabolism after resuscitation
Detailed regional and temporal CBF patterns in the early postresuscitation period have been ascertained from animal models, as patients’ clinical instability does not allow early and serial CBF assessment with current state-of-the-art techniques such as arterial spin label magnetic resonance imaging (ASL-MRI). The pioneering studies in which global CBF was measured in animal models of global ischemia showed that after 15 minutes of global brain ischemia in dogs, CBF transiently increased to levels well above baseline for 15 minutes, followed by progressive reduction to a level below normal for the remainder of the monitoring period (90 minutes). This pattern of early transient postischemic hyperemia and subsequent delayed postischemic hypoperfusion has been observed in many global cerebral ischemia models, including both VF and asphyxial arrest. , The levels of hyperemia and subsequent hypoperfusion vary in relation to the duration of the insult. Although these phases of increased and decreased CBF characterize the net global effect, regional CBF is often heterogeneous, particularly during postischemic hypoperfusion, when areas of decreased and increased perfusion may coexist. , , The ability of antioxidants to blunt reperfusion hyperemia suggests it may be the result of oxidative signaling involving the neurovascular bundle.
The heterogeneous- and duration-dependent nature of postarrest CBF was characterized using contemporary imaging techniques allowing for regional assessment and a clinically relevant model of pediatric asphyxial cardiac arrest. Using ASL-MRI, CBF was measured for the first 3 hours after 8.5, 9, or 12 minutes of asphyxial cardiac arrest in postnatal day 17 rats—approximating a 1- to 4-year-old child in terms of brain development (see Chapter 58 ). Although the pattern of early global hyperemia followed by hypoperfusion similar to that observed after global ischemia was seen after asphyxial arrests lasting 8.5 and 9 minutes, a pattern of global and persistent hypoperfusion was observed as the arrest duration increased to 12 minutes ( Fig. 65.3 ). Remarkably, CBF disturbances were also found to be region dependent after asphyxial arrests lasting 8.5 and 9 minutes, with subcortical hyperemia but cortical hypoperfusion (see Fig. 65.3 ). After a 12-minute asphyxial arrest, hyperemia was absent and only hypoperfusion was observed in both cortical and subcortical regions. CBF was pressure-passive with epinephrine infusion, perhaps indicating loss of autoregulation after a prolonged arrest. This is consistent with descriptions of increased loss of neurovascular coupling with longer global ischemic durations. CBF disturbances after reperfusion also depend on the type of cardiac arrest, asphyxial versus VF. For the same duration of cardiac arrest, asphyxial cardiac arrest produced marked early hyperemia in both cortex and thalamus, whereas VF cardiac arrest produced modest early hyperemia only in the cortex. Thirty minutes postresuscitation, both asphyxial and VF cardiac arrests displayed hypoperfusion, more pronounced in the hippocampus. Invasive measurement of brain tissue oxygenation (PbtO 2 ) is a marker of local oxygen extraction fraction and, when coupled to assessment of CBF, is a surrogate marker of cerebral metabolism. In the rat pediatric asphyxial cardiac arrest model, postresuscitation cortical PbtO 2 values decreased below baseline by 30 minutes and remained low at 2 hours. In contrast, significant hyperoxia was observed in the thalamus 5 minutes after ROSC, decreasing to normal values over 2 hours. Notably, PbtO 2 was a fraction of inspired oxygen (F io 2 ) dose responsive in both brain regions. This suggests that early cortical hypoperfusion after an asphyxial arrest does not represent a coupled blood flow response to reduced cerebral metabolism. Rather, it represents secondary ischemia given the critical values of PbtO 2 that are observed. In contrast to the cortical hypoxia seen after pediatric asphyxia cardiac arrest, cortical PbtO 2 was increased in a swine model of VF arrest, suggesting that the CBF response after cardiac arrest may depend on arrest phenotype. The PbtO 2 changes parallel the early cortical hyperemia after VF and highlight the age and insult type reperfusion differences. Marked hyperoxia was observed in the cortex at 15 minutes after ROSC using an F io 2 of 1.0 and at 1 hour after ROSC, even when the F io 2 was reduced to 0.5.
At the level of the microcirculation, earlier studies described capillary stasis, classically described as the no-reflow phenomenon , as discrete areas of the brain with absent perfusion after ROSC. Recently, in vivo microscopy in animal models of cardiac arrest allowed examination of microcirculatory disturbances and both confirmed and provided a detailed description of the no-reflow phenomenon. After pediatric asphyxial cardiac arrest, vasoconstriction of the pial arterioles was also observed early after the insult, along with capillary stasis in 25% of the capillaries. The no-reflow phenomenon was observed to be a dynamic process, with some capillaries with no reflow early after ROSC regaining flow at later time points and other patent capillaries developing no reflow at a later time point.
In patients with favorable outcomes, global CBF recovers over the subsequent 24 to 72 hours, and carbon dioxide (CO 2 ) reactivity remains intact. Patients who do not regain consciousness or progress to brain death may develop absolute or relative CBF hyperemia with impaired CO 2 reactivity, although the delayed patterns of CBF after cardiac arrest in children merit additional exploration, particularly with regard to their relationship to regional brain injury and overall prognosis. , A theoretic scheme of postarrest global CBF and its relation to neurologic outcome is presented in Fig. 65.4 , and the existing clinical literature is summarized later. Most studies in experimental animal models of asphyxial arrest suggest a similar pattern of CBF and cerebral metabolic rate for oxygen (CMRO 2 ) to that observed after VF cardiac arrest and global ischemia in the early postresuscitation period in humans. , However, there are some exceptions. Results from clinical studies of pediatric asphyxial arrest are scarce and somewhat conflicting regarding the prognostic implications of high or low values of postarrest CBF based on a single measurement. However, loss of CO 2 reactivity appears to be associated with poor outcome in all studies. In studies of children between 24 and 48 hours after drowning, Ashwal and colleagues observed low CBF in the seven nonsurvivors and no relationship between CBF and partial pressure of arterial carbon dioxide (Pa co 2 ) in these patients—again suggesting loss of CBF reactivity to changes in Pa co 2 . In this study, hyperemia was not routinely observed in either survivors in a persistent vegetative state or children who died, but only a single CBF measurement was made in these patients. Beyda obtained serial measurements of postarrest xenon in a series of children who suffered asphyxial arrest from drowning. Children with favorable neurologic outcomes had slightly decreased CBF values at 12 hours that increased to normal during the subsequent 24 to 60 hours. In these children, CBF reactivity to CO 2 was intact. Children with eventual vegetative outcome or brain death exhibited hyperemia with loss or attenuation of CO 2 reactivity. This hyperemia progressed to low or normal flow over the following 12 to 72 hours in children with vegetative outcome (minimally conscious state) and progressed to low and then no flow with the development of brain death. A pilot pediatric study found that time spent under the optimal mean arterial pressure range in which autoregulation was present, based on an infrared cerebral oximetry-arterial pressure–based system, was predictive of poor outcomes. ASL-MRI techniques have been developed that do not require contrast material injections. In a small study that included both adults and children, global hyperemia was demonstrated after cardiac arrest at varying time points. In neonates with HIE, hyperperfusion occurred in regions with concurrent water diffusion abnormalities, implying a potential pathophysiologic linkage between the two observations, but patient outcomes were not reported.
Brain metabolism, as assessed by CMRO 2 , is reduced during the early postischemic period in preclinical models and then progressively recovers to a level that varies depending on the model used and duration of ischemia. , In some models, including VF arrest in dogs, significant recovery of CMRO 2 may occur during the first few hours, despite persistent postischemic hypoperfusion—creating the potential for a secondary ischemic insult during reperfusion. Whether this increase in CMRO 2 represents appropriate synaptic activity, seizures, or basal metabolism is not certain. In other models and in descriptions of adult cardiac arrest, global CBF and CMRO 2 were matched during the first few hours after ischemia with delayed relative global hyperperfusion.
Cerebral microdialysis has been used in pilot studies to assess for alterations in metabolism after cardiac arrest. Using microdialysis in a porcine model of cardiac arrest, increased lactate/pyruvate ratios were found during arrest and again in a delayed fashion, especially if the animals were maintained normothermic versus hypothermic. This same group found increased lactate/pyruvate ratios and glutamate using microdialysis in adult survivors after cardiac arrest, all of whom were treated with hypothermia. Prolonged increases in brain lactate detected using proton MRS after global hypoxia-ischemia in children have also been reported. , , Oxidative stress decreases the function of the pyruvate dehydrogenase, a key enzyme complex in oxidative metabolism, possibly contributing to the shift to anaerobic metabolism. Although routine monitoring of CBF, CMRO 2 , or PbtO 2 has not been applied extensively to the postarrest setting in children, their routine assessment using contemporary methods may possibly lead to an improved understanding of pathophysiology and serve as a potential target for the titration of brain-directed therapy (see Chapter 60 ).
Histopathology of hypoxic-ischemic encephalopathy
Ischemic neuronal change, as first described by Sommer in 1880 and later by Spielmeyer, involves a progression from extensive cellular microvacuolation to a cell that resembles a naked shrunken nucleus. As described by Brierley and colleagues, “this type of neuronal damage is neither ubiquitous nor randomly distributed but is found in regions which exhibit selective vulnerability to hypoxic stress.” As discussed previously, death of selectively vulnerable neurons (e.g., hippocampal CA 1 ) cannot be explained by vascular distribution. Remarkably, these clinical descriptions of cell shrinkage were consistent with apoptosis rather than necrosis. However, the connection between selective vulnerability and apoptosis was made 100 years later. Neuronal death after cardiac arrest is seen not only in the selectively vulnerable neurons but also as a subtle histopathologic finding in the arterial boundary zones. These neurons (not otherwise selectively vulnerable) are in the most poorly perfused areas during or after resuscitation. Neuronal death in the arterial boundary zones was elegantly described by Nemoto and associates in a monkey model of 16 minutes of complete global brain ischemia followed by 7 days of intensive care. Maximal damage appeared to be in the classically described selectively vulnerable zones, but neuronal death was also observed in the most distal distribution of the posterior cerebral artery and in the watershed zones of the anterior and middle cerebral arteries. With sufficient injury in the arterial boundary zone, more severe findings can be seen, such as microinfarction or laminar necrosis. , As previously discussed, even in stroke, neuronal death in an ischemic penumbra can occur either by necrosis, apoptosis, or, potentially, some of the other aforementioned neuronal death pathways, such as necroptosis, ferroptosis, pyroptosis, or autophagy. Thus, it appears that there may be a continuum between apoptosis, alternative neuronal death pathways, and both programmed and “unprogrammed” necrosis that may depend on a large number of factors, such as duration of the insult and brain region in question. Recently, ferroptosis has emerged as potentially playing a key role in ischemia reperfusion injury. Ferroptotic cell death is regulated by numerous biological processes, such as fatty acid metabolism and glutathione synthesis, including induction of the selenoprotein glutathione peroxidase-4 (GPX4). Pharmacologic selenium injection inhibits ferroptotic cell death after both hemorrhagic and ischemic stroke in a GPX4-dependent manner. Importantly, glutathione depletion is thought to be one factor contributing to the pathology of HIE after experimental pediatric asphyxial cardiac arrest, and this appears to be sex dependent. Whereas programmed modes of cell death in a given area often affect only a select percentage of neurons, infarction affects all neurons and all other cell types, including glia and cerebrovascular endothelium. Obviously, if the arrest time is long or if the postischemic conditions are sufficiently poor, infarction of the entire brain can occur.
Vaagenes and colleagues studied neuropathology after primary VF arrest of 10 minutes in dogs. Despite vegetative outcome at 96 hours, only scattered ischemic neuronal changes in the selectively vulnerable neurons and to a much lesser extent in the vascular watersheds were observed. Microinfarct formation was seen in only 5 of 18 dogs, suggesting that patchy ischemic neuronal change is sufficient for vegetative outcome. They then compared this 10-minute VF arrest with an asphyxial episode (airway occlusion) resulting in cardiac arrest with 7 minutes of no flow. Related either to differences in the initial insult or to postischemic events, asphyxial arrest resulted not only in ischemic neuronal change in the selectively vulnerable regions but also in marked microinfarct formation (30 of 32 dogs) and scattered petechial hemorrhages. This more severe histologic injury was seen despite significantly easier ROSC in the asphyxial arrest group ( Fig. 65.5 ). In addition, unlike VF arrest, asphyxial arrest caused some ischemic neuronal changes even after no flow of only 2 minutes. Similarly, worse neurologic injury and neuronal loss was observed in adult rats subjected to asphyxial versus VF cardiac arrest of identical duration (5 minutes) in contemporary studies. Greater neuronal loss was observed after asphyxial cardiac arrest in the hippocampus and cerebellar cortex, despite greater myocardial dysfunction and higher serum lactate after VF of an equal insult duration. These findings may explain the poor outcome generally observed after cardiac arrest in children (usually, asphyxial arrest) compared with that in adult series (often, VF arrest). Indeed, the contemporary report comparing asphyxial versus VF cardiac arrest in rats also included a human observational study in 500 adults that demonstrated similar findings—worse brain injury after asphyxial versus VF cardiac arrest—even when adjusting for insult severity and other confounders. After asphyxial cardiac arrest that results in long-term survival in both adult and pediatric-aged animals, the pattern of neuronal death produced is similar to that reported in human studies, including that of the young victim of asphyxial cardiac arrest, Karen Ann Quinlan, in which a predilection for basal ganglia injury resulting in a persistent minimally conscious state was observed. Finally, studies by Hogler and associates demonstrated the expansion of damage comparing 7 versus 10 minutes of VF cardiac arrest in pigs. Substantial expansion of neuronal death across multiple brain structures—such as the cortex, caudate, and cerebellum—was seen between the 7- and 10-minute durations, and edema appeared in the 10-minute group. These studies shed additional light on the impact of cardiac arrest duration on the extent of neuronal damage given the challenges of defining arrest duration in the human condition.
Advances in magnetic resonance imaging (MRI) during the last decade allow evaluation of regional cerebral volumes and provide anatomic details that corroborate preclinical studies. Reduced hippocampal volumes were observed in eight patients who sustained a brief (<7 minutes) out-of-hospital cardiac arrest. In these patients with favorable neurologic outcome, hippocampi were 10% to 12% smaller at 5 months after cardiac arrest compared with controls. In a similar evaluation of 26 survivors of out-of-hospital cardiac arrest with favorable neurologic outcome, both hippocampal and cortical volumes were reduced at 3 months after cardiac arrest. Furthermore, at 21 days after cardiac arrest, 11 patients in a minimally conscious state had a 26% to 30% reduction of hippocampal volumes and an 8% reduction in temporal lobe volumes. Recent studies attempted to correlate early changes in diffusion-weighted imaging (DWI) with neurologic outcome. Extensive cortical signal abnormalities and hippocampal hyperintensities on DWI may be an indicator of poor prognosis after cardiac arrest.
Clinical outcome and prognostication after pediatric cardiac arrest
Survival and neurologic outcome after out-of-hospital pediatric cardiac arrest are remarkably poor, and evidence suggests meager improvement in outcome as compared with in-hospital pediatric cardiac arrest. , Survival to hospital discharge after out-of-hospital arrest ranges from 8% to 25% and after in-patient arrest from 24% to 51%, with an overall survival of 13%. , , The most common cause of death is neurologic injury for out-of-hospital arrests and cardiovascular failure for in-hospital arrests. Although survival to hospital discharge is higher in pediatric than adult cardiac arrest (except for infants), the proportion of patients with favorable (defined as minimal to no disability) neurologic outcomes is lower, which may reflect in part lesser limitations of life-sustaining therapies in children compared with adults. Favorable neurologic outcome in pediatric patients surviving cardiac arrest is often overestimated using traditional categorical outcome measures such as the Glasgow Outcome Scale score and Pediatric Cerebral Performance Category Scale.
Unlike many other forms of acute brain injury, there is little evidence to support improved functional recovery trajectories between discharge and 1 year postarrest when comparing pediatric with adult cardiac arrest. Late improvements in mobility after cardiac arrest lag those seen after TBI (22% vs. 66%) 2 years after the initial event. In the two Therapeutic Hypothermia after Pediatric Cardiac Arrest (THAPCA) studies, 71% of the 160 surviving children who underwent neuropsychological testing had a favorable outcome on the Vineland Adaptive Behavior Scales–II. However, on further testing, one-quarter of those children had global cognitive impairment and 86% had selective neuropsychological deficits 1 year postarrest, highlighting the need for tracking longitudinal outcomes and support for recovery. Families from the out-of-hospital THAPCA study had increased evidence of burden during the year following their child’s arrest, with burden related to the child’s functional status.
High mortality and poor outcome after cardiac arrest in children generally represent out-of-hospital or unwitnessed cardiac arrests. This is particularly true in infants, for whom the proportion of bystander CPR is the lowest and asphyxial arrests are the highest. , Recovery is much better in children who had witnessed arrests, recovery of pulses prior to hospital arrival, cold water submersion, or isolated respiratory arrest, for whom intact survival rates as high as 44% to 75% have been reported. , , These clinical data seem to reflect the severe neuropathology observed in experimental asphyxia-induced arrest given that asphyxia is the most common mode of cardiac arrest in all of the clinical pediatric series. , , ,
Clinical factors—such as initial pH, number of epinephrine doses, and arrest duration—have been examined in both classical and contemporary studies in an attempt to prognosticate outcome from cardiac arrest. Although sometimes predictive, this information can be misleading. For example, the time delay before analysis of the first blood sample can vary, as can estimates of arrest duration. With asphyxial arrest, even controlled experimental animal studies show that the time from asphyxia until cardiac arrest varies considerably. Currently, the most powerful individual predictor of neurologic outcome after cardiac arrest is the trajectory of neurologic examination over time in the absence of confounding factors such as sedation, neuromuscular blockade, and impaired recovery of other organ function (see Chapter 60 ). As noted in one review, abnormal pupillary reactivity and motor response 24 hours postcardiac arrest in the absence of sedation and muscle relaxation medications are useful for prognostication.
The electroencephalogram (EEG) can also provide prognostic information for patients after cardiac arrest. Scollo-Lavizzari and Bassetti retrospectively examined the relation between first postarrest EEG and clinical outcome in 408 cases. A five-grade classification was used to categorize EEGs. Although permanent severe neurologic damage was observed in some patients with grade I EEG, none of the 208 patients with grade IV or V EEGs had a good neurologic recovery. A single-center retrospective case series in children showed that having a burst suppression or electrocerebral silence pattern was associated with poor outcome at hospital discharge, with a positive predictive value of 90% and negative predictive value of 91%. In children who were treated with hypothermia postarrest, seizures were common, largely nonconvulsive, and occurred most frequently during the rewarming period. Detailed quantitative EEG and EEG reactivity may also be important prognostic tools after cardiac arrest in children. ,
Adjunctive prognostic information also can be obtained from brain-derived protein levels in blood components (i.e., serum, plasma). Serum brain biomarker trajectories, including S100b (from astrocytes), neuron-specific enolase (NSE; from neurons), and myelin basic protein (MBP; from myelin), were noted to differ by brain insult. Biomarker trajectories differ by brain injury etiology: levels peaked earlier after accidental TBI, later after hypoxia, and were in between for children with abusive head trauma. Two single-center prospective studies in children with cardiac arrest found that serum S100b and NSE had excellent prognostication accuracy. , Brain-based biomarkers glial fibrillary acidic protein (from astrocytes) and ubiquitin carboxyl-terminal hydrolase L1 (from neurons) showed promise in predicting outcome in a small study. NSE and other biomarkers may be useful in determining responsiveness to therapeutic interventions in trials and would qualify as pharmacodynamics response biomarkers, using current terminology. ,
Somatosensory-evoked potentials (SSEPs) have been used in an attempt to provide early prognostic information after cardiac arrest. SSEPs have strong positive predictive value for poor outcome as early as 24 hours postarrest in children. Auditory-evoked response testing has also been used in children with cardiac arrest after drowning. Normal evoked responses were observed in all children who recovered neurologically intact. Children who recovered with significant handicaps demonstrated a reduction in wave V amplitude over time and prolonged wave I-V interpeak latencies. In adults, bilaterally absent N20 waves at 24 and 48 hours have a reported specificity of 100% in predicting poor outcome after cardiac arrest. However, note that in many studies, the SSEP results were used to guide medical decision-making. Summary recommendations from Abend and Licht have suggested that the absence of bilateral cortical SSEPs are most reliably predictive of outcome when peripheral SSEP responses are present.
The prospective utility of computed tomography (CT) of the brain and other neuroimaging modalities after cardiac arrest is unknown ( Fig. 65.6 ). A head CT scan takes only a few minutes and is useful for ruling out intracranial lesions contributing to the cause of arrest. In a large retrospective case series of children who had drowned, children with any abnormal CT finding (e.g., loss of gray-white differentiation, infarction) within the first 24 hours of admission died. Of children with an initially normal CT scan on the first day who had a subsequent abnormal CT scan, 96% either died or remained in a coma. Another single-center retrospective study in children with cardiac arrest and head CT scan within 24 hours found that loss of gray-white differentiation and basilar cistern effacement were associated with unfavorable outcomes.
Brain MRI can provide excellent regional evidence of brain injury after cardiac arrest without radiation, but it requires longer transport time outside of the ICU. It is typically employed for prognostication subacutely after the patient stabilizes, but findings evolve over time. In one study that used a novel scoring system, damage seen in the cortex and basal ganglia correlated well with neurologic outcome. Cortical abnormalities seen in DWI and injury to the basal ganglia on conventional MRI were predictive of an unfavorable outcome after pediatric cardiac arrest. In a small study of children surviving cardiac arrest, increased CBF using ASL and water restriction frequently occurred in similar brain regions in children, with an unfavorable outcome. Using brain MRS, decreases in the brain metabolite N -acetylaspartate and increases in lactate in the basal ganglia and cortex can assist in outcome determination in children after drowning and cardiac arrest. , ,
However, no particular test or clinical variable will have sufficient accuracy to prognosticate on its own. Combining clinical variables with testing results improves accuracy of outcome prediction. , Development and prospective validation of tests and panels of tests obtained early after cardiac arrest that reliably predict ultimate outcome would be valuable.
Response of the immature brain to cardiac arrest
Clinical and laboratory studies suggest that the neurologic outcome of newborn animals after a hypoxic-ischemic insult is favorable compared with that of adults, although this may be related to the ability of newborn animals to tolerate asphyxia systemically. This is most evident when neonatal and adult experimental models are compared. In newborn monkeys, even 12 minutes of asphyxia did not result in cardiac arrest. In beagle pups, 15 minutes of asphyxia produced hypotension but not cardiac arrest. By comparison, cardiac arrest due to asphyxia in mature large-animal models generally occurs within 6 to 8 minutes. , , Kirsch and associates showed that newborn piglets had better recovery of SSEP and less postarrest hypoperfusion than young adult pigs in the initial 2 hours after global cerebral ischemia. Thus, not only does the cardiovascular response during asphyxia appear to be more robust in immature animals but also the intrinsic sensitivity of the brain to a hypoxic-ischemic insult may be lower. Studies suggest a selective vulnerability of the neonatal brainstem sensory nuclei to asphyxia. , This selective vulnerability may more correctly represent a relative lack of vulnerability of the neonatal cerebral cortex to asphyxia because anoxic perfusion was tolerated for over 12 minutes in immature monkeys, most of which demonstrated no ischemic neuronal change. However, some mechanisms of secondary damage, such as excitotoxicity, appear to be more injurious in the immature brain. , Further complexity is added to processes such as excitotoxicity when the immature brain is involved, as some degree of excitatory stimulation is essential for neuronal survival and normal development. That fact may underscore the recognized vulnerability of developing neurons to sustained (6–8 hours or longer) exposure to certain anesthetics—a process that occurs in developing primates. Finally, greater plasticity in the immature brain may also allow for improved long-term recovery of function, although this may be more important in focal insults. ,
The poor clinical outcome of infants and children presenting in cardiac arrest may be related to specific mechanisms operating in the setting of the asphyxia. As the asphyxial arrest is developing, cardiac standstill is preceded by a variable period of severe hypoxia with increased CBF. During this period, severely hypoxic perfusion—a form of incomplete ischemia—is produced, which can markedly increase cerebral lactate production. The initial phase of asphyxia can also be accompanied by extreme stress during struggling, which could increase CMRO 2 and may be accompanied by systemic hyperglycemia. The combination of hypoxic perfusion or incomplete hypoxia-ischemia and hyperglycemia can increase cerebral lactate concentration to 30 to 35 μmol/g and decrease tissue pH to levels as low as 6.05. These lactate levels are much higher than those observed during even 30 minutes of complete ischemia (11–14 μmol/g) and are above the threshold of 20 to 25 μmol/g, at which lactic acid can produce local coagulation necrosis. In addition, it has been shown that a veritable storm of neurotransmitters is released to extremely high levels during asphyxia prior to reperfusion. Thus the no-flow period that ultimately develops in asphyxial cardiac arrest—in contrast to VF—is occurring in a brain that is already in a severely biochemically compromised state resulting in increased injury after similar durations of no-flow ischemia. ,
Additional clinical factors may worsen pediatric outcomes after cardiac arrest. The relative resistance of the immature myocardium to asphyxia means that it is easier to restore cardiovascular function in younger patients after longer durations of cardiac arrest than would be possible in adults. Thus, ROSC rates are high in pediatrics despite a higher occurrence of asystole than adults. , , Less than half of pediatric arrests are witnessed , , such that bystander CPR, which is therefore delayed, is not associated with improved outcome , , , as it is consistently in adult cardiac arrest. , , , Finally, first responders appear to have more difficulty providing guideline-recommended resuscitation to smaller children compared with adult-sized adolescents. Thus, although pediatric intensivists have the apparent luxury of dealing with a somewhat resistant and more resilient brain, with capacity for plasticity, this advantage is often trivial compared with the devastating pathobiology of the asphyxial arrest. , ,
Treatment after cardiac arrest
Adequate understanding of the pathobiology of HIE after cardiac arrest in children is possible given the development of contemporary models of pediatric asphyxial arrest. These models will hopefully lead to more etiology-specific evaluation of the postresuscitation syndrome in terms of mechanisms and relevant therapies. , Prospective study of clinical targets for supportive postresuscitation care to optimize outcomes is vital.
Field interventions
Pediatric cardiac arrests are usually not sudden in onset, as in adults. Thus, a window of opportunity exists during which interventions could potentially prevent cardiac arrest and associated poor outcome. As discussed, children sustaining isolated respiratory arrest have a mortality rate as low as 25%, whereas patients with cardiac arrests as a result of hypoxemia have a much higher mortality. , Thus, the sooner the recognition and interventions, the better are the chances for a good outcome. The Airway-Breathing-Circulation approach to CPR for children remains fundamental, with exceptions for children with certain conditions or situations. Early activation of emergency medical services (EMS) holds the greatest promise for improving outcomes from prehospital pediatric cardiac arrest. Dispatcher (911) instructions to provide bystander CPR are associated with improved outcomes after pediatric out-of-hospital cardiac arrest, with one report demonstrating a stronger association when conventional CPR that included rescue breathing was instructed. EMS have developed sophisticated methods for dispatch and transport, but there are logistical limits to the rapidity with which they can provide basic interventions. Nationwide, the average response time is well over 8 minutes, greater than the time required for an infant to progress from apnea to cardiac arrest. As a result, more advanced, traditionally hospital-based, and investigational interventions must also be administered in the prehospital setting in attempts to optimize outcome. The quality of CPR delivered by EMS to younger children (1–11 years old) is inferior to adolescents and adults. Toward this end, use of medical simulation has greatly improved both the understanding of the mechanics of quality CPR as well as teaching and training (see Chapters 38 and 39 ).
Supportive care in the intensive care unit
A hypothetical algorithm for the management of infants and children after cardiac arrest is provided in Fig. 65.7 . Postarrest care centers on multimodal monitoring, organ support, and prevention of secondary injury by actively maintaining ventilation, arterial oxygenation, temperature, and blood pressure goals, along with several other aspects of supportive care to minimize HIE.
There is an association between hyperoxia and outcome in both in vitro and in vivo models of brain injury, thought to be a result of increased oxidative stress. , In neonates, two systematic reviews showed a mortality benefit to resuscitating infants with room air versus 100% oxygen. , No long-term developmental outcomes were available; however, these and other data resulted in changes in the approach to neonatal resuscitation.
Although neonates have lower partial pressure of arterial oxygen (Pa o 2 ) prior to delivery, findings in adults with cardiac arrest may provide more insight for children. Kilgannon and colleagues found that hyperoxia (Pa o 2 >300 mm Hg) and hypoxia (Pa o 2 <60 mm Hg) on first arterial blood gas post-ROSC were associated with mortality in adults with cardiac arrest. Several subsequent reports appear to confirm the increased risk beginning when Pa o 2 exceeds 300 mm Hg. A study in children followed, finding an association of extreme hypoxemia (odds ratio [OR], 1.92; 95% confidence interval [CI], 1.80–2.21 at Pa o 2 of 23 mm Hg) and hyperoxia (OR, 1.25; 95% CI, 1.17–1.37 at Pa o 2 of 600 mm Hg) on first arterial blood gas with PICU mortality. However, a single-center retrospective analysis found no relationship between hyperoxia or hypoxia within the first 24 hours post-ROSC with mortality. Similarly, a multicenter retrospective analysis found that although derangements in oxygenation and ventilation were common, there was no association between blood gas parameters in the first 6 hours post-ROSC and survival with favorable neurologic outcome. A prospective multicenter study found that oxygenation was not associated with mortality, but hypocapnia (Pa co 2 <30 mm Hg) and hypercapnia (Pa co 2 >50 mm Hg) were associated with mortality after pediatric cardiac arrest. However, in a large study from Australia and New Zealand, only hypocapnia (Pa co 2 <35 mm Hg) was associated with mortality. Pediatric guidelines recommend resuscitation with 100% oxygen with subsequent titration of oxygen saturations to 94% or greater post-ROSC. ,
Although the optimal cerebral perfusion pattern for neuronal and functional recovery remains to be defined, blood pressure fluctuations, both high and low, adversely affect outcome. In their classic study of the neuropathology of systemic circulatory arrest in immature monkeys, Miller and Myers found that systolic blood pressures at or below 50 mm Hg during the reperfusion period had devastating effects on survival and neuropathology. This occurred even when the ischemic time was less than the 12-minute minimum that caused brain injury in their model. In contrast, Bleyaert and coworkers showed that intermittent episodes of hypertension (mean arterial pressure 150–190 mm Hg) induced with norepinephrine during the first 24 hours after 16 minutes of global brain ischemia in monkeys worsened neurologic outcome. A beneficial effect of transient hypertension during the immediate postresuscitation period has been suggested, hypothesizing that this improves flow in areas with microvascular sludging. Safar and colleagues suggested that transient hypertension was beneficial after cardiac arrest in dogs. However, it was applied as part of a multifaceted treatment protocol, and its specific benefit remains controversial. In a multicenter, observational cohort of children with cardiac arrest, having a blood pressure less than the fifth percentile for age and sex (56% of cohort) within the first 6 hours post-ROSC was associated with increased mortality and worse neurologic outcome. Similarly, in a post-hoc analysis of the out-of-hospital THAPCA trial, children with a systolic blood pressure less than the fifth percentile for age and sex during the first 6 hours after temperature intervention had worse survival outcomes. Recent multicenter observational data showed that diastolic blood pressures during CPR of 25 mm Hg or greater in infants and 30 mm Hg or greater in children were associated with better survival with favorable outcome. Diastolic hypertension in the immediate post-ROSC period is also associated with improved survival after pediatric cardiac arrest although this was not the result of an intervention.
Although seizures may be seen in 30% to 50% of children after cardiac arrest, the use of continuous EEG and/or prophylactic antiepileptics is not standardized. A prospective study showed that 9 of 19 children who received therapeutic hypothermia and continuous EEG monitoring had seizures, many occurring near or during the rewarming period. In 128 children in a single center, EEG within the first 24 hours postarrest showed that lack of background reactivity and seizures were associated with worse outcomes. There is strong theoretic rationale for treating clinical seizures postarrest; however, continuous EEG monitoring and aggressive treatment of postarrest seizures or use of antiepileptics prophylactically have not been associated with outcome improvement.
In clinical practice, patients are encountered who have been successfully resuscitated from an arrest of unknown etiology or have a clinical history suggestive of trauma who demonstrate focal pupillary dilation and/or signs of brain herniation. In this setting, it is appropriate to hyperventilate or to administer mannitol until CT and clinical examination confirm the absence of trauma or a mass lesion. Sustained elevation of intracranial pressure (ICP; >20 mm Hg) has been shown uniformly to predict poor outcome in four series of pediatric drowning, and the ability to control ICP elevations did not result in meaningful survival. Unfortunately, as in VF arrest, the threshold for poor outcome from asphyxial arrest appears to be below the threshold for the occurrence of intracranial hypertension because some patients experience poor outcome despite normal ICP. Routine ICP monitoring and ICP-directed treatment are not currently recommended after asphyxial arrest. , , However, studies using ICP-directed therapy in the era of contemporary neurointensive care have yet to be performed.
The failure of ICP-directed therapy to improve outcome after cardiac arrest and the commonly observed period of hypoperfusion in the first hours to days after arrest seriously question the application of an intervention with the potential to further reduce CBF, such as hyperventilation. , Although irreversible ischemic brain damage has never been demonstrated with hyperventilation, data suggest that it is probably not wise to intentionally or unintentionally hyperventilate patients routinely after arrest, particularly during the period of postischemic hypoperfusion. , , Clinical studies suggest that postischemic hyperemia is accompanied by loss or severe attenuation of the CBF response to alterations in Pa co 2 resulting from severe ischemia. , However, some postresuscitation patients with delayed hyperemia but an intact CBF response to Pa co 2 have been observed ( eFig. 65.8 ).
