e3 Abstract Status epilepticus is a common pediatric neurologic emergency that requires rapid recognition and intervention An operational definition of status epilepticus recommends adminis tration of[.]
e3 Abstract: Status epilepticus is a common pediatric neurologic emergency that requires rapid recognition and intervention An operational definition of status epilepticus recommends administration of an antiseizure medication after minutes of seizure activity; a predetermined pathway/guideline can expedite management Management goals include general supportive care, termination of status epilepticus, prevention of recurrence, correction of precipitating causes, and prevention and treatment of potential complications The longer seizures continue, the more difficult they are to stop with medications However, in some instances, status epileptics progresses to a refractory or superrefractory state for which induced-anesthetic therapies are required Key words: status epilepticus, refractory status epilepticus, superrefractory status epilepticus, FIRES, induced anesthesia, midazolam, pentobarbital 65 Hypoxic-Ischemic Encephalopathy ERICKA L FINK, MIOARA MANOLE, ROBERT S.B CLARK, CAMERON DEZFULIAN, AND PATRICK M KOCHANEK PEARLS • 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 • 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 • 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 inhospital pediatric cardiac arrest are improving, which is likely multifactorial.1 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.2–6 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.7–10 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.1 A key question is whether more advanced monitoring of the brain with titration of supportive care, at least in part, to brainrelated 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.11 This question is beginning to be addressed in both preclinical and clinical investigations via brain tissue oxygen monitoring and intracerebral microdialysis.12,13 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.14 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 to 20 per 100,000 children per year in the out-of-hospital setting and in of every 1000 pediatric hospital admissions,15–17 resulting in roughly two to three times as many in-hospital as out-of-hospital cases.18 793 794 S E C T I O N V I Pediatric Critical Care: Neurologic Males have an increased frequency of cardiac arrest (60% vs 40% for females), but there are no sex differences in mortality.18 More than half of children with out-of-hospital, and nearly all children with in-hospital, cardiac arrest have underlying comorbidities.18,19 Asphyxia is the most frequent cause of cardiac arrests and the principal cause of HIE in children.20,21 In asphyxial arrest, asystole, bradycardia, or pulseless electrical activity (PEA) is preceded and precipitated by a period of hypoxemic or anoxic perfusion.22 Studies now define the cascade of events that ultimately leads to no flow during asphyxia, revealing specific cardiovascular phases and remarkable brain-heart interactions.23 Hypoxia most commonly results from submersion accidents, airway obstruction, pulmonary aspiration, severe asthma or pneumonia, inhalation injury, drug ingestion, or apnea syndromes.15,18,24 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.18 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.24,25 The largest proportion of unwitnessed out-of-hospital cardiac arrest occurs in infants (86%), the age group with the worst outcomes.25 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 mm Hg, cortical neurons tolerate to additional hours with little histologic change26 (eFig 65.1) If 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 hours Similarly, even 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.27 Although the time limit for consistently normal outcome after normothermic cardiac arrest is unknown, it is certainly closer to to 10 minutes than to 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 week after a 10- to 15-minute cardiac arrest in which only scattered, regional neuronal death is evident.28 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 to 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).29 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.30 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.31 If CBF is restored, recovery of basal cellular metabolism (adenosine triphosphate [ATP] levels, protein synthesis, oxygen consumption) and pH occurs.32 This has been shown in brain tissue samples and intact brain measurements after global ischemic insults that result in a persistent minimally conscious state.27 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).33–35 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.36,37 Selective Vulnerability Certain neurons—such as those in the CA1 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.38,39 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.40 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.41 Calcium accumulation may also depress mitochondrial respiration.42 These conditions, in concert with excessive release of excitatory neurotransmitters (glutamate, glycine, aspartate) lead to excitotoxicity and cell death.43 In neuronal culture, calcium influx accompanies cell death in the presence of anoxia or supraphysiologic levels of excitatory amino acids such as glutamate,26,44 and CA1 cells are the most sensitive to glutamate-mediated injury.45 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.46–49 Of particular interest is that these intrinsically vulnerable cells not have a unique vascular distribution.50 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 Numbers of apoptotic cells e794.e1 300 250 200 150 100 50 sham0.5 12 14 21 28 H H H H H D D D D D D D 0.5 12 (H) 14 21 28 (D) • eFig 65.1 Apoptotic cells in coronal brain sections in rats subjected to hours of middle cerebral artery occlusion and between 0.5 and 28 days of reperfusion. Top, Progressive increase in the numbers of apoptotic cells occurs with increasing reperfusion time to peak at 24 hours However, apoptotic cells are still detectable even after week of reperfusion Bottom, Distribution of apoptosis (dots) and necrotic neurons (shaded areas) Apoptotic cells are localized predominately to the inner boundary zone of infarction D, days; H, hours (From Li Y, Chopp M, Jiang N, Yao F, Zaloga C Temporal profile of in situ DNA fragmentation after transient middle cerebral artery occlusion in the rat J Cereb Blood Flow Metab 1995;15:389–397.) CHAPTER 65 Hypoxic-Ischemic Encephalopathy Cell Death Mechanisms 795 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 contemporary55 despite being conceptualized in the 1990s by Bellamy, Safar, and others.56 See ExpertConsult.com and Chapter 83 for additional details 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.33,51–54 Nevertheless, in any given 100 Ca++ Perfusion pressure (mm Hg) M PL Proteases AA CS ATP O2 ↓ XO AMP X HX M Adenosine ED ATP ↓ PCr ↓ Cell (neuron) Cardiac arrest Complete ischemia • Fig 65.2 Death FFA AA O2 Vasospasm Lipid perox R PGs LTs P-450 ++ nNOS→NO ↑Ca SOD XD M EAA Na+ Ca++↑ Nucleus NECROSIS H2O K+ Fe++ ONOO– e-sel ATP(↓) M Capill · O2– • OH p-sel NO N pl Proteases • OH H2O2 Nucleases ICAM Fe+++ FLR IERG ED UA H2O P53 H O↑ M casp FRSs OSMOL↑ Ca++ ED ED + K PCD QA NO RBC H2O↑ NO NGF←IL-1 iNOS O2 ↑ iNOS Endoth NGF BBB ED (ATP)→ Astrocytes Cell (neuron) sludging (PCr)→ Microglia edema→compression · O2– Reperfusion - reoxygenation of cells after temporary ischemia Diagram of complex, partially hypothesized biochemical cascades in neurons during and after cardiac arrest.56 Normally, the intracellular ([Ca211]i) to extracellular ([Ca211]e) calcium gradient is 1:10,000 Calcium regulators include calcium/magnesium adenosine triphosphatase (ATPase), the endoplasmic reticulum (ER), mitochondria, and arachidonic acid (AA) With stimulation, different cell types respond with an increase in [Ca211]i because of the release of bound Ca211 in the ER and influx of [Ca211]e or both During complete ischemic anoxia (cardiac arrest; left), the level of energy (phosphocreatinine [Pcr] and adenosine triphosphate [ATP]) decreases to near zero in all tissues at different rates, depending on stores of oxygen and substrate It is fastest in the brain (