e806 e1 rates 329 Excessive depth is difficult to achieve and rib fractures are very uncommon in pediatric CPR 344 Therefore, American Heart Association guidelines recommend compression of at least on[.]
e806.e1 Achieving High-Quality Cardiopulmonary Resuscitation Human error is a major source of poor-quality CPR Failure to recognize cardiac arrest and to initiate appropriate therapy by physicians-in-training may add several minutes of no-flow time.334 At the time of EMS activation, only 10% of out-of-hospital cases had ongoing bystander CPR and, despite operator instructions to initiate CPR, these efforts were often delayed by several crucial minutes.335 It should be noted that “early” initiation in some cases means starting CPR during bradycardia preceding pulselessness, which is associated with significantly better survival and neurologic outcomes.336 Error reporting after resuscitation is often based on recall, which falls short compared with actual audiovisual review.337 In addition to delayed CPR initiation, interruptions are common, with long pauses occurring often at the time of changing compressors or rhythm checks.338,339 Placement of fingers on a single pulse site prior to rhythm checks can minimize these pauses.339 The presence of a CPR coach improves guideline adherence.340 Practice divergent from guideline recommendations occurs more often outside the initial minutes of CPR, suggesting rescuer fatigue.338 Compression rate and depth diminish after the first minute of compressions by a single rescuer341,342 though fatigue is often not appreciated until the third minute However, changing compressors is a time when excessive pauses often occur339; therefore, attention to quick execution is needed High-quality CPR is often summarized by the statement “push hard, push fast.” However, pediatric studies suggest that resuscitators push too fast, particularly in young children,343 although little evidence exists to support optimal pediatric compression rates.329 Excessive depth is difficult to achieve and rib fractures are very uncommon in pediatric CPR.344 Therefore, American Heart Association guidelines recommend compression of at least onethird of the anteroposterior chest diameter, which is seldom achieved.345 It should be noted that adult studies have demonstrated a small but measurable decline in survival when excess depths are used, particularly in women,346 for whom one expects smaller body habitus Conversely, in obese children, outcomes are worse,347 presumably owing to difficulty providing adequate compression depth, whereas no difference in outcomes is associated with being underweight The combination of depth and rate at guideline-recommended levels is associated with better blood pressure during in-hospital CPR.348 Another frequent source of reduced CPR quality is excessive leaning, which prevents chest recoil, reducing blood flow.349–353 All these factors appear to improve with the use of audiovisual feedback338,343,350 now present on some commercial devices Ventilation at rates exceeding those recommended by guidelines is common during pediatric resuscitation.354,355 In adult human and animal models, this equates to impaired cardiac output, hypoperfusion, and failure to achieve ROSC.356 It has also been suggested that in the clinically plausible range, hyperventilation may exert its negative impacts by producing hypocarbia,357 which has vasoconstrictive effects in the brain, worsening cerebral hypoperfusion during CPR Despite these physiologic data and a correlation between higher ventilation rates with lower systolic blood pressure after pediatric cardiac arrest, the higher rates were associated with improved, not worsened, outcomes.355 Such data call into question the present guideline recommendations on ventilation rate CHAPTER 65 Hypoxic-Ischemic Encephalopathy studies.369,370 Safar and coworkers286 reported that a multifaceted treatment strategy to increase CBF (“flow promotion”) and reduce cerebral metabolic rate or CMRO2 early after VF in dogs improved outcome This was accomplished by use of cardiopulmonary bypass (CPB), mild hypothermia, hemodilution, and transient hypertension However, more selective therapies may be needed, and potential agents targeting CBF currently being explored, as previously stated, include nitrite, remote ischemic postconditioning, and 20-hydroxyeicosatetraenoic acid inhibitors, among others Phenotype-Directed Management It is increasingly clear that appropriate phenotyping of heterogenous processes on the basis of physiologic, biochemical, and genetic attributes may be needed to better target therapies to the individual’s situation As previously discussed, preclinical and clinical studies demonstrate important differences in the pathology of brain injury,28 which, in turn, may imply different neuronal cell death pathways and alterations in CBF92 after asphyxial versus VF cardiac arrest In addition, differences in myocardial dysfunction371,372 and ventilation373 between these different forms of cardiac arrest may require different management strategies to minimize secondary brain injury In the case of asphyxia, it is clear that the brain senses the insult and has a neurochemical and electrical response long before no flow,23 which may increase the risk for mechanisms such as excitotoxicity and oxidative stress after resuscitation, suggesting a role for therapies specifically targeting these pathways Clinical trials are ongoing evaluating the efficacy of inhaled xenon gas targeting excitotoxicity374 and inhaled hydrogen gas targeting oxidative stress375 after cardiac arrest in adult patients Further studies of phenotype-targeted therapies in targeted subpopulations of cardiac arrest are needed to better define the differences suggested by these preliminary studies Cognitive Rehabilitation After the Intensive Care Unit Increasingly, research studies are raising awareness of the frequency of short- and long-term functional deficits and lesser quality of life for children and families affected by pediatric cardiac arrest.209,210 A meaningful cognitive rehabilitation paradigm, if identified, would be a significant advance and outweigh the value of cardiac rehabilitation in terms of quality of life for survivors of cardiac arrest in both children and adults In TBI, “environmental enrichment” improved cognitive outcomes in experimental models and pharmacologic adjuvants provided during inpatient rehabilitation improved adult recovery outcomes.376,377 In observational studies, children with severe HIE show less potential for recovery than children with TBI.378,379 Studies evaluating post-ICU discharge cognitive rehabilitation strategies in children with HIE are lacking, representing an opportunity to impact recovery This would be of greatest benefit in survivors with mild to moderate (or even grossly undetectable) neurologic and/or cognitive deficits leaving the PICU Futuristic Approaches Mitochondria Targeting Strategies As described earlier, mitochondrial damage and dysfunction play prominent roles in the signaling of nearly every cell death 807 pathway relevant to the pathobiology of HIE In addition, since brain mitochondrial bioenergetics are altered after cardiac arrest,380 the inability to replete high-energy substrates compounds energy failure and exacerbates brain injury As such, mitochondria are logical and clinically relevant therapeutic targets for mitigation of HIE and can be divided into (1) alternative mitochondrial fuels, (2) inhibitors of mitochondrial permeability transition (MPT), and (3) mitochondria-targeted electron scavengers and antioxidants Among the first category, acetyl-L-carnitine was shown to potentiate normalization of brain energy metabolites and improve neurologic outcome after complete global cerebral ischemia reperfusion.381 In addition, strategies to deliver “liquid energy” such as liposomally encapsulated nicotinamide adenine dinucleotide (NAD1) or ATP have shown promise in vitro,382 but systemic delivery into the brain has remained challenging In regard to the second category, experimental studies in cardiac arrest report improved myocardial function and reduction in neuronal damage with an MPT inhibitor cyclosporine when administered at the time of reperfusion or shortly thereafter.383–385 Unfortunately, no benefit was noted when cyclosporine was provided intravenously at the onset of resuscitation from nonshockable cardiac arrest.386 In contrast to the first two strategies, the third class of therapies will selectively accumulate in mitochondria and bind targets within the organelle to exert their effects.111 Several strategies have been used to effectively target mitochondrial localization of small molecules, including conjugation to lipophilic cations such as triphenylphosphonium, which take advantage of negative membrane potential of mitochondria111 and bind to a specific mitochondrial target such as cardiolipin, a phospholipid exclusively found in the inner mitochondrial membrane [80] Administration of mitochondria-targeted sulfide donor AP39 at the time of CPR or minute after ROSC was shown to improve neurologic function and long-term survival rates after an 8-minute cardiac arrest induced by potassium chloride in adult mice.387 A targeted S-nitrosothiol that reduced complex I–mediated free radical generation after myocardial ischemia388 recently showed promise as a therapy after experimental neonatal hypoxia-ischemia.389 Another promising mitochondria-targeted therapy takes advantage of chemical moieties used in antibacterial agents (e.g., gramicidin S) with high affinity for the cardiolipin-rich inner mitochondrial membrane.114 A hemigramicidin-linked nitroxide, XJB-5-131, was shown to partition almost exclusively into neuronal mitochondria in vitro, penetrate the blood-brain barrier, prevent cardiolipin oxidation and caspase activation, and improve neurocognitive outcome after asphyxial cardiac arrest in juvenile rats.112 This hemi-gramicidin has also been used to deliver therapeutics to other druggable mitochondrial targets, including poly(ADPribose) polymerase-1, which has shown promise in experimental models of neuronal ischemia.390 Targeted Temperature Management in a Syringe The concept of “hypothermia in a syringe” was promoted by the late Dr Peter Safar in the 1990s and elegantly resuscitated by Jackson and Kochanek in 2019.391 As one of the main limitations to the clinical application of hypothermia for neuroprotection is the complex cascade of mechanisms triggered both inside and outside the brain (Fig 65.9), a biochemical method to induce potential beneficial effects of hypothermia without inducing the undesirable systemic effects associated with total body cooling may offer a solution These strategies are based on 808 S E C T I O N V I Pediatric Critical Care: Neurologic ↑ Blood viscosity ↓ Neuroinflammation ↓ Oxidative stress ↓ ATP consumption Systemic Cooling pelF2α FGF21 ↓ Metabolism ↓ BBB disruption Hyperglycemia ↓ CBF RBM3 ↓ Seizures ↓ Edema Hypotension (rewarming) Bradycardia/arrhythmias Delayed drug metabolism ? ? ↓ Excitotoxicity Acid/base changes ↓ Irisin Cold diuresis and hypovolemia Thermogenesis ↓ Meteorin-like Coagulopathy Leukopenia Thrombocytopenia • Fig 65.9 Balancing neuroprotective versus undesirable effects of systemic cooling Hypothermia, even mild hypothermia, can lead to potentially protective responses in the brain (green text) In contrast, effects of total body cooling can also lead to undesirable systemic responses, especially at colder temperatures (red text) However, systemic cooling also reactivates cold stress pathways, more prominent in newborns and infants, that may contribute to neuroprotection The cold stress response involves several cold stress hormones, including fibroblast growth factor 21 (FGF21); irisin; meteorin-like; and sex hormone binding globulin; and cold stress proteins, including ribonucleic acid binding motif (RBM3); phosphorylated eukaryotic initiation factor 2a (peIF2a); cold-inducible RNA binding protein; and reticulon-3 ATP, Adenosine triphosphate; BBB, blood-brain barrier; CBF, cerebral blood flow (Modified from Jackson TC, Kochanek PM A new vision for therapeutic hypothermia in the era of targeted temperature management: a speculative synthesis Ther Hypothermia 2019;9:13–47.) the responsivity of “cold stress pathways,” essential for hibernation and torpor, which appear to be present to some degree in newborn and infant humans.320,321 The cold stress response involves several cold stress hormones (CSHs) and cold stress proteins (CSPs) CSHs activate thermogenic pathways to maintain body temperature in warm-blooded animals and include fibroblast growth factor 21 (FGF21); irisin, a glycosylated protein fragment of fibronectin-like III domain containing 5; meteorin-like (metrnl), a factor secreted in fat mobilization; and sex hormone binding globulin (SHBG).391 These CSHs induce CSPs during cold stress that mediate cold adaptation in cells CSPs include RNA binding motif (RBM3); cold inducible RNA binding protein (CIRBP); phosphorylated eukaryotic initiation factor 2a (peIF2a), which stimulates activating transcription factor 4, which leads to increased expression of FGF21; and reticulon-3 (RTN3).391 Importantly, it appears possible to activate these CSHs/CSPs with as little as a 1-degree drop in temperature in immature mammalian neurons.308 The capacity to re-induce these protective cold stress pathways in the maturing or mature human brain is the subject of ongoing investigation The development of “TTM in a syringe” for prevention of HIE—for example, a cocktail including FGF21, irisin, metrnl, SHBG, an RBM3 agonist, a CIRBP agonist, and/or an RTN3 agonist—and/or the induction of these proteins represents a potential futuristic approach to explore in the treatment of cardiac arrest Erythropoietin Erythropoietin (Epo) is better known for its bone marrow stimulation effect,392,393 but it is also required for normal brain development, stimulating neural progenitor cells.394,395 Epo used therapeutically in experimental models of neonatal hypoxia-ischemia has multiple potential mechanisms of neuroprotection, including prevention of apoptosis, protection from oxidative stress, modulation of cellular water permeability, and promotion of neurogenesis and angiogenesis.394,396,397 Therapeutic hypothermia has become standard of care for newborns with moderate/severe HIE,398 leading investigators to find other therapies that complement or synergize with hypothermia Combination therapy with hypothermia and Epo shows promise in experimental models, improving sensorimotor function, with 7-day-old female rats benefiting more than males.399 In a nonhuman primate model of perinatal asphyxia, combination therapy produced superior results over placebo and hypothermia alone in terms of the primary outcome, death, or moderate-severe cerebral palsy.400 Pilot studies have demonstrated pharmacokinetics, feasibility, safety, and, in some instances, improved outcomes.401–405 Efficacy of combination therapy is now being explored in a multicenter randomized controlled trial, High Dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) Trial (RCT; NCT01913340).406 Although adult cardiac arrest studies have shown no benefit of Epo accompanied by increased thrombotic adverse effects,407 similar to hypothermia, it may yet be CHAPTER 65 Hypoxic-Ischemic Encephalopathy shown to be effective in neonates, and perhaps infants and children Finally, another area with potential promise as a pharmacologic adjunct to TTM is with the use of novel nNOS inhibitors.408 Stem Cell Therapy Pluripotent stem cells have the capacity to differentiate into cells with antiinflammatory, immunomodulating, and potentially neuroprotectant properties.409 In experimental brain injury models, stem cells have been shown to localize to injured regions, express neuronal and glial markers, reduce cell death, increase central nervous system cellularity, and improve outcomes.410–413 Treatment efficacy was affected by method of delivery (i.e., intracerebral, intravenous), timing, frequency, type of stem cell, and experimental model, with some reports having neutral effects on outcome and others having adverse effects, such as brain tumor development.414,415 A pilot study in which autologous umbilical cord blood was transfused in neonates with birth asphyxia who also received hypothermia therapy did not reveal serious safety issues.416 At least one randomized clinical trial (RCT) is actively recruiting newborns to determine further safety and feasibility of stem cells in this cohort (ClinicalTrials.gov NCT00593242) Preliminary studies in children with cerebral palsy show promise in safety and feasibility.417–419 An RCT evaluating umbilical cord blood transfusions in combination with Epo showed improvement in motor and cognitive function.420 Two RCTs using autologous umbilical cord blood for treatment of cerebral palsy are ongoing.421,422 Extracorporeal Life Support Extracorporeal life support (ECLS) in the form of CPB initiated immediately after VF arrest in dogs (with cannulas already in place) improves outcome when compared with standard advanced cardiac life support–guided resuscitation.423 CPB produced 64% survival after even 20 minutes of VF arrest, although all dogs were neurologically impaired This supports the concept that cerebral and coronary perfusion during CPR extends tolerated insult time, although studies with vascular cannulation during resuscitation have not been reported These studies would be important in light of the difficulty in obtaining this type of vascular access during arrest in children Nevertheless, ECLS allows control of postarrest blood flow and temperature, and the cardiovascular support provided might allow use of otherwise contraindicated therapies Many studies have shown that rescue ECLS, or extracorporeal cardiopulmonary resuscitation (ECPR), is feasible under varied circumstances Patient selection is an important consideration and necessary resources for ECPR are substantial.424,425 Longterm outcomes were similar to children receiving conventional CPR in the in-hospital THAPCA study This intervention is detailed in Chapter 56.426,427 Summary The social and economic impacts of children left with persistent neurologic injury after cardiac arrest remain staggering Preventive and quality approaches to this problem have positively impacted in-hospital cardiac arrest outcomes but are unlikely to impact largely unanticipated out-of-hospital events Improvements in prognostication after cardiac arrest are on the horizon with a more concerted application of existing methods and new 809 techniques The successful application of novel brain-oriented therapeutic approaches is somewhat more speculative, but it is likely to require intervention beginning in the prehospital setting or emergency department Improved, pathophysiology-guided stratification of postarrest patients is essential to determine which patients have recoverable insults Optimal brain-directed monitoring and pathophysiology-guided interventions and supportive care targeting the prevention of secondary injury should become the standard for contemporary neurocritical care It is also likely that optimized resiliency and rehabilitation strategies will need to be developed and incorporated in the PICU to maximize the potential for a favorable outcome Unfortunately, at present, this group is unlikely to include most patients with prolonged asphyxial arrest and in any single institution represents a small number of cases per year Futuristic, biochemically and physiologically guided, multifaceted pharmacologic and mechanical approaches will almost certainly be required, with their application based on the temporal sequence of pathologic events Acknowledgment This chapter remains dedicated to Peter J Safar, the father of modern-day CPR, who passed away on August 3, 2003 Rest in peace Key References Ashwal S, Holshouser BA, Tomasi LG, et al 1H-magnetic resonance spectroscopy-determined cerebral lactate and poor neurological outcomes in children with central nervous system disease Ann Neurol 1997;41:470-481 Bodsch W, Barbier A, Oehmichen M, et al Recovery of monkey brain after prolonged ischemia II Protein synthesis and morphological alterations J Cereb Blood Flow Metab 1986;6:22-33 Ferguson LP, Durward A, Tibby SM Relationship between arterial partial oxygen pressure after resuscitation from cardiac arrest and mortality in children Circulation 2012;126:335-342 Fink EL, Panigrahy A, Clark RS, et al Regional brain injury on conventional and diffusion weighted MRI is associated with outcome after pediatric cardiac arrest Neurocrit Care 2013;19:31-40 Jackson TC, Kochanek PM A new vision for therapeutic hypothermia in the era of targeted temperature management: a speculative synthesis Ther Hypothermia Temp Manag 2019;9:13-47 Katz LM, Callaway CW, Kagan VE, Kochanek PM Electron spin resonance measure of brain antioxidant activity during ischemia/reperfusion Neuroreport 1998;9:1587-1593 Kitamura T, Iwami T, Kawamura T, et al Conventional and chestcompression-only cardiopulmonary resuscitation by bystanders for children who have out-of-hospital cardiac arrests: a prospective, nationwide, population-based cohort study Lancet 2010;375:1347-1354 Lee JK, Brady KM, Chung SE, et al A pilot study of cerebrovascular reactivity autoregulation after pediatric cardiac arrest Resuscitation 2014;85:1387-1393 Lorek A, Takei Y, Cady EB, et al Delayed (“secondary”) cerebral energy failure after acute hypoxia-ischemia in the newborn piglet: continuous 48-hour studies by phosphorus magnetic resonance spectroscopy Pediatr Res 1994;36:699-706 Manole MD, Foley LM, Hitchens TK, et al Magnetic resonance imaging assessment of regional cerebral blood flow after asphyxial cardiac arrest in immature rats J Cereb Blood Flow Metab 2009;29: 197-205 Northington FJ, Ferriero DM, Graham EM, et al Early neurodegeneration after hypoxia-ischemia in neonatal rat is necrosis while delayed neuronal death is apoptosis Neurobiol Dis 2001;8:207-219 810 S E C T I O N V I Pediatric Critical Care: Neurologic Robertson CM, Joffe AR, Moore AJ, Watt JM Neurodevelopmental outcome of young pediatric intensive care survivors of serious brain injury Pediatr Crit Care Med 2002;3:345-350 Sims NR, Pulsinelli WA Altered mitochondrial respiration in selectively vulnerable brain subregions following transient forebrain ischemia in the rat J Neurochem 1987;49:1367-1374 Topjian AA, French B, Sutton RM, et al Early postresuscitation hypotension is associated with increased mortality following pediatric cardiac arrest Crit Care Med 2014;42:1518-1523 Vaagenes P, Safar P, Moossy J, et al Asphyxiation versus ventricular fibrillation cardiac arrest in dogs Differences in cerebral resuscitation effects—a preliminary study Resuscitation 1997;35:41-52 The full reference list for this chapter is available at ExpertConsult.com ... arrest.386 In contrast to the first two strategies, the third class of therapies will selectively accumulate in mitochondria and bind targets within the organelle to exert their effects.111 Several... rehabilitation strategies in children with HIE are lacking, representing an opportunity to impact recovery This would be of greatest benefit in survivors with mild to moderate (or even grossly undetectable)... promotion”) and reduce cerebral metabolic rate or CMRO2 early after VF in dogs improved outcome This was accomplished by use of cardiopulmonary bypass (CPB), mild hypothermia, hemodilution, and