Because pediatric intensive care units (PICUs) improve survival for a range of acute diseases, attention has turned toward ensuring the best possible functional outcomes after critical illness. The neurocritical care of children is of increasing interest. However, the pediatric population encompasses a heterogeneous set of neurologic conditions, with several possible models of how best to address them. This article reviews the special challenges faced by PICUs with regards to diseases, technologies, and skills and the progress that has been made in treatment, monitoring, and prognostication. Recent advances in translational research expected to modify the field in the near-term are described.
Key points
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Pediatric neurocritical care is focused primarily on 2 sets of problems: (1) injury to the central nervous system and (2) neurogenic respiratory failure.
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A wide range of causes is encompassed, including epileptic, neuromuscular, traumatic, oncologic, immune-mediated, vascular, infectious, and metabolic causes.
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The scope of neurocritical care includes not only medications and surgery for these diseases but neurodiagnostic approaches, neuromonitoring techniques, and neuroprotection strategies as well as clinical and ancillary methods for prognostication.
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The irreversibility of many neurologic injuries implies the necessity of early detection and intervention.
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The role of autoimmune disease in neurocritical illness is greater than previously recognized.
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Although a standardized training route or system for providing neurocritical care does not yet exist, several institutional models are being tried. Better coordination of inpatient and outpatient care is essential for patients who straddle the traditional acute and chronic divide.
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Interinstitutional trials will play an essential role in standardizing and improving care. Several networks have recently formed to facilitate this.
Background and history
The concept of specialized neurologic critical care for pediatric patients has existed for nearly a century. In 1928, Philip Drinker and Louis Shaw developed and tested (on themselves) a device that would later come to be known as the iron lung. The device was first used clinically on an 8-year-old girl with respiratory failure secondary to rapidly advancing poliomyelitis. Although by report she responded remarkably well to this intervention at first, she succumbed to her disease. Although their efforts to save this child failed, their experience set the stage for the emergence and later growth of the modern-day pediatric intensive care unit (PICU). Taking an alternative viewpoint, Drinker and Shaw provided perhaps the first described example of a specialized neurocritical care service for children with neuromuscular diseases.
The advent of modern neurocritical care began in adult intensive care units (ICUs) in the 1980s to provide the necessary infrastructure required to conduct complicated clinical trials testing several emerging neuroprotective strategies for devastating brain injuries, such as ischemic and hemorrhagic stroke, traumatic brain injury (TBI), vasospasm after subarachnoid hemorrhage, and hypoxic-ischemic brain injury after cardiac arrest. These therapies were largely directed toward attenuating the neurotoxicity associated with dying neurons and the concomitant release of excess calcium ions, free radicals, and glutamate, which caused excitotoxic damage. Although the trials themselves uniformly failed to show any benefit to these therapies, the quality of care and outcomes in these diseases nevertheless improved, largely because of the implementation of standardized care pathways, bundles, and uniformity of care. Since that time, numerous studies have shown improved outcomes when neurologically injured patients receive care in specialized neurocritical care units. However, the benefits of these specialized neurocritical care units have been largely championed by key stakeholders in neurology and neurosurgery, such as the United Council of Neurologic Subspecialties, leading others to question the need for separate, specialized, disease-specific or organ system–specific ICUs. The Leapfrog initiative, which was formed in 1998 by a group of large employers to spur greater quality and affordability of purchased health care, has recently supported the concept of specialized, adult neurocritical care units.
In Pediatrics, the establishment of formalized neurocritical care units has been more cautious, because of a variety of factors. Adult critical care encompasses large numbers of patients with few diseases, mostly stroke, TBI, and hypoxic-ischemic injury caused by cardiac arrest. Neurologic causes of disease are more diverse in childhood and include those seen in the adult population as well as primary brain diseases seen more commonly or exclusively in infancy, such as meningitis, encephalitis, and birth asphyxia. At the same time, a variety of both congenital and acquired neuromuscular diseases present, which require different support than is needed for primary brain disease. A recent retrospective review from the Children’s Hospital of Pittsburgh, a leader in advancing the neurocritical care of children, suggested that brain injury was the proximate cause of death in two-thirds of pediatric patients at that institution, highlighting the need for better understanding of brain dysfunction from a myriad of causes.
Neonatal ICUs have been at the forefront of pediatric neurocritical care, largely secondary to the infrastructure required to conduct the large hypothermia trials for hypoxic-ischemic birth injuries. Unlike their adult counterparts in the 1980s that investigated antiexcitotoxic therapies for stroke and TBI, the neonatal hypothermia trials have been positive for certain categories and degrees of severity and have thereby resulted in better outcomes, which require improved neurospecific infrastructure. However, despite the success of these trials, neonatal neurocritical care remains largely institution-specific without formalized training pathways. Pediatric neurocritical care is poised to evolve further with select institutions that provide both specialized pediatric neurocritical care services or units and the availability of a few training pathways open to both pediatric neurologists and intensivists.
Background and history
The concept of specialized neurologic critical care for pediatric patients has existed for nearly a century. In 1928, Philip Drinker and Louis Shaw developed and tested (on themselves) a device that would later come to be known as the iron lung. The device was first used clinically on an 8-year-old girl with respiratory failure secondary to rapidly advancing poliomyelitis. Although by report she responded remarkably well to this intervention at first, she succumbed to her disease. Although their efforts to save this child failed, their experience set the stage for the emergence and later growth of the modern-day pediatric intensive care unit (PICU). Taking an alternative viewpoint, Drinker and Shaw provided perhaps the first described example of a specialized neurocritical care service for children with neuromuscular diseases.
The advent of modern neurocritical care began in adult intensive care units (ICUs) in the 1980s to provide the necessary infrastructure required to conduct complicated clinical trials testing several emerging neuroprotective strategies for devastating brain injuries, such as ischemic and hemorrhagic stroke, traumatic brain injury (TBI), vasospasm after subarachnoid hemorrhage, and hypoxic-ischemic brain injury after cardiac arrest. These therapies were largely directed toward attenuating the neurotoxicity associated with dying neurons and the concomitant release of excess calcium ions, free radicals, and glutamate, which caused excitotoxic damage. Although the trials themselves uniformly failed to show any benefit to these therapies, the quality of care and outcomes in these diseases nevertheless improved, largely because of the implementation of standardized care pathways, bundles, and uniformity of care. Since that time, numerous studies have shown improved outcomes when neurologically injured patients receive care in specialized neurocritical care units. However, the benefits of these specialized neurocritical care units have been largely championed by key stakeholders in neurology and neurosurgery, such as the United Council of Neurologic Subspecialties, leading others to question the need for separate, specialized, disease-specific or organ system–specific ICUs. The Leapfrog initiative, which was formed in 1998 by a group of large employers to spur greater quality and affordability of purchased health care, has recently supported the concept of specialized, adult neurocritical care units.
In Pediatrics, the establishment of formalized neurocritical care units has been more cautious, because of a variety of factors. Adult critical care encompasses large numbers of patients with few diseases, mostly stroke, TBI, and hypoxic-ischemic injury caused by cardiac arrest. Neurologic causes of disease are more diverse in childhood and include those seen in the adult population as well as primary brain diseases seen more commonly or exclusively in infancy, such as meningitis, encephalitis, and birth asphyxia. At the same time, a variety of both congenital and acquired neuromuscular diseases present, which require different support than is needed for primary brain disease. A recent retrospective review from the Children’s Hospital of Pittsburgh, a leader in advancing the neurocritical care of children, suggested that brain injury was the proximate cause of death in two-thirds of pediatric patients at that institution, highlighting the need for better understanding of brain dysfunction from a myriad of causes.
Neonatal ICUs have been at the forefront of pediatric neurocritical care, largely secondary to the infrastructure required to conduct the large hypothermia trials for hypoxic-ischemic birth injuries. Unlike their adult counterparts in the 1980s that investigated antiexcitotoxic therapies for stroke and TBI, the neonatal hypothermia trials have been positive for certain categories and degrees of severity and have thereby resulted in better outcomes, which require improved neurospecific infrastructure. However, despite the success of these trials, neonatal neurocritical care remains largely institution-specific without formalized training pathways. Pediatric neurocritical care is poised to evolve further with select institutions that provide both specialized pediatric neurocritical care services or units and the availability of a few training pathways open to both pediatric neurologists and intensivists.
Disease categories
One of the major challenges in pediatric neurocritical care is the broad number of categories of neurologic disease that are commonly confronted. These categories include central nervous system (CNS)–specific diseases such as brain and spinal cord trauma, status epilepticus from a variety of causes, brain tumors, vascular diseases, metabolic disease, infectious entities, autoimmune diseases, and brain death caused by a variety of both brain-specific and secondary insults. There are also neurogenic respiratory diseases that, because of their severity, are seen almost exclusively in pediatric populations. There are other debilitating neurologic diseases that fail to be placed into any kind of usual categories, all of which require a treatment strategy that is specific or unique to the relevant pathway.
TBI Remains Most Common Cause of Death in Children
TBI occurs commonly in children and is the leading cause of death in children older than 1 year. Treatment of TBI is primarily supportive and has been the subject of numerous attempts at standardized treatment pathways. The first guidelines for the treatment of adult TBI were published in 1993, and since then, treatment has become more uniform, with less use of disproven therapies such as corticosteroids and chronic hyperventilation and more consistent use of therapies directed at intracranial pressure (ICP), which are believed to be beneficial. For pediatric TBI, specific guidelines were first published in 2003 and were recently updated in 2012. Although the mainstays of therapy remain supportive, with avoidance of hypotension and hypoxia, there is emerging literature to guide the choice and timing of interventions after severe pediatric TBI, such as hypothermia, decompressive craniectomy ( Fig. 1 ), and the use of hypertonic saline (rather than mannitol) for intracranial hypertension.
Status Epilepticus Underlies a Vast Assortment of Primary Disorders
Status epilepticus occurs commonly in the critical care setting as a result of a variety of causes. It is the epitome of the neurocritical illness in that its management requires that neurologic findings and interventions be coordinated with the measurement and manipulation of systemic vital parameters. The dose-limiting side effects of GABAergic inhibitory medications (chiefly benzodiazepines and barbiturates) are respiratory depression, which can necessitate tracheal intubation, and hypotension, which can necessitate intravenous fluid resuscitation or the use of vasoactive medications. The patient’s safety depends on careful titration of antiepileptic drugs and therapies to overcome these adverse effects.
The causes of pediatric status are myriad and include primary epilepsy caused by channelopathy or dysplasia, brain tumors, electrolyte derangements such as hyponatremia or hypoglycemia, disorders of metabolism, meningoencephalitis, TBI, intracranial hemorrhage, child abuse, heat stroke, or a variety of other disorders. Traditionally, status epilepticus was defined by at least 30 minutes of continuous convulsive seizures or intermittent seizures without a return to baseline, a time frame in which neuronal injury becomes evident in some animal models. More recently, it has been recognized that most seizures that stop spontaneously will have done so already in less time, so that when they persist, a deleterious steady-state can already be declared present earlier. The increasing refractoriness of seizures with time and the risk of therapy-related injury increases because control may require more than the initial interventions, which have prompted the view that status epilepticus be redefined to include any seizure lasting longer than 5 minutes. Treatment should occur rapidly and without waiting for transfer to the ICU setting and includes a first-line benzodiazepene, typically 0.1 mg/kg of lorazepam or the equivalent (which can be repeated as needed in the event of incomplete effect) followed by a fosphenytoin load of 20 to 30 mg/kg (measured in phenytoin equivalents [PE]). This treatment can be followed by partial redosing (5–10 mg/kg PE) or the loading of a third-line agent if status has not resolved within 10 minutes. Third-line agents include phenobarbital or levetiracetam. At this point, admission to the PICU is required, often for airway management as well as continuous infusion of midazolam or pentobarbital for unremitting status. Although the single most beneficial protocol has not been established in children, it is clear that initial therapy needs to occur rapidly and should be quickly followed by second-line and third-line agents when initial therapy is ineffective. Propofol is less favored in pediatrics, because of the danger of propofol infusion syndrome, especially in the child who may have an as yet unrecognized mitochondrial cytopathy. Prompt electroencephalography (EEG) is helpful to confirm that seizures have been suppressed not only clinically but electrographically as well and to recognize exceptional circumstances such as atypical absence status, for which different pharmacologic choices are made.
Nonconvulsive Status Epilepticus is Increasingly Recognized
Although pediatric intensivists have long appreciated the need for prompt attention to convulsive status epilepticus, the identification and treatment of nonconvulsive status epilepticus (NCSE) has emerged as more of a diagnostic and treatment dilemma. The incidence of nonconvulsive status in critically ill children is unknown, although some reports suggest that the incidence is between 7% and 46%. Institutional experience studies report NCSE as a more common finding in pediatric as opposed to adult altered mental status, suggesting that it may be undersuspected and underinvestigated in children. Although it remains unknown how treatment of nonconvulsive status influences outcome in the pediatric ICU, its occurrence and persistence in both neonatal and adult ICUs is associated with poor outcomes. Pediatric patients known to be at risk for nonconvulsive status are a highly heterogeneous group, so the condition should be considered in all patients with encephalopathy that is unexplained or disproportionate to the child’s medical state. Because an EEG is needed both to make the diagnosis and confirm effect of treatment, early involvement of a pediatric neurologist is essential.
Immune-Mediated Neurologic Disease Occurs Often in Children
Among the most dramatic shifts in the practice of pediatric neurocritical care is in the ability for early diagnosis and aggressive intervention in antibody-mediated neurologic disease. Traditionally, neurocritical care was focused to a large extent on (1) supportive strategies to compensate for deficit (as with mechanical ventilation for weakness of any kind, or intubation for airway protection in the context of depressed mental status) and (2) prevention of its aggravation (especially in trauma and stroke) rather than the (3) reversal of a disease process. In the past decade, this situation has dramatically changed, as immunomodulation has joined anticonvulsant therapy in the neurointensivist’s arsenal of weapons that reverse deleterious processes. Recent identification of putative causative antibodies for a range of neurologic diseases and the availability of treatments directed against antibody-mediated disease, such as intravenous immune globulin (IVIG) transfusion, plasmapheresis, and rituximab, have altered the treatment of central, vascular, and peripheral neurologic conditions. Like seizures, these disorders show that, contrary to stereotype, the differential diagnosis of even the most severe pediatric neurologic presentation is not restricted to inexorably degenerative conditions, but includes recoverable illness. The greater plasticity of the pediatric brain raises the stakes in these conditions, providing both more hope for recovery with rapid recognition and interruption of autoimmune disease but also carrying the threat of maldevelopment as a result of injury of an immature nervous system. The better diagnostic techniques open the possibility and the necessity for head-to-head trials to determine the best therapeutic algorithm for these diseases.
In the CNS, Dalmau syndrome or anti– N -methyl- d -aspartate (NMDA) receptor encephalitis is increasingly recognized to be more common than previously believed in children. Underrecognition prevents accurate incidence estimates, although rate of diagnosis is clearly increasing. Cases may be either paraneoplastic or idiopathic and likely account for much of what in decades past was deemed limbic encephalitis or assumed to be infectious (because of agents that are difficult to culture or not screened for) or postinfectious encephalitis when cerebrospinal fluid (CSF) cultures and viral studies were indeterminate. This disorder can have explosive onset, with rapid loss of cognitive skills and development of movement disorder and seizures coinciding with measurable serum and CSF titers of immunoglobulins against NMDA-type glutamate receptors. ICU admission may be required for multiple reasons, including airway protection, ventilatory support, control of refractory seizures, and severe dysautonomia, including life-threatening arrhythmias. IVIG, plasmapheresis, and, for severe cases, rituximab and cyclophosphamide have been used with apparent success in observational studies. This disorder is probably the most common of what will become recognized as a family of antichannelopathies.
The recognition that Devic disease is caused by antibodies to aquaporin 4 allows early diagnosis and intervention for the pediatric patient presenting with transverse myelitis. These patients, who followed a severe progressive course, were previously difficult to distinguish at initial presentation from those with a monophasic demyelinating attack, multiple sclerosis, or even spinal stroke. Consequently, despite the possible benefit of immunotherapy, severe disability was common before the diagnosis was final. Other autoimmune diseases amenable to immunomodulatory therapy require PICU care as well. Database analysis of 25 centers in the United Kingdom found that one-quarter of patients diagnosed with acute disseminated encephalomyelitis were admitted to PICUs, whether for seizures or inability to protect their airway. In this series, all survived to hospital discharge.
Antibody-mediated disease accounts for some cases of pediatric stroke as well. In addition to prothrombotic disorders such as the antiphospholipid antibody syndrome, pediatric stroke may be triggered by antibodies against the von Willebrand factor–cleaving protease known as ADAMTS13. Although some children suffer the constellation of complications of thrombotic thrombocytopenic purpura (TTP) because of congenital deficiency of this protein, it is now recognized that children, like adults, are also susceptible to the autoimmune version of this disorder. Immunomodulatory therapy can cause the state of hematologic disarray of TTP to remit. TTP in its acute phase is typically a PICU-requiring condition for many reasons, including renal failure as well as stroke.
Pediatric Stroke is Unique
Pediatric stroke, although less common than its adult counterpart, is more common than generally appreciated. Its prevalence is comparable with that of childhood brain tumors, which are collectively the most common type of pediatric solid tumors. Adult stroke is to a large extent attributable to a set of common risk factors (influenced by both heredity and lifestyle) including hypertension, hyperlipidemia, and smoking. The causes in childhood are diverse and, although frequently associated with a major other diagnosis such as cardiac disease, sickle cell, or rheumatologic disorder, are probably multifactorial. That stroke is erroneously thought of as an adult disease may contribute to the remarkably late presentation and slow recognition of pediatric stroke. More so than among adults, childhood stroke is an ICU-disease and requires at least initial management and observation in the PICU setting. High rates of tracheal intubation and surgical intervention described among pediatric stroke cases in California strongly suggest that the ICU status did not merely reflect more cautious triaging by pediatricians. A more likely contributing factor, as the investigators point out, was the greater risk of herniation posed by stroke in children because of both their different epidemiology (higher ratio of large vessel to lacunar infarcts) and their anatomy. The pediatric skull has no extra room to accommodate swelling, because the pediatric brain, unlike the adult, fully occupies the cranial vault.
Primary Metabolic Disease May First Become Manifest in the CNS
Metabolic diseases causing encephalopathy fall largely into 2 categories: (1) those in which the CNS impairment is a consequence of insufficient hepatic (or less often, renal) detoxification (whether because of enzyme deficiency or liver injury) and (2) those in which the biochemical derangement is in the brain itself. Terms such as Reye syndrome or Alpert disease have been used to describe, respectively, acute or chronic conditions in which both factors were present.
Once a regular basis of ICU admissions, Reye syndrome has become increasingly rare. Two major factors likely account for this: (1) the diminished use of salicylates in children with acute febrile illnesses may have reduced the incidence of metabolic crises and (2) the availability of better technology for early specific diagnosis. This factor means that more children with this presentation receive a more precise biochemical (enzyme deficiency) or genetic (DNA mutation) diagnosis rather than the more generic label of Reye syndrome. Diseases that can present in this manner include mitochondrial disorders, including fatty acid oxidation defects, disorders of the urea cycle and adjacent pathways (such as the hyperammonemia, hyperornithinemia, homocitrullinemia syndrome or N -acetylglutamate synthase), disorders of amino acid metabolism including organic acidurias and disorders of gluconeogenesis.
Several fundamental principles guide the management of metabolic crisis. A steady energy source (usually glucose, but in certain conditions, ketone bodies) must be provided, the goal being not merely to provide nutrition, but to exit the catabolic state and restore anabolism. The stressor that triggered the decompensation (often a concomitant infection) must be controlled. Substrates for escape pathways which, depending on the disorder, may include glycine or carnitine, are provided. Those vitamins which are cofactors for impaired enzymes should be provided in pharmacologic quantities. Diagnostic screening tests (such as lactate, pyruvate, ammonia) and metabolic panels (organic acids and acylcarnitines) are often most informative during the crisis to help localize the biochemical defect and identify the symptom-causing metabolite.
Pediatric-Specific Neuromuscular Disease Requires Innovative Respiratory Support
Neuromuscular diseases causing respiratory failure can be classified by locus in the motor unit, by acuity, and by cause ( Table 1 ). In acute or relapsing diseases, it may be the respiratory insufficiency that prompts ICU admission. In the chronic diseases, common reasons for ICU stay include the initial presentation, perioperative state from spinal or gastrostomy surgery, disease progression (which raises the need for higher respiratory support or tracheostomy), or intercurrent respiratory illness.
