All patients admitted to the PICU are at risk of acquired morbidity during critical illness. One study found that up to 10% of all patients admitted to the PICU develop a new functional disability at discharge as measured by the Pediatric Cerebral Performance Category (PCPC) and Pediatric Overall Performance Category (POPC) (5). In contrast, another study found just under 5% of general PICU patients report new morbidity. Studies exploring the development of newly acquired morbidity in general PICU admissions have identified the following risk factors: an increased baseline PCPC, longer duration of chest compressions, lower oxygen saturations, the requirement of vasoactive medications, longer duration of invasive mechanical ventilation and longer stays in the PICU (6–8).

Patients admitted to the PICU with neurocritical illness are at an even higher risk of acquired morbidity compared to those with non-neurocritical illness. As many as 61% of children admitted to the PICU with neurocritical illness have a PCPC of 4–6 at discharge, consistent with severe disability, persistent vegetative state, or death (9, 10).

Outcomes are reported as worse in children admitted with stroke, cardiac arrest, and status epilepticus compared to traumatic brain injury (TBI) (9–11). TBI has a consensus protocol for management based on the severity of injury tier, while no such consensus exists in the management of other domains of neurocritical care. It is widely accepted that a protocolized approach to treating TBI that guideline adherence is associated with improved outcomes and thus may be confounded here. Vavilala et al. demonstrated for every 1% increase in adherence to guidelines in patients with TBI, there was a 1% decrease in unfavorable outcomes at discharge (12). Williams et al., looking at outcomes of children aged greater than or equal to 3 years admitted to the PICU with TBI, stroke, an infectious or inflammatory disorder, or hypoxic-ischemic injury, 56% of children with acquired brain injury reported sleep-wake disturbance and noted as severe in 46%. In this study, older median age and the presence of preadmission chronic medical conditions were significantly associated with sleep-wake disturbance at discharge from the PICU (13).

Children with severe traumatic brain injury suffer worse outcomes compared to children who suffer mild to moderate TBI. Children with mild to moderate TBI may continue to follow a developmental trajectory that, although within the normal range, is lower than their peers. Children with severe TBI, however, do not follow a typical developmental trajectory, with disparities becoming more evident over time (14). A meta-analysis examining the effects of injury severity and time since injury demonstrated children with moderate TBI performed more poorly than those with mild TBI but considerably better than those with severe TBI. Children in the moderate TBI group had a modest recovery of intellectual function and attention; however, two years post-injury had not caught up developmentally to demographically matched peers. Children with severe TBI were left with significant and persistent impairments with little recovery of function and did not make appropriate developmental gains. This disparity in recovery left them far behind their peers. Notably, younger age at injury was also associated with larger divergences from peers (15).

A Melbourne study of 48 children with TBI noted that increased severity of TBI was linked with a more significant impact on global functioning with significant differences in IQ across the groups compared to both each other and the control group. Preinjury adaptive function was noted to be the strongest predictor of post-injury performance. Additionally, while educational outcomes were variable, this may have been impacted by socioeconomic factors in conjunction with injury (16). Some functional domains may be more vulnerable than others. Across all severity groups and remaining post-injury, visual perceptual functioning may be the neurocognitive domain least affected. Fluency and problem-solving appear most vulnerable to disruption across all severity groups (15).

Children with abusive head trauma may have worse outcomes in gross motor, personal/social, and problem-solving aspects of development (14). A systematic review found that preinjury familial environment and styles are linked to TBI outcomes. The pre- and post-injury family environment predicted chronic changes, suggesting that the disruption of illness, injury, and other adverse events would either be buffered or exacerbated by the familial or home environment (17).

Depressive symptoms are more common post-TBI compared to noninjured or orthopedic injury populations. Risk factors for the development of depression and/or depressive symptoms may be injury-related (such as brain lesions or pain) and noninjury-related (such as older age at injury, lower SES) (18). The prevalence of depressive symptoms in children injured at age 12 years or older was reported as high as sixfold that of children who sustained an injury at age less than 9 years (19). The presence of self-reported depressive symptoms is a predictor of poor sleep quality in adolescents with mild, moderate, and severe TBI, in addition to poorer school functioning at 12- and 24 months post-injury (20).

In children aged 3–18 years, just over two-thirds experienced clinically significant sleep-wake disturbance associated with executive function outcomes after discharge (21). A meta-analysis found sleep disturbance to be highly prevalent in the acute phase of recovery in children, within the first 1 week to 1 month, and improved as time since injury increased. Approximately 20% of children reported sleep disturbance at three months post-TBI. Older age at the time of injury was related to worse sleep outcomes (22).

Pediatric stroke can be divided into perinatal stroke (less than or equal to 28 days old) and childhood stroke (occurring between 28 days and 18 years). Perinatal stroke is reported in 1 in 2,300 live births, whereas childhood stroke is reported in 1–13 per 1,000 (23–25). This categorization is important as there are differences between the two age groups in etiology, risk factors, presentation, and outcomes.

Data on outcomes after pediatric stroke show wide variance with no clear consensus in literature, likely due to variances in location of insult, etiology, among other factors. The percentage of children who are left with moderate to severe disability following stroke is reported as anywhere between 30% and 60%. Studies in Europe report a moderate to severe disability (as defined by modified Rankin score > 2) in up to 1/3 of patients following pediatric stroke (26, 27). A Canadian registry, which included neonatal and childhood stroke, reported moderate to severe deficits in 1/3 of cases (28). A single-center study in London reported poorer outcomes interfering with daily life in up to 60% of patients (29). However, a study from the Netherlands reported no severe disability in a population of 27 patients (30).

Outcomes following pediatric stroke most consistently are reported to be associated with age at stroke, location of stroke, etiology (hemorrhagic vs. ischemic), and the development of epilepsy following injury. Age at injury has conflicting associations across published studies. While some reports note a younger age at the time of stroke to be associated with a worse outcome, some studies do not report a poorer outcome with younger age, irrespective of lesion size or location in domains of cognitive flexibility, processing speed, and verbal learning (29, 31–35). Early childhood stroke had significantly worse cognitive outcomes compared to neonatal or late childhood stroke (36).

A re-analysis of the vascular effects of infection in pediatric stroke (VIPS study) found an association between larger infarct volume and younger age at stroke with poorer outcomes. However, the authors did note the strength of those associations was limited (37). The location of the infarct is also tied to the outcome. Infarcts that interrupted key networks had a disproportionate impact on outcomes following acute ischemic stroke. Infarcts involving uncinate fasciculus, angular gyrus, insular cortex, or that extended from cortex to subcortical nuclei were significantly associated with worse outcomes in the VIPS study (37). Compared to survivors of anterior circulation acute ischemic stroke, children with posterior circulation strokes had more favorable outcomes but were also more likely to receive anti-thrombotic agents (38). A single institution study in Colorado noted acute cerebral arteriopathy and elevated d dimer levels were identified as prognostic factors for poor outcomes (39).

Neuropsychological problems, learning difficulties, and mental health issues are among the commonly reported long-term issues following pediatric stroke. Learning disabilities and lower IQ compared to siblings or healthy counterparts have also been reported (29, 32). A pediatric stroke registry in Switzerland found processing speed and auditory short-term memory were particularly affected in approximately 75% of survivors (31). One study following outcomes ten years after childhood stroke reported that 80% of patients had a complete recovery or mild deficit on a modified ranking score, but over 1/4 of them also self-reported mental health issues compared to 5% of healthy counterparts aged three to 17 years old who report anxiety and depression at the time of this study. It is important to note that in the general population, self-reporting of mental health issues such as depression and anxiety have trended up significantly following the COVID-19 pandemic, and while this is not the scope of this review, it does highlight that studies of mental health issues following neurocritical illness, should be taken within the context of public health data collected concurrently (40, 41).

Measuring outcomes following pediatric stroke presents many challenges. The complex interaction between normal childhood development of the brain and recovery mechanisms following a stroke leads to an evolving neurologic exam and functional ability assessment throughout childhood. This represents a unique challenge to studying stroke outcomes in children compared to their adult counterparts (42–44). Another limitation to measuring outcomes in pediatric stroke is using the pediatric stroke outcome measure, a quantitative validated measure of outcome in pediatric stroke based on five domains of neurologic function. It may overestimate the consequences of pediatric stroke compared to the modified Rankin Scale as the latter focuses on function rather than neurologic impairment. The heterogeneity of study populations and the lack of consensus in outcome measurement make data difficult to compare between studies.

Inflammatory changes due to central nervous system infections cause brain injury and lead to varying outcomes. Mortality following meningoencephalitis has been reported anywhere between 5% and 30%. Of those who survive, up to 50% have neurologic sequelae, and approximately 40% report some degree of developmental delay (45, 46). Earlier age at diagnosis and age under 12 months have been linked to poorer neurologic outcomes. Additional risk factors include thrombocytopenia, need for mechanical ventilation, delayed presentation, anemia, underweight, or seizures at presentation (47–49).

The most common acquired morbidities reported are hearing loss, developmental delay, behavioral problems, difficulties with sleep, and a decline in school performance (50–53). One study of Dutch children reported that children with bacterial meningitis were twice as likely to repeat a school year as healthy peers or siblings (54). School problems, difficulty with educational achievements, and difficulty concentrating, in addition to lower rates of economic self-sufficiency later in life, are reported among survivors of central nervous system infection (54, 55). A study of survivors of childhood bacterial meningitis reported that 41% had some developmental delay, with almost one-third reporting psychomotor delay. Residual cognitive dysfunction has been reported in 5% of children at three-year follow-up in a study of children with enterovirus encephalitis (46, 56).

The etiology of encephalitis and geographical location are also important predictors of outcome (53, 57). While the etiology of encephalitis is an important predictor of outcome, the epidemiology is geographically dependent. A 2021 study comparing outcomes among children with bacterial meningitis in Finland, Angola, and Latin America found significant geographic variability in outcomes, likely due to a combination of public health and individual factors (49). The study highlighted those children with anemia who were underweight, presented late, or had seizures as part of their presentation had worse outcomes. Outcomes with less reported morbidity observed in countries like Finland may be attributed to multifactorial influences, including public health infrastructure and individual health characteristics.

Convulsive status epilepticus has its highest incidence during the first three years of life. This period represents a critical window of neurological development, thus increasing susceptibility to early neurologic insults (58–61). Following at least one episode of convulsive status epilepticus, whether a prolonged febrile seizure or non-febrile convulsive status, developmental impairments evident at six weeks post-acute event remain significant at 12 months (62). Within the first year after a prolonged febrile seizure, affected children often present with recognition memory impairments (63).

Despite scoring within clinically normal ranges, children who had experienced at least one episode of prolonged febrile seizure within the first three years of life underperformed on developmental assessments compared to controls (63). Mortality rates for convulsive status epilepticus can be as high as 20% (58, 64–67). For survivors, cognitive and motor disabilities are reported in up to 56% of cases (68–71). Factors associated with worse outcomes following convulsive status epilepticus include a higher Pediatric Cerebral Performance Category (PCPC) at baseline, diazepam-resistant convulsive status epilepticus, conversion to refractory or super refractory status epilepticus, the need for invasive mechanical ventilation, abnormal electroencephalogram (EEG) background, and non-convulsive status epilepticus (72).

While electrographic status epilepticus (ESE) and status epilepticus (SE) may serve as clinical indicators of brain dysfunction, they also contribute to secondary injury. This is associated with worse adaptive behavioral global composite scores, poorer long-term outcomes, lower quality of life, and an increased risk of epilepsy (73). One study involving 200 children undergoing continuous EEG monitoring in the PICU found that ESE was linked to an increased risk of mortality and a worsening of the PCPC at discharge, in contrast to electrographic seizures (ES), which showed no increased risk of mortality or PCPC worsening (74).

Within the last 20 years, there has been a shift from thinking of pediatric cardiac arrest as a futile medical condition to one that has been the focus of many studies intending to improve mortality. Recent literature shows that survival to hospital discharge rates and pediatric out-of-hospital cardiac arrest (8.2%–8.6%) approaches that of adults (8.8%) (75, 76). Despite advances in resuscitation techniques and post-resuscitation care leading to higher survival rates, survivors of pediatric cardiac arrest can be left with significant neurological sequelae that are not well elucidated in current literature.

Approximately 20,000 children sustain cardiac arrest annually in the United States. Of these, 15,000 children are resuscitated for in-hospital cardiac arrest (IHCA). When compared to out-of-hospital cardiac arrest (OHCA), pediatric IHCA has higher rates of survival (77–80). Among children who survive pediatric cardiac arrest, neurologic injury is the leading cause of morbidity and mortality. Of patients who survive IHCA, as few as 22% have been reported to have good neurologic outcomes (81). Patients who survive cardiac arrest but are discharged with poor neurologic status carry a significant risk of death, as high as 54% (82).

Outcomes following cardiac arrest are largely dependent on the location of cardiac arrest. Children who have an IHCA tend to receive more rapid resuscitation and, thus, less injury to the brain. Many studies have explored long-term neurologic outcomes in children who have survived hospital cardiac arrest. Still, due to the nature of pediatric OHCA, these studies have been limited by small sample size, single-site studies, narrow age range, or limited number of etiologies (83–89).

In studies examining long-term outcomes following OHCA by age group, there have been inconsistent findings. Some studies suggest that older age at the time of cardiac arrest and follow-up is associated with worse outcomes in neuropsychological and neurobehavioral testing (86). One such study examining neurobehavioral outcomes at 12 months in children who survived OHCA found that older children tended to have significant morbidity in all functional domains and sub-domains, with motor and daily living skills most affected (90). Other studies found that while overall favorable neurologic outcomes were reported to be over a wide range (10%–71%) more adolescents tended to have a favorable neurologic outcome at follow-up compared to infants (91, 92). At 24 months, OHCA survivors have worse intellectual functioning compared with normal data across various neuropsychological tests, including total IQ, verbal IQ, selective attention, sustained attention, processing speed, verbal memory, and cognitive flexibility (92, 93).

Prognostication for post-cardiac arrest neurologic outcome presents many challenges. Certain risk factors, such as the use of vasoactive-inotropic drugs before cardiac arrest, a previous PCPC scale score greater than 2, an underlying hemato-oncologic disease, and the total duration of CPR, are associated with poorer outcomes (81). Trauma or neurologic illness as etiology for IHCA and lactic acidemia more than 24 h following ROSC were found to be associated with a worse long-term neurological outcome (94). Blood-based brain injury biomarkers may be associated with outcomes following pediatric cardiac arrest as reported in several small observational studies and one large prospective multi-center cohort study The identified biomarkers of brain injury include glial fibrillary acidic protein (GFP), ubiquitin carboxyl-terminal esterase L1 (U CH-L1), Tau protein, and especially neurofilament light (NfL-1), are associated with death and or a more unfavorable outcome at 12 months post cardiac arrest. While concentrations of all biomarkers were higher in children with an unfavorable outcome compared to those with a favorable outcome at 1 year, both NfL1 and UCH-L1 had higher overall accuracy and reliability for 1 year post arrest outcomes (95–97).

Like other studies of long-term outcomes following pediatric neurocritical illness, studies describing outcomes after pediatric cardiac arrest are limited by the heterogeneity of the study population, loss to follow-up, and lack of consensus on outcome measures often leading to conflicting data. It is an interesting finding within this cohort that older children tend to have worse outcomes following cardiac arrest compared to younger counterparts which suggests there may be either some previously unidentified vulnerability and or a need for more sensitive testing for our younger populations that has not previously been explored that differentiates the neuro trajectory for older children Table 1.