Post-Intensive Care Syndrome in Pediatric Critical Care Survivors: Therapeutic Options to Improve Outcomes after Acquired Brain Injury

Abstract

Purpose:

Children surviving the Pediatric Intensive Care Unit (PICU) with neurologic illness or injury have long-term morbidities in physical, cognitive, emotional, and social functioning termed Post-Intensive Care Syndrome (PICS). In this article, we review acute and longitudinal management strategies available to combat PICS in children with acquired brain injury.

Findings:

Few intervention studies in this vulnerable population target PICS morbidities. Small studies show promise for both inpatient and outpatient initiated therapies, mainly focus on a single domain of PICS, and evaluate heterogeneous populations. While evaluating the effects of interventions on longitudinal PICS outcomes is in its infancy, longitudinal clinical programs targeting PICS are increasing. A multidisciplinary team with inpatient and outpatient presence is necessary to deliver the holistic integrated care required to address all domains of PICS in patients and families.

Summary:

While PICS is increasingly recognized as a chronic problem in PICU survivors with acquired brain injury, few interventions have targeted PICS morbidities. Research is needed to improve physical, cognitive, emotional, and social outcomes in survivors and their families.

Introduction:

Neurologic injury and disease accounts for >20% of Intensive Care Unit (ICU) admissions in children and includes traumatic brain injury (TBI), stroke, cardiac arrest (CA), and infectious and inflammatory diseases.[1–3] Each year, tens of thousands of children receive specialized Pediatric Neurocritical Care (PNCC) to treat the primary insult and minimize secondary neuronal injury in an effort to improve outcomes. Many interventions have little evidence base relying on adult data or small observational studies.[1] Even with specialized care and available therapies, PNCC patients have the highest rates of death and long-term morbidity in pediatric critical care.[2–4]

Impairments in physical, cognitive, emotional, and social function, termed Post-Intensive Care Syndrome (PICS), affect these children years after discharge and similarly affect family members (PICS-F).[5–8] PICS is increasingly recognized, though few therapeutic interventions have been studied specifically targeting this important entity. In this article, we review therapeutic treatment options with a focus on PICS outcomes in PNCC patients (Tables 1,2). In addition to therapies administered during hospitalization, we review treatment options for PICS delivered longitudinally by multidisciplinary providers that include Pediatric Critical Care, Pediatric Neurology, and Pediatric Neuropsychology.[9, 10] We also highlight gaps in knowledge related to interventions for PICS and the need for future research to improve outcomes through prevention and treatment among these vulnerable children and families.

Table 1.

Highlighted studies evaluating inpatient initiated treatments for the prevention or treatment of Post-Intensive Care Syndrome

First Author/Year	Study Design	Population	Intervention	Primary Outcomes	Study Conclusions	Study Limitations
Esses et al., 2019	Pilot randomized trial	62 caregivers of PICU patients and 19 nurses	Each caregiver randomly received 1 of 3 educational strategies: brochures, scripted conversation, or a 3-minute video; nurses were asked how the intervention affected work flow	PRISM framework for effectiveness of the education, the effect of each educational intervention, and costs	All strategies had notable improvement in understanding of PICS, with no single strategy being superior; nurses reported that all 3 interventions minimally disrupted workflow	Small sample; unsure of duration of the duration effect of each of the 3 strategies
Rennick et al., 2018	Pilot randomized controlled trial	20 subjects aged 2–14 years who are admitted to the PICU; n=10 intervention and control group	PICU soothing consisted of (1) parental comforting (touch and reading), followed by (2) a quiet period with music via soft headbands, administered once daily throughout hospitalization	Participation rates, observation, measurement completion rates, semistructured interviews, telephone calls; psychological well-being was assessed using measures of distress, sleep, and child and parent anxiety in the PICU, on the wards, and 3 months post discharge	70% of parents responded positively to comforting and 100% to music; intervention data suggested lower child and parent anxiety after transfer from PICU to the ward	Non-blinded, small sample; relatively high study refusal rate
Moler et al., 2017	Randomized controlled trial	329 subjects aged 0–18 years after in-hospital cardiac arrest requiring chest compressions ≥ 2 minutes	Targeted Temperature Management, either therapeutic hypothermia (target temperature, 33°C) or therapeutic normothermia (target temperature, 36.8°C)	VABS-II	No significant difference between the groups in the primary outcome of survival with a favorable neurobehavioral outcome at 12 months (VABS≥70)	Trial stopped early because of an assessment of futility; long time from the return of circulation to the achievement of a temperature within the target temperature range; no pretrial phase-in; did not use only high-enrolling sites
Moler et al., 2015	Randomized controlled trial	295 subjects aged 0–18 years after out-of-hospital cardiac arrest requiring chest compressions for ≥2 minutes	Targeted Temperature Management, either therapeutic hypothermia (33°C) or therapeutic normothermia (target temperature, 36.8°C)	VABS-II	No significant difference between the groups in the primary outcome of survival with a favorable neurobehavioral outcome at 12 months (VABS≥70)	Caregiver/research staff awareness of treatment assignment; no pretrial phase-in; did not use only high-enrolling sites
Adelson et al., 2013	Randomized, controlled trial	77 subjects aged 0–17 years with non-penetrating brain injury (GCS 3–8) and motor GCS <6 after resuscitation	Targeted Temperature Management: hypothermia (32–33°C) for 48–72 hours versus normothermia	Mortality at 3 months, Global function at 3months with the Glasgow Outcome Scale	No difference in mortality or global function	Terminated early for futility; Small sample; variability of pathology seen on imaging despite similar GCS score
Linton et al., 2008	Pilot study	35 questionnaires to gather transfer information to develop brochure and 21 questionnaires about the brochure from families of children who had spent 1–28 days in the PICU	Discharge information brochure from PICU to the ward	12 question questionnaire with 5 point Likert scale	95% of parents believed the brochure was easy to read, understand, and helpful in improving their understanding of what to expect on the ward	No validated measure of stress or anxiety; Low response rate; English speaking only
Melnyk et al., 2004	Randomized, controlled trial	174 mothers and their 2- to 7-year old children who were admitted to the PICU	3-phase educational-behavioral intervention program (COPE program) delivered: (1) 6–16 hours after PICU admission, (2) 2–16 hours after transfer to the ward, (3) 2–3 days after discharge from hospital	1, 3, 6, and 12 month follow up: Maternal anxiety, negative mood state, depression, maternal beliefs, parental stress, parent participation in their children’s care, child adjustment assessed with BASC	Mothers who received the COPE intervention experienced less stress, improved maternal functional and emotional coping outcomes, and participated more in their child’s care; Children had significantly fewer withdrawal symptoms, fewer negative behavioral symptoms and externalizing behaviors at 12months; Mothers reported children had less hyperactivity and greater adaptability	High rate of attrition through 12 months; questionnaire based assessments; English speaking only

Acronyms for Table (alphabetical order): BASC = Behavioral Assessment System for Children, COPE = Creating Opportunities for Parent Empowerment, GCS = Glasgow Coma Score, PICU = Pediatric Intensive Care Unit, PRISM = Practical, Robust Implementation and Sustainability Model, VABS-II = Vineland Adaptive Behavior Scales, second edition

Table 2.

Highlighted studies evaluating outpatient initiated treatments for Post-Intensive Care Syndrome

First Author/Year	Study Design	Population	Intervention	Primary Outcomes	Study Conclusions	Study Limitations
Treble-Barna et al., 2016	Open-label controlled pilot trial	13 subjects with complicated mild-to-severe TBI (average 5 years post-injury) and 11 healthy comparison subjects aged 9–15 years	AIM program cognitive intervention	TEAch subtests, D-KEFs, BRIEF, GAS	Children with TBI demonstrated significant improvement post intervention on a neuropsychological measure of sustained attention; reported expected or more-than-expected personalized goal attainment	Small sample; high attrition rate; lack of long-term follow-up
Samuel et al., 2015	Randomized controlled trial	209 parents of 145 children consecutively admitted to the PICU	High risk parents (n=78) randomized to follow-up clinic appointment 2 months after discharge versus control	Parents were assessed for risk of developing posttraumatic stress disorder at discharge with the Posttraumatic Adjustment Scale; Impact of Event Scale-Revised and Hospital Anxiety and Depression Scale were completed at 6 months	There was no significant differences between the intervention and control groups, but there was a small positive impact on symptoms of anxiety and depression in a group prospectively identified as at risk of poorer psychological outcome	Only 37% of parents randomized to clinic appointment intervention completed the appointment; follow-up data for only 75% overall
Wade et al., 2015	Randomized controlled trial	132 subjects aged 12–17 years with TBI	6, 12, and 18 month assessment after CAPS intervention or internet resource only control	Children and Functional Assessment Scale; IFIRS	Significant improvement in overall rates of impairment and school/work functioning with CAPS when compared to control particularly among families of lower SES	Potential for selection bias and confounders of therapist interactions
Als et al., 2015	Pilot randomized controlled trial	31 parents of children aged 4–16 years admitted to the PICU	Psychoeducational tool within 7 days of discharge, supported by a telephone call within 14 days of receiving the tool	Number of feasibility criteria successfully met (linked to the intervention and the study design)	Parents who received intervention reported lower post-traumatic stress symptoms in themselves and fewer emotional and behavioral difficulties in their children	Small sample, single-center study
Catroppa et al., 2015	Pilot observational study	10 subjects aged 8–13 years with ABI	18 week intervention program, pre-intervention, immediate, and 6 month post-intervention assessments	Attention and memory, assessed by Amat-c using both neuropsychological and ecologically sensitive measures	Improvement of post-intervention (immediate and 6 month) attention and memory, with generalization to everyday life	Small sample; lack of control group; assessors and parents were not blind to intervention
Ho et al., 2011	Prospective observational study	15 subjects aged 11–17 years with mild, moderate, or severe ABI 1–12 years since injury (9 TBI; 3 had strokes, 2 near drowning accidents, and 1 infection)	6 week treatment protocol using diaries and self-instruction training	Attention and memory, assessed by TEAch subtests	Although memory was the primary outcome targeted by treatment, attention scores improved significantly after the training (selective/focuses attention and attentional control)	Self-selected cohort; not randomized; small sample; limited cognitive testing
Colville et al., 2010	Exploratory randomized controlled trial	154 families of children admitted to the PICU (82 intervention; 72 control)	Follow-up clinic appointment 2 months after discharge versus control	Parent’s baseline stress assessed using Parental Stressor Scale: PICU; post-traumatic stress, anxiety and depression were assessed at 5 months using Impact of Event Scale and the Hospital Anxiety and Depression Scale	No significant differences were found between the intervention and control groups as a whole; parents with higher baseline stress reported lower rates of post-traumatic stress and depression at 5 months if they had been offered an appointment than if they had not	Only 18/82 families chose to attend the follow up clinic appointment; outcome data were provided by 55/82 parents in intervention group and 50/72 in control group screening measures were used to establish psychopathology rather than full diagnostic interviews
Wade et al., 2008	Pilot observational trial	9 subjects aged 11–18 years with TBI (2 severe and 7 moderate) less than 24 months prior; either TOPS with or without audio	TOPS intervention; 10 core sessions and up to 4 supplemental sessions	Adolescent and family psychosocial functioning	Significant improvements in parent-reported adolescent internalizing behaviors, self-reported adolescent depressive symptoms, parental depression, and parent-adolescent conflict; providing audio may enhance some outcomes	Small sample; lack of control group; self-reported measures
King et al., 2007	Randomized controlled trial	11 school-aged children with sickle cell disease and memory deficits	2-year education rehabilitation program, including tutoring with (intervention group) or without memory training (control)	Neuropschological evaluation prior to intervention; at 1st test session, WASI; all sessions included CVLT-C, Digit Span subtest, Wechsler Individual Achievement Tests-Second Edition	Children with memory deficits receiving educational rehabilitation may improve with general tutoring alone; some students may have greater improvement after receiving general tutoring and targeted memory strategies	Small sample
Wade et al., 2006	Randomized controlled trial	32 subjects aged 5–16 years with moderate-to-severe TBI	7 sessions of problem-solving/skill-building intervention over 6-month period (FPS) or control	Child Behavior Checklist, Brief Symptom Inventory, Conflict Behavior Questionnaire	FPS group reported significantly greater improvements in their children in internalizing symptoms, anxiety, depression, and withdrawal	Small and heterogeneous sample; structure of intervention
Hooft et al., 2005	Randomized controlled trial	38 subjects aged 9–16 years with ABI	17 week cognitive program for 30 minutes per day with a teacher or parent	Attention and memory, assessed by neuropsychological tests at end of program	Significant improvements of the treatment group in the majority of neuropsychological tests of sustained and selective attention as well as in memory performance	Small sample; no long-term effects tested
Braga et al., 2005	Randomized controlled trial	87 subjects aged 5–12 years with chronic impairment after TBI	1 year of intensive services either family-supported (intervention) or clinician delivered (control)	Physical outcome with Sarah scales and cognitive outcome with WISC-III	Family-supported intervention sample efficiently acquired the skills needed to deliver physical and cognitive interventions within the context of everyday routines of the child’s life at home and showed significant improvements on outcome measures compared to control group	Multiple interpretations of interventions; relatively small sample size
Yerys et al., 2003	Pilot observational study	6 children with sickle cell disease-related infarcts	8 weekly 1-hour sessions; 3/6 children received additional memory training	Sessions 1 (pre-intervention) and 8 (post-intervention), children completed learning and memory assessments (Numbers subtest from CMS, CVLT-C)	Children who received additional memory training appeared to improve more than that of children receiving only tutoring	Small sample; limited testing period

Acronyms for Table (alphabetical order): ABI = Acquired Brain Injury, AIM = Attention Improvement and Management, Amat-c = Amsterdam Memory and Attention Training for Children, BRIEF = Behavior Rating Inventory of Executive Function, CAPS = Counselor-Assisted Problem Solving, CVLT-C = California Verbal Learning Test – Children’s Version, CMS= Children’s Memory Scale, D-KEFS = Delis-Kaplan Executive Function System, FPS = family-centered problem solving intervention, FPST = Family Problem-Solving Therapy, GAS = Goal Attainment Scale, GCS = Glasgow Coma Score, IFIRS = Iowa Family Interaction Rating Scale, IRC = Internet resource comparison, MVC = Motor Vehicle Collision, PICS = Post-Intensive Care Syndrome, PICU = Pediatric Intensive Care Unit, SES = socioeconomic status, TBI = Traumatic Brain Injury, TEAch = Test for Everyday Attention for Children, TOPS = Teen Online Problem Solving Intervention, WASI = Wechsler Abbreviated Scale of Intelligence; WISC-III = Weschler Intelligence Scale for Children, third edition

Inpatient Treatment

Much of the inpatient care provided to PNCC patients relies on data extrapolated from adult populations or observational studies.[1, 11] To date, large intervention trials among PNCC patients have failed to show benefit or suffered from lack of recruitment.[12–15] Despite challenges, these large studies created infrastructure to study acute interventions in PNCC populations, provided meaningful secondary analyses highlighting the high prevalence of PICS outcomes in children with acquired brain injury, and informed consensus guidelines.[11, 16–22] While a review of therapeutic strategies in all PNCC populations is beyond the scope of this review, we highlight existing PNCC intervention trials and potential therapeutic targets to impact PICS outcomes in the acute phase.

Likely the best data on interventions in PNCC populations comes from trials of targeted temperature management (TTM). Hyperthermia after brain injury increases neuronal injury and excitotoxicity, and fever is associated with worse outcomes.[23] Hypothermia is effective at lowering intracranial pressure (ICP) when refractory to medical therapy.[11, 24] However, multiple randomized trials evaluating therapeutic hypothermia with TTM in pediatric TBI and CA populations failed to show benefit for mortality or gross functional outcome improvements compared to normothermia 1-year after discharge.[12–14, 25, 26] TTM with active normothermia is considered standard of care by many PNCC providers for comatose patients with brain injury, but improvements in PICS outcomes have not been documented.

Another promising trial in PNCC, the Thrombolysis in Pediatric Stroke study, closed early due to poor enrollment from delays in pediatric stroke diagnosis.[15] Thus, there remain no randomized clinical trials for acute stroke treatment in children. Pediatric stroke patients may still be offered thrombolysis or mechanical thrombectomy based on adult data. Since the advent of multiple successful thrombectomy trials in adults,[27] particularly those extending the therapeutic window to 16 or 24 hours,[28, 29] there has been increasing enthusiasm and case series on the use of thrombectomy in children.[30–33] Studies report low complication rates and improved physical and cognitive outcomes, but these results may be limited by publication bias.[30–33]

Seizures lead to secondary brain injury and complicate admissions in 10–40% of critically ill children, particularly PNCC patients. Patients with status epilepticus due to a range of etiologies have a higher mortality and worse Pediatric Cerebral Performance Category.[34–36] Higher seizure burden is also associated with a significant neurological decline during critical care hospitalization and worse neurobehavioral outcomes after discharge.[37, 38] However, the intensity of treatment of seizures with sedating medications like benzodiazepines may be associated with unintended sequelae, such as prolonged ICU stays and intubation, which are risk factors for delirium in the acute setting and ultimately PICS.[39, 40] There are few studies that address the impact of seizures, seizure burden, or seizure treatment on PICS, but seizures offer a potentially modifiable target for intervention studies.

ICU Liberation

Implementation of the ABCDEF bundle improves outcomes in adult critical care.[41, 42] The bundle geared toward assessing and treating pain, early extubation, minimizing over-sedation, identifying and treating delirium, early mobility, and family engagement may mitigate PICS and PICS-F.[41–43] Many institutions have implemented protocols in critically ill children addressing some or all of these components, but it is unclear if similar benefits on outcomes can be achieved in pediatrics.[44–49]

Early and intensive rehabilitation can improve outcomes in critical care patients, stroke, and TBI, but the exact timing and regimens that will provide optimal outcomes in PNCC survivors remain unknown.[42–44, 46, 49, 50] Early mobilization in critically ill patients has potential to reduce delirium, decrease length of mechanical ventilation, and decrease length of stay, but the longitudinal benefits of early mobilization related to PICS in children are unknown.[44, 46–48, 51] Research on mobilization therapies implemented in the pediatric ICU, especially among PNCC patients, is in its infancy and may offer one route to improving PICS morbidities. Fink et al showed early protocolized mobilization was well tolerated and feasible in PNCC.[47]

PNCC patients are at risk for delirium, which is associated with worse outcomes including death, functional outcome, quality of life, and psychosocial morbidity in adult critical care populations.[39, 40] Studies in children show increased mortality, length of stay, and mechanical ventilation duration.[40] Relationships between delirium and long-term PICS outcomes have not been studied well in children, but delusional memories are associated with increased risk of post-traumatic stress.[52] Environmental strategies to reduce delirium are considered first line and include attention to light, noise, and sleep. Weaning from sedatives and narcotics, early mobilization, and early extubation are additional strategies to reduce delirium.[44, 53] While pharmacologic interventions such as dexmedetomidine and atypical anti-psychotics are used, these therapies are not approved for delirium in children and the safety profile in the PNCC population is unknown.[39]

Sedatives, anesthetics, and analgesics commonly used in the pediatric ICU are linked to delirium and worse cognitive outcomes in children.[54] Many of these medications are shown to induce neuronal apoptosis and likely have detrimental effects on the developing brain in addition to increasing risk of delusional memories and delirium.[52, 55, 56] While these medications are necessary for the acute care of many critically ill children, clinicians should be mindful of potentially harmful effects, minimize overall exposure as able, and ensure patients and families are aware of the need for longitudinal monitoring of cognition and development.

Outpatient Treatment

Outpatient management of PNCC survivors requires multiprofessional care and attention to the unique differences in screening and treatment for different ages and developmental stages. PNCC survivors and families suffer chronic morbidities in all domains of PICS that require systematic screening, identification, and management.[9] Similar to inpatient management strategies, little evidence base exists to guide care in regards to outpatient prevention and treatment of PICS and PICS-F.

Physical Sequelae Treatment

PNCC patients are at higher risk for ongoing functional impairments compared to other critical care survivors.[4] Physical impairments may include headaches, pain, sleep disturbances, fatigue, weakness, or spasticity- limiting independence and leading to impaired quality of life.[6, 57] Referrals to occupational, physical, and speech therapies as well as discharge to rehabilitation services are common in PNCC.[3, 9]

Headache and chronic pain are reported in over 20% of all PNCC survivors.[9] Headache is best studied in the pediatric TBI population, showing a prevalence >40% and persistence for years after injury.[58, 59] No evidenced based headache interventions exist, [60] and treatment is often multifaceted combining pharmaceutical intervention, diet and lifestyle modifications, and behavioral therapies to concurrently address comorbidities like sleep disturbance, anxiety, or depression.[60] Opioids should be avoided. Acetaminophen, ibuprofen, and non-steroidal anti-inflammatory medications can be used in the acute period, but chronic overuse should be avoided due to risk of adverse effects including rebound headaches. Triptans can be used for migrainous headaches. Amitriptyline, gabapentin, and topiramate are alternatives for headache prevention when other measures fail. Other sources of chronic pain in the PNCC population are less studied, but both headache and general pain are associated with cognitive and psychosocial sequelae in children similar to PICS suggesting pain management is an important research gap in PNCC patients.[61, 62]

Sleep disturbances and fatigue are reported in over half of PNCC survivors.[9] Sleep disturbances are known to be common and pervasive in TBI literature, but few studies focus on injuries more severe than concussion such as those in PNCC patients.[63] Insomnia, daytime somnolence, and fatigue are the most commonly reported phenotypes, all showing associations with worse cognitive, behavioral, psychosocial, and quality of life outcomes.[64–69] There are no evidenced based therapies for the management of sleep disturbances in PNCC patients.[65, 70–72] Clinicians are left to extrapolate treatment options from adult literature or studies in children with chronic conditions such as epilepsy or neurodevelopmental disorders.[70, 72–75] It is vital to treat comorbidities like pain, depression, anxiety, and post-traumatic stress when present. Many clinicians begin with behavior and lifestyle modifications or melatonin supplementation, and then consider adding additional pharmacological support like trazadone or clonidine if sleep disturbances persist depending on the sleep phenotype.[76] Healthy sleep is vital for brain maturation and neuronal healing after injury and sleep represents a crucial area of intervention research in PNCC survivors.[64, 77–80]

Seizures can additionally complicate chronic recovery after PNCC and outpatient providers are tasked with management of seizure medications. Many PNCC patients start antiepileptic medications to treat early seizures as well as for prophylaxis of seizures. In severe TBI, guidelines recommend 7 days of prophylaxis for early post-traumatic seizures.[11] There is a lack of data on optimal duration of therapy for many PNCC patients with seizures secondary to primary processes like TBI, meningitis, or stroke and known adverse effects of many antiepileptic drugs. Some medications like phenobarbital are associated with cognitive and developmental delays.[81] One of the most common medications for treating seizures in the acute PNCC setting, levetiracetam, is associated with aggression and irritability that is likely to impact a return to normal daily life and confound screening for PICS after discharge.[82] There is evidence that concomitant treatment with pyridoxine may mitigate some behavioral side effects, however these data are limited.[83]

Spasticity is often managed medically with physical therapy and medications,[84] including baclofen, gabapentin, clonidine, botox injections, and benzodiazepines. Most of these therapies have side effects like sedation and unstudied effects on cognitive and psychosocial outcomes in PNCC patients.[84] Other interventions to optimize physical rehabilitation for paresis and spasticity have mostly focused on pediatric stroke using constraint-induced movement therapy (CIMT) and transcranial stimulation—either transcranial direct current stimulation (tDCS) or transcranial magnetic stimulation (TMS). Study populations have been limited to perinatal stroke, but demonstrate the ability to enhance recovery years after initial injury. CIMT involves splinting the non-affected upper extremity to limit its use and force use of the weak upper extremity to promote motor function in the affected extremity.[85, 86] Although safe and feasible, trials of tDCS for pediatric stroke motor recovery have been largely negative to date.[87] Repetitive TMS paired with CIMT or motor learning may enhance upper extremity function in stroke.[88]

Cognitive Sequelae Treatment

Over 50% of all PNCC survivors report cognitive sequelae in memory and attention, and benefit from early evaluation and management with neuropsychologists.[9, 10] A recent systematic review of cognitive morbidities associated with pediatric critical care found lower scores across cognitive domains (attention, processing speed, executive functioning, and memory).[54] Few studies have investigated cognitive rehabilitation interventions in the PNCC population. Current strategies for cognitive rehabilitation involve interventions designed to reestablish previously learned behaviors or establish new patterns of compensatory mechanisms in impaired cognitive domains.[89, 90] Attention and memory may be improved through daily attention training in children with heterogeneous neurologic diseases or brain malignancy.[90, 91] Self-instruction and diary training improved everyday memory, attention, and mood in a small cohort of children with acquired brain injury from TBI, stroke, and CA.[92] Data in ICU survivors also suggests cognitive benefit of combining physical and cognitive therapies in multifaceted rehabilitation programs.[93, 94] Age and developmental stage at time of injury likely affect response to cognitive rehabilitation and an individual patient’s trajectory of recovery.[95] Data supporting effectiveness of specific cognitive rehabilitation strategies in PNCC survivors is limited.

Among children with TBI, cognitive sequelae persist for years in domains of executive function, learning, attention, processing speed, and memory that significantly affect school performance and developmental trajectories.[95, 96] Many cognitive sequelae are severity of injury related, but even patients with mild TBI have chronic cognitive deficits in some studies.[95, 96] A few small studies have evaluated interventions in pediatric TBI patients showing promise for computerized and in-person cognitive rehabilitation programs.[97–99] Limited evidence supports the use of pharmacologic management with stimulants like methylphenidate after TBI, though they are often used in patients with concurrent attention deficit/hyperactivity disorder.[98] Evidence suggests early interventions targeting parental education and problem solving can improve function after pediatric TBI particularly among low socioeconomic status families,[100–102] and that family function is a key determinant of patient outcome.[103] Intensive supports for rehabilitation delivered by families can also improve cognitive outcomes.[104]

Approximately 50% of all children with ischemic or hemorrhagic stroke will have long-term cognitive problems.[105–107] Although therapeutic interventions have not specifically targeted the cognitive effects post-stroke, efforts to reduce infarct size and minimize physical deficits may improve cognitive outcomes, as these are potentially modifiable factors associated with worse cognitive outcomes.[106, 107] Memory training, paired with academic tutoring, may improve cognitive outcomes in children after ischemic stroke in the setting of sickle cell disease.[108, 109]

Emotional, Social, and Family Sequelae Treatment

A growing body of research shows negative psychological sequelae in critical care survivors, including increased levels of anxiety, depression, post-traumatic stress symptoms (PTSS) or disorder (PTSD), and behavioral symptoms.[110, 111] Among PNCC patients, mood disturbances are commonly reported at follow-up including anxiety (35%), behavior changes (26%), and depressive symptoms (16%).[9] Parents of PNCC survivors report significant social sequelae in their child and themselves including loss of employment, high financial burden, loss of relationships with family and friends, and difficulty making new friends.[5, 21, 112] Parents also suffer high rates of emotional and psychological sequelae including anxiety, depression, PTSS, and PTSD.[113–115] Understanding, preventing, and treating PICS-F is not only important for the wellbeing of the family members, but also directly impacts the child through interference with the ability to provide ongoing care and emotional support for the child.[116–118] The research is still in its infancy, but data suggest interventions can reduce child and family morbidity,[113] most using psychoeducational and direct intervention methodology.

Psychoeducational interventions include handouts, face-to-face communication, videos, computer modules, and directed activities. Simple interventions like providing informational brochures to parents are feasible and helpful to reduce parent anxiety.[119, 120] Esses et al examined the effectiveness of educating parents on PICS and PICS-F via three different modes of delivery (brochure, scripted conversation, short video) and found that all interventions increased knowledge about and understanding of PICS.[121] Studies also demonstrate that parents who spoke about their feelings during the admission,[122] experienced greater social support during the ICU admission,[123] and those who were involved with medical decision making[124] had better psychological outcomes. Involvement of psychology and social work during the inpatient stay can also improve the family experience during hospitalization and help prepare the family for discharge.[125] ICU diaries are an emerging intervention with limited pediatric data, but studies show good feasibility and acceptability among families of critically ill children.[126] A systematic review of the impact of ICU diaries on psychological outcomes of adult ICU patients and their families found significant evidence that ICU diaries decrease anxiety and depression among ICU survivors and improve health related quality of life.[127]

Direct intervention studies often focus on parents as opposed to children. Melnyk et al evaluated the Creating Opportunities for Parent Empowerment (COPE) program showing reduced parent stress during pediatric critical care hospitalization, reduced parent psychological sequelae after hospitalization, and improved emotional and behavioral outcomes in children 12 months post-discharge.[128] A study of soothing intervention, the Touch & Talk (T&T) program, promoted quicker return to physiological baseline following invasive procedures in infants and toddlers in the ICU.[129] A later iteration of the intervention consisting of comforting touch, reading, and music via soft headbands in children showed the intervention lowered child and parent anxiety in the hospital and after discharge.[130] Peer support both during and after the ICU is of growing interest in adult critical care with promising results on PICS and PICS-F,[131] but the impact of support groups on patient and family outcomes in pediatrics is unknown.

ICU Follow-up

Several studies have evaluated the feasibility and impact of offering follow-up to patients and families after discharge. A study evaluating the combination of a psychoeducational tool and follow-up phone call for critically ill children showed the majority of parents found the intervention was useful (82%) and reduced anxiety and concern (77%), with small effects on lowering PTSD and depressive symptoms in parents and behavioral concerns in the children.[132] Literature shows follow-up clinics are feasible as a method to deliver interventions and typically include a paired visit with a psychologist/psychiatrist and medical staff (physician or nurse) within 8 weeks of discharge.[9, 10, 133–135] High risk parents may particularly benefit from reductions in anxiety and depressive symptoms.[134] Multidisciplinary programs spanning inpatient and outpatient care are increasing, have high rates of follow-up, and offer exciting opportunities to learn more about PICS and PICS-F.[9, 10] Programs that include Pediatric Critical Care, Neurology, and Neuropsychology in combined follow-up visits report high rates of follow-up (≥66%), frequent symptoms requiring ongoing care in 85% of children, and high rates of parent satisfaction.[9, 10] Having multiple professions in one clinic allows an individualized and holistic approach to treatment of PICS. For instance, headaches may be treated pharmacologically, but treatment paired with sleep management strategies and psychotherapeutic intervention for comorbidities like anxiety and acute stress, may improve effectiveness. Similarly, cognitive interventions that include management of physical sequelae like sleep disturbance and pain, in addition to strategies harnessing relative cognitive strengths, will maximize effectiveness. It is clear that focusing on one domain of PICS in isolation would substantially limit recovery potential and requires a multidisciplinary approach. Follow-up clinics are ideal to deliver this coordinated care.

Conclusion

Children surviving PNCC and their families suffer chronic morbidities encompassed by PICS. Few interventions have been studied in this population and clinicians managing children and families with PICS are left with little evidence base to guide care. The breadth of PICS morbidities requires multidisciplinary management integrated into clinical care beginning with the acute admission and extending longitudinally after discharge. Research on acute interventions to prevent PICS and therapeutic interventions to treat PICS are needed across the spectrum of physical, cognitive, emotional, and social domains of PICS in children and families.