Delirium Associated with COVID-19 in Critically ill Children: An Observational Cohort Study.

OBJECTIVE: Delirium is an under-recognized problem in critically ill children. Although delirium is common in adults hospitalized with COVID-19, the relationship between pediatric COVID-19 and delirium has not been described. To address this gap, we characterized delirium in critically ill children with different manifestations of COVID-19 and investigated associations among demographic, disease, and treatment factors. We hypothesized that multisystem inflammatory syndrome in children (MIS-C) would be associated with a higher incidence of delirium given its underlying pathophysiology of hyperinflammation. DESIGN: Retrospective, single-center cohort study. SETTING: Quaternary-care pediatric intensive care unit (PICU). PATIENTS: Children less than 18 years of age hospitalized in the PICU between March 2020 and March 2023 with either active SARS-CoV-2 infection or serological evidence of prior infection. MEASUREMENTS AND MAIN RESULTS: The cohort included 149 PICU hospitalizations among children with evidence of COVID-19. Patients were categorized by reason for PICU admission: 75 (50%) for COVID-19 respiratory disease, 36 (24%) MIS-C, and 38 (26%) any other primary reason with positive COVID-19 testing. Delirium was diagnosed in 43 (29%) patients. Delirium incidence was highest in patients requiring invasive mechanical ventilation (IMV) (56% vs 7.5% in patients who did not require IMV, p < .001). Patients who were exposed to opioids, dexmedetomidine, paralytics or benzodiazepines more frequently experienced delirium compared to those unexposed (p < .001, p < .001, p < .001 and p = .001, respectively). After multivariable adjustment, delirium was associated with IMV (HR 3 [95% CI 1.5-5.7]), female sex (HR 2.4 [1.2-4.7]), and developmental disability (HR 3.4 [95% CI 1-11.1]). There was no association between delirium and reason for PICU hospitalization. CONCLUSIONS: Delirium was common among children hospitalized with COVID-19. The overall incidence was much less than has been reported in adults with COVID-19. Delirium reduction efforts should focus on children with developmental disability and minimizing ongoing risks during IMV.

EMPOWER: A Multi-Site Pilot Trial to Reduce Distress in Surrogate Decision-Makers in the ICU.

CONTEXT: Efforts to reduce the psychological distress of surrogate decision-makers of critically ill patients have had limited success, and some have even exacerbated distress. OBJECTIVES: The aim of this study was to determine the feasibility, acceptability, and preliminary efficacy of EMPOWER (Enhancing and Mobilizing the POtential for Wellness and Resilience), an ultra-brief (∼2-hour), 6-module manualized psychological intervention for surrogates. METHODS: Surrogates who reported significant anxiety and/or an emotionally close relationship with the patient (n=60) were randomized to receive EMPOWER or enhanced usual care (EUC) at one of three metropolitan hospitals. Participants completed evaluations of EMPOWER's acceptability and measures of psychological distress pre-intervention, immediately post-intervention, and at 1- and 3-month follow-up assessments. RESULTS: Delivery of EMPOWER appeared feasible, with 89% of participants completing all 6 modules, and acceptable, with high ratings of satisfaction (mean=4.5/5, SD = .90). Compared to EUC, intent-to-treat analyses showed EMPOWER was superior at reducing peritraumatic distress (Cohen's d = -0.21, small effect) immediately post-intervention and grief intensity (d = -0.70, medium-large effect), posttraumatic stress (d = -0.74, medium-large effect), experiential avoidance (d = -0.46, medium effect), and depression (d = -0.34, small effect) 3 months post-intervention. Surrogate satisfaction with overall critical care (d = 0.27, small effect) was higher among surrogates randomized to EMPOWER. CONCLUSIONS: EMPOWER appeared feasible and acceptable, increased surrogates' satisfaction with critical care, and prevented escalation of posttraumatic stress, grief, and depression 3 months later.

Screening for Delirium During Pediatric Brain Injury Rehabilitation.

OBJECTIVE: To assess feasibility of routine delirium screening using the Cornell Assessment of Pediatric Delirium (CAPD) in children admitted for rehabilitation with acquired brain injury (ABI), report on the prevalence of positive delirium screens in this population, and explore longitudinal trends in CAPD scores and their association with rehabilitation outcomes. DESIGN: Retrospective study. SETTING: Pediatric inpatient rehabilitation unit. PARTICIPANTS: 144 children (median 10.8 years) with ABI (N=144). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Percent compliance with twice daily delirium screening; prevalence of positive delirium screens; trajectories in CAPD scores and their relation with FIM for Children (WeeFIM) scores. RESULTS: Screening was feasible (mean 75% compliance for each of 144 children). Of 16,136 delirium screens, 29% were positive. 62% of children had ≥1 positive screen. Four primary patterns of CAPD trajectories were identified: Static Encephalopathy (10%), Episodic Delirium (10%), Improving (32%), and No Delirium (48%). Validity of these trajectories was demonstrated through association with WeeFIM and CALS outcomes. Younger age at admission was associated with positive delirium screens, and rehabilitation length of stay was significantly longer for the Improving group. CONCLUSIONS: Delirium occurs frequently in children with ABI during inpatient rehabilitation. Routine delirium screening provides clinically relevant information including the potential to facilitate early detection and intervention for medical complications. Longitudinal ratings of delirium symptoms may also have a role in developing a standardized definition for Post Traumatic Confusional State (PTCS) stage of recovery in children.

Delirium in the NICU.

Delirium in the NICU is an underrecognized phenomenon in infants who are often complex and critically ill. The current understanding of NICU delirium is developing and can be informed by adult and pediatric literature. The NICU population faces many potential risk factors for delirium, including young age, developmental delay, mechanical ventilation, severe illness, and surgery. There are no diagnostic tools specific to infants. The mainstay of delirium treatment is to treat the underlying cause, address modifiable risk factors, and supportive care. This review will summarize current knowledge and areas where more research is needed.

Caring for Critically Ill Children With the ICU Liberation Bundle (ABCDEF): Results of the Pediatric Collaborative.

OBJECTIVES: Assess clinical outcomes following PICU Liberation ABCDEF Bundle utilization. DESIGN: Prospective, multicenter, cohort study. SETTING: Eight academic PICUs. PATIENTS: Children greater than 2 months with expected PICU stay greater than 2 days and need for mechanical ventilation (MV). INTERVENTIONS: ABCDEF Bundle implementation. MEASUREMENT AND MAIN RESULTS: Over an 11-month period (3-mo baseline, 8-mo implementation), Bundle utilization was measured for 622 patients totaling 5,017 PICU days. Risk of mortality was quantified for 532 patients (4,275 PICU days) for correlation between Bundle utilization and MV duration, PICU length of stay (LOS), delirium incidence, and mortality. Utilization was analyzed as subject-specific (entire PICU stay) and day-specific (single PICU day). Median overall subject-specific utilization increased from 50% during the 3-month baseline to 63.9% during the last four implementation months ( p < 0.001). Subject-specific utilization for elements A and C did not change; utilization improved for B (0-12.5%; p = 0.007), D (22.2-61.1%; p < 0.001), E (17.7-50%; p = 0.003), and F (50-79.2%; p = 0.001). We observed no association between Bundle utilization and MV duration, PICU LOS, or delirium incidence. In contrast, on adjusted analysis, every 10% increase in subject-specific utilization correlated with mortality odds ratio (OR) reduction of 34%, p < 0.001; every 10% increase in day-specific utilization correlated with a mortality OR reduction of 1.4% ( p = 0.006). CONCLUSIONS: ABCDEF Bundle is applicable to children. Although enhanced Bundle utilization correlated with decreased mortality, increased utilization did not correlate with duration of MV, PICU LOS, or delirium incidence. Additional research in the domains of comparative effectiveness, implementation science, and human factors engineering is required to understand this clinical inconsistency and optimize PICU Liberation concept integration into clinical practice.

Association between Platelet Transfusion and Delirium in Critically Ill Children.

Delirium is a frequent, serious, and preventable complication in critically ill children. Inflammation has been implicated as a mechanism for the development of delirium. Platelet transfusions may potentiate the body's pro-inflammatory responses. We hypothesized that receipt of platelets would be associated with delirium development in a pediatric intensive care unit (PICU). We performed a single-center retrospective cohort analysis including children admitted to the PICU between 2014 and 2018 who were transfused platelets within the first 14 days of admission. Data obtained included severity of illness, level of respiratory support, exposure to medications and blood products, as well as daily cognitive status. To account for time-dependent confounding, a marginal structural model (MSM) was constructed to delineate the relationship between platelet transfusion and next-day delirium. MSM demonstrated a 75% increase in the development of next-day delirium after transfusion of platelets (aOR 1.75, 95% CI 1.03-2.97). For every 1 cc/kg of platelet transfused, odds of next-day delirium increased by 9% (odds ratio 1.09, 95% CI 1.03-1.51). We reported an independent association between platelet transfusion and next-day delirium/coma after accounting for time-dependent confounders, with a dose-response effect. Minimizing platelet transfusions as much as clinically feasible may decrease delirium risk in critically ill children.

Pediatric Critical Care in the Twenty-first Century and Beyond.

Pediatric critical care addresses prevention, diagnosis, and treatment of organ dysfunction in the setting of increasingly complex patients, therapies, and environments. Soon burgeoning data science will enable all aspects of intensive care: driving facilitated diagnostics, empowering a learning health-care environment, promoting continuous advancement of care, and informing the continuum of critical care outside the intensive care unit preceding and following critical illness/injury. Although novel technology will progressively objectify personalized critical care, humanism, practiced at the bedside, defines the essence of pediatric critical care now and in the future.

Factors Associated With Delirium in Children: A Systematic Review and Meta-Analysis.

OBJECTIVES: Pediatric delirium (PD) is a neuropsychiatric syndrome caused by a complex interplay between predisposing factors (e.g., age, cognitive impairment), acute illness, and environmental triggers. PD is associated with substantial morbidity and mortality. The objective of this study is to systematically review and evaluate factors associated with PD in hospitalized pediatric patients. DATA SOURCES: A systematic search of PubMed, Embase, Ovid Medline, Web- of-Science, Cochrane, CIHNAL, and Google Scholar databases was conducted for relevant studies (1990-2022). STUDY SELECTION: We included studies that compared pediatric patients with and without delirium. Reviews, editorials, congress abstracts, or studies that did not report factors for PD were excluded. No restrictions were imposed on language. DATA EXTRACTION: Title and abstract were independently screened by two reviewers. Individual characteristics, study design, and outcomes were independently extracted. DATA SYNTHESIS: Categorical dichotomous data were summarized across groups using Mantel-Haenszel odds ratios (ORs) with 95% 95% CIs. Either fixed-effect or random effects models were used as indicated by the results of a heterogeneity test. Of 1,846 abstracts, 24 studies were included. We identified 54 factors studied in univariate analyses, and 27 of these were associated with PD in multivariable analyses. In pooled analyses, greater odds of PD were associated with developmental delay (OR 3.98; 95% CI 1.54-10.26), need for mechanical ventilation (OR 6.02; 95% CI 4.43-8.19), use of physical restraints (OR 4.67; 95% CI 1.82-11.96), and receipt of either benzodiazepines (OR 4.10; 95% CI 2.48-6.80), opiates (OR 2.88; 95% CI 1.89-4.37), steroids (OR 2.02; 95% CI 1.47-2.77), or vasoactive medication (OR 3.68; 95% CI 1.17-11.60). CONCLUSIONS: In this meta-analysis, we identified seven factors associated with greater odds of developing delirium during pediatric critical illness.

Use of Electronic Health Records to Identify Exposure-Response Relationships in Critically Ill Children: An Example of Midazolam and Delirium.

Adverse drug events are common in critically ill children and often result from systemic or target organ drug exposure. Methods of drug dosing and titration that consider pharmacokinetic alterations may improve our ability to optimally dose critically ill patients and reduce the risk for drug-related adverse events. To demonstrate this possibility, we explored the exposure-response relationship between midazolam and delirium in critically ill children. We retrospectively examined electronic health records (EHRs) of critically ill children <18 years of age hospitalized in the pediatric intensive care unit at Duke University; these children were administered midazolam during mechanical ventilation and had ≥1 Cornell Assessment of Pediatric Delirium (CAPD) score. We used individual-level data extracted from the EHR and a previously published population pharmacokinetic (PK) model developed in critically ill children to simulate plasma concentrations at the time of CAPD scores in 1,000 representative datasets. We used multilevel repeated measures models, with clustering at patient and simulation levels, to evaluate the associations between measures of drug exposure (e.g., concentration and area under concentration time curve) and delirium scores. We included 61 children, median age 1.5 years (range = 0.1-16.3), with 181 CAPD assessments. We identified similarities between simulated Empirical Bayesian parameter estimates from the EHR cohort and those from the PK model population. We identified a stronger association between drug concentration at the time of score and CAPD scores (coefficient 1.78; 95% confidence interval: 1.66-1.90) compared with cumulative dose per kilogram and CAPD scores (coefficient -0.01; 95% confidence interval: -0.01 to -0.01). EHR and PK models can be leveraged to investigate exposure-response relationships in critically ill children.

Pediatric Delirium and All-Cause PICU Readmissions Within 1 Year.

OBJECTIVES: Delirium in critically ill children is associated with increased in-hospital morbidity and mortality. Little is known about the lingering effects of pediatric delirium in survivors after hospital discharge. The primary objective of this study was to determine whether children with delirium would have a higher likelihood of all-cause PICU readmission within 1 calendar year, when compared with children without delirium. DESIGN: Retrospective cohort study. SETTING: Tertiary care, mixed PICU at an urban academic medical center. PATIENTS: Index admissions included all children admitted between September 2014 and August 2015. For each index admission, any readmission occurring within 1 year after PICU discharge was captured. INTERVENTION: Every child was screened for delirium daily throughout the PICU stay. MEASUREMENTS AND MAIN RESULTS: Among 1,145 index patients, 166 children (14.5%) were readmitted at least once. Bivariate analyses compared patients readmitted within 1 year of discharge with those not readmitted: complex chronic conditions (CCCs), increased severity of illness, longer PICU length of stay, need for mechanical ventilation, age less than 6 months, and a diagnosis of delirium were all associated with subsequent readmission. A multivariable logistic regression model was constructed to describe adjusted odds ratios for readmission. The primary exposure variable was number of delirium days. After controlling for confounders, critically ill children who experienced greater than 2 delirium days on index admission were more than twice as likely to be readmitted (adjusted odds ratio, 2.2; CI, 1.1-4.4; p = 0.023). A dose-response relationship was demonstrated as children with longer duration of delirium had increased odds of readmission. CONCLUSIONS: In this cohort, delirium duration was an independent risk factor for readmission in critically ill children. Future research is needed to determine if decreasing prevalence of delirium during hospitalization can decrease need for PICU readmission.

Sedation Practices in the PICU: An Unexpected Casualty of COVID-19.

Pediatric intensivists often use an "analgosedation" approach in mechanically ventilated children. By prioritizing analgesia and minimizing sedation, patients experience less delirium. However, when COVID-19 surged, our pediatric intensive care unit providers were tasked with caring for adults with severe acute hypoxemic respiratory failure (AHRF). As documented in the literature, adults with COVID-19-AHRF received significantly higher doses of sedatives than matched cohorts with non-COVID-19 AHRF. Surprisingly, when the pediatric intensive care unit returned to caring for children, a quality review showed that we were unintentionally using far more sedatives than that prior to COVID-19. This experience is not unique to our institution, or to COVID-19. Lingering effects of crisis care can persist beyond the event itself. We seek to share our experience in order to extend the conversation regarding the unexpected effects of crises on best practices and to stress the need for high-quality research on interventions to support mental health and resilience in frontline healthcare providers.

Simultaneous detection of a panel of nine sedatives and metabolites in plasma from critically ill pediatric patients via UPLC-MS/MS.

Sedative use can result in adverse drug reactions. Intensive care unit patients are especially at risk and pharmacokinetic modeling of drug concentrations is an approach to develop precision dosing strategies. However, limited blood sampling availability in critically ill children and need for multiple assays to quantify a variety of commonly used sedatives creates logistical challenges. The goal of this project was to develop a sensitive and selective assay for the simultaneous quantification of a panel of sedatives comprised of midazolam (MDZ), alpha hydroxymidazolam (1- OH MDZ), dexmedetomidine (DEX), morphine (MOR), morphine-3-glucuronide (M3G), morphine-6-glucuronide (M6G), fentanyl (FEN), norfentanyl (NF), and hydromorphone (HM) in small volume pediatric plasma samples. A sensitive and efficient ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS/MS) method was developed following FDA guidance for bioanalytical validation. Minimal sample preparation consisting of simple protein precipitation extraction using acetonitrile with internal standards was utilized. Analyte separation was achieved using a gradient mixture of (A: 0.15% formic acid in water and B: Acetonitrile) and a Waters Acquity C18, 1.7 µm (2.1 × 100 mm) column. Assays were linear over the clinical concentration ranges: MDZ, MOR, HM: 0.5-125 ng/mL; 1-OH MDZ, M3G, M6G: 5-500 ng/mL; and DEX, FEN, NF: 0.05-7.5 ng/mL (R2 > 0.99 for all). Assay run time was 10 min and required only 100 µL of plasma. Initial testing of samples from pediatric patients demonstrates adequacy of assay to measure sedatives and metabolites at clinical concentrations confidently in low volumes of plasma. This novel highly-sensitive and specific method to measure a total of nine different analytes (five sedatives, four metabolites) simultaneously enables comprehensive analysis of a panel of sedatives in small volumes such as in pediatric ICU patients.

The brain in pediatric critical care: unique aspects of assessment, monitoring, investigations, and follow-up.

As survival after pediatric intensive care unit (PICU) admission has improved over recent years, a key focus now is the reduction of morbidities and optimization of quality of life for survivors. Neurologic disorders and direct brain injuries are the reason for 11-16% of admissions to PICU. In addition, many critically ill children are at heightened risk of brain injury and neurodevelopmental difficulties affecting later life, e.g., complex heart disease and premature birth. Hence, assessment, monitoring and protection of the brain, using fundamental principles of neurocritical care, are crucial to the practice of pediatric intensive care medicine. The assessment of brain function, necessary to direct appropriate care, is uniquely challenging amongst children admitted to the PICU. Challenges in assessment arise in children who are unstable, or pharmacologically sedated and muscle relaxed, or who have premorbid abnormality in development. Moreover, the heterogeneity of diseases and ages in PICU patients, means that high caliber evidence is harder to accrue than in adult practice, nonetheless, great progress has been made over recent years. In this 'state of the art' paper about critically ill children, we discuss (1) patient types at risk of brain injury, (2) new standardized clinical assessment tools for age-appropriate, clinical evaluation of brain function, (3) latest evidence related to cranial imaging, non-invasive and invasive monitoring of the brain, (4) the concept of childhood 'post intensive are syndrome' and approaches for neurodevelopmental follow-up. Better understanding of these concepts is vital for taking PICU survivorship to the next level.

2022 Society of Critical Care Medicine Clinical Practice Guidelines on Prevention and Management of Pain, Agitation, Neuromuscular Blockade, and Delirium in Critically Ill Pediatric Patients With Consideration of the ICU Environment and Early Mobility.

RATIONALE: A guideline that both evaluates current practice and provides recommendations to address sedation, pain, and delirium management with regard for neuromuscular blockade and withdrawal is not currently available. OBJECTIVE: To develop comprehensive clinical practice guidelines for critically ill infants and children, with specific attention to seven domains of care including pain, sedation/agitation, iatrogenic withdrawal, neuromuscular blockade, delirium, PICU environment, and early mobility. DESIGN: The Society of Critical Care Medicine Pediatric Pain, Agitation, Neuromuscular Blockade, and Delirium in critically ill pediatric patients with consideration of the PICU Environment and Early Mobility Guideline Taskforce was comprised of 29 national experts who collaborated from 2009 to 2021 via teleconference and/or e-mail at least monthly for planning, literature review, and guideline development, revision, and approval. The full taskforce gathered annually in-person during the Society of Critical Care Medicine Congress for progress reports and further strategizing with the final face-to-face meeting occurring in February 2020. Throughout this process, the Society of Critical Care Medicine standard operating procedures Manual for Guidelines development was adhered to. METHODS: Taskforce content experts separated into subgroups addressing pain/analgesia, sedation, tolerance/iatrogenic withdrawal, neuromuscular blockade, delirium, PICU environment (family presence and sleep hygiene), and early mobility. Subgroups created descriptive and actionable Population, Intervention, Comparison, and Outcome questions. An experienced medical information specialist developed search strategies to identify relevant literature between January 1990 and January 2020. Subgroups reviewed literature, determined quality of evidence, and formulated recommendations classified as "strong" with "we recommend" or "conditional" with "we suggest." Good practice statements were used when indirect evidence supported benefit with no or minimal risk. Evidence gaps were noted. Initial recommendations were reviewed by each subgroup and revised as deemed necessary prior to being disseminated for voting by the full taskforce. Individuals who had an overt or potential conflict of interest abstained from relevant votes. Expert opinion alone was not used in substitution for a lack of evidence. RESULTS: The Pediatric Pain, Agitation, Neuromuscular Blockade, and Delirium in critically ill pediatric patients with consideration of the PICU Environment and Early Mobility taskforce issued 44 recommendations (14 strong and 30 conditional) and five good practice statements. CONCLUSIONS: The current guidelines represent a comprehensive list of practical clinical recommendations for the assessment, prevention, and management of key aspects for the comprehensive critical care of infants and children. Main areas of focus included 1) need for the routine monitoring of pain, agitation, withdrawal, and delirium using validated tools, 2) enhanced use of protocolized sedation and analgesia, and 3) recognition of the importance of nonpharmacologic interventions for enhancing patient comfort and comprehensive care provision.

Transfusion-Associated Delirium in Children: No Difference Between Short Storage Versus Standard Issue RBCs.

OBJECTIVES: Primary objective is to determine if transfusion of short storage RBCs compared with standard issue RBCs reduced risk of delirium/coma in critically ill children. Secondary objective is to assess if RBC transfusion was independently associated with delirium/coma. DESIGN: This study was performed in two stages. First, we compared patients receiving either short storage or standard RBCs in a multi-institutional prospective randomized controlled trial. Then, we compared all transfused patients in the randomized controlled trial with a single-center cohort of nontransfused patients matched for confounders of delirium/coma. SETTING: Twenty academic PICUs who participated in the Age of Transfused Blood in Critically Ill Children trial. PATIENTS: Children 3 days to 16 years old who were transfused RBCs within the first 7 days of admission. INTERVENTIONS: Subjects were randomized to either short storage RBC study arm (defined as RBCs stored for up to seven days) or standard issue RBC study arm. In addition, subjects were screened for delirium prior to transfusion and every 12 hours after transfusion for up to 3 days. MEASUREMENTS AND MAIN RESULTS: Primary outcome measure was development of delirium/coma within 3 days of initial transfusion. Additional outcome measures were dose-response relationship between volume of RBCs transfused and delirium/coma, and comparison of delirium/coma rates between transfused patients and individually matched nontransfused patients. We included 146 subjects in the stage I analysis; 69 were randomized to short storage RBCs and 77 to standard issue. There was no significant difference in delirium/coma development between study arms (79.5% vs 70.1%; p = 0.184). In the stage II analysis, adjusted odds for delirium in the transfused cohort was more than eight-fold higher than in the nontransfused matched cohort, even after controlling for hemoglobin (adjusted odds ratio, 8.9; CI, 2.8-28.4; p < 0.001). CONCLUSIONS: RBC transfusions (and not anemia) are independently associated with increased odds of subsequent delirium/coma. However, storage age of RBCs does not affect delirium risk.