Clinical Context

Previous research has suggested that approximately 30% of patients discharged from the pediatric intensive care unit (PICU) suffer subsequent neurologic and functional morbidity, and that this effect may be more pronounced among young children. Shein and colleagues assessed the prevalence of neurologic morbidity among previously admitted children admitted to the PICU between the ages of 0 and 2 years; their results were published in the December 2017 issue of Pediatric Critical Care Medicine.^[1]

A total of 3751 children had data at hospital discharge after bronchiolitis, and 9516 were followed at subsequent hospitalizations for evidence of neurologic complications or disability: 18.6% of children had a neurologic complication or disability at discharge, and the rate of these outcomes at subsequent hospitalization was 11.6%. The application of mechanical ventilation was significantly associated with a higher risk for neurologic complications or disability in the short- and long-term, but children's age at admission, sex, and race/ethnicity were not.

The current study expands on this previous research by focusing on the neurologic outcomes of children admitted to the PICU with respiratory failure.

Study Synopsis and Perspective

Children who survive an episode of acute respiratory failure that requires invasive mechanical ventilation may be at risk for slightly lower long-term neurocognitive function, new research suggests.

Investigators found lower IQs in children without previous neurocognitive problems who survived PICU admission for acute respiratory failure compared with their biological siblings.

Although this magnitude of difference was small on average, more than twice as many patients than siblings had an IQ of 85 or lower, and children hospitalized at the youngest ages did worse than their siblings.

"Children surviving acute respiratory failure may benefit from routine evaluation of neurocognitive function after hospital discharge and may require serial evaluation to identify deficits that emerge over the course of child's continued development to facilitate early intervention to prevent disability and optimize school performance," study investigator R. Scott Watson, MD, MPH, professor of pediatrics, University of Washington School of Medicine, Seattle, told Medscape Medical News.

The study was published online March 1 in JAMA.^[2]

"Approximately 23 700 US children undergo invasive mechanical ventilation for acute respiratory failure annually, with unknown long-term effects on neurocognitive function," the authors write.

"With improvements in pediatric critical care over the past several decades, critical illness-associated mortality has improved dramatically, [but] as survivorship has increased, we are starting to learn that many patients and their families suffer from long-term morbidity associated with the illness and its treatment," said Dr Watson, who is the associate division chief, Pediatric Critical Care Medicine, Seattle Children's Hospital, Center for Child Health, Behavior, and Development.

Animal studies "have found that some sedative medications commonly used to keep children safe during mechanical ventilation may have detrimental neurologic effects, particularly in the developing brain," Dr Watson added.

To gain a better understanding of this potential association, the researchers turned to a subset of participants in the previously conducted Randomized Evaluation of Sedation Titration for Respiratory Failure (RESTORE) trial of pediatric patients receiving mechanical ventilation for acute respiratory failure.

For the current study (RESTORE-Cognition), multiple domains of neurocognitive function were assessed 3 to 8 years after hospital discharge in trial patients who did not have a history of neurocognitive dysfunction, as well as matched, healthy siblings.

To be included in the study, the children had to be 8 years old or younger at trial enrollment, have a Pediatric Cerebral Performance Category (PCPC) score of 1 (normal) before PICU admission, and have no worse than moderate neurocognitive dysfunction at PICU discharge.

Siblings of enrolled patients were required to be between 4 and 16 years old at the time of neurocognitive testing, have a PCPC score of 1, have the same biological parents as the patient, and live with the patient.

The primary outcome was IQ, estimated by the age-appropriate Vocabulary and Block Design subtests of the Wechsler Intelligence Scale. Secondary outcomes included attention, processing speed, learning and memory, visuospatial skills, motor skills, language, and executive function. Enough time was allowed after hospitalization "for transient deficits to resolve and longer-lasting neurocognitive sequelae to manifest."

Of the 121 sibling pairs (67% non-Hispanic White, 47% from families in which 1 or both parents worked full-time), 116 were included in the primary outcome analysis, and 66 to 119 were included in analyses of secondary outcomes.

Patients had been in the PICU at a median (IQR) age of 1.0 (0.2-3.2) years and had received a median of 5.5 (3.1-7.7) days of invasive mechanical ventilation.

The median age at testing for patients and matched siblings was 6.6 (IQR, 5.4-9.1) and 8.4 (IQR, 7.0-10.2) years, respectively. Interviews with parents and testing of patients were conducted a median of 3.8 (IQR, 3.2-5.2) and 5.2 (IQR, 4.3-6.1) years, respectively, after hospitalization.

The most common etiologies of respiratory failure were bronchiolitis and asthma and pneumonia (44% and 37%, respectively). Beyond respiratory failure, most patients (72%) also had experienced multiple organ dysfunction syndrome.

Patients had a lower mean estimated IQ compared with the matched siblings (101.5 vs 104.3; mean difference, −2.8 [95% confidence interval (CI), −5.4 to −0.2]), and more patients than siblings had an estimated IQ of 5 or less but not of 70 or less.

Patients also had significantly lower scores on nonverbal memory, visuospatial skills, and fine motor control (mean differences, −0.9 [95% CI, −1.6 to −0.3], −0.9 [95% CI, −1.8 to −0.1], and −3.1 [95% CI, −4.9 to −1.4], respectively) compared with matched siblings. They also had significantly higher scores on processing speed (mean difference, 4.4 [95% CI, 0.2-8.5]). There were no significant differences in the other secondary outcomes.

Differences in scores between patients and siblings varied significantly by age at hospitalization in several tests--for example, Block Design scores in patients were lower than those of siblings for patients hospitalized at younger than 1 year vs those hospitalized between ages 4 and 8 years.

"When adjusting for patient age at PICU admission, patient age at testing, sibling age at testing, and duration between hospital discharge and testing, the difference in estimated IQ between patients and siblings remained statistically significantly different," the authors note.

The investigators point out several limitations, including the fact that "little is known about sibling outcomes after critical illness, nor about whether parenting of siblings or child development differs based on birth order or on relationship between patient critical illness and the birth of siblings.... If siblings also incur negative effects related to the critical illness, differences between critically ill children and the control siblings would be blunted."

Despite the statistical significance of the difference between the patients and the matched controls, ultimately, the magnitude of the difference was "small and of uncertain clinical importance," the authors conclude.

Commenting on the findings for Medscape Medical News, Alexandre T. Rotta, MD, professor of pediatrics and chief of the Division of Pediatric Critical Care Medicine, Duke University Medical Center, Durham, North Carolina, said the study "addresses an important yet vastly understudied gap: long-term neurocognitive morbidity in children exposed to critical care."

Dr Rotta, who is also a coauthor of an accompanying editorial, noted that the fact that the "vast majority of children with an IQ significantly lower than their siblings were under the age of 4 years suggests that the developing immature brain may be particularly susceptible to the effects of critical illness and therapies required to treat it."^[3]

The study "underscores the need to include assessments of long-term morbidity as part of any future trial evaluating interventions in pediatric critical care," he added.

The study was supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development for RESTORE-Cognition and by grants for the RESTORE trial from the National Heart, Lung, and Blood Institute and the National Institute of Nursing Research, National Institutes of Health. Dr Watson and coauthors have disclosed no relevant financial relationships. Dr Rotta has received personal fees from Vapotherm Inc for lecturing and development of educational materials and from Breas US for participation in a scientific advisory board, as well as royalties from Elsevier for editorial work outside the submitted work. His coauthor has disclosed no relevant financial relationships.

JAMA. Published online March 1, 2022.

Clinical Implications

• A study of previously healthy children admitted to the PICU with bronchiolitis found that 18.6% of children had a neurologic complication or disability at discharge, and the rate of these outcomes at subsequent hospitalization was 11.6%. The only significant risk factor for neurologic complication or disability was mechanical ventilation.
• The current study finds a small IQ deficit in comparing children who were intubated in the PICU compared with their siblings. Results were mixed with regard to deficits in specific cognitive domains.
• Implications for the healthcare team: The healthcare team should be aware that mechanical ventilation in young children may be associated with later neurocognitive deficits, although the practical effect on children's function remains uncertain.

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