Delirium and Benzodiazepines Associated With Prolonged ICU Stay in Critically Ill Infants and Young Children

Heidi A. B. Smith, MD, MSCI; Maalobeeka Gangopadhyay, MD; Christina M. Goben, MD; Natalie L. Jacobowski, MD; Mary Hamilton Chestnut, NP; Jennifer L. Thompson, MPH; Rameela Chandrasekhar, PhD; Stacey R. Williams, NP; Katherine Griffith, NP; E. Wesley Ely, MD, MPH; D. Catherine Fuchs, MD; Pratik P. Pandharipande, MD, MSCI

Disclosures

Crit Care Med. 2017;45(9):1427-1435. 

In This Article

Abstract and Introduction

Abstract

Objectives: Delirium is prevalent among critically ill children, yet associated outcomes and modifiable risk factors are not well defined. The objective of this study was to determine associations between pediatric delirium and modifiable risk factors such as benzodiazepine exposure and short-term outcomes.

Design: Secondary analysis of collected data from the prospective validation study of the Preschool Confusion Assessment Method for the ICU.

Setting: Tertiary-level PICU.

Patients: Critically ill patients 6 months to 5 years old.

Interventions: None.

Measurements and Main Results: Daily delirium assessments were completed using the Preschool Confusion Assessment Method for the ICU. Associations between baseline and in-hospital risk factors were analyzed for likelihood of ICU discharge using Cox proportional hazards regression and delirium duration using negative binomial regression. Multinomial logistic regression was used to determine associations between daily risk factors and delirium presence the following day. Our 300-patient cohort had a median (interquartile range) age of 20 months (11–37 mo), and 44% had delirium for at least 1 day (1–2 d). Delirium was significantly associated with a decreased likelihood of ICU discharge in preschool-aged children (age-specific hazard ratios at 60, 36, and 12 mo old were 0.17 [95% CI, 0.05–0.61], 0.50 [0.32–0.80], and 0.98 [0.68–1.41], respectively). Greater benzodiazepine exposure (75–25th percentile) was significantly associated with a lower likelihood of ICU discharge (hazard ratio, 0.65 [0.42–1.00]; p = 0.01), longer delirium duration (incidence rate ratio, 2.47 [1.36–4.49]; p = 0.005), and increased risk for delirium the following day (odds ratio, 2.83 [1.27–6.59]; p = 0.02).

Conclusions: Delirium is associated with a lower likelihood of ICU discharge in preschool-aged children. Benzodiazepine exposure is associated with the development and longer duration of delirium, and lower likelihood of ICU discharge. These findings advocate for future studies targeting modifiable risk factors, such as reduction in benzodiazepine exposure, to mitigate iatrogenic harm in pediatric patients.

Introduction

Pediatric delirium is a syndrome of acute brain dysfunction that is highly prevalent among the critically ill, with rates of up to 30% in older children[1–4] and over 50% in infants and toddlers.[5] The creation of highly valid and reliable pediatric delirium tools has made delirium screening and monitoring in the PICU setting not only practical[1,2,5,6] but provides the means to further understand the impact of delirium in our most fragile population. In critically ill adults, delirium has been associated with poorer outcomes including prolonged ICU and hospital length of stay (LOS), long-term cognitive impairment (LTCI), and even death.[7–9] Small cohort studies in critically ill children have demonstrated similar associations between delirium and longer ICU stay and higher costs,[10,11] whereas a recent point prevalence study on delirium reported associated risk factors to include age, mechanical ventilation, benzodiazepines, opioids, use of physical restraints, and exposure to vasopressors and antiepileptics.[4] The etiology of delirium can be multifactorial, with the end result being a disruption of the fragile balance between excitatory and inhibitory neurotransmission.[12] This imbalance manifests through characteristic behaviors that are commonly observed and can range from hyperactivity and agitation to a patient appearing withdrawn and sedate.[13,14]

Delirium risk factors have been well delineated in adults to include iatrogenic factors such as immobilization, sleep deprivation, and a strong association with benzodiazepine exposure.[15–19] The iatrogenic harm resulting from benzodiazepine use in adults has been consistently demonstrated to include greater development and duration of delirium, increased duration of mechanical ventilation, and longer ICU and hospital LOS.[20–22] This realization is pertinent as up to 90% of mechanically ventilated infants and children receive continuous sedation,[23] commonly centered around the use of high-dose midazolam for multiple days.[24,25] In fact, high-dose oral benzodiazepines have been associated with paradoxical agitation, and thus, it is plausible that high-dose IV benzodiazepines, frequently administered to critically ill patients, could predispose patients to delirium.[26]

Thus, the hypothesis for this large prospective study is that delirium is associated with worse clinical outcomes among critically ill infants and young children and that routine sedation protocols using benzodiazepines predispose patients to delirium.

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