Opioid Use Is Associated with ICU Delirium in Mechanically Ventilated Children

Delirium is a significant problem in a pediatric intensive care unit (PICU), with a prevalence ranging from 25-50% [1,2]. It is characterized by acute to sub-acute onset of altered and fluctuating consciousness and cognition, and may be associated with a reduced awareness of the environment, impaired attention, and disorganized thinking [3, 4, 5]. It can present as three subtypes – hyperactive, hypoactive and mixed, with hypoactive and mixed conditions being more common in critically ill children [6,7]. Delirium is often associated with significant short and long-term consequences including prolonged mechanical ventilation, increased hospital and PICU length of stay [8, 9, 10, 11], increased healthcare costs [12,13] long-term cognitive impairment, physical disability and mortality [6,14].

The pathophysiology of pediatric delirium is complex and the etiology is typically multifactorial [8,15]. Factors associated with delirium include the use of benzodiazepines, opioids, steroids and anti-cholinergic agents, prolonged period of immobilization in an ICU, the presence of invasive lines and monitors, and the disruption of the patient’s sleep-wake cycle [1,16]. Recently significant advances have been made in an attempt to diagnose and manage pediatric delirium.

A single center prospective study by Silver et al. (2015) reported factors that predicted delirium which included preschool age (2-5 years), developmental delay and requirement for mechanical ventilation [8]. Various validated delirium screening tools have been developed recently for screening of delirium in critically ill children including Cornell Assessment of Pediatric Delirium (CAPD) [17] and Pediatric Confusion Assessment Method for Intensive Care Unit (pCAM-ICU) scales [18].

Despite these developments, there is still a paucity of significant literature in pediatric delirium, especially in a subset of mechanically ventilated and sedated children in an ICU, who are the most critically ill. Moreover, while most studies look at the association of daily use of medications, especially benzodiazepines and opioids, and delirium [19], the effect of cumulative doses of these medications which could possibly be related to a higher risk of delirium, has rarely been reported [20]. Children on mechanical ventilation is a subset of pediatric patients found in an ICU, which often requires the use of increased opioid and benzodiazepine doses for prolonged period [21]. This places the children at a higher risk of developing delirium. Given the higher exposure of these delirigenic medications, it is reasonable to consider the effect of cumulative doses of these medications on the development of delirium in this patient population.

The aim of the study was to identify factors associated with delirium in this high-risk pediatric ICU population including demographics, admission diagnosis, daily and cumulative doses of potentially deliriogenic medications, length of pediatric ICU stay, duration of mechanical ventilation and severity of illness.

The Null hypotheses are:

A total of 95 patient visits met the inclusion criteria. 53 patients (56%) were males. With respect to ethnicity, 49 patients (52%) were white and 40 patients (42%) were African American (Table 1).

The most common diagnosis for admission to the PICU was respiratory failure (61%) followed by septic shock (14%). 69% patients had some comorbidity and 31% had developmental delay (Table 1).

The overall prevalence of delirium in the study was 20%.

Factors associated with delirium were age (Fisher’s exact test: p= 0.012), use of vasoactive medications (58% versus 30%, Chi-square test: p= 0.033), duration of mechanical ventilation (349 hours in the delirium group versus 153 hours in no delirium group, Wilcoxon rank-sum test: p<0.001) and median PICU length of stay (16 days versus 8 days, Wilcoxon rank-sum test: p<0.001).

When compared to those without delirium, children with delirium had received a higher daily dose of opioids (3 mg/ kg/day versus 1 mg/ kg/day, Wilcoxon ranksum test: p= 0.023), and benzodiazepines (2 mg/kg/ day versus 1 mg/kg/day, Wilcoxon rank-sum test: p= 0.009), as well as a higher cumulative dose of opioids (37 mg/kg versus 13 mg/kg, Wilcoxon rank-sum test: p<0.001) and cumulative benzodiazepine dose (33 mg/ kg versus 9 mg/kg, Wilcoxon rank-sum test: p<0.001).

There was no difference among the two groups with respect to the severity of illness based on the PIM scores (Wilcoxon rank-sum test: p=0.527), daily steroid dose (Wilcoxon rank-sum test: p=0.154), daily (Wilcoxon rank-sum test: p=0.941) or cumulative (Wilcoxon rank-sum test: p=0.177) dexmedetomidine dose.

Table 2 shows the results of Firth’s multivariable logistic regression including the daily dose of opioids and benzodiazepines, among other variables, as predictors of delirium. Although a higher Odds Ratio was noted with increasing age, this was statistically significant only for the age group >12 years (Firth’s logistic regression: p= 0.004).

Compared to the reference group (i.e. < 2 years), this age group had 25 times higher odds of developing delirium. (OR=25.326, 95% CI 2.8-227, p=0.004).

With respect to medications, 1 mg/kg/day increase in the daily opioid dose was associated with 97% increase in the development of delirium (OR 1.97, 95% CI= 1.129–3.463, Firth’s logistic regression: p=0.017). Increase in daily dose of benzodiazepines was not associated with delirium. Increase in one hour spent on ventilator was associated with a 0.4% rise in development of delirium (OR 1.004, 95% CI=1.001-1.01, Firth’s logistic regression: p=0.007).

Table 3 shows the results of Firth’s multivariable logistic regression including cumulative doses of opioids and benzodiazepines, among other variables, as predictors of delirium.

Similar to Model 1, increasing age was associated with delirium. For example, age greater than 12 years was associated with increased odds of development of delirium compared to those younger than 2 years (OR=13.122, 95% CI 1.8-93, Firth’s logistic regression: p=0.01).

With respect to medications, 1 mg/kg increase in the cumulative opioid dose was associated with 3.5% increase in the development of delirium (Firth’s logistic regression: p=0.022).

Upon multivariate regression, cumulative benzodiazepine dose (Firth’s logistic regression: p= 0.401) and time spent on ventilator (Firth’s logistic regression: p= 0.143) were not associated with delirium.

Delirium is a common problem in a pediatric ICU. Although several studies have shown mechanical ventilation to be an independent risk factor for the development of delirium, there is little reported in the literature of other factors associated with delirium in this vulnerable patient population [23]. Identifying these risk factors is important for timely diagnosis and early management, as well as to prevent the development of delirium in this patient population. The prevalence of delirium in the present study (20%) was similar to those previously reported [1,6].

The present study showed several factors that were associated with delirium. Firstly, daily as well as cumulative doses of opioids were associated with delirium. Although the association of daily opioid use has been established in the literature, the association of cumulative opioid dosage with delirium has not been previously described [20]. This association, though minimal, a 3.5% increase in risk of delirium with an increase in opioid use by 1 mg/ kg was reported, it is of clinical importance and may be considerd as a means of reducing the incidence of delirium by using the lowest possible dose of opioids.

Another factor associated with development of delirium was time spent on mechanical ventilation. Although this was highlighted in the multivariate logistic regression statistics using daily medication as the predictor, similar results were not observed when cumulative medication was used as the predictor.

In the current study, neither daily nor cumulative use of benzodiazepines were associated with delirium using multivariate regression analysis. This particular finding is in contrast to previously published literature where both daily as well as cumulative doses of benzodiazepines have been associated with delirium [21]. The findings of this study require additional explanation. Firstly, sedation practices have changed over time with a considerable decrease in the use of benzodiazepines and an increasing use of dexmedetomidine as well as opioids. Also, easily available tools such as CAPD help with the early identification of patients with delirium and consequently, prompt treatment. Recently, the use of dexmedetomidine for sedation has increseed in the pediatric ICU setting. In this study, although dexmedetomidine use, daily as well as cumulative, was not associated with delirium, the cumulative dose was higher in the delirium group. This could be explained by the fact that many patients showing signs of delirium were weaned off benzodiazepines and opioids by substituting these with dexmedetomidine. This could also explain our study's contentious results with respect to benzodiazepines.

There are increasing reports, specifically related to adult treatment, alluding to the beneficial effect of dexmedetomidine on delirium in ICU patients including reduced incidence, more delirium free days and longer ventilator-free time [24, 25, 26]. Likewise, Smith et al. (2011) reported shorter stay in the ICU in pediatric patients exposed to dexmedetomidine[19]. Further studies are needed to determine the long-term effects of dexmedetomidine on delirium in patients in the PICU.

Another factor associated with delirium in this study was age. In an attempt to maintain uniformity with previous studies, age groups were chosen which were similar to those categorized in these studies [1,8]. Children greater than 12 years had increased odds of developing delirium compared to those < 2 years old. This is in contrast to the majority of the previous results reported in the literature [1,8]. However, a systematic review by Holly et al. (2018) showed a higher prevalence of delirium in 16-18 years old children compared to <3 years olds [27,28].

Our study did not show any association between delirium and gender, anticholinergic use, severity of disease or the presence of comorbidities. Although many studies [8,28], including a recently published systematic review, have shown a correlation between developmental delay and delirium, this was not the case in the present study. This might reflect the challenges in appropriately diagnosing delirium in developmentally delayed patients, even with the use of a validated delirium screening tool. This could reflect a potential limitation of the CAPD scale to appropriately identify delirium in developmentally delayed children and those with sensory deficits [17].

Although CAPD was used for the diagnosis of delirium, the findings from the current study do reflect an issue related to the implementation of this scale, especially in children with developmental delay. The original study, which validated CAPD, showed a poor performance in children with developmental delay, with specificity reaching only 51%, thus indicating a significantly high number of false positives [17]. Moreover, the utility of CAPD in the diagnosis of delirium in mechanically ventilated patients is not completely understood. CAPD was originally validated using DSM-IV criterion as the gold standard for delirium diagnosis. However, assessing altered consciousness in mechanically ventilated patients is often difficult due to the sedation and analgesia they receive. Thus, the newer DSM-5 criteria, which include disturbance in awareness and attention, seems to be more appropriate for diagnosing delirium in ventilated patients [29,30]. Ideally, a modification of CAPD to reflect the changes in these DSM criteria seems a more plausible solution to this issue.

The present study has several strengths. Being conducted in a tertiary care center, it reflects a population with a myriad of varied etiologies. A subset of the pediatric ICU population was studied which represents the most vulnerable cohort to develop delirium and the least reported in the literature. Another strength of the study is that it looked at the effect of cumulative doses of potentially deliriogenic medications and the development of delirium. To our knowledge, previous studies have not looked at this in detail or reported the effect of cumulative does of opioids.

As with other observational studies, it is prone to bias. Actual patients’ weights were used to calculate the cumulative and daily medication doses instead of ideal body weight which might have falsely underestimated the medication doses in patients with obesity. Nor did the study distinguish between hypoactive and hyperactive delirium preventing further analysis between these delirium subtypes. Due to the small sample size of our data, the current findings may not be generalizable. A larger, multi-center study is needed to identify the factors associated with delirium in this subset of the population. A retrospective power analysis was performed based on the current sample using GPower [31]. Using the asymptotic relative efficiency method of Wilcoxon rank-sum test power analysis, we found that the power (1-β error prsobability) ranged from 0.1 to 0.9 when testing the hypotheses.

Age, daily and cumulative opioid dosage were associated with delirium in sedated and mechanically ventilated children in the pediatric ICU. This has practical implications for practitioners and supports the efforts of ICU Liberation goals currently being employed across the country [32]. While recent focus has been on limiting benzodiazepine use as an effective strategy to reduce the incidence of ICU delirium, the study has additionally identified the need for reducing opioid use to the lowest effective dose. This additional strategy may aid in decreasing the incidence of delirium in this most at-risk population.