Infection Was Associated With Intensive Care Unit Pediatric Delirium in Children Younger Than 2 Years Old: A Single-Center Observational Study


 Objective: The primary objective of this study was to investigate the prevalence of intensive care unit (ICU) pediatric delirium in Shanghai, China. Secondary objectives were to determine the association of hypoxia and infection with ICU pediatric delirium, and the impact between different age. Design: Prospective single-center observational study. Setting: Two pediatric intensive care unit (PICU) within a tertiary-A general hospital. Patients: Patients age between 1 month to 7 years in PICU who stayed at least 1 day were included. Convenance sampling was used. Interventions: None. Measurements and Main Results: Pediatric patients (n=639) were screened twice a day for the prevalence of ICU pediatric delirium by Cornell Assessment of Pediatric Delirium, 300 (46.95%) of them had infection and 213 (33.33%) had hypoxia in PICU. Children who suffered hypoxia remained more than three times likely to be delirious during their hospitalization compared with children who were not hypoxia, after controlling other covariates, the odds of pediatric delirium for subjects with hypoxia was 3.26 times (95% CI, 1.98-5.38) the odds without hypoxia. Also, the odds of pediatric delirium for subjects with infection was 2.55 times (95% CI, 1.58-4.11) the odds without infection adjusting for other covariates. After subgrouping by age, the occurrence of ICU pediatric delirium with infection for children younger than two years old was 5.37 times (95% CI, 3.09-9.33) compared with patients who were never infection, while that for the children equal to or older than two years old was no statistically significant relationship. Conclusions: The prevalence of ICU pediatric delirium was 31.30%, while there is an independent association of infection and hypoxia with ICU pediatric delirium. Furthermore, children younger than two years old took more risks on pediatric delirium when they were infected in this study, while there was no relationship between infection and pediatric delirium who aged 2 years or older.


Introduction
Delirium is the general term of all acute or subacute generalized cognitive impairments (1). Pediatric delirium is usually characterized by changes in psychomotor activity, including delayed response, sustained and agitated physical activity, and crying that is difficult to soothe or abnormal. ICU pediatric delirium not only leads to increased hospital mortality, prolonged mechanical ventilation, and length of hospital stay; but brings a series of short-term and long-term hazards to pediatric patients as well (2)(3)(4); meanwhile, pediatric delirium is associated with a substantial increase in pediatric intensive care unit (PICU) medical expenditures (5). The longer the duration of ICU pediatric delirium, the more harmful it is (6).
Children at young age (<2 years), disease severity, infectious diseases, inflammation, mechanical ventilation, physical restraint, vasopressors, and antiepileptic drugs are proved to be risk factors for ICU pediatric delirium (10,16,17). Preventions on pediatric delirium could be designed considering risk factors, thus, it's vital to make sure the independent risk factors of pediatric delirium. Maldonado (18,19) summarized that at least six pathophysiology and seven neuropathogenesis theories develop delirium, and their combination of several or all helps to explain how delirium occurs and develops in hospitalized patients, among them, hypoxia and infection are routine collected indicators which are more objective and relatively easier controlled in PICU. They are associated with a high occurrence of delirium in the adult population group.
Engel and Romano proposed Oxidative Stress Hypothesis (OSH) which demonstrates many physiologic processes such as hypoxia and infections may finally contribute to delirium cognitive and behavioral symptoms (20). In addition, infection may introduce triggering factors giving rise to the inflammatory cascade activation including hypoxia, blood transfusions, elevated hormone levels and so on. Furthermore, systemic inflammation which may be caused by injury (including surgery) or infection has long been considered a triggering cause of delirium (19).
At the same time, the complex association between hypoxia, infection and ICU pediatric delirium might provide an insight into the possible therapeutic measures in ICU. What' s more, the prevalence of ICU pediatric delirium and the association of hypoxia and infection with ICU pediatric delirium have remained unclear in China. Therefore, we aimed to investigate the prevalence of delirium in a Chinese PICU as well as the impact of hypoxia and infection.

Study Design, Setting, and Patients
This prospective observational study was conducted in 2 PICU at Xinhua

Outcome Measure and Data Collection
The primary outcome is ICU pediatric delirium, each patient was screened for delirium twice daily by the researcher using the Cornell Assessment of Pediatric Delirium (CAPD) (8,10,15,21,22). The RASS> -3 and CAPD score> 9 were considered pediatric delirium positive and a patient who has been screened for pediatric delirium positive at least once during intensive care is defined as ICU pediatric delirium. What's more, the data collectors were the researcher herself and ICU nurses, and the researcher has been authorized by the scale inventor and the translator for the Chinese version.
The pilot experiment (n = 20) in this study measured Cronbach 's α of CAPD as 0.97, and the scale reliability was good. Severity of illness was measured by Pediatric Risk of Mortality score IV (PRISM IV) (23) within 4 hours from every patient admitted in the PICU. The higher the score, the more critical the patients are. Demographic and clinical indicators were recorded from Hospital Information System, while laboratory results, treatment and nursing data were recorded from Hospital Information System and ICU nursing record every study day. When the patient's white blood count, neutrophil ratio, and daily maximum body temperature were out of normal range, the patient was judged to be infected; when the patient's arterial blood oxygen pressure (PaO 2 ) was less than 80mmHg, the patient was judged to be hypoxia.

Statistical Analysis
SPSS 22.0 (IBM Corp., Armonk, NY, USA) was used for data analysis. For normal distribution data, the (mean ± standard deviation) was used for description; for non-normal distribution data, the median and interquartile range (IQR) were used for description, and for categorical data, frequency and percentage were used for description; measurement data comparison between groups were all compared by univariate logistic analysis.
Multivariable Logistic regression following univariate logistic analysis was performed. The multivariable logistic-forward-maximum likelihood ratio (LR) test conditional method was used for regression analysis. The significant level of the deleted variables was 0.05, and the significant level of the excluded variables was 0.10. All hypothesis testing was two-tailed, and statistical significance was assessed at the 0.05 level.

Results
During the study period, 639 patients in the PICU met the criteria were finally admitted in this study and the prevalence of ICU pediatric delirium was 31.30%.
The age range is 1-84 months, and the average age is (19.

Multivariable logistic regression model for association of hypoxia and infection
with ICU pediatric delirium based on age is shown in Table 3. We divided data into subgroups by age. After adjusting, the occurrence of ICU pediatric delirium with infection for children younger than two years old was 5.37 times (95% CI, 3.09-9.33) compared with patients who were never infection, while that for the children aged two years or older was no statistically significant relationship.

Discussion
To our knowledge, this is the first single-center, prospective observational study reported to date investigating the association between hypoxia and infection with the prevalence of ICU pediatric delirium in China. We report a significant association between hypoxia and infection with the occurrence of ICU pediatric delirium.
Although the association about hypoxia with pediatric delirium has not been explored previously in children, studies in adults have reported conflicting effects of hypoxia on the occurrence and development of delirium. Jayaswal has shown hypoxia significantly worsened ICU delirium (24). Similarly, hypoxia was a risk factor contributing to delirium in Palliative Care Unit (25)  Furthermore, the association between hypoxia and infection are scientifically plausible. More than half of participants experiencing delirium who are adult (≥18 years) medical or surgical ICU patients with respiratory failure, shock, or both had hypoxic, hypoxia and sepsis have well established mechanisms of cellular injury that can affect the brain (30). Whereas intermittent hypoxia is known to cause brain damage (31,32), Lopez (33) has reported that intraoperative oxidative damage was independently associated with increased postoperative delirium. In addition, among a group of patients undergoing on-pump cardiac surgery, preoperative regional cerebral oxygen saturation could predict delirium after cardiac surgery, as low baseline cerebral hemoglobin O 2 saturations was associated with increased postoperative delirium (34). What's more, delirium is also regarded as a secondary complication of systemic infection (35) and is thought to be a result of neuroinflammation in a brain with increased release of brain cytokines resulting in direct neuronal damage (18), infection may lead to the inflammation stress, and finally increase the prevalence of delirium.
There are several limitations in this study. Foremost, it is an observational study with convenient sampling and can only suggest an association and not establish causality. Although we reported the relationship between hypoxia and infection and ICU pediatric delirium, we did not collect intraoperative cerebral oxygenation, the degree of hypoxia and infection, therefore, the relationship should be further explored in the future studies. In addition, there are factors that may lead to the occurrence of delirium, such as sleep disturbance and deprivation, parents visiting, or noise and light level, which we did not include in our analysis. Finally, this study was conducted in a single center in Shanghai, thus, the research outcomes may not be widely generalizable. Multi-centered studies are needed to validate the association between hypoxia and infection and ICU pediatric delirium.

Conclusions
In conclusion, this study demonstrated that patients who experienced infection and hypoxia in ICU carried a high risk for progression to ICU pediatric delirium, and there is an independent association of infection and hypoxia with ICU pediatric delirium. Furthermore, children younger than two years old took more risks on pediatric delirium when they were infected in this study. These notable findings deserve more consideration when it comes to pathophysiology and treatment that will determine its practical and clinical benefit in critical care pediatric patients.