Delirium Assessment in Critically Ill children during the COVID-19 Epidemic

Delirium is a clinical syndrome of acute neurological dysfunction, which is characterized by inattention, changes in the level of consciousness, and fluctuating changes in cognition. It is a common complication in critically ill children. Delirium was very common in ICU before the COVID-19 epidemic, ranging from 4.5% to 44% in PICU in different reports [1,2], and the incidence of delirium in children under 2 years old can reached up to 30%-56% [3]. Delirium not only causes unplanned extubation, falling off the bed and other accidents [4], but also is not conducive to the recovery of the primary disease and the stability of the autonomic nervous system and endocrine system, resulting in prolonged hospital stay, increased treatment costs, increased mortality and long-term cognitive impairment, which seriously affects the quality of life of children [5-7]. Early identification of delirium allows for earlier treatment and recovery and also optimizes nonpharmacological measures and reduces distress.

Delirium is one of the most common neuropsychiatric complications during COVID-19 [8]. However, the management of critically ill children, including the assessment of delirium, has been challenged due to the shortage of staff, the surge in workload, and the use of personal protective equipment caused by the outbreak. This article summarizes our team's practical recommendations and protocols for delirium screening during COVID-19, tools for delirium screening, and delirium-related concerns.

Studies have reported that delirium occurs in two-thirds of COVID-19-induced ARDS due to direct virus invasion or induction by inflammatory mediators in the central nervous system during COVID-19 [9]. Other risk factors include mechanical ventilation, sedative drug use, braking, electrolyte disturbance, lack of accompany from family members, PICU environment, etc. Before the COVID-19 epidemic, 75% delirium in adults missed diagnosis [10]. The difficulties in assessment caused by the COVID-19 epidemic will make the missed diagnosis rate even higher. Table 1 is a summary of the challenges and solutions for delirium screening summarized by our team during COVID-19. 

Table1: Implications of COVID-19 for delirium assessment and solutions

The erupts of epidemic led to the surge of infected children and the shortage of medical staff. It should be recognized that delirium assessment is not only the responsibility of nurses, but also the responsibility of all team members and even interdisciplinary teams. Even if nurses continue to screen for delirium twice daily, the fixed timing of assessments would miss some symptoms. Therefore, doctors, nurses, rehabilitation therapists and other members should be trained to understand the clinical manifestations and risk factors of delirium and have a good grasp of delirium screening. Every member plays a role at the bedside. They should initiate screening whenever suspicious symptoms are noted. Our team's experience during COVID-19 is to make full use of the intensive rehabilitation and nursing integrated team. Rehabilitation physicians and therapists took part in the screening during the daily rehabilitation treatment. Immediate feedback to intensivists and nurses may influence clinical decision making and usage of medication. They will also pay attention to the risk of self-injury and falling out of bed. In order to save time, we recommended to use rapid screening tools. In addition, our team prepared the scales used for screening and printed them into booklets in advance for quick access.

On the other hand, the general condition provided by family members is also important for the judgment of delirium. Delirium is characterized by acute onset, volatility, and changes in the state of consciousness. For example, the Sophia Children's Observation Scale for Withdrawal and Delirium (SOS-PD) was specially designed to increase the questioning of parents. In PICU, family visits were limited, especially during the epidemic, which made it more difficult to obtain baseline information. Our team made full use of the communication face to face or telephone contact with parents to collect the cognitive behavior performance of the child and the response to external stimuli before hospitalization to help the judgment of delirium.

In order to reduce the risk of transmission in the special environment, secondary barrier was adopted in ICU, including routine work clothes, isolation gowns, work caps, protective masks, latex gloves, and shoe covers. Doctors and nurses were also equipped with protective face screens because a large number of operations in ICU involved airway opening. As a result, children are not easy to develop a sense of trust with the staff with certain barriers. Especially the ability to interact and the observation of pacification effect are limited in delirium assessment.

In order to build relationship with children as soon as possible, for infants the team members used colors and toys to attract their attention to obtain their cooperation. For older children, they showed their work cards and tried to introduce the purpose of assessments to obtain their understanding. Wearing protective equipment can interfere with the transmission of sound, and the staff should raise the volume in order to make the expression clearer and ensure that the child can get the information. In addition, the team always paid attention to the change of prevention and control level. When the level of prevention and control is lower, timely adjustment of protective measures will help the clinical evaluation. A transparent mask called 12mask (https://www.12-mask.com/) developed by a team at Lingnan University in Hong Kong can block 99 percent of viruses, When the protection level is reduced, the mask can be considered to meet the requirements of epidemic prevention and promote the communication between children and doctors.

We noted that the medical history of delirium in the PICU often used nonstandard terms to describe the manifestations, rarely described as delirium, such as "disturbance of consciousness," "agitation," "hallucinations," "confusion of speech", "crying", "apathy", "mood disorder", etc. For one reason, the absence of assessment makes the diagnosis of "delirium" in the medical history unwarranted, and on the other hand, clinicians believe that the term does not fully represent the clinical symptoms of the child. In fact, the specific classification of delirium has a high summary function of symptoms, however lots of medical staffs do not realize various subtypes of delirium, including "high activity type", "low activity type" and "mixed type".

It is necessary to screen delirium in children with central nervous system infection during COVID-19. Encephalitis and encephalopathy belong to etiological diagnoses, while delirium describes a clinical syndrome that manifests the neuropsychiatric state of children. This diagnosis helps to remind clinicians to pay attention to the use of sedative and analgesic drugs, timely rehabilitation intervention, and environmental improvement. In addition, to diagnose delirium is operational, practical and reliable, and there are standardized management to achieve homogeneous management compared with other terms of mental status. At the same time, the assessment process itself is meaningful, because it creates an opportunity to communicate with these children, then it will relief the pain of children.

the cornell assessment of pediatric delirium?CAPD) as a revision of the PAED, was developed in 2012 by Gabrielle Silver, a pediatric psychiatrist, and Chani Traube, a PICU physician. CAPD also assess delirium by observing children's behavioral status and is applicable to children of all ages and developmental states. Hypoactive delirium can also be identified [11].

Before the evaluation, The Richmond Agitation Sedation Scale (RASS) should be used to evaluate consciousness and the degree of sedation of children, and children with a score ≥-3 could continue to be evaluated for CAPD [12]. CAPD consists of 8 items, each item is 0-4 points. When the total score is between 7-9 points, the potential delirium should be noted and reevaluated. Delirium was defined as a score ≥10. In order to detect changes in cognitive function in delirium diagnosis, the revised CAPD(CAPD(R)) added assessment of the ability to express needs and wishes, and set specific judgment points for children under 2 years of age according to their developmental characteristics and the specific environment of the PICU. In 50 PICU patients (3 months to 21 years old, 24% with developmental delay), the agreement between nurses and psychiatrists reached 82%. The optimal cut-off value was 9 points (sensitivity 94%, specificity 79%) [13].

The European Society of Paediatric and Neonatal Intensive Care (ESPNIC) recommends CAPD as an assessment tool for delirium in critically ill infants and children (recommendation grade A).  Screening and evaluation should be finished every 8-12 hours [12]. Children's Hospital of Chongqing Medical University has translated CAPD into Chinese, and the main table items have high discrimination and good reliability and validity [14]. The scale can be used for rapid and real-time screening of delirium in PICU. And it is easy and convenient for nurses and bedside caregivers to use, which means popularization and application in clinical practice is easy to achieve.

Generally, the patient screening can be completed within 2 minutes. However, considering protective equipment impede the communication and reduce the cooperation degree of children, the screening time will be relatively prolonged, and the screening can generally be completed within 5 minutes. The evaluation process is shown in Figures 1-3. 

STEP 1 Level of Consciousness Assessment

RICHMOND AGITATION-SEDATION SCALE (RASS) 

 Figure 1: Richmond Agitation Sedation Scale (RASS)

The Cornell Assessment for Pediatric Delirium (CAPD)

STEP 2 Screening delirium for children in PICU

Figure 2: The Cornell Assessment for Pediatric Delirium (CAPD)

 Figure 3: The anchor point for children≤2 years old.

In consideration of the high oxygen consumption caused by irritability, children in PICU are often in a state of continuous sedation and analgesia. Sedative drugs, especially benzodiazepines, are closely related to delirium and prolonged hospital stay [15].

The surge in workload, shortage of medical staff, suspension of family visits and relative shortage of protective equipment have led to the staff spending less time stay bedside and communicating less, not to mention the fact that unnecessary contact with infected patients is reduced. Several studies in adult patients have explored the use of sedatives during COVID-19. One study collected 58 adult patients with critical ARDS from four centers and continuously monitored the depth of sedation and delirium using electroencephalogram depth of sedation (DOS) and CAM-ICU. Excessive sedation was found in 38 patients (86.4%) with delirium [16]. In addition, the dose of sedative drugs received in the treatment of severe acute hypoxic respiratory failure (AHRF) caused by COVID-19 in adult patients was also significantly higher than that in the non-COVID-19 cohort [17]. Another study found that PICU providers used more sedatives when returning to the PICU after treating adults with AHRF. The above study indicates the need for quality control and standardized management of medical staff's clinical practice, including the use of sedative drugs, during and after emergency events such as COVID-19.

The probable pathophysiological mechanism of COVID-19 related neurological complications is related to direct virus invasion or immune-mediated inflammation. It is reported that the excessive inflammatory response caused by COVID-19 triggers autoimmune central nervous system diseases [18]. Severe infection can lead to the release of a large number of inflammatory cytokines and then become cytokine storm [19], which can destroy the integrity of the blood-brain barrier and increase its permeability. Finally, the virus spread through the blood-brain barrier. SARS-CoV-2 itself can also induce anti-NMDA receptor autoantibodies and cause autoimmune encephalitis (AE) [20].

The most common type in patients with AE is limbic encephalitis, followed by anti-NMDA receptor encephalitis. AE is characterized by clinical manifestations such as delirium, behavioral and mental status changes, epilepsy, insomnia, dyskinesia, anxiety and emotional instability. These symptoms often arise several days after respiratory symptoms. When delirium is found in patients during the period of COVID-19, the possibility of autoimmune encephalitis caused by SARS-CoV-2 infection should be considered. The diagnosis of encephalitis requires combination of brain MRI and electroencephalogram. The tests of inflammatory factors can also be performed. Severe COVID-19 patients have higher levels of inflammatory factors such as IL-2R, IL-6, IL-8, IL-10 and TNF-α compared with non-severe patients [21]. And IL-6 can promote the production of autoantibodies in anti-NMDA receptor encephalitis [22]. When encephalitis appears, nucleic acid and antigen tests of SARS-CoV-2 are always negative. In order to find the etiological evidence of delirium caused by AE, SARS-CoV-2 antibody testing is necessary.

Electroencephalography (EEG) is widely used in the study of delirium in children. After general anesthesia, children with delirium show increased activity of theta wave and decreased activity of alpha and beta wave [23], which is similar to studies in adult patients [24,25]. However, Okumura A [26] took an experiment on 15 children with influenza accompanied by delirium showed that 13 children had abnormal EEG, including slow rhythm background and the appearance of high voltage of slow waves such as theta wave. The EEG turn to be normal when delirium disappeared.

A prospective cohort study of children and adolescents graded the background severity of EEG from 0 to 5 and found close relationship between EEG grade and neurotoxicity scores and CAPD scores [27]. Some scholars have also found the relationship between EEG characteristic findings and delirium. Koch [28] observed the EEG of 62 children aged 6 months to 8 years and found that children with postoperative delirium were more likely to have epileptic wave during preoperative anesthesia induction than those without delirium.

Quantitative electroencephalography (qEEG) is a method that converts the time domain signals of EEG into frequency domain signals for analysis. It can not only monitor the brain function in real time, but also be easier and clearer for clinical medical staff to read and interpret. In the diagnosis of epilepsy, qEEG can help to diagnose more swiftly than original EEG. qEEG can help to predict the clinical outcome as well. A study of febrile delirium in children found that 65% of children had an increase in the relative power of the delta band, and a decrease in the relative power of the delta band was the best parameter to suggest clinical improvement [29]. Sudhin [30] screened 23 critically ill children for delirium every 12 hours and retrospectively analyzed qEEG, in which the δ/α ratio (DAR) was positively correlated with the occurrence of delirium and CAPD score.

In the face of COVID-19 and possible emergency events in the future, team members' understanding of the connotation of delirium should be emphasized. interdisciplinary collaboration should be advocated so that all team members can participate in screening delirium. EEG and other multimodal assessment methods are helpful to improve the accuracy and objectivity of delirium screening in children, and these methods should be fully used in emergency events. Meanwhile, quality control should be strengthened. Follow-up studies need to continue exploration of detailed management processes and programs.

National Natural Science Foundation of China, Grant No. 82101624

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