Delirium in children

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief:

Synonyms and keywords: Delirium in kids/acute confusional state/ICU psychosis/organic psycho-syndrome/encephalopathy

Overview

Delirium in children is a serious but understudied neuropsychiatric disorder. Delirium is an acute change in attention, awareness, cognition , perceptual disturbances sometimes causing hallucinations, and psychomotor agitation. Because of its heterogeneous clinical presentation there is no clear definition about it. Numerous conditions can cause delirium; therefore, early recognition and treatment are critical. Hypoactive subtype of delirium is often missed by pediatric practitioners, but can be reduced by mitigating risks and effectively managed by early detection.

Historical Perspective

• Paul Eugen Bleuler (1857-1939) was a Swiss psychiatrist he though children become delirious very often and ignored delirium in children considering it a normal phenomenon.
• Then Pediatric delirium was described for the first time in Leo Kanner’s 1935 in his textbook and until 1990 the condition remain ignored then child psychiatry was introduced in text-books.
• In the early 1960s, Eckenhoff et al. were the first to report the signs of hyperexcitation in young patients emerging from anesthesia (cyclopropane, ketamine ) especially when administered for surgery like tonsillectomy, thyroidectomy, and circumcision in children.
• With the introduction of the new, short-acting, volatile anesthetics sevoflurane and desflurane into clinical practice, as compare to long acting halothane during surgical procedures the problem of emergency Delirium reemerged in children.
• Awareness is rapidly increasing in last few years and further research is still going on.

Classification

There are two types of benign delirium:

• Emergence delirium/agitation:
  • It presents immediate in postoperative period and after anesthesia withdrawal and is short-lived~ 30-45 minutes, resolves completely in 30-45 minutes.

• Common/general practice delirium:
  • Occurs with infections as fevers, confusion and has a waxing/waning course with worse at night. It resolves within 2-3 days.
  • If persistent, or already present in the morning, it requires emergency medical evaluation by physician.

Based on psychomotor activity

• Hyperactive: An increased psychomotor activity, which may co-occur with, increased mood lability, agitation, and/or non cooperative attitude towards medical treatment.
• Hypoactive: A hypoactive level of psychomotor activity, which may exist along with increased sluggishness, lethargy or stupor.
• Mixed level of activity: A normal level of psychomotor activity, individuals with rapidly fluctuating activity are also included in this category.

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Pathophysiology

• Delirium represents global cerebral dysfunction due to the direct physiologic effects of an underlying medical illness or its treatment. The decrease in oxidative metabolism in the brain causes cerebral dysfunction due to fluctuations of various neurotransmitter systems.
• The pathogenesis of delirium in pediatric patients is describe as the role of brain maturation in the development of this phenomenon. It is thought that if we compare a child brain to normal age-related regressive process with a consequent changes in norepinephrine, acetylcholine, dopamine, and γ-aminobutyric acid (GABA) may underlie the different symptoms and clinical presentations of delirium. Thus, the decline of of cholinergic function and the hippocampus may suggest clues about the relative susceptibility of younger children to delirium.
• Since cytokines can influence the activity of various neurotransmitter systems, the inflammatory hypothesis suggest that release of cytokines from body during physically stressful event can alter neurotransmitter mechanism, transmission, and release that can contribute towards development of delirious state.
• The disruption of intra-neuronal signaling pathway because of critical illness can affect second messenger system and leads to neuronal slowing.
• Severe sickness can affect hormone metabolism causing euthyroid sick syndrome and HPO axis causing changes in neurotransmitter synthesis and release of cytokines consequently affecting brain cognition and alertness.
• One of the reason is alteration in blood brain barrier permeability because of physiological stress.

Causes

The most common cause of severe delirium is a critical illness i-e severity of disease is a major risk factor for delirium. Other causes are mentioned in Table:

Infection	pneumonia, UTIs, encephalitis, malaria, sepsis, pyelonephritis, meningitis
Trauma	post-operative trauma, skull fracture, bone fracture, pelvic injury, Head injury
Heavy Metals	lithium, mercury, lead, arsenic
CNS pathology	epilepsy, stroke, hemorrhage, tumor
Toxicity	narcotics, salicylates, alcohol barbiturates, benzodiazepines
Metabolic failure	electrolyte imbalance, renal failure, hepatic failure,
Hypoxic deficiency	Anemia, Congestive heart failure, cardiac embolism, hypercoagulable states, Cyanotic/non-cyanotic heart diseases
Hypovolemia	Blood loss, fever, dehydration, decrease oral intake
Endocrine pathologies	parathyroid, pituitary, adrenals, pheochromocytomas, thyroid pathologies
Vitamin Deficiencies	D, B12, B9, A, thiamine
Mineral Deficiencies	Zn, Fe, Cu, Ca
Iatrogenic	mechanical ventilation, restraints, sleep disturbance, catheters, IV lines
Environmental	hospital, ward, pediatric ICU

Differentiating delirium in children from other Diseases

• The possibility of non- convulsive status epilepticus, catatonic inhibition and major depressive disorder should be excluded always.
• Delirium may be confused with agitation, but it may also be a cause of agitation. As most of the literature on this subject cannot differentiate between these two terms. For further information about the differential diagnosis, click Agitation .

Epidemiology and Demographics

• 20-30% of critically ill children
• Children experienced post anesthesia agitation more often than adults (12%–13% vs 5.3%)
• Odds ratio of having one or more new-onset postoperative maladaptive behavior changes like delirium/agitation is 1.43 for children with marked emergence status when compared with children with no symptoms of Delirium.
• The incidence of emergency delirium largely depends on age, anesthetic technique, surgical procedure, and use of adjunct medication. Generally, it ranges from 10% to 50%, but may be as high as 80%
• Parents claim the Child's behavior upon emergence of anesthesia after surgery was the same as when he was suddenly awakened from deep sleep .

Age

• Patients of all age groups may develop delirium but it is more commonly observed among patients old aged as compare to young. It has been less addressed in children and adolescents
• Older children and adults usually become oriented rapidly after surgery, whereas preschool-aged children, tend to become agitated and delirious who are less able to cope with environmental stresses because psychological immaturity of preschool children
• The subpopulation of those aged 2–5 yr seems to be the most vulnerable as they are easily confused and frightened by unexpected and unpredictable experiences

Gender

• It affects men and women equally.

Race

• There is no racial predilection for delirium in children.

Risk Factors

Non-modifiable risk factors of delirium include

• Young age (age <2 years)
• Cognitive or neurological disabilities
• Need for invasive mechanical ventilation
• Severe underlying illness
• Pre-existing chronic conditions
• Poor nutritional status.
• Developmental delay
• Previous episode

Children who are more emotional, more impulsive, introvert, and stubborn to environmental changes were identified to be at risk for developing post anesthesia delirium.

Etiological risk factors of pediatrics emergence delirium post-operatively includes:

• Rapid emergence
• Intrinsic characteristics of anesthesia
• Medication use like anticholinergics, droperidol, barbiturates, opioids, benzodiazepines, and metoclopramide
• Surgery type
• Post-operative pain
• Anxious child
• Child's temperature

Natural History, Complications and Prognosis

• There are limited studies on the long term sequelae of pediatric delirium.
• Long hospital stay
• Child can suffer from Post traumatic stress disorder because of unpleasant experience.
• Delirium is often caused by a potentially life-threatening underlying condition and carries a poor prognosis specifically in children if unrecognized. However if recognized early and treated properly it has no long term sequelae.

Diagnosis

Diagnostic Criteria

• Diagnosing delirium occurs at the bedside by the emergency physician and includes objective screening measures for level of consciousness and cognition followed by confirmatory testing. Further evaluation, including interviewing any available surrogates, medications review, considering a broad differential diagnosis, including infection, trauma, stroke, and performing comprehensive diagnostic testing and addressing physical symptoms for example a full bladder, full bowel, stomach distension, hunger, thirst, itching, pain due to lines, IV lines, catheters. To investigate and develop a risk scale for Emergency Delirium(ED), only children who are pain free should be studied because pain shares many of the characteristics of ED.
• DSM-V Criteria by American Psychiatric Association, 2013 for delirium: Disturbance of attention(attention is the first to be lost and the last back)/awareness, Changes in cognition, Develops quickly and fluctuates, Typically worse in evening, Likely result of medical condition or treatment, Excludes coma .
• ICD-10 by World Health Organization, 2015 describes delirium as an etiologically nonspecific organic cerebral syndrome characterized by disturbances of consciousness and attention, perception, psychomotor behavior, emotion, thinking, memory, and the sleep-wake cycle. The duration is variable and the degree of severity ranges from mild to very severe

• There more than 15 different rating scales to measure Delirium in clinical investigations suggests that none are sufficiently specific and sensitive to assess children's behavior upon emergence because of difficult to interpret behavior in small children who are not able to verbalize pain, anxiety, hunger, or thirst.

SOME RATING SCALES FOR DIAGNOSIS OF DELIRIUM

	AGE	CLINICAL VARIABLES ASSESSED	SENSITIVITY	SPECIFICITY	CLINICAL UTILITY
PAED: Pediatric Anesthesia Emergence Delirium scale (Janssen et al, 2011).	1-17	eye contact purpose action awareness restlessness inconsolable	91	98	feasible bedside utility
pCAM-ICU: Pediatric Confusion Assessment Method-Intensive Care Unit (Smith et al, 2011).	>5	Acute presentation fluctuation in mental status inattention altered consciousness thinking problems	84	99	feasible
CAP-D: Cornell Assessment of Pediatric Delirium (Silver et al, 2012; Traube et al, 2013);	0-21	eye contact purpose action awareness of surrounding communication restlessness inconsolable underactivity response to comfort	94	79	Bedside utility
SOS-PD: Sophia Observation withdrawal Symptoms-Pediatric Delirium scale (van Dijk et al, 2012; Ista et al, 2014). *There is no score range.	0-16	agitation attention deficit speech problems tremors muscle tone purposeful actions sleeplessness hallucinations disorientation sweating acute chang/fluctuations	91	97	feasible

• Predictors for mortality in pediatric delirium used were the Pediatric Index of Mortality (PIM) and Pediatric Risk of Mortality (PRISM II) for ruling in, or out, patients at risk of pediatric delirium.

• Most authors developed 3–5-point rating scales that used either crying or thrashing requiring restraint as their threshold for delirium, which had a significant influence on the calculated incidence of the event. Cravero et al. recorded delirium in 80% of sevoflurane patients considering crying as a threshold for delirium, but in 33% of patients only when thrashing was applied as the threshold for delirium. Several studies have tried to distinguish pain-related agitation from other sources by incorporating both pain and agitation scales into the methodology.
• Przybylo et al. described an assessment tool that is based on the items listed in the Diagnostic and Statistical Manual of Mental Disorders-IV for the diagnosis of delirium but eliminated signs and symptoms that required children participation like verbalization or skill demonstration as it is difficult in young children who are unable or unwilling to answer sometimes. Their scoring system studied perceptual disturbances, hallucinations, and psychomotor agitation in 25 children aged 2–9 yr. The authors concluded that while 44% of children showed altered behavior upon awakening after surgery, only 20% had complex symptoms that were consistent with delirium. Furthermore, none of these children either verbalized pain or received pain medication during the assessment period, reflecting the measurement of the phenomenon that was independent of pain-induced agitation.[14][14][13][13][13][13][13][13][13][13][13][10][10][10][10][10][10][10]
• Sikich and Lerman developed the pediatric anesthesia emergence delirium (PAED) rating scale that consists of five psychometric items for the measurement of ED in children. According to the Diagnostic and Statistical Manual of Mental Disorders -IV, three of these items are an important part of delirium and may be crucial to its differentiation from pain . A decreased ability of the child to make eye contact with the caregiver and a declined awareness of his surroundings reflect disturbances in consciousness with a reduced ability to focus, sustain, or shift attention. Less purposeful actions suggest cognitive changes that include perception and memory impairment as well as disorganized thinking patterns. Two other items, restlessness and inconsolable crying, reflect a disturbance in psychomotor behavior and emotion. But pain was not controlled appropriately during study which may have contributed towards compromised results.

Sign and Symptoms:

Patient appear in dissociated state of consciousness in which the child is

• Irritability
• Uncompromising
• Uncooperative
• Incoherent
• Inconsolably crying
• Moaning
• Kicking
• Thrashing
• Paranoid delusions
• Combative behavior
• These children do not recognize or identify familiar objects or people around them.

Physical Examination

• Hyperactive Signs:

-Agitation

--Irritability

---Increased motor activity

• Hypoactive signs:

-Apathetic

--Uninterested

• Mixed/combination of both

Laboratory Findings

• There are no specific laboratory findings associated with disease. A few biomarkers, including hemoglobin-beta, S100 calcium-binding protein B, and IL-6 for delirium are being investigated; however, they are not routinely used to make the diagnosis.

Electroencephalogram

An EEG may be helpful in excluding epilepsy, hypoactive seizure and catatonia, although frequently there is a mix of conflicting or co-occurring signs and potential explanations. EEG shows diffuse slowing in only 60-80% of pediatric cases.

X-ray

There are no x-ray findings associated with delirium.

Echocardiography or Ultrasound

There are no echocardiography/ultrasound findings associated with it.

CT scan

There are no CT scan findings associated with it.

MRI

There are no MRI findings associated with it.

Treatment

Medical Therapy

Treatment of delirium includes treating the underlying cause as well as careful administration of antipsychotic drugs when nonpharmacologic treatments are insufficient.

• Emergency delirium usually occurs during recovery from anesthesia within the first 30 min and is self-limited (5–15 min), and often resolves spontaneously so, the mainstay of therapy is supportive care.

• If delirium persists, The management of its symptoms depends on the off-label use of antipsychotics, while avoiding agents that precipitate or worsen delirium.
• Use of antipsychotics as Olanzapine, quetiapine, and risperidone are presently considered first-line drugs, usually replacing haloperidol because of its extra-pyramidal side-effects .
• Other medications have shown good results are those that improve sleep disturbances that is important characteristic of delirium, it include melatonin and dexmedetomidine, an α2-agonist.
• Avoid use of benzodiazepines and opioids that may worsen delirium. Except Benzodiazepines and clonidine are used in the treatment of delirium due to benzodiazepine withdrawal; clonidine and methadone are used in the treatment of delirium due to opiate withdrawal.

Prevention

To reduce delirium in hospitalized children, health-care providers should optimize the hospital environment by

• Reducing sleep disruption
• Keep the child stimulated and awake during the day
• Good pain management
• Decrease sedation especially decrease use of benzodiazepines
• Presence of caregiver
• Familiar surrounding
• noise reduction and familiar music/sounds
• frequent reorientations
• early mobilization
• Effective measures for the primary prevention of Post-operative delirium is by reducing preoperative anxiety, removing postoperative pain, and providing a quiet, stress-free environment for postanesthesia recovery. Parents who witness delirium may worry about permanent sequelae in their children.