Etiology Risk Factors and Epidemiology

The most common cause of delirium in children and adolescents is probably infection due to viral, bacterial, fungal, and parasitic agents, usually with CNS involvement (Turkel and Tavaré 2003) (see Tables 5-4 and 5-5). Delirium due to medication is common and is associated with a variety of drug classes, including narcotics and other anticholinergics, sedative-hypnotics, benzodiazepines, anesthetics, and others. Delirium occurs in patients with CNS systemic lupus erythematosus (Turkel et al. 2001) and other vasculitides, such as periarteritis nodosa. Kidney, heart, lung, and bone marrow transplant patients are also at risk for delirium. In these cases, delirium may be related to the medications needed to maintain the transplant, to infection, or to an additional intercurrent illness. Leukemia, lymphoma, and other malignancies, especially CNS tumors, may be associated with delirium. This may be due to direct CNS invasion, sepsis or other infection, multiple medications, or neurotoxic chemotherapy (Turkel and Tavaré 2003). Typically, pediatric patients with delirium are very sick, with a long hospital stay and high mortality risk (Turkel and Tavaré 2003). Mortality is highest in patients with organ failure and lowest in patients with delirium following surgery or trauma (Turkel and Tavaré 2003).

The etiologies of delirium are typically severe diseases that result in serious metabolic and physiological changes, and its pathogenesis appears to be best explained by theories relating to abnormalities of oxidative metabolism, inflammation, and other causes of tissue injury. Any cause of inflammation, either locally in the CNS (e.g., encephalitis or meningitis) or diffuse (e.g., sepsis or systemic lupus erythematosus), can cause delirium. Postoperative,

Table 5-3. Definitions of motor subtypes of delirium

Motor subtypea

Clinical presentation

Hyperactive

Increased motor activity

subtype

Loss of control of activity

Restlessness

Reduced awareness of

surroundings

Wandering

Hypoactive

Decreased motor activity

subtype

Decreased speed of actions

Decreased amount of speech

Decreased speed of speech

Listlessness

Reduced alertness/withdrawal

Mixed motor

Evidence of both hyperactive

subtype

and hypoactive subtype in

the past 24 hours

No motor

No evidence of either

subtype

hyperactive or hypoactive

subtype in the past 24 hours

aActivity represents change from pre-delirium baseline. Source. Reprinted from Meagher DJ, Moran M, Raju B, et al: "A New Data-Based Motor Subtype Schema for Delirium." Journal of Neuropsychiatry and Clinical Neurosciences 20:190, 2008. Copyright 2008, American Psychiatric Press. Used with permission.

Table 5-4. Differential diagnosis of pediatric delirium: the "I WATCH DEATH" mnemonic

Infection

Encephalitis,a meningitis,a syphilis, HIV, or sepsisa

Withdrawal

Alcohol, barbiturates, or sedative-hypnoticsa

Acute metabolic

Acidosis, alkalosis, electrolyte disturbance,a hepatic failure, or renal failure

Trauma

Closed-head injury,a heatstroke, postoperative,a or severe burnsa

CNS pathology

Abscess, hemorrhage, hydrocephalus, subdural hematoma, infection,a seizures,a stroke, tumors, metastases, or vasculitisa

Hypoxia

Anemia, carbon monoxide poisoning, hypotension, pulmonary failure, or cardiac failure

Deficiencies

Vitamin B12, folate, niacin, or thiamine

Endocrinopathies

Hyper/hypoandrenocorticism, hyper/hypoglycemia, myxedema, or hyperparathyroidism

Acute vascular

Hypertensive encephalopathy, stroke, arrhythmia, or shocka

Toxins or drugs

Medications,a illicit drugs, pesticides, or solvents

Heavy metals

Lead, manganese, or mercurya

aMore commonly seen in pediatric delirium.

Source. Reprinted from Wise MG, Brandt G: "Delirium," in American Psychiatry Press Textbook of Neuropsychiatry, 2nd Edition. Edited by Hales RE, Yudofsky SC. Washington, DC, American Psychiatric Press, 1992, p. 302. Copyright 1992, American Psychiatric Press. Used with permission.

toxic, and drug-related causes are also common (Turkel and Tavare 2003). Although delirium is frequent in children with fever, a temporal relationship has been described between use of antipyretics and delirious behavior, which suggests that this common treatment may be problematic (Okumura et al. 2006). Steroids may contribute to delirium or may be used to treat it, depending on the etiology. Commonly used antibiotics have been associated with neurotoxic reactions. Neuropsychiatric symptoms have been seen with antifungal agents and cepha-losporins (Snavely and Hodges 1984).

Postoperative delirium is probably related to exposure to anesthetics, narcotics, benzodiazepines, and anticholinergic medications (Marcantonio et al. 1994). Anticholinergic effects have been associated with impairment in memory and attention in normal subjects and may cause or exacerbate delirium in susceptible patients (Tune et al. 1992). Delirium related to anticholinergic side effects of medications is especially pertinent to the etiology of delirium in young people. Anticholinergic side effects occur with many commonly used medications, including antihistamines and opioids, and are additive when multiple anticholinergic agents are used together.

Sedative and analgesic medications used in the ICU to relieve anxiety and pain associated with intubation may contribute to the development of delirium. Although adequate sedation for mechanical ventilation in the ICU can be achieved in the short term with a combination of parenteral benzodiaz-epines and opioids (typically short-acting midazolam and fentanyl), long-term continuous infusion of these agents results in physiological tolerance and the need for dose escalation to maintain an appropriate level of sedation (Tobias 2000). Lorazepam has been reported to be an independent risk factor for transition to delirium (Pandharipande et al. 2006). Mechanically ventilated children often re

Table 5-5. Etiology of pediatric delirium

Diagnosis

n (%)

Infection

28 (33)

Drug-induced

16 (19)

Trauma

8 (9)

Autoimmune

7 (8)

Post-transplant

7 (8)

Post-operative

6 (7)

Neoplasm

6 (7)

Organ failure

6 (7)

Total

84 (100)

Source. Reprinted from Turkel SB, Tavare CJ: "Delirium in Children and Adolescents." Journal of Neuropsychiatry and Clinical Neurosciences 15:432, 2003. Copyright 2003, American Psychiatric Publishing. Used with permission.

main anxious, agitated, or combative despite or because of escalating doses of opioids and benzodiaz-epines (Harrison et al. 2002). In some children, additional doses seem paradoxically to exacerbate agitation and confusion, and antipsychotic medication is required, even in very young patients (Harrison et al. 2002).

Emergence delirium, emergence agitation, and postanes-thetic excitement are terms referring to instances when patients experience alteration in orientation, confusion, lethargy, or violent behavior following administration of general anesthesia (Scott and Gold 2006). The introduction of newer inhaled anesthetics into pediatric practice has led to a greater incidence of emergence delirium in young patients. The severity may vary, and treatment with analgesics or sedatives is usually required and may risk prolonging delirium (Vlajkovic and Sindjelic 2007). Sevoflu-rane, desflurane, and possibly isoflurane are associated with a higher incidence of emergence delirium than are halothane and propofol, although repeated use of propofol has itself been associated with psychosis (Vlajkovic and Sindjelic 2007). The Pediatric Anesthesia Emergence Delirium Scale (Sikich and Lerman 2004) may be useful in documenting the incidence, presentation, risk factors, and treatment of emergence delirium in children.

Benzodiazepines and propofol have high affinity for the GABA receptor in the CNS, and GABA-mimetic effects can alter levels of numerous neuro-transmitters believed to be deliriogenic. Novel sedative agents that are GABA receptor sparing may help to reduce some of the cognitive dysfunction seen postoperatively and in the ICU. Dexmedetomidine, an a2-adrenergic agonist for short-term sedation in the ICU, is expensive but may be a viable alternative to benzodiazepines (Buck and Willson 2008). It has been shown to be helpful in decreasing the incidence and severity of emergence delirium when administered perioperatively to children undergoing general anesthesia with sevoflurane (Shukry et al. 2005). Compared to propofol and midazolam, dexmedeto-midine is associated with a significantly lower incidence of postoperative delirium (Pandharipande et al. 2006).

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