The consulting psychiatrist can recommend a change in sedatives or anesthesia, after which dosing and management would be at the discretion of the intensivist or anesthesiologist. In addition to addressing underlying medical etiologies, staff can implement environmental changes that assist with comforting, reorienting, and promoting normal sleep for delirious patients. While environmental or sensory disruptions alone will not cause delirium, a calm and nonthreatening environment helps reduce distress and agitation in the disoriented patient and should be a goal for all hospitalized patients. When possible, clustering of nursing care (to reduce interruptions at night and preserve sleep), frequent reorientation of the patient, preservation of day/night cues (e.g., lights on in the day, off at night), early mobilization even in the PICU, and encouraging oral hydration can all improve sleep quality and reduce disorientation and agitation in delirious and at-risk patients (Silver et al. 2014).

While addressing these factors, if symptom management is required for reasons of safety or distress (e.g., the child is pulling lines and tubes, hallucinating, or frightened), the off-label use of low-dose atypical antipsychotics is the recommended intervention in adults and children (Turkel and Hanft 2014). Use of atypical antipsychotics has been found to be safe in low doses and often allows for reduced use of other sedatives, which may be causing delirium and normalization of sleep/wake cycle. As sleep disruption is now understood to be a critical mechanism and core symptom of delirium, it is not surprising that studies are investigating use of melatonin to reset (or prevent disruption of) circadian rhythm in patients at risk or already experiencing delirium. Melatonin and melatonin agonist studies in adults, which have been small, have found they are well tolerated with modest benefit in prevention but not resolution of delirium. As melatonin is known to be safe and helpful in multiple types of pediatric sleep disorders, it is reasonable to consider its use in targeted cases of sleep disruption (Turkel and Hanft 2014; Chakraborti et al. 2014; Özcan and Dönmez 2014).

Since antihistamines and benzodiazepines are routinely used in daily pediatric oncology care, it is common to see children who have “paradoxical” reactions and become agitated, enraged, hyperactive, disinhibited or present with the full syndrome of delirium. In general, antihistamines and benzodiazepines should be avoided for children with a history of paradoxical reactions; however, sometimes these medications are unavoidable (e.g., blood transfusions requiring premedication with antihistamines) and concomitant use of a low-dose atypical antipsychotic may be needed to offset these adverse effects. Antipsychotics and other dopaminergic drugs like metoclopramide can induce extrapyramidal symptoms (EPS) (e.g., oculogyric crisis, torticollis) or akathisia (a type of psychomotor agitation, often described as “ants in pants” or a “restless leg” type of feeling all over the body). A careful history about the timing of medications and the development of symptoms can help differentiate these types of symptoms in a patient who may have an evolving delirium in the context of polypharmacy, which is very common. Further discussion of doses and scheduling follows in the Medications section.

Some patients with cancer experience chronic symptoms such as pain, nausea, and anxiety, which may necessitate long-term administration of habit-forming medications such as opiates or benzodiazepines. This can occur in an inpatient setting (e.g., during a prolonged critical illness or stem cell transplant) or with chronic comorbidities (e.g., avascular necrosis of joints related to corticosteroids, phantom limb pain, persistent nausea) of cancer therapy as an outpatient. Acute or subacute changes in a patient’s clinical status (for better or worse) may result in the rapid reduction of these medications and cause opiate or benzodiazepine withdrawal symptoms if a patient had developed physiological dependence to the drug. It is common for these sorts of dose changes, made 2–3 days prior to presentation of withdrawal symptoms, to be overlooked when a patient’s medical problems are complex, acute, and fluctuating. Therefore, careful review of the medications dispensed over the course of the symptoms is important.

While the classic syndrome of opiate withdrawal includes hypertension, tachycardia, vomiting, diarrhea, and diaphoresis, milder symptoms experienced by patients still on some dose of opiate often appear psychiatric in nature, including dysphoria, anxiety, emotional lability, tremulousness, fatigue, myalgias, and nausea. With the recognition of withdrawal, these symptoms can be easily treated and reversed. For patients on a short course of opiate therapy (less than 14 days), the World Health Organization (WHO) guidelines recommend discontinuation by a taper which decreases the original dose by 10–20 % every 8 hours, gradually increasing the time interval. However, for patients on opiates for longer periods, dose reduction should not exceed 10–20 % per week and management should include a measurement of withdrawal symptoms using a standard scoring system (World Health Organization 2012). The treatment of cancer-related and treatment-related pain in children is covered in Chap. 3 and in the WHO Guidelines on the Pharmacological Treatment of Persisting Pain in Children with Medical Illnesses.

Benzodiazepine withdrawal can present similarly, with symptoms of nausea, agitation, anxiety, tremulousness, myalgia, tachycardia, and hypertension. Benzodiazepine withdrawal, like alcohol withdrawal, can cause dangerous hypertension and seizures and should be considered in any new onset seizure in a medically complex patient who has recent exposure to benzodiazepines. As with opiates, tapers in chronic users should be slow and based on prevention of objective signs of withdrawal (like the Withdrawal Assessment Tool (WAT-1) or the Sophia Observation Withdrawal Scale). Research in the area of monitoring and guidelines for tapering of sedation and other uses of opiates and benzodiazepines in pediatrics is urgently needed (Poh et al. 2014; Galinkin et al. 2014; Ista et al. 2013).

Many cancer treatments cause iatrogenic psychiatric symptoms. Administration of corticosteroids, which is commonly used for the treatment of ALL and lymphoma, causes varying degrees of irritability, mood lability, impulsivity, lethargy and/or insomnia (Ularntinon et al. 2010). These changes can be intense but are usually limited to the duration of the treatment. Psychoeducation may be sufficient in supporting a patient and family through their course of corticosteoids, but if significant impairment is present, a short-acting agent like risperidone can be extremely helpful in reducing impairment and distress. If chronic steroid use is needed for graft versus host disease (GVHD) or other illnesses, frank clinical depression or anxiety disorders may develop which warrant other targeted therapies.

Another medication that warrants close monitoring of psychiatric symptoms is isotretinoin (Accutane), most commonly used for severe cystic acne, but due to its effect on inhibition of tumorigenesis, it has also been used in regimens treating neuroblastoma, medulloblastoma, and other skin and brain cancers. Prescription of isotretinoin in the United States can only occur if patient is registered and monitored on an FDA-administered website due to its side effects of severe teratogenicity, blood dyscrasias, and psychiatric effects, which include depression and mood lability and, rarely, suicidal ideation or completed suicide. It is often well tolerated. If needed, atypical antipsychotics can be useful for offsetting any mild to moderate psychiatric effects, but the presentation of severe psychiatric symptoms warrants reevaluating the risks and benefits of the treatment.

Interferon alpha (IFN-alpha), an immunotherapy used for treatment of metastatic melanoma, hepatitis B and C, giant cell tumors, and rarely other disorders, carries significant side effects including flu-like symptoms, fatigue, anorexia, and neuropsychiatric symptoms like depression, mania, and psychosis. It is generally better tolerated in children than adults but symptoms, if present, often respond well to targeted therapy with antidepressant, antimanic, or antipsychotic medication.

The evaluation and management of neurocognitive adverse effects of cancer illness and therapy in children and adolescents are discussed in Chap. 10. As part of a differential diagnosis during psychiatric evaluation, neurocognitive symptoms may include impairment of any domain of cognition, in particular, memory, attention, processing speeds, and visual motor integration (Castellino et al. 2014). A patient with acquired neurocognitive impairment may present to psychiatric evaluation with secondary anxiety or frustration with daily tasks (e.g., due to reduced ability to attend or process information), amotivation, or underachievement in academics. For the assessment of inattention and other cognitive symptoms after cancer treatments, an ADHD framework is insufficient, as many at-risk patients will not meet diagnostic criteria (Kahalley et al. 2011). Of note, depression, anxiety, and PTSD can also have cognitive symptoms like attention impairment and should be ruled out. Neuropsychological testing is an essential part of evaluation and treatment planning for patients with these types of symptoms. Some patients with attentional issues due to ADHD or acquired cognitive deficits may benefit from stimulant therapy to improve performance on focused tasks (Pao et al. 2006). In pediatric cancer survivors who received CNS directed therapy (ALL with cranial radiation and brain tumors), response to methylphenidate (MPH) is less robust (45 %) than in the ADHD population (75 %) . A history of preexisting inattention/ADHD is the best predictor of response. Given that the safety and tolerability are favorable, and similar to the ADHD population, and nearly half will have a response, Conklin et al. recommend a trial of methylphenidate with a slow titration and close monitoring of treatment response and side effects (Conklin et al. 2014). See Table 8.5, Stimulants, for specific medication information.