Atypical Antipsychotic Medications to Control Symptoms of Delirium in Children and Adolescents

Abstract

Background:

Atypical antipsychotics have been documented to be effective in the management of delirium in adults, but despite considerable need, their use has been less studied in pediatric patients.

Objective:

A retrospective chart review was done to describe the use of atypical antipsychotics in controlling symptoms of delirium in children and adolescents.

Methods:

Pharmacy records at Children's Hospital Los Angeles were reviewed to identify patients to whom antipsychotic agents were dispensed over a 24-month period. Psychiatric inpatient consultations during the same 24-month period were reviewed. Patients 1–18 years old diagnosed with delirium given antipsychotics constituted the study population. Delirium Rating Scale-Revised-98 (DRS-R98) scores were retrospectively calculated, when possible, at time antipsychotic was started to confirm the initial diagnosis of delirium and evaluate symptom severity, and again when antipsychotic was stopped, to assess symptom response.

Results:

Olanzapine (n=78), risperidone (n=13), and quetiapine (n=19) were used during the 2 years of the study. Mean patient age, length of treatment, and response were comparable for the three medications. For patients with two DRS-R98 scores available (n=75/110), mean DRS-R98 scores decreased significantly (p<0.001) with antipsychotic without significant adverse side effects.

Conclusion:

Although randomized placebo-controlled studies are needed, atypical antipsychotic medications appeared to be effective and safe for managing delirium symptoms in pediatric patients while underlying etiology was addressed.

Introduction

D elirium is a disorder of impaired consciousness that can occur in seriously ill patients of all ages. Delirium is precipitated by a wide variety of medical, surgical, pharmacologic, and traumatic etiologies. Key features of delirium include association with a serious underlying condition, acute onset, fluctuating course, inattention, disorganized thinking, and altered level of consciousness (American Psychiatric Association 2000).

Delirium is described most frequently in the elderly, perhaps because of the high occurrence of multiple medical problems and multiple medications in this population (Rummans et al. 1995). These same risk factors may also occur in the seriously medically ill child or adolescent. Delirium is associated with longer hospital stays and high morbidity and mortality in children and adolescents (Turkel and Tavaré 2003; Schieveld and Leentjens 2005; Schieveld et al. 2007) as in adults (Girard et al. 2008).

Delirium has been reported in children and adolescents in association with central nervous system (CNS) infections and sepsis, human immunodeficiency virus/acquired immune deficiency syndrome, cancer, chemotherapy, closed head injuries, seizures, emergence from anesthesia, organ failure, hypoxia, fractures, trauma, and related to the use of sedative-hypnotic and/or anticholinergic medications (Turkel and Tavare 2003; Schieveld et al. 2007).

Delirium management is predicated on identification and treatment of its underlying cause. Current medications should be reviewed and modified to limit exacerbation of delirium symptoms (Michaud et al. 2007). Environmental interventions are usually employed to maintain diurnal routine and decrease confusion (Michaud et al. 2007). Antipsychotic medication may also be needed to manage symptoms of agitation and confusion and to prevent harm caused by inadvertent extubation, disconnected lines, or falls (Meagher 2001; Martini 2005). Medication may help reduce stress on patients and family by addressing the psychotic symptoms of delirium and by providing more periods of cognitive clarity.

There is a lack of double-blind randomized or placebo-controlled clinical trials (American Psychiatric Association 1999; Bourne et al. 2008; Trzepacz et al. 2008), and currently no agents have FDA approval for delirium treatment in either adults or children (American Psychiatric Association 1999; Smith et al. 2009). Although the evidence base for effective drug use in delirium is limited, antipsychotics have been clinically shown to address symptoms in adults with delirium and are widely used.

Current approaches for pediatric patients with delirium are modeled on experience in adults (Martini 2005). Either haloperidol or atypical antipsychotics appear to be generally well tolerated and effective in reducing the symptoms and associated hazards of delirium (American Psychiatric Association 1999; Meagher 2001; Bourne et al. 2008). While haloperidol has been used most often (Harrison et al. 2002. Ratcliff et al. 2004; Schieveld et al. 2007), it is associated with a risk of extrapyramidal symptoms, dystonia, akathesia, and hyperpyrexia (Harrison et al. 2002), and hypotension and cardiac irregularities may be more common in children younger than 12 years (Stoddard et al. 2006).

The atypical antipsychotics have broad and varied neurotransmitter effects. Their use has become a reasonable first-line approach to managing the symptoms of delirium in adults (Schwartz 1999; Lonegran et al. 2007), and their efficacy is comparable to haloperiodol (Boettger and Breitbart 2005). Risperidone, olanzapine, and quetiapine appear to be similarly effective with a relatively low burden of side effects (Boettger and Breitbart 2005), although the experimental evidence of safety and efficacy is limited and inconclusive (Peritogiannis et al. 2009).

Instruments developed to confirm the diagnosis of delirium consist of operationalized criteria, usually in the form of a checklist, incorporating information from patient observation and the medical record. The Delirium Rating Scale (DRS) was based on Diagnostic and Statistical Manual of Mental Disorders, 3rd edition (DSM-III) (American Psychiatric Association 1980) criteria (Trzepacz 1999), and has been cross-validated in different settings with excellent reliability and good validity (Rockwood et al. 1996).

The DRS was revised as the Delirium Rating Scale-Revised-98 (DRS-R98) to expand symptom assessment (Trzepacz et al. 2001). It is congruent with Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) (American Psychiatric Association 1994) and is frequently used in clinical studies of delirium, particularly when repeated measurement is required (Trzepacz et al. 2001). The DRS-R98 is comprised of 16 items in two sections (diagnostic and severity) reflecting the patient's symptoms, and items are scored from 0 to 3 (Trzepacz et al. 2001). The use of the DRS has been described in children and adolescents (Turkel et al. 2003), with scores similar to adults, although so far the DRS-R98 has not.

It is difficult to generalize from previous studies of pediatric delirium because they have not used a consistent method for assessing severity and symptoms, and the few open-label reports describe small groups of patients under varying circumstances. This retrospective study was undertaken to describe delirium in a larger number of young patients than previously reported, to delineate the underlying etiology of delirium in a systematic way, and to describe the use of antipsychotic agents to address symptoms of delirium in this understudied population.

Methods

Children's Hospital Los Angeles (CHLA) had 286 licensed beds and 10,900 annual admissions and discharges during the 2-year period of the study. This study was approved by the CHLA Committee for Clinical Investigations (Institutional Review Board).

Pharmacy records were screened for patients to whom antipsychotic agents were dispensed at CHLA from January 1, 2005, to December 31, 2006. Patients who had the diagnosis of delirium were identified from corresponding psychiatric inpatient consultation records. They constituted the study population.

The clinical diagnosis of delirium was based on Diagnostic and Statistical Manual of Mental Disorders, 4th edition, Text Revision (DSM-IV-TR) (American Psychiatric Association 2000) criteria and was made at the time of psychiatric consultation. The presence of an underlying serious medical illness, acute onset, fluctuating course, impaired attention, and disorganized thinking or behavior was required for the diagnosis of delirium (Trzepacz 1999).

During this time, oral formulations of olanzapine, risperidone, and quetiapine and oral and parenteral haloperidol were available on the hospital's formulary. Oral medications were administered by mouth or via nasogastric, gastric, or gastrojejunal tubes. Starting dosage was estimated based on age and size. No distinction was made between hypoactive, hyperactive, or mixed delirium.

Antipsychotic medication was typically started at bedtime. Additionally, a limited number of the same or lower doses were used as needed to control persistent hallucinations, confusion, insomnia, agitation, and potentially dangerous behavior. A routine daily dose was established based on the total amount needed to gain control of symptoms. Improved clinical status, excess daytime sedation or other side effects indicated when the dose could be reduced, and antipsychotic was discontinued as soon as possible.

Patient demographics, medical diagnoses, antipsychotic agent used, dosage, target symptoms, and side effects were compiled from clinical records. The DRS-R98 was used to confirm the clinical diagnosis of delirium, systematically record presenting symptoms, and determine any change in symptoms coincident with antipsychotic use. The DRS-R98 was retrospectively rated by clinicians trained in the diagnosis of delirium, based on psychiatric evaluations prior to antipsychotic use and again when antipsychotic was no longer given. While not scored at the time of evaluation, clinical information in the psychiatric records were prospectively noted to facilitate later scoring. If data were incomplete, the DRS-R98 was not scored. Data were analyzed using a commercially available statistics software program (Minitab^® 1984).

Results

One hundred and ten pediatric patients (56 males and 54 females) were included in the study. Study patients received olanzapine (n=78), risperidone (n=13), quetiapine (n=19), and none received haloperidol.

Patients ranged in age from 1 to 18 years, with overall mean age of 10.5 years. The mean for children 1–12 years (n=61, 55%) was 7.0 years, and for adolescents 13–18 years (n=49, 45%) was 15.0 years. The ratio of children to adolescents was not significantly different for the three medications used (chi-square test, p=0.633).

The initial total DRS-R98 scores ranged from 11 to 32, and the final DRS-R98 scores ranged from 1 to 13. The overall mean (±standard deviation [SD]) initial DRS-R98 score was 19.8 (±5.3), and the overall mean (±SD) final DRS-R98 score was 4.8 (±3.2) (Table 1). Final DRS-R98 scores were similar for all three medications (analysis of variance [ANOVA], p=0.17). The mean difference in scores for children (14.8) was similar to that for adolescents (15.2) (ANOVA, p=0.796). For the overall group of 75/110 patients, and for patients grouped by medication, final DRS-R98 scores were significantly lower than scores at diagnosis (paired t-tests, p<0.001).

Table 1.

Total Delirium Rating Scale-Revised-98 Scores

	Mean (SD); Median (range)
	Olanzapine	Risperidone	Quetiapine	p (ANOVA); p (Kruskal-Wallis)
Age (years)	10.8 (4.9); 12 (1–18)	8.6 (5.4); 8 (1–16)	10.8 (4.5); 11 (3–18)	0.33; 0.37
Pretreatment score^a	20.4 (5.0); 20 (11–32)	21.0 (5.7); 22 (11–30)	16.9 (5.1); 18 (8–32)	0.03; 0.03
Posttreatment score^b	4.7 (3.0); 4 (1–13)	6.7 (4.3); 6 (2–13)	4.3 (3.0); 4 (1–11)	0.17; 0.36
Prescore minus postscore^c	15.7 (5.6); 15 (4–29)	15.3 (6.0); 14 (6–24)	12.4 (5.2); 12 (3–25)	0.11; 0.10

Excludes 13 olanzapine and 3 risperidone cases with limited initial evaluation.

Excludes 22 olanzapine, 4 risperidone, and 3 quetiapine cases with limited final evaluation.

Includes 75 cases with both pre- and posttreatment scores.

SD=standard deviation; ANOVA=analysis of variance.

The DRS-R98 could not be completely scored when the patient was asleep, nonverbal, or sometimes when intubated. Visual-spatial assessment was the most difficult item to assess. Of 110 patients, the DRS-R98 could be scored both at diagnosis and at the end of antipsychotic use in only 75 patients, so the differences between scores were determined in them (68%) (Table 2).

Table 2.

Mean Antipsychotic Dosages (mg)

	Mean (range)
	Olanzapine (n=78)	Risperidone (n=13)	Quetiapine (n=19)
Starting daily dose	4 (0.625–30)	0.6 (0.25–1)	30 (12.5–100)
Ending daily dose	5.4 (1.25–20)	0.7 (0.25–2)	70 (12.5–300)
Minimum daily dose	3 (0.625–5)	0.5 (0.15–1)	25 (12.5–50)
Maximum daily dose	10 (1.25–60)	1 (0.25–2)	75 (12.5–300)
Total dose received over course of treatment	292 (1.25–3072.5)	18 (0.75–48)	2025 (25–5625, 10275)
Days on medication	26.5 (1–132, 178)	17.5 (2–54)	35.1 (1–108, 118)
Average daily dose	10 (1–52.5)	1.3 (0.375–4)	56 (12.5–125)

The total daily dose of antipsychotic included both routine and as needed doses (Table 3). Dosages were the highest when delirium was drug induced. The length of treatment was not significantly different for patients who received any of the three medications (ANOVA, p>0.3).

Table 3.

Scoring of Individual Delirium Rating Scale-Revised-98 Items

	Olanzapine		Risperidone		Quetiapine		Combined
Mean score	Pretreatment	Posttreatment	Pretreatment	Posttreatment	Pretreatment	Posttreatment	Pretreatment	Posttreatment
Diagnostic items
Acute onset	2.6	—	2.8	—	2.4	—	2.5	—
Fluctuating course	1.7	—	1.8	—	1.7	—	1.7	—
Physical disorder	2.0	—	2.0	—	2.0	—	2.0	—
Severity items
Sleep–wake cycle	2.4	0.6	2.6	0.8	2.8	0.7	2.5	0.7
Perceptual change	1.2	0.1	1.1	0.0	1.2	0.3	1.2	0.1
Delusions	0.4	0.0	0.3	0.0	0.2	0.2	0.3	0.0
Affect lability	1.8	0.2	1.4	0.5	0.7	0.2	1.6^a	0.3
Language	1.7	0.2	2.7	1.8	1.3	0.7	1.7^a	0.8
Thought process	1.1	0.1	0.7	0.0	0.4	0.3	1.0	0.1
Motor agitation	1.8	0.0	1.8	0.2	1.2	0.0	1.7	0.0
Motor retardation	0.7	0.0	0.3	0.2	0.8	0.0	0.7	0.5
Disorientation^b	1.9	0.9	2.4	2.2	1.2	0.8	1.8^a	1.0
Inattention	2.2	1.0	2.5	1.3	1.4	0.9	2.1^c	1.0
Short-term memory	1.7	0.1	0.0	0.0	0.0	0.0	1.0^a	0.1
Long-term memory	1.8	0.2	0.0	—	0.0	0.0	1.3	0.2
Visual-spatial	1.5	0.4	—	—	—	—	1.5	0.4

ANOVA comparing three antipsychotics.

Significant difference in pretreatment scores, p<0.01.

Significant difference in posttreatment scores, p<0.001.

Significant difference in pretreatment scores, p<0.001.

It was difficult to determine the definitive cause of delirium in these patients. They were all seriously ill and delirium was most likely multifactorial. Infection and drug-induced delirium, usually from opioids and/or benzodiazepines, were found most often (Table 4). Malignancies in the CNS and elsewhere were next, followed by postoperative and posttraumatic causes. Autoimmune disorders, other CNS disorders, and organ failure were seen in similar numbers, and posttransplantation was least frequent.

Table 4.

Underlying Disorder Associated with Delirium: Frequency (%)

	Olanzapine (n=78)	Risperidone (n=13)	Quetiapine (n=19)	Total (n=110)
Drug induced	18 (23%)	1 (8%)	5 (26%)	24 (22%)
Infection	9 (12%)	5 (38%)	9 (47%)	23 (21%)
Neoplasm	18 (23%)	1 (8%)	0	19 (17%)
Other central nervous system disorder	6 (7%)	4 (19%)	2 (11%)	12 (11%)
Autoimmune	6 (8%)	1 (8%)	2 (11%)	9 (8%)
Postoperative	9 (12%)	0	0	9 (8%)
Organ failure	6 (8%)	0	2 (11%)	8 (7%)
Trauma	5 (6%)	1 (8%)	0	6 (5%)
Posttransplant	1 (1%)	0	1 (5%)	2 (2%)

One patient treated with olanzapine developed mild dystonia, which resolved when the dose was decreased. There were no other significant adverse side effects. No patient developed arrhythmia, and changes suggesting the metabolic syndrome were not found. Four patients died of their underlying medical condition during the study period: one child (on olanzapine) and three adolescents (one on each antipsychotic).

Discussion

This study was a retrospective, descriptive study of the use of atypical antipsychotic medications for symptom management in a cohort of child and adolescent patients with delirium. Studies such as this have inherent limitations. There was no randomization, the medication group sizes were unequal, no placebo or control group was used, DRS-R98 scoring was not blinded, and drug choice and baseline delirium severity were not without potential bias. Adverse effects were clinically closely monitored, but were not systematically collected according to predetermined criteria.

It is not possible to conclude that the observed reduction in delirium symptoms, as reflected by lower DRS-R98 scores, was due to the antipsychotic alone. The decrease in DRS-R98 score may reflect reduction in delirium symptoms as the underlying medical condition improved, control of the factors predisposing to delirium, beneficial environmental interventions, or removal of medications exacerbating delirium.

This retrospective descriptive study included children as young as 1 year, who have a limited sense of time or place. The DRS-R98 relies on a higher level of baseline cognitive function than is commonly found in younger patients. While this may have compromised DRS-R98 scores, they were not significantly different from the DRS scores noted in a previous study of pediatric delirium (Turkel et al. 2003).

No significant adverse effects of psychotropic medications were noted in this group of pediatric patients with delirium. The absence of the metabolic syndrome may reflect that these patients were all seriously ill and often were not fed, and duration of antipsychotic use was brief. Although parenteral haloperidol was available, it was not chosen during the study period. The use of oral disintegrating tablets or liquid formulations seemed to obviate the need for intravenous administration, and oral atypical antipsychotics were easy to administer and well tolerated.

The distribution of underlying medical diagnoses was similar to previous reports (Turkel and Tavaré 2003; Schieveld and Leentjens 2005; Schieveld et al. 2007). Drug-induced delirium was common in this patient population, and was most often related to high doses of opioids and benzodiazepines used for sedation in the intensive care unit (Maldonado 2008). Antipsychotic dose was highest when delirium was considered drug induced. While the patients were all seriously ill, mortality in this study was relatively low (4/110) (Turkel and Tavaré 2003).

While olanzapine, quetiapine, and risperidone were all associated with reduction in DRS-R98 scores, no definitive statement comparing efficacy or safety of the three antipsychotic agents can be made with this study design. Future prospective, randomized, and placebo-controlled studies of antipsychotic use in pediatric delirium, with adequate powering in each drug arm, would be needed to allow such conclusions.

Conclusions

While there remains a need for further randomized, prospective research in the phenomenology, etiology, treatment, and outcomes of delirium in children and adolescents, this study was intended to provide data to inform further research. It supports the clinical supposition that atypical antipsychotics can be helpful in the management of pediatric patients with delirium.

Clinical Significance

The management of delirium in adults, especially the elderly, has been well studied, but despite considerable need, it has been less studied in pediatric patients. This retrospective report describes the use of olanzapine, risperidone, and quetiapine in managing the symptoms of delirium in children and adolescents. Using the DRS-R98 to confirm the diagnosis and assess response, all three agents were found to be useful (p<0.001) without significant adverse side effects.

Footnotes

Disclosures

Susan Beckwitt Turkel, Julienne Jacobson, Elizabeth Munzig, and C. Jane Tavaré have no conflicts of interest, no institutional or other funding source, no commercial interest, and no pharmaceutical affiliation to disclose.

References

American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 3rd(DSM-III)Washington, DC: American Psychiatric Association, 1980.

American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th(DSM-IV)Washington, DC: American Psychiatric Association, 1994.

American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4thText Revision (DSM-IV-TR)Washington, DC: American Psychiatric Association, 2000.

American Psychiatric Association:. Practice Guidelines for the Treatment of Patients with Delirium. Am J Psychiatry, 156,Suppl:1–20. 1999.

Boettger

, Breitbart

. Atypical antipsychotics in the management of delirium: A review of the empirical literature. Palliat Supp Care, 3:227–238. 2005.

Bourne

, Tahir

, Borthwick

, Sampson

. Drug treatment of delirium: Past, present and future. J Psychosom Res, 65:273–282. 2008.

Girard

, Pandharipande

, Ely

. Review: Delirium in the intensive care unit. Crit Care, 12,Suppl 3:S3–S12. 2008.

Harrison

, Lugo

, Lee

, Appachi

, Boudakos

, Davis

, McHugh

, Weise

. The use of haloperidol in agitated critically ill children. Clin Pediatr, 41:51–54. 2002.

Lonegran

, Britton

, Luxenberg

. Antipsychotics for delirium. Cochrane Database Syst Rev, CD005594. 2007.

10.

Maldonado

. Delirium in the acute care setting: Characteristics, diagnosis, and treatment. Crit Care Clin, 24:657–722. 2008.

11.

Martini

. Commentary: The diagnosis of delirium in pediatric patients. J Am Acad Child Adol Psychiat, 44:395–398. 2005.

12.

Meagher

. Delirium: Optimizing management. Brit M J, 322:144–149. 2001.

13.

Michaud

, Bula

, Berney

, Camus

, Voellinger

, Steifel

, Burnard

. The Delirium Guidelines Group: Delirium: Guidelines for general hospitals. J Psychosom Res, 62:371–383. 2007.

14.

Minitab^® . Statistical Software. State College, PA: Minitab, 1984.

15.

Peritogiannis

, Stefanou

, Lixouriotis

, Gkogkos

, Rizos

. Atypical antipsychotics in the treatment of delirium. Psychiat Clin Neurosci, 63:623–631. 2009.

16.

Ratcliff

, Meyer

, Cuervo

, Villareal

, Thomas

, Herndon

. The use of haloperidol and associated complications in the agitated, acutely ill pediatric burn patient. J Burn Care Rehabil, 25:472–478. 2004.

17.

Rockwood

, Goodman

, Flynn

, Stolee

. Cross-validation of the Delirium Rating Scale in older patients. J Am Geriatr Soc, 44:839–842. 1996.

18.

Rummans

, Evans

, Krahn

, Fleming

. Delirium in elderly patients: Evaluation and management. Mayo Clin Proc, 70:989–998. 1995.

19.

Schieveld

, Leentjens

AFG

. Delirium in severely ill young children in the pediatric intensive care unit (PICU) J Am Acad Child Adol Psychiatr, 44:392–394. 2005.

20.

Schieveld

, Leeroy

, van

Os J

, Nicolai

, Vos

, Leentjens

AFG

. Pediatric delirium in critical illness: Phenomenology, clinical correlates and treatment response in 40 cases in the pediatric intensive care unit. Intensive Care Med, 33:1033–1040. 2007.

21.

Schwartz

. Delirium in hospitalized older patients. New Engl J Med, 341:369–370. 1999.

22.

Smith

, Fuchs

, Pandharipande

, Barr

, Ely

. Delirium: An emerging frontier in the management of critically ill children. Crit Care Clin, 25:593–614. 2009.

23.

Stoddard

, Usher

, Abrams

. Psychopharmacology in pediatric critical care. Child Adol Psychiatr Clin NA, 15:611–655. 2006.

24.

Trzepacz

, Bourne

, Zhang

. Designing clinical trials for the treatment of delirium. J Psychosomatic Res, 65:299–307. 2008.

25.

Trzepacz

, Mittal

, Torres

, Kanary

, Norton

, Jimerson

. Validation of the delirium rating scale-revised-98: Comparison with the delirium rating scale and the cognitivie test for delirium. J Neuropsychiat Clin Neurosci, 13:229–242. 2001.

26.

Trzepacz

. The delirium rating scale: Its use in consultation-liaison research. Psychosomatics, 40:193–204. 1999.

27.

Turkel

, Braslow

, Tavare

, Trezpacz

. The Delirium Rating Scale in Children and Adolescents. Psychosomatics, 44:126–129. 2003.

28.

Turkel

, Tavare

. Delirium in children and adolescents. J Neuropsychiatry Clin Neurosci, 15:431–435. 2003.