Psychosomatics 48:253-257, June 2007
doi: 10.1176/appi.psy.48.3.253
© 2007 Academy of Psychosomatic Medicine
Subtypes of Pediatric Delirium: A Treatment Algorithm
Niranjan S. Karnik, M.D., Ph.D.,
Shashank V. Joshi, M.D.,
Caroline Paterno, B.A., and
Richard Shaw, M.B., B.S.
Received January 2, 2006; revised May 5, 2006; accepted May 24, 2006. From the Division of Child and Adolescent Psychiatry, Stanford Univ. School of Medicine, Lucile Salter Packard Children’s Hospital, Palo Alto, CA. Send correspondence and reprint requests to Niranjan Karnik, M.D., Ph.D., Div. of Child and Adolescent Psychiatry, Stanford Univ. School of Medicine, 401 Quarry Rd., Palo Alto, CA 94305. e-mail: nkarnik{at}stanford.edu
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ABSTRACT
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Delirium in adult populations of hospitalized patients has been well characterized into hyperactive, hypoactive, and mixed subtypes. The degree to which these subtypes apply to pediatric populations has yet to be fully demonstrated. In this case report, the authors present two cases of delirium that serve as examples of the hyperactive and hypoactive/mixed types and then discuss treatment. They find marked differences in the response of different delirium subtypes to haloperidol and risperidone and theorize as to the neurochemical pathways by which these pharmacological agents might work. This framework provides an algorithm for the treatment of pediatric delirium.
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INTRODUCTION
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Pediatric delirium is a phenomenon that has been well documented and characterized in the context of anesthesia,1–7 in burn victims,8,9 and in the intensive care unit (ICU).10–12 It is less well characterized in the context of pediatric chemotherapy and steroid treatment. Turkel and Tavaré reported one of the largest samples of pediatric delirium cases and documented a 20% mortality.13 These findings agree with data from an earlier metaanalysis, which showed a 20% mortality after 6 months for delirium in elderly hospital patients.14 In adult populations, delirium has been found to be an independent predictor of mortality in mechanically-ventilated patients.15
In pediatric delirium, there has been widespread use of haloperidol as the primary treatment agent.13,16 However, little research has been done on the different effects of the available formulations of haloperidol (oral, intravenous, or intramuscular) in the treatment of pediatric delirium. Limited evidence from studies of adult patients suggests that intravenous use of haloperidol is more reliable in terms of increased rates of absorption; fewer extrapyramidal reactions; and minimal effects on blood pressure, respiration, and heart rate.17,18
The newer atypical antipsychotic agents, including olanzapine, risperidone, and quetiapine have also been reported to be useful in the pharmacological management of delirium.19 Olanzapine has also been used effectively in studies of adult patients, whereas risperidone has been posited as a good alternative to haloperidol, with potentially fewer side effects.20–22 However, there are no reports of the use of these agents in children, with the exception of one recent report on the use of risperidone in a 15-year-old girl with delirium in the context of HIV dementia23 and a single case report of a child with hypoxic brain injury.22 Also, data are still lacking on appropriate doses and specific treatment protocols, particularly in pediatric patients.
Whereas three major subtypes of delirium (hypoactive, hyperactive/agitated, and mixed)24–27 have been noted in the geriatric population, the extent to which these subtypes translate to the pediatric population has yet to be understood. Also, best practices for the treatment of these subtypes of delirium have yet to be determined. In this report, we describe the onset of delirium in two young women with distinct delirium subtypes derived from different preexisting disease states, and we describe an approach to treatment based on putative etiologies of the delirium.
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Case Report #1: Hypoactive/Mixed Delirium
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"Ms. A" is a 16-year-old young woman with a history of acute lymphoblastic leukemia (ALL) with CNS disease who was first diagnosed in 1999. At that time, she received four-drug induction, which included two doses of intrathecal chemotherapy. At the end of induction, Ms. A experienced acute mental status changes that eventually required hospitalization. In the hospital, Ms. A. experienced two witnessed seizures before becoming comatose for a 2-week period. Medical work-up revealed that she had herpes simplex virus (HSV) encephalitis, and she was treated with intravenous acyclovir. Ms. A suffered two more episodes of HSV encephalitis, in 1999 and 2000, and a hemorrhagic stroke in 2001. Since 2001, she had done quite well and was able to attend high school and interact with her family and friends without evidence of verbal, physical, or psychological deficits. However, residual damage to her frontal lobes was still evident on MRI.
Ms. A remained stable before having a relapse in her ALL. She was restarted on a four-drug reinduction regimen of methotrexate, vincristine, danurubicin, and asparaginase. After her second dose, Ms. A reported bilateral lower-leg myalgia, nausea, and dizziness. Later that day, she developed neutropenia and fever, which was treated with ceftazidime and predinose (40 mg/day).
On Hospital Day 3, Ms. A was noted to have pressured speech, periods of confusion, and occasional disorientation. A pediatric psychiatry consultation was requested because of concerns about possible delirium. She was noticed to be sleeping much less, with 4 hours of sleep per night. Her level of activity was also increased, and nursing staff reported that she would spend significant periods of time cleaning and ordering items in her hospital room. She had a score of 17/32 on the Delirium Rating Scale (DRS),28 and she was diagnosed with acute delirium. She denied any past symptoms of this nature, despite previous treatment with steroids in 1999. There was no past history of psychiatric illness. Ms. A was initially treated with risperidone 0.5 mg qhs. She seemed to improve on this regimen, with better sleep and less pressured activity, but continued to have episodes of increased confusion, disorientation, and pressured speech during the day. Her risperidone dose was increased to 0.5 mg bid, with the addition of zolpidem 5 mg qhs for insomnia. She showed improvement on this regimen and gradually returned to her baseline by Hospital Day 8, at which time she had a score of 5/32 on the DRS. Ms. A was discharged on this regimen and continued on steroids through Hospital Day 14. At discharge, she was no longer taking steroids, but was maintained on risperidone 0.5 mg bid, and zolpidem was discontinued. One week after discharge, she was titrated down to risperidone 0.5 mg qhs, and, after 5 days, this medication was discontinued. Both she and her mother reported that her mood and affect remained appropriate, and she did not exhibit any further evidence of steroid-induced psychosis or mania. Her score on the DRS was 0/32 at this time.
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Case Report #2: Hyperactive Delirium
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"Ms. B" is a 14-year-old Hispanic female patient with a history of systemic lupus eyrthematosus (SLE) and antiphospholipid-antibody syndrome. She initially presented with complaints of dizziness, headache, abdominal pain, nausea, and palpitations. She had no previous psychiatric history, but had, in the days before admission, become more anxious and socially isolated. Ms. B was admitted because of unstable vital signs and diarrhea. Shortly after admission, she was started on high-dose methylprednisone, and then, 2 days later, Decadron was added for treatment of her SLE.
One day after admission, Ms. B began to exhibit disorientation and increasing anxiety, and reported "memory loss" and "hearing messages." She reported that when she heard the voices, people would disappear from her hospital room. She indicated that she heard the phrase "God is the most important person" repeatedly. Over the next 2 days, her symptoms worsened, and she reported that she was seeing angels in her room. She subsequently accused a priest who was visiting her and her family of "having the devil inside him." On Day 2 of her hospitalization, she received a total of 5 mg of lorazepam, and then 2 mg on each subsequent day until the day of her transfer to another facility.
Despite treatment, Ms. B became progressively more disoriented over the following 3-day period, and she was transferred to a university-based, tertiary-care medical center for treatment of presumptive lupus cerebritis. Shortly after transfer, she was started on risperidone 0.5 mg twice daily, but continued to exhibit increased symptoms of agitation over the first 24-hour period. Her dosage of risperidone was subsequently increased to 1 mg bid, with 0.25 mg q6 hours as needed for agitation. The patient showed mild signs of improvement on this regimen for a 2-day period and, on average, total daily doses of risperidone of 3 mg per day. At this point, Ms. B began to exhibit signs of increased agitation and confusion. She began to yell at staff and was grabbing aggressively at people who would approach her bed. At this point, she had a score of 28/32 on the DRS. After 5 days on the risperidone regimen and continued treatment with high-dose steroids for the lupus cerebritis, she continued to show only marginal improvement and still required 24 hours on 1-to-1 observation. Her continued high level of agitation and a lack of full clinical response led to the decision to change her antipsychotic medication regimen from risperidone to haloperidol, prescribed at a dose of 0.5 mg bid and 0.25 mg q2 hours as needed for agitation. After this change, she showed rapid improvement, with decreased agitation and greater capacity for more appropriate communication with her family. She did not require any prn doses. Her DRS score on Hospital Day 8 was 8/32.
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Discussion
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Although there are good data on the use of risperidone in the treatment of psychiatric disorders,29 these case reports are one of the first reports of the use of risperidone in the treatment of pediatric delirium. There is, however, a substantial literature demonstrating the efficacy of risperidone in the treatment of delirium in adult patients,30–35 including two open-label studies36,37 and one double-blind study of risperidone versus haloperidol.19 Results from the latter study of 28 patients demonstrated little difference between risperidone and haloperidol in terms of treatment efficacy, but noted one report of akathisia in the haloperidol group. Both open-label studies found low-dose risperidone to be effective for in the treatment of acute delirium. There has been one retrospective study comparing risperidone and haloperidol in the treatment of hyperactive delirium, showing that psychiatrists seem to prefer risperidone for moderate hyperactivity and older patients, whereas haloperidol was preferred for more agitated patients.32 Generally, the literature on the treatment of delirium has shown a trend toward the use of atypical antipsychotics because of the lower frequency of extrapyramidal symptoms, decreased likelihood of neuroleptic malignant syndrome, and decreased potential for acute dystonia.35
From these cases and a review of the literature on pediatric delirium, we propose a model for use in the treatment of delirium in children (Figure 1). This model draws heavily on the functional pharmacokinetic differences between the compounds that are commonly used in treating delirium; specifically, risperidone and haloperidol. It has been hypothesized that patients with delirium have a profoundly increased sensitivity to dopamine and cholinergic dysregulation, which, in general, responds to treatment with antipsychotic agents.38 The small number of comparative studies generally find that risperidone and haloperidol are both effective in the treatment of delirium.19,32,39 However, only Liu and colleagues32 examined this in the context of different subtypes of delirium. Although their study found that risperidone was effective for hyperactive symptoms, they note that clinicians prefer haloperidol for treatment of extreme agitation in adult patients.32 Our case reports suggest that although there may be benefits from the use of risperidone for patients with hypoactive/mixed delirium, those with hyperactive delirium appear to respond differentially and preferentially to treatment with haloperidol.
In explaining these differing clinical responses, it may be helpful to look at the difference in patterns of receptor activity between these compounds (Table 1). It is believed that risperidone has wider receptor effects than haloperidol, which relatively narrowly targets the D2 receptor.40 This is one reason why atypical antipsychotics are believed to have fewer and less-severe side effects than typical antipsychotic agents.41 Risperidone has simultaneous effects on the 5HT2A receptor that modulates dopamine levels in different pathways, and it is these effects that are believed to help reduce the side effects that occur when there is more complete dopamine blockade, as in treatment with haloperidol. Evidence from studies of atypical antipsychotics show that they may lead to increased prefrontal dopamine release, whereas haloperidol does not.41–43 Specifically, atypical antipsychotics are known to increase dopamine in the medial prefrontal cortex, as part of the mesocortical pathway, via indirect activation of 5HT1A,44 thus resulting in cognitive enhancement and improvement in the negative symptoms of schizophrenia. In the mesolimbic pathway, however, dopamine antagonism predominates in serotonin-dopamine antagonist treatment, and the result is an improvement in the positive symptoms of psychosis, which may resemble symptoms of hyperactive delirium.
On the basis of the differential response to haloperidol and risperidone, in the context of our present understanding of delirium,35,38 we hypothesize that there are two major pathways to delirium (Figure 1). The pathway to hyperactive/active delirium originates with a high dopaminergic state, leading to agitation and aggression, and features that are reminiscent of the positive symptoms of schizophrenia, as seen in the case of Ms. B. In this case, risperidone, with its potential to selectively increase dopamine in some pathways, may exacerbate certain elements of the hyperactive delirium, particularly agitation, which is known side effect of this medication.45 This may explain why Ms. B failed to respond fully to risperidone, but then rapidly cleared after treatment with haloperidol. Atypical antipsychotics seem to lack full efficacy in these cases, as Scharko and colleagues demonstrated23 at the conclusion of their recent case report on delirium in the context of HIV-dementia in a 15-year-old girl. Just as we reported in the case of Ms. B, Sharko and colleagues report having to change from risperidone to haloperidol for the treatment of agitated delirium.
In contrast, the hypoactive/mixed pathway is one in which low or normal levels of dopamine predominate. Also, there is notable cholinergic dysregulation accompanying the dopamine dysregulation, and these combined features make this subtype of delirium more amenable to treatment with risperidone. We suspect that Ms. A would have responded to haloperidol, but that she would have faced significant cognitive blunting and may have required substantially more time to recover from the delirium, given the selectivity of haloperidol. We speculate that risperidone’s broad receptor coverage allowed re-regulation of both the dopaminergic and cholinergic systems. Although these putative etiologies are largely theoretical and inferential at this time, we do believe that they point to the need for laboratory-based research on the functions of these agents and the further need for physiological studies of pediatric delirium.
These cases highlight the need for careful screening and management of pediatric patients with delirium and, in particular, the need to pay attention to different delirium subtypes. Given the independent effect on mortality and the high degree of morbidity associated with delirium,46 child psychiatrists and pediatricians should be attentive to mental status changes. Both haloperidol and risperidone are likely to have important roles to play in the treatment of pediatric delirium.
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ABSTRACT
INTRODUCTION
