1. 종양혈액내과 R4 김태영 / prof. 정재헌

2. INTRODUCTION the most common, serious neuropsychiatric complication in cancer patients increased morbidity and mortality, hospitalization, higher health care costs This article reviews: - the best evidence of pharmacologic and nonpharmacologic management of delirium in patients with cancer

3. DELIRIUM PREVALENCE, ETIOLOGY, AND PATHOPHYSIOLOGY The prevalence of delirium in cancer: 10% to 30% in hospitalized patients and up to 85% in terminally ill patients with cancer direct effects of cancer on the CNS (eg, metastatic brain lesions) indirect CNS effects of the disease or treatments (eg, medications, electrolyte imbalance, dehydration, major organ failure, infection, vascular complications, paraneoplastic syndromes) Chemotherapeutic immunotherapeutic agents (eg, vincristine, corticosteroids, and interferon) medications used in supportive care (eg, opioids, antiemetics, BDZ) Use of opioids and cognitive, liver, or renal impairment => major risk factors for delirium final common pathway in prefrontal, posterior parietal cortex, anteromedial thalamus + imbalance in the neurotransmitters Ach and dopamine

4. DELIRIUM ASSESSMENT: DIAGNOSTIC FEATURES AND PHENOMENOLOGY Clinical diagnostic gold standard for delirium Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria MDAS, DRS-R-98, CAM : maximize diagnostic precision the hyperactive subtype restlessness, agitation, hallucinations, and delusions more perceptual disturbances, delusions alcohol and drug withdrawal, drug intoxication, adverse effects of drug higher mortality risk the hypoactive subtype psychomotor retardation, lethargy, and reduced awareness due to hypoxia, metabolic disturbances, or hepatic encephalopathies mixed subtype

5. Clinical features of delirium

6. DELIRIUM ASSESSMENT: DIAGNOSTIC WORKUP Assessment of potentially reversible causes of delirium detailed history from family alcohol or other substance opioid analgesics, benzodiazepines, and anticholinergic drugs infection or dehydration, visual impairment, deafness polypharmacy, renal impairment, and malnutrition hypercalcemia, hypoxia or DIC EEG (to rule out seizures) brain imaging studies (to rule out brain metastases, intracranial bleeding, or ischemia) Lumbar puncture (leptomeningeal carcinomatosis or meningitis)

7. TREATMENT OF DELIRIUM IN PATIENTS WITH CANCER Pharmacologic Interventions in the Treatment of Delirium Pharmacologic Interventions in the Prevention of Delirium Nonpharmacologic Management of Delirium The goal of care in the terminally ill : providing comfort through the judicious use of sedatives at the expense of alertness

8. Pharmacologic Interventions in the Treatment of Delirium Antipsychotics blocking the postsynaptic mesolimbic dopamine receptors typical (conventional or first-generation)-Haloperidol, Chlorpromazine -extrapyramidal adverse effects (striatal D2 receptor block) (acute dystonic reactions, pseudoparkinsonism, or akathisia) atypical (second-generation) antipsychotics -risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole -high degree of occupancy of the serotoninergic receptors, weight gain cholinesterase inhibitor alpha-2 agonists No medication approved by the FDA (treatment, prevention)

9. Retrospective studies,Open-label, Small sample size

10. too few patients

11. Pharmacologic Interventions in the Treatment of Delirium Antipsychotic medications: Review of the adverse effects of antipsychotics extrapyramidal adverse effects sedation, anticholinergic adverse effects possible drug-drug interactions cardiac arrhythmias- QTc prolongation and torsades de pointes Schneider et al 17 placebo-controlled trials patients with dementia. The risk of death with atypical antipsychotic 1.6 to 1.7 times greater 23,000 older patients found higher mortality rates associated with typical than with atypical antipsychotics—whether or not the patients had dementia A retrospective case-control analysis of 326 elderly hospitalized patients with delirium (OR) of death was 1.53  not significant

13. Pharmacologic Interventions in the Treatment of Delirium Antipsychotic medications: Evidence-based recommendations for the use of antipsychotics in the treatment of delirium APA practice guidelines (1999) antipsychotics as the first-line in the treatment of symptoms A 2004 Cochrane review -haloperidol,most suitable medication near the end of life, with chlorpromazine alternative A 2007 Cochrane review low-dose haloperidol (3.5 mg/d) lower extrapyramidal adverse effects atypical antipsychotics effective alternatives (eg, olanzapine and risperidone)

15. Pharmacologic Interventions in the Treatment of Delirium Psychostimulants: Evidence-based recommendations for the use of psychostimulants in the treatment of delirium (methylphenidate, modafinil)  not recommended, precipitating agitation and exacerbating psychotic symptoms Cholinesterase inhibitors: Evidence-based recommendations for the use of cholinesterase inhibitors in the treatment of delirium  not recommended

16. Pharmacologic Interventions in the Prevention of Delirium No delirium prevention trials in oncology settings Evidence-based recommendations for the use of pharmacologic interventions in the prevention of delirium (A 2007 Cochrane review)  Not recommanded Antipsychotics (RCT): not reducing delirium incidence decrease delirium severity and duration Cholinesterase inhibitors: not effecitve Melatonin: Potential protective agent against development of delirium Alpha-2 agonists Dexmedetomidine: prevention, treatment in ICU no studies  no recommendations of these medications in the prevention of delirium in oncology settings.

17. Nonpharmacologic Management of Delirium Nonpharmacologic intervention studies on the treatment of delirium - Two randomized trials: no difference in mortality, duration - trial of 174 geriatric patients with delirium: not show difference - 148 patients with delirium, the use of a delirium room : improved functioning, and equal length of stay and mortality patients without delirium Nonpharmacologic interventions for the prevention of delirium - Gagnon et al :no benefit - Inouye et al 852 patients (age>70), prevention intervention delirium developed in 9.9% vs 15.0% (matched OR, 0.60) total days with delirium (105 vs 161 days P.02) total number of delirium episodes (62 vs 90 episodes P.03) severity, recurrance rate: not different  primary prevention of delirium the most effective treatment strategy

18. Nonpharmacologic Management of Delirium Evidence-based recommendations for the use of nonpharmacologic interventions in the treatment and prevention of delirium - encouraging results in reducing delirium incidence and decreasing delirium duration and severity in geriatric patient populations

20. Conclusions