Drug induced delirium Knut Erik Hovda, MD, PhD, FACMT, FEAPCCT The Norwegian CBRNe Centre of Medicine Department of Acute Medicine Oslo University hospital
Content 1. Introduction 2. Risk factors 3. Prevalence 4. Management 1. Non-pharmacological 2. Pharmacological 5. Summary
1. Introduction De lirium = off the track go off the furrow, "a plowing metaphor What is delirium? Criterion for diagnosis Tool for diagnosis Drug induced delirium (DiD) Subtypes Thanks to Leiv Otto Watne
DSM-5 criteriae for delirium (Diagnostic and Statistical Manual of Mental Disorders) A A disturbance in attention (i.e., reduced ability to direct, focus, sustain, and shift attention) and awareness (reduced orientation to the environment). Attention Awareness B The disturbance develops over a short period of time (usually hours to a few days), represents a change from baseline attention and awareness, and tends to fluctuate in severity during the course of a day. Acute change Fluctuate C An additional disturbance in cognition (e.g. memory deficit, disorientation, language, visuospatial ability, or perception). D The disturbances in Criteria A and C are not better explained by a pre-existing, established or evolving neurocognitive disorder and do not occur in the context of a severely reduced level of arousal, such as coma. E There is evidence from the history, physical examination or laboratory findings that the disturbance is a direct physiological consequence of another medical condition, substance intoxication or withdrawal, or exposure to a toxin, or is due to multiple etiologies Disturbance in cognition Not «only» dementia A direct consequense of another medical condition American Psychiatric Association
Drug Induced Delirium (DDD) subtypes 3 clinical sub-types 1. Hyperactive 2. Hypoactive 3. Mixed Lipowski 1 1. Hyperactive 15% 2. Hypoactive 19% 3. Mixed 52% 4. Unclassified 14% - Problem; often overlooked (esp. the hypoactive form ) - Solution: Formal and repeated assessment of cognitive status (e.g. by Confusion Assessment Method CAM 2 ) - Cornerstone of diagnosis: Careful drug history temporal relationship 3 1 Lipowski ZJ N Engl J Med 1989: 320 (9): 578-82 2 Inouye SK et al. Ann Intern Med 1990: 15;113(12):941-8. 3 Carter GL et al. Drug Saf. 1996;15(4):291-301.
From the original paper: - Can be completed in less than 5 minutes - Sensitivity 94-100 % - Specificity 90-95 % Inouye S et al. Ann Intern Med 1990; 113(12):941-8
2. Risk Factors for Delirium Severe dementia Severe chronic illness Multisensory Impairment Fit, elderly Person Major surgery ICU stay Multiple psychoactive medications Sleep deprivation One dose of sleeping medication Inouye SK et al. Lancet 2014; 383(9920): 911-22.
Modifiable or permanent triggers? O Regan et al. Int J Surgery 2013;11: 136-44
Risk factors (cont.) Delirium often multifactorial (underlying vulnerability + precipitating factors) 1 likely relevant for DiD too: Advanced age Pre-existing cognitive impairment Severe chronic illness Functional impairment ICU-stay Major surgery etc. The increased risk of DiD in the elderly may be because of altered pharmacokinetics 2, comorbid disease 1,3,4, and/or polypharmacy 5,6 1 lnouye SK. Am J Med 1994:97(3): 278-88 2 Berlinger WG. Spector R. Geriatrics 1984; 39 (5): 45-6. 50-2, 57-8 3 Francis J et al. JAMA 1990: 263(8): 1097-101 4 Jitapunkul S et al. Q J Med 1992: 83 (300): 307-14 5 Hutchinson T el al. J Chronic Dis 1986; 39: 533-42 6 Larson E, et al. Ann Intern Med 1987; 107 : 1 69-73
Drugs typically causing delirium Lipowski ZJ, editor. Delirium: acute confusional states. New York: Oxford University Press, 1990: 229-76.
Major drug classes inducing delirium Anticholinergic agents Opioid and non-opioid analgesics NSAIDS Hypno-sedatives Corticosteroids H 2 -receptor antagonists Anti-infectives Cardiovascular drugs (including ACE-inhibitors and other anti-hypertensives)
3. Prevalence Prevalence of delirium itself varies from study to study, and depends on the aetiology of the delirium; 10-15% of medical and surgical inpatients 1,2 30-50% of elderly medical inpatients 2 Some studies deal with DiD specifically 3,4,5, but few deals with the overall prevalence of DiD. Still, drug toxicity is considered a leading cause of delirium in hospital settings 1,6 1 Lipowski ZJ, editor. Delirium: acute confusional states. New York: Oxford University Press, 1990: 229-76. 2 Engel GL et al, editors. Comprehensive textbook of psychiatry. Baltimore: Williams and Wilkins, 1967: 711-6. 3 Berlinger WG. Spector R. Geriatrics 1984; 39 (5): 45-6. 50-2, 57-8 4 Tune LE, et al. Lancet 1981 ;11(8248): 651-2 5 Foy A. et al.. J Gerontol: Series A - Biol Sci Med Sci 1995:50 (2): M99-106 6 Francis J et al. JAMA 1990: 263(8): 1097-101
3. Prevalence (cont.) Examples from different populations In a study of 15800 psychiatric hospitalizations, 0.7% were because of adverse drug reactions, of whom 12.5% were DiD 1 In a prospective cohort-study of 418 pts (age 59-88) in a general hospital (normal cognition on admission), 10.8% developed cognitive impairment from BZD 2 1500 neurological consultations: 7% delirium, where a single cause of delirium not identified in 47%, and drug effect represented 17% 1 Wolf B et al. Compr Psychiatry 1989; 30 (6): 534-45 2 Foy A. et al.. J Gerontol: Series A - Biol Sci Med Sci 1995:50 (2): M99-106 3 Moses Ill H. Kaden I. Am J Med 1986; 81 (6): 955-8
4. Management A. General management 1,2 Early recognition of the condition Diagnosis Treatment of the specific underlying aetiologies Management of agitation and disruptive behavior General supportive care B. Specific management 1,2 Recognition Discontinuation of offending drug Optimization of overall health Avoid medicines unless necessary and beneficial Caution also with OTC-medication Reduce number of drugs Use medications least likely to cause delirium 1 Carter GL et al. Drug Saf. 1996;15(4):291-301. 2 Francis J: CNS Drugs 1996;5(2):103-14.
Non-pharmacological treatment 33% of delirium cases can be prevented Inouye SK. NEJM 1999: 340(9): 669-76.
What was the intervention? Cognitive impairment: communication to reorientate to the surroundings Sleep deprivation: noise reduction strategies, relaxition music, warm drink, back massage Immobility: exercises three times daily Visual impairment: visual aids Hearing impairment: amplifying devices, earwax disimpaction Dehydration: encouragement of oral intake of fluids i.e. addressing some of the most common risk factors.
Pharmacological treatment Delirium per se is not an indication for pharmacological treatment, but manifestations (behavioral or psychological) may be: Aggression, risk of harm to self or others, hallucinations, distress, (insomnia), need for compliance to important procedures (ICU, decontamination procedures etc.) 1 Pharmaceuticals can reduce agitation and behavioral symptoms, but no evidence shows that antipsychotics or sedatives improves prognosis. Moreover, they might switch the patient s delirium from hyperactive to hypoactive, making it more difficult to acknowledge 2 1 Carter GL et al. Drug Saf. 1996;15(4):291-301. 2 Inouye SK et al. Lancet 2014; 383(9920): 911-22
Randomized trials for treatment of delirium Study Drug N Population Breitbart (1996) haloperidol vs. chlorpromazine vs lorazepam 30 AIDS Han (2004) haloperidol vs. risperidone 28 Mixed medical/surgical Skrobik (2004) haloperidol vs. olanzapine 73 Medical/ surgical ICU Lee (2005) amisulpride vs. quetiapine 40 Mixed medical/surgical Hu (2006) olanzapine vs. haloperidol vs. control 175 senile delirium Raede (2009) haloperidol vs dexmedetomedine 20 Medical/surgical ICU Devlin et al. (2010) quetiapine vs. placebo 36 Medical/surgical ICU Tahir et al. (2010) quetiapine vs. placebo 42 Mixed medical/surgical Girard et al. (2010) haloperidol vs. ziprasidone vs. placebo 103 Medical/surgical ICU Kim et al. (2010) risperidone vs. olanzapine 32 Mixed medical/surgical/cancer van Eijk et al. (2010) rivastigmine vs. placebo 109 Medical/surgical ICU Overshott et al. (2010) rivastigmine vs. placebo 15 Medical wards Grover et al. (2011) haloperidol vs. olanzapine vs. risperidone 74 Mixed medical/surgical Maneeton (2013) quetiapine vs haloperidol 52 Mixed medical/surgical Page (2013) haloperidol vs placebo 141 Medical/surgical ICU Thanks to Leiv Otto Watne
Pharmacological treatment for Drug induced Delirium (I) No controlled studies specifically looking at DiD Most common approach: Antipsychotics and/or BZD Antipsychotics: Haloperidol considered safest and most effective for most conditions (e.g. restless or agitated delirium) Major advantage: relative lack of anticholinergic activity, -adrenergic blockade, cardiotoxicity and sedation 1 Benzodiazepines (e.g. diazepam): Recommended as sedation in hyperactive patients being aggressive or dangerous 1 1 Carter GL et al. Drug Saf. 1996;15(4):291-301.
Pharmacological treatment - 2 agonists profylactic use Study Drug N Population Pandharipande (2007) Riker (2009) Maldonado 1 (2009) Shebabi (2009) dexmedetomidine vs lorazepam dexmedetomidine vs midazolam dexmedetomidine vs propofol vs midazolam dexmedetomidine vs morphine 106 Surgical/Medical ICU. Mechanically ventilated 375 Surgical/Medical ICU. Expected mechanical ventilation >24 h 90 Surgical ICU 299 Surgical ICU Rubino (2010) clonidine vs placebo 30 Surgical ICU 1 Maldonado JR. Psychosomatics. 2009 May-Jun;50(3):206-17
Maldonado 1, 2009 1 Maldonado JR. Psychosomatics. 2009 May-Jun;50(3):206-17
Dexmedetomidin for treatment Patients undergoing mechanical ventilation; extubation not possible due to agitated delirium, n=20 Drug: Dexmedetomidin vs. Placebo Dex significantly shortened time to extubation (p=0.016) and LOS in ICU (p=0.004) Conclusion: Promising agent for the treament of ICU-associated delirious agitation 1 Reade MC et al. Crit Care. 2009;13(3):R75.
Summary Delirium common and serious, but the diagnosis is often missed, especially the hypoactive forms Drug induced delirium - 3 types: hyper-, hypoactive and mixed Risk factors: Often multi-factorial. Be aware of the elderly (pharmacokinetic issues, comorbidity, poly-pharmacy) Drugs causing delirium: Most are possible, some more likely (anti-cholinergic agents, analgesics, hypno-sedatives etc.) Prevalence: Not well studied for DiD in particular, but likely fairly common, especially in multi-factorial cases Effective management involves recognition, cessation or dose reduction, reorientation strategies and supportive medical care. Specific antidotes rarely indicated. Pharmacological (haloperidol diazepam - dexmedetomidin (?))
Acknowledgements Leiv Otto Watne, MD, PhD for invaluable input
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