1. Delirium in critical illness

2. Delirium An acute medical condition An acute medical condition Common in UK critical care patients Common in UK critical care patients Serious adverse outcomes Serious adverse outcomes Bedside diagnosis Bedside diagnosis May be first sign of a new infection May be first sign of a new infection Pathological not psychological Pathological not psychological

3. Delirium Disturbance of consciousness Disturbance of consciousness Acute change in mental status Acute change in mental status Fluctuating course – worse at night Fluctuating course – worse at night Develops over short time, hours to days Develops over short time, hours to days Impaired attention Impaired attention Disorganised thinking Disorganised thinking

4. Delirium motoric types Hyperactive – psychomotor agitation Hyperactive – psychomotor agitation Hypoactive – psychomotor lethargy and sedation, appears quiet & co-operative BUT with inattention and disorganised thinking. Hypoactive – psychomotor lethargy and sedation, appears quiet & co-operative BUT with inattention and disorganised thinking. Mixed – fluctuating hypo/hyperactive symptoms Mixed – fluctuating hypo/hyperactive symptoms

5. “Acute brain dysfunction” Prevalence of up to 80% quoted in ITU 100 ITU surgical patients: 69% with delirium Longer ventilation & ITU stay – 4 days Midazolam use strongest modifiable predictor Pandiharipande et al. 2006 SCCM 118 ITU medical patients over 65: 31% on admission. 70% during hospitalisation McNicoll J AM Geriatri Soc. 2003;51(5):591

6. Pathophysiology Neuroimaging – 42% ↓CBF, atrophy Neuroimaging – 42% ↓CBF, atrophy Psychoactive drugs 3-11 fold ↑RR delirium Psychoactive drugs 3-11 fold ↑RR delirium Related to surgery – multifactorial Related to surgery – multifactorial Biomarkers – serum anticholinergic activity Biomarkers – serum anticholinergic activity Neurotransmitters – imbalance in all monoamines, GABA, glutamate and Ach Neurotransmitters – imbalance in all monoamines, GABA, glutamate and Ach Sepsis: blood brain barrier breakdown or damage by metabolic/inflammatory mediators Sepsis: blood brain barrier breakdown or damage by metabolic/inflammatory mediators Yokota. Psych.Clin.Neurosci 2003, Fong. J Geront A Biol Sci Med Sci 2006, Koponen J Nerv Ment Dis 1989, Hopkins Brain Inj 2006, Chang R Neurosig 2006 Inoyue Am J Med 1999, Pandharipande Anesth 2006, Marcantonio JAMA 1994 Tune Lancet 1981, Mussi J Geriatri Psych Neurol 1999, Marcantonio J Geront A Biol Sci Med Sci 20 Goyette Semin Resp CCM 2004, Sharshar ICM 2007

7. Delirium is often invisible The vast majority of delirium in ICU is either hypoactive “quiet” subtype (35%) or mixed (64%) The vast majority of delirium in ICU is either hypoactive “quiet” subtype (35%) or mixed (64%) Very little (1%) is the pure hyperactive subtype. Very little (1%) is the pure hyperactive subtype. Older age is a strong predictor of hypoactive delirium Older age is a strong predictor of hypoactive delirium Hypoactive delirium has worse outcomes Hypoactive delirium has worse outcomes Onset: ICU day 2 (+/- 1.7) Onset: ICU day 2 (+/- 1.7) How long: 4.2 (+/- 1.7) days How long: 4.2 (+/- 1.7) days Ely et al JAMA 2001;286:2703-2710 Ely et al CCM 2001;9:1370-1379 Ely et al JAMA 2001;286:2703-2710 Ely et al CCM 2001;9:1370-1379 Peterson et al JAGS 2006 in press McNicholl JAGS 2003;51:591-598 Peterson et al JAGS 2006 in press McNicholl JAGS 2003;51:591-598

8. Risk factors Host factors Acute illness Iatro/environ Elderly Severe sepsis Sedative/analges Co-morbiditiesARDSImmobilisation Pre-existing cognitive impair MODSTPN Hearing/vision impairment Drug OD or illicit drugs Sleep deprivation Neurological dis Nosocomial inf. Malnutrition Alcohol/smoker Met. disturbance Anaemia

9. Precipitating factors INFECTION INFECTION Hyponatraemia Hyponatraemia Temperature Temperature Maintenance of arterial pressure Maintenance of arterial pressure Glucose Glucose Benzodiazepines Benzodiazepines Hypoxia, hypercarbia Hypoxia, hypercarbia Vaquero et al. Sem in Liver Dis. 2003;32:59-69

10. Medications cause delirium Different drugs implicated in different studies Benzodiazepines, esp. lorazepam Benzodiazepines, esp. lorazepam ?related to dose ?related to dose Corticosteroids Corticosteroids Morphine Morphine Maybe propofol and fentanyl Maybe propofol and fentanyl Anticholinergics Anticholinergics Pandharipande et al. Anesth;104(1):21-26,2006Dubois ICM 2001;27:1297-1304, Marcantonio. JAMA, 1994;272:1518-1522, Gadreau J of Clin Onc. 23(27):6712-6718 Marcantonio. JAMA, 1994;272:1518-1522, Gadreau J of Clin Onc. 23(27):6712-6718

11. Does it matter? After adjusting for age, gender, race, pre-existing comorbidity & cog impairment, ICU diagnosis and severity of illness 3 fold higher rate of death by 6 months 3 fold higher rate of death by 6 months 1.6 fold increase in ICU costs. 1.6 fold increase in ICU costs. Longer hospital stays Longer hospital stays Nearly 10x rate cognitive impairment on discharge. Nearly 10x rate cognitive impairment on discharge. 1 in 3 survivors with delirium develop cognitive impairment. 1 in 3 survivors with delirium develop cognitive impairment. Institutionalisation Institutionalisation

12. Does it matter? Increased ICU LOS 8 vs. 5 days Increased ICU LOS 8 vs. 5 days Increased Hosp. LOS 21 vs. 11 days Increased Hosp. LOS 21 vs. 11 days Increased time on vent 9 vs. 4 days Increased time on vent 9 vs. 4 days Higher costs $22 000 vs. $13 000 Higher costs $22 000 vs. $13 000 3 fold increased risk of death 3 fold increased risk of death Poss. incrd longterm cognitive impairment Poss. incrd longterm cognitive impairment Ely ICM 2001;27,1892-1900, Ely JAMA 2004;291:1753-1762, Lim SM, CCM 2004;32:2254-2259, Milbrandt E, CCM 2004;32:955-962, Jackson Neuropsychology Review 2004;14:87-98 Ely ICM 2001;27,1892-1900, Ely JAMA 2004;291:1753-1762, Lim SM, CCM 2004;32:2254-2259, Milbrandt E, CCM 2004;32:955-962, Jackson Neuropsychology Review 2004;14:87-98

13. Delirium and death In 275 medical ITU patients Independent predictor 6 month mortality: 34% with delirium v. 15% without p=0.03 After adjusting for covariates Hazard ratio death: 3.2 (CI 1.4 – 7.7) 203 general medical patients Adj. relative mortality risk 1.8 Median survival 510 days v. 1122 days Rockwood Age & Aging 1999;28(6):551-6, Ely et al JAMA 2004;291:1753-1762

14. Dementia after delirium 203 patients, 38 with delirium – 22 with dementia, 16 without. 32 month follow up. Incidence of dementia 5.6% per year without delirium, 18.1% with. Relative risk of death adjusted incr 1.8 + significantly shorter median survival time Rockwood et al, Age and aging 1999;28:551-556

15. Medical ITU patients 11 of 34 patients neuropsychologically impaired. 11 of 34 patients neuropsychologically impaired. Generally diffuse but primarily areas of psychomotor speed, visual & working memory, verbal fluency and visuo- construction. Generally diffuse but primarily areas of psychomotor speed, visual & working memory, verbal fluency and visuo- construction. Clinically significant depression in 36% these patients. Clinically significant depression in 36% these patients. Jackson CCM 2005;31(4):1226-1234

16. Delirium and outcome 40 year old ARDS ICU survivor college graduate 40 year old ARDS ICU survivor college graduate “I have been out of hospital and trying to get on with my life for the past 2 years. I have trouble with people’s names that I have worked with for years. I can’t remember where I put things at home. I can’t help my children with their homework because I can’t remember how to do simple multiplication problems.”

17. Neurological monitoring Level of sedation. Drugs are given with specific agreed target of effect. Screen for delirium Confusion assessment method for the ICU CAM-ICU, sensitivity/specificity 95% V. high inter-rater reliability Ely et al CCM;29:1370-1379, 2001, Ely et al JAMA;286:2703-2710, 2001

18. Delirium screening CAM-ICU – 4 features Altered mental status Inattention; Indentify As in 10 letter spoken sequence SAVE A HAART Disorganised thinking Altered level of consciousness ICDSC – 8 items Over one shift. 4 or more = delirium Ely JAMA 2001, Bergeron ICM 2001

19. CAM-ICU Incorporates 4 key features from definition of delirium, 1 minute to do Incorporates 4 key features from definition of delirium, 1 minute to do 1. Change in mental status from baseline or fluctuating course. 2. Inattention 3. Disorganised thinking 4. Altered level of consciousness Needs 1 & 2 with either 3 or 4.

20. The Assessment tool! Feature 1 : Acute onset of mental status changes, or Fluctuating course. Feature 2 : Inattention AND Feature 3 : Disorganised thinking Feature 4 : Altered level of consciousness OR

21. CAM-ICU Sedation level at least eye-opening to voice with or without eye contact. Feature 1: is patient different from baseline? Or: any fluctuations in mental status 24/12? Feature 2: looking for inattention – ASE letters, if unclear status – ASE pictures using hand squeeze. If both positive: Feature 3: Disorganised thinking, a) 4 questions – 2 or more incorrect responses is positive. b) Holding up fingers. Feature 4: Altered conscious level i.e. drowsy +

22. Management: treat cause(s) & reduce risks Treat underlying infection and CCF Treat underlying infection and CCF Correct metabolic disturbance & hypoxia Correct metabolic disturbance & hypoxia Frequent reorientation of patient Frequent reorientation of patient Goal directed sedation/analgesia &/or daily wakeup. Goal directed sedation/analgesia &/or daily wakeup. Stop ventilator each day to test readiness Stop ventilator each day to test readiness Early mobilisation Early mobilisation Attention to optimising sleep patterns Attention to optimising sleep patterns Inouye. NEJM 1999;340(9):669 Inouye. NEJM 1999;340(9):669

23. Management Pharmacological therapy Antipsychotics: Haloperidol: dopamine receptor antagonist D 2, variable sedation side effects: torsades de pointes (QTc) extrapyramidal. Newer atypicals: Olanzepine, Quetiapine Benzodiazepines: Deliriogenic, alcohol withdrawal.

24. Haloperidol 1950 shortly after chlorpromazine 1950 shortly after chlorpromazine D2 blockade mesolimbic pathways D2 blockade mesolimbic pathways Blockade in nigrostriatal pathway – EPS Blockade in nigrostriatal pathway – EPS Fewer vasomotor, cardiac central effects Fewer vasomotor, cardiac central effects 60% bioavailability 60% bioavailability Metabolised by oxidative dealkylation Metabolised by oxidative dealkylation Various dose schedules Various dose schedules 2.5mgs to 5mgs starting dose 2.5mgs to 5mgs starting dose

25. Delirium and Negative outcome Cause-and-effect? Systemic infections & injury ► brain dysfunction generation of CNS inflammatory response ► Production of cytokines, cell infiltration & tissue damage. Systemic infections & injury ► brain dysfunction generation of CNS inflammatory response ► Production of cytokines, cell infiltration & tissue damage. CNS immune activation accompanied by peripheral production of TNF, interleukin 1 & interferon δ contributing to MOF. CNS immune activation accompanied by peripheral production of TNF, interleukin 1 & interferon δ contributing to MOF. Bergeron Critical Care 2005;9:R375-381

26. www.icudelirium.co.uk www.icudelirium.org