Delirium in critical illness

Delirium

An acute medical conditionAn acute medical condition Common in UK critical care patients Common in UK critical care patients Serious adverse outcomesSerious adverse outcomes Bedside diagnosisBedside diagnosis May be first sign of a new infectionMay be first sign of a new infection Pathological not psychologicalPathological not psychological

Delirium

Disturbance of consciousnessDisturbance of consciousness Acute change in mental status Acute change in mental status Fluctuating course – worse at nightFluctuating course – worse at night Develops over short time, hours to daysDevelops over short time, hours to days Impaired attentionImpaired attention Disorganised thinkingDisorganised thinking

Delirium motoric types

Hyperactive – psychomotor agitation Hyperactive – psychomotor agitation Hypoactive – psychomotor lethargy and Hypoactive – psychomotor lethargy and

sedation, appears quiet & co-operative BUT sedation, appears quiet & co-operative BUT with inattention and disorganised thinking.with inattention and disorganised thinking.

Mixed – fluctuating hypo/hyperactive Mixed – fluctuating hypo/hyperactive symptomssymptoms

“Acute brain dysfunction”

Prevalence of up to 80% quoted in ITU Prevalence of up to 80% quoted in ITU 100 ITU surgical patients:100 ITU surgical patients:

69% with delirium69% with deliriumLonger ventilation & ITU stay – 4 daysLonger ventilation & ITU stay – 4 daysMidazolam use strongest modifiable predictorMidazolam use strongest modifiable predictor

Pandiharipande et al. 2006 SCCMPandiharipande et al. 2006 SCCM

118 ITU medical patients over 65:118 ITU medical patients over 65:31% on admission.31% on admission.70% during hospitalisation70% during hospitalisation

McNicoll J AM Geriatri Soc. 2003;51(5):591McNicoll J AM Geriatri Soc. 2003;51(5):591

PathophysiologyPathophysiology Neuroimaging – 42% ↓CBF, atrophyNeuroimaging – 42% ↓CBF, atrophy Psychoactive drugs 3-11 fold ↑RR deliriumPsychoactive drugs 3-11 fold ↑RR delirium Related to surgery – multifactorialRelated to surgery – multifactorial Biomarkers – serum anticholinergic activityBiomarkers – serum anticholinergic activity Neurotransmitters – imbalance in all Neurotransmitters – imbalance in all

monoamines, GABA, glutamate and Achmonoamines, GABA, glutamate and Ach Sepsis: blood brain barrier breakdown or Sepsis: blood brain barrier breakdown or

damage by metabolic/inflammatory damage by metabolic/inflammatory mediatorsmediators

Yokota. Psych.Clin.Neurosci 2003, Fong. J Geront A Biol Sci Med Sci 2006, Koponen J Nerv Ment Dis 1989, 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 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 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 2007Goyette Semin Resp CCM 2004, Sharshar ICM 2007

Delirium is often invisible

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

Risk factorsHost factorsHost factors Acute illnessAcute illness Iatro/environIatro/environ

ElderlyElderly Severe sepsisSevere sepsis Sedative/analgesSedative/analges

Co-morbiditiesCo-morbidities ARDSARDS ImmobilisationImmobilisation

Pre-existing Pre-existing cognitive impaircognitive impair

MODSMODS TPNTPN

Hearing/vision Hearing/vision impairmentimpairment

Drug OD or Drug OD or illicit drugsillicit drugs

Sleep Sleep deprivationdeprivation

Neurological disNeurological dis Nosocomial inf.Nosocomial inf. MalnutritionMalnutrition

Alcohol/smokerAlcohol/smoker Met. disturbanceMet. disturbance AnaemiaAnaemia

Precipitating factors Precipitating factors

INFECTIONINFECTION HyponatraemiaHyponatraemia TemperatureTemperature Maintenance of arterial pressureMaintenance of arterial pressure GlucoseGlucose BenzodiazepinesBenzodiazepines Hypoxia, hypercarbiaHypoxia, hypercarbiaVaquero et al. Sem in Liver Dis. 2003;32:59-69Vaquero et al. Sem in Liver Dis. 2003;32:59-69

Medications cause delirium

Different drugs implicated in different studiesDifferent drugs implicated in different studies Benzodiazepines, esp. lorazepam Benzodiazepines, esp. lorazepam

?related to dose?related to dose CorticosteroidsCorticosteroids MorphineMorphine Maybe propofol and fentanylMaybe propofol and fentanyl AnticholinergicsAnticholinergicsPandharipande et al. Anesth;104(1):21-26,2006Dubois ICM 2001;27:1297-1304,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):6712-6718Marcantonio. JAMA, 1994;272:1518-1522, Gadreau J of Clin Onc. 23(27):6712-6718

Does it matter?After adjusting for age, gender, race, pre-existing After adjusting for age, gender, race, pre-existing

comorbidity & cog impairment, ICU diagnosis and comorbidity & cog impairment, ICU diagnosis and severity of illnessseverity of illness

3 fold higher rate of death by 6 months3 fold higher rate of death by 6 months 1.6 fold increase in ICU costs.1.6 fold increase in ICU costs. Longer hospital staysLonger hospital stays Nearly 10x rate cognitive impairment on discharge.Nearly 10x rate cognitive impairment on discharge. 1 in 3 survivors with delirium develop cognitive 1 in 3 survivors with delirium develop cognitive

impairment.impairment. InstitutionalisationInstitutionalisation

Does it matter?

Increased ICU LOS 8 vs. 5 daysIncreased ICU LOS 8 vs. 5 days Increased Hosp. LOS 21 vs. 11 daysIncreased Hosp. LOS 21 vs. 11 days Increased time on vent 9 vs. 4 daysIncreased time on vent 9 vs. 4 days Higher costs $22 000 vs. $13 000Higher costs $22 000 vs. $13 000 3 fold increased risk of death3 fold increased risk of death Poss. incrd longterm cognitive impairmentPoss. incrd longterm cognitive impairment Ely ICM 2001;27,1892-1900, Ely JAMA 2004;291:1753-1762, Lim SM, CCM 2004;32:2254-2259, 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;14:87-98Milbrandt E, CCM 2004;32:955-962, Jackson Neuropsychology Review 2004;14:87-98

Delirium and death

In 275 medical ITU patients In 275 medical ITU patients Independent predictor 6 month mortality: Independent predictor 6 month mortality: 34% with delirium v. 15% without p=0.0334% with delirium v. 15% without p=0.03After adjusting for covariatesAfter adjusting for covariatesHazard ratio death: 3.2 (CI 1.4 – 7.7)Hazard ratio death: 3.2 (CI 1.4 – 7.7)203 general medical patients203 general medical patients

Adj. relative mortality risk 1.8Adj. relative mortality risk 1.8Median survival 510 days v. 1122 daysMedian survival 510 days v. 1122 days

Rockwood Age & Aging 1999;28(6):551-6, Ely et al JAMA 2004;291:1753-1762Rockwood Age & Aging 1999;28(6):551-6, Ely et al JAMA 2004;291:1753-1762

Dementia after delirium

203 patients, 38 with delirium – 22 with 203 patients, 38 with delirium – 22 with dementia, 16 without. 32 month follow up.dementia, 16 without. 32 month follow up.

Incidence of dementia 5.6% per year without Incidence of dementia 5.6% per year without delirium, 18.1% with.delirium, 18.1% with.

Relative risk of death adjusted incr 1.8 + Relative risk of death adjusted incr 1.8 + significantly shorter median survival timesignificantly shorter median survival time

Rockwood et al, Age and aging 1999;28:551-556Rockwood et al, Age and aging 1999;28:551-556

Medical ITU patients

11 of 34 patients neuropsychologically 11 of 34 patients neuropsychologically impaired.impaired.

Generally diffuse but primarily areas of Generally diffuse but primarily areas of psychomotor speed, visual & working psychomotor speed, visual & working memory, verbal fluency and visuo-memory, verbal fluency and visuo-construction.construction.

Clinically significant depression in 36% Clinically significant depression in 36% these patients.these patients.

Jackson CCM 2005;31(4):1226-1234Jackson CCM 2005;31(4):1226-1234

Delirium and outcome

40 year old ARDS ICU survivor college graduate40 year old ARDS ICU survivor college graduate

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

Neurological monitoring

Level of sedation.Level of sedation.Drugs are given with specific agreed Drugs are given with specific agreed target of effect.target of effect.

Screen for deliriumScreen for deliriumConfusion assessment method for the ICUConfusion assessment method for the ICUCAM-ICU, sensitivity/specificity 95%CAM-ICU, sensitivity/specificity 95%V. high inter-rater reliabilityV. high inter-rater reliability

Ely et al CCM;29:1370-1379, 2001, Ely et al JAMA;286:2703-2710, 2001Ely et al CCM;29:1370-1379, 2001, Ely et al JAMA;286:2703-2710, 2001

Delirium screeningDelirium screening

CAM-ICU – 4 featuresCAM-ICU – 4 features

Altered mental statusAltered mental status

InattentionInattention; Indentify As in 10 letter spoken sequence; Indentify As in 10 letter spoken sequence

SAVE A HAARTSAVE A HAART

Disorganised thinkingDisorganised thinking

Altered level of consciousnessAltered level of consciousness

ICDSC – 8 itemsICDSC – 8 items

Over one shift. 4 or more = deliriumOver one shift. 4 or more = delirium

Ely JAMA 2001, Bergeron ICM 2001Ely JAMA 2001, Bergeron ICM 2001

CAM-ICU Incorporates 4 key features from Incorporates 4 key features from

definition of delirium, 1 minute to dodefinition of delirium, 1 minute to do

1.1. Change in mental status from baseline or Change in mental status from baseline or fluctuating course.fluctuating course.

2.2. InattentionInattention

3.3. Disorganised thinkingDisorganised thinking

4.4. Altered level of consciousnessAltered level of consciousness

Needs 1 & 2 with either 3 or 4.Needs 1 & 2 with either 3 or 4.

The Assessment tool!The Assessment tool!Feature 1: Acute onset of mental

status changes, or Fluctuating course.

Feature 2: Inattention

AND

AND

Feature 3: Disorganised thinking

Feature 4: Altered level of consciousness

OR

CAM-ICUSedation level at least eye-opening to voice with or without Sedation level at least eye-opening to voice with or without

eye contact.eye contact.Feature 1:Feature 1: is patient different from baseline? is patient different from baseline?Or: any fluctuations in mental status 24/12?Or: any fluctuations in mental status 24/12?Feature 2: Feature 2: looking for inattention – ASE letters, if unclear looking for inattention – ASE letters, if unclear

status – ASE pictures using hand squeeze.status – ASE pictures using hand squeeze.If both positive:If both positive:Feature 3: Feature 3: Disorganised thinking, a) 4 questions – 2 or more Disorganised thinking, a) 4 questions – 2 or more

incorrect responses is positive. b) Holding up fingers.incorrect responses is positive. b) Holding up fingers.Feature 4: Feature 4: Altered conscious level i.e. drowsy + Altered conscious level i.e. drowsy +

Management: treat cause(s) & reduce risks

Treat underlying infection and CCFTreat underlying infection and CCF Correct metabolic disturbance & hypoxiaCorrect metabolic disturbance & hypoxia Frequent reorientation of patientFrequent reorientation of patient Goal directed sedation/analgesia &/or daily Goal directed sedation/analgesia &/or daily

wakeup.wakeup. Stop ventilator each day to test readinessStop ventilator each day to test readiness Early mobilisationEarly mobilisation Attention to optimising sleep patterns Attention to optimising sleep patterns Inouye. NEJM 1999;340(9):669Inouye. NEJM 1999;340(9):669

ManagementManagementPharmacological therapyPharmacological therapy

Antipsychotics:Antipsychotics:Haloperidol: dopamine receptorHaloperidol: dopamine receptor

antagonist Dantagonist D2, 2, variable sedation variable sedation

side effects: torsades de pointes (QTc)side effects: torsades de pointes (QTc)extrapyramidal.extrapyramidal.Newer atypicals: Olanzepine, QuetiapineNewer atypicals: Olanzepine, QuetiapineBenzodiazepines:Benzodiazepines:Deliriogenic, alcohol withdrawal.Deliriogenic, alcohol withdrawal.

Haloperidol

1950 shortly after chlorpromazine1950 shortly after chlorpromazine D2 blockade mesolimbic pathwaysD2 blockade mesolimbic pathways Blockade in nigrostriatal pathway – EPSBlockade in nigrostriatal pathway – EPS Fewer vasomotor, cardiac central effectsFewer vasomotor, cardiac central effects 60% bioavailability60% bioavailability Metabolised by oxidative dealkylationMetabolised by oxidative dealkylation Various dose schedulesVarious dose schedules 2.5mgs to 5mgs starting dose2.5mgs to 5mgs starting dose

Delirium and Negative outcomeCause-and-effect? Systemic infections & injury Systemic infections & injury ►► brain brain

dysfunction generation of CNS dysfunction generation of CNS inflammatory response inflammatory response ►►Production of Production of cytokines, cell infiltration & tissue damage.cytokines, cell infiltration & tissue damage.

CNS immune activation accompanied by CNS immune activation accompanied by peripheral production of TNF, interleukin 1 peripheral production of TNF, interleukin 1 & interferon & interferon δ contributing to MOF.δ contributing to MOF.

Bergeron Critical Care 2005;9:R375-381Bergeron Critical Care 2005;9:R375-381

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