Delirium in critical illnessProf. Bowirrat Abdalla M.D., Ph.D.Boston University School of Medicine

DeliriumAn acute medical conditionCommon in UK critical care patients Serious adverse outcomesBedside diagnosisMay be first sign of a new infectionPathological not psychological

DeliriumDisturbance of consciousnessAcute change in mental status Fluctuating course worse at nightDevelops over short time, hours to daysImpaired attentionDisorganised thinking

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

Acute brain dysfunctionPrevalence of up to 80% quoted in ITU 100 ITU surgical patients:69% with deliriumLonger ventilation & ITU stay 4 daysMidazolam use strongest modifiable predictorPandiharipande et al. 2006 SCCM118 ITU medical patients over 65:31% on admission.70% during hospitalisationMcNicoll J AM Geriatri Soc. 2003;51(5):591

PathophysiologyNeuroimaging 42% CBF - cerebral blood flow , atrophyPsychoactive drugs 3-11 fold RR deliriumRelated to surgery multifactorialBiomarkers serum anticholinergic activityNeurotransmitters imbalance in all monoamines, GABA, glutamate and AchSepsis: blood brain barrier breakdown or damage by metabolic/inflammatory mediators

Delirium is often invisible

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

Risk factors

Host factorsAcute illnessIatro/environElderlySevere sepsisSedative/analgesCo-morbiditiesARDS Acute Respiratory Distress SyndromeImmobilisationPre-existing cognitive impairMODS multiple organ dysfunction syndrome TPN - Total parenteral nutrition Hearing/vision impairmentDrug OVER DOSE (OD) or illicit drugsSleep deprivationNeurological disNosocomial inf.MalnutritionAlcohol/smokerMet. disturbanceAnaemia

CASE STUDY

A patient with short bowel syndrome manifesting psychiatric deterioration was demonstrated. Four years after extensive small bowel resection the patient developed various psychological manifestations. Laboratory data did not indicate the specific causes but showed extensive hyponutritional state. After 2 weeks therapy by total parenteral nutrition (TPN), laboratory data returned to normal, but her psychiatric condition remained almost unchanged. When trace elements (copper, cobalt, manganese and zinc) were added to TPN, her psychiatric impairment rapidly improved. Although the mechanism involved in this situation may be multifactorial, the trace elements were primarily responsible for recovering from abnormal psychiatric condition.

Precipitating factors

INFECTIONHyponatraemiaTemperatureMaintenance of arterial pressureGlucoseBenzodiazepinesHypoxia, hypercarbiaVaquero et al. Sem in Liver Dis. 2003;32:59-69

Medications cause deliriumDifferent drugs implicated in different studiesBenzodiazepines, esp. lorazepam ?related to doseCorticosteroidsMorphineMaybe propofol and fentanylAnticholinergicsPandharipande 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

Does it matter?After adjusting for age, gender, race, pre-existing comorbidity & cog impairment, ICU diagnosis and severity of illness3 fold higher rate of death by 6 months1.6 fold increase in ICU costs.Longer hospital staysNearly 10x rate cognitive impairment on discharge.1 in 3 survivors with delirium develop cognitive impairment.Institutionalisation

Does it matter?Increased ICU LOS 8 vs. 5 daysIncreased Hosp. LOS 21 vs. 11 daysIncreased time on vent 9 vs. 4 daysHigher costs $22 000 vs. $13 0003 fold increased risk of deathPoss. incrd longterm cognitive impairmentEly 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

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

Dementia after delirium203 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

Medical ITU patients11 of 34 patients neuropsychologically impaired.Generally diffuse but primarily areas of psychomotor speed, visual & working memory, verbal fluency and visuo-construction.Clinically significant depression in 36% these patients.Jackson CCM 2005;31(4):1226-1234

Delirium and outcome 40 year old ARDS ICU survivor college graduateI have been out of hospital and trying to get on with my life for the past 2 years. I have trouble with peoples names that I have worked with for years. I cant remember where I put things at home. I cant help my children with their homework because I cant remember how to do simple multiplication problems.

Neurological monitoringLevel of sedation.Drugs are given with specific agreed target of effect.Screen for deliriumConfusion assessment method for the ICUCAM-ICU, sensitivity/specificity 95%V. high inter-rater reliabilityEly et al CCM;29:1370-1379, 2001, Ely et al JAMA;286:2703-2710, 2001

Delirium screeningCAM-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

CAM-ICUIncorporates 4 key features from definition of delirium, 1 minute to doChange in mental status from baseline or fluctuating course.InattentionDisorganised thinkingAltered level of consciousnessNeeds 1 & 2 with either 3 or 4.

The Assessment tool!Feature 1: Acute onset of mental status changes, or Fluctuating course.

Feature 2: Inattention ANDANDFeature 3: Disorganised thinkingFeature 4: Altered level of consciousnessOR

CAM-ICUSedation 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 +

Management: treat cause(s) & reduce risks

Treat underlying infection and CCFCorrect metabolic disturbance & hypoxiaFrequent reorientation of patientGoal directed sedation/analgesia &/or daily wakeup.Stop ventilator each day to test readinessEarly mobilisationAttention to optimising sleep patterns Inouye. NEJM 1999;340(9):669

ManagementPharmacological therapyAntipsychotics:Haloperidol: dopamine receptorantagonist D2, variable sedation side effects: torsades de pointes (QTc)extrapyramidal.Newer atypicals: Olanzepine, QuetiapineBenzodiazepines:Deliriogenic, alcohol withdrawal.

Haloperidol1950 shortly after chlorpromazineD2 blockade mesolimbic pathwaysBlockade in nigrostriatal pathway EPSFewer vasomotor, cardiac central effects60% bioavailabilityMetabolised by oxidative dealkylationVarious dose schedules2.5mgs to 5mgs starting dose

Delirium and Negative outcomeCause-and-effect?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 contributing to MOF.Bergeron Critical Care 2005;9:R375-381

*Delirium is an underrecognised form of brain dysfunction. V. common in icu due to factors such as co-morbidity, critical illness and iatrogenesis. Associated with death, prolonged hospital stays and ongoing cognitive deficits. Neurologic dysfunction compromises patients ability to wean or achieve full recovery/independence.*Patients ability to receive, process, store and recall information is strikingly impaired. Usually reversible, direct consequence of a medical condition, substance intoxication or withdrawal, use of medication, toxin exposure or a combination. Often worse at night. Confusion is a characteristic occurring in delirium. *ICU psychosis now abandoned as an entity. Almost every patient receives benzos or opiates during stay with little modification of dose depending on age. Patients are frequently sedated to the point of stupor or coma to improve oxygenation, alleviate agitation and prevent them from removing support devices suspended animation. The pathophysiology is unclear.**Acute confusional states go unrecognised by managing physicians and nurses 32-66% of cases. Motoric types hyperactive, hypoactive and mixed, where purely hyperactive (ICU psychosis) is rare, hypoactive and mixed predominate about 45% - studies include one of 613 patients with 20 000 observations. Hypoactive more common in older patients and needs to be looked for. Peaceful patients are often assumed to be thinking clearly hypoactive delirium is characterised by decreased mental and physical activity and inattention. Hypoactive delirium may lead to reintubation (10 fold incr risk of nosocomial pneumonia.) and other conditions associated with immobility.

*Increasing number of elderly patients being treated. Respiratory failure requiring ippv rises 10-fold from age 55 to 85. 3 or more risk factors increase the likelihood of developing delirium to around 60% or higher, most icu patients have over 10 risk factors. Some can be looked at in terms of prevention or intervention. Psychoactive medications are the leading iatrogenic risk factors for delirium. Metabolic causes include hypocalcaemia, hyponatraemia, hyperbilirubinaemia. Most promising delirium interventions could be centred on delivery patterns of medications. **Dependent on study. One showed significant grtr no. patients with delirium received continuous iv sedation with midaz + fent. In another patients with delirium had grtr daily and cumulative doses of benzos. Marcantonios study implicated meperidine, and longer acting benzos stronger association than shorter, viz higher doses. Dubois study highlighted as risk factors HT, smoking, abnormal bilirubin as well as morphine. Gadreau again showed an association with benzos, and opioids, as well as corticosteroids.*Original study in JAMA Ely 275 consecutive patients 2158 days, 51 persistent coma and died, 183 developed delirium mortality 34 v. 15%, 10 days longer in hospital persisted after adjusting for variables. One study found 1 in 3 survivors of critical illness develop cognitive impairment.*Higher severity and duration of delirium are associated with incrementally greater costs On average figure of 60% af all ICU days patients older than 65. When adjusted for all known potential confounders including age, organ dysfunction, comorbidity delirium is associated with 39% higher ICU costs and 31% (95% CI 1-70%) hospital costs.*Prospective study, general medical patients. 8 studies on the relationship between delirium and cognitive function that have consistently demonstrated a link between acute and long term cognitive impairment. Cause is unclear, delirium may give rise to brain injury resulting in predisposition or initiation of dementia consistent with view of dementia as aberrant brain repair, or delirium may serve as a marker of a subclinical dementing process.*Used a battery of neuropsychological tests looking at 7 domains includiing mental status, psychomotor speed and verbal fluency. The findings of this study suggests that cognitive impairment is common in ventilated patients after discharge and confirms a diminished quality of life and depression in the survivors. The abnormalities were commensurate with clinical dementia of at least mild severity.*McCusker studied hospitalised elderly patients after treatment in emergency dept and found MMSE scores were nearly 5 points lower than those without delirium at 1 year after controlling for premorbid function, co-morbid disease and illness severity.*SCCM suggest patients are simultaneously monitored for level of sedation and delirium. Sedation scales present a common language. Potent psychoactive drugs should only be given with a specific agreed target level of effect, usually at least opening eyes to voice. All patients responsive to verbal stimuli can be assessed for delirium. Confusion assessment method for itu is designed to be used as serial assessment tool for use by bedside clinicians. Validated against reference standard in 293 paired evaluations. Takes only 1 minute on average to complete requiring minimal training.ICDSC: Inattention, disorientation, hallucination-delusion-psychosis, psychomotor agitation or retardation, inappropriate speech or mood, sleepwake disturbance, symptom fluctuation, altered level of consciousness. High sensitivity, lower specificity 64%.**As defined by the diagnostic statistical manual iv of the american psychiatric association. Need both *Translated into several languages including chinese.*A multicomponent intervention has been shown to benefit patients 852 medical patients over 70 (total number of days and episodes) & while this was not sustained at 6 months, the patients were in a different patient group, older general medical patients addresses 6 risk factors, cognitive impairment, sleep deprivation, immobility, visual impairment, hearing impairment and dehydration. Because of the high rate and inevitability of del in itu greater room for improvement.*Newer sedatives dexmedetomidine, remi. Haloperidol most widely used neurolept does not surpress resp drive, note dosing, emergency control v. 1mg. QTc greatere than 450ms*Note common pathological processed underlying delirium and dementia.