This document discusses delirium in the ICU. It begins with definitions of delirium and discusses its high prevalence among ICU patients, up to 70%. The pathophysiology is not fully understood but may involve disturbances in neurotransmitters like acetylcholine. Precipitants include medications, infections, metabolic disturbances and physical immobilization. Diagnosis involves tools like the Confusion Assessment Method. Management prioritizes prevention, treating underlying causes, and supportive care with low-dose short-acting medications as needed to manage severe symptoms.

1. DELIRIUM IN THE ICU
JOÃO MELO ALVES, MD
LISBOA, PORTUGAL
--
GENERAL ICU
DIRECTOR: PROF. CHARLES SPRUNG, MD
DEPARTMENT OF ANESTHESIOLOGY AND INTENSIVE CARE
HADASSAH EIN KEREM UNIVERSITARY HOSPITAL
JERUSALEM
HEAD OF DEP.: PROF. CHARLES WEISSMAN, MD
Der Schrei der Natur,
by Edvard Munch, circa 1893-1910

2. 2João Melo Alves, MD (Lisboa, Portugal) March 2015, GICU Hadassah Ein Kerem Universitary Hospital, Jerusalem
INDEX
THE DISEASE
DIAGNOSIS
MANAGEMENT

3. THE DISEASE
El sueño de la razón produce monstruos
(by Francisco Goya, circa 1797-1799
(Metropolitan Museum of Art, New York)

4. 4João Melo Alves, MD (Lisboa, Portugal) March 2015, GICU Hadassah Ein Kerem Universitary Hospital, Jerusalem
Delirium
Vs.
Acute confusional state / Encephalopathy
THE DISEASE
DIAGNOSIS
MANAGEMENT
DEFINITIONS

5. 5João Melo Alves, MD (Lisboa, Portugal) March 2015, GICU Hadassah Ein Kerem Universitary Hospital, Jerusalem
DSM-IV: four key features
 Disturbance of consciousness with reduced ability to focus, sustain or shift attention
 Change in cognition or new perceptual disturbance not explained by preexisting
dementia
 Acute onset (hours to days), fluctuating course
 Evidence that it is secondary to a medical condition, intoxication or side effect (history,
physical examination, laboratory results, …)
 Psychomotor behavioral disturbances
 Emotional disturbances
THE DISEASE
DIAGNOSIS
MANAGEMENT
DEFINITIONS
Diagnostic and Statistical Manual 4th ed. American
Psychiatric Association. APA Press, 2013.

6. 6João Melo Alves, MD (Lisboa, Portugal) March 2015, GICU Hadassah Ein Kerem Universitary Hospital, Jerusalem
Wherever there are (old) sick people…
30% of older medical patients experience delirium during hospitalization
Francis J, J Am Geriatr Soc 1992; 40(8)
Up to 50% of older surgical patients
Dyer CB et al., Arch Intern Med 1995; 155(5)
70% ICU patients
McNicoll L et al. J Am Geriatr Soc 2003; 51 (5)
THE DISEASE
DIAGNOSIS
MANAGEMENT
EPIDEMIOLOGY

7. 7João Melo Alves, MD (Lisboa, Portugal) March 2015, GICU Hadassah Ein Kerem Universitary Hospital, Jerusalem
THE DISEASE
DIAGNOSIS
MANAGEMENT
PATHOGENESIS
Pathophysiology is poorly understood
Many different etiologies

8. 8João Melo Alves, MD (Lisboa, Portugal) March 2015, GICU Hadassah Ein Kerem Universitary Hospital, Jerusalem
Global disturbance of cortical
function
EEG
Romano J, Engel GL. Arch Neurol Psych 1944; 51
Brainstem auditory evoked
potentials
Somatosensory evoked potentials
Neuroimaging
Trzepacz PT. Psychosomatics. 1994; 35(4)
THE DISEASE
DIAGNOSIS
MANAGEMENT
NEUROBIOLOGY OF ATTENTION
Ascending reticular activating
system (ARAS) – arousal and
attention
“Nondominant” parietal and
frontal lobes – attention
Higher order cortical function
– insight and judgement

9. 9João Melo Alves, MD (Lisboa, Portugal) March 2015, GICU Hadassah Ein Kerem Universitary Hospital, Jerusalem
Acetylcholine disturbance – a final common pathway?
Anticholinergic drugs (vs. cholinesterase inhibitors)
Medical conditions that decrease acetycholine synthesis
Alzheimer’s disease
Mach JR et al. J Am Geriatr Soc 1995; 43 (5)
Campbell N et al. Clin Interv Aging 2009; 4
Golinger RC et al. Am J Psychiatry 1987; 144 (9)
Other neurotransmitters
Pro-inflammatory cytokines
(…)
THE DISEASE
DIAGNOSIS
MANAGEMENT
NEUROBIOLOGY OF ATTENTION

10. 10João Melo Alves, MD (Lisboa, Portugal) March 2015, GICU Hadassah Ein Kerem Universitary Hospital, Jerusalem
Baseline vulnerability
Dementia
Stroke
Parkinson’s
Elie M et al. J Gen Intern Med 1998; 13 (3)
Fick DM et al. J Am Geriatr Soc 2002; 50(10)
THE DISEASE
DIAGNOSIS
MANAGEMENT
ETIOLOGY
Precipitants
Drugs and toxins
Infections
Metabolic derangements
Brain disorders
Systemic organ failure
Physical disorders
Immobility & restraints

11. 11

12. DIAGNOSIS
Ward rounds
by Robert Riggs, circa 1940
(Harvey Cushing/John Hay Whitney Medical Library, Yale University)

13. 13João Melo Alves, MD (Lisboa, Portugal) March 2015, GICU Hadassah Ein Kerem Universitary Hospital, Jerusalem
Critically ill patients with…
Disturbance of consciousness
Change in cognition
Acute onset, fluctuating course
(Agitation, sleep disturbances, emotional disturbances…)
THE DISEASE
DIAGNOSIS
MANAGEMENT
CLINICAL PRESENTATION

14. 14João Melo Alves, MD (Lisboa, Portugal) March 2015, GICU Hadassah Ein Kerem Universitary Hospital, Jerusalem
Classical medical approach is
limited on ICU patients
When in doubt…
Formal mental status testing
Specific validated tools
THE DISEASE
DIAGNOSIS
MANAGEMENT
RECOGNIZING THE DISORDER

15. 15

16. 16João Melo Alves, MD (Lisboa, Portugal) March 2015, GICU Hadassah Ein Kerem Universitary Hospital, Jerusalem
Confusion assessment method (CAM)
94-100% sensitivity, 90-95% specificity
Inouye SK et al. Ann Intern Med 1990; 113
Standard screening device in clinical studies
5’ to perform
Best of 11 bedside delirium dx tools
Wong CL et al. JAMA 2010; 304
CAM-ICU
Validated for mechanically ventilated patients
Ely EW et al. JAMA 2001; 286
Intensive Care Delirium Checklist for Screening
THE DISEASE
DIAGNOSIS
MANAGEMENT
ICU SCREENING TOOLS
MedCalc ©
Pascal Pfiffner, Mathias Tschopp

17. 17João Melo Alves, MD (Lisboa, Portugal) March 2015, GICU Hadassah Ein Kerem Universitary Hospital, Jerusalem
Targeted investigation
Fluid & electrolytes
Infections
Toxicity & withdrawal of drugs (abuse, BZD, SSRI, barbiturates, alcohol)
Metabolic derangements (glycemia, calcemia, uremia, liver, thyroid)
Low perfusion states
Inflammatory states
Hypercarbia and/or hypoxia
Seizures
Wernicke’s
Addison’s
CNS infection
Trauma
THE DISEASE
DIAGNOSIS
MANAGEMENT
INVESTIGATING THE CAUSE

18. 18João Melo Alves, MD (Lisboa, Portugal) March 2015, GICU Hadassah Ein Kerem Universitary Hospital, Jerusalem
Primary CNS problems
 Focal syndromes
• Language – Wernicke’s afasia
• Memory – TGA (bitemporal dysfunction)
• Vision – Anton’s syndrome of cortical blindness
• Bifrontal lesions – akinetic mutism, lack of spontaneity/judgement, loss of working
memory, blunted emotions
 Review of brain CTs for “altered mental status” in ICU pts (n=123): 21% positive, 9% new
diagnosis, 5% management change
Salemo D et al. J Intensive Care 2009; 24
 Lumbar puncture: delirium >> classic triad of meningites on old critically ill
• Mandatory when cause is not obvious
• Low treshold for delirious febrile pts (even with more obvious concurrent causes)
Nonconvulsive status epilepticus
 EEG in altered consciousness in critically ill (n=570) – 19% prevalence
Claassen J et al. Neurology 2004; 62
Dementia
Psychiatric disorders
THE DISEASE
DIAGNOSIS
MANAGEMENT
DIFFERENTIAL DIAGNOSIS AND WORKUP

19. MANAGEMENT
Extraction of the Stone of Folly,
by Hieronymus Bosch circa 1488 - 1516
(Rijks Museum, Amsterdam)

20. Why should
we care?

21. 21João Melo Alves, MD (Lisboa, Portugal) March 2015, GICU Hadassah Ein Kerem Universitary Hospital, Jerusalem
70% incidence on ICU patients
McNicoll L et al. J Am Geriatr Soc 2003; 51 (5)
Prolonged hospitalization
Higher mortality
Functional and cognitive decline
Higher risk for institucionalization
Robinson TN et al. Ann Surg 2009, 249(1)
Inouye SK et al. J Gen Intern Med 1998, 13(4)
McAvay GJ et al. J Am Geriatr Soc 2006, 54(8)
Witlox J et al. JAMA 2010, 304(4)
Fong TG et al. Ann Intern Med 2012, 156(12)
(…)
THE DISEASE
DIAGNOSIS
MANAGEMENT
THE PROBLEM

22. 22João Melo Alves, MD (Lisboa, Portugal) March 2015, GICU Hadassah Ein Kerem Universitary Hospital, Jerusalem
Duration of delirium (a modifiable factor) on mechanically ventilated ICU pts is
independently associated with long term cognitive impairment (unlike duration of
ventilation)
Girard TD et al. Crit Care Med 2010, 38(7)
Long-term cognitive impairment after critical illness (n=821)
 Medical and surgical ICU pts
 6% pts w baseline impairment, 74% new onset delirium in hospital,
• 3 months: 40% had cognitive scores 1.5 SD below population controls (= moderate TBI) and
26% 2 SD (= mild Alzheimer’s),
• 12 months: at 12m 34% and 24%
 Longer duration was independently associated with worse global cognition and executive function
 Sedatives and analgesics were not associated with cognitivr impairment
Pandharipande PP et al. NEJM 2013, 369 (14)
SR/MA, 17 trials (n=2849)
 effective interventions (drugs, multimodal, nonpharmacological) don’t improve short term
mortality (RR 0.90; 95% CI, 0.76-1.06; p = 0.19)
Al-Qadheeb NS et al. Crit Care Med 2014, 42(6)
THE DISEASE
DIAGNOSIS
MANAGEMENT
THE PROBLEM

23. 23João Melo Alves, MD (Lisboa, Portugal) March 2015, GICU Hadassah Ein Kerem Universitary Hospital, Jerusalem
Expert consensus
Observational studies
(few RCT)
SCCM guidelines (2013)
NICE guidelines (2010)
THE DISEASE
DIAGNOSIS
MANAGEMENT
MANAGEMENT

24. 24João Melo Alves, MD (Lisboa, Portugal) March 2015, GICU Hadassah Ein Kerem Universitary Hospital, Jerusalem
Principles
1. PREVENTION – avoiding risk factors
2. TREAT THE CAUSE – identifying and treating underlying acute illness
3. SYMPTOM MANAGEMENT – supportive care // low dose, short
acting pharmacological therapy PRN
THE DISEASE
DIAGNOSIS
MANAGEMENT
MANAGEMENT

25. 25João Melo Alves, MD (Lisboa, Portugal) March 2015, GICU Hadassah Ein Kerem Universitary Hospital, Jerusalem
Modifying risk factors
 Orientation protocols
 Cognitive stimulation
 Physiologic sleep
• Earplugs, RCT n=138
Van Rompaey B et al. Crit Care 2012, 16 (3)
 Early mobilization, avoiding restraints
• Early physical and occupational
therapy, RCT n=104
Schweickert WD et al. Lancet 2009, 373 (9678)
 Visual/hearing aids
 Monitor orders (e.g. bzd)
 Pain
• RCT n=58, 3 vs 31%
Hudetz JA et al. J Cardiothorac Vasc Anesth 2009, 23(5)
THE DISEASE
DIAGNOSIS
MANAGEMENT
1. PREVENTION
Intervention bundles
cognitive impairment, sleep
deprivation, immobility, visual
impairment, hearing impairment,
dehydration
 Prospective, n=872 (ward), 62 vs 90
episodes, 105 vs 161d
Inouye SK et al. NEJM 1999, 340(9)

26. 26João Melo Alves, MD (Lisboa, Portugal) March 2015, GICU Hadassah Ein Kerem Universitary Hospital, Jerusalem
Medications?
 Cholinesterase inhibitors
 Antipsychotics
• SR+MA, prophylatic neuroleptics post-operative (6 studies,
n=1689)
Hirota T, Kishi T. J Clin Psychiatry 2013, 74(12)
 Melatonin / ramelteon
 Analgesics
THE DISEASE
DIAGNOSIS
MANAGEMENT
1. PREVENTION

27. 27

28. 28João Melo Alves, MD (Lisboa, Portugal) March 2015, GICU Hadassah Ein Kerem Universitary Hospital, Jerusalem
Metabolic derangements
Infections
Systemic organ failure
Drugs and toxins
Brain disorders
Physical disorders
Immobility & restraints
THE DISEASE
DIAGNOSIS
MANAGEMENT
2. DIRECTED TREATMENT

29. 29João Melo Alves, MD (Lisboa, Portugal) March 2015, GICU Hadassah Ein Kerem Universitary Hospital, Jerusalem
Hyperactive delirium
 Less common in older patients
 Alternates with hypoactive delirium
 n=614 MICU pts
• 71.8% incidence 65+ yo
• Hyperactive 1.6% vs mixed 54.9% vs hypoactive 43.5%
Peterson JF et al. J Am Geriatr Soc 2006, 54(3)
 Falls, removal of catheters, acidental extubation (…)
Hypoactive delirium – no role for symptomatic treatment
Nonpharmacollogical interventions – the mainstay of therapy
Physical restrains as a last resort!
Cautious PRN trial of low dose, short acting drugs might be warranted
THE DISEASE
DIAGNOSIS
MANAGEMENT
3. SYMPTOMATIC TREATMENT

30. 30João Melo Alves, MD (Lisboa, Portugal) March 2015, GICU Hadassah Ein Kerem Universitary Hospital, Jerusalem
Severe agitation only!
Very limited data…
 SR 1980-2010, elderly patients with delirium – studies with severe methodological
limitations
Flaherty JH et al. J Am Geriatr Soc 2011, 59 suppl 2
 Multicenter RCT, n=101 ICU pts – no benefit nor risk (but feasible)
MIND placebo RCT. Girard TD et al. Crit Care Med 2010, 38(2)
THE DISEASE
DIAGNOSIS
MANAGEMENT
3. SYMPTOMATIC TREATMENT - DRUGS

31. 31João Melo Alves, MD (Lisboa, Portugal) March 2015, GICU Hadassah Ein Kerem Universitary Hospital, Jerusalem
Haloperidol
 Standard therapy
 Adverse effects: extrapyramidal; QT prolongation & TdP (++IV)
 0.5-1mg PRN PO/IV/IM (max 5mg qd); onset 30 min
Atypical antipsychotics – quetiapine, risperidone, ziprasidone, olanzapine
 Fewer side effects, similar efficacy
Benzodiazepines
 Role limited to sedative/alcohol withdrawal or 2nd line therapy
Carnes M et al. J Am Geriatr Soc 2003, 51(2)
 Lorazepam ∆20% RR in ICU pts
Pandharipande P et al. Anesthesiology 2006, 104(1)
 Midazolam 77% vs dexmedetomidine 54% in ICU mechanically ventilated pts
Riker RR et al. JAMA 2009, 301 (5)
Cholinesterase inhibitors
 Placebo RCT (n=104) stopped due to higher mortality (22 vs 8%)
Van Ejik MM et al. Lancet 2010, 376 (9755)
THE DISEASE
DIAGNOSIS
MANAGEMENT
3. SYMPTOMATIC TREATMENT - DRUGS

32. KEY MESSAGES
 Delirium is a disturbance of consciousness and cognition of acute onset and fluctuating course,
secondary to a medical condition, intoxication or side effect
 It is highly incident in the elderly sick, reaching 70% in the ICU
 Underlying brain disease increases the risk, but common causes can precitate delirium even in its
absence
 The recognition of its clinical presentation should prompt formal screening with validated bedside
tools (e.g. CAM-ICU) and targeted investigation for the underlying culprit
 The relevance of the entity lies on the association with bad outcomes, namely higher mortality and
long-term cognitive impairment, which can be prevented to an extent with the appropriate timely
measures
 There are available clinical guidelines, based on the limited evidence and expert consensus
 Management is based on prevention (risk factors), cause-directed treatment, and symptom
management
 Nonpharmacological interventions are the mainstay of symptom management, but antipsychotics
might be warranted on severe hyperactive delirium
 The pharmacological treatment relies on antipsychotics, mainly typical (e.g. haloperidol) but atypical
show promise with similar efficacy and better side effect profile

33. CORE REFERENCES
1. Barr J et al. Clinical practice guidelines for the management of pain, agitation and delirium in adult
patients in the intensive care unit. Crit Care Med 2013; 41(1):263
2. National Institute of Health and Care Excelence (NICE). Delirium: diagnosis, prevention and
management. NICE clinical guideline 103, July 2010. @ guidance.nice.org.uk/cg103
3. McNicoll et al. Delirium in the intensive care unit: ocurrence and clinical course in older patients. J Am
Geriatr Soc. 2003; 51(5):591
4. Ely EW, Inouye SK, Bernard GR, et al. Delirium in mechanically ventilated patients: validity and reliability
of the confusion assessment method for the intensive care unit (CAM-ICU). JAMA 2001; 286:2703
5. Pandharipande PP et al. Long-term cognitive impairment after critical illness. NEJM 2013;
369(14):1306
6. Francis J, Young GB. Diagnosis of delirium and confusional states. UpToDate, Jan 2015, version 14.0
7. Francis J. Delirium and acute confusional states: prevention, treatment and prognosis. UpToDate, Jan
2015, version 10.0