1. Delirium in the ICU
Alex Yartsev, 22/06/11

2. Symptoms associated with delirium
Disorientation
Hyper-arousal, agitation
Apathy and withdrawal
Incooperation / incomplete cooperation
Aggression
Hallucinations(visual > auditory), delusions
Altered sleep-wake cycle
Gleason OC (March 2003). "Delirium". Am Fam Physician 67 (5): 1027–34

3. Definition of delirium:
Chief features agreed upon
Classification varies depending on source
Gleason OC (March 2003). "Delirium". Am Fam Physician 67 (5): 1027–34

4. The psychiatrists’ definition: DSM-IV, revised 2002
Acute confusional state
Disturbance of consciousness (i.e., reduced clarity of awareness of the environment) with reduced ability to focus, sustain or shift attention
Change in cognition not better accounted for by a preexisting, established or evolving dementia
Develops over a short period of time, and fluctuates during the course of the day
the disturbance is caused by the direct physiological consequences of a general medical condition.
American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision. 2002

5. The WHO description (ICD-10), revised 1992
Disorder characterized by concurrent disturbances:
Impairment of consciousness and attention: Inability to direct it, focus, sustain or shift
Global disturbance of cognition: hallucinations, delusions, impairment of abstract thinking, delusions, incoherence, impairment of immediate recall, disorientation
Psychomotor disturbance: hypo or hyperactivity, enhanced startle
Disturbance of sleep-wake cycle: reduced or absent sleep, daytime drowsyness, symptoms worst at night
Emotional disturbance: depression, anxiety, fear, euphoria, or “wondering perplexity”
Rapid in onset, and course is diurnally fluctuating
“clinical picture is so characteristic that a fairly confident diagnosis of delirium can be made even if the underlying cause is not clearly established.”
The ICD-10 Classification of Mental and Behavioural Disorders; World Health Organization, Geneva, 1992

6. The classifications DSM- IV Intoxication delirium Withdrawal delirium
Delirium due to multiple aetiologies
“delirium not otherwise specified”
WHO ICD-10
Delirium NOT induced by intoxication
Delirium superimposed on dementia
Delirium NOT superimposed on dementia
“other delirium”
American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision. 2002

7. Oh’s Intensive Care manual, 6th edition, ch. 42
Differential explanations
Frustration - inability to communicate something
Pain – she was lying on top of a forgotten 10ml syringe
Dementia – this is what he is normally like at the nursing home
Psychosis – we accidentally stopped his risperidone and started an MAOI
Intoxication – APS team started ketamine
Withdrawal – he drinks
Delirium Tremens– he REALLY drinks
Encephalopathy– An alteration in the level or content of consciousness
due to a process extrinsic to the brain
(metabolic vs structural)
Oh’s Intensive Care manual, 6th edition, ch. 42

8. Oh’s Intensive Care manual, 6th edition, ch. 42
A moment for Encephalopathy
ICU DELIRIUM
…also…
Sepsis
Hepatic failure
Renal Failure
Hypoxia or hypercapnea
Hyper or hyponatremia
Hyper or hypoglycaemia
Hyper or hypothyroidism
Acidosis
Addisonian crisis…………………..many others
Oh’s Intensive Care manual, 6th edition, ch. 42

9. Oh’s Intensive Care manual, 6th edition, ch. 42
ICU Delirium
so, it’s the 5th-7th day of your admission.
Or you are the night reg and its your 5th - 7th night shift
You havent slept
Your circadian rhythm is disturbed
You are full of mind-altering drugs
You are constantly uncomfortable
Your environment is noisy
Your day is monotonous
Diagnosis of exclusion
Oh’s Intensive Care manual, 6th edition, ch. 42

10. Why is this a problem? Irritates the nurse and doctor
Staff may get attacked
Tubes and lines get dislodged - damage to the patient and to the budget
Total tissue oxygen consumption increases
Quality of monitoring is compromised
Duration of stay is increased
Extubation is delayed (bolusbolusbolus)
Higher incidence of nosocomial pneumonia (aspiration or otherwise)
GL Fraser, RR Riker The frequency and cost of patient-initiated device removal in the ICU, - Pharmacotherapy, 2001 vol 21 issue 1
Pun BT, et al The importance of diagnosing and managing ICU delirium Chest. 2007 Aug;132(2):
Pandharipande P, Delirium: acute cognitive dysfunction in the critically ill Curr Opin Crit Care. 2005 Aug;11(4):360-8.
Jacobi J, Fraser GL, Coursin DB, Riker RR, Fontaine D, Wittbrodt ET, Chalfin DB, Masica MF, Bjerke HS, Coplin WM. Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult.Crit Care Med 2002;30:119–141

11. How much of a problem is this?
Prevalence between 30% and 80%
Delirium is an independent predictor of
Increased mortality at 6 months (3.2 HR, hazard ratio)
Increased length of stay (HR 2.0)
In some studies, strongest independent determinant of length of stay
Equivalent to organ failure ! In comparison, ARF in ICU = HR 4.9
Weirdly, aggressive delirium has a better prognosis than “quiet” delirium
Increased cost of care:
In some studies, cost increased by 39% ICU costs, 31% higher total hospital costs
From medical device removal alone, 1997 annual cost to one American 42-bed ICU was $ 250,000 ( = $351,968 adjusted for inflation)
;GL Fraser, RR Riker The frequency and cost of patient-initiated device removal in the ICU, - Pharmacotherapy, 2001 vol 21 issue 1
Wesley Ely et al. Delirium as a Predictor of Mortality in Mechanically Ventilated Patients in the Intensive Care Unit JAMA. 2004;291(14):
Ely et. al, The impact of delirium in the intensive care unit on hospital length of stay. INTENSIVE CARE MEDICINE Volume 27, Number 12, 
Pandharipande P, Delirium: acute cognitive dysfunction in the critically ill Curr Opin Crit Care. 2005 Aug;11(4):360-8.
Jacobi J, Fraser GL, Coursin DB, Riker RR, Fontaine D, Wittbrodt ET, Chalfin DB, Masica MF, Bjerke HS, Coplin WM. Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult.Crit Care Med 2002;30:119–141
Milbrandt et.al, Costs associated with delirium in mechanically ventilated patients Critical Care Medicine: April Volume 32 - Issue 4 - pp

12. Risk factors for “ICU delirium”
Prolonged sedation
Prolonged ventilation
Severity of illness
Use of sedatives and
analgesics (benzos>opiates)
Age
Most studies don’t seem to differentiate
between causes of delirium.
Lin SM et al, Risk factors for the development of early-onset delirium and the subsequent clinical outcome in mechanically ventilated patients. J Crit Care. 2008 Sep;23(3): Epub 2007 Jan 31.
Ouimet S et. al. Incidence, risk factors and consequences of ICU delirium. Intensive Care Med. 2007 Jan;33(1): Epub 2006 Nov 11.

13. Risk factors for delirium
from any cause, in the ICU
Age over 65: OR 1.17
Lorazepam use: OR 1.2
Severity of illness: OR increases by per 5pt increment of APACHE-II
Morphine use: OR 1.58
Art line: OR 1.83
Hypertension: OR 1.88
Lives alone: OR 1.94
Smoking >10/day : OR 2.04
Underlying cognitive impairment: OR 2.18
Alcohol use: OR 2.03 – 3.23
No visible daylight: OR 2.39
Midazolam use: OR 2.75
Single ICU room: OR 2.89 (in comparison, open ICU bed = OR 1.43)
Sedation “used to induce coma”: OR 3.2
Nil By Mouth: OR 3.75
No visitors: OR 3.73
Indwelling catheter: OR 5.75
NG tube: OR 7.80
Endotracheal tube or tracheostomy: OR 8.07
Sedation of any sort: OR 13.77
Use of physical restraints: OR from to !!
Lin SM et al, Risk factors for the development of early-onset delirium and the subsequent clinical outcome in mechanically ventilated patients. J Crit Care. 2008 Sep;23(3): Epub 2007 Jan 31.
Ouimet S et. al. Incidence, risk factors and consequences of ICU delirium. Intensive Care Med. 2007 Jan;33(1): Epub 2006 Nov 11.
Pandharipande et al, Lorazepam Is an Independent Risk Factor for Transitioning to Delirium in Intensive Care Unit Patients Anesthesiology: January Volume Issue 1 - pp 21-26
Dubois, MJ, Bergeron, N, Dumont, M, et al Delirium in an intensive care unit: a study of risk factors. Intensive Care Med 2001;27,1297
Bart Van Rompaey et al Risk factors for delirium in intensive care patients: a prospective cohort study. Critical Care 2009, 13:R77

14. Assessment of delirium in the ICU
Several validated tools available:
Richmond Agitation-Sedation Scale (RASS)
Confusion Assessment Method in the ICU (CAM-ICU)
Intensive Care Delirium Screening Checklist  (ISCDS)
Jacobi et.al. (2002) – clinical practice guideline - recommends the use of the Confusion Assessment Method in the ICU (CAM-ICU)
2 minutes to complete.
requires some degree of cooperation (from staff and patients)
Jacobi J, Fraser GL, Coursin DB, Riker RR, Fontaine D, Wittbrodt ET, Chalfin DB, Masica MF, Bjerke HS, Coplin WM. Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult.Crit Care Med 2002;30:119–141

15. The CAM-ICU

16. The CAM-ICU

17. The ICDSC

18. Monitoring for delirium
Frequent reproducible assessment for pain and delirium
Jacobi et a. (2002, multidisciplinary task force)
recommend the use of a validated agitation/sedation measurement tool
Kress JP, Pohlman AS, O'Conner MF, et al. Daily interruption of sedation infusions in critically ill patients undergoing mechanical ventilation. N Engl J Med 2000; 342: 1471–7
Jacobi J, Fraser GL, Coursin DB, Riker RR, Fontaine D, Wittbrodt ET, Chalfin DB, Masica MF, Bjerke HS, Coplin WM. Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult.Crit Care Med 2002;30:119–141
Freedman NS et al., Patient perception of sleep quality and etiology of sleep disruption in the intensive care unit. Am J Resp Crit Care Med 1999;159: 1155–1162
Shehabi Y, Sedation and delirium in the intensive care unit: an Australian and New Zealand perspective. Botha JA, Boyle MS, Ernest D, Freebairn RC, Jenkins IR, Roberts BL, Seppelt IM. Anaesth Intensive Care Jul;36(4):570-8.
Chlan L: Effectiveness of a music therapy intervention on relaxation and anxiety for patients receiving ventilatory assistance. Heart Lung 1998;27:169–176. 

19. Delirium in the Australian ICU
According to a 2008 survey, only 9% of all Australian units use any sort of delirium scale.
In a snapshot survey, midazolam and propofol were the most frequently used sedatives
Delirium was found in 21% of assessable patients.
Jacobi J, Fraser GL, Coursin DB, Riker RR, Fontaine D, Wittbrodt ET, Chalfin DB, Masica MF, Bjerke HS, Coplin WM. Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult.Crit Care Med 2002;30:119–141
Shehabi Y, Sedation and delirium in the intensive care unit: an Australian and New Zealand perspective. Botha JA, Boyle MS, Ernest D, Freebairn RC, Jenkins IR, Roberts BL, Seppelt IM. Anaesth Intensive Care Jul;36(4):570-8.

20. Just calm down, Sir. You are in hospital.
MANAGEMENT OF ICU DELIRIUM:
Preventative vs. reactive
Non-pharmacological vs pharmacological

21. Prevention of ICU delirium
Mostly non-pharmacological measures
Mostly involving changes in the behaviour of the nurse and the intensivist, not the patient.
Mostly financially inexpensive
Mostly requiring greater effort than ad-hoc pharmacological interventions . 

22. Sedation holidays Sedation Holidays
2000 study by Kress: landmark paper; 128 pts;
length of stay reduced from 9.9 to 6.6 days
9 vs 16 pts needed delirium workup
According to a 2008 survey, only 30% of Australian units use sedation holidays
According to the same survey, in a snapshot of 23 level III ICUs only 10% of patients have had the sedation turned off in the preceding 12 hr period
Kress JP, Pohlman AS, O'Conner MF, et al. Daily interruption of sedation infusions in critically ill patients undergoing mechanical ventilation. N Engl J Med 2000; 342: 1471–7
Shehabi Y, Sedation and delirium in the intensive care unit: an Australian and New Zealand perspective. Botha JA, Boyle MS, Ernest D, Freebairn RC, Jenkins IR, Roberts BL, Seppelt IM. Anaesth Intensive Care Jul;36(4):570-8. . 

23. Quiet environment
EPA recommends a noise level below 45 dB during the day and 35dB at night
ICUs have a mean 84 dB
Patient survey: 203 survivors report nursing conversation and monitor alarms as the most irritating source of noise
noise levels in ICU have remained essentially unchanged despite advances in unit design
Seems as if white noise is preferred to intermittent noises
Kahn DM, Cook TE, Carlisle CC, et al: Identification and modifi cation of environmental noise in an ICU setting. Chest 114:535–540,199
Freedman NS et al., Patient perception of sleep quality and etiology of sleep disruption in the intensive care unit. Am J Resp Crit Care Med 1999;159: 1155–1162
Christensen, 2007: Noise levels in a general intensive care unit: a descriptive study Nursing in Critical Care Volume 12, Issue 4, pages 188–197,

24. Music
Chlan (1998)- statistically significant fall in blood pressure in ICU patients exposed to music picked by their families.
Decreases postoperative confusion outside the ICU in ortho geries patients
No studies of music as preventative or curative of delirium in ICU population
Most published work is an authors’ opinion. No trials.
Chlan L: Effectiveness of a music therapy intervention on relaxation and anxiety for patients receiving ventilatory assistance. Heart Lung 1998;27:169–176.
Ruth M. et al, The effect of music listening on acute confusion and delirium in elders undergoing elective hip and knee surgery. J Clin Nurs. 2004 Sep;13(6B):91-6.
Guzzetta CE: Effects of relaxation and music therapy on patients in a coronary care unit with presumptive acute myocardial infarction.
Heart Lung 18(6):609–616, 1989
Byers JF, Smyth KA: Effect of a music intervention on noise annoyance, heart rate, and blood pressure in cardiac surgery patients. Am
J Crit Care 6:183–191, 199

25. Diurnal rhythm, a good sleep
As part of a multicomponent strategy, nonpharmacological sleep pattern maintenance decreased incidence of delirium in elderly hospitalized patients
from 15.5 to 9.9%
Influence of sleep on delirium is not well studies in the ICU population
ICU patients on average sleep ~ 2 hrs per day (as per polysomnography), but we tend to think that they sleep more.
Propofol coma is not sleep for the purpose of rest.
Rong-Fang Hu et al, Non-pharmacological interventions for sleep promotion in the intensive care unit. Cochrane database.
(protocol in progress)
Gerald L Weinhous et al., Bench-to-bedside review: Delirium in ICU patients – importance of sleep deprivation Critical Care 2009, 13:234
Inouye SK, Bogardus ST Jr, Charpentier PA, Leo-Summers L: A multicomponent intervention to prevent delirium in hospitalized older patients.
N Engl J Med 1999, 340:
Ely EW, Inouye SK, Bernanrd GR et al. Delirium in mechanically ventilated patients: validity and reliability of the confusion assessment method for the intensive care unit (CAM-ICU). J Am Med Assoc 2001; 286:
Mundigler G, Delle-Karth G, Koreny M, et al: Impaired circadian rhythm of melatonin secretion in sedated critically ill patients with severe sepsis. Crit Care Med 30:536–540, 2002
Edwards GB, Schuring LM: Pilot study: Validating staff nurses’ observations of sleep and wake states among critically ill patients using polysomnography. Am J Crit Care 2:125–131, 1993

26. Increased family presence
OR of delirium in unvisited patients is 3 times greater
in one particular study which measured this.
No good scientific reason to restrict visitor presence
Presently, no solid evidence of benefit either.
Tullman DF, Dracup K: Creating a healing environment for elders. AACN Clin Issues 11(1):34–50, 2000
Bart Van Rompaey et al Risk factors for delirium in intensive care patients: a prospective cohort study. Critical Care 2009, 13:R77

27. Increased medical presence
Does a daily visit from a geriatrician prevent delirium?
Marcantonio (2001) – orthopedic geries patients
Daily geriatrician review vs. management by the ortho team
….. The geriatrician was limited by study protocol to only making five
recommendations per visit.
Areas of recommendation were of the following nature:
maintain CNS oxygen delivery
Treat severe pain
Eliminate unnecessary medications
Appropriate environmental stimuli
Bladder/bowel control
CAM measurements were performed.
Yes it does. NNT = 6. OR 0.48.
Marcantonio ER, Flacker JM, Wright RJ, Resnick NM. Reducing delirium after hip fracture: a randomized trial. Journal-of-the-American-Geriatrics-Society2001;49(5):516-22

28. Thiamine well established role in prevention of
Wernicke’s encephalopathy
- effect of thiamine deficinecy on astrocytes
- change in glutamate uptake results in excitotoxicity
- early stages are reversible
Non-specific delirium?
Kress JP, Pohlman AS, O'Conner MF, et al. Daily interruption of sedation infusions in critically ill patients undergoing mechanical ventilation. N Engl J Med 2000; 342: 1471–7
Jacobi J, Fraser GL, Coursin DB, Riker RR, Fontaine D, Wittbrodt ET, Chalfin DB, Masica MF, Bjerke HS, Coplin WM. Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult.Crit Care Med 2002;30:119–141
Freedman NS et al., Patient perception of sleep quality and etiology of sleep disruption in the intensive care unit. Am J Resp Crit Care Med 1999;159: 1155–1162
Shehabi Y, Sedation and delirium in the intensive care unit: an Australian and New Zealand perspective. Botha JA, Boyle MS, Ernest D, Freebairn RC, Jenkins IR, Roberts BL, Seppelt IM. Anaesth Intensive Care Jul;36(4):570-8.
Chlan L: Effectiveness of a music therapy intervention on relaxation and anxiety for patients receiving ventilatory assistance. Heart Lung 1998;27:169–176. 

29. Pharmacological prophylaxis for Prevention of ICU delirium:
Siddiqi et al. (2009): Cochrane meta-analysis
Interventions for preventing delirium in hospitalised patients
Salient findings:
Aizawa (2002): post-op geries in ICU. “delirium-free protocol”
Control sleep cycle with diazepam and pethidine. OR of delirium = 0.10.
But, no difference in length of admission.
Bergren (1987): halothane vs epidural for #NOF geries. No difference in delirium.
Diaz (2001): citicoline (nootrope) vs placebo for post-op geries. No difference.
Kalisvaart (2005): haloperidol prophylactically, ortho geries. No difference.
Liptzin (2005): donepezil(Ach-ase inhibitor), post op geries. No difference. . 
Siddiqi N, Holt R, Britton AM, Holmes J. Interventions for preventing delirium in hospitalised patients. Cochrane Database of Systematic Reviews 2007, Issue 2. Art. No.: CD

30. The path less travelled
CORRECT MAGNESIUM.
63 pts, 2009 RCT by Esen et al.: target ,
in addition to remi + midaz:
Of the delirious pts, the magnesium group had fewer days of delirium (55% vs 89%) and needed less sedation
Desired RASS score was reached at a lower dose,
and maintained for longer.
That is the only such study
Previously, magnesium has also been used in the treatment of delirium tremens – subsequently falling out of favour
Esen F et. al. Effect of magnesium on the incidence of delirium occurrence in the ICU Critical Care 2009 vol 13 supp 1P412
Beroz et al, PARENTERAL MAGNESIUM IN THE PROPHYLAXIS AND TREATMENT OF DELIRIUM TREMENS Am J Psychiatry 118: , May 1962
Jermain DM; Controversies over the use of magnesium sulfate in delirium tremens. Ann Pharmacother. 1992 May;26(5):650-2. b

31. Pharmacological Arsenal
Benzodiazepines
Opiates
Classical antipsychotics
Atypical antipsychotics
Cholinergic drugs
Dexmedetomidine / clonidine

32. Choice of chemical restraints
Cochrane contributions:
- Benzodiazepines for delirium
Antipsychotics for delirium
Cholinesterase inhibitors for delirium
Jacobi J, Fraser GL, Coursin DB, Riker RR, Fontaine D, Wittbrodt ET, Chalfin DB, Masica MF, Bjerke HS, Coplin WM. Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult.Crit Care Med 2002;30:119–141
Lonergan et.al., Benzodiazepines for delirium. Cochrane Database of Systematic Reviews 2009, Issue 4
Lonergan E, Britton AM, Luxenberg J. Antipsychotics for delirium. Cochrane Database of Systematic Reviews 2007, Issue 2.
Milbrandt et.al. Haloperidol use is associated with lower hospital mortality in mechanically ventilated patients. Crit Care Med. 2005 Jan;33(1):226-9; discussion

33. Benzodiazepines Cochrane:
only one trial fit their criteria, lorazepam vs. dexmedetomidine.
Authors conclusion: dex is better.
Recommendations: no evidence to support use of benzodiazepines outside of alcohol or benzo withdrawal-related delirium
In all other settings, benzodiazepines are found to be either ineffective
or harmful (i.e. increase incidence of delirium)
Jacobi J, Fraser GL, Coursin DB, Riker RR, Fontaine D, Wittbrodt ET, Chalfin DB, Masica MF, Bjerke HS, Coplin WM. Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult.Crit Care Med 2002;30:119–141
Lonergan et.al., Benzodiazepines for delirium. Cochrane Database of Systematic Reviews 2009, Issue 4

34. Opioids Consensus is that they contribute more to generate delirium.
Limited role for delirium in general
Specific aetiologies:
delirium due to opioid withdrawal (controversial)
delirium due to severe pain
Jacobi J, Fraser GL, Coursin DB, Riker RR, Fontaine D, Wittbrodt ET, Chalfin DB, Masica MF, Bjerke HS, Coplin WM. Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult.Crit Care Med 2002;30:119–141
Paintal et al, Management of Alcohol, Sedative-Hypnotic, and Opioid Withdrawal in the ICU PCCSU Article | .

35. Antipsychotics ? Is the patient actually psychotic? Nevermind.
There are so many! Which one?
Typical vs atypical
Which specific one to use?
Are there situations which might
favour one over another?
Jacobi J, Fraser GL, Coursin DB, Riker RR, Fontaine D, Wittbrodt ET, Chalfin DB, Masica MF, Bjerke HS, Coplin WM. Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult.Crit Care Med 2002;30:119–141
Lonergan E, Britton AM, Luxenberg J. Antipsychotics for delirium. Cochrane Database of Systematic Reviews 2009, Issue 2.
Milbrandt et.al. Haloperidol use is associated with lower hospital mortality in mechanically ventilated patients. Crit Care Med. 2005 Jan;33(1):226-9; discussion

36. Classical antipsychotics:
Haloperidol
Jacobi et al (2002) clinical practice guidelines recommend Haloperidol
(level C data, small studies and case report series)
Cochrane library agrees to some extent:
Lonergan et.al. (2007) compared haloperidol with risperidone and olanzapine
Conclusion: haloperidol is better than placebo, but…
- no better then atypical antipsychotics at low doses
- still no better but with more side effects at high doses
Jacobi J, Fraser GL, Coursin DB, Riker RR, Fontaine D, Wittbrodt ET, Chalfin DB, Masica MF, Bjerke HS, Coplin WM. Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult.Crit Care Med 2002;30:119–141
Lonergan et.al., Benzodiazepines for delirium. Cochrane Database of Systematic Reviews 2009, Issue 4
Lonergan E, Britton AM, Luxenberg J. Antipsychotics for delirium. Cochrane Database of Systematic Reviews 2007, Issue 2.
Milbrandt et.al. Haloperidol use is associated with lower hospital mortality in mechanically ventilated patients. Crit Care Med. 2005 Jan;33(1):226-9; discussion

37. Classical antipsychotics:
Chlorpromazine
one double blind trial comparing it to lorazepam and haloperidol.
Not in an ICU setting (hospitalized AIDS patients)
- No treatment effect difference between haloperidol and chlorpromazine, but both were equally better than lorazepam.
Concern re. anticholinergic side effects.
Jacobi J, Fraser GL, Coursin DB, Riker RR, Fontaine D, Wittbrodt ET, Chalfin DB, Masica MF, Bjerke HS, Coplin WM. Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult.Crit Care Med 2002;30:119–141
Lonergan E, Britton AM, Luxenberg J. Antipsychotics for delirium. Cochrane Database of Systematic Reviews 2007, Issue 2.
Breitbart et al, A Double-Blind Trial of Haloperidol, Chlorpromazine, and Lorazepam in the Treatment of Delirium in Hospitalized AIDS Patients American Journal of Psychiatry 1996; 153:231–237

38. Atypical antipsychotics:
Olanzapine
Quetiapine
Risperidone
Aripiprazole
Amisulpride
Clozapine
Which is best?
Jacobi J, Fraser GL, Coursin DB, Riker RR, Fontaine D, Wittbrodt ET, Chalfin DB, Masica MF, Bjerke HS, Coplin WM. Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult.Crit Care Med 2002;30:119–141
Lonergan et.al., Benzodiazepines for delirium. Cochrane Database of Systematic Reviews 2009, Issue 4
Lonergan E, Britton AM, Luxenberg J. Antipsychotics for delirium. Cochrane Database of Systematic Reviews 2007, Issue 2.
Milbrandt et.al. Haloperidol use is associated with lower hospital mortality in mechanically ventilated patients. Crit Care Med. 2005 Jan;33(1):226-9; discussion

39. Has anyone compared these drugs?
…yes, but rarely, and on a small scale.
Kim et al (2010): risperidone vs olanzapine for delirium
32 SUBJECTS ONLY. Median age 70.
No significant difference in response in the under-70 age group
Olanzapine response was better in the over-70 age group
Devlin et al: amisulpride vs quetiapine for delirium
No significant difference
Kim et al, Risperidone versus olanzapine for the treatment of delirium. Hum Psychopharmacol. 2010 Jun;25(4):
Devlin JW et al: Efficacy and safety of quetiapine in critically ill patients with delirium: A prospective, multicenter, randomized, double-blind, placebo-controlled pilot study. Crit Care Med 38: , 2010
Lonergan E, Britton AM, Luxenberg J. Antipsychotics for delirium. Cochrane Database of Systematic Reviews 2007, Issue 2.
Lee et al, Amisulpride versus quetiapine for the treatment of delirium: a randomized, open prospective study International Clinical Psychopharmacology:
November Volume 20 - Issue 6 - pp

40. Non-comparison studies
Devlin et al (2010): quetiapine vs placebo in ICU delirium
Doing something was 50% better than doing nothing.
40% vs 90% delirium resolution by 3rd day of treatment.
Straker et al (2006): aripiprazole vs placebo in general delirium
Suggests it may be a better choice than others because of minimal QTc effect
Lonergan et al (2009):
Cochrane review of antipsychotics in delirium
Insufficient data to differentiate between atypicals
Kim et al, Risperidone versus olanzapine for the treatment of delirium. Hum Psychopharmacol. 2010 Jun;25(4):
Devlin JW et al: Efficacy and safety of quetiapine in critically ill patients with delirium: A prospective, multicenter, randomized, double-blind, placebo-controlled pilot study. Crit Care Med 38: , 2010
Lonergan E, Britton AM, Luxenberg J. Antipsychotics for delirium. Cochrane Database of Systematic Reviews 2007, Issue 2.
Straker et al. Aripiprazole in the Treatment of Delirium Psychosomatics 47: , September-October 2006 .

41. Clonidine No broad studies of clonidine in delirium.
Formerly, popular for delirium tremens and opioid withdrawal
Rubino et al (2010) – cardiothoracic ICU patients post aortic dissection repair
30 pts, clonidine infusion vs placebo
clonidine group weaned from ventilator faster, had lower delirium scores
Verner et al (1990) – post Ivor Lewis patients from German ICUs
…all of who were withdrawing from alcohol
clonidine group had fewer “psychovegetative” symptoms
Jacobi J, Fraser GL, Coursin DB, Riker RR, Fontaine D, Wittbrodt ET, Chalfin DB, Masica MF, Bjerke HS, Coplin WM. Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult.Crit Care Med 2002;30:119–141
Rubino et al. Impact of clonidine administration on delirium and related respiratory weaning after surgical correction of acute type-A aortic dissection: results of a pilot study. Interact CardioVasc Thorac Surg 2010;10:58-62
Verner et al, Clonidine supplemented analgesia and sedation in prevention of postoperative delirium Anasth Intensivther Notfallmed. 1990 Aug;25(4):
Gold et al, CLONIDINE BLOCKS ACUTE OPIATE-WITHDRAWAL SYMPTOMS The Lancet, Volume 312, Issue 8090, Pages , 16 September 1978

42. Dexmedetomidine
More to minimize development of delirium than relieve its symptoms?
Dex plus propofol? Ruokonen et al (2009): 87 pts;
adding Dex has no effect on length of stay, but decreases length of ventilation.
Dex vs Midazolam? Riker et al (2009): 375 pts;
prevalence of delirium 54%(dex) vs 76% (midaz), also faster extubation
Dex vs lorazepam? Pandharipande et al (2007): 106 pts;
Dex group: median 7 days without delirium, vs 3 for lorazepam
Dex vs haloperidol? Reade et.al (2009)
20 pts in whom extubation was impossible because of delirium:
= dex reduced mean time to extubation from 42 hrs to 20 hrs
…haloperidol was given as an infusion (?)
Mirski et al, Cognitive improvement during continuous sedation in critically ill, awake and responsive patients: The Acute Neurological ICU Sedation Trial (ANIST) Intensive Care Medicine 2010 vol 36 issue
Ruokonen et alDexmedetomidine versus propofol/midazolam for long-term sedation during mechanical ventilation.  Intensive Care Medicine vol 35 issue
Riker RR, et al Dexmedetomidine vs midazolam for sedation of critically ill patients: a randomized trial. JAMA : the journal of the American Medical Association Feb 301 issue 5
Jacobi J, Fraser GL, Coursin DB, Riker RR, Fontaine D, Wittbrodt ET, Chalfin DB, Masica MF, Bjerke HS, Coplin WM. Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult.Crit Care Med 2002;30:119–141
Pandharipande et al, Effect of Sedation With Dexmedetomidine vs Lorazepam on Acute Brain Dysfunction in Mechanically Ventilated Patients- The MENDS Randomized Controlled Trial. JAMA. 2007;298(22):
Reade et al., Dexmedetomidine vs. haloperidol in delirious, agitated, intubated patients: a randomised open-label trial Critical Care 2009, 13:R75

43. Acetylcholinesterase inhibitors
Cochrane dementia and cognitive
improvement group: found lots of
poor quality published work on
Donepezil
Galantamine
Rivastigmine
Tacrine
Only one trial met quailty criteria,
the already mentioned Liptzin (2005)
( donepezil not useful in preventing post-op delirium)
Conclusion: cant recommend them.
The exception:
Physostigmine has a defined role to play in the narrow context of
delirium due to anticholinergic poisoning
Overshott R, Karim S, Burns A. Cholinesterase inhibitors for delirium. Cochrane Database of Systematic Reviews 2008, Issue 1
Duvoisin et al, Reversal of Central Anticholinergic Syndrome in Man by Physostigmine. JAMA. 1968;206(9):
Burns et al. A comparison of physostigmine and benzodiazepines for the treatment of anticholinergic poisoning Annals of Emergency Medicine Volume 35, Issue 4 , Pages , April 2000 .

44. Physical restraints NOT IDEAL.
Increases the risk of PTSD, tissue injury, pressure areas. Inhumane.
Increases risk of delirium!...
Consensus: use the least restrictive therapy available.
ACCCM task force ( ) recommends use of restrains be reviewed every 24 hours
LY Chang, KWK Wang… Influence of physical restraint on unplanned extubation of adult intensive care patients: a case-control study - American Journal of Critical Care, 2008 – AACN 2008;17:  
George J. Annas, J.D., M.P.H. The Last Resort — The Use of Physical Restraints in Medical Emergencies N Engl J Med 1999; 341:
Jones C, Backman C, Capuzzo M, Flaatten H, Rylander C, Griffiths RD. (2007) Precipitants of post-traumatic stress disorder following intensive care: a hypothesis generating study of diversity in care. Intensive Care Med;33:978-85
Macciolli et.al, Clinical practice guidelines for the maintenance of patient physical safety in the intensive care unit: Use of restraining therapies—American College of Critical Care Medicine Task Force 2001–2002 Crit Care Med 2003 Vol. 31, No. 11
Carrion MI, Ayuso D, Marcos M, et al: Accidental removal of endotracheal and nasogastric tubes and intravascular catheters. Crit Care Med 2000; 28:63– 66
Tominaga GT, Rduzwick H, Scannell G, et al: Decreasing unplanned extubations in the surgical intensive care unit. Am J Surg 1995; 170:586 –590
Girard et. al, Risk factors for post-traumatic stress disorder symptoms following critical illness requiring mechanical ventilation: a prospective cohort study Crit Care. 2007;11(1):R28.
Minnick A, Leipzig RM, Johnson ME: Elderly patients’ reports of physical restraints experiences in intensive care units. Am J Crit Care 2001; 10:168 –171

45. An argument for safe restraints
Tominaga et.al (1995) – no restraints = significant increase in self-extubations
Carrion et al (2000) – hand restraints = significantly reduced self-extubations
LY Chang, KWK Wang… Influence of physical restraint on unplanned extubation of adult intensive care patients: a case-control study - American Journal of Critical Care, 2008 – AACN 2008;17:  
George J. Annas, J.D., M.P.H. The Last Resort — The Use of Physical Restraints in Medical Emergencies N Engl J Med 1999; 341:
Jones C, Backman C, Capuzzo M, Flaatten H, Rylander C, Griffiths RD. (2007) Precipitants of post-traumatic stress disorder following intensive care: a hypothesis generating study of diversity in care. Intensive Care Med;33:978-85
Macciolli et.al, Clinical practice guidelines for the maintenance of patient physical safety in the intensive care unit: Use of restraining therapies—American College of Critical Care Medicine Task Force 2001–2002 Crit Care Med 2003 Vol. 31, No. 11
Carrion MI, Ayuso D, Marcos M, et al: Accidental removal of endotracheal and nasogastric tubes and intravascular catheters. Crit Care Med 2000; 28:63– 66
Tominaga GT, Rduzwick H, Scannell G, et al: Decreasing unplanned extubations in the surgical intensive care unit. Am J Surg 1995; 170:586 –590
Girard et. al, Risk factors for post-traumatic stress disorder symptoms following critical illness requiring mechanical ventilation: a prospective cohort study Crit Care. 2007;11(1):R28.
Maccioli et al, Clinical practice guidelines for the maintenance of patient physical safety in the intensive care unit: Use of restraining therapies—American College of Critical Care Medicine Task Force 2001–2002 Crit Care Med 2003 Vol. 31, No. 1

46. Question and answer time.