1. Delirium: How ER Physicians Can Impact Course
Emergency Medicine Palliative Care Series
Alan Bates, MD, PhD, FRCPC
Provincial Practice Leader for Psychiatry
BC Cancer Agency

2. In 1959…
Engel and Romano
“…while most physicians have a strong bias toward an organic etiology of mental disturbances, … they seem to have little interest in … the one mental disorder presently known to be based on derangement of cerebral metabolism.”
“… deficiencies in the education of many physicians ill equip them to recognize any but the most flagrant examples of delirium…”

3. In 1959… Engel and Romano continued
“Only … a management problem on a medical or surgical service is likely to result in a psychiatric consultation.”
“[The psychiatrist] … seeing the patient in the home territory of the “organic” specialists … is less likely or able to pursue an understanding of the underlying physiologic derangements, which are generally conceived to be the proper domain of the internist.”

4. In 1959… Engel and Romano continued
“Unhappily, the unfortunate patient’s malfunctioning brain rests in limbo, an object of attention and interest neither to the medical man nor to the psychiatrist.”
“Not only does the presence of delirium often complicate and render more difficult the treatment of a serious illness, but also it carries the serious possibility of permanent irreversible brain damage.”

5. In 1959… Engel and Romano continued
“With increasing life expectancy … we are now beginning to see an increasing incidence of so-called senile and arteriosclerotic dementias.”
“The physician who is greatly concerned to protect the functional integrity of the heart, liver, and kidneys … has not yet learned to have similar regard for the functional integrity of the brain.”

6. From Cresswell III et al.
Organic
Functional
Age
< 12 or > 40 years old
12 – 40 years old
Onset
Sudden
Gradual
Consciousness
Decreased
Normal
Hallucinations
Visual
Auditory
Course
Fluctuates
Continuous
Orientation
Disoriented
Scattered thoughts
Vitals
Abnormal
Psych Hx No
Yes

7. DSM-5 Criteria Disturbance in attention and awareness
Develops over short time, change from baseline, fluctuates in severity over course of a day
An additional cognitive disturbance (e.g. memory, orientation, language, visuospatial, perception)
Not another neurocognitive disorder, not coma
Direct consequence of another medical condition

8. Meagher et al., 2007 100 palliative care patients
Attention – 97% (e.g. distractibility, digit span)
Sleep-wake cycle – 97% (?cause of fluctuation, early)
Long-term memory – 89%
Short-term memory – 88%
Orientation – 76% (misses ¼)
Visuospatial ability – 87%
Motor agitation – 62% (early)
Motor retardation – 62% (early)
Language – 57%
Perceptual – 50% (motor agitation = retardation)

9. Incidence
Hospitalized elderly patients – 25% (van Blanken et al., 2005)
ICU – 70% at some point (McNicoll et al., 2003)
30% of critically ill children (Smith et al., 2013)
Post-operative delirium in patients over 60 after cardiac surgery – 52% (Rudolph et al., 2009)
Terminal illness – 88% (Massie etl al., 1983; Lawlor et al., 2000)

10. Incidence and detection - ER
Elie et al., 2000
10% of 447 ER patients over 65 delirious
Detection by ED physician
Sensitivity: 35%, Specificity: 99%
Han et al., 2014
12% of 406 ER patients over 65 delirious
Detection by ED physician using CAM-ICU
Sensitivity: 72% (better than RAs)
Specificity: 99%
CC of “altered mental status”: 38% sensitivity, 99% specificity (when not coma, non-verbal etc.)

12. Impact (reviewed by Maldonado et al., 2009)
Clear immediate increase in suffering of patient and family
Increased morbidity and mortality
Prolonged hospital stays
Increased cost of care
Increased hospital-acquired complications
Poor functional and cognitive recovery
Decreased quality of life
Increased placement in intermediate- and long-term care facilities

13. Impact – ER specific Han et al., 2010 / 2011
628 ER patients over age 65
17% delirious
6-month mortality:
37% in delirious group
14% in non-delirious group
Median length of stay:
2 days for delirious
1 day for non-delirious

14. Distress
Rate of diagnosable PTSD was 9.2% at 3 months post-ICU in 238 post-ventilated patients with a strong association between PTSD and recall of delusional memories (Jones et al., 2007)
Delirium is even more distressing for spouses than for patients (Breitbart et al., 2002)

15. Milbrandt et al., 2004
224 consecutive mechanically ventilated ICU patients (after excluding 51 with coma leading to death)
82% developed delirium, mean duration 2 days

16. Barrough, 1601
“It commeth to passe also that the soporiferous diseases being ended, there ensueth forgetfulnesse: which when it chanceth then a cold distempure is the cause that the memorie is perished or grievously hurt.”

17. Witlox et al., 2010 Meta-analysis of elderly patients with delirium
Delirium associated with increased risk of death (38% vs. 28% in controls at average follow-up of 23 months)
Delirium associated with increased risk of institutionalization (33% vs. 11% in controls at average follow-up of 15 months)
Delirium associated with increased risk of dementia (63% vs. 8% in controls at average follow-up of 4 years)
Above results are independent of age, sex, comorbid illness, illness severity, and baseline dementia

18. Risk factors Infection Withdrawal Acute metabolic Trauma
CNS (structural)
Hypoxia
Deficiency of vitamins
Endocrine
Acute vascular
Toxins/Medications (Lexicomp is your friend)
Heavy metals

19. Deleriogenic Medications
Anticholinergic
e.g. diphenhydramine, hydroxyzine, atropine, amitriptyline, imipramine, paroxetine, doxepin, furosemide, prochlorperazine
Benzodiazepines
Barbiturates
Opiates
Especially meperidine
? Morphine > Hydromorphone > Oxycodone (rotation can help)
Incontinence meds
e.g. oxybutynin
Cardiac meds
e.g. digitalis, quinidine, procainamide, lidocaine, beta-blockers
GI meds
H2-blockers (e.g. cimetidine, ranitidine), PPIs, metoclopramide
Many others: e.g. phenytoin, steroids

20. Sockalingam et al. 2005

21. van der Mast et al., 1996
“Of all the reported differences in the studies, only year of publication is significantly related to the incidence of delirium after cardiac surgery, the later publications showing a tendency towards a lower incidence.”
“… a cautious conclusion may be drawn that no strong risk factor has been identified…”

22. Pathophysiology: Neurotransmitters (Reviewed by Trzepacz, 1994)
Acetylcholine
Anticholinergic drugs induce delirium
Correlation between poor cognitive function and serum anticholinergic level
Serum anticholinergic levels decrease as delirium resolves
Reversal of anticholinergic delirium with physostigmine

23. Pathophysiology: Neurotransmitters (Reviewed by Trzepacz, 1994)
Dopamine
Effective treatment with dopamine receptor blockers like loxapine or haloperidol
Norepinephrine
Glutamate
Serotonin
GABA
Histamine

24. Pathophysiology (Maldonado, 2008)

25. Pathophysiology

26. Wrist actigraphy
Osse et al. (2009): motor activity at the wrist over five 24hr cycles after elective cardiac surgery

27. Definitive treatment:
Find the underlying cause or causes and treat it/them

28. Non-pharmacological interventions (Inouye et al., 1999)
In a study of 852 elderly patients admitted to a general medical service, Inouye et al. reduced the incidence of delirium from 15% to 9% with a number of non-pharmacological interventions including promotion of sleep with sleep inducing stimuli (e.g. relaxation tapes, warm milk) and a sleep promoting environment (e.g. through noise reduction)

29. Patel et al., 2014
Screened for ICU delirium before (n=167) and after (n=171) implementing measures to promote sleep
Noise and light reduction at night, minimize care that interrupts sleep at night, reduce daytime sedation when possible, address pain early, early mobilization
Found reduced incidence (14% vs. 33%) and duration (1.2 vs. 3.4 days) of delirium

30. Melatonin
Al-Aama et al. (2011) demonstrated decreased incidence of delirium in older adult patients on a general medicine unit who received 0.5mg of melatonin nightly
Evidence that melatonin could actually aid in treating ongoing delirium is mostly limited to case studies (e.g. Hanania and Kitain, 2002)
Other findings suggest melatonin isn’t helpful (e.g. Ibrahim et al., 2006)

31. Haloperidol Standard treatment in most places
Relatively little anticholinergic effect
Little effect on orthostatic hypotension
Less sedation good for hypoactive delirium
Risk of QT prolongation
Relatively high risk of extrapyramidal effects
No difference between IV and PO
Menza et al. (1987) and Maldonado (2000) both seriously flawed
Are reports of EPS with IV (Blitzstein & Brandt, 1997)
Small doses (e.g. 0.5mg IV BID or 1mg IV QHS)

32. Methotrimeprazine Also sedating and can be given SC or IV
Significant analgesic effect
Need to be cautious of hypotension
e.g mg Q1H PRN for agitation
Can go as high as 50mg Q4H

33. Quetiapine
When we use low dose quetiapine at night, it’s primarily acting as an antihistamine
Maneenton et al. (2013) found no difference between mg/day of quetiapine HS and 0.5-2mg/day of haloperidol HS in a double-blind, randomized trial of delirious patients eliciting CL consult
e.g. quetiapine 25mg PO QHS
e.g. quetiapine 50mg PO QHS
Caution re orthostatic hypotension

34. Olanzapine
A number of studies also support use of olanzapine (e.g. Breitbart et al., 2002; Skrobik et al., 2004; Grover et al., 2011)
e.g. Olanzapine oral dissolving 2.5mg QHS
e.g. Olanzapine oral dissolving 5mg QHS
Promotes appetite
Reduces nausea
Promotes sleep
Pro-cholinergic at lower doses, but becomes anticholinergic at larger doses

35. Loxapine (Bates et al., submitted)
In 31 patients over 55 with post-operative delirium referred to the CL service, loxapine was associated with a mean decrease of 8.48 on the DRS-98-R over the first 2 days of treatment
Only 3 participants had a worsening of delirium, and each of those 3 showed improvement from day 2 to day 4
Mean number of days to resolution of delirum (DRS < 10) was 3.2
There was not a significant increase in QTc

36. Loxapine (Bates et al., submitted)

37. Terminal Illness
Delirium interferes with identification of sources of distress like pain
How much should one investigate?
Definitive etiology discovered in less than 50%, and often irreversible when found (Bruera et al. 1992)
However, Tuma and DeAngelis (1992) report 68% can be improved even when 30-day mortality is 31%
Lawlor et al. (2000):
49% reversibility in advanced cancer patients admitted to palliative care
Reversibility associated with opioids, other meds, and dehydration being primary causes

38. Terminal Illness Some view delirium as natural part of dying process
Some worry that antipsychotic will make patient more delirious
Evidence is that antipsychotic generally safe and effective at reducing distress
“Unfortunately, the hallucinations in delirium are rarely sugarplum fairies.”

40. Jacobson et al., 2008 Elderly delirious postoperative patients:
Fewer nighttime minutes resting
Fewer minutes resting over 24hrs
Greater mean activity at night
Smaller change in activity from day to night
Delirium may be simultaneous wakefulness and sleep
REM intrusion into wakefulness might cause visual hallucinations

41. Slatore et al., 2012
Assessed sleep quality and screened for delirium in veterans referred to hospice (55% had cancer) using the Pittsburgh Sleep Quality Index (PSQI) and the Confusion Assessment Method (CAM)
Sleep quality was significantly worse in 33 participants who became delirious than in 42 who did not
Hazard ratio for developing delirium of 2.37 for every point of worse sleep on the PSQI (where 1 = very good; 4 = very bad)

42. Glymphatic system
Xie et al. (2013) demonstrated that sleep is associated with a 60% increase in the interstitial space causing striking increase in exchange between CSF and interstitial fluid
Increased rate of β–amyloid clearance

43. Maldonado et al., 2009
90 patients who underwent valve procedures randomly assigned to post-op sedation with dexmedetomidine, propofol, or midazolam
(From Aantaa & Jalonen, 2006)

44. Maldonado et al., 2009
Incidence of delirium was 50% for both propofol and midazolam groups and only 3% for dexmedetomidine group
Possible benefits of dexmedetomidine: not GABAergic, not anticholinergic, sedating, promotes physiologic sleep pattern without significant respiratory depression, lowers opioid requirements

45. Chlorpromazine
The double-blind randomized trial by Breitbart et al. (1996) is frequently cited as evidence haloperidol should be chosen over other antipsychotics
However, the findings showed the superiority of both haloperidol and chlorpromazine (a sedating low-potency antipsychotic) over lorazepam while showing equal effectiveness between the two antipsychotics
Sedating antipsychotic with IV option
An example of dosing: chlorpromazine 25mg IV Q6H standing (give over 30min; hold for SBP < 90; hold for sedation)

46. Maclullich et al., 2009
Reviewed 9 recent studies with total of 2025 patients
8/9 studies found a significant association between delirium and cognitive impairment
What is the relationship?
CNS insult causes both in parrallel?
Premorbid dementing process unmasked in form of delirium by stress/insult?
Delirium causes things like dehydration, poor nutrition, suboptimal care etc. and this leads to long-term cognitive impairment?
Delirium is a neurotoxic state?
Delirium management is neurotoxic?

47. Cardiac Surgery Risk Factors
Giltay et al. (2006): 8139 consecutive patients undergoing CABG and/or valve procedure
Post-op psychotic symptoms associated with age, renal failure, dyspnea, heart failure, and LVH pre-operatively and hypothermia, hypoxemia, low hematocrit, renal failure, high sodium, infection, and stroke perioperatively