Patient Behaviour Case Based

Presentation: Delirium

S. Mountain
AHD April 17, 2008
 The Case
► Itis a gray day in January, and you are on
morning rounds, leading your large and
inquisitive team from bedside to bedside.

► You arrive at bed 17, and find your patient deeply

sedated, on A/C, not overriding the vent. This is a
bit of a surprise to you, as yesterday the patient
was weaning nicely on moderately high PSV, and
you were hopeful to wean and possibly extubate
him today.
 The Case
► Thepatient is a 72 year old ex-logger,
who lives in a single room hotel on the
Downtown East Side. He presented 5
days ago with pneumonia, and was
intubated for rapidly progressive
hypoxemic respiratory failure. He has
progressed well both clinically and
radiographically, and is now requiring
40% FiO2, and a PEEP of 10 with good
blood gases.
 The Case
► When you inquire of the nurse, and your team, as to
why he is so sedated, you are told that last night, as
his sedation was turned off in anticipation of
extubation today, he became extremely agitated.
He started bucking and coughing on the vent, which
was alarming continuously, and was pulling at all his
lines and tubes. He dislodged his NG tube, and
since the resident was concerned that he might pull
his ETT, he ordered the patient to be started back
on morphine and midazolam infusions to settle him.
He has required large amounts of both throughout
his ICU stay, and is now on infusions of 15 mg of
each medication, and has settled nicely.
 The Case
► The nurse says to you, “Doctor, clearly this
patient is delirious, and cannot be safely
weaned from his sedation.” At this
statement one of the more animated
medical students looks puzzled. You note
her confusion, and ask what she is thinking.
“Well,” she says, “how can you tell if a
patient is delirious in the ICU?”
Naisan:
1. What is delirium? What
types of delirium are there?
What are the diagnostic criteria?

2. What is a RASS score? How

is it calculated?
 Delirium: Definition
► Delirium is an organic mental
syndrome defined as an acute,
potentially reversible impairment of
consciousness and cognitive function
that fluctuates in severity

Hansen-Flaschen J Crit Care Clin 1994 Oct;10(4):659-71.

 DSM IV Criteria
► Disturbance of consciousness with reduced ability to focus,
sustain, or shift attention.
► A change in cognition or the development of a perceptual
disturbance that is not better accounted for by a preexisting,
established, or evolving dementia.
► The disturbance develops over a short period of time (usually
hours to days) and tends to fluctuate during the course of the
day.
► There is evidence from the history, physical examination, or
laboratory findings that the disturbance is caused by a
medical condition, substance intoxication, or medication side
effect.
 DSM IV Criteria
► Additional
features that may accompany
delirium and confusion include the following:
 Psychomotor behavioral disturbances such as
hypoactivity, hyperactivity with increased
sympathetic activity, and impairment in sleep
duration and architecture.
 Variable emotional disturbances, including fear,
depression, euphoria, or perplexity.
 Pathophysiology
► “Delirium is a syndrome of global cerebral
insufficiency analogous to organ system failures
observed in sites remote from the brain”

► Neurotransmitter imbalances
 GABA, serotonin, acetylcholine, dopamine
► Inflammation
► Neuroanatomic lesions
► Electrophysiologic changes

Stevens RD & Nyquist PA Crit Care Clin 2007

 Delirium subtypes
► Hypoactive delirium
 more common in older
patients
 withdrawal, flat affect,
apathy, lethargy,
decreased responsiveness
 may be misdiagnosed as
depression

► Mixed

► Hyperactive
 “ICU psychosis”
 rare
Peterson et al. J Am Geriatr Soc 2006
Yoan:
3. Are there validated methods to
diagnose delirium in the ICU?
What is the CAM-ICU, what is
the evidence for it, and how
does it work?
► Several validated methods:
 Intensive Care Delirium Screening checklist
►Bergeron et al Int Care Med 2001
 Confusion assessment method in the ICU
►Ely at al JAMA 2001
ICDSC
 Main differences (Poldermans ICM
2007)
ICDSC CAM-ICU
► Decreased LOC, ► Decreased LOC = part of
sedation: not possible Dx criteria for delirium
to assess: no delirium ► Many exclusion criteria
► Few exclusions (if will (> 50% pts)
die in < 24h) ► Steps:
► Steps: 1. Fluctuate
 No steps, all criteria get 2. Inattention
points 3. Decreased LOC
 > 4 /8 points = Delirium 4. Decreased mentation
► Validation: 875 pts, ICM ► Validation: 275 pts,
2007 CCM2004
 The Case - Continued
► At this point one of the senior medicine residents, who
is clearly trying to impress the juniors with his cynicism
and world weary attitude, chimes in. “Of course,” he
declares, “all the patients in the ICU are delirious
because of the effects of the sedatives. It doesn’t
matter, because they all get better as soon as you wake
them up anyway.”
► Concerned that he does not quite seem to grasp the
prevalence, impact, or nature of critical care brain
dysfunction, you decide to do him a favour and set him
straight.
4. How common is delirium in the
ICU? How about in older patients,
or patients with dementia?
5. What is the impact of delirium on
critically ill patients in terms of
mortality, cost, length of stay, etc.?
 Delirium - Epidemiology
► Develops in 50 – 80% of mechanically
ventilated patients
► Estimated to be unrecognized in 66% - 84%
of patients (ICU, hospital ward, ER)
► Independent predictor of:
 prolonged ICU and hospital LOS
 higher 6 month mortality
 higher costs
 higher rate of cognitive dysfunction
Impact of Delirium in ICU

CAM-Ely et al JAMA
2001

ICDSC- CAM-Millbrand
Skrobik et + Ely JAMA
al, ICM 2004
2007
 Delirium as a Predictor of Mortality in Mechanically
Ventilated Patients in the Intensive Care Unit
Ely EW et al JAMA. 2004;291:1753-1762.

► Delirium was associated with a more than 3 times higher

risk of dying by 6 months
(after adjusting for 11 covariates including preexisting comorbidities,
severity of illness, coma incidence and sedative and analgesic use)

► Each additional day spent in delirium was associated with

a 10% increased risk of death
Delirium in ICU patients is a risk factor for 6-month mortality.

H.R. = hazard ratio. Data in parenthesis indicate confidence interval.

Ely EW et al.JAMA.2004
Delirium in ICU patients is a risk factor for prolonged hospital
length of stay.

Ely EW et al.JAMA.2004
Milbrandt et al. Crit Care Med 2004
Dave:
6. What are some conditions that
can contribute to the
development of delirium? What
is the differential diagnosis in
this patient?
 Risk factors
► predisposing factors ► precipitating factors
 age  primary neurologic disease
 male gender  infection
 cognitive impairment or  shock
dementia  hypoxia
 poor functional status  electrolyte abnormalities
 malnutrition  surgery
 substance or ethanol use  pharmacologic agents
 coexisting medical conditions ► benzodiazepines, opiates,
 History of smoking, anticholinergics
hypertension  substance withdrawal
 genetic predisposition?  mechanical ventilation
 bladder and central venous
catheterization
 restraints
 sleep deprivation

From: Stevens RD & Nyquist PA Crit Care Clin 2007

 DDx
► Delirium
► Drug reaction
► Withdrawal
► Dementia (Alzheimer’s, Lewy body dis.)
► Sundowning
► New infection
► Structural brain injury (infarct, bleed, neoplasm, etc.)
► Underlying psychiatric illness
► NCSE
► Wernicke’s
► Anton’s syndrome (cortical blindness and confabulation - focal
occipital lesion).
Delirium Risk Factors- New Studies
► MIND-ICU Study: Delirium and Dementia in
Veterans Surviving ICU Care
 Vanderbilt University – Ely
 Purpose: to define the epidemiology of and identify
modifiable risk factors for long-term cognitive
impairment and functional deficits of ICU survivors

► BRAIN ICU Study: Bringing to Light the Risk

Factors
 Vanderbilt University – Ely
 Purpose: to identify potentially modifiable risk factors
of long-term cognitive impairment (i.e. development
of delirium and exposure to sedative and analgesic
medications) in ICU patients
Anesthesiology 2006;104:21-6
 The Case - Continued
► The nurse, who is from Australia, is getting
annoyed at the amount of conversation at her
bedside. She clearly has more important work
to do. Somewhat disgruntled, and clearly
missing the January sun, she grumbles “I don’t
know why the people in this country have such
ancient ideas about sedation anyway. At home,
we just put everyone on propofol, and that
treats all their delirium just fine. We never have
any problems there at all.”
 The Case - Continued
► Suspecting that her fading memories of
home have caused her to have a somewhat
rose-colored view of patient care, you
nevertheless take this opportunity to review
prevention and treatment of ICU delirium
with your team. Besides, you’re in no hurry
to move on, since, as a well trained ICU
Fellow, you have come to realize that eating
lunch more than three times per week is a
luxury reserved for the weak.
7. What are some non-
pharmacologic methods that
can be used to prevent and
treat delirium?
 Delirium Prevention
► Nonpharmacologic
 Risk factor modification
►Reorientation, cognitively stimulating activities, early
mobilization, rom exercises, removal of catheters and
restraints, glasses, hearing aids, reduce noise,
adequate hydration
 Protocols
 Sleep
► APPENDIX 5---NON-PHARMACOLOGICAL INTERVENTIONS FOR DELIRIUM MANAGEMENT
►
► Vibration
► Distraction
► Position patient in a position that minimizes discomfort
► Apply heat or cold
► Relaxation
► Massage
► Therapeutic touch
► Acupressure
► Minimize stimulation (Take conversations away from the bedside)
► Minimize tethers (Lines, tubes, and monitoring devices)
► Provide set rest periods—aim for one 90 minute uninterrupted rest period during day.
► Provide 1:1 or 1:2 nursing care as needed. Have a “patient sitter” prn.
► Plan care in clumps of time
► Maximize comfort (Is bowel care needed?)
► Hunt for the underlying cause (Refer to “ICU DELERIUMS" Appendix 4)
► Maximize rest and sleep periods – preferably without drugs, (e.g. dim room lighting, private room, close doors to
reduce noise, turn down bedside alarm volume on monitor, diminish faceplate lights on pumps, reduce nuisance
alarms, etc.)
► Provide frequent calm reassurance and reorientation
► Make sure patient is wearing his glasses and/or hearing aides
► Keep familiar objects in the patient’s line of sight
► Play familiar music
► Use family support if they help calm the patient
► Provide adequate nutrition and hydration
► Assess for electrolyte imbalance
► Establish and maintain a clear day/night pattern—i.e. sleep during night and awake during day except for either short
naps or 1-90min. rest period.
► Use plain language in face to face communications with patient
► Ask questions that can be answered with “Yes” or “No” either verbally or non-verbally.
► Establish a consistent approach to care and provide it in a calm unhurried manner
► Provide cognitively stimulating activities several times a day
► Consider consults to Nutrition, OT, Speech Therapy, Gerontology, Psychiatry, Social Work, Chaplain prn.
► Early mobilization and/or frequent Range-of-Motion exercises
Gord:
8. What pharmacologic agents exist
in Canada to treat ICU delirium?
Which is best? What is the
evidence?
 Treatment of Delirium
► No drugs have FDA-approval for the
treatment of delirium
► The American Psychiatric Association and
the Society of Critical Care Medicine clinical
practice guidelines (Jacobi J, et al., Crit Care
Med 2002; 30:119-141) recommend
haloperidol for the treatment of delirium
(level C data).
 Treatment of Delirium
► Atypicalantipsychotics may be as effective
as haloperidol, and may be associated with
fewer side effects (Stevens and Nyquist Crit
Care Clin 2007)

► Severalstudies on use of antipsychotics to

treat delirium in ICU patients are currently
underway
Olanzapine vs Haldol:treating delirium in a critical care setting
(Skrobik et al Int Care Med 2004)
Olanzapine vs Haldol:treating delirium in a critical care setting
(Skrobik et al Int Care Med 2004)
Olanzapine vs Haldol:treating delirium in a critical care setting
(Skrobik et al Int Care Med 2004)

► Treatment alternative; no real difference

found.
► May be useful in :
 Parkinson’s
 Prolonged QT
 Oropharyngeal dysfunction
► Limited by:
 Only available enterally
 New Trials
 ORIC-1: Optimizing recovery from intensive
care: mechanical ventilation and delirium
►University of Pittsburgh and NHLBI – Mildebrandt EB
►Purpose – to determine if treating delirious icu pts
with haloperidol improves mortality
►Delirious mechanically ventilated pts will be treated
with haldol 5mg iv q 12 h or placebo
 New Trials
 A pilot study of haloperidol to treat critical illness
delirium
► University of Colorado – Douglas IS

 Randomized controlled trial of dexmedetomidine for the

treatment of ICU delirium
► Brigham and Women’s Hospital – Weinhouse, GL
► Comparison of dex to haldol and lorazepam

 A comparison of dexmedetomidine and haloperidol in

patients with icu-associated agitation and delirium
► Austin Health – Bellomo R
9. What new sedative agents
exist that may impact our future
care of agitated patients?
Remind us of the evidence for
or against their use; i.e. what
are the pros and cons?
Dexmedetomidine (Precedex®)

•Alpha-2 receptor agonist

•Reduced release of NE and

inhibition of postsynaptic
activation

•CNS excitation is attenuated,

esp. in locus coeruleus
In a study of 8 female surgical patients, Precedex was infused postoperatively by computer-
controlled infusion protocol (CCIP) for 60 minutes, targeting a plasma concentration of 600
pg/mL
Plasma norepinephrine concentrations decreased on average by 72% (range 40% to 97%)
Plasma epinephrine decreased by 72% (range 47% to 92%)
 Dexmedetomidine
►“cooperative sedation”
►Therapeutic uses:
 ICU sedation
►adults and peds, drug withdrawal, ventilator
weaning
 Perioperative use
►sympatholysis, analgesic and sedative properties
 Neurosurgery
►potential to decrease cerebral blood flow,
optimize cerebral O2 supply, neuroprotection
(reduces glutamine release), decrease ICP (in
animal studies)
 For outpatient procedural sedation
►no respiratory depression
 Dexmedetomidine
► Adverse reactions:
 Hypotension – at lower doses
 Hypertension – at higher doses (activation of
peripheral alpha-2b receptors)
 Nausea
 Bradycardia
 Dry mouth
Effect of Sedation With Dexmedetomidine vs Lorazepam on Acute
Brain Dysfunction in Mechanically Ventilated Patients
The MENDS Randomized Controlled Trial
Pratik P. Pandharipande
, MD, MSCI; Brenda T. Pun, RN, MSN, ACNP; Daniel L. Herr, MD; Mervyn
Maze, MB, ChB; Timothy D. Girard, MD, MSCI; Russell R. Miller, MD, MPH;
Ayumi K. Shintani, MPH, PhD; Jennifer L. Thompson, MPH; James C. Jackson,
PsyD; Stephen A. Deppen, MA, MS; Renee A. Stiles, PhD; Robert S. Dittus
, MD, MPH; Gordon R. Bernard, MD; E. Wesley Ely, MD, MPH

JAMA. 2007;298(22):2644-2653.

Objective:  To determine whether dexmedetomidine reduces

the duration of delirium and coma in mechanically ventilated
ICU patients while providing adequate sedation as compared
with lorazepam.
 MENDS
► Double blind randomized controlled trial
► 106 ventilated pts – med and surg - randomized
to continuous infusion of either lorazepam or
dexmedetomidine
► Infusion titrated to goal RASS set by medical
team
► Infusion continued until extubation or 120 hrs at
which point pts were sedated according to
standard practice for that ICU
► Apparent pain treated with fentanyl bolus or
infusion
► If max dose of study drug did not give adequate
sedation, fentanyl infusion could be started
► For sudden agitation – propofol boluses
 MENDS
► Daily cessation of sedatives and spontaneous
breathing trials – not mandated
► Primary outcomes:
 delirium-free and coma-free days, efficacy of
sedation regimen
► Secondary outcomes:
 lengths of stay with ventilation, in ICU, in
hospital, neuropsych testing post-ICU, 28 day
mortality, 12 month survival
► CAM-ICU performed twice daily
 Screening, Enrollment, and Randomization

Pandharipande, P. P. et al. JAMA 2007;298:2644-2653.

Pandharipande, P. P. et al. JAMA 2007;298:2644-2653.
Pandharipande, P. P. et al. JAMA 2007;298:2644-2653.
Time to Death Within 28 Days of Enrollment for All Patients

Pandharipande, P. P. et al. JAMA 2007;298:2644-2653.

Median infusion rate for dex was .74ug/kg/hr (.39 – 1.04 ug/kg/hr)
Median infusion rate for lorazepam was 3 mg/hr (2.2 – 6mg/hr)

Pandharipande, P. P. et al. JAMA 2007;298:2644-2653.

Fentanyl Dose While Receiving Study Drug According to Depth of Target
Sedation

The difference in fentanyl dosage was more

notable when patients were more deeply sedated.

Pandharipande, P. P. et al. JAMA 2007;298:2644-2653.

 MENDS
► Safety – no more adverse events with
dexmedetomidine
► Cost – overall costs were more for
dexmedetomidine, but P values were not
significant
 MENDS
► Conclusion:
 Sedation with dexmedetomidine infusion
resulted in 4 more days alive without delirium or
coma and significantly more time at the desired
level of sedation as compared with lorazepam
infusion

 Dexmedetomidine was safe

 New trials
► Dexmedetomidine Versus Midazolam for Continuous
Sedation in the ICU (MIDEX)
► Dexmedetomidine Versus Propofol for Continuous
Sedation in the ICU (PRODEX)

► Both trials sponsored by Orion Pharma

► various centres in Europe
► Purpose: to show that dexmedetomidine is at least as
effective as midazolam/propofol for sedation, and that
it is associated with shorter duration of mechanical
ventilation
 New Trials
►A Pilot Study of Effect of Dexmedetomidine on
Sleep and Inflammation in Critically Ill Patients
 University of Arizona – Parthasarathy
 Purpose – to assess the short-term effect of
sympatholysis on sleep quality and inflammation in
critically ill patients

► Oral Melatonin in Critically Ill High-Risk Patients

 University of Milan – Mistraletti
 Purpose – to analyze the potential of oral melatonin as
a sedative and free-radical scavenger for critically ill
patients and secondarily for preventing delirium during
their ICU stay and PTSD after ICU discharge
 New Trials
 “The MIND Study: Modifying the Incidence of Delirium”
or “Delirium in the ICU: a Prospective randomized Trial
of Placebo vs. Haloperidol vs. Ziprasidone
► Vanderbilt – Ely
► a pilot study of feasibility to begin assessing the role of
antipsychotics in management of ICU delirium
► aims of study are:
 determine whether antipsychotics reduce incid and duration of
delirium in high risk mech vent pts
 determine whether antipsychotics reduce severity of neuropsych
dysfn at hospital dischg in high risk mech vent pts
 The Case - Continued
► Your latest diatribe on delirium seems to have lulled
some of your less enthusiastic residents into a small
coma of their own. You decide to get back to the task
at hand, in order to wake them up. Now that you have
established how you are going to treat this patient’s
delirium, you ask the resident in charge how they
would like to go about weaning this patient from
sedation and ventilation. The resident says, “I don’t
know, but you’d think there would be some kind of
protocol or something, isn’t there?”
► “Well,” you say, “as a matter of fact...”
Steve:
10. Is there any recent evidence to
show standardized sedation or
ventilator weaning protocols reduce
the incidence of delirium or coma?
What other impacts have they been
shown to have (i.e. what is the
evidence for or against their use?)
 Prevention - Protocols
► Sedation/analgesia/delirium protocols

► Outcomes can be improved by:

 Daily interruption of sedation and sedation protocols
 Ventilator weaning protocols including spontaneous
breathing trials

► ABC trial
Notice that pt APACHE score wasn’t that high.
Lancet 2008;371:126-34
 ABC Trial
► Multicentre, randomized controlled trial

► Purpose: to assess the efficacy and safety of a

protocol of daily spontaneous awakening trials
(SATs) paired with spontaneous breathing trials
(SBTs) versus a standard SBT protocol in patients
receiving patient-targeted sedation as part of
usual care
 ABC Trial
►4 large centres

► Inclusion criteria
 18 yrs or older
 Mechanical ventilation > 12 hrs
 Full ventilatory support or weaning

► Exclusion criteria
 Admitted post cardiopulmonary arrest, ventilated >2 weeks,
moribund, withdrawal of life support, profound neuro deficit,
enrolled in another trial
 ABC Trial

► Patientsrandomly assigned to management

with either paired SAT and SBT protocols or
usual care including patient-targeted
sedation and an SBT protocol
ABC Trial
 ABC Trial
► Primary endpoint
 Number of days breathing without assistance (had
to last at least 48 hrs) during the 28-day study
period

► Secondary endpoints
 Time to discharge from ICU and hospital
 All-cause 28 day mortality
 1 year survival
 Duration of coma and delirium
 ABC Trial

► Patients
were assessed using RASS and
CAM-ICU
 Conclusions
► Compared to usual care, a paired sedation
and ventilator weaning protocol consisting
of daily SATs plus SBTs resulted in:
 more time off mechanical ventilation
 less time in coma
 less time in the ICU and hospital
 improved 1-year mortality
 Criticism
► There were more failures of SBT in controls
- too sedated?
► Could stress of repeated SBTs contribute to
worse outcomes?
 New Trials
► The
SOMNUS Study: Sedation Optimization Via
Monitoring Neurological Status
 Vanderbilt – Watson and Ely
 Purpose: To show that a combine strategy of RASS
clinical targeting plus BIS guided sedation in
mechanically ventilated, critically ill patients will
decrease time on mechanical ventilation, decrease
duration of ICU delirium and coma and will improve
subacute neurocognitive function when compared to
sedation guided by RASS targeting alone
 The Case - Continued
► Now that you are finally ready to leave the bedside and
move on to the next patient, you realize you forgot to
address the patient’s sleep disturbance. When you
mention it, one of the residents says “I thought we were
trying to wake this guy up. Why are you so worried about
his sleep now? Let’s just get him awake so we can
extubate him.”
► You’re a bit concerned that the resident may have missed
the entire point of the conversation up to now.
Unfortunately, you don’t have time to review the whole
thing. So you decide to make a few well informed
comments about sleep in the ICU instead.
11. How does sleep disturbance
impact cognitive function in
critically ill patients?
 Delirium Prevention - Sleep
► Critically
ill patients have severe sleep deprivation and
disrupted sleep architecture

► Adverse consequences of sleep deprivation include:

 increased risk for cognitive dysfunction and delirium
 reduced cellular and humoral immunity
 elevated inflammatory cytokines

► Multiple causes, many potentially modifiable, including:

 psychoactive medications (sedatives and analgesics)
 mechanical ventilation
► Limitation of the above study was that sleep quantity and
quality was assessed subjectively by nursing staff and that
it can only infer correlation, not causality. Other negative
impacts of poor sleep; increased catecholamines, impaired
immunological function, potentially increased BP,
potentially increased cardiac arrythmias, long term
alteration of sleep cycles, may impact overall morbidity and
mortality.
► Problems with assertion of a causal link between lack of
sleep and delirium; studies are correlational, healthy
volunteers exposed to sleep deprivation show none of the
aspects of delirium, sleep disturbances may be a
consequence rather than a cause of delirium, disturbance
of sleep tends to correlate with the degree of illness and is
therefore a strong confounder, some studies have found
no correlation between sleep disturbance and delirium.
(From McGuire 2000)
12. What ventilator strategies
have been explored to improve
sleep in the ICU? Do they
work?
► 11 pt had sleep polysomnography during PS or AC ventilation. PS led
to hypocapnia with resultant hypoventilation and more periods of
wafefulness than AC.
► Also
adding dead space ventilation
decreased periods of wakefulness.
Apparently this study shows that PSV is associated with more apneas during sleep .

Discusses the nuances of altering ventilation settings during sleep.

Sleep and mechanical ventilation
► Bosma et al 2007 Crit Care Med:

 PAV resulted in better quality of sleep compared

to PSV

 reduction in patient-ventilator asynchronies

 PAV responds to the normal down-regulation of

respiratory muscles during sleep and therefore
preserves the physiologic increase in PaCO2
 Summary
► Delirium (mixed and hypoactive) is very common and is
associated with significant long term morbidity and
mortality

► We may be able to improve on our current methods of

monitoring for, preventing, and treating delirium
 Sedation/analgesia/delirium protocol
► Alterhow we monitor delirium
► Consider adding vent weaning protocol
 PAV during sleep
 Medications
► Dexmedetomidine?
► Antipsychotics – should we use them more?