Post-operative delirium is a significant problem in the
elderly associated with excessive morbidity and mortality, prolonged hospital lengths
of stay, poor long-term functional and cognitive outcomes, discharge to places
other than home, and excessive costs. Estimates of its occurrence range up to
65%, even higher when patients require ICU care. So the search for
interventions to prevent postoperative delirium has been important. Many of our
prior columns on delirium (see the list below) have focused on multi-component
non-pharmacological approaches to prevention (and treatment) of delirium.
However, the improvements have been modest.
Pharmacologic interventions to prevent or treat delirium
have been elusive. A recent literature review (Tremblay 2016)
found fourteen articles that reported a reduced incidence of post-operative
delirium using pharmacological agents: eight with antipsychotics, two with
statins, one with melatonin, one with dexamethasone, one with gabapentin, and
one with diazepam. However, Tremblay concludes that study designs,
methodological issues, or authors' interpretations raise questions on these
conclusions and that further double-blinded randomized clinical trials should
be conducted before administering pharmacological agents to reduce postoperative
delirium in a non-research setting.
One drug that has generated significant interest over the
past several years is dexmedetomidine, an
α2-adrenoreceptor agonist, often used as a sedation agent in the ICU
because it might be associated with less delirium. In our February 10, 2009
Patient Safety Tip of the Week Sedation
in the ICU: The Dexmedetomidine Study we
discussed the SEDCOM (Safety and Efficacy of Dexmedetomidine
Compared With Midazolam) Study, which concluded that dexmedetomidine
was as effective as midazolam at keeping patients in the desired sedation range
and was associated with a reduced prevalence of delirium and reduced time to extubation (Riker 2009).
However, we urged caution in interpreting the conclusions of that study because
of several methodological and other concerns outlined in our column. We again
discussed dexmedetomidine in our June 16, 2015 Patient Safety Tip of
the Week Updates
on Delirium. And in our April 2016 What's New in the Patient Safety World
column Dexmedetomidine
and Delirium we
discussed the Dexmedetomidine to Lessen ICU Agitation
(DahLIA) study was a double-blind,
placebo-controlled, parallel-group randomized clinical trial in 15 ICUs in
Australia and New Zealand (Reade 2016).. Subjects were ICU patients who were deemed
to be ready for extubation except that they had
delirium. Dexmedetomidine increased ventilator-free
hours at 7 days compared with placebo and reduced time to extubation
and accelerated resolution of delirium.
See those previous
columns for our cautions and concerns about dexmedetomidine
despite several promising studies.
More recently, Su
and colleagues did a randomized, double-blind, placebo-controlled trial in two
tertiary-care hospitals in Beijing, China on patients aged 65 years or older
who were admitted to intensive care units after non-cardiac surgery (Su
2016). They randomly assign patients to receive either low-dose
(sub-sedative) intravenous dexmedetomidine or placebo
from intensive care unit admission on the day of surgery until 0800 h on the
first day after surgery. The CAM-ICU was the tool used to assess for delirium.
Their reported results are remarkable. The incidence of delirium in the dexmedetomidine group was just 9%, compared to 23% in controls.
That translates to a number needed to treat (NNT) of 7.4! The results applied
equally whether patients were intubated or not and applied to all 3 subtypes of
delirium. And there were significant benefits in the dexmedetomidine
group compared to the control group for ICU length of stay, time to extubation (in those who were intubated), sleep quality,
and early hospital discharge. There was no difference in the incidence of
overall adverse events or 30-day mortality. Moreover, the safety profile of dexmedetomidine was excellent. Patients receiving dexmedetomidine did not have higher rates of bradycardia or
hypotension (as is often seen with higher doses) and actually had lower rates
of hypertension, tachycardia, and hypoxemia than the placebo group. There was
also a suggestion that the delirium-reducing effect was dose-dependent in that
the dexmedetomidine dose (the rate of the infusion x
the duration of the infusion) was negatively correlated with the occurrence of
delirium.
These results sound too good to be true! Such pronouncements always raise our hype
radar or spin radar (see our February 16, 2010 Patient Safety Tip of the
Week Spin/Hype
Knowing
It When You See It).
In the editorial accompanying the Su study, Kronzer and Avidan (Kronzer
2016) provide a very thoughtful assessment of the methodology in the
Su study that should temper our enthusiasm about the reported results. They
note that the consent for participation took place after surgery and that
patients families provided consent in 58% of the cases. That raises the
possibility (or should we say likelihood) that some of the patients may have
already had delirium before they were even entered into the study. They also
note that the CAM-ICU was the tool used to ascertain the presence of delirium.
The CAM-ICU is an excellent tool for assessing intubated ICU patients who are
unable to speak but it is a non-verbal assessment tool that is not as good as
those in which verbal communication can help better identify the presence of
delirium. And there was no baseline assessment for delirium or cognitive
function. Lastly, they challenge the biological plausibility (i.e. that a
sub-sedative very low dose of a sedative agent could be given to awake,
non-delirious patients to prevent delirium). They felt such was
counterintuitive. Kronzer and Avidan
point out the numerous instances in which initially promising interventions
turn out not to work when large well-conducted studies are done. They therefore
consider the work by Su et al to be hypothesis-generating and look for
replication of the findings in other studies.
While Kronzer and Avidan may have a good point about the biological
plausibility, we actually think Su and colleagues had some good rationale for
doing this study. They had noted several previous studies touting dexmedetomidine for prevention of delirium but all had used
higher doses and the control groups were receiving active sedative drugs like
benzodiazepines. Because dexmedetomidine provides anxiolysis, sedation, and modest analgesia and is touted
not to be associated with significant respiratory depression, many have felt it
has the potential to be an ideal candidate for prophylaxis against development
of delirium. And they chose the low (sub-sedative) dose of dexmedetomidine
because they felt it would likely not have the bradycardia or hypotension seen
with higher doses. And a previous study had shown nighttime infusions of dexmedetomidine were associated with sleep improvements.
Nevertheless, we think the criticisms raised by Kronzer and Avidan are legitimate
and we agree that prophylactic use of dexmedetomidine
to prevent delirium should not be adopted as a usual practice until further
validation studies are done.
Perhaps the biggest factor pushing everyone to look at dexmedetomidine is its purported minimal respiratory
depression. Now, even that has been called into question by a new study that compared
ventilatory responses to hypoxia and hypercapnia
during sedation with dexmedetomidine and propofol in healthy male volunteers (Lodenius
2016). Those researchers found that dexmedetomidine-induced
sedation reduces ventilatory responses to hypoxia and
hypercapnia to a similar extent as sedation with propofol.
This finding implies that sedation with dexmedetomidine
interacts with both peripheral and central control of breathing.
So, given that there is currently no clearcut
pharmacological agent to prevent post-op delirium, what are we to do? A very
interesting pragmatic clinical trial recently addressed delirium prevention in
patients age 65 and older who underwent surgery for hip fracture (Freter
2016). Rather than intervene with all the elements of multifactorial
interventions that have been used for delirium prevention, the researchers used
only those that lent themselves to easy incorporation into postoperative
preprinted orders. Those that fit included interventions for nausea, nighttime
sedation, pain control, and bowel and bladder care. The postoperative
preprinted orders had the same elements as the standardized postoperative
orders for hip surgery patients with several differences:
Delirium occurred significantly less frequently (27% vs. 42%
in controls on POD#1 and 7% vs. 30% in controls on POD#5) despite the fact that
more patients in the intervention group had pre-existing dementia, a known risk
factor for delirium. More patients in the intervention group had early
postoperative bowel movements and more urinary catheter removals on POD#2.
Significantly, intervention patients received less opioid analgesia (24 mg
morphine equivalents vs. 44 mg morphine equivalents in controls). But, although
the intervention group had less postoperative delirium, there were no
differences in length of stay, mortality, or nursing home placement rates.
While we anxiously
await studies that might validate use of pharmacological agents, such as dexmedetomidine, to prevent postoperative delirium we need
to stick with multi-component non-pharmacological interventions such as HELP, the Hospital Elder Life Program (see
our October 21, 2008 Patient Safety Tip of the Week Preventing
Delirium and our September 2011 What's New in the Patient Safety World
column Modified
HELP Helps Outcomes in Elderly Undergoing Abdominal Surgery) or tools like
the ABCDEF Bundle (see our September 20, 2016 Patient Safety Tip of the Week Downloadable
ABCDEF Bundle Toolkits for Delirium).
Some of our prior
columns on delirium assessment and management:
·
October
21, 2008 Preventing
Delirium
·
October
14, 2008 Managing
Delirium
·
February
10, 2009 Sedation
in the ICU: The Dexmedetomidine Study
·
March
31, 2009 Screening
Patients for Risk of Delirium
·
June 23,
2009 More
on Delirium in the ICU
·
January
26, 2010 Preventing
Postoperative Delirium
·
August
31, 2010 Postoperative
Delirium
·
September
2011 Modified
HELP Helps Outcomes in Elderly Undergoing Abdominal Surgery
·
December
2010 The
ABCDE Bundle
·
February
28, 2012 AACN
Practice Alert on Delirium in Critical Care
·
April 3, 2012 New
Risk for Postoperative Delirium: Obstructive Sleep Apnea
·
August
7, 2012 Cognition,
Post-Op Delirium, and Post-Op Outcomes
·
February
2013 The
ABCDE Bundle in Action
·
September
2013 Disappointing
Results in Delirium
·
October
29, 2013 PAD:
The Pain, Agitation, and Delirium Care Bundle
·
February
2014 New
Studies on Delirium
·
March
25, 2014 Melatonin
and Delirium
·
May 2014
New
Delirium Severity Score
·
August
2014 A
New Rapid Screen for Delirium in the Elderly
·
August
2014 Delirium
in Pediatrics
·
November
2014 The
3D-CAM for Delirium
·
December
2014 American
Geriatrics Society Guideline on Postoperative Delirium in Older Adults
·
June 16,
2015 Updates
on Delirium
·
October
2015 Predicting
Delirium
·
April
2016 Dexmedetomidine
and Delirium
·
April
2016 Can
Antibiotics Lead to Delirium?
·
July
2016 New
Simple Test for Delirium
·
September
20, 2016 Downloadable
ABCDEF Bundle Toolkits for Delirium
References:
Tremblay P, Gold S. Prevention of Post-Operative Delirium in
the Elderly Using Pharmacological Agents. Can Geriatr
J 2016; 19(3): 113-126
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5038927/
Riker RR, Shehabi Y, Bokesch PM, et al for the SEDCOM (Safety and Efficacy of Dexmedetomidine Compared With
Midazolam) Study Group. Dexmedetomidine vs Midazolam
for Sedation of Critically Ill Patients. A Randomized Trial. JAMA. 2009;
301(5):489-499. Published online February 2, 2009
http://jama.jamanetwork.com/article.aspx?articleid=183300
Reade MC, Eastwood GM, Bellomo R,
et al. Effect of Dexmedetomidine Added to Standard
Care on Ventilator-Free Time in Patients With Agitated Delirium: A Randomized
Clinical Trial. JAMA 2016; Published online March 15, 2016
http://jama.jamanetwork.com/article.aspx?articleid=2503421
Su X, Meng Z-T, Wu X-H, et al. Dexmedetomidine for prevention of delirium in elderly
patients after non-cardiac surgery: a randomised,
double-blind, placebo-controlled trial. The Lancet 2016; 388(10054): 1893-1902 Published:
15 October 2016
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)30580-3/fulltext
Kronzer VL, Avidan
MS. Preventing postoperative delirium: all that glisters is not gold
Vanessa L Kronzer.
The Lancet 2016; 388(10054): 1854-1856 Published: 15 October 2016
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)31353-8/fulltext
Lodenius A, Ebberyd
A, Hεrdemark A, et al. Sedation with Dexmedetomidine or Propofol
Impairs Hypoxic Control of Breathing in Healthy Male Volunteers: A Nonblinded, Randomized Crossover Study. Anesthesiology
2016; 125(4): 700-715
http://anesthesiology.pubs.asahq.org/article.aspx?articleid=2540550&resultClick=3
Freter S, Koller
K, Dunbar M, MacKnight C, Rockwood
K. Translating Delirium Prevention Strategies for Elderly Adults with Hip
Fracture into Routine Clinical Care: A Pragmatic Clinical Trial. J Am Geriatr Soc 2016; Early View 22
NOV 2016
http://onlinelibrary.wiley.com/doi/10.1111/jgs.14568/epdf
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