Pharmacologic interventions to prevent or treat delirium
have been elusive. Antipsychotic drugs have sometimes been touted to be
successful but the evidence has not been very convincing. A meta-analysis of antipsychotic treatment in
patients with delirium (Kishi
2015) suggested that second
generation antipsychotics have a benefit for the treatment of delirium with
regard to efficacy and safety compared with haloperidol but emphasized that further
study using larger samples is required. But another recent systematic review and meta-analysis found that current evidence does not support
the use of antipsychotics for prevention or treatment of delirium (Neufeld
2016). Those authors found antipsychotic
use was not associated with reduction in delirium incidence, change in delirium
duration, severity, or hospital or ICU length of stay.
For several years
now there has been interest in the use of dexmedetomidine,
an α2-adrenoreceptor agonist, 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”.
Now another study
has addressed the use of dexmedetomidine in intubated
ICU patients with delirium (Reade 2016).
The Dexmedetomidine
to Lessen ICU Agitation (DahLIA) study was a
double-blind, placebo-controlled, parallel-group randomized clinical trial in
15 ICU’s in Australia and New Zealand. 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 (median, 144.8 hours vs
127.5 hours, respectively). Among several secondary outcome measures they also
found that dexmedetomidine reduced time to extubation (median, 21.9 hours vs 44.3 hours with placebo),
and accelerated resolution of delirium (median, 23.3 hours vs 40.0 hours).
Again, this sounds
encouraging, particularly since our pharmacologic armamentarium for managing
delirium is so limited. Yet there are again some red flags that urge us to be
cautious in recommending widespread use of dexmedetomidine.
First of all, this study applies only to a very select group of patients –
those who were already well enough to be being considered for extubation except for their delirium. The authors note that
they screened 21,500 patients to recruit just the 74 patients randomized in the
study! That small sample size (actually only 71 patients after 3 withdrawals
for various reasons). Even more importantly, the study was terminated before
its planned recruitment of 96 patients. Studies with early termination
typically show more exaggerated effect sizes. Early termination was apparently
done because the funding source ceased funding beyond the originally defined
period. The authors note that the funding source had no role in the design of
the study and had no access to study data during the study, and the authors
performed sensitivity analyses suggesting the abbreviated sample size was unlikely
to alter the primary conclusion. Nevertheless, such occurrences 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”).
So while we are
somewhat encouraged by the results of the DahLIA
study, we’re not yet ready to jump on the dexmedetomidine
bandwagon for more widespread use. Remember, this was a very narrow patient
population and it would be premature to extrapolate the results to patients
with delirium earlier in their ICU course (i.e. before they were deemed
otherwise ready for extubation). The good news,
though, is that the dexmedetomidine seemed to be well
tolerated in this study and adverse events were rare. We therefore look forward
to further studies on the use of dexmedetomidine for
either prevention or treatment of 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”
·
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 “Can
Antibiotics Lead to Delirium?”
References:
Kishi T, Hirota
T, Matsunaga S, Iwata N. Antipsychotic medications for the treatment of
delirium: a systematic review and meta-analysis of randomised
controlled trials. J Neurol Neurosurg
Psychiatry 2015; Published online first September 4, 2015
http://jnnp.bmj.com/content/early/2015/09/04/jnnp-2015-311049.abstract
Neufeld KJ, Yue J, Robinson TN, et al. Antipsychotic
Medication for Prevention and Treatment of Delirium in Hospitalized Adults: A
Systematic Review and Meta-Analysis. Journal of the American Geriatrics Society
2016; published online 23 March 2016
http://onlinelibrary.wiley.com/doi/10.1111/jgs.14076/abstract
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
Print “April
2016 Dexmedetomidine and Delirium”
When confronted with patients having delirium our first
approach is to look for and remove any precipitating or contributing factors.
One such factor we tend to forget about is the use of antibiotics. Given the
high prevalence of delirium in the ICU and post-operative settings, it would
not be surprising to find antibiotic use frequent in such patients.
A recent review of antibiotic-associated encephalopathy (Bhattacharyya
2016) is very timely and identifies 3 unique clinical phenotypes: encephalopathy commonly accompanied by
seizures or myoclonus arising within days after antibiotic administration
(caused by cephalosporins and penicillin);
encephalopathy characterized by psychosis arising within days of antibiotic
administration (caused by quinolones, macrolides, and procaine penicillin); and
encephalopathy accompanied by cerebellar signs and MRI abnormalities emerging
weeks after initiation of antibiotics (caused by metronidazole). Those clinical
features of each phenotype can and should lead to recognition of the pathogenetic role being played by the antibiotic and lead
to its discontinuation.
The phenotype
characterized by myoclonus and/or seizures (Type 1 AAE) is often due to
penicillin or cephalosporins and often occurs in the
setting of renal insufficiency. It usually appears within days of antibiotic
administration. Seizures associated with cephalosporin-associated
encephalopathy were frequently nonconvulsive. EEG may
show generalized slowing but often shows periodic discharges with triphasic morphology or epileptiform discharges. MRI is
normal in these cases. The encephalopathy usually resolves within days of
discontinuation of the offending antibiotic.
Type 2 AAE also typically begins within days of antibiotic
initiation and is characterized by frequent occurrence of psychosis and
resolution within days of
discontinuation of the offending antibiotic. Seizures are rare in this
type and the EEG is more likely to be normal (or show nonspecific findings).
MRI is usually normal. This phenotype may occur with procaine penicillin,
sulfonamides, fluoroquinolones, and macrolides.
The third type (Type 3 AAE) occurs with metronidazole begins
weeks after initiation and is characterized by frequent occurrence of
cerebellar dysfunction. Seizures are rare and EEG usually shows only
nonspecific abnormalities but the MRI is typically abnormal, showing a typical
pattern of T2 hyperintensities in the dentate nuclei
of the cerebellum
with variable involvement of the
brainstem, corpus callosum, or other regions.
The authors also note that isoniazid (INH) may cause an
encephalopathy that does not fit nicely into one of the 3 above phenotypes.
Onset is weeks to months after INH initiation. Psychosis is common but seizures
are rare and EEG may just show nonspecific abnormalities.
The Bhattacharyya paper acknowledges the issue of strength
of association with antibiotic use in each phenotype and also has a nice
discussion on the possible pathophysiologies of each
phenotype and the pharmacokinetic and patient-related factors that are
important.
Overall this is an important contribution to the clinical
management of the patient with delirium and a key reminder to evaluate all
aspects of care.
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”
·
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”
References:
Bhattacharyya S, Darby RR, Raibagkar
P, et al. Antibiotic-associated encephalopathy. Neurology 2016; published
online before print February 17, 2016
http://www.neurology.org/content/early/2016/02/17/WNL.0000000000002455
Print “April
2016 Can Antibiotics Lead to Delirium?”
Our What's New in the Patient Safety World columns for
February 2015 “17%
Fewer HAC’s: Progress or Propaganda?” and January 2016 “HAC’s
Have Declined Since 2010” discussed
interim data sets from AHRQ which showed that there was a 17% reduction in
hospital-acquired conditions (HAC’s) between 2010 and 2014. Over the 4-year
period the biggest reductions in HAC’s percentage-wise were seen for CLABSI’s
(-72%), CAUTI’s (-38%), and post-op venous thromboembolism (-43%).
AHRQ’s Chartbook on Patient Safety
summarizes patient safety measures, including overall hospital-acquired
conditions (HAC’s) and hospital-associated infections (HAI’s), highlighting the
trends between 2010 and 2014 (AHRQ
2016). Similarly, CDC has reported
substantial reductions in CLABSI’s, CAUTI’s, surgical site infections (SSI’s),
hospital-onset C. difficile infections, and hospital-onset MRSA bacteremias over a roughly similar time frame (CDC
2016).
While we’ve had some degree of skepticism in interpretation
of the data, overall we’ve felt comfortable that true progress is being made.
One of the many interventions cited as contributing to the
apparent improvement in HAI and HAC rates is the financial penalty hospitals
pay for poor performance in these rates (primarily for CMS/Medicare patients
but also for some other insurers). We’ve always been concerned about how coding
changes have obfuscated some quality parameters. For example, we’ve always been
concerned about changes in sepsis coding may have artificially lowered
mortality rates for both sepsis and pneumonia (see our
March 2016 What's New in the Patient Safety World column “Finally…A
More Rationale Definition for Sepsis”). Now a study from the Stanford Graduate School of Business questions
whether coding practices have similarly impacted quality reporting for the
HAI’s reported to CMS as well (Bastani
2015).
Bastani and colleagues note that CMS does not
directly monitor the occurrence of the various HAI’s. Rather it collects
administrative (billing) data from hospitals and does chart reviews of a small
sampling to assess validity. The Stanford researchers used more sophisticated
techniques to assess how rampant “upcoding” might be.
In particular, one form of upcoding would be
assigning a designation present-on-admission (POA) to an infection when it was,
in fact, a hospital-acquired infection. Upcoding
would be financially beneficial to hospitals either by increasing reimbursement
or avoiding penalties.
They compared rates
of HAI’s in states that require strict reporting of HAI’s to those in states
that have weaker reporting requirements. Overall, they found hospitals in the
more weakly regulated states reported lower rates of HAIs and higher rates of
POA infections. They estimate there are more than 10,000 upcoded
infections annually, resulting in an added costs of $200 million to CMS.
Bastani and colleagues are careful to not impute a
motive to such “upcoding” While such could be
intentional in attempt to avoid the CMS penalties, they also note it might
reflect lack of clinical knowledge by “coders” or lack of communication between
clinicians and coders (talk about being tactful and politically correct!).
They conclude that
their findings suggest, contrary to widely-held beliefs, increasing financial
penalties alone may not reduce HAI incidence and may even exacerbate the problem.
They make several policy recommendations based on their results, including a
new measure for targeted HAI auditing and suggestions for effective adverse
event reporting systems.
Interesting
perspective.
References:
AHRQ (Agency for Healthcare Quality and Research). Chartbook on Patient Safety. March 2016
CDC (Centers for Disease Control and Prevention). National and
State Healthcare Associated Infections Progress Report. 2016
http://www.cdc.gov/HAI/pdfs/progress-report/hai-progress-report.pdf
Bastani H, Goh J, Bayati M. Evidence of Strategic Behavior in Medicare Claims
Reporting. Stanford Graduate School of Business 2015; Working Paper No. 3396; July
13,,2015
Print “April
2016 HAI’s: Gaming the System?”
Our July 7, 2009
Patient Safety Tip of the Week “Nudge:
Small Changes, Big Impacts” reviewed the book “Nudge”
by Richard Thaler and Cass Sunstein.
Yes, that’s the one that leads in with the story about how painting a picture
of a fly in a male urinal resulted in 80% decreased spillage! The theme
obviously is that small changes which cost little or nothing (i.e. nudges) can
result in big impacts. The book is full of examples of how nudges can help
steer people to make better choices in their personal life (savings,
investments, healthcare, etc.) or from a societal perspective (improve the
environment, improve organ donations, etc.).
In that 2009 column
and in our February 18, 2014 Patient Safety Tip of the Week “Nudged,
But Who Nudged Who?” we gave examples of how such small changes or “nudges”
may lead to desirable changes in behavior in healthcare.
Hand hygiene is one
area in which nudges may be helpful and that applies not only to healthcare
personnel but also to visitors. A new study looked at factors related to
use of alcohol-based hand sanitizers by
visitors to a hospital (Hobbs
2016). The key finding was that when the hand sanitizers were placed in the
middle of the lobby (with limited
landmarks or barriers) visitors were 5.28 times more likely to use them. But
the other key finding was that group behavior is important as well. In the
Hobbs study individuals in a group were 39% more likely to use alcohol-based
hand sanitizers. We’ve often viewed the same scenario with healthcare workers.
A team in a teaching hospital (attending, several residents and students, and
maybe a nurse or two) is doing rounds. If the attending stops to do hand
hygiene before interacting with the patient, the whole team does hand hygiene.
If he/she does not do hand hygiene, no one does. That’s a “nudge” that has a
powerful impact.
So that addresses
healthcare workers and visitors. What about patients themselves? After
publication of a study last month (Cao
2016) we may need a “nudge” for them, too. Cao and colleagues did cultures
of the hands of patients being admitted to post-acute care facilities from
acute care hospitals. They found that 24.1% had at least one
multidrug-resistant organism (MDRO) on their hands. Of course, other body parts
may be colonized with hospital-acquired organisms but the patients’ hands are
most likely to have been in contact with environmental surfaces, health care workers’ hands, or even other
patients. Clearly, further studies need to be done to see how to intervene and
prevent spread of such organisms in patients being discharged. Adding hand
hygiene to patients being admitted to long-term care facilities would make
sense. But adding hand hygiene to the discharge checklist of patients being
discharged from acute care hospitals may make more sense since even those going
home may be spreading MDRO’s. So a little “nudge” may be needed at discharge.
Maybe putting another alcohol-based hand sanitizer in the lobby facing the
other way will get both patients and visitors to perform hand hygiene on the
way out, too!
“Nudges” do have positive
impacts and we need to learn how to better deploy them.
Some of our other
columns on hand hygiene:
January 5, 2010
“How’s
Your Hand Hygiene?”
December 28, 2010 “HAI’s:
Looking In All The Wrong Places”
May 24, 2011 “Hand
Hygiene Resources”
October 2011 “Another
Unintended Consequence of Hand Hygiene Device?”
March 2012 “Smile…You’re
on Candid Camera”
August 2012 “Anesthesiology
and Surgical Infections”
October 2013 “HAI’s:
Costs, WHO Hand Hygiene, etc.”
November 18, 2014 “Handwashing
Fades at End of Shift, ?Smartwatch to the Rescue”
January 20, 2015 “He
Didn’t Wash His Hands After What!”
September 2015 “APIC’s
New Guide to Hand Hygiene Programs”
November 2015 “Hand
Hygiene: Paradoxical Solution?”
References:
Thaler RH, Sunstein
CR. Nudge. Improving Decisions about Health, Wealth, and Happiness. New Haven:
Yale University Press, 2008
http://www.amazon.com/Nudge-Improving-Decisions-Health-Happiness/dp/014311526X
Hobbs MA, Robinson S, Neyens DM,
Steed C. Visitor characteristics and alcohol-based hand sanitizer dispenser
locations at the hospital entrance: Effect on visitor use rates.
Am J Infection Contol 2016;
44(3): 258-262
http://www.ajicjournal.org/article/S0196-6553%2815%2901158-X/abstract
Cao J, Min L, Lansing B, Foxman B, Mody
L. Multidrug-Resistant Organisms on Patients’ Hands. A Missed Opportunity. JAMA
Intern Med 2016; Published online March 14, 2016
http://archinte.jamanetwork.com/article.aspx?articleid=2500025&resultClick=1
Print “April
2016 Nudge: An Example for Hand Hygiene”
Print “April
2016 What's New in the Patient Safety World (full
column)”
Print “April
2016 Dexmedetomidine and Delirium”
Print “April
2016 Can Antibiotics Lead to Delirium?”
Print “April
2016 HAI’s: Gaming the System?”
Print “April
2016 Nudge: An Example for Hand Hygiene”
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