Rivastigmine in the treatment of postoperative delirium: A pilot clinical trial

Article (PDF Available)inInternational Journal of Geriatric Psychiatry 27(9):986-8 · September 2012with26 Reads
DOI: 10.1002/gps.2801 · Source: PubMed


Rivastigmine in the treatment of postoperative delirium: a
pilot clinical trial
Postoperative delirium (POD) is a common complica-
tion among the older people that is associated with in-
creased mortality, morbidity, and prolonged hospital
stay. Delirium represents the clinical manifestation of
a diffuse, reversible impairment of cerebral oxidative
metabolism and an ensuing imbalance of neurotrans-
mitters. Cerebral acetylcholine synthesis is particularly
sensitive to perioperative physiologic disturbances.
Several recent trials have considered commercially
available cholinesterase inhibitors in the treatment of
POD in patients undergoing cardiac (Gamberini
et al., 2009) and non-cardiac surgery (Liptzin et al.,
2005, Sampson et al., 2007) with mixed results. How-
ever, methodological issues and erratic and unpredict-
able absorption of the oral formulation of the drugs
and postoperative ileus precluded the authors from
reaching denitive conclusions.
We designed a clinical t rial to examine whether pre-
operative administration of transdermal rivastigmine
(Exelon Patch, Novartis Corporation,Basel,Switzerland)
reduces the incidence of POD in older patients undergo-
ing major surgery. The objective of the study was to esti-
mate the proportion of older patients with one o r more
episodes of postoperative confusion following the ad-
ministration of transdermal rivastigmine or placebo.
The study was executed as a randomized, placebo-
controlled, double-blind clinical trial. Approval wa s
obtained from the Institutional Review Board of the
New York University Langone Medica l Center. Patients
of 65 years and older admitted for elective surgery under
general anesthesia were screened. Only patients at risk for
developing POD were considered for recruitment. That
risk was based on the presence of at least one of ve pre-
dictive factors: (1) preoperative cognitive impa irme nt
(Mini mental state examination (MMSE) < 24); (2)
advanced age (>70 years); (3) preoperative use of psy-
choactive drugs; (4) history of prior delirium; and/or
(5) severe illness or comorbidity.
Eligible patients received a rivastigmine 5-cm
transdermal patch or a placebo patch. The primary
outcome of the study was dened as the proportions
of patients who experienced at least one episode of
POD. Recovery of cognitive function as diagnosed by
the MMSE was treated as a secondary outcome.
The Confusion Assessment Method was used as a
screening test for delirium on postoperative days one
through three. The assessments were performed 2 h
after surgery and twice per day thereafter.
Descriptive statistics were used to characterize de-
mographics and MMSE values for different visits as a
function of drug group and delirium status. Pairwise
comparisons were performed with t-test or ranked
comparison (Wilcoxon) as appropriate. Repeated
measure ANOVA incorporated MMSE (dependent
variable) values for multiple visits in a model with
drug group, delirium, age, and years of education.
Twenty-eight patients completed the study (11 rivas-
tigmine and 17 placebo). The incidence of POD was
not affected by rivastigmine treatment. Six patients
with delirium were proportionally distributed between
the two randomized groups (rivastigmine: 2/11, 18%;
placebo: 4/17, 23%, p = 0.785). There were no differ-
ences in demographic parameters such as age, years
of education, and baseline MMSE score between the
groups. The study was halted prematurely because of
a warning letter issued by the rivastigmine manufac-
turer (Novartis) indicating the possibility of increased
mortality associated with the oral administration of
the drug in critically ill patients (van Eijk et al., 2010).
Analysis of postoperative MMSE scores displayed a
potential therapeutic impact of rivastigmine. MMSE
scores were higher in the rivastigmine group com-
pared with the placebo group on postoperative day
one and day two (Figure 1).
Our study did not demonstrate a signicant difference
between rivastigmine and placebo groups in the occur-
rence of POD. However, the treated group had higher
postoperative MMSE values, suggesting that rivastigmine
may improve cognitive function postoperatively.
Copyright # 2012 John Wiley & Sons, Ltd. Int J Geriatr Psychiatry 2012; 27: 986988.
Several studies have examined the efcacy of anti-
cholinesterase inhibitors in the prevention of POD.
Liptzin et al. (2005) were unable to demonstrate the
benet of the treatment with donapezil. Sampson
et al. (2007) conducted a similar study and reported
a trend suggesting a possible benet. The study popu-
lation of both trials included relatively young as well as
cognitively intact older patients in reasonably good
general health. Thus, the relative risk of POD in that
study population is low, and neither study was suf-
ciently powered to detect the differences between
study groups. In contrast, the patients in our study
were older and had at least one risk factor associated
with the development of POD.
Gamberini et al. (2009) conducted a randomized
trial to test if a short-term administration of oral rivas-
tigmine reduced the incidence of POD in after cardiac
surgery. POD developed in 30% of patients in the pla-
cebo group versus 32% in the rivastigmine group. The
authors as well as the accompanying editorial stressed
that the negative results of the trial do not compel-
lingly rule out the potential salutatory effect of AChE
inhibitors in preventing POD because of a number
of methodological issues. They hypothesized that
transdermal application of rivastigmine would be ad-
vantageous because of the inconsistent absorption of
the oral drug formulation during the perioperative pe-
riod. Our study design attempted to take into account
such previous experience and suggestions.
However, study recruitment was halted because of a
warning letter issued by the rivastigmine manufacturer
(Novartis) in conjunction with the results of a multicen-
ter trial, which studied the efcacy and safety of rivastig-
mine as an adjunct to haloperidol in critically ill patients
(van Eijk et al., 2010). The trial suggested that oral
administration of rivastigmine might have increased
mortality under certain circumstances in critically ill
patients. In addition, the study found that rivastigmine
had no benecial effect in the treatment of delirium.
On the other hand, previous trials that examined the
use of AChE inhibitors (including rivastigmine) in the
treatment of delirium in the older patients suggested
that this class of drugs may be safe and effective alterna-
tive for the treatment of potential POD in critically ill
patients (Oldenbeuving et al., 2008)
Patients scheduled for elective surgery are generally
medically optimized. Thus, the negative results of the
multicenter trial (van Eijk et al., 2010) obtained in
severely debilitated patients are not necessarily appli-
cable to perioperative care. Our study suggests im-
proved MMSE scores in patients treated with
rivastigmine with or without delirium. Therefore, we
believe that further investigation into the effects of riv-
astigmine for POD is justied. Future studies of cen-
tral AChE inhibitors should focus on selecting
patients who are at high risk for the development of
delirium following surgery under general anesthesia
and, possibly, compare various dosing schedules.
Figure 1 Bar graph illustrating means of Mini mental state examination (MMSE) scores for four time periods presurgical, postoperative visit one, two,
and three. Graphed in red and blue are placebo and rivastigmine groups, respectively. Note higher MMSE values in the rivastigmine group compared
with the placebo group on postoperative visit one and visit two (values: placebo28.84, 28.13, 27.00, 28.87; rivastigmine29.55, 29.27, 29.00, 28.50).
Key points
Rivastigmine does not reduce the incidence of POD
but may improve a recovery of cognitive function
as measured by the Mini mental examination.
Support was provided, in part, by the Empire
Clinical Research Investigator Program, New York
State Department of Health, Graduate Medical
Education Unit, Albany, New York.
987Letter to the Editor
Copyright # 2012 John Wiley & Sons, Ltd. Int J Geriatr Psychiatry 2012; 27: 986988.
Conict of interest
None declared.
Gamberini M, Bolliger D, Lurati Buse GA, et al. 2009. Rivastigmine for the preven-
tion of postoperative delirium in elderly patients undergoing elective cardiac
surgerya randomized controlled trial. Crit Care Med 37: 17621768.
Liptzin B, Laki A, Garb JL, Fingeroth R, Krushell R. 2005. Donepezil in the prevention
and treatment of post-surgical delirium. Am J Geriatr Psychiatry 13:11001106.
Oldenbeuving AW, De Kort PLM, Jansen BPW, Kappelle J, Roks G. 2008 A pilot study of
rivastigmine in the treatment of delirium after strok e: a safe alternative. BMC Neurol 8:-.
Sampson EL, Raven PR, Ndhlovu PN, et al. 2007. A randomized, double-blind,
placebo-controlled trial of donepezil hydrochloride (Aricept) for reducing the
incidence of postoperative delirium after elective total hip replacement. Int J
Geriatr Psychiatry 22: 343349.
Van Eijk MM, Roes KC, Honing ML, et al. 2010. Effect of rivastigmine as an adjunct
to usual care with haloperidol on duration of delirium and mortality in critically ill
patients: a multicentre, double-blind, placebo-controlled randomised trial. Lancet
376: 18291837.
Departments of Anesthesiology, NYU Langone Medical
Center, New York, NY, USA
Departments of Surgery, NYU Langone Medical Center,
New York, NY, USA
Departments of Psychiatry, NYU Langone Medical Center,
New York, NY, USA
Published online in Wiley Online Library
DOI: 10.1002/gps.2801
988 Letter to the Editor
Copyright # 2012 John Wiley & Sons, Ltd. Int J Geriatr Psychiatry 2012; 27: 986988.
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