I DENTIF Y ING A ND MA NA GING P SY C HIATRIC EMER GE N CIE S

Delirium: Treatment and Prevention (Part 2)

KALYA VARDI, MD; COLIN J. HARRINGTON, MD

A BST RA C T agents for the treatment of delirium.1,2 Based on these and

Delirium management begins with non-pharmacologic other consensus statements, antipsychotic agents remain
interventions and treatment of the underlying causes. the treatment of choice for delirium and related agitation.
There are no FDA-approved medications for delirium-re-
lated psychosis and agitation, although numerous agents
have been studied. Small sample size, narrow inclusion NON-P HA RMA C OLOGIC INTERV ENTION S
criteria, lack of placebo controls and variable methodolo- The landmark study by Inouye et al tested a multi-disciplinary
gies limit the generalizability of findings to date. Studies protocol of non-pharmacologic interventions to reduce delir-
and expert guidelines support the use of antipsychotics for ium incidence, duration and severity in 852 elderly patients
delirium-related psychosis and agitation, and demonstrate admitted to the general medical service of an academic hospi-
comparable efficacy and safety between first- and second- tal.3 The protocol consisted of both global interventions and
generation agents. Mounting evidence also suggests targeted interventions for patients with specific risk factors.
that antipsychotics and dexmedetomidine are effective Interventions included early mobilization, noise reduction
in preventing delirium in surgical and mechanically- and scheduling adjustments to minimize sleep disruption,
ventilated patients, respectively. early recognition and treatment of dehydration, orientation
K E YWORD S: delirium, encephalopathy, cognitive disorder, boards and frequent verbal reorientation for patients with
agitation cognitive impairment, and communication aids for patients
with visual and hearing impairment. The incidence of de-
lirium was 40% lower in the intervention group compared
with the control group. The total number of days spent in
delirium was also significantly lower in the intervention
INTRO D U C T I O N group. Zaubler et al replicated these results and reported
Delirium management begins with evaluation and treatment $841,000 in cost savings over 9 months in a community
of its causes, discontinuation of potential offending agents, hospital setting.4 These protocols are considered the stan-
and institution of non-pharmacologic strategies to limit its dard of care and have been put in place at institutions across
incidence, course and complications. Pharmacologic treat- the country. Similar non-pharmacologic interventions have
ment is typically reserved for neurobehavioral symptoms of been designed and implemented by the Brown-based Geri-
agitation and psychosis that are unresponsive to these prima- atric Medicine Program, and form the basis of the Close
ry interventions. Despite its high prevalence and association Observation Medical Unit (COMU) and other elder-care
with multiple adverse outcomes, there are no FDA-approved protocols at Rhode Island Hospital and The Miriam Hos-
treatments for delirium. pital, respectively (L. McNicoll, personal communication,
Studies of delirium management have explored both treat- July 2012).
ment and prevention, have been conducted in general medical-
surgical patients and in critically ill, intensive care unit
(ICU) populations, and have included both pharmacologic P HA RMA C OLOGIC INTERV ENTIONS
and non-pharmacologic interventions. Unfortunately, small – TREATMENT A ND P REV ENTION
sample size, narrow inclusion criteria, lack of placebo con- Overview
trols, and variable methodologies limit the generalizability First generation antipsychotics (FGA), such as haloperidol,
of findings to date. are the mainstay for treating the neurobehavioral symptoms
Numerous agents have been studied for delirium manage- of delirium.1,5,6 Their utility is thought to derive from dopami-
ment including antipsychotics, benzodiazepines, cholines- nergic blockade, based on the hypothesis that dopaminergic
terase inhibitors and other pro-cholinergic drugs, ketamine, hyperactivity and cholinergic deficiency contribute to the
and, more recently, dexmedetomidine. Published guidelines onset and persistence of delirium. For this reason, cholin-
from numerous subspecialty societies and recent meta- esterase inhibitors have also been tried with mixed results.6
analyses recommend haloperidol and other antipsychotic Haloperidol has minimal hemodynamic side effects and

W W W. R I M E D . O R G | RIMJ ARCHIVES | J U N E W E B PA G E JUNE 2014 RHODE ISLAND MEDICAL JOURNAL 24

 I DENTIF Y ING A ND MA NA GING P SY C HIATRIC EMER GE N CIE S

remains the best studied and most recommended treatment and high-dose IV haloperidol have the most significant QT
for delirium-related agitation. Haloperidol can be adminis- prolonging effects of the antipsychotic agents. Although the
tered orally, intramuscularly (IM) or intravenously (IV), has a degree of QTP and absolute risk of TdP associated with these
wide therapeutic window, and can be titrated across a broad agents is small, most guidelines advise caution when using
dose range, from 0.5 mg as needed to 10 mg hourly, with IV haloperidol in patients with risk factors for QTP or TdP
onset of action between 30-60 minutes for the IV and IM (Table 1). The absolute risk of TdP for IV haloperidol has
routes of administration. Peak serum concentrations occur been estimated at 0.27%.5
2-6 hours after oral administration. There are case reports of
safe and effective haloperidol administration up to 500 mg Table 1. Assessing and Monitoring Risk for Drug-Induced QTc
per day.5 Intravenous and IM forms of haloperidol are partic- Prolongation (QTP)
ularly helpful in uncooperative patients and in critically ill Risk Factors for QTP:
patients where gastrointestinal absorption is unreliable. Nu-
• Advanced cardiac disease
merous reports suggest that IV administration is associated
with less risk of extrapyramidal symptoms (EPS).5 Emerging • Known history of long-QT syndrome
data suggests that, in addition to its anti-dopaminergic ac- • Baseline QTc > 450 msec
tion, haloperidol may also counter delirium by decreasing • Hypokalemia
oxidative stress and inflammation via σ-1 receptor blockade
• Hypomagnesemia
and interleukin-1 antagonism.6
There is a literature supporting the use of second- • Concomitant use of other QTc prolonging agents
generation antipsychotics (SGAs) in the treatment of delirium- Prior to Initiating a QTc Prolonging Drug:
related agitation and psychosis.2,5-9 SGAs studied to date • Obtain electrocardiogram to measure baseline QTc interval
include risperidone,10,11 quetiapine,12 olanzapine,9,13 ziprasi-
• Obtain serum potassium and magnesium levels
done,5 and aripiprazole.5 The main advantage of the SGAs
over haloperidol is their relatively reduced risk of EPS, • Correct any electrolyte abnormalities
which is particularly relevant in patients with parkinsonian • Review medication list for QTc-related interactions
syndromes such as dementia with Lewy bodies (DLB) and After Initiating a QTc Prolonging Drug:
idiopathic Parkinson’s disease (PD). Quetiapine is least like-
• Repeat electrocardiogram at regular intervals (typically once daily)
ly to produce or exacerbate EPS and is the agent of choice
in treating agitation and psychosis in parkinsonian patients.
Unlike haloperidol, none of the SGAs are available IV. Olan- Dexmedetomidine is a highly selective, centrally-acting
zapine, ziprasidone, and aripiprazole can be administered in alpha-2 agonist with sedative, analgesic and anxiolytic prop-
immediate-release intramuscular forms and are indicated erties, and has been studied for both prevention of delirium
when the oral route is unavailable and haloperidol is con- and treatment of delirium-related agitation in ICU patients.
traindicated. Risperidone and paliperidone are available in Trials comparing dexmedetomidine to benzodiazepine and
long-acting intramuscular depot formulations which are opioid ICU sedation protocols have demonstrated its effica-
utilized in the treatment of patients with chronic psychotic cy, safety and favorable side effect profile.15-19 Unlike most
illnesses, but are not indicated in delirium. other sedatives employed in the ICU, dexmedetomidine is
The FDA issued “black box” warnings in April 2005 and not associated with significant respiratory depression; how-
June 2008 regarding the use of antipsychotic agents in the ever, hypotension and bradycardia can complicate its use,
elderly. These warning were based upon evidence of in- especially at high infusion rates.6,15-19 Multiple studies have
creased cerebrovascular events and all-cause mortality in reported decreased opiate requirements in ICU and post-op-
studies of extended courses of antipsychotic treatment in erative patients sedated with dexmedetomidine.5 Reduced
elderly, demented nursing home patients.14 The relevance of opioid use likely contributes to the lower incidence of delir-
these findings and warnings to the short-term use of these ium observed in dexmedetomidine-treated patients. Dexme-
agents in patients with delirium is unclear. Given the high detomidine is also thought to have mild cholinergic activity
prevalence of co-morbid dementia in delirium patients, these which may favorably affect the sleep-wake cycle.5
warnings should be taken into consideration when weigh- Benzodiazepines are potentially deliriogenic. Except for
ing the potential risks and benefits of brief antipsychotic cases of alcohol and sedative-hypnotic withdrawal where
treatment against those of untreated delirium. they are the treatment of choice, benzodiazepines are not
Haloperidol and all SGAs carry a risk of QTc prolongation considered first-line agents in the treatment of delirium-re-
(QTP) and QTP is the best predictor of torsade de pointes lated agitation.20 Adjunctive use of benzodiazepines is ap-
(TdP), a malignant ventricular dysrhythmia. The QT pro- propriate in cases of agitation related to certain toxidromes
longing effects of antipsychotic and other agents are cata- and neuroleptic-malignant syndrome, or when delirium is
logued at www.torsades.org. Low-dose oral haloperidol has complicated by catatonia or severe EPS that limit the use of
minimal QT prolonging effects. Thioridazine, ziprasidone antipsychotic agents.

W W W. R I M E D . O R G | RIMJ ARCHIVES | J U N E W E B PA G E JUNE 2014 RHODE ISLAND MEDICAL JOURNAL 25

 I DENTIF Y ING A ND MA NA GING P SY C HIATRIC EMER GE N CIE S

The existing literature is summarized below with special duration of coma between groups, a measure included due to
attention to differences between general medical-surgical concern that the sedating effects of antipsychotics may pro-
patients versus ICU patients. Outcome measures vary long coma. Rates of EPS, including akathisia, were compara-
across these studies and include delirium incidence, severity ble across groups. Extrapyramidal signs and symptoms were
and duration, length of hospitalization, length of time in the assessed by physical exam. Akathisia in particular, could
ICU, number of ventilator dependent days, and disposition to only be assessed when patients were neither comatose nor
home versus other medical facilities or institutional settings. delirious, and could participate in the assessment. A 2013
Typical teaching recommends the use of antipsychotic international study used similar methods to compare IV hal-
agents for the treatment of delirium-related psychosis and operidol to placebo for prevention and treatment of delirium
agitation but not for the delirium syndrome proper. Animal in mechanically-ventilated patients, and found no signif-
studies suggest that dopaminergic mechanisms play a role icant difference between groups in duration of delirium.24
in the development of delirium irrespective of the presence Devlin et al randomized 36 delirious, ICU patients to re-
or absence of agitated behavior. Additionally, recent studies ceive oral quetiapine or placebo.12 Treatment with quetia-
and personal accounts suggest that a significant proportion pine was associated with shorter total duration of delirium,
of non-agitated, “hypoactive” delirium patients experience shorter time to first resolution of delirium, and less hours of
distressing psychotic symptoms and that these frightening agitation compared with placebo. Significantly more adverse
symptoms may drive the development of a post-traumatic effects were reported in the quetiapine group, especially
stress disorder (PTSD)-like syndrome.21,22 Taken together, sedation; however, no EPS or QTP were observed.
these observations may argue for more liberal use of dopa- In a small, open-label trial, mechanically-ventilated ICU
mine-blocking agents in the treatment of delirium, even in patients with severe agitation secondary to delirium were
the absence of problem behaviors. randomized to receive a continuous infusion of either dex-
medetomidine or haloperidol.15 The dexmedetomidine group
spent more time with minimal or no delirium symptoms,
T REAT M E N T S T U D I E S less time intubated, less time in the ICU and less time in
General Medical and Surgical Patients mechanical restraints. Three patients receiving haloperidol
Multiple case reports and small, open-label trials suggest could not be extubated and underwent tracheostomy, com-
that SGAs (including risperidone, quetiapine, olanzapine, pared with none in the dexmedetomidine group. Haloperidol
aripiprazole and ziprasidone) are effective and safe in the was discontinued early in one patient due to QTP.
treatment of delirium.5,9-13 Several single-blind, randomized A qualitative meta-analysis of antipsychotic use for de-
trials comparing SGAs to haloperidol for the treatment of lirium in ICU patients reviewed three studies including the
delirium found no significant differences between the two MIND and Devlin trials and a study by Skrobik et al of 73
interventions in treatment outcomes or adverse effects.5 delirious ICU patients randomized to oral olanzapine or hal-
One double-blind RCT of risperidone versus haloperidol operidol.9 Evidence was strongest for the beneficial effects of
in 28 delirious patients reported comparable improvement quetiapine in the treatment of delirium. Guidelines from the
across groups.10 A 2007 Cochrane review of antipsychotic American College of Critical Care Medicine (ACCM) report
use in delirium included a meta-analysis of haloperidol, similar evidence for quetiapine and other SGAs in compar-
olanzapine, risperidone and placebo treatment studies, and ison to haloperidol in reducing the duration of delirium in
concluded that (1) haloperidol does not significantly reduce ICU patients.2,9
delirium incidence compared with placebo, (2) low-dose An RCT of rivastigmine versus placebo as adjunct to halo-
haloperidol reduces delirium severity and duration in peridol for ICU delirium was stopped early due to increased
post-operative patients, (3) low-dose haloperidol and the mortality in the rivastigmine group.25 The median duration
SGAs have similar efficacy and EPS incidence, and (4) higher of delirium, severity of delirium, length of ICU stay, and
dose haloperidol is associated with more severe EPS.8 cumulative doses of as needed haloperidol, lorazepam and
propofol were all higher in the rivastigmine group. The dos-
ICU Patients ing schedule for rivastigmine was different from the regimen
In the MIND study, which evaluated prevention and treat- used in Alzheimer’s disease, with increases allowed every
ment, 101 mechanically-ventilated ICU patients were ran- 2-3 days based on the assumption that correction of the func-
domized to receive oral haloperidol, oral ziprasidone, or tional cholinergic deficit of delirium would be more rapid
placebo for up to 14 days according to a protocol which than that of chronic dementia.25 The ACCM advises against
allowed for dose adjustments based on delirium severity, using rivastigmine for delirium in adult ICU patients.2
level of sedation and side effects.23 Neither agent significant-
ly reduced the duration of delirium, although the study was
most likely underpowered due to small sample size, inclu- P REV ENTION STU D IES
sion of patients without delirium at baseline, and open-label General Medical and Surgical Patients
IV haloperidol use across groups. There was no difference in At least three studies have examined prophylactic anti-

W W W. R I M E D . O R G | RIMJ ARCHIVES | J U N E W E B PA G E JUNE 2014 RHODE ISLAND MEDICAL JOURNAL 26

 I DENTIF Y ING A ND MA NA GING P SY C HIATRIC EMER GE N CIE S

psychotic use in patients undergoing orthopedic or gastro- and required less norepinephrine. Dexmedetomidine use was
intestinal surgery. In a double-blind study, Kalisvaart et al associated with significantly higher incidence of bradycardia.
randomized 430 hip surgery patients to receive oral haloper- Dexmedetomidine is an expensive drug, but a recent cost
idol or placebo from admission until the third post-opera- analysis comparing it to midalozam for sedation in mechan-
tive day.26 The incidence of delirium was similar between ically-ventilated ICU patients reported a median savings of
groups; however, delirium episodes were shorter and less $9,679 per ICU stay in dexmedetomidine treated patients.19
severe in the haloperidol group. Kaneko et al randomized 78 Two placebo controlled studies reported no benefit of cho-
gastrointestinal surgery patients to receive haloperidol or linesterase inhibitors for delirium prevention in surgical
normal saline IV on post-operative days one through five.7 ICU patients.6 In contrast, ketamine administered during
The incidence, severity and duration of delirium were sig- anesthesia induction was associated with a lower incidence
nificantly lower in the haloperidol group. In a double-blind of postoperative delirium compared to placebo in cardiac
study, Larsen et al randomized 400 patients undergoing hip surgery patients (3% versus 31%).28
or knee replacement surgery to receive one dose of olanzap-
ine or placebo immediately pre- and post-operatively.13 De-
lirium incidence was significantly lower in the olanzapine C ONC LU SION
group (14.3% vs. 40.2%, p < 0.0001) and more patients in the Studies and expert guidelines support the use of anti-
olanzapine group were discharged to home. Notably, when psychotics for the treatment of delirium-related psychosis
delirium did occur in the olanzapine group, it lasted longer and agitation. First- and second-generation agents have
and was more severe. The latter findings were attributed to demonstrated comparable efficacy and safety. Non-phar-
the unexpected development of alcohol withdrawal in five macologic interventions significantly reduce delirium in-
of the 28 patients in the treatment group versus none in the cidence, duration and severity. There is growing evidence
control group. that antipsychotics and dexmedetomidine are effective in
preventing delirium in surgical and mechanically-ventilated
ICU Patients patients, respectively.
Two studies have examined prophylactic antipsychotic use
in postoperative ICU patients. Prakanrattana et al random-
ized 126 cardiac surgery patients to receive a single dose of References
risperidone or placebo postoperatively.11 Delirium incidence 1. American Psychiatric Association: Practice guideline for
the treatment of patients with delirium. Am J Psychiatry.
was significantly lower in the risperidone group. Wang et al
1999;156(5 suppl):1–20.
randomized 457 cardiac surgery patients to receive a contin- 2. Barr J, Fraser GL, Puntillo K, et al. Clinical practice guidelines
uous infusion of either haloperidol or normal saline post- for the management of pain, agitation, and delirium in adult
operatively.27 Haloperidol treatment was associated with a patients in the intensive care unit. Crit Care Med. 2013;41(1):
263-306.
lower 7-day incidence of delirium, longer time to delirium
3. Inouye SK, Bogardus ST, Charpentier PA, et al. A multicompo-
onset, and a greater number of delirium free-days. A recent nent intervention to prevent delirium in hospitalized older pa-
meta-analysis of studies examining delirium prevention in tients. N Engl J Med. 1999;340(9):669-76.
general and ICU surgical patients calculated a relative risk of 4. Zaubler TS, Murphy K, Rizzuto L, et al. Quality improvement
and cost savings with multicomponent delirium interventions:
0.5 for developing delirium in patients receiving prophylac-
replication of the Hospital Elder Life Program in a community
tic antipsychotic medication compared with placebo.7 hospital. Psychosomatics. 2013;54(3):219-26.
Three RCTs have examined the incidence of delirium 5. Maldonado JR. Delirium in the acute care setting: characteris-
among ICU patients sedated with dexmedetomidine versus tics, diagnosis and treatment. Crit Care Clin. 2008;24(4):657-
722, vii.
benzodiazepines or opioids. The MENDS trial randomized
6. Bledowski J, Trutia A. A review of pharmacologic management
106 mechanically-ventilated ICU patients to sedation with and prevention strategies for delirium in the intensive care unit.
dexmedetomidine or lorazepam.16 The number of days alive Psychosomatics. 2012;53(3):203-11.
without coma or delirium was significantly higher in the 7. Teslyar P, Stock VM, Wilk CM, Camsari U, Ehrenreich MJ,
Himelhoch S. Prophylaxis with antipsychotic medication re-
dexmedetomidine group. Maldonado et al randomized 118
duces the risk of post-operative delirium in elderly patients: a
mechanically-ventilated, cardiac surgery patients to dex- meta-analysis. Psychosomatics. 2013;54(2):124-31.
medetomidine, propofol or midazolam sedation protocols.17 8. Lonergan E, Britton AM, Luxenberg J, Wyller T. Antipsychotics
Delirium incidence was significantly lower in the dexmede- for delirium. Cochrane Database Syst Rev. 2007;(2):CD005594.
tomidine group but there were no significant differences in 9. Devlin JW, Skrobik Y. Antipsychotics for the prevention and
treatment of delirium in the intensive care unit: what is their
length of ICU or hospital stay. In the DEXCOM study, 306 car- role? Harv Rev Psychiatry. 2011;19(2):59-67.
diac surgery patients were randomized to either dexmedeto- 10. Han CS, Kim YK. A double-blind trial of risperidone and hal-
midine or morphine for sedation and analgesia on admission operidol for the treatment of delirium. Psychosomatics.
2004;45(4):297-301.
to the ICU.18 Delirium incidence was comparable, but dex-
11. Prakanrattana U, Prapaitrakool S. Efficacy of risperidone for pre-
medetomidine-treated patients spent three fewer days in de- vention of postoperative delirium in cardiac surgery. Anaesth
lirium, were extubated earlier, experienced less hypotension Intensive Care. 2007;35(5):714-9.

W W W. R I M E D . O R G | RIMJ ARCHIVES | J U N E W E B PA G E JUNE 2014 RHODE ISLAND MEDICAL JOURNAL 27

 I DENTIF Y ING A ND MA NA GING P SY C HIATRIC EMER GE N CIE S

12. Devlin JW, Roberts RJ, Fong JJ, et al. Efficacy and safety of que- Authors
tiapine in critically ill patients with delirium: a prospective, Kalya Vardi, MD, is a Psychiatry Resident, General Psychiatry
multicenter, randomized, double-blind, placebo-controlled pilot
Residency Training Program at Butler Hospital and the Alpert
study. Crit Care Med. 2010;38(2):419-27.
Medical School of Brown University.
13. Larsen KA, Kelly SE, Stern TA, et al. Administration of olanzap-
ine to prevent postoperative delirium in elderly joint-replace- Colin J. Harrington, MD, is Director, Consultation Psychiatry
ment patients: a randomized, controlled trial. Psychosomatics. and Neuropsychiatry Education, Rhode Island Hospital and
2010;51(5):409-18. Associate Professor (clinical), Clinician Educator, Departments
14. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafety- of Psychiatry and Medicine at the Alpert Medical School of
InformationforPatientsandProviders/ucm124830.htm. Accessed Brown University.
January 22, 2014.
15. Reade MC, O’Sullivan K, Bates S, Goldsmith D, Ainslie WR, Correspondence
Bellomo R. Dexmedetomidine vs. haloperidol in delirious, ag- Colin J. Harrington, MD
itated, intubated patients: a randomized open-label trial. Crit Rhode Island Hospital, APC 9
Care. 2009;13(3):R75. 593 Eddy St.
16. Pandharipande PP, Pun BT, Herr DL, et al. Effect of sedation Providence, RI 02903
with dexmedetomidine vs lorazepam on acute brain dysfunc-
tion in mechanically ventilated patients: the MENDS random- 401-444-5480
ized controlled trial. JAMA. 2007;298(22):2644-53. Fax 401-444-3492
17. Maldonado JR, Wysong A, Van der starre PJ, Block T, Miller C, [email protected]
Reitz BA. Dexmedetomidine and the reduction of postopera-
tive delirium after cardiac surgery. Psychosomatics. 2009;50(3):
206-17.
18. Shehabi Y, Grant P, Wolfenden H, et al. Prevalence of delirium
with dexmedetomidine compared with morphine based therapy
after cardiac surgery: a randomized controlled trial (DEXmede-
tomidine COmpared to Morphine-DEXCOM Study). Anesthesi-
ology. 2009;111(5):1075-84.
19. Dasta JF, Kane-Gill SL, Pencina M, et al. A cost-minimization
analysis of dexmedetomidine compared with midazolam for
long-term sedation in the intensive care unit. Crit Care Med.
2010;38(2):497-503.
20. Mayo-Smith MF, Beecher LH, Fischer TL, et al. Management of
alcohol withdrawal delirium. An evidence-based practice guide-
line. Arch Intern Med. 2004;164(13):1405-12.
21. Misak CJ. The critical care experience: a patient’s view. Am J
Respir Crit Care Med. 2004;170(4):357-9.
22. Jones C, Griffiths RD, Humphris G, Skirrow PM. Memory,
delusions, and the development of acute posttraumatic stress
disorder-related symptoms after intensive care. Crit Care Med.
2001;29(3):573-80.
23. Girard TD, Pandharipande PP, Carson SS, et al. Feasibility, effi-
cacy, and safety of antipsychotics for intensive care unit deliri-
um: the MIND randomized, placebo-controlled trial. Crit Care
Med. 2010;38(2):428-37.
24. Page VJ, Ely EW, Gates S, et al. Effect of intravenous haloperidol
on the duration of delirium and coma in critically ill patients
(Hope-ICU): a randomised, double-blind, placebo-controlled tri-
al. Lancet Respir Med. 2013;1(7):515-23.
25. van Eijk MM, Roes KC, Honing ML, et al. Effect of rivastigmine
as an adjunct to usual care with haloperidol on duration of deliri-
um and mortality in critically ill patients: a multicentre, double-
blind, placebo-controlled randomised trial. Lancet. 2010;376
(9755):1829-37.
26. Kalisvaart KJ, De jonghe JF, Bogaards MJ, et al. Haloperidol
prophylaxis for elderly hip-surgery patients at risk for deliri-
um: a randomized placebo-controlled study. J Am Geriatr Soc.
2005;53(10):1658-66.
27. Wang W, Li HL, Wang DX, et al. Haloperidol prophylaxis de-
creases delirium incidence in elderly patients after noncar-
diac surgery: a randomized controlled trial*. Crit Care Med.
2012;40(3):731-9.
28. Hudetz JA, Patterson KM, Iqbal Z, et al. Ketamine attenuates
delirium after cardiac surgery with cardiopulmonary bypass. J
Cardiothorac Vasc Anesth. 2009;23(5):651-7.

W W W. R I M E D . O R G | RIMJ ARCHIVES | J U N E W E B PA G E JUNE 2014 RHODE ISLAND MEDICAL JOURNAL 28