Impact of Dexmedetomidine on the Incidence of Delirium in Elderly Patients after Cardiac Surgery: A Randomized Controlled Trial

1. Pokhara University
School of Health and Allied Sciences
Impact of Dexmedetomidine on the
Incidence of Delirium in Elderly
Patients after Cardiac Surgery: A
Randomized Controlled Trial
Deepa kumari karn
Seminar 1st , Mpharm (C.P)1st sem
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2. Pokhara University
School of Health and Allied Sciences
Table of Content
• Introduction
– Delirium
– Dexmedetomidine
• Research Question
• Literature review
• Objective
– General Objective
– Specific Objective
• Rational of the study
• Methods
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3. Pokhara University
School of Health and Allied Sciences
– Study design
– Participants
– Randomization, intervention and anesthesia management
– Outcome assessment and follow-up schedule
– Statistical analysis
• Results
– Patient population
– Effectiveness analysis
– Safety analysis
 Discussion
 Conclusion
 References
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Introduction
 Delirium
• Delirium is common complication after cardiac
surgery, with reported incidences varied from 3% to
47%
• Occurrence of delirium after cardiac surgery is
associated with worse outcomes:
increased rate of complications
prolonged duration of mechanical ventilation
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5. Pokhara University
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Prolonged length of stay in ICU and hospital
increased medical expenses during hospitalization
• Pathogenesis of postoperative delirium is not fully
understood
• Previous studies demonstrated that deep anesthesia
during surgery and use of high doses opiates and/or
sedatives after surgery are important predisposing
factors
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 Dexmedetomidine
 Highly selective alpha 2-adrenoceptor agonist with
anxiolytic, sedative, and analgesic properties
 Widely used as an adjuvant during general anesthesia
and for sedation during mechanical ventilation after
surgery
• Hypothesized that use of dexmedetomidine as an
anesthetic adjuvant during cardiac surgery decreased
the incidence of delirium, possibly by sparing the
consumption of general anesthetics5/29/2017 7

8. Pokhara University
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Research Question
• Can the use of dexmedetomidine during and shortly
after cardiac surgery decrease the incidence of
delirium in elderly patients?
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Literature review
• Dexmedetomidine inhibits the noradrenergic nuclei in
the locus ceruleus of the brainstem, inhibits
nociception in spinal cord
• Decreases sympathetic outflow and circulating
catecholamines
• Intraoperatively it provides stable haemodynamic
profile by attenuating stress response during tracheal
intubation, during surgery and emergence from
anesthesia.5/29/2017 9

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Mechanism of action of DEX
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• According to the American Psychiatric Association's
Diagnostic and Statistical Manual of Mental
Disorders (DSM-IV), delirium is defined as “a
disturbance of consciousness with reduced ability to
focus, sustain, or shift attention; a change in
cognition; or the development of a perceptual
disturbance that occurs over a short period of time
and tends to fluctuate over the course of the day
• Van Gemert and Schuurmans defined delirium as a
frequent form of psychopathology in elderly
hospitalized patients; it is a symptom of acute
somatic illness”5/29/2017 11

12. Pokhara University
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• Literature showed that 10 to 30% of patients
admitted to a general hospital develop delirium and
a prevalence of up to 60% is recognized in frail
elderly patients
• A delirium is also often misdiagnosed as depression
or dementia, or considered normal behavior in
elderly patients due to the lack of knowledge and
awareness of nurses and doctors
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Objectives
General Objective:
• To investigate the effect of the dexmedetomidine
administered during and after cardiac surgrey on the
incidence of delirium in the elderly patient
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14. Pokhara University
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Specific Objective:
 Assessment of the patient for the eligibility for the
inclusion for the research
 Assessment for the delirium
 Assessment of the level of sedation on the basis of RAS
scale
 Maintenance of the haemodynamic during the surgery
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15. Pokhara University
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Rational of the study
• Studies suggest that the use of dexmedetomidine in
patient under going the cardiac surgery , decrease the
consumption of the opioids and other anesthetic drugs
which provide the baseline idea for this research
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Methods
 Study design
 Randomized, double-blind, and placebo-controlled
two-center trial
• Study protocol was approved by the Ethics
Committees of Peking University First Hospital and
Beijing Fuwai Hospital , and was registered with
ClinicalTrials.gov number, NCT02267538
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 Participants
 Inclusion criteria:-
– Elderly patients (age 60 years) who were scheduled to
undergo elective coronary artery bypass graft and/or valve
replacement surgery
• Exclusion criteria:-
– Previous history of schizophrenia, epilepsy, Parkinson
disease, or severe dementia
– Inability to communicate because of severe visual/auditory
dysfunction or language barrier
– Previous history of functional neurosurgery or brain injury;
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– Preoperative sick sinus syndrome, severe bradycardia,
second-degree or above atrioventricular block without
pacemaker
– Severe hepatic insufficiency
– Severe renal insufficiency
– Patient refused to participate in the study
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Randomization, intervention and anesthesia
management
• Center-stratified randomization with a block size of 4
was done using the SAS statistical package version
9.3
• Study drugs, either dexmedetomidine hydrochloride
200 μg /2 ml or 0.9% sodium chloride 2 ml, were
provided as clear aqueous solutions in the same 3 ml
bottles
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20. Pokhara University
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• Encoded according to the randomization order by an
independent pharmacist who did not participated in
the rest of the study
• Study drugs were diluted with normal saline to 50 ml
before administration, for dexmedetomidine the final
concentration was 4 μg/ml
• Drug infusion was started once the intravenous
access was established, firstly at a rate of [0.9 × kg]
ml/h (i.e., 0.6 μg/kg for dexmedetomidine) for 10
minutes, then at a rate of [0.1 × kg] ml/h (i.e., 0.4
μgkg-1h-1 for dexmedetomidine) until the end of
surgery.
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21. Pokhara University
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• After surgery, study drug infusion was continued at a
rate of [0.025 × kg] ml/h (i.e., 0.1 μgkg-1h-1 for
dexmedetomidine) until the end of mechanical
ventilation
• Anesthesia was induced with midazolam, etomidate,
sufentanil, and propofol, and was maintained with
sufentanil and propofol infusion and/or sevoflurane
inhalation
• All patients were transferred to the intensive care unit
(ICU) after surgery
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22. Pokhara University
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• Patients who required additional analgesia, opiates
were administered either intravenously or orally
• For patients who required sedation (i.e., patients
undergoing mechanical ventilation), propofol
intravenous infusion was the first choice
• For all enrolled patients, Penehyclidine hydrochloride
and scopolamine were prohibited, and open-labled
Dexmedetomidine was not allowed during the whole
study period
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 Outcome assessment and follow-up schedule
• Prior to the study, two investigators (XL and YZ) who
performed interview and delirium assessments were
trained to follow standard procedures and to use the
Confusion Assessment Method (CAM) and the CAM
for the Intensive Care Unit (CAM-ICU) by a
psychiatrist
• Before surgery, detailed baseline data including
demographics, comorbidities, medication, laboratory
test results, diagnosis, and ASA classification were
collected. Preoperative evaluations were performed
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Tab: Baseline data5/29/2017 24

25. Pokhara University
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• Intraoperative data including type of surgery, duration
of anesthesia and surgery, names and doses of
anesthetic drugs, use and duration of
cardiopulmonary bypass and aortic crossclamping,
transfusion of blood products, and fluid balance were
recorded
• Delirium was assessed daily (from 8 to 10 am) during
postoperative days 1 to 5
• For patients who were discharged or died before
postoperative day 5, the results of last delirium
assessment were used as the missing data5/29/2017 25

26. Pokhara University
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• On postoperative day 6, cognitive function was
reevaluated using the MMSE; the duration of
mechanical ventilation, the length of stay in the ICU
and hospital after surgery, and the occurrence of non-
delirium complications were recorded
• The primary endpoint was the incidence of delirium
within the first five days after surgery.
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27. Pokhara University
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• Secondary endpoints included the cognitive function
assessed on postoperative days 6 and 30, the overall
incidence of non-delirium complications within 30
days after surgery, and the all-Dexmedetomidine and
delirium after cardiac surgery cause 30-day mortality
• Other predefined endpoints included the severity of
pain and subjective sleep quality during the first 5
days after surgery, the duration of mechanical
ventilation, the length of stay in ICU and hospital
after surgery, and the re-hospitalization rate within 30
days after surgery
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Tab: Intra and postoperative data5/29/2017 28

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 Statistical analysis
 Sample size estimation
– It was assumed that the incidence of delirium after cardiac
surgery was 30% in the CTRL group patients
– A meta-analysis showed that the incidence of delirium was
reduced by 63% when dexmedetomidine was used for
sedation in patients after cardiac surgery
– Sample size calculation was performed with the PASS 11.0
software
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30. Pokhara University
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 Outcome analyses
– Continuous variables with normal distribution were
analyzed using the unpaired t-test
– Continuous variables with abnormal distribution or ordinal
data were analyzed with Mann-Whitney U test
– Outcome and safety data were analyzed in the intent-to-
treat population
– Statistical analysis was performed with SAS statistical
package
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31. Pokhara University
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Results
 Patient population
Fig :- Flow Diagram of the study. DEX, dexmedetomidine;
CTRL, control; ITT, Intention-to-Treat.
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32. Pokhara University
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 Effectiveness analysis
• There was no significant difference between the two
groups regarding the incidence of delirium during the
first 5 days after surgery
• There were no significant differences between the
two groups regarding the overall incidence of non-
delirium complications within 30 days after surgery
• The intensity of pain both at rest and with coughing
as well as the subjective sleep quality at postoperative
days 1 to 5 were similar between the two groups
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33. Pokhara University
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• The duration of mechanical ventilation was shorter in
the DEX group than in the CTRL group, the
percentage of patients extubated within 24 hours after
surgery was higher in the DEX group than in the
CTRL group
• There were no significant differences between the
two groups regarding the incidence of coma within 5
days after surgery, the duration of delirium, the
lengths of stay in ICU and hospital after surgery, and
the rate of re-hospitalization within 30 days after
surgery
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 Safety analysis
• The percentage of patients requiring intraoperative
treatment for tachycardia was lower in the DEX
group than in the CTRL group
• The percentage of patients requiring postoperative
treatment for hypotension was higher in DEX group
than in the CTRL group
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35. Pokhara University
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Tab: Effectiveness outcome5/29/2017 35

36. Pokhara University
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Discussion
• Dexmedetomidine infusion decreased the required
treatment for intraoperative tachycardia but
increased the required treatment for postoperative
hypotension
• In this research, the incidence of delirium in the CTRL
group was 7.7%, much lower than our and others'
previous studies because of :-
– Anticholinergic drugs were less used in the current study
– benzodiazepines were much less used than previously
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37. Pokhara University
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– delirium-preventing measures were used more commonly
in daily nursing practice, including reorientation, cognitive
stimulating,sleep promotion, and hearing/vision aids
• Dexmedetomidine produces a mild analgesic effect
by activating the α2 adrenoceptors in the spine cord
• Dexmedetomidine produces a hypnotic effect by
activating the endogenous sleep-promoting pathway
and improves the sleep quality in mechanically
ventilated patients
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38. Pokhara University
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• Use of dexmedetomidine did not decrease the overall
incidence of nondelirium complications, but it tended
to decrease the incidence of pulmonary complications
after surgery
• Duration of mechanical ventilation was shortened and
the percentage of extubation within 24 hours after
surgery was increased in the DEX group
• Decrease the required t/t for intraoperative
tachycardia; increase the required t/t for postoperative
hypotension and thus, its safety, other benefits and
long-term outcome are subjected to study further5/29/2017 38

39. Pokhara University
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• Several limitations of this study was:-
– Patients who were unable to communicate due to
visual/auditory dysfunction, language barrier or psychiatric
disease, and those with severe hepatic or kidney disease
were excluded
– Delirium was assessed once daily in the present study
– Because of the low incidence of delirium in the CTRL
group, this trial was underpowered to detect difference
between the two groups
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40. Pokhara University
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Conclusions
• Dexmedetomidine administered during anesthesia
and early postoperative period did not decrease the
incidence of postoperative delirium in elderly patients
undergoing elective cardiac surgery
• Dexmedetomidine decreased the required treatment
for intraoperative tachycardia, but increased the
required treatment for postoperative hypotension
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Reference
1. Li X, Yang J, Nie, Zhang Y, Huan L, Wang D, Ma D
(2017), Impact of dexmedetomidine on the
incidence of delirium in elderly patients after
cardiac surgery: A randomized controlled trial. PLoS
ONE 12(2): e0170757. doi:10.1371/journal
pone.0170757, 1-15.
2 Jethva K and Shan R, Dexmedetomidine as an
Adjuvant in General Anaesthesia (2013)
International Journal for Scientific Research , 2(11),
355-357.5/29/2017 41

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3. Koster S, Delirium in Cardiac Surgery (2011)
University of Twente , 1-150.
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