DEXMEDETOMIDINE

IN PATIENTS
FOLLOWING
CARDIAC SURGERY
Erica Helen Rath and Lincy Varughese
Pharm.D. candidates 2016
Pediatrics 4657

OBJECTIVES
Refresh knowledge of dexmedetomidines place in therapy
Identify complications of prolonged mechanical ventilation
Determine patients that would benefit from the use of

dexmedetomidine and patients in which dexmedetomidine

should be avoided

Evaluate clinical evidence regarding the role of

dexmedetomidine for facilitating extubation

PRECEDEX
(DEXMEDETOMIDINE)
FDA approval
1999 as continuous infusion in ICU for up to 24 hours

during mechanical ventilation

Dosing
1mcg/kg IV over 10 minutes followed by maintenance 0.20.7mcg/kg/hr up to 1.5mcg/kg/hr

Dexmedetomidine In: Lexi-Drugs [database online]. Hudson, Ohio: LexiComp, Inc.

MECHANISM OF ACTION
Potent centrally acting 2-agonist
Activation of G-proteins alpha-2a adrencoeptors in the
brainstem which results in the inhibition of norepinephrine
release
Selectivity for 2 vs. 1 is roughly 1600:1

Dexmedetomidine In: Lexi-Drugs [database online]. Hudson, Ohio: LexiComp, Inc.

PHARMACOKINETICS
Onset of action: 15minutes
Distribution half-life: 6 minutes
Elimination half-life: 2 hours
Metabolism: hepatic to an inactive metabolite via CYP

2A6 and glucuronidation

Excretion: 95% in urine

Dexmedetomidine In: Lexi-Drugs [database online]. Hudson, Ohio: LexiComp, Inc.

PRECEDEX
(DEXMEDETOMIDINE)
Sedative and anxiolytic effects
Locus coeruleus in the CNS
2a receptors: antinociceptive receptors, sedative,
sympatholytic, hypothermic, behavioral actions
Induces arousable sedation
Similar/superior efficacy in providing sedation when
compared to commonly used ICU sedatives during
mechanical ventilation

Szumita P et al. Am J Health-Syst Pharm 2007; 64:37-44.

West R et al. Intensive Care Medicine. New York: Springer; 2009.
906-914.

PRECEDEX
(DEXMEDETOMIDINE)
Analgesic effects
Theory: activation of 2c receptor
Synergistic analgesic effect with -opioid agonist
Opioid analgesic sparing effect however does not meet total
analgesic effect needed for ICU patients
Less respiratory depression compared to other sedative
agents.

Szumita P et al. Am J Health-Syst Pharm 2007; 64:37-44.

West R et al. Intensive Care Medicine. New York: Springer; 2009.
906-914.
Maldonado J et al. Psychosomatics 2009; 50:206-217.

DEXMEDETOMIDINE
WEANING
Patients on long-term (>3days) sedation with

dexmedetomidine must be weaned to avoid withdrawal

symptoms
Tachycardia, hypertension, agitation

Patients commonly weaned using clonidine due to the

similar structure

Clonidine affinity to 2: 1=200:1

Previous studies use clonidine patches
50-100mcg/24-hr
~9mcg/kg/day
Lardieri A et al. J Pediatr Pharmacol Ther. 2015; 20:
45-53.

DEXMEDETOMIDINE
2007- Pandharipande et al.
Dexmedetomidine appears to decrease prevalence and duration of acute
brain dysfunction and may be effective in achieving target sedation
compared to lorazepam
2009-Maldonado et al.
Dexmedatomidine for postoperative sedation appears to reduce the
incidence and duration of delirium compared to propofol or midazolam
2009- Riker et al.
Used in conjunction with other sedative practices, dexmedetomidine
decreases time to extubation and reduces prevalence of delirium when
compared to midazolam
Pandharipande P et al. JAMA 2007; 298:26442653
Maldonado et al. Psychosomatics 2009; 50:

MECHANICAL VENTILATION
Assist Control Ventilation
Delivers set amount of air upon patient initiated breath
Pressure Support Ventilation
Supports patients breathing by delivering air at a predetermined
pressure
Synchronized Intermittent Mandatory Ventilation
Intermittently supplies mandatory frequency of breaths at predetermined
volume or pressure that is synchronized with patient breathing efforts
Continuous Positive Airway Pressure
Constant pressure maintained above atmospheric pressure throughout
the respiratory cycle
Cawley M et al. Pharmacotherapy 2007;
27:250-266.

10

COMPLICATIONS OF
MECHANICAL VENTILATION
Patient discomfort
Additional sedative and/or neuromuscular blockade

requirements

Infection-ventilator acquired pneumonia

Increased intracranial pressure
Gastric ileus

Fessler M et al. Chapter 27. In: Hanley M Welsh C, Eds. Current

Diagnosis & Treatment in Pulmonary Medicine. New York: McGrawHill; 2003.

11

MORBIDITY, MORTALITY,
ECONOMICS RELATED TO
PROLONGED MECHANICAL
VENTILATION
In-hospital mortality up to 52%
Survival to acute care facility discharge: 49-92%
Economics: mechanical ventilation >7 days: 37% total ICU

resources consumed

Mechanical ventilation cost: $2,000/day

Costs associated with prolonged mechanical ventilation
Inpatient charges: 120-135,000 per patient
ICU charges: $24 billion per year

Carson S et al. Crit Care Clin 2002; 18:461476.

12

COOK CHILDRENS SPECIFIC

PRICING
Dexmedetomidine drip: $396
Fentanyl drip: $109
Midazolam drip: $130
Propofol: $150

13

DEXMEDETOMIDINE IN
CONCLUSION
Patients that would benefit:
Patients who have difficulty weaning from mechanical
ventilation due to
Agitation or delirium
Excessive sedative and/or analgesic use with

benzodiazepines/ propofol/opioids

Do not uses in these patients:

Hypovolemia or hypotension
Previous history of cardiac arrhythmias
14

15

INTRAOPERATIVE
DEXMEDETOMIDINE
REDUCES POSTOPERATIVE
MECHANICAL
VENTILATION IN INFANTS
AFTER OPEN HEART
SURGERY

Achuff BJ, Nicolson SC, Elci OU, Zuppa AF. Pediatr Crit Care Med.
2015 Jun;16(5):440-7.

ABBREVIATIONS
DEX: Dexmedetomidine
MV: Mechanical Ventilation
CHD: Congenital Heart Defect
CICU: Cardiac Intensive Care Unit
OR: Operating Room
CPB: Cardiopulmonary Bypass
DHCA: Deep Hypothermic Circulatory Arrest
RACHS: Risk Adjustment for Congenital Heart Surgery Score
16

BACKGROUND
Dexmedetomidine
Decreased the need for opioids
Decreased prevalence of ventricular and supraventricular

tachyarrhythmias
Attenuates the hemodynamic and neuroendocrine response
Minimal respiratory depression and allows for earlier
tracheal extubation
Reduced needs for other sedative/analgesic drugs in the
operating room
Achuff BJ, et al. Pediatr Crit Care Med. 2015
Jun;16(5):440-7.

17

OBJECTIVE
Dexmedetomidine bolus at or about the time of

sternal closure is associated with a decrease in the

use of mechanical ventilation in the immediate
postoperative periods.

Achuff BJ, et al. Pediatr Crit Care Med. 2015

Jun;16(5):440-7.

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STUDY DESIGN
Retrospective cohort study
Single pediatric tertiary cardiac center
Study period from 2008 to 2012 [Five years]
No interventions were made in this study

Achuff BJ, et al. Pediatr Crit Care Med. 2015

Jun;16(5):440-7.

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PATIENT POPULATION
1,057 total encounters, with 441 meeting inclusion

criteria

Infants undergoing surgical intervention for

congenital heart defects requiring cardiopulmonary

bypass
Age: 30-365 days

Achuff BJ, et al. Pediatr Crit Care Med. 2015

Jun;16(5):440-7.

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MOST FREQUENT
PROCEDURES
Bidirectional glenn [including Bilateral BDG] (26%)
Tetralogy of fallot repair with and with out

transannular patch (35%)

Ventricular septal defect repair (17%)

Hemi-Fontan (7%)

Achuff BJ, et al. Pediatr Crit Care Med. 2015

Jun;16(5):440-7.

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INCLUSION/EXCLUSION
CRITERIA
Inclusion

Exclusion

Surgical repair of CHD

Significant comorbidities

Age 30-365 days

Prematurity <34 weeks gestational age

CHD surgery requiring CPB

Genetic abnormalities
Hemodynamically significant arrhythmia
Postoperative bleeding
Delayed sternal closure

Achuff BJ, et al. Pediatr Crit Care Med. 2015

Jun;16(5):440-7.

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PRIMARY ENDPOINT
The use of any mechanical ventilation upon arrival to

the cardiac intensive care unit

Achuff BJ, et al. Pediatr Crit Care Med. 2015

Jun;16(5):440-7.

23

DATA COLLECTION
Sources:
CICU database
Anesthesia record
Hospital electronic/paper record

Entry:
Microsoft Excel

Credibility review:
10% of charts randomly chosen by different members of the
study team
Achuff BJ, et al. Pediatr Crit Care Med. 2015
Jun;16(5):440-7.

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EXPOSURE
DEX: infants who received a bolus dose of DEX at the

appropriate time of sternal closure

Non-DEX: those who did not receive DEX in the OR

prior to arrival to the CICU

Achuff BJ, et al. Pediatr Crit Care Med. 2015

Jun;16(5):440-7.

25

COVARIATES
Factors that could impact the decision for MV in the

postoperative period:
Date of the procedure
Age
Weight

Intraoperative dose of opioid

CPB time
The use of deep hypothermic circulatory arrest
Risk adjustment for congenital heart surgery score
Achuff BJ, et al. Pediatr Crit Care Med. 2015
Jun;16(5):440-7.

26

STATISTICS
Descriptive statistics used to compare subjects

for MV on arrival to the CICU

Categorical variables:
Frequency counts and percentages
TEST: chi-square tests of independence
Continuous variables:
Mean with standard deviation
Median with range
TEST: two-sample t test
Achuff BJ, et al. Pediatr Crit Care Med. 2015
Jun;16(5):440-7.

27

STATISTICS
Logistic regression models used to assess the association between the

use of DEX and receiving MV upon arrival to the CICU with and without
variable adjustment

The significance level for two-sided hypothesis testing was set at 0.05
Multivariable logic regression considered:
The use of DEX
Date of procedure
Age
Weight
Intraoperative dose of opioid
CPB time
Use of DHCA
Use of RACHS-1

Achuff BJ, et al. Pediatr Crit Care Med. 2015

Jun;16(5):440-7.

28

BASELINE CHARACTERISTICS
AND COVARIATES
Variable

Total, n (%)

Dex Group

Non-Dex Group

441 (100)

252 (57.1)

189 (42.9)

56 (12.7)
385 (87.3)

21 (37.5)
231 (60.0)

35 (62.5)
154 (40.0)

5.84 (1.40)

5.85 (1.37)

5.83 (1.44)

Yes
No

118 (26.8)
323 (73.2)

58 (49.2)
194 (60.1)

60 (50.8)
129 (39.9)

<75 min
>75 min

361 (81.9)
80 (18.1)

212 (58.7)
40 (50.0)

149 (41.3)
40 (50)

0-4.99 g/kg
5-10.0 g/kg
>10 g/kg

84 (19.0)
228 (51.7)
129 (29.3)

57 (67.9)
139 (61.0)
56 (43.4)

27 (32.1)
89 (39.0)
73 (56.6)

Characteristics
Mechanical Ventilation Use
Yes
No
Weight, kg
Deep hypothermic circulatory arrest

Length of cardiopulmonary bypass

Fentanyl use

Achuff BJ, et al. Pediatr Crit Care Med. 2015

Jun;16(5):440-7.

29

BASELINE CHARACTERISTICS AND

COVARIATES CONTINUED
Variable

Total, n (%)

Dex Group

Non-Dex Group

30-90 d old
91-180 d old
181-360 d old

85 (19.3)
233 (52.8)
123 (27.9)

48 (56.5)
137 (58.8)
67 (54.5)

37 (43.5)
96 (41.2)
56 (45.5)

Risk Adjustment for Congenital Heart Surgery

score
1
2
3
4
6

9 (2.0)
370 (83.9
43 (9.8)
8 (1.8)
11 (2.5)

4 (44.4)
213 (57.6)
24 (55.8)
5 (62.5)
6 (54.5)

5 (55.6)
157 (42.4)
19 (44.2)
3 (37.5)
5 (45.5)

113 (25.6)
83 (18.8)
96 (21.8)
69 (15.6)
80 (18.1)

42 (37.2)
42 (50.6)
52 (54.2)
51 (73.9)
65 (81.3)

Age

Year
2008
2009
2010
2011
2012

Achuff BJ, et al. Pediatr Crit Care Med. 2015

Jun;16(5):440-7.

71
41
44
18
15

(62.8)
(49.4)
(45.8)
(26.1)
(18.8)
30

ADMINISTRATION
DEX dose for all patients was 0.84mg/kg/dose
DEX+/MVS+ average dose was 0.78 mg/kg/dose

Achuff BJ, et al. Pediatr Crit Care Med. 2015

Jun;16(5):440-7.

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RESULTS
Evaluation of mechanical ventilation use
Relationship between MV support and the use of DEX

and other variables

Achuff BJ, et al. Pediatr Crit Care Med. 2015

Jun;16(5):440-7.

32

RELATIONSHIPS BETWEEN THE

PROPORTION OF SUBJECTS WHO
RECEIVED MV AND THE USE OF DEX
AND OTHER VARIABLES
Significant associations
existed with MV:
The use of DEX
Length of CPB
Fentanyl equivalent
dose
RACHS-1 score
Date of procedure
No associations existed
with MV:
Age
Weight

Achuff BJ, et al. Pediatr Crit Care Med. 2015

Jun;16(5):440-7.

33

Variable

ASSOCIATION BETWEEN INDIVIDUAL

VARIABLES AND MECHANICAL VENTILATION
USE
MV Yes n (%)

MV No n (%)

56 (12.7)

385 (87.3)

5.58 (1.51)

5.88 (1.38)

0.1712

Yes (n = 252)
No (n =189)

21 (8.3)
35 (18.5)

231 (91.7)
154 (81.5)

0.0016

Deep hypothermic circulatory arrest

Yes (n = 118)
No ( n = 323)

21 (17.8)
35 (10.8)

97 (82.2)
288 (89.2)

0.0592

Cardiopulmonary bypass time

75min (n = 80)
< 75min (n = 361)

31 (38.8)
25 (6.9)

49 (61.3)
336 (93.1)

< 0.0001

Mechanical Ventilation Support

Weight, kg

Dexmedetomidine

Achuff BJ, et al. Pediatr Crit Care Med. 2015

Jun;16(5):440-7.

34

ASSOCIATIONS CONTINUED
Variable

MV Yes n (%)

MV No n (%)

5 (6.0)
21 (9.2)
30 (23.3)

79 (94.0)
207 (90.8)
99 (76.7)

0.0001

15 (17.6)
28 (12.0)
13 (10.6)

70 (82.4)
205 (88.0)
110 (89.4)

0.3117

Risk Adjustment for Congenital Heart Surgery score

3, 4, or 6 (n = 62)
1 or 2 (n = 379)

18 (29.0)
38 (10.0)

44 (71.0)
341 (90.0)

0.0002

Year
2008
2009
2010
2011
2012

19 (16.8)
16 (19.3)
7 (7.3)
4 (5.8)
10 (12.5)

94 (83.2)
67 (80.7)
89 (92.7)
65 (94.2)
70 (87.5)

0.0266

Fentanyl use
04.99 (n = 84)
59.99 (n = 228)
> 10.0 (n = 129) 30 (23.3) 99 (76.7)
Age, d
3090 (n = 85)
91180 (n = 233)
181360 (n = 123)

(n
(n
(n
(n
(n

=
=
=
=
=

113)
83)
96)
69)
80)

Achuff BJ, et al. Pediatr Crit Care Med. 2015

Jun;16(5):440-7.

35

RELATIONSHIP BETWEEN MECHANICAL

VENTILATION SUPPORT AND DEXMEDETOMIDINE
USE AND
OTHER Unadjusted
VARIABLES
Variable
Unadjusted
Adjusted
Adjusted
Dexmedetomidine use
Yes vs no
Deep hypothermic circulatory
arrest
Yes vs no
Length of cardiopulmonary bypass
075 vs > 75 (min)
Fentanyl use (g/kg)
510 vs 04.99
> 10 vs 04.99
> 10 vs 510

OR (95%) CI

p - value

OR (95%) CI

p - value

0.40
(0.22, 0.71)

0.0019

0.50
(0.25, 1.00)

0.0501

1.78 (0.99,
3.21)

0.0545

0.78 (0.34,
1.79)

0.5537

0.12 (0.06,
0.22)

< 0.0001

0.11 (0.05,
0.26)

< 0.0001

1.60 (0.58,
4.40) 4.79
(1.77, 12.92)
2.99 (1.63,
5.48)

0.3600
0.0020
0.0004

1.28 (0.40,
4.07) 3.02
(0.98, 9.31)
2.36 (1.16,
4.83)

0.6783
0.0542
0.0183

Achuff BJ, et al. Pediatr Crit Care Med. 2015

Jun;16(5):440-7.

36

Variable

RELATIONSHIPS CONTINUED
Unadjusted
OR (95%) CI

Unadjusted
p - value

Adjusted
OR (95%) CI

Adjusted
p - value

0.64 (0.32,
1.26)
0.55 (0.25,
1.23 0.86
(0.43, 1.74)

0.1969
0.1458
0.6845

1.27 (0.51,
3.13)
0.45 (0.12,
1.73)
0.35 (0.13,
0.99)

0.6065
0.2439
0.0473

3.67 (1.93,
6.99)

0.0001

4.01 (1.86,
8.65)

0.0004

Age (d)
91180 vs 3090
181365 vs 3090
181365 vs 91180

Risk Adjustment for Congenital

Heart Surgery score
346 vs 12
Year
2009 vs 2008
2010 vs 2008
2011 vs 2008
2012 vs 2008
2010 vs 2009
2011 vs 2009

1.18 (0.57,
2.47) 0.39
(0.16, 0.97)
0.30 (0.10,
0.94) 0.71
(0.31, 1.62)

0.6570
1.14 (0.52,
0.0432
2.49) 0.38
0.0383
(0.13, 1.09)
0.4107
0.24 (0.06,
Achuff BJ,
et al. Pediatr Crit0.99)
Care Med.
0.0211
0.682015
Jun;16(5):440-7.
0.0207
(0.24, 1.87)

0.7519
0.0707
0.0488
0.4499
0.0356
0.0283

37

RESULTS OF LOGISTIC
REGRESSION MODEL
Statistically significant association was found for

intraoperative DEX administration with less use of MV in the

postoperative period [p = 0.0019]
The odds of receiving MV were estimated to be 2.5 times higher in those

not receiving DEX

Associations remained significant after adjusting for age, weight, date of
procedure, intraoperative dose of opioid, CPB time, DHCA use, and
RACHS-1

Subjects who received >10 g/kg intraoperative fentanyl dose

were 2.4 and 3.02 times more likely to recieve MV than those
who recieved lower doses

Those who had CPB >75 minutes were 8.8 times more likely to
Achuff BJ, et al. Pediatr Crit Care Med. 2015

require MV posteoperatively [p <0.0001]

Jun;16(5):440-7.

38

RESULTS CONTINUED
Within the first 24 hours:
Six reintubation events occurred for respiratory failure
One postoperative hemothorax
Three of these reintubations received DEX and 3 patients did not

One event required ECMO after cardiopulmonary

resuscitation for bradycardiac arrest

This patient had not received DEX

Achuff BJ, et al. Pediatr Crit Care Med. 2015

Jun;16(5):440-7.

39

DISCUSSION
DEX bolus in the OR at the time of sternal closure was

associated with:

A reduced need for MV in the immediate post-operative

period
Less MV or immediate extubation postoperatively in this
cohort
The use of lower doses of other medications with respiratory
depression that might limit the ability to extubate
immediately
Achuff BJ, et al. Pediatr Crit Care Med. 2015
Jun;16(5):440-7.

40

STRENGTHS VS.
LIMITATIONS
Strengths

Limitations

Five year study

Single center study

Adjustment of variables

Incomplete chart documentation

Inclusion of single-ventricle defect repair

Immediate extubation decision

Narrow age range

Physician familiarity with DEX

Changes in anesthesia/surgeon teams

Achuff BJ, et al. Pediatr Crit Care Med. 2015

Jun;16(5):440-7.

41

AUTHORS CONCLUSION
In conclusion, this study demonstrates an association

with reduced use of MV for infants following cardiac

surgery after receiving a bolus dose of DEX at or
about the time of sternal closure. After adjusting for
the multiple variables that can impact the opportunity
for immediate postoperative extubation, there
remains a difference in MV between exposed and
unexposed patients.

Achuff BJ, et al. Pediatr Crit Care Med. 2015

Jun;16(5):440-7.

42

FUTURE RESEARCH
The effect of DEX bolus on:
Leading to immediate extubation on patient flow
Time to reinitiation of feeds
Cost
The use of DEX in neonatal cardiac surgery

43

GRATITUDE
Dr. Alice Yeh, Pharm D.

44

REFERENCES

Dexmedetomidine In: Lexi-Drugs [database online]. Hudson, Ohio: Lexi-Comp, Inc. Updated

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Szumita PM, Baroletti SA, Anger KE, Wechsler ME. Sedation and analgesia in the intensive care unit:

evaluating the role of dexmedetomidine. Am J Health Syst Pharm. 2007;64(1):37-44.

West R, Rhodes A, et al. Section XXIII: The role of dexmedetomidine in intensive care. In: Vincent J,

eds. Intensive Care Medicine. New York: Springer; 2009. 906-914.

Maldonado JR, Wysong A, Van der starre PJ, Block T, Miller C, Reitz BA. Dexmedetomidine and the

reduction of postoperative delirium after cardiac surgery. Psychosomatics. 2009;50(3):206-17.

Lardieri AB, Fusco NM, Simone S, Walker LK, Morgan JA, Parbuoni KA. Effects of Clonidine on

Withdrawal From Long-term Dexmedetomidine in the Pediatric Patient. J Pediatr Pharmacol Ther.
2015;20(1):45-53.
Pandharipande PP, Pun BT, Herr DL, et al. Effect of sedation with dexmedetomidine vs lorazepam on

acute brain dysfunction in mechanically ventilated patients: the MENDS randomized controlled trial.
JAMA. 2007;298(22):2644-53.
Riker RR, Picard JT, Fraser GL. Prospective evaluation of the Sedation-Agitation Scale for adult

critically ill patients. Crit Care Med. 1999;27(7):1325-9.

Cawley MJ. Mechanical ventilation: a tutorial for pharmacists. Pharmacotherapy. 2007;27(2):250-66.

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46

QUESTIONS??