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The effect of Intravenous Ketamine during Cardiopulmonary Bypass on Postoperative
Agitation
1 Mansoor Soltanzadeh*, MD, 2 Ahmad Ebadi, MD,3 Mehdi Dehghani Firoozabadi, MD.
4 Seyyed Kamaladdin Tabatabee, MD, 5 Anahita Babaee, MD
1 Associate Professor, Anesthesia Department, Jundishapur University of Medical Sciences, Ahvaz
2 Associate Professor, Anesthesia Department, Jundishapur University of Medical Sciences, Ahvaz
3 Assistant Professor, Anesthesia Department, Jundishapur University of Medical Sciences, Ahvaz
4 Assistant Professor, Anesthesia Department, Jundishapur University of Medical Sciences, Ahvaz
5 Assistant, Anesthesia Department, Jundishapur University of Medical Sciences, Ahvaz
ARTICLE INFO
Article history:
Received 20.01.2014
Accepted 15.03.2015
Keywords:
Heart surgery, Agitation,
Ketamine
⁎ Corresponding Author
Mansoor Soltanzadeh
Associate
Professor,
Anesthesia
Department,
Jundishapur University of
Medical Sciences, Ahvaz
e-mail:
[email protected]
QR
ABSTRACT
and objective: Postoperative cognitive dysfunctions are
prevalent in cardiac surgeries. Ketamine - as a NMDA (N-Methyl-DAspartate) receptor antagonist - exerts neuroprotective effects. We
studied the effect of intravenous Ketamine on postoperative agitation
during open-heart surgery.
Material Methods: In a double blind clinical trial, 40 males (at least 55
years) undergoing open heart surgery were randomly divided into 2
groups: intervention group (received 0.5 mg/kg IV ketamine before
sternotomy and the same dose before pumping) and control group (the
same volume of normal saline at the same interval). After the end of
surgery, agitation signs were assessed by every 2 hours until 8h and then
every 8 hours until 3 days.
Results: Incidence of agitation on 2nd and 3rd days after operation was
significantly lower in patients received ketamine as compared to control
group. In 6, 16, and 24h after surgery, again number of agitated patients
in control group was higher than ketamine group. Yet, the difference was
not significant.
Conclusion: Intravenous ketamine administration during open-heart
surgery can reduce post-operative agitation by its neuroprotective effect.
Background
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Introduction
Agitation means excessive irritation and akathisia resulted
from internal dysfunction or irritations (1 & 2). Agitation
is a prevalent dysfunction in patients admitted at ICU. It
is reported in %71 patients (2).
Agitation etiology is not well understood. Yet, among its
factors are underling diseases, metabolic dysfunctions,
pain, anxiety, and delirium (2). In agitation, patient’s
movements are continuous and aimless. Invasive agitation
can be dangerous. It can lead to patient’s disharmony with
ventilator, oxygen consumption increase, unwanted
separation of equipments and counters connected to
patient, and further consequences and mortality (1 & 2).
Cardiac surgeries can be accompanied by neurological
consequences due to factors such as cardiopulmonary
pump and the probability of macro and micro embolus (6
& 7). Among neurological consequences, neuro-focal
deficiencies, cognitive dysfunctions such as delirium,
agitation, memory loss, concentration suppression,
illusions, and delusion can be implied (3, 4 & 5).
Despite considerable attention paid to delirium issue in
cardiac surgeries, these patients are barely examined with
specific respect to agitation. Regarding the fact that there
is no reliable preventive treatment for postoperative
agitation, carrying out an applied study for coping with
this dysfunction seems necessary.
Numerous clinical and laboratory evidences show
ketamine protective effects during topical and generalized
cerebral ischemia (8-10), trauma (11), chronic cerebral
hypoperfusion resulted from hypocapnia (12), and
cerebral vasogenic (distributive) edema (13).
Ketamine is a N-Methyl-D-Aspartate (NMDA) receptor
antagonist. It alleviates neurons loss in cortex via
preventing from injuries resulted from brain evoked
response (14) and apoptosis after cerebral ischemia (9). It
also maintains brain blood circulation via increasing
sympathetic nervous system activity (11). Ketamine can
also protect brain by hindering systemic inflammatory
reactions and central nervous system (3). It also protects
brain against post cardiac surgery cognitive dysfunctions
in elders (15). Ketamine can also be effective in
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Visual Outcome after Penetrating Keratoplasty
alleviating pain and increasing sleep depth at the time of
sternotomy as well as in warming stage (in the end of
placing patient on cardiopulmonary pump). This study
determines the effect of intravenous ketamine during
cardiopulmonary bypass surgeries on postoperative
agitation in these patients.
Materials and Methods
In this double blind clinical trial, 40 male candidates (at
least 55 years of age) of cardiopulmonary bypass via open
heart surgery were selected. Patients’ mental and physical
status was examined by neurological and psychological
assessment a week before surgery.
Omission measure included CVA history in three past
years, the existence of permanent pacemaker, hepatic
dysfunctions with AST and ALT higher than twice
normal level, chronic kidney disease (keratin>2), delirium
incidence history a week before surgery, proved cognitive
dysfunctions, taking drug for treating psychosis and drug
abuse.
Patients were randomly divided into 2 similar groups:
intervention and control groups. Intervention group
received 0.5mg/kg ketamine twice; that is, first before
sternotomy and second the same dose before pumping.
Control group received %0.9 saline with the same volume
and at the same time. All patients underwent medication
with 0.1mg/kg intramuscular morphine and 0.5mg/kg
intramuscular promethazine 30min before operation.
Then, anesthetic induction was carried out by 0.15mg/kg
diazepam, 3-10𝜇g/kg fentanyl, 2mg/kg thiopental sodium,
and 0.5 mg/kg atracurium or 0.15mg/kg Cis atracurium
were administered. Nanasthetics also included 0.3 mg/kg
atracurium or Cis atracurium, 50𝜇g/kg/min propofol and
%0.4-1.6 isoflurane.
All patients underwent the standard sternotomy of cardiac
surgery. Heart protection includes using 15cc/kg cold
hypercalcemic cardioplegic solution in 20min intervals
(by the aids of normal saline) and systemic hypothermia
(temperature on pump was 32℃). Blood flow speed on
pump was 2.4-2.5l/min/m2 and mean arterial blood
pressure 60-80mmHg.
300unit/kg heparin was prescribed for systemic
anticoagulation so as to keep active coagulation time over
480s. After surgery, 1.3mg protamine sulfate was
administered for each 1mg heparin to return its effect.
All patients underwent postoperative agitation signs
assessment every 2h during the first 8h after surgery and
then every 8h until two days after operation (totally, 3
days). Assessment was carried out separately for each
patient by experienced anesthesiology resident using
Riker Sedation-Agitation Scale (SAS) (Table 1).
Data was analyzed by SPSS19. Demographic data was
compared using chi-square and Fisher exact test.
Hemodynamic data and SAS score were compared
between control and test groups in hours under study
using t-test. Significance level was considered 0.05.
Soltanzadeh et al, 2015
VOL: 1, No: 2(march 2015) 33-36
Results
Mean patients age was 61.27±5.85 (55-77 years old).
Mean surgery time was 206.75±42.46min. There was no
significant difference between two groups regarding mean
age, class, and operation time (Table 2).
Patients’ neurological and psychological assessment
results a week before surgery showed that none of them
suffered from any known cognitive dysfunctions and
neurological diseases.
Postoperative agitation was examined by SAS during 72h
after surgery. Based on SAS score>4, there was
significant difference between ketamine and placebo
groups regarding agitation in 32, 40, 48, 56, and 64h after
surgery. That is, number of agitated patients was lower in
ketamine groups (versus placebo group) (Table 3)
(p<0.05). In 6, 16, and 24h after surgery, again number of
agitated patients in control group was higher than
ketamine group. Yet, the difference was not significant
(p>0.05).
There was also no significant difference between two
groups regarding heart rate and mean arterial blood
pressure at the time of anesthetic induction, before
pumping, after pumping, and before and after sternotomy
(p<0.05) (Table 4).
Table 1: The sedation agitation scale
Table 2: Comparing demographic data and operation time
between two groups under study
Ketamine
Placebo
p-value
Mean age
60/55±5/48
62/00±6/27
0/44
Mean
208±46/97
205/5 ±38/62 0/85
execution
time
ASA Class
Class 1
%0
%5
Class 2
%85
%80
0/59
Class 3
%15
%15
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Soltanzadeh et al, 2015
Visual Outcome after Penetrating Keratoplasty
Table 3: Comparing number
two groups under study
Time (h)
Ketamine
2
0(0%)
4
0(0%)
6
0(0%)
8
3(15%)
16
4(20%)
24
3(15%)
32
4(20%)
40
5(25%)
48
1(5%)
56
1(5%)
64
2(10%)
72
2(10%)
of agitated patients between
Placebo
0(0%)
0(0%)
3(15%)
3(15%)
9(45%)
9(45%)
12(60%)
13(65%)
10(50%)
11(55%)
9(45%)
1(5%)
p-value
1
1
0/23
1
0/176
0/082
0/02
0/025
0/003
0/001
0/031
1
Table 4: Comparing hemodynamic data between two
groups under study
Time
Ketamine
Placebo
pvalu
e
Mean
Anestheti 88/30±16/4 96/75±18/5 0/13
arterial c
3
1
5
blood
induction
pressur Before
62/6±12/41 63/75±7/58 0/72
e
CPB
6
After
61/8±11/63 57/2±14/08 0/26
CPB
7
Before
80/80±8/30 79/1±7/9
0/51
sternotom
y
After
79/25±7/63 83/15±6/5
0/09
sternotom
y
Heart
Anestheti 74/25±16/0 80/35±11/7 0/17
rate
c
3
6
8
induction
Before
71/20±13/3 71/2±11/08 1
sternotom 9
y
After
70/8±14/20 77/05±8/87 0.1
sternotom
y
Discussion
Based on results, intravenous ketamine during cardiac
surgery significantly suppresses postoperative agitation
on the 2nd and 3rd days as compared to control group.
Although again agitation cases in ketamine group were
less than control group during the first 24h after surgery,
the difference was insignificant.
Postoperative cognitive dysfunctions can be a
combination of neural injuries resulted from surgery
stress, inflammatory responses, coagulation increase,
anesthetics, and factors related to hospital environment
(16).
Ketamine is bound to phencyclidine bind locus on NMDA
receptor (17). This receptor has also other loci for binding
to glutamate and glycine. It allows sodium and calcium to
enter into cell by the aids of ion channels (18). As a
VOL: 1, No: 2(march 2015) 33-36
NMDA receptor non-competitive antagonist, ketamine
can suppress brain ischemia by several mechanisms. First,
it can prevent from cells necrosis by inhibiting brain
evoked response injuries (14 & 19). Ischemic neurons
release glutamate into extracellular space. It leads to
NMDA receptor hyperactivity and cells death (20).
Ketamine protects brain by temporarily inactivating these
receptors. Then, receptors are barely apt to activation after
ischemia and reperfusion (15). Second, ketamine changes
apoptosis-regulating proteins (9). Apoptosis can alleviate
cerebral ischemia intensity. Third, ketamine can disrupt
cerebral and systemic inflammatory response to cardiac
surgery (21). It seems that inflammatory response plays a
critical role in neural damage after cardiopulmonary
bypass (3). Ketamine suppresses IL6 response after
cardiopulmonary bypass (22). It also hinders TNFα, IL6,
and IL8 production mediated by lipopolysacchardies (23).
Ketamine controls kB nucleus factor participating in
copying proinflammatory cytokine codifying genes (24 &
25).
In texts review, no studies were found specifically
examining the effect of ketamine on postoperative
agitation. Yet, several clinical trials have been carried out
on human using NMDA receptor antagonists regarding
ischemic cerebral injuries and cognitive dysfunctions (15,
16, 26, and 27).
Arrowsmith et al studied remacemide (a NMDA receptor
antagonist) effect on neuroprotection of brain after
cardiopulmonary bypass (26). In that study, despite low
number of patients manifested neuro-psychological
dysfunction, significant patients’ improvement was
observed totally in three out of nine tests.
Hudetz et al carried out two studies on the effect of
ketamine on cognitive dysfunctions and delirium after
cardiac surgery. They have approved the effect of
intravenous ketamine on brain protection and reduction of
cognitive dysfunctions (15).
In our study, patients had similar hemodynamic status in
both groups. It may indicate that the reduction of
postoperative agitation in intervention group is not
resulted from changes in cerebral blood flow.
Here, we used low dose of ketamine. This is because it
was shown in previous studies that ketamine antiinflammatory response is seen in lower doses as
compared to dose required for anesthesia. High doses of
ketamine are not recommended due to cardiovascular and
psychotropic consequences (22, 28, and 29).
y. 2002; 667.
Conclusion
Prescribing intravenous ketamine during cardiopulmonary
bypass can lead to protective effects on patients’ brain
and cardiopulmonary pump. As a result, it reduces
postoperative agitation.
Acknowledgements: Hereby, we thank all colleagues
contributing to the fulfillment of this design.
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