In the name of God
Title: Is cardiovascular effects of intravenous ketamine during open-heart surgery
effective in reducing postoperative agitation?
Authors:
Mansoor Soltanzadeh, Associated professor, Ahwaz Jundishapur university of Medical Sciences, Anesthesia
department. Email: Sultanman84@yahoo.com
Ahmad Ebadi, Associated professor, Ahwaz Jundishapur university of Medical Sciences, Anesthesia
department. Email: Ida1959mad@yahoo.com
Seied Kamalaldine Tabatabaeii, Assistant professor, Ahwaz Jundishapur university of Medical Sciences,
Anesthesia department.
Mehdi Dehghani Firoozabadi, Assistant professor, Ahwaz Jundishapur university of Medical Sciences,
Anesthesia department.
Anahita Babaie, Anesthesiology assistant of Ahwaz Jundishapur university of medical sciences, Anesthesiology
department. Email: ahmadhendizadeh@yahoo.com
Corresponding author: Mansoor Soltanzadeh. Email:Sultanman84@yahoo.com
Address: Golestan hospital - Golestal St. – Ahvaz – Iran Tel:0098-611-3743017
1
Abstract:
Introduction: Open-heart surgery has been associated with a higher risk of neurologic complications than other
major types of surgery. In this study we are seeking to determine whether cardiovascular effects of ketamine
incur in reducing neurological disorders after open-heart surgery or not?
Methods: In a randomized, double -blind, prospective study, Forty Patients were selected in two equal groups.
In the intervention group, ketamine (0.5 mg/kg) was injected during operation. Heart rate and mean arterial
blood pressure of all patients were recorded during induction of anesthesia, before sternotomy, after sternotomy,
prior to the pump and after the pump. After the operation, patients were examined for agitation.
Results: The results showed that percentage of agitated patients were significant between both groups in the
32th, 40th, 48th, 56th and 64th hours after operation with the ketamine group having less agitated patients than the
placebo group (P<0.05). Both groups did not have any significant difference in their mean of Heart rate and
mean arterial pressure during induction of anesthesia, before sternotomy, after sternotomy, prior to the pump
and after the pump (P<0.05)
Conclusion: Administration ketamine during open-heart surgery reduces agitation not by cardiovascular
effects, but by protective effects on patient’s brain.
Keywords: Agitation – Cardiac surgery - Ketamine
2
Introduction:
Open-heart surgery has been associated with a higher risk of neurologic complications than other major types of
surgery1. Since the introduction of the cardiopulmonary bypass in the early 1950s, the neurological
complications of cardiac surgery have been the major concern.
In patients who have undergone myocardial revascularization an incidence of ischemic stroke with motor deficit
ranging between 2% and 6% have reported2-6.
Aside from stroke, different degrees of decrease in neuropsychological function may be observed during the
immediate postoperative period of cardiac surgery. Up to 10% patients can range from prolonged emergence,
confusion or stupor with no focal motor deficit, to a state of prolonged cognitive deterioration7.
Several etiologic factors have been proposed, including previous unrecognized neurological abnormality,
cerebral microemboli, cerebral edema, hypoperfusion, altered cerebral blood flow, cerebral hypoxia and
systemic inflammatory response to cardiopulmonary bypass8-11.
Identification of etiological factors of postoperative neurologic complications can lead to the development of
physical and pharmacological neuroprotective strategies for reduction of these postoperative complications.
3
Hudetz and his colleagues in their two studies demonstrated that the administration of a single dose (0.5 mg/kg)
of ketamine during the induction of anesthesia reduces post-operative cognitive dysfunction and delirium in
patients undergoing cardiac surgery using CPB12,13.
In this study we are seeking to determine: Is cardiovascular effects of ketamine influence in reducing
neurological disorders after open-heart surgery or not?
Material and Methods:
This study was approved with the institutional ethics committee. In a randomized, double -blind, prospective
study, Forty Patients were included if they were at least 55 years of age, provided written informed consent
before the initiation of any study-related procedures and were scheduled for elective coronary artery bypass
graft surgery with CPB.
The exclusion criteria were as follows: a history of cerebrovascular accident within recent 3 years, permanent
ventricular pace maker, previously defined cognitive deficits, patients receiving psychoactive drugs for the
treatment of psychosis, delirium within a week before operation, patients with hepatic disorder[aspartate
aminotransferase or alanine aminotransferase more than twice the upper limit of normal] or chronic renal
insufficiency [creatinine ˃2.0 mg/dL].
The patients were randomized in two equal groups (intervention and control). In the intervention group,
intravenous ketamine (0.5 mg/kg) was injected to patients on two occasions, one before Sternotomy and the
other one before pumping and in the control group, 0.9% normal Saline was injected with the same volume and
in the same times. Choosing a low dose for ketamine in the intervention group was to ensure that cardiovascular
effects of ketamine did not occur in patients who received it14-16.
Premedication for all patients were intramuscular morphine (0.1mg/kg) and Promethazine (0.5 mg/kg) half an
hour before operation. All patients were given 0.15 mg/kg diazepam, 3-10 µg/kg fentanyl, 2mg/kg sodium
4
thiopental and 0.4 to 0.5 mg/kg cis-atracurium intravenously to induce general anesthesia. Both groups were
received 5 to 9 µ/kg/min cis-atracurium, 50 µ/kg/min Propofol and %0.4- %1.6 Isoflurane for maintaining
anesthesia.
All of patients underwent standard sternotomy heart surgery. Cardio-protection included: cold hyperkalemic
cardioplegia (15cc/kg) at intervals of every 20 minutes, topical hypothermia (with cold saline) and systemic
hypothermia (pump temperature being 32 ° C). The blood flow infusion by the pump was maintained on 2.4-2.5
L/min/ m2 and mean arterial pressure on the pump was maintained on 60-80 mmHg.
Heparin in a dose of 3mg/kg was administered for systemic blood anticoagulation with activated coagulation
time (ACT) last over 480 seconds. At the time weaning patients of cardiopulmonary pump, anticoagulant
effects of heparin was revered by protamine sulfate in a dose of 1.3 mg per 1 mg heparin.
Heart rate and mean arterial blood pressure of all patients were recorded during induction of anesthesia, before
sternotomy, after sternotomy, prior to cardiopulmonary pump and after weaning patients of the pump.
After the operation, all the patients were examined by a trained resident of anesthesia for sign of agitation using
Riker Sedation-Agitation Scale (SAS)17 in intervals of every 2 hours during the first 8 hours and then every 8
hours for two days (totally 3 days).
After collecting the data from both groups, they were analyzed by SPSS static software 19th edition. The study
data were expressed as mean ± standard deviation for the quantitative variables and percentages for the
categorical variables. The parametric data of the patients were compared using the student t-test for comparison
of SAS scores in both groups and the chi-square test and Fisher exact test for demographic variables. In this
study a P-value < 0.05 was considered significant.
Results and Discussion:
5
Both groups didn’t have any significant difference in mean of age, ASA class and operation time (Table 1).
Agitation was examined during the first 72 hours after the surgery using Riker Sedation-Agitation Scale (SAS).
The results showed that percentage of agitated patients based on SAS score higher than 4 were significant
between both groups in the 32th, 40th, 48th, 56th and 64th hours after operation with the ketamine group having
less agitated patients than the placebo group (Table 2) (P<0.05). The number of Agitated patients in the control
group was more than the Ketamine group during the 6th, 16th and 24th hours but this difference was not
statistically significant (P>0.05). Both groups did not have any significant difference in their mean of Heart rate
and mean arterial pressure during induction of anesthesia, before sternotomy, after sternotomy, prior to the
pump and after the pump (P<0.05) (Table 3).
The outcome of this study shows that the Ketamine administered during open-heart surgery, significantly
reduces the rate of postoperative agitated patients during the third and second days in comparison to the control
group. Although in the first 24 hours after the surgery the number of agitated patients in ketamine group were
less than the control group, but this difference was not significant. In our study, the hemodynamic status of
patients were similar in both groups and the groups did not have any significant difference in the average of
heart rate and mean arterial pressure during induction of anesthesia, prior to the pump, after the pump and
before and after sternotomy (P< 0.05)(Table 3). This similar hemodynamic status of patients in the both groups
may imply that the cardiovascular effects of ketamine in the intervention group did not have a role on the brain
blood flow and agitation reduction and therefore for reduced rate of postoperative agitation in ketamine group
must be sought other mechanisms of ketamine. In this study, we used of low dose ketamine because the prior
studies had shown that anti-inflammatory effects of ketamine also occur with low doses of intravenous
ketamine without its cardiovascular and psychotropic effects14-16.
In an attempt to explain the decreased postoperative agitated patients in ketamine group should be noted that
ketamine binds on the binding site of the Phencyclidine on the N-Methyl-D-aspartate (NMDA) reseptor18. Also,
this receptor has binding sites for glutamate and glycine that in corporation with ion channels allows calcium
6
and sodium to enter the cell19. Ketamine as a non-competitive NMDA receptor antagonist, can reduce the
severity of ischemic brain by several mechanisms. First, it can prevent stimulating brain injuries and therefore
preventing the necrotic cell death20,21. Ischemic neurons release glutamate into extracellular space and cause the
NMDA receptor to become overactive and the cells death22. Ketamine may combat ischemic injury associated
with glutamate- calcium overload, reducing cell loss and improving the neurological outcome. Ketamine may
cause a preconditioning-like effect by temporary inactivation of NMDA receptors after ischemia and
reperfusion injury12.Second, Ketamine changes the Apoptosis regulatory proteins23. Apoptosis can cause
reduction of ischemic brain severity. Third, Ketamine can interfere with cerebral and systemic inflammatory
responses during open-heart surgery24. It seems that inflammatory responses plays a major role in causing nerve
damage after cardiopulmonary bypass25. Ketamine reduces the response of Interleukin 6 after cardiopulmonary
bypass26. It also inhibits production of Tumor necrosis factor alpha, Interleukin 6 and Interleukin 827,29.
Conclusion
Administration of intravenous ketamine during open-heart surgery reduces agitation not by cardiovascular
effects, but by protective effects on patient’s brain.
Acknowledgment
We are indebted to all physicians, staff and patients who participated in this study.
References:
1. Shaw PJ, Bates D, Cartlidge NEF, et al: Neurologic and neuropsychological Morbidity following major
surgery: comparison of Coronary artery bypass and peripheral vascular surgery. Stroke. 1987; 18:700–707.
7
2.Shaw PJ, Bates D, Cartledge N. Early neurological complications of coronary artery bypass surgery. Br Med
J. 1985; 291: 1384–1387.
3.Roach G, Kanchuger M, Mangano CM, et al. Adverse outcomes after coronary bypass surgery. Multicenter
Study of Perioperative Ischemia Research Group and the Ischemia Research and Education Foundation
Investigators. New England Journal of Medicine. 1996; 335:1857-1863.
4.Llinas R, Barbut D, Caplan LR. Neurologic complications of cardiac surgery. Prog Cardiovasc Dis. 2000;
43(2):101-112.
5. Barbut D, Caplan LR. Brain complications of cardiac surgery. Curr Probl Cardiol. 1997; 22(9):449-480.
6.Bucerius J, Gummert JF, Borger MA, et al. Stroke after cardiac surgery: a risk factor analysis of 16184
consecutive patients. Ann Thorac Surg. 2003; 75(2):472-478.
7. Breuer AC, Furlan AJ, Hanson M et al. Central nervous system complications of coronary artery bypass graft
surgery: prospective analysis of 421 patients. Stroke. 1983; 14(5):682-687.
8. Brooker FR, Brown WR, DM Moody, et al. Cardiotomy suction: a major source of brain lipid emboli during
cardiopulmonary bypass. Ann Thorac Surg. 1998; 65:1651–1655.
9. Baker AJ, Naser B, Benaroia M, Mazer CD. Cerebral microemboli during coronary artery bypass using
different cardioplegia techniques. Ann Thorac Surg 1995, 59:1187–1191.
10. Rogers AT, Neuman SP, Prough DS. Neurologic effects of cardiopulmonary bypass. In: Gravlee GP, Davis
RF, Utley JR. Cardiopulmonary Bypass: Principles and Practice. Baltimore: Williams & Wilkins, 1993:542–
576.
11. Stockard JJ, Bickford RG, Schaube JF. Pressure dependent cerebral ischaemia during cardiopulmonary
bypass. Neurology 1973; 23:521–529.
8
12- Hudetz JA, Iqbal Z, Gandhi SD, et al. Ketamine attenuates postoperative cognitive dysfunction after cardiac
surgery. Acta Anaesthesiol Scand. 2009; 53: 864–872
13.Hudetz J H, Patterson K M, Iqbal Z, et al. Ketamine Attenuates Delirium After Cardiac Surgery With
Cardiopulmonary Bypass. Journal of Cardiothoracic and Vascular Anesthesia. 2009; 23( 5): 651-657
14- Roytblat L, Talmor D, Rachinsky M, et al. Ketamine attenuates the interleukin-6 response after
cardiopulmonary bypass. Anesth Analg. 1998; 87:266–271
15. Bartoc C, Frumento RJ, Jalbout M, Bennett-Guerrero E, Du E, Nishanian E. A randomized, double-blind,
placebocontrolled study assessing the anti-inflammatory effects of ketamine in cardiac surgical patients. J
Cardiothorac Vasc Anesth. 2006; 20: 217–222
16. Slogoff S, Allen GW, Wessels JV, Cheney DH. Clinical experience with subanesthetic ketamine. Anesth
Analg. 1974; 53: 354–358
17. Riker RR, Picard JT, Fraser GL. Prospective evaluation of the Sedation-Agitation Scale for adult critically
ill patients. Crit Care Med. 1999; 27(7):1325-1329.
18. Nau C, Strichartz. Drug chirality in anesthesia. Anesthesiology . 2002; 97:497–502.
19. Granry JC, Dube L, Turroques H, et al. Ketamine: new uses for an old drug. Curr Opin Anaesthesiol. 2000;
13:299–302.
20. Himmelseher S, Pfenninger E, Georgieff M: The effects of ketamine-isomers on neuronal injury and
regeneration in rat hippocampal neurons. Anesth Analg. 1996; 83:505-512.
21. Nishizawa Y. Glutamate release and neuronal damage in ischemia. Life Sci 2001; 69: 369–381.
9
22. Meldrum B. Glutamate as a neurotransmitter in the brain: review of physiology and pathology. J Nutr.
2000; 130:1007–1015.
23. Engelhard K, Werner C, Eberspacher E, et al: The effect of the alpha 2-agonist dexmedetomidine and the
N-methyl-D-aspartate antagonist ketamine on the expression of apoptosis-regulating proteins after incomplete
cerebral ischemia and reperfusion in rats. Anesth Analg 2003; 96:524-531.
24. Taggart DP, Sundaram S, McCartney C, et al. Endotoxemia, complement, and white blood cell activation in
cardiac surgery: a randomized trial of laxatives and pulsatile perfusion. Ann Thorac Surg. 1994; 57: 376–382.
25. Laffey JG, Boylan JF, Cheng DC. The systemic inflammatory response to cardiac surgery: Implications for
the anesthesiologist. Anesthesiology. 2002; 97: 215-252.
26. Roytblat L, Talmor D, Rachinsky M, et al. Ketamine attenuates the interleukin-6 response after
cardiopulmonary bypass. Anesth Analg. 1998; 87:266–271.
27. Kawasaki T, Ogata M, Kawasaki C, et al. Ketamine suppresses proinflammatory cytokine production in
human whole blood in vitro. Anesth Analg. 1999; 89:665–669.
28. Sakai T, Ichiyama T, Whitten CW, Giesecke AH, Lipton JM. Ketamine suppresses endotoxin-induced NFkappa B expression. Can J Anaesth. 2000; 47: 1019–1024.
29. Baldwin AS. The NF-kappa B and I kappa B proteins: new discoveries and insights. Annu Rev Immunol.
1996; 14: 649–683.
10
Ketamine
Placebo
P Value
Age (Mean)
60.55±5.48
62.00±6.27
0.44
Operation duration (Mean)
208±46.97
205.5±38.62
0.85
Class I
0%
5%
Class II
85%
80%
Class III
15%
15%
ASA class
0.59
Table 1: Demographic comparison of data and operation duration in two groups
11
time (hour)
Ketamine
Placebo
P Value
2
0(0%)
0(0%)
1
4
0(0%)
0(0%)
1
6
0(0%)
3(15%)
0.23
8
3(15%)
3(15%)
1
16
4(20%)
9(45%)
0.176
24
3(15%)
9(45%)
0.082
32
4(20%)
12(60%)
0.02
40
5(25%)
13(65%)
0.025
48
1(5%)
10(50%)
0.003
56
1(5%)
11(55%)
0.01
64
2(10%)
9(45%)
0.031
72
2(10%)
1(5%)
1
Table 2: Agitated patients comparison between two groups
12
Duration
Ketamine
Placebo
P Value
88.30±16.43
96.75±18.51
0.138
Before CPB (pump)
62.6±12.41
63.75±7.58
0.726
After CPB (pump)
61.8±11.63
57.2±4.08
0.267
Before Sternotomy
80.80±8.30
79.1±7.9
0.51
After sternotomy
79.25±7.63
83.15±6.5
0.09
74.25±16.03
80.35±11.76
0.178
Induction of
anesthesia
Mean
Arterial
Pressure
Induction of
Heart
anesthesia
Rate
Before sternotomy
71.20±13.39
71.2±11.08
1
After sternotomy
70.8±14.20
77.05±8.87
0.1
Table 3: Hemodynamic comparison between two groups
13