Ketamine has no effect on oxygenation indices following elective coronary artery bypass grafting under cardiopulmonary bypass Parthasarathi G, Raman SP, Sinha PK, Singha SK, Karunakaran J - Ann Card Anaesth
Cardiopulmonary bypass is known to elicit systemic inflammatory response syndrome and organ dysfunction. This can result in pulmonary dysfunction and deterioration of oxygenation after cardiac surgery and cardiopulmonary bypass. Previous studies have reported varying results on anti-inflammatory strategies and oxygenation after cardiopulmonary bypass. Ketamine administered as a single dose at induction has been shown to reduce the pro-inflammatory serum markers in patients undergoing cardiopulmonary bypass. Therefore we investigated if ketamine can result in better oxygenation in these patients. This was a prospective randomized blinded study. Eighty consecutive adult patients undergoing elective coronary artery bypass grafting under cardiopulmonary bypass were included in the study. Patients were divided into two groups. Patients in ketamine group received 1mg/kg of ketamine intravenously at induction of anesthesia. Control group patients received an equal volume of saline. All patients received standard anesthesia, operative and postoperative care.Paired t test and independent sample t test were used to compare the inter-group and between group oxygenation indices respectively. Oxygenation index and duration of ventilation were analyzed. Deterioration of oxygenation index was noted in both the groups after cardiopulmonary bypass. However, there was no significant difference in the oxygenation index at various time points after cardiopulmonary bypass or the duration of ventilation between the two groups. This study shows that the administered as a single dose at induction does not result in better oxygenation after cardiopulmonary bypass.
How to cite this article: Parthasarathi G, Raman SP, Sinha PK, Singha SK, Karunakaran J. Ketamine has no effect on oxygenation indices following elective coronary artery bypass grafting under cardiopulmonary bypass. Ann Card Anaesth 2011;14:13-8
How to cite this URL: Parthasarathi G, Raman SP, Sinha PK, Singha SK, Karunakaran J. Ketamine has no effect on oxygenation indices following elective coronary artery bypass grafting under cardiopulmonary bypass. Ann Card Anaesth [serial online] 2011 [cited 2014 Mar 5];14:13-8. Available from: http://www.annals.in/text.asp?2011/14/1/13/74394
Cardiopulmonary bypass (CPB) frequently elicits systemic inflammatory response.  The manifestations are varied from mild to severe signs and symptoms.  In the lungs it can lead to acute lung injury, deterioration of oxygenation index, ventilation perfusion mismatch and decrease in lung compliance. 
Various anti inflammatory strategies have been studied. , Ketamine has been shown to have anti inflammatory properties in animal models of sepsis, , to attenuate the increase in pro-inflammatory serum markers , and delirium  after cardiopulmonary bypass due to its anti-inflammatory effect. To our knowledge, data on clinical benefits of the anti-inflammatory effects of ketamine on the lungs is scanty. We investigated if administration of ketamine during induction of anesthesia in patients undergoing coronary artery bypass graft (CABG) surgery under CPB would result in better oxygenation in the postoperative period by virtue of its anti inflammatory property.
Materials and Methods
Institutional ethical committee approved the study. Eighty consecutive adult patients undergoing elective CABG under CPB in a single university hospital were included in the study. All surgeries were performed by a single surgeon. Exclusion criteria were patients undergoing CABG with valve repair/replacement, re-do or emergency surgery, patients with ejection fraction (EF) <35%, congestive cardiac failure, preexisting lung disease such as chronic obstructive pulmonary disease, asthma, tuberculosis, bronchiectasis, preoperative creatinine >1.8 mg/dl, body mass index >35 and history of treatment with steroids. Patients who underwent postoperative re-exploration for bleeding were also excluded from the study.
Patients were recruited for this study from June 2007 to June 2008. Patients were randomized into two groups by the research assistant. The allocation was by the numbers in a container and it was concealed until allocation. The attending anesthesiologist, the patient and the person who collected the data were blinded. Both ketamine and saline were prepared in equal volumes in five ml syringe and handed over to the attending anesthesiologist by a research assistant.
All cardiac medications were continued preoperatively. Premedication consisted of diazepam 0.1 mg/kg orally, morphine 0.1mg/kg and glycopyrrolate 10 μg/kg intramuscularly one hour prior to surgery. In the operating room, after placement of routine non invasive monitors, an arterial line was inserted under local anesthesia and an arterial blood gas (baseline) value was obtained with patient breathing room air. Anesthesia was induced with midazolam 40 μg/kg, fentanyl 5-8 μg/kg and propofol as required. The treatment group (ketamine group) received ketamine 1mg/kg intravenously and the control group received an equal volume of saline, immediately following induction. Pancuronium was used for neuromuscular blockade and tracheal intubation. The lungs were mechanically ventilated with tidal volume of 10 ml/ kg using oxygen, air and isoflurane. The respiratory rate was adjusted to obtain end tidal carbon dioxide value of 35-40 mm Hg. Anesthesia was maintained with morphine, midazolam and isoflurane. A central venous catheter was placed after induction of anesthesia. Corticosteroids, antifibrinolytics and antioxidants such as vitamin E, vitamin C, were not used in any of the patients. Preoperative statins were withheld from all patients.
Crystalloid solution (10 ml/kg) was used intraoperatively. Left pleura was opened to harvest internal mammary artery in all patients. The right pleura was opened by the surgeon only if required for facilitating the surgery. All patients received supplemental midazolam and pancuronium before the institution of CPB. The lungs were deflated during CPB and no air or oxygen was administered. Neither heparin coated circuit nor leukocyte filters were used. Anticoagulation was achieved with heparin to maintain activated coagulation time of more than 480 sec throughout CPB. Hypothermic CPB (28ºC) with a membrane oxygenator and a crystalloid prime (1.5 L lactated ringers solution, 50 ml sodium bicarbonate, and 100 ml of 20% mannitol) was used in all patients. Non-pulsatile flows were maintained in all patients between 2.4 to 2.8 L/min/m 2 and a perfusion pressure of 50-70 mm Hg. Intermittent antegrade blood cardioplegia was used in all patients. Alpha-stat blood gas management was followed. Separation from CPB was achieved with the help of either epinephrine, dobutamine, or noradrenaline at the discretion of the anesthesiologist. The lungs were reinflated manually with oxygen to ensure no visible pockets of atelectasis remained before connecting to the ventilator. No other ventilatory recruitment maneuvers were carried out in any of the patients. Anticoagulation was reversed with protamine which was administered over 20 minutes to return the activated coagulation time to preoperative values.
Once stable hemodynamic was achieved after separation from CPB, an arterial blood gas (ABG) value was obtained while the lungs were ventilated with 100% oxygen for at least 10 minutes. Thereafter the patient was ventilated with 50% oxygen in air and a positive end expiratory pressure (PEEP) of 5 cm of H 2 O. Another ABG value was obtained after 30 minutes. If the partial pressure of arterial oxygen (PaO 2 ) was more than 60 mm Hg, the patient was ventilated with 50% oxygen and 5 cm of H 2 O PEEP until extubation of the trachea. If the PaO 2 of 60 mm Hg was not achieved, then the FIO 2 was increased in increments until a PaO 2 of 60 mm Hg was obtained. Subsequent ABGs were obtained at 10 (ICU- P1) minutes, 3 hrs (ICU- P2) and 6hrs (ICU- P3) after reaching intensive care unit (ICU), and while the patient was on pressure support ventilation (ICU- PS). Two more ABGs were obtained 30 minutes (E1) and 3 hours (E2) after extubation of trachea. Postoperative pain was managed with intravenous patient controlled analgesia with morphine. Inotropes, vasopressors and vasodilators were continued as needed. Maintenance fluid was given at the rate of 2 ml/kg/hr. Further fluids were given if necessary. Weaning from mechanical ventilation was assessed every 30 minutes by the ICU physician. Criteria for weaning were peripheral temperature > 35ºC, stable hemodynamics, urine output >0.5 ml/Kg/hr, minimal or no bleeding, PaO 2 > 60 mmHg with an FIO 2 of 0.5. Patients were extubated if they were able to achieve a good tidal volume (> 6 ml/kg) and a respiratory rate <20.
Chest radiographs were obtained preoperatively, after arrival in the ICU, on postoperative day 1 and after extubation. The following parameters were collected for the purposes of analysis - oxygenation index (PaO 2 / FIO 2 ) and duration of ventilation. In addition, the need for inotropic or vasopressor support, amount of bleeding, serum creatinine levels, development of arrhythmia, wound infection and other complications were also noted.
A priori power analysis revealed that 40 patients are required in each group to determine 20% difference in oxygenation between the groups at an alpha error of 0.05 and a power of 0.8.
SPSS 10.0 (SPSS Inc. Chicago, IL, USA) statistical package was used for the analysis. Within group analysis of the oxygenation index as compared with baseline was performed by paired sample t test. Between groups analysis at the same time points was performed by Student's t test. Multiple comparisons were compensated with post hoc correction. The parameters such as CPB time, aortic cross clamp (ACC) time, duration of mechanical ventilation, amount of bleeding were compared with t test. Nominal data were compared with Chi square test. All values were mentioned as mean ± standard deviation.
There were 39 patients in the control group and 41 in ketamine group. One patient in control group was excluded because of re-exploration due to bleeding in the immediate postoperative period. There was no mortality in either group. Patient characteristics were similar in each group [Table 1].
The operative data are shown in [Table 2]. The mean duration of surgery is longer in ketamine group compared with the control group but the CPB and ACC times were similar. The control group received more fentanyl than ketamine group.
Postoperative data are shown in [Table 3]. There was no difference in the number of patients requiring inotropic support. Two patients in each group required the use of all three inotropes epinephrine, norepinephrine and dopamine. None of the patients received any other inotrope such as milrinone. None of the patient in either group had stroke or renal failure that required dialysis or ventilated for more than 48 hours. There were no adverse effects such as tachycardia and hallucinations in the treatment group.
The comparison of oxygenation index between groups is shown in [Table 4]. The oxygenation index at baseline was higher in both the groups as compared to all other values. However, there was no statistically significant difference in the oxygenation index between the groups at any time points [Table 4].
Table 4 :Comparison of oxygenation index between the two groups
Comparison of the baseline oxygenation index with various post-CPB values within the same group was performed by paired t test. In both the groups the baseline oxygenation was better and statistically significant as compared to all other values [Figure 1] and [Figure 2].
Figure 1 :Comparison of the baseline oxygenation index with various post CPB values within the same group (Ketamine Group). P/F value= PaO2/FIO2= Oxygenation Index; P/F 1 = Post CPB at 100% oxygen; P/F 0.5 = Post CPB at 50% oxygen; P/F p1 = 10 minutes after reaching ICU; P/F p2 = 3 hrs after reaching ICU; P/F p3 = 6 hrs after reaching ICU; and P/F ps = Pressure Support ventilation; P/F e1 = 30 minutes after extubation; P/F e2 = 3 hrs after extubation; *= P ≤ 0.05
Figure 2 :Comparison of the baseline oxygenation index with various post CPB values within the same group (Control Group). P/F value= PaO2/FIO2= Oxygenation Index; P/F 1 = Post CPB at 100% oxygen; P/F 0.5 = Post CPB at 50% oxygen; P/F p1 = 10 minutes after reaching ICU; P/F p2 = 3 hrs after reaching ICU; P/F p3 = 6 hrs after reaching ICU; and P/F ps = Pressure Support ventilation; P/F e1 = 30 minutes after extubation; P/F e2 = 3 hrs after extubation; *= P ≤ 0.05
This study shows that in patients undergoing CABG under CPB, administration of a single dose of ketamine 1mg/kg intravenously at induction does not result in better oxygenation as determined by PaO 2 /FIO 2 ratio.
Patients undergoing cardiac surgery under CPB experience systemic "host" response to surgery which is termed as an inflammatory response to CPB.  Such inflammatory response can have detrimental changes in pulmonary and cardiac function. Activation of neutrophils with subsequent trapping in the pulmonary circulation causes profound pulmonary endothelial, epithelial and interstitial damage. This damage may contribute to increased pulmonary capillary endothelial permeability, decrease in lung compliance and impaired gas exchange. 
Various pharmacological agents such as corticosteroids, aprotinin and antioxidants such as vitamin E and C, deferrioxamine and coenzyme Q10 have been tried in the past to reduce the effects of inflammation post
CPB.  Previous studies have examined the possibility of reduction in the pulmonary damage and the resultant gas exchange abnormality using anti-inflammatory strategies. , A prospective randomized controlled trial involving 30 patients showed that the exclusion of an artificial oxygenator from the CPB circuit by Drew Anderson technique significantly attenuated the inflammatory response, with a trend toward lower IL-8 and IL-6 release and a diminished alveolar-arterial oxygen gradient.  However, the investigation of methyprednisolone on pulmonary function has shown that its use in patients undergoing cardiopulmonary bypass is associated with prolonged tracheal extubation times, increase in alveolar arterial oxygen gradient and shunt. 
Ketamine has been investigated for its anti-inflammatory activity in cardiac surgery. Ketamine as a single dose 0.25 mg/kg administered before cardiopulmonary bypass in high risk cardiac patients is shown to attenuate the increase in C Reactive Protein (CRP), Interleukin 6 (IL-6) and 10 (IL-10). This study also showed better hemodynamic performance in ketamine group with significant differences in mean arterial pressure, heart rate and systemic vascular resistance.  In addition, ketamine in a single dose of 0.25 mg/kg administered before CPB in patients undergoing elective CABG is shown to attenuate the serum IL 6 levels post CPB for seven days.  Ketamine has also been shown to decrease superoxide anion production by neutrophils after CPB.  Therefore we investigated if administration of a single dose of ketamine at induction would result in better oxygenation in the post CPB period, but our study did not show any benefit. There was neither clinical nor radiographic evidence of pleural effusion or pulmonary edema in any of the patients. The authors used 50% oxygen in air and PEEP in all our patients for ventilation in the post bypass period, as it has been shown that using lower (0.5) inspired oxygen concentration  and PEEP  is helpful in reducing atelectasis formation.
The authors chose to use a single dose of 1mg/kg of ketamine, which is higher than that used in previous studies, to ensure definite suppression of inflammatory response. Single dose of ketamine at induction has been shown to attenuate serum inflammatory markers for seven days post-CPB.  Higher doses of ketamine (more than 1 mg/kg) are associated with sympathetic stimulation, especially tachycardia, and therefore are best avoided in the setting of coronary artery bypass graft surgery.
The authors used PaO 2 /FIO 2 as an index of oxygen exchanging status of the lung in this study. It has been shown that PaO 2 /FIO 2 is a useful estimate of the degree of gas exchanging abnormality under usual clinical conditions  and to correlate closely with venous admixture in patients with stable hemodynamics.  Moreover it is simple and easy to obtain and can be used both in intubated and spontaneously breathing patients. 
It does appear from this study that ketamine, like glucocorticoids, though successful in reducing serum level of inflammatory markers in the post-CPB period, does not produce improvement in readily measured clinical markers of pulmonary function. Though corticosteroids have been shown to reduce the serum inflammatory markers, , neither systemic nor inhaled corticosteroids have been shown to offer clinical benefits measured in terms of pulmonary dysfunction, oxygenation, duration of mechanical ventilation, hemodynamic benefit, or improvement in pain control in patients undergoing CPB. ,,
In addition, Cho et al, have studied 50 patients undergoing off-pump CABG and concluded that administration of 0.5 mg/kg of ketamine at induction of general anesthesia did not result in significant changes in serum levels of CRP, IL 6, TNF alpha and cardiac enzymes  even though off- pump CABG has been shown to induce marked and similar inflammatory response as that of CPB. , Ketamine has been shown not to decrease the IL-6 levels in the tracheobronchial aspirate of infants undergoing cardiac surgery. 
In this study the control group had received more fentanyl than the ketamine group whereas the morphine use was similar during surgery. It has been shown that morphine rather than fentanyl suppesses inflammatory response after cardiopulmonary bypass.  So the results of this study could not have been influenced by the inadvertent administration of higher dose of fentanyl in the control group. Both groups of patients received similar amounts of morphine in the postoperative period.
The duration of CPB and surgery in our study is slightly longer in the ketamine group. It is known that surgical trauma and CPB are potent inducers of inflammation. However, the duration of CPB has not been shown to correlate with IL-6 peak levels (r = 0.307, P = 0.054).  To our knowledge, the relationship between the duration of surgery and the magnitude of inflammation has not been studied so far.
The possible reasons for the lack of effect of ketamine in this study could be due to various factors. First, this study was done in low risk surgical patients and therefore the activation of inflammatory reaction could be in a controlled state. As this study involved measuring oxygenation index, we could not have included high risk patients who would have had disturbances in oxygenation due to cardiac dysfunction. Secondly, the deterioration of oxygenation index post CPB may not be due to pulmonary inflammation alone. It has been shown that the epithelial lining fluid levels of IL 6, IL 8 and neutrophil elastase in the airway of patients after CPB did not correlate with the degree of hypoxemia in eleven patients who underwent aortic arch repair. 
Our study did not show any benefit of ketamine on other outcome parameters such as use of inotropes or vasopressors, bleeding, blood transfusion, postoperative ventilation, incidence of arrhythmias and infection. But our study was not powered to detect these outcome variables.
The limitation of this study is that the serum concentration of inflammatory markers was not measured.
Ketamine 1 mg/kg administered intravenously as a single dose at induction for patients undergoing CABG under CPB did not result in better oxygenation in the post bypass period. Further studies with either a higher dose or a continuous infusion of ketamine may be required to evaluate the clinical anti-inflammatory activity of ketamine.
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