Evaluation of Low-Dose Ketamine on Inflammatory Biomarker Profile Following Off-Pump Coronary Artery Bypass Grafting

Introduction

The burden of atherosclerotic disease continues to escalate with a heightened number of comorbid patients presenting with coronary artery disease. This emanates largely as a combination of an increased life expectancy and improved diagnostic modalities. Albeit, the development of the spectrum of interventions employed to re-perfuse the ischemic myocardium, like thrombolysis, percutaneous coronary angioplasty, and surgical revascularization continues to be the mainstay of treatment for the patient cohort with multivessel disease and complex anatomy.¹, ²

Conventionally, systemic inflammatory response syndrome (SIRS) is inexorably linked to the conduct of cardiac surgery employing cardiopulmonary bypass (CPB) which detrimentally affects the postoperative outcomes.³, ⁴, ⁵ Therefore, an increasing number of surgical centers are contemplating beating heart surgical revascularization. However, an off-pump coronary artery bypass grafting (OPCAB) also incurs varying degree of inflammatory response activation which is accentuated by the accompanying myocardial ischemia–reperfusion injury (IRI).⁶, ⁷ This reduced but yet not completely obliterated inflammatory response continues to influence postoperative cardiac function and clinical outcomes following OPCAB.

Various anti-inflammatory strategies and pharmacological agents have been evaluated in the cardiac surgical arena over the last decade. These include (not limited to) leukocyte filtration, corticosteroids, aprotinin, and nitric-oxide donor compounds.⁸, ⁹, ¹⁰, ¹¹ Considering a favorable cost-benefit ratio and an acceptable adverse effect profile of anti-inflammatory modalities, several anesthetic agents have been proposed to demonstrate a protective role against IRI and subsequent SIRS. The putative mechanisms of protection include: attenuation of Ca²⁺ overload, anti-inflammatory and antioxidant effects, pre- and postconditioning effects.

N-methyl-D-aspartate (NMDA) receptor antagonist, ketamine has demonstrated anti-inflammatory role in recent studies¹², ¹³, ¹⁴, ¹⁵ by decreasing the serum levels of proinflammatory markers, such as C-reactive protein (CRP) and interleukin-6 (IL-6) following CPB.¹⁶, ¹⁷ Amelioration of SIRS with ketamine is thought to be mediated through inhibition of nuclear factor (NF)-kB,⁷ which regulates the transcription of genes that encode the production of proinflammatory cytokines.¹⁸, ¹⁹ This positive modulation confers an anti-inflammatory potential to the drug by limiting the exacerbation of systemic inflammation with minimal effect on the local healing processes.

Therefore, we evaluated whether the low dose of ketamine administered during induction of anesthesia would reduce the activity of proinflammatory mediators in patients undergoing OPCAB in a prospective, randomized double-blind study.

Materials and Methods

After obtaining approval from the Institutional Review Board and Institutional Ethics Committee, this prospective observational study was conducted at our tertiary cardiac center from November, 2015 to March, 2017. Sixty patients posted for elective OPCAB were allocated to either control (C group, not receiving ketamine) or test (T group, receiving ketamine) by computer-based randomization. Patients were excluded from the study if they met one of the following criteria: recent (<14 days) myocardial infarction, unstable angina with elevated creatine kinase-MB (CK-MB) elevated serum creatinine (>1.3 mg/dL) before surgery, previous cardiac surgery, previous stroke or pulmonary disease, history of treatment with steroid or nonsteroidal anti-inflammatory drugs within a month, patients who are on vasoactive medications, patients undergoing re-exploration surgery or ejection fraction less than 40%, and intraoperative hemodynamic instability necessitating conversion to on pump.

A thorough preoperative evaluation was performed, and a written informed consent was obtained from all the patients. The included subjects were fasted preoperatively as per The American Society of Anesthesiologists guidelines and received tablet alprazolam 0.25 mg and ranitidine 150 mg orally, the night before surgery and on the morning of surgery. After wheeling in the patient into the operating room, pulse oximeter (SpO2) and five lead electrocardiogram electrodes were applied and patient’s noninvasive vital parameters were recorded which include heart rate (HR), systolic and diastolic blood pressures (BPs), and mean arterial pressure (MAP). After local anesthetic infiltration and under all aseptic precautions, a wide bore intravenous cannula and a 20-G intra-arterial right radial artery catheter were secured. Anesthesia was induced with propofol (2 mg/kg) and bolus of ketamine 1% (0.5 mg/kg) in the test group or propofol (2 mg/kg) and same volume of normal saline (as ketamine) in the control group, according to randomization. Apart from the induction agent, rest of the anesthesia technique was similar in both the groups as per the institutional protocol.

After induction a Swan-Ganz catheter (Edwards Life Sciences, Irwine, California, United States) was positioned in the pulmonary artery through 7-Fr sheath inserted in the right internal jugular vein. The hemodynamic parameters in the form of HR, BP, central venous pressure (CVP), pulmonary capillary wedge pressure (PCWP), cardiac output (CO) (by FloTrac continuous cardiac output monitor), cardiac index (CI), systemic vascular resistance and systemic vascular resistance index (SVR and SVRI), and pulmonary vascular resistance and pulmonary vascular resistance index (PVR and PVRI) were monitored continuously. Surgical revascularization was contemplated in the background of activated clotting time value of more than 300 seconds following administration of heparin in the dosage of 1 mg/kg. The intraoperative hemodynamic parameters were titrated within 20% of the baseline values with the initiation of vasopressor agents (if, SVRI <1,500 dyne/s/cm⁵/m²) or inotropic agents (if CI <2.5 L/min/m²), to maintain MAP of more than 60 mm Hg. Intravascular volume replacement was managed with crystalloid and colloid solutions to maintain PCWP between 8 and 16 mm Hg according to the baseline values. The hemodynamic parameters in the form of HR, BP, CVP, PCWP, CO (by FloTrac/Vigileo continuous cardiac output monitor), CI, SVR and SVRI, and PVR and PVRI were monitored continuously. Heparin was reversed with protamine in dose of 1.3 times the dose of heparin administered. All patients were transferred to the intensive care unit after surgery.

Results

A total of 60 patients completed the study. The demographic factors and surgical data were comparable in the two groups (Table 1). There was no significant difference in the perioperative hemodynamic profile of the two groups (Table 2).

The inflammatory markers were compared between the two groups. All the biomarkers (IL-6, CRP, TNF-α, CK-MB, and TnT) were comparable at T0. The serum CRP and IL-6 levels were significantly (p < 0.05) lower at all postoperative time points (T1,T2,T3,T4) in the ketamine group in contrast to the control group (Table 3). However, the postoperative TNF-α, TnT, and CK-MB levels were comparable between the two groups. The time trend analysis of postoperative CRP and IL-6 levels is depicted in Fig. 1, wherein both the groups demonstrate an increase in the inflammatory marker profile. It is noteworthy that the elevation in the inflammatory marker profile was higher in group C as compared with group T. The postoperative outcomes were comparable between the two groups. However, it was noteworthy that the highest postoperative VIS_h (vasopressor inotrope score in the first postoperative 48 hours) was significantly higher for the patients in control group as opposed to the test group (Table 4). Interestingly, the average postoperative CRP and IL-6 levels positively correlated with the VIS_h with the r values of 0.733 (p < 0.001) and 0.704 (p < 0.001), respectively (Fig. 2).

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Fig. 1

Comparison of biochemical marker trends in the control and test group.

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Fig. 2

The correlation plots of average postoperative CRP and IL-6 with the highest postoperative vasopressor inotrope score (VIS_H). CRP, C-reactive protein; IL-6, interleukin-6.

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Discussion

The major finding of the study is constituted by the demonstration of lower proinflammatory markers like CRP and IL-6 with addition of low-dose ketamine to the anesthetic induction regimen in the patients undergoing OPCAB. The statistically significant difference in the postoperative CRP and IL-6 levels persisted throughout the study period which lasted for the first postoperative 48 hours. Interestingly, these results are in contrast to a similar study by Cho et al²⁰ who failed to demonstrate anti-inflammatory potential of ketamine in OPCAB setting. However, there are several studies elucidating the anti-inflammatory effect of ketamine in on-pump coronary artery bypass grafting (CABG)¹³, ¹⁴, ¹⁵ and noncardiac surgeries.¹² Despite the reduction in CRP and IL-6, the index study outlined a comparable postoperative TNF-α levels in the ketamine group. At the same time there was no significant difference in the postoperative markers of the myocardial damage (TnT and CK-MB) in the two groups.

Ketamine, a noncompetitive NMDA receptor antagonist, in addition to its anesthetic activity possesses a positive immunomodulatory impact which can be of special interest in cardiac surgical patient.²¹, ²² The anti-inflammatory effects of ketamine are mediated by inhibition of NF-kB, which regulates the transcription of genes that encode the production of proinflammatory cytokines.⁷ In most studies¹³, ¹⁴, ¹⁶ anti-inflammatory effect of ketamine has been demonstrated mainly in terms of reducing the serum levels of proinflammatory mediators, such as CRP, IL-6, and TNF-α.

There are other proposed mechanisms promoting the anti-inflammatory properties of ketamine. Various studies reveal that ketamine favorably modulates the cellular immunity and neurohumoral response mechanism²² in conjunction to anti-analgesic effects. Low-dose ketamine during induction of general anesthesia influences cellular immunity as outlined by an attenuation of neutrophil superoxide production in CABG.¹⁴ Moreover, ketamine has also been shown to inhibit transcription factors NF-kβ and activator protein 1 (AP-1) in human blood neutrophils.²³ These transcription factors regulate the transcription of genes encoding the production of proinflammatory cytokines such as IL-6, TNF-α, IL-1, and IL-8. Therefore, inhibition of transcription factors, AP-1 and NF-kβ is a key mechanism by which ketamine attenuates the cytokine release and resultant inflammatory response observed in cardiac surgery.

Several caveats surface on a closer evaluation of this clinical area of recent interest, aimed at demonstrating anti-inflammatory effect of anesthetic agents like ketamine in cardiac surgical patients. First, the available literature elucidates that the anti-inflammatory effect of ketamine is dose-related²⁴ and higher doses of ketamine can attenuate inflammatory reactions to a greater extent. However, owing to its sympathomimetic effects, ketamine can elicit adverse hemodynamic modifications toward an increase in myocardial oxygen consumption.²⁵ Therefore, subanesthetic dose, as low as 0.5 mg/kg was employed in this study. Second, this low dose of ketamine did not result in untoward hemodynamic perturbations such as significant elevation in PVR. Moreover, all patients in the study received midazolam to prevent ketamine-induced hallucinations. Finally, the conduct of the study in a tertiary care center by a single experienced cardiac surgeon and adherence to standard institutional protocol constitute the inherent strength of the study.

The study had a few inherent limitations. The study did not assess anti-inflammatory mediator such as IL-10, other proinflammatory makers such as IL-8 and IL-2 and therefore could not assess any effects of ketamine on these mediators. Conflicting results have been reported regarding the ketamine’s effect on the IL-10, and although low-dose ketamine was reported to attenuate increases in IL-10 in OPCAB.¹³ Other studies²⁶ have shown significantly higher levels of IL-10 at the end of surgery. The other limitation of the study was the duration of follow-up after surgery which was kept as 48 hours. Studies¹⁷ have shown that inflammatory markers, namely IL-6 and CRP did not return to the baseline level even after 30 days postoperatively. This protracted period of activation of the inflammatory reaction parallels an increase in the risk of cardiovascular events in the recovery phase after the surgery.

Conclusion

The results of the study indicate that administration of low dose of ketamine prior to induction of anesthesia in patients undergoing OPCAB, induces a statistically significant attenuation in the production of proinflammatory mediators, IL-6 and CRP. No significant difference was observed in the levels of TNF-α, CK-MB, TnT, and hemodynamic parameters between the ketamine and control group.

The findings of the study substantiate the anti-inflammatory potential of ketamine in preventing immune function alterations attributable to anesthesia and cardiac surgery.