Randomized, double-blinded, placebo controlled study of neuroprotection with lidocaine in cardiac surgery

Joseph P Mathew, G Burkhard Mackensen, Barbara Phillips-Bute, Hilary P Grocott, Donald D Glower, Daniel T Laskowitz, James A Blumenthal, Mark F Newman, Neurologic Outcome Research Group (NORG) of the Duke Heart Center, Joseph P Mathew, James A Blumenthal, Hilary P Grocott, Frederick W Lombard, G Burkhard Mackensen, Joseph P Mathew, David McDonagh, Terri Monk, Mark F Newman, Barbara Phillips-Bute, Mihai V Podgoreanu, Andrew D Shaw, Mark Stafford-Smith, Madhav Swaminathan, David Warner, William D White, Narai Balajonda, Lauren Baker, Bonita L Funk, Roger L Hall, Kimberly Martin, Felisa W Anderson, Gladwell Mbochi, Charles R Peters, Prometheus T Solon, Peter Waweru, Michael A Babyak, James A Blumenthal, Daniel B Mark, Michael H Sketch Jr, Ellen R Bennett, Carmelo Graffagnino, Daniel T Laskowitz, Warren J Strittmatter, Kathleen A Welsh-Bohmer, Kevin Collins, Greg Smigla, Ian Shearer, Thomas A D'Amico, Duane Davis, Jeffrey G Gaca, Donald D Glower, R David Harpole, G Chad Hughes, James Jaggers, Shu Lin, Andrew Lodge, James E Lowe, Carmelo Milano, Mark Onaitis, Peter K Smith, Joseph P Mathew, G Burkhard Mackensen, Barbara Phillips-Bute, Hilary P Grocott, Donald D Glower, Daniel T Laskowitz, James A Blumenthal, Mark F Newman, Neurologic Outcome Research Group (NORG) of the Duke Heart Center, Joseph P Mathew, James A Blumenthal, Hilary P Grocott, Frederick W Lombard, G Burkhard Mackensen, Joseph P Mathew, David McDonagh, Terri Monk, Mark F Newman, Barbara Phillips-Bute, Mihai V Podgoreanu, Andrew D Shaw, Mark Stafford-Smith, Madhav Swaminathan, David Warner, William D White, Narai Balajonda, Lauren Baker, Bonita L Funk, Roger L Hall, Kimberly Martin, Felisa W Anderson, Gladwell Mbochi, Charles R Peters, Prometheus T Solon, Peter Waweru, Michael A Babyak, James A Blumenthal, Daniel B Mark, Michael H Sketch Jr, Ellen R Bennett, Carmelo Graffagnino, Daniel T Laskowitz, Warren J Strittmatter, Kathleen A Welsh-Bohmer, Kevin Collins, Greg Smigla, Ian Shearer, Thomas A D'Amico, Duane Davis, Jeffrey G Gaca, Donald D Glower, R David Harpole, G Chad Hughes, James Jaggers, Shu Lin, Andrew Lodge, James E Lowe, Carmelo Milano, Mark Onaitis, Peter K Smith

Abstract

Background and purpose: Cognitive decline after cardiac surgery remains common and diminishes patients' quality of life. Based on experimental and clinical evidence, this study assessed the potential of intravenously administered lidocaine to reduce postoperative cognitive dysfunction after cardiac surgery using cardiopulmonary bypass.

Methods: After IRB approval, 277 patients undergoing cardiac surgery were enrolled into this prospective, randomized, double-blinded placebo controlled clinical trial. Subjects were randomized to receive: (1) Lidocaine as a 1 mg/kg bolus followed by a continuous infusion through 48 hours postoperatively, or (2) Placebo bolus and infusion. Cognitive function was assessed preoperatively and again at 6 weeks and 1 year postoperatively. The effect of lidocaine on postoperative cognition was tested using multivariable regression modeling; P<0.05 was considered significant.

Results: Among the 241 allocated subjects (Lidocaine: n=114; Placebo: n=127), the incidence of cognitive deficit in the lidocaine group was 45.5% versus 45.7% in the placebo group (P=0.97). Multivariable analysis revealed a significant interaction between treatment group and diabetes, such that diabetic subjects receiving lidocaine were more likely to suffer cognitive decline (P=0.004). Secondary analysis identified total lidocaine dose (mg/kg) as a significant predictor of cognitive decline and also revealed a protective effect of lower dose lidocaine in nondiabetic subjects.

Conclusions: Lidocaine administered during and after cardiac surgery does not reduce the high rate of postoperative cognitive dysfunction. Higher doses of lidocaine and diabetic status were independent predictors of cognitive decline. Protective effects of lower dose lidocaine in nondiabetic subjects need to be further evaluated.

Figures

Figure 1
Figure 1
CONSORT diagram showing the flow of participants.
Figure 2 (Online only)
Figure 2 (Online only)
Diabetic patients receiving lidocaine were more likely to experience cognitive decline (2a) or cognitive deficit (2b). Delta Cognitive Index = (6 week – preoperative cognitive index); Cognitive Deficit = dichotomous outcome.
Figure 2 (Online only)
Figure 2 (Online only)
Diabetic patients receiving lidocaine were more likely to experience cognitive decline (2a) or cognitive deficit (2b). Delta Cognitive Index = (6 week – preoperative cognitive index); Cognitive Deficit = dichotomous outcome.
Figure 3
Figure 3
Lidocaine levels with standard deviations in patients receiving lidocaine or placebo. CPB = cardiopulmonary bypass.
Figure 4 (Online Only)
Figure 4 (Online Only)
C-reactive protein (4a), S-100β (4b), caspase-3 (4c), interleukin-8 (4d), matrix metalloproteinase-9 (4e), and vascular endothelial growth factor (4f) levels with standard deviations in patients receiving lidocaine or placebo. Values have been log-transformed to achieve normality. CPB = cardiopulmonary bypass; XCL = aortic cross clamp.
Figure 4 (Online Only)
Figure 4 (Online Only)
C-reactive protein (4a), S-100β (4b), caspase-3 (4c), interleukin-8 (4d), matrix metalloproteinase-9 (4e), and vascular endothelial growth factor (4f) levels with standard deviations in patients receiving lidocaine or placebo. Values have been log-transformed to achieve normality. CPB = cardiopulmonary bypass; XCL = aortic cross clamp.
Figure 4 (Online Only)
Figure 4 (Online Only)
C-reactive protein (4a), S-100β (4b), caspase-3 (4c), interleukin-8 (4d), matrix metalloproteinase-9 (4e), and vascular endothelial growth factor (4f) levels with standard deviations in patients receiving lidocaine or placebo. Values have been log-transformed to achieve normality. CPB = cardiopulmonary bypass; XCL = aortic cross clamp.
Figure 4 (Online Only)
Figure 4 (Online Only)
C-reactive protein (4a), S-100β (4b), caspase-3 (4c), interleukin-8 (4d), matrix metalloproteinase-9 (4e), and vascular endothelial growth factor (4f) levels with standard deviations in patients receiving lidocaine or placebo. Values have been log-transformed to achieve normality. CPB = cardiopulmonary bypass; XCL = aortic cross clamp.
Figure 4 (Online Only)
Figure 4 (Online Only)
C-reactive protein (4a), S-100β (4b), caspase-3 (4c), interleukin-8 (4d), matrix metalloproteinase-9 (4e), and vascular endothelial growth factor (4f) levels with standard deviations in patients receiving lidocaine or placebo. Values have been log-transformed to achieve normality. CPB = cardiopulmonary bypass; XCL = aortic cross clamp.
Figure 4 (Online Only)
Figure 4 (Online Only)
C-reactive protein (4a), S-100β (4b), caspase-3 (4c), interleukin-8 (4d), matrix metalloproteinase-9 (4e), and vascular endothelial growth factor (4f) levels with standard deviations in patients receiving lidocaine or placebo. Values have been log-transformed to achieve normality. CPB = cardiopulmonary bypass; XCL = aortic cross clamp.
Figure 5
Figure 5
Decline in cognition with increasing total dose of lidocaine. The shaded area represents 95% confidence intervals. The threshold for cognitive decline appears to be at an approximately 35 mg/kg of lidocaine. Delta CI = (6 week – preoperative cognitive index).

Source: PubMed

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