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| Year : 2023
| Volume
: 26 | Issue : 1 | Page
: 114-116 |
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| Ketamine, interleukin-6, and vasoplegia: Is prevention the best medicine? |
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Jamel P Ortoleva
Department of Anesthesiology and Perioperative Medicine, Tufts Medical Center, Boston, MA, United States, USA
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| Date of Submission | 29-Mar-2021 |
| Date of Acceptance | 12-Jul-2021 |
| Date of Web Publication | 03-Jan-2023 |
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How to cite this article:
Ortoleva JP. Ketamine, interleukin-6, and vasoplegia: Is prevention the best medicine?. Ann Card Anaesth 2023;26:114-6 |
Vasoplegia continues to be a major challenge facing clinicians during the periprocedural care of cardiac surgical patients. The incidence of vasoplegia, particularly in the heart transplant from the left ventricular assist device population, maybe as high as approximately 50%.[1],[2] The precise pathophysiology of vasoplegia is not known but is thought to be related to a combination of dysregulation of nitric oxide synthase and cyclic guanylate cyclase, as well as elevated levels of interleukins and other inflammatory molecules.[3],[4],[5] Treatments have included high doses of vasoconstrictors such as norepinephrine and vasopressin, corticosteroids, and alternatives such as methylene blue, hydroxocobalamin, and angiotensin II.[6],[7],[8],[9] While these treatments have some efficacy, they have risks, and it may be time to approach the problem from a new perspective: prevention.
IL-6 has been monitored in patients undergoing cardiac surgical procedures and has been found to increase significantly in the time after cross-clamp removal.[4] IL-6 also has a vasodilatory effect, and may contribute to the drop in systemic vascular resistance that is commonly encountered after cross-clamp removal.[5] It stands to reason that perhaps inhibiting or blocking IL-6 may mitigate the hypotension encountered after cross-clamp removal, particularly in patients that over-express it. Tocilizumab (Actemra®), an IL-6 receptor antibody, is garnering increased interest as a treatment for coronavirus infectious disease (COVID-19) patients with hyperimmune responses.[10] The tocilizumab food and drug administration (FDA) package insert cites the most common hemodynamic adverse event in patients receiving it over a long period (24 weeks) as hypertension (in 6% of the patients).[11] More importantly, when used for the treatment of cytokine release syndrome, tocilizumab frequently resolves hypotension within hours.[12] Comparing the IL-6 inhibiting properties of ketamine and tocilizumab is challenging because the mechanisms of the blockade are not identical: ketamine decreases IL-6 levels while tocilizumab competitively binds IL-6 receptors (increasing IL-6 levels, but preventing binding).
Ketamine, a potent analgesic and amnestic, is known to have IL-6-inhibiting properties.[13],[14],[15] Ketamine comes in two forms: racemic (most commonly available), and S-ketamine (esketamine, Spravato®). The combination of anti-inflammatory and sympathomimetic properties of ketamine may play a role in reducing the risk of vasoplegia in high-risk cardiac surgery, such as left ventricular assist device (LVAD) to transplant. An analysis of the potency of IL-6 inhibition by ketamine in cardiac surgery is best seen in a meta-analysis from 2012: ketamine seems to decrease IL-6 levels to one-third that of patients not receiving ketamine.[15] The ketamine dosage to achieve this reduction in IL-6 may be quite high: in one study by Welters et al.[16] in 2011, a 1–3 mg/kg bolus of esketamine during induction of general anesthesia followed by a drip at 2–4 mg/kg/h was used in cardiac surgical patients as a sedation adjunct in comparison to a group anesthetized with no ketamine. In this study, Welters et al.[16] found one-third IL-6 levels after aortic cross-clamp removal in the esketamine group versus the group without esketamine (56.75 picograms/mL vs. 172.64 picograms/mL). Of note, esketamine is approximately twice the potency of racemic ketamine, meaning the equivalent dose of the more commonly used form would be 4–8 mg/kg/h, which would likely have a significant effect on the extubation time. At our institution, we frequently administer ketamine infusions at doses of 0.3–1 mg/kg/h during cardiac transplantation and have noted no complications since instituting this practice. The minimum dose of ketamine necessary to impact IL-6 levels in cardiac surgical patients is not currently known.
A randomized trial comparing ketamine infusion to placebo in heart transplant, a high-risk vasoplegia population, will shed light on the interaction of ketamine on the risk of vasoplegia. Hemodynamic differences, vasoconstrictor, and inotrope doses should be the primary endpoint. Obtaining IL-6 levels preinduction, postinduction but preincision, after the initiation of cardiopulmonary bypass but before cross-clamp placement, and hourly after cross-clamp removal could provide biomarker plausibility on the hypothesis that ketamine may reduce vasoplegia risk through IL-6 inhibition. Given that vasoplegia in the LVAD to transplant population is approximately 50%, the number needed to enroll for a 20% relative reduction in vasoplegia would be 774 (387 patients per group). For a 40% reduction (i.e., an incidence of vasoplegia of 50% in placebo versus 30% in the ketamine group), the sample size would be 186 (93 patients per group). A multicenter, randomized trial is needed.
The concept of ketamine being an agent to possibly prevent vasoplegia is a microcosm of the premise that anesthetic agents can play larger roles than merely sedation and analgesia. Alternative uses for pharmacologic agents utilized in anesthesia include the use of ketamine as a potent antidepressant, ketamine as a treatment for refractory status epilepticus, and methylnaltrexone possibly increasing survival in cancer patients.[17],[18],[19] Hopefully in the future, ketamine or other agents that modulate inflammation in cardiac surgical care can be used to address vasoplegia as a preventative strategy.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
 References | |  |
| 1. | Ali JM, Patel S, Catarino P, Vuylsteke A, Pettit S, Bhagra S, et al. Vasoplegia following heart transplantation and left ventricular assist device explant is not associated with inferior outcomes. J Thorac Dis 2020;12:2426-34.  |
| 2. | Asleh R, Alnsasra H, Daly RC, Schettle SD, Briasoulis A, Taher R, et al. Predictors and clinical outcomes of vasoplegia in patients bridged to heart transplantation with continuous-flow left ventricular assist devices. JAHA 2019;8. Available from: https://www.ahajournals.org/doi/100.1161/JAHA.119.013108. [Last acessed on 2021 Mar 13]. |
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| 4. | Wan S, Marchant A, DeSmet JM, Antoine M, Zhang H, Vachiery JL, et al. Human cytokine responses to cardiac transplantation and coronary artery bypass grafting. J Thorac Cardiovasc Surg 1996;111:469-77. |
| 5. | Vila E, Salaices M. Cytokines and vascular reactivity in resistance arteries. Am J Physiol Heart Circ Physiol 2005;288:H1016-21. |
| 6. | Ortoleva JP, Cobey FC. A systematic approach to the treatment of vasoplegia based on recent advances in pharmacotherapy. J Cardiothor Vasc Anesth 2019;33:1310-4. |
| 7. | Fischer GW, Levin MA. Vasoplegia during cardiac surgery: Current concepts and management. Semin Thorac Cardiovasc Surg 2010;22:140-4. |
| 8. | Shapeton AD, Mahmood F, Ortoleva JP. Hydroxocobalamin for the treatment of vasoplegia: A review of current literature and considerations for use. J Cardiothorac Vasc Anesth 2019;33:894-901. |
| 9. | Omar S, Zedan A, Nugent K. Cardiac vasoplegia syndrome: Pathophysiology, risk factors and treatment. Am J Med Sci 2015;349:80-8. |
| 10. | REMAP-CAP Investigators, Gordon AC, Mouncey PR, Al-Beidh F, Rowan KM, Nichol AD, et al. Interleukin-6 receptor antagonists in critically Ill patients with covid-19. N Engl J Med 2021;384:1491-502. |
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| 13. | Shaked G, Czeiger D, Dukhno O, Levy I, Artru AA, Shapira Y, et al. Ketamine improves survival and suppresses IL-6 and TNFalpha production in a model of Gram-negative bacterial sepsis in rats. Resuscitation 2004;62:237-42. |
| 14. | Beilin B, Rusabrov Y, Shapira Y, Roytblat L, Greemberg L, Yardeni IZ, et al. Low-dose ketamine affects immune responses in humans during the early postoperative period. Br J Anaesth 2007;99:522-7. |
| 15. | Dale O, Somogyi AA, Li Y, Sullivan T, Shavit Y. Does intraoperative ketamine attenuate inflammatory reactivity following surgery? A systematic review and meta-analysis. Anesth Analg 2012;115:934-43. |
| 16. | Welters ID, Feurer MK, Preiss V, Müller M, Scholz S, Kwapisz M, et al. Continuous S-(+)-ketamine administration during elective coronary artery bypass graft surgery attenuates pro-inflammatory cytokine response during and after cardiopulmonary bypass. Br J Anaesth 2011;106:172-9. |
| 17. | Höfler J, Trinka E. Intravenous ketamine in status epilepticus. Epilepsia 2018;59:198-206. |
| 18. | Murrough JW, Iosifescu DV, Chang LC, Al Jurdi RK, Green CE, Perez AM, et al. Antidepressant efficacy of ketamine in treatment-resistant major depression: A two-site randomized controlled trial. Am J Psychiatry 2013;170:1134-42. |
| 19. | Janku F, Johnson LK, Karp DD, Atkins JT, Singleton PA, Moss J. Treatment with methylnaltrexone is associated with increased survival in patients with advanced cancer. Ann Oncol 2016;27:2032-8. |
Correspondence Address:
Jamel P Ortoleva
Department of Anesthesiology and Perioperative Medicine, Tufts Medical Center, 800 Washington Street, Ziskind Building 6th Floor. Boston, MA. 02111
USA
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/aca.aca_31_21
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