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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.
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Conflicts of interest
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References 
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
CheckDOI: 10.4103/aca.aca_31_21
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