Abstract

Severe sepsis is a major healthcare problem with a reported incidence of 1–2% in all hospitalizations. It is a major cause of death in the intensive care units worldwide and is the second leading cause of death in noncoronary intensive care unit patients.¹ Mortality remains high at 30–50% despite a better understanding of sepsis pathophysiology and improved advanced care in the past decade.² Sepsis is defined as a systemic inflammatory response syndrome, the culprit of which ought to be an identifiable focus of infection. Beyond the primary damage to the organism, activation of leukocytes causes an enrichment of inflammatory mediators, such as proinflammatory cytokines, nitric oxide, and reactive oxygen species, that may induce cell injury, platelet activation, and endothelial dysfunction. These pathophysiological mechanisms contribute to the impairment of the microcirculation and tissue perfusion, leading to dysfunction of organs. Considered together, these uncovered findings suggest the possibility that strategies aimed at altering the priming events that occur during sepsis might exert beneficial effects in terms of preventing organic injury.

Structurally, ketamine is a derivative of phencyclidine that could exert an antagonistic effect on the N-methyl-d-aspartate receptor. Ketamine may also stimulate opioid, dopamine, norepinephrine, serotonin, and muscarinic cholinergic receptors.3, 4 Therefore, it has amnestic, anesthetic, and analgesic properties that enable it to serve as an adjunct for general anesthesia and sedative for surgical procedures.⁵ The studies about intravenous anesthetics interacting with immune cellular system were well reported since 1916.6, 7 Like other intravenous anesthetics, ketamine may also affect the septic course, possibly due to immunosuppression via blocking the nonconventional receptor on immune cells.⁸

In this issue of Acta Anaesthesiologica Taiwanica, Liu and colleagues review the modulating effects of ketamine on immune cells and its possible mechanism. They describe that ketamine affects many pathways leading to inflammation cascade during sepsis. First, ketamine has an immunosuppressive effect on immune cells such as NK cell cytotoxic activity, neutrophil adhesion to endothelium, and chemotactic activity of neutrophils. Second, ketamine decreases Toll-like receptor expression, nuclear factor-κB activity, and Raf/Raf cascade. Third, ketamine suppresses cytokines, superoxide, and nitric oxide productions, and reduces the mitochondrial membrane potential in macrophages. Finally, ketamine prevents the alteration of immune function in patients early after a major surgery, and increases survival in rats with sepsis. Most patients with sepsis will survive after a hyperinflammatory response and develop a protracted hypoinflammatory, immunosuppressive state manifested by the development of secondary infections.⁹ Several studies have demonstrated excessive apoptosis in septic patients and animals—mainly in the intestine, lymphoid organs, and circulating lymphocytes10, 11—that is believed to contribute to immune suppression and link to disease pathogenesis and the resultant mortality. Therefore, inhibition of apoptosis has recently been suggested as a novel therapeutic approach for the prevention and treatment of sepsis.¹² Inducers of apoptosis include cytokines such as tumor necrosis factor-α, interleukin-1 and interleukin-6, oxygen free radicals, and nitric oxide,¹¹ which could be suppressed by ketamine. This suggests that ketamine inhibits immune cell death during sepsis. Recent reports further demonstrate that ketamine causes neuronal cell death in developing rodents and nonhuman primates.13, 14 However, few studies have focused on whether ketamine triggers or inhibits immune cell apoptosis induced by endotoxin or sepsis either in vivo or in vitro.

In addition, because of the dissociative effects of ketamine, it has abuse potential and is classified as a schedule III nonnarcotic substance.¹⁵ Therefore, it is not suitable to use this compound for long-term sedation. Even if anesthesia with bolus of ketamine rather than sevoflurane potentially reduces acute inflammatory response following surgery stress, postoperative infection might not be improved unless bacterial growth is well controlled by antibiotics.¹⁶ Furthermore, it is noteworthy that if a powerful therapeutic agent is administered in the late stage of sepsis, it may be ineffective or even harmful. However, few studies are aimed at whether ketamine has a protective effect on sepsis in vivo, if the administration is delayed.

When we consider the published studies on this topic together with the current work of Liu et al, it appears reasonable to investigate the role of ketamine in the early stage of the critical illness. Since ketamine administration may contribute to arterial hypertension, tachycardia, myocardial depression, and dissociative effects, further clinical studies are needed to elucidate the safety and efficacy of intravenous ketamine in sepsis. If the experimental results reviewed by the current authors are reliable in humans, ketamine may become an attractive agent of anesthesia and sedation, especially in hemodynamically unstable conditions, such as acute heart failure or sepsis-related myocardial depression. We hope that in the near future we will able to determine whether septic patients should be treated with ketamine in anesthesia for postoperative immune modulation in addition to its effects of sedation and analgesia.