Effects of Ketamine on Pulmonary Inflammatory Responses and Survival in Rats Exposed to Polymicrobial Sepsis

Abstract

-PURPOSE.Ketamine is reported to suppress production of proinflammatory cytokines and activity of nuclear factor-kappa B (NF-κB) after lipopolysaccharide (LPS) stimulation. Our study was designed to investigate the effects of ketamine on pulmonary inflammatory responses and survival in a clinically relevant model of polymicrobial sepsis, induced by cecal ligation and puncture (CLP). METHODS. After the induction of sepsis or sham-operation, animals were treated with ketamine (0.5, 5 or 10 mg/kg) or saline (10 ml/kg) at 3h after operation. At 6 h post-operation, the levels of tumor necrosis factor alpha (TNF-α) and interleukin (IL)-6, activity of NF-κB, expression of Toll-like receptor 2 (TLR2) and Toll-like receptor 4 (TLR4) of the lungs were measured. And the mortality was recorded for 7 days. RESULTS. TNF-α and IL-6 production, NF-κB activity, TLR2 and TLR4 expression in rat lungs were increased after CLP. Ketamine at the doses of 5 mg/kg and 10 mg/kg suppressed CLP-induced elevation of TNF-α and IL-6 production, NF-κB activity and TLR2 expression. Ketamine 0.5, 5 and 10 mg/kg inhibited TLR4 expression in sepsis. Ketamine 5mg/kg and 10 mg/kg after CLP improved the survival of rats. CONCLUSIONS. Ketamine at sub-anesthetic doses could suppress the production of inflammatory cytokines such as TNF-α and IL-6, attenuate NF-κB activity, and inhibit TLR2 and TLR4 expression in polymicrobial sepsis. These anti-inflammatory effects of ketamine may correlate with improved survival in sepsis.

The Effects of Ketamine, Midazolam and Ketamine/Xylazine on Acute Lung Injury Induced by α-Naphthylthiourea in Rats*

“…On the other hand, ketamine's role in neuroanesthesia is limited because of its association with increased intracranial pressure and other side effects such as psychotropic properties, tachycardia and hypertension [26]. Recent years studies have shown that ketamine plays a protective role against lung injury, via its anti-inflammatory properties [8][9][10]. Under ketamine anesthesia, neurogenic pulmonary edema is less pronounced in a rat model of spinal cord injury, and the mortality of severely burnt rats is reduced [28].…”

“…Ketamine has been shown to attenuate symptoms of endotoxemia in a lipopolysaccharide-induced rat model of sepsis, by reducing nuclear factor kappa B (NF-kappa B) activity and tumor necrosis factor-alpha (TNF-α) production [29], and decreasing the expression of iNOS in various rat tissues [30]. Furthermore, Yu et al found that ketamine at sub-anesthetic doses also suppress the production of inflammatory cytokines on lung tissue such as TNF-α and interleukin-6 (IL-6), attenuate NF-kappa B activity, and inhibit toll-like receptor 2 (TLR2) and TLR4 expression in polymicrobial sepsis [8]. In addition, ketamine has weak suppressive effect on reactive oxygen species (ROS) production by neutrophils and modulate the stimulated adhesion molecule expression [31].…”

“…The exact mechanisms of the effects of ketamine on pleural effusion are still obscure. But these mechanisms might be related to the effects of ketamine on immune/inflammatory cells, ROS and iNOS expression [8,9,[29][30][31]. These mechanisms are also known to play a role in ANTU-mediated damage [6,16,18].…”

“…Ketamine and midazolam are preferred drugs in intensive care units for sedation and anesthesia. The anti-inflammatory effects of these agents have been demonstrated in previous experimental animal models [8][9][10]; however, there are no findings about the effects of these agents on ANTU induced pulmonary edema and pleural effusion. The rodenticide ANTU causes acute pulmonary vascular injury in animals [11].…”

“…Aside from its anaesthetic properties, these agents have been shown to induce physiological changes that suggest a powerful anti-inflammatory effect [6,8,9]. Ketamine and midazolam are preferred drugs in intensive care units for sedation and anesthesia.…”