AIM: To investigate the effects of ketamine anesthesia on the motility alterations and tissue injury caused by ischemia/reperfusion in rats.

METHODS: Thirty male Wistar rats weighing 200-250 g were used. Ischemia was induced by obstructing blood flow in 25% of the total small intestinal length (ileum) with a vascular clamp for 45 min, after which either 60 min or 24 h of reperfusion was allowed. Rats were either anesthetized with pentobarbital sodium (50 mg/kg) or ketamine (100 mg/kg). Control groups received sham surgery. After 60 min of reperfusion, the intestine was examined for morphological alterations, and after 24 h intestinal basic electrical rhythm (BER) frequency was calculated, and intestinal transit determined in all groups.

RESULTS: The intestinal mucosa in rats that were anesthetized with ketamine showed moderate alterations such as epithelial lifting, while ulceration and hemorrhage was observed in rats that received pentobarbital sodium after 60 min of reperfusion. Quantitative analysis of structural damage using the Chiu scale showed significantly less injury in rats that received ketamine than in rats that did not (2.35 ± 1.14 vs 4.58 ± 0.50, P < 0.0001). The distance traveled by a marker, expressed as percentage of total intestinal length, in rats that received pentobarbital sodium was 20% ± 2% in comparison with 25.9% ± 1.64% in rats that received ketamine (P = 0.017). BER was not statistically different between groups.

CONCLUSION: Our results show that ketamine anesthesia is associated with diminished intestinal injury and abolishes the intestinal transit delay induced by ischemia/reperfusion.

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Figure 1 A: Control A group showing normal mucosa; B: SK A. Changes in intestinal mucosa structure following 45 min of ischemia and 60 min reperfusion; C: KET A. Less damage was observed (all × 40).

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Figure 2 Bar diagram illustrating the Chiu score of mucosal injury after 60 min of reperfusion. Lower damage score was observed in a KET A group than in the SK A group. ^aP < 0.0001 vs control A; ^bP < 0.0001 vs KET A.

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Figure 3 Bar diagram illustrating the distance travelled by the marker, expressed as a percentage of total intestinal length from pylorus to cecum. Intestinal I/R caused transit delay that was corrected by the administration of ketamine as anesthetic. ^aP = 0.00019 vs control B; ^bP = 0.0004 vs KET B.

Mesenteric ischemia is a clinical entity with a mortality rate between 60% and 100% that usually requires surgical resection of the necrotic intestinal segment[1]. Although there have been advancements in the treatment of ischemic injury, an ideal treatment has not been defined, and new options should be considered. A promising strategy is the use of anesthetic and sedative agents that might exert protective effects on the injured tissue. Ketamine is an agent that has been recommended for this purpose in clinical situations of sepsis, renal ischemia, cerebral ischemia and serious burn injuries[2-4].

The small intestine is very sensitive to ischemic insult[5]. Reperfusion causes additional damage through the release of free radicals, pro-inflammatory cytokines, leukotrienes and other related products[6]. Intestinal ischemia/reperfusion (I/R) damages the intestinal mucosa and alters gastrointestinal motility[7]. The histological damage induced by I/R includes alterations in capillary permeability, mucosal barrier dysfunction, necrosis, epithelial shredding. The damage is reversed in a period of approximately 24 h[8].

The NMDA (N-methyl-D-Aspartate) receptor family is a heterogeneous group of excitatory ionotropic voltage and ligand gate dependent receptors. Ketamine is a parenteral anesthetic that non-competitively blocks the NMDA receptor[9]. It has been shown that ketamine protects various tissues from I/R injury, such as brain[10], myocardium[11] and skeletal muscle[12]. To the best of our knowledge, no previous studies have evaluated the effects of ketamine on intestinal motility impairment and tissue damage induced by I/R.

The alterations on intestinal motility caused by I/R are directly related to the length of both ischemia and reperfusion[14]. The functional alterations caused by I/R have been previously identified[15]. These changes consist of reversible alterations in smooth muscle contractility and intestinal transit, as well as characteristic changes in electrical activity such as a decrease in BER frequency during ischemia[7,16]. Nitric oxide is one of the mediators thought to participate in the changes caused by I/R on intestinal motility in the rat[17].

The structural damage caused by ischemia is aggravated by the restitution of blood flow. The physiopathology of intestinal mucosal damage by I/R is not completely understood. But, it is believed that cytotoxic substances such as free radicals, nitric oxide, serotonin, complement, as well as neutrophil infiltration and nuclear transcription factors play important roles[18]. Macrophages have been also implicated in the initial damage caused by intestinal I/R[19]. I/R has also been shown to induce apoptosis[20]. Bacterial translocation and mucosal barrier dysfunction have been implicated in the damage caused by I/R in the gut[21]. This damage is also related to an increase in circulating levels of pro-inflammatory cytokines such as interleukin-6 and tumor necrosis factor alpha (TNF-alpha), liberated by the intestine itself[22].

Recently, anti-inflammatory properties of ketamine have been described in various experimental models. Interleukin-1, 6, 8 and TNF-alpha levels are reduced after the administration of ketamine[23-25]. Neutrophil adhesion, migration, and free radical release is inhibited by ketamine[26,27], as is nitric oxide production by macrophages[28]. Further studies are needed to determine whether one of these effects is responsible for the mucosal protection against I/R that we observed in this study.

Glutamate is an excitatory neurotransmitter in the central nervous system, and it participates in the modulation of intestinal function through the enteric nervous system, where NMDA receptors have been found[29]. It has been shown that the glutamate system is involved in the pathogenesis of I/R in brain and intestine[30]. Glutamate release and NMDA receptor activation induces nitric oxide, and other free radicals that cause tissue injury[31]. Glutamate release during I/R could also cause toxicity in the enteric nervous system, which could cause motility alterations[32]. One recent study found that intestinal I/R causes myenteric plexus ganglion cell reduction and death[33]. This suggests that the NMDA receptor could be related to the functional alterations induced in the intestine by I/R. In one study, the NMDA antagonist MK-801 diminished nitric oxide production, and prevented the changes in the intestinal transit caused by intestinal ischemia/reperfusion[34]. We showed that ketamine, an NMDA receptor antagonist, also corrects the intestinal transit delay caused by intestinal I/R, but we did not find any changes in the frequency of the BER after 24 h of reperfusion. Further studies are needed in order to determine whether our results are explained by ketamine acting as an NMDA receptor antagonist in the gut.

Ketamine protects the intestine against other types of non-ischemic insults. Ketamine has been shown to protect the gut against endotoxemia induced injury in rats through diminished pro-inflammatory cytokine release[35]. Ketamine also decreased enterocyte apoptosis in a model of thermal burn induced intestinal injury[36]. However, this is the first study to demonstrate that ketamine anesthesia reduces I/R induced injury in intestinal mucosa.