Ketamine attenuates liver injury attributed to endotoxemia: Role of cyclooxygenase-2

University of Houston, Houston, Texas, United States
Surgery (Impact Factor: 3.11). 09/2005; 138(2):134-40. DOI: 10.1016/j.surg.2005.03.024
Source: PubMed

ABSTRACT Endotoxic shock can cause end-organ dysfunction and liver injury. Critically ill patients frequently require surgical intervention under general anesthesia for source control. However, the effects of anesthetics on organ function during sepsis and their influence on inflammatory mediators such as cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) remain to be fully elucidated. Because ketamine anesthesia has anti-inflammatory effects in some tissues, we hypothesized that it would attenuate lipopolysaccharide (LPS)-induced liver injury.
Adult rats were given no anesthesia (saline), continuous isoflurane inhalation, or intraperitoneal (i.p.) injection of ketamine 70 mg/kg. One hour later, the rats received saline or LPS (20 mg/kg i.p.) for 5 hours. The rats were killed, and serum hepatocellular enzymes, liver COX-2, iNOS protein (Western immunoblot), and nuclear factor kappa B (NF-kappaB)-binding activity (electrophoretic mobility shift assay) determined. In a separate study, the role of COX-2 in LPS-induced liver injury was examined by pretreating rats with the selective COX-2 inhibitor NS-398 (3 mg/kg, i.p.) and the role of iNOS examined with the use of the selective inhibitor aminoguanidine (45 mg/kg, i.p.) 1 hour before LPS.
LPS increased serum aspartate aminotransferase and alanine aminotransferase levels, hepatic iNOS and COX-2 protein, and nuclear factor NF-kappaB. Ketamine, but not isoflurane, attenuated these effects caused by LPS. COX-2 inhibition with NS-398 as well as iNOS inhibition with aminoguanidine diminished LPS-induced changes in aspartate aminotransferase and alanine aminotransferase levels.
These data indicate that anesthetics differ in their effects on liver injury caused by LPS. Ketamine has hepatoprotective effects, while isoflurane does not. Moreover, the protective effects of ketamine are mediated, at least in part, through a reduction in COX-2 and iNOS protein that could be regulated via changes in NF-kappaB-binding activity.

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    • "When exposed to ketamine, hepatocytes showed an inhibition of oxidative phosphorylation (Chang et al., 2009), increased apoptotic insults (Lee et al., 2009) and reactive oxygen species (ROS) production (Reinke et al., 1998). Contrarily, ketamine also showed hepatoprotective effects which are attributed to its anti-inflammatory properties (Suliburk et al., 2005). Despite several in vitro studies (Chang et al., 2009; Lee et al., 2009; Markham et al., 1981), there is still little information on ketamine chronic effects on liver mitochondria and oxidative stress responses when in vivo models are used. "
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    ABSTRACT: Aim Ketamine can induce hepatotoxicity which has been suggested to be dependent on mitochondrial impairment. This study investigated the long-term effects of chronic low-dose ketamine on liver mitochondria function, oxidative stress parameters, liver histology and glycogen content. Main methods Adult rats were administered with saline or ketamine (5 or 10mg/kg) twice a day for a fourteen-day period in order to mimic chronic treatments. Effects between groups were compared ten days after the treatment had end. Liver mitochondrial function was monitored in isolated mitochondrial extracts through evaluation of respiration parameters and activity of respiratory complexes, as well as oxidative stress, through lipid peroxidation, protein oxidation and superoxide dismutase activity. The hepatic histology and liver glycogen content were also evaluated. Key findings Ketamine groups showed a decreased evolution in body weight gains during the treatment period. Ketamine had no effect either on serum liver enzymes or on the oxidative stress parameters of liver mitochondria. Ketamine decreased the hepatic glycogen content, inhibited mitochondrial complex I and oxygen consumption when glutamate-malate substrate was used. Significance These findings reflect a long-term mitochondrial bioenergetic deterioration induced by ketamine, which may explain the increased susceptibility of some patients to its prolonged or repeated use.
    Life sciences 08/2013; DOI:10.1016/j.lfs.2013.08.001 · 2.30 Impact Factor
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    • "The mechanism for these effects on cytokine production is not fully understood . However, ketamine has been shown to reduce nuclear factor kappa-B production in the lung, brain, liver, and intestine [17] [18] [19] [20]. Taken together, "
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    ABSTRACT: Total intravenous anesthesia (TIVA) is frequently used for major operations requiring general anesthesia in critically ill burn patients. We reviewed our experience with this approach. During a 22-month period, 547 major burn surgeries were performed in this center's operating room and were staffed by full-time burn anesthesiologists. The records of all 123 TIVA cases were reviewed; 112 records were complete and were included. For comparison, 75 cases were selected at random from a total of 414 non-TIVA general anesthetics. Some patients had more than one operation during the study: as appropriate for the analysis in question, each operation or each patient was entered as an individual case. For inter-patient analysis, exposure to 1 or more TIVAs was used to categorize a patient as member of the TIVA group. Excision and grafting comprised 78.2% of the operations. 14 TIVA regimens were used, employing combinations of 4 i.v. drugs: ketamine (K, 91 cases); i.v. methadone (M, 62); fentanyl (F, 58); and propofol (P, 21). The most common regimens were KM (34 cases); KF (26); KMF (16); and K alone (8). Doses used often exceeded those used in non-burn patients. TIVA was preferred for those patients who were more critically ill prior to surgery, with a higher ASA score (3.87 vs. 3.11). Consistent with this, inhalation injury (26.7 vs. 1.6%), burn size (TBSA, 36.3 vs. 15.8%), and full-thickness burn size (FULL, 19.8 vs. 6.5%) were higher in TIVA than in non-TIVA patients. Despite this, intraoperative pressor use was as common in TIVA as in non-TIVA cases (23.9 vs. 22.7%). TIVA was used in patients whose inhalation injury rate and TBSA were greater than those of non-TIVA patients. TIVA cases were not associated with increased hemodynamic instability. TIVA is a viable approach to general anesthesia in critically ill burn patients.
    01/2013; 3(2):108-14.
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    • "Historically, some of the markers of LPS mediated hepatic damage have included increased serum activity of the hepatic intracellular enzymes alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) (Suliburk et al., 2005), hepatic neutrophil transmigration (Vadjova et al., 2000; Bautista, 2002), apoptosis (Tsuchiya et al., 2004) and hepatocellular necrosis (Ou et al., 1997; Yee Introduction Lipopolysaccharide (LPS, endotoxin), a component of the cell wall of gram-negative bacteria residing in the mammalian intestinal tract is considered to play an important role in the septic shock syndrome in humans (Bautista, 2002; Parillo, 1993). Clinical manifestations of LPS-associated sepsis usually include systemic response to infection (tachycardia, tachypnea, alterations in body temperature and leukocytosis) and those related to multiple organ dysfunction (cardiovascular, respiratory, renal and hepatic) (Parillo, 1993). "
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    ABSTRACT: Several studies have investigated the role of neutrophils during endotoxin-mediated liver injury, yet the precise mechanism for endotoxin-mediated hepatic neutrophil transmigration is unknown. The primary objective of this study was to establish a reliable lipopolysaccharide (LPS)-mediated necro-hepatitis model to investigate the mechanisms of hepatic neutrophil infiltration following LPS administration. Male Sprague Dawley rats were administered a single (5 or 10 mg kg(-1), i.v.) or repeated injection of LPS (10 mg kg(-1), i.v., 24 h apart) with appropriate controls (i.v. saline) and were killed at various time points following LPS injection. Significant hematologic changes included neutrophilia, elevation of the neutrophil to lymphocyte ratio and toxic changes in neutrophils. Biochemical changes were observed in several liver (aspartate aminotransferase AST, gamma glutamyl transferase GGT) and kidney (blood urea nitrogen BUN) associated parameters generally at the earliest time points. Histopathology revealed a time-dependent neutrophil and mononuclear infiltration around the periportal areas in the single dose study and multifocal midzonal coagulative necrosis in the repeated dose study. The neutrophil adhesion molecule, CD 11b was up-regulated in single and repeat dose studies. Based on these studies, a reliable LPS-mediated hepatitis model with necrosis was developed by intravenous administration of LPS in a repeat dose fashion. Midzonal hepatic necrosis, peripheral neutrophilia, hepatic neutrophil infiltration and up-regulation of CD11b were the most significant and consistent markers of LPS mediated effects in this model.
    Journal of Applied Toxicology 11/2007; 27(6):602-11. DOI:10.1002/jat.1243 · 3.17 Impact Factor
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