Jian-Gang Song

Remifentanil Preconditioning Reduces Hepatic Ischemia― Reperfusion Injury in Rats via Inducible Nitric Oxide Synthase Expression

BACKGROUND Opioid preconditioning against ischemia reperfusion injury has been well studied in myocardial and neuronal tissues. The objective of this study was to determine whether remifentanil could attenuate hepatic injury and to investigate the mechanisms. METHODS A rat model of hepatic ischemia reperfusion injury and a hepatocyte hypoxia reoxygenation (HR) injury model were used, respectively, in two series of experiments. Remifentanil was administered before ischemia or hypoxia and the experiments were repeated with previous administration of naloxone, L-arginine and N-ω-nitro-L-arginine methyl ester, a nonselective opioid receptor antagonist, a nitric oxide donor, and nitric oxide synthase (NOS) inhibitor, respectively. Serum aminotransferase, cytokines, and hepatic lipid peroxidation were measured. Histopathology examination and apoptotic cell detection were assessed. For the in vitro study, cell viability, intracellular nitric oxide, apoptosis, and NOS expression were evaluated. RESULTS Remifentanil and L-arginine pretreatment reduced concentrations of serum aminotransferases and cytokines, decreased the concentrations of hepatic malondialdehyde and myeloperoxidase activity, and increased superoxide dismutase, nitric oxide, and inducible NOS expression in vivo. Decreased histologic damage and apoptosis were also seen in these two groups. These changes were prevented by previous administration of N-ω-nitro-L-arginine methyl ester but not naloxone. There was an increase in inducible NOS protein expression but not endogenous NOS in remifentanil and L-arginine pretreated groups compared with control, naloxone, and N-ω-nitro-L-arginine methyl ester groups. CONCLUSION Pretreatment with remifentanil can attenuate liver injury both in vivo and in vitro. Inducible NOS but not opioid receptors partly mediate this effect by exhausting reactive oxygen species and attenuating the inflammatory response.

Electroacupuncture improves survival in rats with lethal endotoxemia via the autonomic nervous system.

Background: Recent advances have indicated a complex interplay between the autonomic nervous system and the innate immune system. Targeting neural networks for the treatment of sepsis is being developed as a therapeutic strategy. Because electroacupuncture at select acupoints can modulate activities of the autonomic nervous system, we tested the hypothesis that electroacupuncture at specific acupoints could modulate systemic inflammatory responses and improve survival via its impact on the autonomic nervous system in a rat model of sepsis. Methods: Sprague-Dawley male rats received electroacupuncture for 45 min before and at 1, 2, or 4 h after a lethal dose of intraperitoneal lipopolysaccharide injection (6 mg/kg). Outcomes included survival and systemic cytokine responses. Also, the possible roles of neural circuitry, including the hypothalamic-pituitary-adrenal axis and the autonomic nervous system, were evaluated. Results: Electroacupuncture pretreatment at the Hegu acupoints significantly attenuate systemic inflammatory responses and improve survival rate from 20% to 80% in rats with lethal endotoxemia. Such a site-specific effect requires the activation of muscarinic receptors in the central nervous system, but not increasing central sympathetic tone. In the periphery synergistic, rather than independent, action of the sympathetic and parasympathetic systems is also necessary. Conclusions: Electroacupuncture pretreatment has a dramatic survival-enhancing effect in rats with lethal endotoxemia, which involves the activation of efferent neural circuits of the autonomic nervous system (e.g., cholinergic antiinflammatory pathway). This approach could be developed as a prophylactic treatment for sepsis or perioperative conditions related to excessive inflammation.

A Comparison of Liver Function After Hepatectomy with Inflow Occlusion Between Sevoflurane and Propofol Anesthesia

BACKGROUND:In this study, we compared liver function tests after hepatectomy with inflow occlusion as a function of propofol versus sevoflurane anesthesia. METHODS:One hundred patients undergoing elective liver resection with inflow occlusion were randomized into a sevoflurane group or a propofol group. General anesthesia was induced with 3 &mgr;g/kg fentanyl, 0.2 mg/kg cisatracurium, and target-controlled infusion of propofol, set at a plasma target concentration of 4 to 6 &mgr;g/mL, or sevoflurane initially started at 8%. Anesthesia was maintained with target-controlled infusion of propofol (2–4 &mgr;g/mL) or sevoflurane (1.5%–2.5%). The primary end point was postoperative liver injury assessed by peak values of liver transaminases. RESULTS:Transaminase levels peaked between the first and the third postoperative day. Peak alanine aminotransferase was 504 and 571 U/L in the sevoflurane group and the propofol group, respectively. Peak aspartate aminotransferase was 435 U/L after sevoflurane and 581 U/L in the propofol group. There were no significant differences in peak alanine aminotransferase or peak aspartate aminotransferase between groups. Other liver function tests including bilirubin and alkaline phosphatase, and peak values of white blood cell counts and creatinine, were also not different between groups. CONCLUSIONS:Sevoflurane and propofol anesthetics resulted in similar patterns of liver function tests after hepatectomy with inflow occlusion. These data suggest that the 2 anesthetics are equivalent in this clinical context.

Awakening Concentration of Desflurane Is Decreased in Patients with Obstructive Jaundice

Background:Some studies suggest that behavioral complications of cholestasis, such as fatigue and pruritus, may be associated with altered neurotransmission in the brain. Because inhaled anesthetics primarily act on ion channels and receptors on the neuronal cell membrane and alter synaptic transmission in the central nervous system, it is possible that altered sensitivity to inhaled anesthetics may occur in cholestatic patients. Therefore, the authors compared the minimum alveolar concentration (MAC)-awake of desflurane in obstructive jaundiced patients with the MACawake in nonjaundiced patients. Methods:Patients underwent inhalational induction of anesthesia with desflurane. MACawake was determined in each patient by observing the response to a verbal command (open eyes on request). An end-tidal anesthetic concentration was maintained at an initial target level of 1.4% for 15 min before a command. If a positive response was observed, the concentration of desflurane was increased by 0.1% and again kept constant for 15 min. The verbal command was then continued. This process was repeated until an end-tidal concentration was reached at which the patient did not respond to command. The anesthetic concentration midway between the value permitting the response and that just preventing the response was defined as MACawake for each patient. Results:The MACawake of desflurane for patients with obstructive jaundice (1.78 ± 0.19%) was significantly less than those observed for the control group (2.17 ± 0.25%; P < 0.001) and correlated significantly with serum total bilirubin (r = −0.67, P = 0.0004). Conclusions:The MACawake of desflurane is reduced in obstructive jaundiced patients compared with nonjaundiced controls.

A clinical prospective comparison of anesthetics sensitivity and hemodynamic effect among patients with or without obstructive jaundice

Background: To compare isoflurane anesthesia in patients with or without hyperbilirubinemia undergoing hepatobiliary surgery.

Baroreflex Sensitivity Is Impaired in Patients with Obstructive Jaundice

Background:Obstructive jaundice is associated with enhanced susceptibility to hypotensive shock, renal failure, and toxic effects of endotoxin, which results in high perioperative morbidity and mortality. Since the normal arterial baroreflex function is necessary for hemodynamic homeostasis and improving survival in sepsis, this study aimed to determine whether baroreflex sensitivity was impaired in jaundiced patients. Methods:Thirty-five patients with obstructive jaundice scheduled for surgery were included, and 30 nonjaundiced patients served as controls. A modified Oxford pharmacologic technique was used for evaluating baroreflex sensitivity immediately before the surgery. Potential factors that may affect baroreflex sensitivity in jaundice, such as liver biochemistry, plasma concentrations of methionine-enkephalin, atrial natriuretic peptide and nitrate, were also measured. Results:Patients with obstructive jaundice had decreased sensitivity in both the sympathetic and vagal components of the baroreflex, as compared with the controls (P < 0.01). There was a significant inverse correlation between plasma atrial natriuretic peptide concentration and decreased sympathetic baroreflex sensitivity in the jaundiced group (r = −0.44, P = 0.008). Conclusions:Baroreflex sensitivity is impaired in patients with obstructive jaundice, which may contribute to their enhanced susceptibility to the well-known perioperative complications. The underlying mechanisms for such a change may be associated with an increased level of plasma atrial natriuretic peptide.

Volatile anesthetics might be more beneficial than propofol for postoperative liver function in cirrhotic patients receiving hepatectomy.

Hepatic inflow occlusion during the liver surgery may result in a transient ischemia period followed by reperfusion, and may initiate liver injury and lead to postoperative liver dysfunction. Especially in cirrhotic patients, the tolerance time of ischemia is much shorter and the outcome would be worse. Recently, clinical trials had proved that volatile anesthetics rather than propofol can protect myocardial cells from ischemia reperfusion (IR) injury in cardiac surgery. Meanwhile, animal studies had revealed that volatile anesthetics could induce some endogenous protective molecules in the liver such as hypoxia induced factor-1 (HIF-1), heme oxygenase (HO) enzyme system and inducible nitric oxide synthase (iNOS), which make the volatile anesthetics posing the extraordinary anti-oxidative, anti-inflammatory, anti-apoptotic, and vasodilatory characteristics. However, there is still lack of trials to compare the postoperative outcomes such as liver function in cirrhotic patients undergoing liver surgery with inflow occlusion between volatile anesthetics and propofol anesthesia. Hence we hypothesize that with its anti-IR injury characteristics, volatile anesthetics might be the more appropriate choice in cirrhotic patients undergoing liver surgery with occlusion.

Vagal modulation of high mobility group box-1 protein mediates electroacupuncture-induced cardioprotection in ischemia-reperfusion injury

Excessive release of high mobility group box-1 (HMGB1) protein from ischemic cardiomyocytes activates inflammatory cascades and enhances myocardial injury after reperfusion. Here we report evidence that electroacupuncture of mice at Neiguan acupoints can inhibit the up-regulation of cardiac HMGB1 following myocardial ischemia and attenuate the associated inflammatory responses and myocardial injury during reperfusion. These benefits of electroacupuncture were partially reversed by administering recombinant HMGB1 to the mice, and further potentiated by administering anti-HMGB1 antibody. Electroacupuncture-induced inhibition of HMGB1 release was markedly reduced by unilateral vagotomy or administration of nicotinic receptor antagonist, but not by chemical sympathectomy. The cholinesterase inhibitor neostigmine mimicked the effects of electroacupuncture on HMGB1 release and myocardial ischemia reperfusion injury. Culture experiments with isolated neonatal cardiomyocytes showed that acetylcholine, but not noradrenaline, inhibited hypoxia-induced release of HMGB1 via a α7nAchR-dependent pathway. These results suggest that electroacupuncture acts via the vagal nerve and its nicotinic receptor-mediated signaling to inhibit HMGB1 release from ischemic cardiomyocytes. This helps attenuate pro-inflammatory responses and myocardial injury during reperfusion.

ERK1/2-Egr-1 Signaling Pathway-Mediated Protective Effects of Electroacupuncture in a Mouse Model of Myocardial Ischemia-Reperfusion

Early growth response- (Egr-) 1 is an upstream master switch in controlling inflammatory responses following myocardial ischemia-reperfusion (I/R). Activation of extracellular signal-regulated protein kinase-1 and kinase-2 (ERK1/2) signaling is known to upregulate Egr-1. ERK1/2 pathway has been previously shown to mediate the therapeutic action of electroacupucture (EA). Thus, we hypothesized that EA would reduce myocardial I/R injury and inflammatory responses through inhibiting Egr-1 expression via the ERK1/2 pathway. Mice were pretreated with EA, U0126, or combination of EA and U0126 and then underwent 1 h myocardial ischemia and 3 h reperfusion. We investigated that EA significantly attenuated the I/R-induced upregulation of both Egr-1 and phosporylated-ERK1/2 (p-ERK1/2), decreased myocardial inflammatory cytokines including tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), and reduced the infarct size and the release of cardiac troponin I (cTnI). U0126 treatment also exhibited the same effect as EA on Egr-1 level and subsequent cardioprotective effects. There was no additive effect of cotreatment with EA and U0126 on the expression of Egr-1 and its downstream target genes (TNF-α, IL-1β) or serum cTnI level. Collectively, these observations suggested that EA attenuates myocardial I/R injury, possibly through inhibiting the ERK1/2-Egr-1 signaling pathway and reducing the release of proinflammatory cytokines.

The etomidate requirement is decreased in patients with obstructive jaundice.

BACKGROUND: Patients with obstructive jaundice have increased sensitivity to inhaled anesthetics. In rodent brain, bilirubin can enhance &ggr;-aminobutyric acid A/glycinergic synaptic transmission. Etomidate is a nonbarbiturate hypnotic that induces sedation through &ggr;-aminobutyric acid A receptors in the central nervous system. We tested the hypothesis that patients with obstructive jaundice have an altered sensitivity to etomidate. METHODS: The study design was a comparison of etomidate requirements to reach a Bispectral Index of 50 in patients with obstructive jaundice versus patients with chronic cholelithiasis and normal bilirubin levels. Etomidate was infused at 30 &mgr;g/kg/min until this end point was reached. RESULTS: The etomidate requirement in the obstructive jaundice group was lower than that in the control group (150 ± 46 &mgr;g/kg vs 206 ± 74 &mgr;g/kg, P = 0.007). The average decrease in etomidate requirement was 56 &mgr;g/kg (95% confidence interval: 16–96 &mgr;g/kg). In addition, we found a significant negative correlation between serum total bilirubin and etomidate requirement with Pearson r of −0.545, and 95% confidence interval for r value (−0.791 to −0.148). All subjects were hemodynamically stable during the study. CONCLUSIONS: Etomidate requirements to reach a level of anesthesia defined by a Bispectral Index of 50 are reduced in patients with obstructive jaundice.