Surgical Apgar score is strongly associated with postoperative ICU admission.

Immediate postoperative intensive care unit (ICU) admission can increase the survival rate in patients undergoing high-risk surgeries. Nevertheless, less than 15% of such patients are immediately admitted to the ICU due to no reliable criteria for admission. The surgical Apgar score (SAS) (0-10) can be used to predict postoperative complications, mortality rates, and ICU admission after high-risk intra-abdominal surgery. Our study was performed to determine the relationship between the SAS and postoperative ICU transfer after all surgeries. All patients undergoing operative anesthesia were retrospectively enrolled. Among 13,139 patients, 68.4% and < 9% of whom had a SASs of 7-10 and 0-4. Patients transferred to the ICU immediately after surgery was 7.8%. Age, sex, American Society of Anesthesiologists (ASA) class, emergency surgery, and the SAS were associated with ICU admission. The odds ratios for ICU admission in patients with SASs of 0-2, 3-4, and 5-6 were 5.2, 2.26, and 1.73, respectively (P < 0.001). In general, a higher ASA classification and a lower SAS were associated with higher rates of postoperative ICU admission after all surgeries. Although the SAS is calculated intraoperatively, it is a powerful tool for clinical decision-making regarding the immediate postoperative ICU transfer.

Phosphoinositide 3-Kinase Is Involved in Mediating the Anti-inflammation Effects of Vasopressin.

Vasopressin possesses potent anti-inflammatory capacity. Phosphoinositide 3-kinase (PI3K) and its downstream activator Akt contribute to endogenous anti-inflammation capacity. We sought to elucidate whether PI3K is involved in mediating the anti-inflammation effects of vasopressin. Macrophages (RAW264.7 cells) were randomized to receive endotoxin, endotoxin plus vasopressin, or endotoxin plus vasopressin plus the nonselective PI3K inhibitor (LY294002) or the selective isoform inhibitor of PI3Kα (PIK-75), PI3Kß (TGX-221), PI3Kδ (IC-87114), or PI3Kγ (AS-252424). Compared to macrophages treated with endotoxin, the concentrations of cytokines (tumor necrosis factor-α, interleukin-6) and chemokine (macrophage inflammatory protein-2) in macrophages treated with endotoxin plus vasopressin were significantly lower (all P < 0.05). The concentrations of phosphorylated nuclear factor-κB p65 (p-NF-κB p65) in nuclear extracts and phosphorylated inhibitor-κBα (p-I-κBα) in cytosolic extracts as well as NF-κB-DNA binding activity were also lower (all P < 0.05). Of note, except for macrophages treated with endotoxin plus vasopressin plus PIK-75, the concentrations of cytokines, chemokine, p-NF-κB p65, and p-I-κBα as well as NF-κB-DNA binding activity in macrophages treated with endotoxin plus vasopressin plus LY294002, TGX-221, IC-87114, or AS-252424 were significantly higher than those in macrophages treated with endotoxin plus vasopressin (all P < 0.05). In contrast, the phosphorylated Akt concentration in macrophages treated with endotoxin plus vasopressin was significantly higher than that in macrophages treated with endotoxin or in macrophages treated with endotoxin plus vasopressin plus LY294002, TGX-221, IC-87114, or AS-252424, but not PIK-75. These data confirmed that PI3K, especially the isoforms of PI3Kß, PI3Kδ, and PI3Kγ, is involved in mediating the anti-inflammatory effects of vasopressin.

Cepharanthine mitigates pro-inflammatory cytokine response in lung injury induced by hemorrhagic shock/resuscitation in rats.

BACKGROUND: Cepharanthine possesses strong anti-inflammation capacity. We sought to clarify whether cepharanthine could mitigate pro-inflammatory cytokine production in acute lung injury induced by hemorrhagic shock/resuscitation (HS/RES). The involvement of heme oxygenase-1 (HO-1) was also investigated. METHODS: Male Sprague Dawley rats were allocated to receive HS/RES, HS/RES plus iv cepharanthine or HS/RES plus cepharanthine plus the HO-1 activity inhibitor tin protoporphyrin (SnPP) and denoted as the HS/RES, HS/RES+CEP, and HS/RES+CEP+SnPP group, respectively. HS/RES was achieved by blood drawing to lower mean arterial pressure (40-45 mmHg for 60 min) followed by shed blood/saline mixtures re-infusion. The rats were monitored for another 5h before sacrifice. RESULTS: Arterial blood gas, lung permeability and histologic assays (including histopathology, neutrophil infiltration, and lung water content) confirmed that HS/RES induced significant lung injury. Significant increases in pulmonary levels of tumor necrosis factor-α, interleukin-1ß, interleukin-6, prostaglandin E2 and cyclooxygenase-2 confirmed that HS/RES induced a significant inflammatory response in the lungs. Cepharanthine significantly attenuated the pulmonary pro-inflammatory cytokine production and lung injury induced by HS/RES. However, the protective effects of cepharanthine were blocked by SnPP, the potent HO-1 activity inhibitor. CONCLUSION: Cepharanthine significantly mitigates pro-inflammatory cytokine response in acute lung injury induced by HS/RES in rats. The mechanism may involve the HO-1 pathway.

Cepharanthine mitigates lung injury in lower limb ischemia-reperfusion.

BACKGROUND: Oxidation and inflammation caused by lower limb ischemia-reperfusion (I/R) readily induce lung injury. We elucidated whether cepharanthine, a potent antioxidative and anti-inflammatory drug, can mitigate lung injury induced by lower limb I/R. Role of heme oxygenase 1 (HO-1) was also investigated. MATERIALS AND METHODS: Adult male Sprague-Dawley rats were randomized to receive I/R, I/R plus cepharanthine, or I/R plus cepharanthine plus the HO-1 activity inhibitor tin protoporphyrin (SnPP; n = 12 in each group). Sham control groups were run simultaneously. I/R was induced by applying rubber band tourniquets high around each thigh for 3 h followed by reperfusion for 24 h. RESULTS: Rats receiving I/R had significant increases in concentrations of nitric oxide, malondialdehyde (lipid peroxidation marker), and inflammatory molecules (including interleukin 6, macrophage inflammatory protein 2, and prostaglandin E2) in plasma, and the lungs, indicating that I/R caused significant oxidation and inflammation in rats. Rats receiving I/R also had significant increases in concentration of phosphorylated inhibitor-κB, indicating that I/R caused significant nuclear factor κB activation. Assays of arterial blood gas, biochemistry, and histopathology confirmed that I/R-induced significant lung injury in rats. Cepharanthine significantly reduced the oxidation, inflammation, nuclear factor κB activation, and lung injury induced by I/R. Of note, cepharanthine significantly enhanced pulmonary HO-1 expression after I/R. Moreover, these previously mentioned effects of cepharanthine were partially reversed by inhibiting the activity of HO-1. CONCLUSIONS: Cepharanthine mitigates lung injury induced by bilateral lower limb I/R in rats. The mechanisms may involve its effects on reducing oxidation and inflammation. The mechanisms may also involve enhancing HO-1 expression.

Phosphoinositide 3-kinase ß, phosphoinositide 3-kinase δ, and phosphoinositide 3-kinase γ mediate the anti-inflammatory effects of magnesium sulfate.

BACKGROUND: We previously demonstrated that inhibiting phosphoinositide 3-kinase (PI3K) or activating L-type calcium channels blocked the anti-inflammatory effects of magnesium sulfate (MgSO4). However, the question as which class I PI3K isoform (PI3Kα, PI3Kß, PI3Kδ, or PI3Kγ) is involved in this regard remains unstudied. The question as whether MgSO4 and L-type calcium channels interact to influence PI3K activation also remains unstudied. We therefore designed this study to test two hypotheses: (1) inhibiting PI3Kα, PI3Kß, PI3Kδ, or PI3Kγ would block the anti-inflammatory effects of MgSO4 and (2) activating L-type calcium channels would block the effects of MgSO4 on activating PI3K. MATERIALS AND METHODS: PI3K isoform investigation: macrophages (RAW264.7 cells) were treated with endotoxin, endotoxin plus MgSO4, or endotoxin plus MgSO4 plus the selective inhibitor of PI3Kα (PIK-75), PI3Kß (TGX-221), PI3Kδ (IC-87114), or PI3Kγ (AS-252424). Calcium channel investigation: macrophages were treated with endotoxin, endotoxin plus MgSO4, or endotoxin plus MgSO4 plus the L-type calcium channel activator BAY-K8644. RESULTS: The endotoxin plus MgSO4 group presented lower concentrations of inflammatory mediators (macrophage inflammatory protein 2, tumor necrosis factor α, and interleukin 6, lower nuclear concentration of phosphorylated nuclear factor κB, lower cytosolic concentration of phosphorylated inhibitor κBα, and higher concentration of phosphorylated Akt (PI3K activation marker) than the endotoxin group (all P < 0.05). These effects of MgSO4 were significantly reduced by TGX-221, IC-87114, or AS-252424, but not PIK-75. Additionally, BAY-K8644 blocked the effect of MgSO4 on activating PI3K. CONCLUSIONS: MgSO4 exerts its anti-inflammatory effects through activating PI3Kß, PI3Kδ, and PI3Kγ. The underlying mechanism appears to involve inhibition of L-type calcium channels.

Vasopressin inhibits endotoxin binding in activated macrophages.

BACKGROUND: Vasopressin possesses potent anti-inflammatory effects. Endotoxin recognition (mediated by cluster of differentiation 14 [CD14]), endotoxin binding, and subsequent nuclear factor-κB (NF-κB) activation are essential mechanisms for initiation of the inflammatory response. We elucidated the effects of vasopressin on these essential mechanisms of inflammation with the hypothesis that vasopressin could inhibit CD14 expression, endotoxin binding, and NF-κB activation in activated macrophages. METHODS: Murine macrophage-like cell line RAW264.7 cells were stimulated with endotoxin (lipopolysaccharide [LPS]; 100 ng/mL) or LPS plus vasopressin (1000 pg/mL; designated as the LPS and the LPS + V groups, respectively). After reaction, between-group differences in inflammatory molecule concentrations and levels of NF-κB activation, endotoxin-macrophages binding, and CD14 expression were compared. Analysis of variance was performed for statistical analysis. RESULTS: The concentrations of chemokine macrophage inflammatory protein 2 and cytokine interleukin 6 of the LPS + V group were significantly lower than those of the LPS group (P = 0.004 and P < 0.001). The nuclear concentration of phosphorylated NF-κB p65 and cytosolic concentration of phosphorylated inhibitor-κBα of the LPS + V group were significantly lower than those of the LPS group (all P < 0.05). In addition, the level of endotoxin-macrophages binding of the LPS + V group was significantly lower than that of the LPS group (P < 0.001). The level of surface CD14 expression of the LPS + V group was also significantly lower than that of the LPS group (P = 0.019). CONCLUSIONS: This study confirmed the potent anti-inflammatory effects of vasopressin. The mechanisms underlying the anti-inflammatory effects of vasopressin may involve its effects on inhibiting CD14 expression, endotoxin binding, and subsequent NF-κB activation.

Simvastatin attenuates sepsis-induced blood-brain barrier integrity loss.

BACKGROUND: Systemic inflammation and oxidative stress are crucial in mediating blood-brain barrier (BBB) integrity loss during sepsis. Simvastatin possess potent anti-inflammation and antioxidation capacity. We sought to elucidate whether an acute bolus of simvastatin could mitigate BBB integrity loss in a rodent model of polymicrobial sepsis. METHODS: A total of 96 adult male rats (200-250 g) were randomized to receive cecal ligation and puncture (CLP), CLP plus simvastatin, sham operation, or sham operation plus simvastatin (n = 24 in each group). After maintaining for 24 h, BBB integrity in the surviving rats was determined. RESULTS: CLP significantly induced BBB integrity loss, as grading of Evans blue staining of the brains, BBB permeability to Evans blue dye, and brain edema levels in rats receiving CLP were significantly higher than those receiving sham operation. In contrast, grading of Evans blue staining (P = 0.020), BBB permeability to Evans blue dye (P = 0.031), and brain edema levels (P = 0.009) in rats receiving CLP plus simvastatin were significantly lower than those receiving CLP alone. Tight junction proteins claudin-3 and claudin-5 in endothelial cells are major structural components of BBB. Our data revealed that concentrations of claudin-3 and claudin-5 in rats receiving CLP were significantly lower than those receiving CLP plus simvastatin (P = 0.010 and 0.007). Immunohistochemistry further revealed significant fragmentation of claudin-3 and claudin-5 in rats receiving CLP. Moreover, levels of claudin-3 and claudin-5 fragmentation in rats receiving CLP plus simvastatin were significantly lower than those receiving CLP. CONCLUSIONS: Simvastatin mitigates BBB integrity loss in a rodent model of polymicrobial sepsis.

Dexmedetomidine-ketamine combination mitigates acute lung injury in haemorrhagic shock rats.

AIM OF THE STUDY: Upregulation of pulmonary inflammatory molecules is crucial in mediating the development of acute lung injury induced by haemorrhagic shock. Dexmedetomidine and ketamine possess potent anti-inflammatory capacity. We sought to elucidate whether dexmedetomidine, ketamine, or dexmedetomidine-ketamine combination could mitigate acute lung injury in haemorrhagic shock rats. METHODS: Fifty adult male Sprague-Dawley rats were randomized to the sham-instrumented, haemorrhagic shock (HS), HS plus dexmedetomidine (HS-D), HS plus ketamine (HS-K), or HS plus dexmedetomidine-ketamine (HS-D+K) group (n=10 in each group). Haemorrhagic shock was induced by blood withdrawing and the mean blood pressure was maintained at 40-45mmHg for 120min. Resuscitation was then performed by infusion of shed blood/saline mixtures. After monitoring for another 8h, rats were sacrificed. RESULTS: Histology findings and lung injury score analysis revealed moderate lung injury in rats of the HS, HS-D, and HS-K groups, whereas those of the HS-D+K group revealed mild lung injury. The effects of haemorrhagic shock on increasing cell number and protein concentration in bronchoalveolar lavage fluid as well as water content, leukocyte infiltration, and myeloperoxidase activity of lung tissues were significantly attenuated by dexmedetomidine-ketamine combination but not by dexmedetomidine or ketamine alone. Dexmedetomidine-ketamine combination, but not dexmedetomidine or ketamine alone, also significantly inhibited haemorrhagic shock-induced upregulation of pulmonary inflammatory molecules, including nitric oxide, prostaglandin E(2), chemokine (e.g., macrophage inflammatory protein-2), and cytokines [e.g., interleukin (IL)-1beta, and IL-6]. CONCLUSIONS: Dexmedetomidine-ketamine combination mitigates acute lung injury in haemorrhagic shock rats.

Chronic intrathecal infusion of minocycline prevents the development of spinal-nerve ligation-induced pain in rats.

BACKGROUND AND OBJECTIVES: Minocycline is a second-generation tetracycline with multiple biological effects, including inhibition of microglial activation. Recently, microglial activation has been implicated in the development of nerve injury-induced neuropathic pain. In this study, the authors examined the effects of continuous intrathecal minocycline on the development of neuropathic pain and microglial activation induced by L5/6 spinal-nerve ligation in rats. METHODS: Under isoflurane anesthesia, male Sprague-Dawley rats (200-250 g) received right L5/6 spinal-nerve ligation and intrathecal catheters connected to an infusion pump. Intrathecal saline or minocycline (2 and 6 microg/h) was given continuously after surgery for 7 days (n = 8 per group). The rat right hind paw withdrawal threshold to von Frey filament stimuli and withdrawal latency to radiant heat were determined before surgery and on days 1 to 7 after surgery. Spinal microglial activation was evaluated with OX-42 immunoreactivity on day 7 after surgery. RESULTS: Spinal-nerve ligation induced mechanical allodynia and thermal hyperalgesia on the affected hind paw of saline-treated rats. Intrathecal minocycline (2 and 6 microg/h) prevented the development of mechanical allodynia and thermal hyperalgesia induced by nerve ligation. It also inhibited nerve ligation-induced microglial activation, as evidenced by decreased OX-42 staining. No obvious histopathologic change was noted after intrathecal minocycline (6 microg/h) infusion. CONCLUSIONS: In this study, the authors demonstrate the preventive effect of continuous intrathecal minocycline on the development of nociceptive behaviors induced by L5/6 spinal-nerve ligation in rats. Further studies are required to examine if continuous intrathecal minocycline could be used safely in the clinical setting.

Propofol significantly attenuates iNOS, CAT-2, and CAT-2B transcription in lipopolysaccharide-stimulated murine macrophages.

BACKGROUND: Propofol significantly inhibits inducible nitric oxide synthase (iNOS) expression and nitric oxide (NO) biosynthesis in stimulated macrophages. L-arginine transport mediated by the isozymes of type-2 cationic amino acid transporter (including CAT-2 and CAT-2B) has been reported to play a crucial role in regulating iNOS activity. We sought to evaluate the effects of propofol on L-arginine transport and transcription of CAT-2 and CAT-2B. METHODS: Confluent murine macrophages (RAW264.7 cells) were stimulated with lipopolysaccharide (LPS) to induce NO production, L-arginine transport and the transcriptions of iNOS, CAT-2, and CAT-2B. Propofol (25, 50, and 75 microM) was added to the cells 4 hours before, immediately after, or 4 hours after LPS administration. After reacting with LPS for 18 hours, cell cultures were harvested and assayed. RESULTS: Propofol administered 4 hours before LPS had no significant effects on NO production, L-arginine transport, and the transcriptions of iNOS and CAT-2. To our surprise, NO production and iNOS transcription were significantly enhanced by 25 microM propofol administered immediately after LPS. NO production and iNOS transcription were not affected by 50 microM propofol but significantly inhibited by 75 microM propofol administered immediately after LPS. CAT-2 transcription and L-arginine transport were significantly inhibited by 50 and 75 microM but not 25 microM propofol administered immediately after LPS. When administered 4 hours after LPS, 75 but not 25 and 50 microM propofol significantly inhibited NO production, L-arginine transport, and the transcription of iNOS and CAT-2. In addition, CAT-2B transcription was significantly inhibited by propofol that was administered 4 hours before, immediately after, or 4 hours after LPS. CONCLUSIONS: Propofol had significantly inhibitory effects on LPS-induced NO production, L-arginine transport, and the expressions of iNOS, CAT-2 and CAT-2B in stimulated murine macrophages in a dose-dependent manner. In addition, timing of administration also affected this regulatory effect of propofol.

Lidocaine inhibition of inducible nitric oxide synthase and cationic amino acid transporter-2 transcription in activated murine macrophages may involve voltage-sensitive Na+ channel.

Lidocaine has been reported to inhibit nitric oxide (NO) production in activated murine macrophages, but the role of inducible NO synthase (iNOS) in lidocaine-induced inhibition of NO has not been explored. In addition, type-2 cationic amino acid transporter (CAT-2) and guanosine triphosphate cyclohydrolase I (GTPCH) also regulate iNOS activity. The effects of lidocaine on CAT-2 and GTPCH are unknown. To explore further these effects, confluent immortalized murine macrophages (RAW264.7 cells) were incubated with lipopolysaccharide (LPS) or in combination with lidocaine (5, 50, or 500 microM) for 18 h before harvesting. We also used tetrodotoxin (TTX) and veratridine to elucidate the possible role of voltage-sensitive Na+ channel. Our data demonstrated that LPS significantly upregulated transcription of iNOS and CAT-2 but not GTPCH in stimulated macrophages. In a dose-dependent manner, lidocaine significantly attenuated the LPS-induced upregulation of iNOS and CAT-2. Conversely, lidocaine significantly increased GTPCH transcription in LPS-stimulated macrophages. The effects of TTX on iNOS, CAT-2, and GTPCH expression were comparable to those of lidocaine. In addition, veratridine significantly attenuated the effects of lidocaine and TTX. We therefore concluded that lidocaine significantly inhibits iNOS and CAT-2 and, in turn, enhances GTPCH transcription in LPS-stimulated macrophages via a mechanism that possibly involves the voltage-sensitive Na+ channel.

Predicting postoperative pain by preoperative pressure pain assessment.

BACKGROUND: The goal of this study was to evaluate whether preoperative pressure pain sensitivity testing is predictive of postoperative surgical pain. METHODS: Female subjects undergoing lower abdominal gynecologic surgery were studied. A pressure algometer was used preoperatively to determine the pressure pain threshold and tolerance. A visual analog scale (VAS) was used to assess postoperative pain. A State-Trait Anxiety Inventory was used to assess patients' anxiety. Subjects received intravenous patient-controlled analgesia for postoperative pain control. The preoperative pain threshold and tolerance were compared with the postoperative VAS pain score and morphine consumption. RESULTS: Forty women were enrolled. Their preoperative pressure pain threshold and tolerance were 141 +/- 65 kPa and 223 +/- 62 kPa, respectively. The VAS pain score in the postanesthesia care unit and at 24 h postoperatively were 81 +/- 24 and 31 +/- 10, respectively. Highly anxious patients had higher VAS pain scores in the postanesthesia care unit (P < 0.05). Pressure pain tolerance was significantly correlated with the VAS at 24 h postoperatively (P < 0.001, r = -0.52). Pressure pain tolerance after fentanyl administration (mean, 272 +/- 68 kPa) correlated significantly with morphine consumption in the first 24 h postoperatively (P < 0.002, r = -0.48). CONCLUSIONS: Assessment of preoperative pressure pain tolerance is significantly correlated with the level of postoperative pain. Pain tolerance assessment after fentanyl was administered and fentanyl sensitivity predicted the dose of analgesics used in the first 24 h after surgery. The algometer is thus a simple, useful tool for predicting postoperative pain and analgesic consumption.

Pulmonary transcription of CAT-2 and CAT-2B but not CAT-1 and CAT-2A were upregulated in hemorrhagic shock rats.

Hemorrhagic shock stimulates nitric oxide (NO) biosynthesis through upregulation of inducible NO synthase (iNOS) expression. Trans-membrane l-arginine transportation mediated by the isozymes of cationic amino acid transporters (e.g. CAT-1, CAT-2, CAT-2A, and CAT-2B) is one crucial regulatory mechanism that regulates iNOS activity. We sought to assess the effects of hemorrhage and resuscitation on the expression of these regulatory enzymes in hemorrhage-stimulated rat lungs. Twenty-four rats were randomized to a sham-instrumented group, a sustained shock group, a shock with blood resuscitation group, or a shock with normal saline resuscitation group. Hemorrhagic shock was induced by withdrawing blood to maintain MAP between 40 and 45mmHg for 60min. Resuscitation by infusing blood/saline mixtures (blood resuscitation group) or saline alone (saline resuscitation group) was then performed. At the end of the experiment (300min after hemorrhage began), rats were sacrificed and enzymes expression as well as pulmonary NO biosynthesis and lung injuries were assayed. Our data revealed that hemorrhage-induced pulmonary iNOS, CAT-2, and CAT-2B transcription which was associated with pulmonary NO overproduction and subsequent lung injury. Resuscitation significantly attenuated the hemorrhage-induced enzyme upregulation, pulmonary NO overproduction, and lung injury. Blood/saline mixtures were superior to saline as a resuscitation solution in treating hemorrhage-induced pulmonary NO overproduction and lung injury. Hemorrhage and/or resuscitation, however, did not affect the expression of pulmonary CAT-1 and CAT-2A. It is, therefore, concluded that the expression of pulmonary iNOS, CAT-2, and CAT-2B is inducible and that of CAT-1 and CAT-2A is constitutive in hemorrhagic shock rat lungs.