Patient-reported nausea after implementation of an enhanced recovery after surgery protocol for gynae-oncology patients.

OBJECTIVES: This study aimed to analyze the adherence to strategies to prevent post-operative nausea and vomiting after implementation of an enhanced recovery after surgery (ERAS) protocol for gynae-oncology patients. Patient-reported nausea before and after ERAS was also studied. METHODS: This prospective observational study included all patients undergoing laparotomy for a suspicious pelvic mass or confirmed advanced ovarian cancer before (pre-ERAS) and after the implementation of ERAS (post-ERAS) at Oslo University Hospital, Norway. Patients were a priori stratified according to the planned extent of surgery into two cohorts (Cohort 1: Surgery of advanced disease; Cohort 2: Surgery for a suspicious pelvic tumor). Clinical data including baseline characteristics and outcome data were prospectively collected. RESULTS: A total of 439 patients were included, 243 pre-ERAS and 196 post-ERAS. At baseline, 27% of the patients reported any grade of nausea. In the post-ERAS cohort, statistically significantly more patients received double post-operative nausea and vomiting prophylaxis (64% pre-ERAS vs 84% post-ERAS, p<0.0001). There was no difference in the need for rescue medication (82% pre-ERAS vs 79% post-ERAS; p=0.17) and no statistically significant difference between pre- and post-ERAS or between the surgical cohorts in patient-reported nausea of any grade on day 2. Patients who reported none/mild nausea on day 2 had significantly less peri-operative fluid administered during surgery than those who reported moderate or severe nausea (median 12.5 mL/kg/hour vs 16.5 mL/kg/hour, p=0.045) but, in multivariable analysis, fluid management did not remain significantly associated with nausea. CONCLUSION: Implementation of an ERAS protocol increased the adherence to post-operative nausea and vomiting prevention guidelines. Nausea, both before and after laparotomy, remains an unmet clinical need of gynae-oncology patients also in an ERAS program. Patient-reported outcome measures warrant further investigation in the evaluation of ERAS.

Prospective evaluation of an enhanced recovery after surgery (ERAS) pathway in a Norwegian cohort of patients with suspected or advanced ovarian cancer.

OBJECTIVE: This prospective cohort study evaluated the introduction of an enhanced recovery after surgery (ERAS) pathway in a tertiary gynecologic oncology referral center. Compliance and clinical outcomes were studied in two separate surgical cohorts. METHODS: Patients undergoing laparotomy for suspected or verified advanced ovarian cancer at Oslo University Hospital were prospectively included in a pre- and post-implementation cohort. A priori, patients were stratified into: cohort 1, patients planned for surgery of advanced disease; and cohort 2, patients undergoing surgery for suspicious pelvic tumor. Baseline characteristics, adherence to the pathway, and clinical outcomes were assessed. RESULTS: Of the 439 included patients, 235 (54%) underwent surgery for advanced ovarian cancer in cohort 1 and 204 (46%) in cohort 2. In cohort 1, 53% of the patients underwent surgery with an intermediate/high Aletti complexity score. Post-ERAS, median fasting times for solids (13.1 hours post-ERAS vs 16.0 hours pre-ERAS, p<0.001) and fluids (3.7 hours post-ERAS vs 11.0 hours pre-ERAS, p<0.001) were significantly reduced. Peri-operative fluid management varied less and was reduced from median 15.8 mL/kg/hour (IQR 10.8-22.5) to 11.5 mL/kg/hour (IQR 9.0-15.4) (p<0.001). In cohort 2 only there was a statistically significant reduction in length of stay (mean (SD) 4.3±1.5 post-ERAS vs 4.6±1.2 pre-ERAS, p=0.026). Despite stable readmission rates, there were significantly more serious complications reported in cohort 1 post-ERAS. CONCLUSIONS: ERAS increased adherence to current standards in peri-operative management with significant reduction in fasting times for both solids and fluids, and peri-operative fluid administration. Length of stay was reduced in patients with suspicious pelvic tumor. Despite serious complications being common in patients with advanced disease undergoing debulking surgery, a causal relationship with the ERAS protocol could not be established. Implementing ERAS and continuous performance auditing are crucial to advancing peri-operative care of patients with ovarian cancer.

The matri-cellular proteins 'cysteine-rich, angiogenic-inducer, 61' and 'connective tissue growth factor' are regulated in experimentally-induced sepsis with multiple organ dysfunction.

Organ failure is a severe complication in sepsis for which the pathophysiology remains incompletely understood. Recently, the matri-cellular cysteine-rich, angiogenic induced, 61 (Cyr61/CCN1); connective tissue growth factor (Ctgf/CCN2); and nephroblastoma overexpressed gene (Nov/CCN3) (CCN)-protein family have been attributed organ-protective properties. Their expression is sensitive to mediators of sepsis pathophysiology but a potential role in sepsis remains elusive. To provide an initial assessment, 50 rats were subjected to 18 h of cecal-ligation and puncture or sham operation. Hepatic and pulmonary CCN1 mRNA displayed an average 7.4- and 3.3-fold induction, while its cardiac expression was unchanged. The changes coincided with excessive hepatic and pulmonary inflammatory gene activation and a restricted cardiac inflammation. Furthermore, hepatocytes displayed a dosage-dependent CCN1 mRNA response in vitro, supporting a cytokine-mediated CCN1 regulation in sepsis. CCN2 mRNA was 2.2-fold induced in the liver, while 2.0-fold and 1.4-fold repressed in the heart and lung. Meanwhile, it did not respond to TNF-α exposure in vitro, which indicates different means of regulation than for CCN1. Taken together, this study provides the first evidence for multi-organ regulation of CCN1 and CCN2 in early stages of sepsis, and implies the eruption of inflammatory mediators as a potential mechanism behind the observed CCN1 regulation.

Liver X receptor protects against liver injury in sepsis caused by rodent cecal ligation and puncture.

BACKGROUND: Liver X receptor (LXR) is a transcription factor of the nuclear receptor family, regulating genes involved in metabolism, inflammation, and apoptosis. In the present investigation, we examined the role of LXR in organ injury and systemic inflammation in rodent models of polymicrobial peritonitis caused by cecal ligation and puncture (CLP). METHODS: Rats were subjected to CLP sepsis or a sham operation. Some were treated with the synthetic LXR agonist GW3965 0.3 mg/kg 30 min prior to the CLP procedure, and organs and plasma were harvested at 3, 10, 18, or 24 h. Organs were analyzed for RNA expression by quantitative polymerase chain reaction or for morphologic differences by histologic review. Organ injury and inflammatory markers were measured in plasma. RESULTS: Expression of the LXRα gene was decreased in the livers of CLP rats compared with sham-operated rats. Administration of a synthetic agonist of LXR (GW3965) reduced biochemical indices of liver injury in the blood of CLP rats. We also demonstrated that liver injury associated with CLP is aggravated in LXRα- and LXRαß-deficient mice compared with wild-type and LXRß-deficient mice, indicating a role for LXRα in protecting the liver. The enhanced liver injury in LXR-deficient mice was associated with elevated plasma concentrations of high mobility group box 1, a late mediator of inflammation and a known factor in the pathology of this model. CONCLUSIONS: Collectively, these results argue in favor of a role for LXRα in protection against liver injury in experimental sepsis induced by CLP.

Cecal ligation and puncture sepsis is associated with attenuated expression of adenylyl cyclase 9 and increased miR142-3p.

The host inflammatory response in sepsis may be resolved by endogenous anti-inflammatory immune cell responses, avoiding fatal pathogenesis, organ injury, and death. The intracellular signaling mediator cyclic 3'5'-adenosine monophosphate is a potent modulator of inflammatory responses and initiates the polarization of immune cells in a direction that suppresses inflammatory activation. Cyclic 3'5'-adenosine monophosphate is enzymatically produced by adenylyl cyclases (ACs). The expression of ACs is previously shown to be reduced in rat organs after in vivo endotoxemia, concurrent with the progressing systemic inflammation. In the present study, tissue AC gene expression and regulation are explored in a rat model of cecal ligation and puncture (CLP) sepsis. Eighteen hours after CLP operation, expression of several AC isoforms in the liver, spleen, and kidney was reduced, significantly so for AC9 in all tissues. AC9 expression is regulated by the microRNA miR142-3p in T cells. When microRNA was extracted and amplified for miR142-3p expression, it was increasingly expressed 18 h after CLP. A correlation between increased miR142-3p and decreased AC9 expression was found in the liver, kidney, and spleen, and when hepatocytes, Kupffer cells (KCs), and liver sinusoidal endothelial cells were isolated after CLP, reduced AC expression and increased miR142-3p expression were found in KCs and liver sinusoidal endothelial cells. Transfecting a miR142-3p inhibitor probe in rat KCs abolished LPS-mediated AC9 inhibition in vitro. These results indicate that CLP leads to miR142-3p-mediated AC9 reduction in liver macrophages, which may further limit cyclic 3'5'-adenosine monophosphate signaling and the ability of macrophages to resolve the proinflammatory response.

Liver X receptor agonist GW3965 dose-dependently regulates lps-mediated liver injury and modulates posttranscriptional TNF-alpha production and p38 mitogen-activated protein kinase activation in liver macrophages.

Modulation of the host inflammatory response to infection may be a key approach to improve the outcome of patients with sepsis and organ injury. We previously reported that pretreatment of rats with the liver X receptor (LXR) agonist GW3965 reduced the liver injury associated with endotoxemia and attenuated the production of TNF-alpha by rat Kupffer cells. Here, we examine the dose-dependent effect of GW3965 on liver injury and cytokine production in a rat model of endotoxemia and explore the mechanisms underlying TNF-alpha attenuation in Kupffer cells. Low doses of GW3965 (0.1 or 0.3 mg/kg) administered 30 min before infusion of LPS and peptidoglycan significantly attenuated the increase in plasma levels of the liver injury markers alanine aminotransferase and bilirubin (6 h) as well as the inflammatory mediators TNF-alpha (1 h) and prostaglandin E2 (6 h) associated with endotoxemia. In contrast, pretreatment with a higher dose of GW3965 (1.0 mg/kg) had no such effect. Studies in primary cultures of rat Kupffer cells demonstrated that LXR agonist treatment attenuated both the secreted and cell-associated levels of TNF-alpha, whereas TNF-alpha mRNA levels were not altered. Phosphorylated p38 mitogen-activated protein kinase, which plays a major role in production of TNF-alpha at the posttranscriptional level, was attenuated by GW3965 treatment in Kupffer cells. Experiments in murine LXR-deficient Kupffer cells demonstrated enhanced production of TNF-alpha in Kupffer cells from LXR-alpha(-/-) mice when challenged with LPS compared with LXR-beta(-/-) and wild-type Kupffer cells. Taken together, these results argue in favor of a novel mechanism for LXR-mediated attenuation of liver injury by interfering with posttranscriptional regulation of TNF-alpha in Kupffer cells.

Activation of the liver X receptor protects against hepatic injury in endotoxemia by suppressing Kupffer cell activation.

Recent reports have demonstrated that liver X receptors (LXRs) of the nuclear receptor family have anti-inflammatory effects on macrophages. Here we examine whether activation of LXR by the synthetic agonist GW3965 can ameliorate the liver injury/dysfunction caused by endotoxins in the rat. Male Wistar rats received GW3965 (0.3 mg/kg) or vehicle (50% dimethyl sulfoxide) 30 min before coadministration of lipopolysaccharide (LPS, 5 mg/kg i.v.) and peptidoglycan (1 mg/kg i.v.). Treatment with GW3965 attenuated the increase in the plasma levels of alanine aminotransferase and bilirubin (markers of liver injury/dysfunction) as well as the focal hepatocyte necrosis (histology) caused by coadministration of LPS and peptidoglycan. This protective effect of GW3965 treatment was associated with reduced infiltration of mast cells in the liver (histopathology) and reduced gene expression of the chemokines eotaxins 1 and 2, whereas MIP-2 mRNA levels were not affected. Plasma levels of tumor necrosis factor alpha and prostaglandin E2 were significantly attenuated by GW3965, whereas plasma interleukins 6 and 10 were not altered. High expression of LXRalpha mRNA was observed in Kupffer cell cultures, suggesting that Kupffer cells are targets of GW3965. Subsequent in vitro studies in Kupffer cells demonstrated that exposure to GW3965 attenuated the LPS-induced release of tumor necrosis factor alpha and prostaglandin E2 in a dose-dependent manner. In conclusion, this study demonstrates that activation of LXR by GW3965 protects against liver injury and dysfunction in a rat model of endotoxemia, in part by exerting an anti-inflammatory effect on Kupffer cells.

Peptidoglycan of Staphylococcus aureus induces enhanced levels of matrix metalloproteinase-9 in human blood originating from neutrophils.

Enhanced plasma levels of matrix metalloproteinase 9 (MMP-9) detected in patients with severe sepsis are thought to contribute to the development of organ dysfunction in endotoxemia. We have recently reported that peptidoglycan, the major wall component of gram-positive bacteria, increases MMP-9 levels in lung and liver and organ injury in the rat. Thus far, it is unclear whether MMP-9 is part of the septic response to peptidoglycan in human blood. The aim of the present study was to examine the regulation of MMP-9 by peptidoglycan in human leukocytes. The addition of peptidoglycan to whole human blood caused enhanced levels of MMP-9 after 1 h of incubation (306 vs. 75 ng/mL, P < or = 0.05) and onward, as measured by enzyme-linked immunoabsorbant assay. In neutrophil cultures, MMP-9 values increased significantly after 30 min of incubation with peptidoglycan (242 vs. 121 ng/mL, P < or = 0.05), whereas muramyl dipeptide had no effect. In contrast, adherent monocytes released insignificant amounts of MMP-9. To examine whether the released MMP-9 resulted from de novo synthesis, intracellular and secreted MMP-9 was measured during stimulation of neutrophils. The total MMP-9 values (the sum of intracellular and secreted MMP-9) before and after stimulation were mainly unaltered. The enhanced MMP-9 levels induced by peptidoglycan was attenuated by inhibitors of p38 mitogen-activated protein kinases (MAPK), (SB202190, 25 microM) and ERK1/2 (PD98059, 25 microM) and inhibitors of Src Tyrosine kinase (PP2, 5 microM) and PI3-K (LY294002, 25 microM).

Peptidoglycan of S. aureus causes increased levels of matrix metalloproteinases in the rat.

Matrix metalloproteinases (MMPs) have been suggested to contribute to the organ injury in septic patients. We recently demonstrated that peptidoglycan (PepG) of S. aureus causes organ injury in the rat. A possible role for MMPs in the septic response to PepG is unknown. In the present study, we have examined whether the release of MMP-9 (gelatinase B) and MMP-2 (gelatinase A) is induced by PepG in the anesthetized rat. Male Wistar rats were injected intravenously with PepG (10 mg/kg), LPS (1 mg/kg), or a combination of LPS and PepG (1 mg/kg of each). After 1 or 3 h, liver, lung, and plasma were harvested. MMP-9 and MMP-2 levels were analyzed in organ homogenates and in plasma samples by zymography. MMP-9 levels were significantly increased in the lung within 1 h after injection of PepG, LPS, or combined treatment, compared with sham animals (P < or = 0.05). In the liver and plasma, MMP-9 was clearly increased by PepG or LPS at both 1 and 3 h compared with sham animals (P < or = 0.05). Considerable basal amounts of MMP-2 protein were seen in the liver and in plasma. In the lung, MMP-2 levels were elevated by combined LPS/PepG at 1 h and by LPS at 3 h (P < or = 0.05). In contrast, MMP-2 activity in the liver was significantly reduced by bacterial products. In the plasma, no major alterations of MMP-2 levels were observed. Our data show that PepG of S. aureus causes a rapid elevation of MMP-9 protein in the liver, lung, and blood of the rat. Based on these and previous data, we hypothesize that the release of MMP-9 in lung, liver, and blood is part of the septic host response to systemic PepG.