Realizing the vast medical benefits of validated protocols, recommendations and practice guidelines requires acceptance and implementation by frontline care providers. Knowledge translation is the science of accelerating the transfer of knowledge to practice by understanding and creatively addressing the barriers that prevent adoption of new professional standards. In an attempt to improve patient care and reduce mortality, the Surviving Sepsis Campaign and The Institute for Healthcare Improvement created the resuscitation and management bundles for patients with severe sepsis and septic shock. These bundles have been accepted as best practice by many clinicians since multiple clinical trials have produced similar positive results when they were implemented. However, transferring these research outcomes-based guidelines to the clinical practice arena has been associated with poor compliance due to important barriers to implementation. Delays in the adoption of sepsis bundles are not surprising since the time from validation to implementation of a new clinical practice is typically 17 years. Using sepsis bundles as a model, this article explores why guidelines are important, examines physician adherence to protocols, and reviews the literature on strategies to improve clinical compliance and enhance knowledge translation.

Severe sepsis is one of the most common reasons for critically ill patients to be admitted to an intensive care unit (ICU) and has very high associated morbidity and mortality. The Surviving Sepsis Campaign was initiated with the hope that mortality might be reduced by standardizing care informed by data from an increasing number of clinical trials. Important methods for reducing mortality identified by recent studies include aggressive fluid resuscitation, early goal-directed therapy (EGDT), early administration of antibiotics, and the administration of activated protein C to eligible patients.

Evaluation of: Thiel SW, Asghar MF, Micek ST, Reichley RM, Doherty JA, Kollef MH. Hospital-wide impact of standardized order set for the management of bacteremic severe sepsis. Crit. Care Med. 37(3), 819-824 (2009). Aggressive standardized diagnostic and therapeutic approaches to acute diseases such as acute myocardial infarction, trauma and stroke have led to improved patient survival. A standardized order set for severe sepsis and septic shock represents a similar approach. In 2001, Rivers et al., using a standardized operating procedure to treat severe sepsis and septic shock, showed a relative risk reduction of 0.34 and absolute risk reduction of 16%, with a decrease in healthcare resource consumption for patients presenting to the emergency department. Since then, similar studies have shown similar or better results. This study in particular highlights a hospital-wide initiative that further confirms that standardized order sets and operating procedures for severe sepsis and septic shock result in a significant reduction in morbidity, mortality and healthcare resource consumption. With these robust findings, future emphasis should be placed on overcoming logistical, institutional and professional barriers to the implementation of standardized order sets, which can save the life of one out of every five to six patients presenting with severe sepsis and septic shock.

OBJECTIVE To analyze the factors which influence the mortality of patients transferred or re-admitted to intensive care unit (ICU), and investigate the method to decrease mortality of patients in ICU. METHODS The patients died in ICU from November 2002 to October 2004 were divided into three groups: control group (n=39), transferred group (n=25) and re-admitted group (n=23). The acute physiology and chronic health evaluation II(APACHEII) score, causes of death and therapeutic protocol of each patient were studied. RESULTS The total mortality of patients in control group was lower than those of transferred and re-admitted group within 48 hours after admission to ICU (both P<0.05). The top three main causes of death were hemorrhagic shock/severe trauma, central nervous system (CNS) injury or disease and cardiac failure in control group, and sepsis, respiratory failure, cardiac failure or hemorrhagic shock/severe trauma in transferred group, and respiratory failure, cardiac failure and sepsis in re-admitted group. Among the three groups, APACHEII scores on admission of each group [(18.67+/-3.28) scores,(20.84+/-4.16) scores, and (20.39+/-3.15) scores, respectively] were obviously higher than the mean value of other patients admitted to ICU [(4.28+/-1.52) scores, all P<0.01]. The scores of re-admitted patients at the time of discharge from ICU [(12.83+/-2.76) scores] were also obviously higher than the mean value of other patients discharged from ICU [(3.28+/-3.42) scores, P<0.01]. CONCLUSION It is important to emphasize to monitor the circulation or respiration and early intervention of critical patients, to improve the clinical evaluation of the patients discharged from ICU, in order to decrease the mortality of patients re-admitted to ICU.

OBJECTIVE To observe the effect of hydroxyethyl starch 130/0.4 (voluven) on P38 mitogen-activated protein kinases (MAPK) signal transduction pathway, with the aim of investigating the mechanism of its protective effect on acute lung injury (ALI) due to infection. METHODS Thirty male Sprague-Dawley (SD) rats were randomly divided into control group, lipopolysaccharide (LPS 10 mg/kg) group, voluven groups (LPS 10 mg/kg, and hydroxyethyl starch 130/0.4 15 ml/kg or 30 ml/kg) and alone voluven group (hydroxyethyl starch 130/0.4 30 ml/kg), with 6 rats in each group. Rats were sacrificed at 6 hours, the lungs were harvested for observation of pathological changes. The expression of p-P38, P38, p-P44/42 and P44/42 were detected with Western blotting. Activating protein-1 (AP-1) activation was measured with electrophoretic mobility shift assay (EMSA). RESULTS Compared with control, p-P38, p-P44/42 and AP-1 were significantly higher in LPS group (P<0.05 or P<0.01). The expressions of p-P38 and AP-1 activation were significantly reduced in both voluven groups (all P<0.05). But there was no statistically significant difference between voluven 15 ml/kg and 30 ml/kg groups (all P>0.05). CONCLUSION Hydroxyethyl starch 130/0.4 can inhibit LPS-induced ALI by depressing expression of p-P38 and AP-1 activation in lung.

OBJECTIVE To observe the effect of electroacupuncture (EA) on cytokines in the cardiac surgical patient and to evaluate the application of combined acupuncture anesthesia to cardiac surgery. METHODS Thirty patients with atrial septal defect were divided into 3 groups, general anesthesia group (A), acupuncture anesthesia group (B) and combined general anesthesia and EA group (C). Peripheral blood samples were collected before anesthesia, before cardiopulmonary bypass (CPB), 30 min after CPB and 24 h after operation to determine the levels of interferon-gamma (IFN-gamma), interleukin-2 (IL-2), IL-6 and IL-10. RESULTS The levels of IFN-gamma and IL-2 decreased in the 3 groups after CPB and further decreased 24 h after operation, and in the group C were higher than those in the group B. The levels of IL-6 and IL-10 significantly increased 24 h after operation in the 3 groups with no significant difference among the 3 groups. CONCLUSION The general anesthesia combined with EA can not completely improve the decrease of IFN-gamma and IL-2 induced by CPB, indicating that the good response of the general anesthesia combined with EA to stress can partially improve the immunosupression induced by CPB. Acupuncture does not have significant effect on inflammatory cytokine reaction induced by cardiac surgery.

Objectives  The aim of the study was to prepare and to characterize two polymorphs of lornoxicam, a water-insoluble non-steroidal anti-inflammatory drug, which has thus far received no exploration of its polymorphs. Methods  Form I and form II of lornoxicam were prepared by recrystallization and characterized by X-ray powder diffractometry (XRPD), thermal analysis, Fourier transform infrared spectroscopy and scanning electron microscopy. The solubility and dissolution of both polymorphs were also determined and compared to provide the basis for polymorph selection in formulation. Key findings  The crystal structures of the two polymorphs were established by the experimental XRPD patterns. Form I was demonstrated to be triclinic with two kinds of intermolecular hydrogen bonds, while form II was orthorhombic with two kinds of intramolecular hydrogen bonds. The morphologies of form I and form II were observed to be rectangle and approximately oval, respectively. Conclusions  Form II had the significantly higher solubility and dissolution and would be the suitable polymorph for the preparation of oral and injectable dosage forms of lornoxicam.

A series of alkali metal complexes supported by two bulky tetraphenols were synthesized and characterized. The reactions of α,α,α',α'-tetra(3,5-di-tert-butyl-2-hydroxyphenyl)-p-xylene(para-tetraphenol) with (n)BuLi, sodium, and KSi(NMe(2))(3) gave bimetallic complexes 1, 2, and 3, respectively. Treatments of the α,α,α',α'-tetra(3,5-di-tert-butyl-2-hydroxyphenyl)-m-xylene(meta-tetraphenol) with 2 or 4 equiv of (n)BuLi afforded complexes 4 or 5, while the reactions of meta-tetraphenol with sodium and KSi(NMe(2))(3) gave only trimetallic complexes 6 and 7 for the additional p-π interaction. Complexes 1-7 were all characterized by single-crystal X-ray diffraction techniques. In the presence of benzyl alcohol, all complexes are active catalysts for the ring-opening polymerization of l-lactide. Comparatively, bimetallic complexes 1, 2, and 3 are more efficient catalysts because of their symmetric structures, in which complex 3 presents as a rare highly active potassium catalyst for the ring-opening polymerization of lactide, leading to polymers with good molecular weight control and narrow molecular weight distributions.

Using a newly developed strategy whose key step is the regioselective propargylation of hydroxyxanthone substrates, 99 structurally diverse Garcinia natural product-like xanthones based on gambogic acid were designed and synthesized and their in vitro antitumor activity was evaluated. A set of 40 related compounds was chosen for determination of their physicochemical properties including polar surface area, log D7.4, aqueous solubility and permeability at pH 7.4. In the light of the in vitro antitumor activity and the physicochemical properties, 2 compounds were advanced into in vivo efficacy experiments. The antitumor activity of compound 112, administered po, showed more potent in vivo oral antitumor activity than gambogic acid.

As systemically used therapeutics for treatmenting acute or chronic pains or inflammations, non-steroidal anti-inflammatory drugs (NSAID) also associate with the adverse gastrointestinal and renal effects and cardiovascular risks. Thus, it is beneficial to develop topical gels that selectively inhibit cyclooxygenase-2 (COX-2) for the management of local inflammation. In this work, we demon-strate that the covalent conjugation of D-amino acids to naproxen (i.e., an NSAID) not only affords supramolecular hydrogelators for the topical gels, but also unexpectedly and significantly elevates the selectivity towards COX-2 about 20 times at little expense of the activity of naproxen. This work illustrates a previously unexplored approach that employs D-amino acids for the development of functional molecules that have dual or multiple roles and exceptional biostability, which offers a new class of molecular hydrogels of therapeutic agents.

Microbacterium sp. 4N2-2, isolated from a wastewater treatment plant, converts the antibacterial fluoroquinolone, norfloxacin, to N-acetylnorfloxacin and three other metabolites. Because N-acetylation results in loss of antibacterial activity, identification of the enzyme responsible is important for understanding fluoroquinolone resistance. The enzyme was identified as glutamine synthetase (GS); N-acetylnorfloxacin was produced only under conditions for GS expression. The GS gene (glnA) was cloned and the protein (53 kDa) was heterologously expressed and isolated. Optimal conditions and biochemical properties (K(m) and V(max)) of purified GS were characterized; the purified enzyme was inhibited by Mn(2+), Mg(2+), ATP and ADP. The contribution of GS to norfloxacin resistance was shown by using a norfloxacin-sensitive Escherichia coli strain carrying glnA derived from Microbacterium sp. 4N2-2. The GS of Microbacterium sp. 4N2-2 was shown to act as an N-acetyltransferase for norfloxacin, which produced low-level norfloxacin resistance. Structural and docking analysis identified potential binding sites for norfloxacin at the ADP-binding site and for acetyl-CoA at a cleft in GS. The results suggest that environmental bacteria whose enzymes modify fluoroquinolones may be able to survive in the presence of low fluoroquinolone concentrations.

Gambogic acid (GA), a natural product, was identified as a promising antitumor agent. To further explore the structureactivity relationship of GA and discover novel GA derivatives as antitumor agents, 19 novel GA derivatives modified at C(34) were synthesized and evaluated against A549, BGC-823, U251, HepG2, and MB-231 cancer cell lines by cellular assays. Among them, 15 compounds were found to be more potent than GA against some cancer cell lines. Notably, compound 3 possessed potent inhibitory activities against five cell lines with IC(50) values ranging between 0.24 and 1.09 μM. Compounds 9 and 18 were seven to eightfold more active than GA against A549 cell line. Chemical modification at C(34) of GA by introducing of hydrophilic aliphatic amines resulted in increased activity and improved drug-like properties. These findings will enhance our understanding of the SAR of GA and can lead to the discovery of novel GA derivatives as potential antitumor agents.

The ubiquitin/proteasome pathway plays a vital role in plant development. But the effects of proteasome malfunction on root growth, and the mechanism underlying this involvement remains unclear. In the present study, the effects of proteasome inhibitors on Arabidopsis root growth were studied through the analysis of the root length, and meristem size and cell length in maturation zone using FM4-64, and cell-division potential using GFP fusion cyclin B, and accumulation of ubiquitinated proteins using immunofluorescence labeling, and autophagy activity using LysoTracker and MDC. The results indicated that lower concentration of proteasome inhibitors promoted root growth, whereas higher concentration of inhibitors had the opposite effects. The accumulation of cyclin B was linked to MG132-induced decline in meristem size, indicating that proteasome malfunction prevented cell division. Besides, MG132-induced accumulation of the ubiquitinated proteins was associated with the increasing fluorescence signal of LysoTracker and MDC in the elongation zone, revealing a link between the activation of autophagy and proteasome malfunction. These results suggest that weak proteasome malfunction activates moderate autophagy and promotes cell elongation, which compensates the inhibitor-induced reduction of cell division, resulting in long roots. Whereas strong proteasome malfunction induces severe autophagy and disturbs cell elongation, resulting in short roots.

Dysfunctions of the L-arginine (L-arg)/nitric-oxide (NO) pathway are suspected to be important for the pathogenesis of multiple organ dysfunction syndrome (MODS) in septic shock. Therefore plasma concentrations of L-arg and asymmetric dimethylarginine (ADMA) were measured in 60 patients with septic shock, 30 surgical patients and 30 healthy volunteers using enzyme linked immunosorbent assay (ELISA) kits. Plasma samples from patients with septic shock were collected at sepsis onset, and 24 h, 4 d, 7 d, 14 d and 28 d later. Samples from surgical patients were collected prior to surgery, immediately after the end of the surgical procedure as well as 24 h later and from healthy volunteers once. In comparison to healthy volunteers and surgical patients, individuals with septic shock showed significantly increased levels of ADMA, as well as a decrease in the ratio of L-arg and ADMA at all timepoints. In septic patients with an acute liver failure (ALF), plasma levels of ADMA and L-arg were significantly increased in comparison to septic patients with an intact hepatic function. In summary it can be stated, that bioavailability of NO is reduced in septic shock. Moreover, measurements of ADMA and L-arg appear to be early predictors for survival in patients with sepsis-associated ALF.

Context: Multiple organ dysfunction syndrome (MODS) is a major cause of death in critically patients. It has been hypothesized that inactivation or removal of pro-inflammatory molecules may prevent or reverse MODS. Objective: The purpose of this paper was to investigate the efficacy of continuous veno-venous hemodiafiltration (CVVHDF) as treatment for MODS in an established animal model. Materials and methods: Male Beagle dogs (n = 18) were used to establish the model and were randomly assigned to a CVVHDF, sham, or control group. The serum levels of ALT, AST, Cr, BUN, PaO(2), and PaCO(2) were measured as functional makers of major organs. Apoptosis, DLA-DR expression, and cytokine levels of peripheral monocytes were determined. Results: The MODS model was successfully established. After CVVHDF treatment, the WBC and neutrophil counts were lower and the monocyte count and percentage were greater, but these were unchanged in the sham and control groups. Apoptosis of CD14+ monocytes was significantly lower in the CVVHDF group than in the sham and control groups. The fraction of DLA-DR(+) monocytes and IL-1β secretion was significantly greater in the sham and control groups than in the CVVHDF group. Moreover, IL-4 secretion increased significantly in the CVVHDF group but not in the control group. Discussion and Conclusion: Our study of an experimental model of MODS indicated that MODS leads to significant disruption of physiological and immune functions. CVVHDF treatment alleviated some of these symptoms due to the improvement of monocyte function, reduction of monocyte apoptosis, and increase of anti-inflammatory cytokines.

HASH(0xf834290)

Although early and appropriate antibiotic therapy remains the cornerstone of success for the treatment of septic shock, few data exist to guide antibiotic dose optimization in critically ill patients, particularly those with multiple organ dysfunction syndrome (MODS). It is well known that MODS significantly alters the patient's physiology, but the effects of these variations on pharmacokinetics have not been reviewed concisely. Therefore, the aims of this article are to summarize the disease-driven variations in pharmacokinetics and pharmacodynamics and to provide antibiotic dosing recommendations for critically ill patients with MODS. The main findings of this review are that the two parameters that vary with greatest significance in critically ill patients with MODS are drug volume of distribution and clearance. Disease- and clinician-driven changes lead to an increased volume of distribution and lower-than-expected plasma drug concentrations during the first day of therapy at least. Decreased antibiotic clearance is common and can lead to drug toxicity. In summary,"front-loaded" doses of antibiotic during the first 24 h of therapy should account for the likely increases in the antibiotic volume of distribution. Thereafter, maintenance dosing must be guided by drug clearance and adjusted to the degree of organ dysfunction.

The therapeutic effects of intensive insulin therapy in treatment of traumatic shock combined with multiple organ dysfunction syndrome (MODS) were investigated. A total of 114 patients with traumatic shock combined with MODS were randomly divided into two groups: control group (n=56) treated with conventional therapy, and intensive insulin therapy group (n=58) treated with conventional therapy plus continuous insulin pumping to control the blood glucose level at range of 4.4-6.1 mmol/L. White blood cells (WBC) counts, prothrombin time (PT), serum creatinine (SCr), alanine aminotransferase (ALT), serum albumin and PaO(2) were measured before and at the day 1, 3, 5, 7 and 14 after treatment. The incidence of gastrointestinal dysfunction, the incidence of MODS, hospital stay and the mortality were also observed and compared. After intensive insulin therapy, the WBC counts, SCr, ALT and PT were significantly reduced (P<0.05), but the level of serum albumin was significantly increased (P<0.05) at the day 3, 5, 7 and 14. In the meantime, the PaO2 was significantly elevated at the day 3, 5 and 7 (P<0.01) after intensive insulin therapy. The incidence of gastrointestinal dysfunction, the incidence of MODS, the length of hospital stay and the mortality were markedly decreased (P<0.01). The results suggest early treatment with intensive insulin therapy is effective for traumatic shock combined with MODS and can decrease the length of hospital stay and the mortality.

Severe acute pancreatitis is a common critical disease, which may cause severe complications such as sepsis and multiple organ dysfunction syndrome (MODS), and has a high mortality. A 31-year-old woman with 25-weeks pregnancy presented with hyperlipidemic pancreatitis, sepsis and MODS. Based on conventional treatment, 125 h of continuous veno-venous hemofiltration (CVVH) and 3 sessions of hemoperfusion (HP) were carried out. The treatment turned out to be very successful. We suggest that early intervention by blood purification therapy, and CVVH combined with HP could be effective in severe acute pancreatitis.

Some patients with perianal infection fall into a critical condition with severe sepsis and septic shock (lethal perianal infection). The objective of this study is to clarify the clinicopathological characteristics of, and treatment strategies for, lethal perianal infection. The clinical records of 7 patients with lethal perianal infection were examined. For two rapidly dying cases (within 3 days), we performed resection of the rectum or local anal drainage as a primary management of damage control. These patients were transferred to our center because of septic shock and multiple organ dysfunction syndrome (MODS) and had received insufficient fluid resuscitation in the previous hospital. Another nonsurviving case who died on the 16th day was transferred without MODS and underwent perianal drainage but could not recover from shock, even after repeated surgical procedures were performed. To prevent a perianal infection from becoming lethal, it should be managed as early as possible with sufficient fluid resuscitation with adequate drainage.

Background: Advanced gastric cancer has a low survival rate while traditional Chinese medicine (TCM) therapy has effects in inhibiting tumor growth, lengthening survival time and improving the quality of life. Objective: To analyze the effects of integrated traditional Chinese and Western medicine therapy on the survival time and quality of life of advanced gastric cancer patients. Design, setting, participants and interventions: A total of 95 advanced gastric cancer patients were enrolled and divided into comprehensive group (48 cases) and control group (47 cases). The patients in the comprehensive group from the First Department of Oncology, Longhua Hospital, were treated with TCM therapy and chemotherapy based on the gastric cancer treatment guidelines made by the First Department of Oncology of Longhua Hospital, and the patients in the control group from Renji Hospital and Ruijin Hospital in Shanghai were treated with chemotherapy only. Main outcome measures: The survival time in the two groups were observed and compared. The Karnofsky score, body weight, the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30) score, response rate and chemotherapy-related adverse events in the comprehensive group were observed. Results: The estimated median survival time in the comprehensive group was 16.12 months, longer than 9.64 months in the control group (P<0.05). The scores of function and symptom of EORTC QLQ-C30 in the comprehensive group decreased, while the overall health status increased, and the results indicated that the quality of life of the patients in the comprehensive group was improved. In the comprehensive group, the body weight after treatment was higher than that before treatment (P=0.037), while there was no difference in Karnofsky scores between that before and after treatment (P=0.061). All the patients in the comprehensive group were assessable. The complete response rate was 0, 3 cases had a partial response, 34 cases had stable disease, and 11 cases had disease progression. The overall response rate was 6.25%(3/48), and the disease control rate was 77.08%(37/48). No patient withdrew because of severe adverse events and there was no chemotherapy-related death. Conclusion: Integrated traditional Chinese and Western medicine can prolong the survival time and improve the quality of life of advanced gastric cancer patients, and enhance the comprehensive effects.

OBJECTIVE To evaluate the therapeutic effects of knife needle on third lumbar transverse process syndrome. METHODS From 2007.3 to 2007.12, patients were divided into treatment group and control group according to the random digits table, 34 and 35 patients respectively. Patients in both groups were separately treated for 3 weeks, with knife needle in treatment group and electroacupuncture in control group. In treatment group, 12 patients were male and 22 patients were female, the average age was (42.33 +/- 7.86) years. In control group, 16 patients were male and 19 patients were female, the average age was (44.73 +/- 10.34) years. The changes of biomechanics, local tension and tenderness index were observed and recorded respectively before and after the therapy, and the results obtained from two groups were then compared with each other. The JOA score was used to evaluate the clinical effect. RESULTS Sixty patients finished the clinical observation. The treatment efficacy was evaluated according to the JOA score in 60 cases. The soft tissue tension in treatment group was lower than that in the control group (P=0.00004). Excellent result was found in 18 cases, good in 9 cases, fair in 3 cases and poor in 0 case. CONCLUSION Tension relaxation by needle knife can effectively improve the clinical symptoms and signs of third lumbar transverse process syndrome.

The records of all canine patients (86) that had been diagnosed with babesiosis and that were admitted to the Clinic for Internal Diseases, Faculty of Veterinary Medicine, Zagreb from January 2007 to December 2007 were reviewed retrospectively. All dogs that had been diagnosed with canine babesiosis and that had systemic inflammatory response syndrome (SIRS) followed by multiple organ dysfunction syndrome (MODS), and refractory hypotension, were included in this study. Of 86 patients diagnosed with canine babesiosis that were admitted during the study period, 10 had evidence of septic shock and were included in this study. Seven of the 10 dogs had a level of parasitaemia above 1%, with the highest level being 20.2%, seven of the 10 dogs were anaemic and three of the 10 dogs were leucopoenic. Thrombocytopenia was present in nine dogs. Hypoglycaemia was noted in two dogs, and bilirubinaemia in nine dogs. Four patients had involvement of two organs, five had involvement of three organs, and one had involvement of four organs. The organ that was most frequently involved was the kidney (nine cases). Central nervous system dysfunction was the rarest complication noted (one case). The mortality rate in non-septic shock canine babesiosis was 2.6%. All dogs that developed septic shock died between the first and the fourth day after admission. The 100% mortality rate that is reported here reflects the fact that in cases in which progression of the inflammatory response leads to the development of septic shock, an unfavourable outcome should be expected.