Expert recommendations about the use of gadoxetic acid in patients with liver metastases in Spain.

BACKGROUND AND AIMS: Magnetic resonance imaging (MRI) with gadoxetic acid is widely used in clinical practice in Spain for the diagnosis, treatment, and follow-up of patients with liver metastases, although its use varies. This paper aims to provide recommendations for the use of MRI with gadoxetic acid in the detection and diagnosis of liver metastases in clinical practice in Spain. MATERIAL AND METHODS: This project was undertaken by a group of nine experts who analyzed a series of recommendations about the use of gadoxetic acid extracted from international consensus documents. From this analysis, the experts decided to reject, adopt, contextualize, or adapt each of the recommendations. Once established, the final recommendations were voted on by the same group of experts. RESULTS: The experts reached a consensus about five recommendations related to the use of this imaging technique in the management of liver metastases in three clinical situations: (i) in the detection, (ii) in the diagnosis and preoperative characterization, and (iii) in the detection after a chemotherapy treatment. CONCLUSION: The results support a clinical benefit for MRI with gadoxetic acid in the detection of liver metastases, favoring preoperative planning, especially in metastases measuring less than 1 cm, thus facilitating early diagnosis of metastatic spread.

Randomised clinical trial of moxifloxacin versus ertapenem in complicated intra-abdominal infections: results of the PROMISE study.

Antibiotic therapy for complicated intra-abdominal infections (cIAIs) should provide broad-spectrum coverage both Gram-positive and Gram-negative microorganisms. The PROMISE study compared the clinical and bacteriological efficacy and safety of moxifloxacin versus ertapenem for the treatment of cIAIs. This randomised, prospective, double-dummy, double-blind, multicentre trial was designed as a non-inferiority study. The safety and efficacy of 5-14 days of daily intravenous moxifloxacin (400mg) or ertapenem (1g) were compared in patients with cIAIs requiring surgery and parenteral antibiotic therapy. The primary and secondary endpoints included clinical and bacteriological responses at 21-28 days after the end of treatment (TOC), respectively. Of 830 enrolled patients, 699 were efficacy valid. Moxifloxacin was non-inferior to ertapenem regarding clinical success [89.5% (315/352) versus 93.4% (324/347); 95% confidence interval (CI) -7.9%, 0.4%]. There were no significant differences between groups for any of the primary causes or types of cIAI regarding clinical response. Bacteriological success was achieved in 86.5% (257/297) of moxifloxacin-treated patients and 90.2% (249/276) of ertapenem-treated patients (95% CI -9.0%, 1.5%). There were no major differences between groups regarding the frequency or types of organisms eradicated. The incidence of adverse events (AEs) was higher with moxifloxacin than ertapenem (P=0.039), however a similar number of drug-related AEs was seen in each group (P=1.000). Wound infections, nausea and increased lipase were the most commonly reported AEs with both agents. The results show that moxifloxacin is a valuable treatment option for a range of community-acquired cIAIs with mild-to-moderate severity.

Randomized, placebo-controlled trial of the anti-tumor necrosis factor antibody fragment afelimomab in hyperinflammatory response during severe sepsis: The RAMSES Study.

OBJECTIVE: This study investigated whether treatment with the anti-tumor necrosis factor-alpha monoclonal antibody afelimomab would improve survival in septic patients with serum interleukin (IL)-6 concentrations of >1000 pg/mL. DESIGN: Multicenter, double-blind, randomized, placebo-controlled study. SETTING: Eighty-four intensive care units in academic medical centers in Europe and Israel. PATIENTS: A total of 944 septic patients were screened and stratified by the results of a rapid qualitative immunostrip test for serum IL-6 concentrations. Patients with a positive test kit result indicating IL-6 concentrations of >1000 pg/mL were randomized to receive either afelimomab (n = 224) or placebo (n = 222). Patients with a negative IL-6 test (n = 498) were not randomized and were followed up for 28 days. INTERVENTIONS: Treatment consisted of 15-min infusions of 1 mg/kg afelimomab or matching placebo every 8 hrs for 3 days. Standard surgical and intensive care therapy was otherwise delivered. MEASUREMENTS AND MAIN RESULTS: The study was terminated prematurely after an interim analysis estimated that the primary efficacy end points would not be met. The 28-day mortality rate in the nonrandomized patients (39.6%, 197 of 498) was significantly lower (p <.001) than that found in the randomized patients (55.8%, 249 of 446). The mortality rates in the IL-6 test kit positive patients randomized to afelimomab and placebo were similar, 54.0% (121 of 224) vs. 57.7% (128 of 222), respectively. Treatment with afelimomab was not associated with any particular adverse events. CONCLUSIONS: The IL-6 immunostrip test identified two distinct sepsis populations with significantly different mortality rates. A small (3.7%) absolute reduction in mortality rate was found in the afelimomab-treated patients. The treatment difference did not reach statistical significance.

[Evidence-based medicine in antimicrobial surgical prophylaxis]. / Medicina basada en la evidencia en profilaxis quirúrgica antimicrobiana.

INTRODUCTION: The main objective of antibiotic prophylaxis in surgery is to reduce morbidity and mortality associated with wound infection, which has a favorable impact on quality of care and overall health-care costs. The bases of antibiotic prophylaxis have been known for decades, but the appearance of new pharmacological agents, alternative routes of administration, modern surgical procedures, and previously unknown antimicrobial resistances involve the need for reviewing these bases. OBJECTIVE: To re-evaluate some of the general principles of the use of antibiotic prophylaxis in surgery and highlight the quality of the evidence supporting our clinical decisions found in the literature. METHOD: Review of the literature with special attention to prospective, randomized, evidence-based clinical trials on the need for antibiotic prophylaxis in surgery, mainly general surgery. RESULTS: The method for demonstrating the effectiveness of an antibiotic in prophylaxis continues to be the prospective, randomized clinical trial. Evidence of the need for antibiotic prophylaxis in clean-contaminated surgery and when prosthetic materials are used is good. CONCLUSIONS: Most studies on the general principles of prophylaxis have been carried out in general surgery and it is difficult to extrapolate their results to other fields or surgical specialties. Therefore, new clinical trials in each specialty are needed to establish specific recommendations. However, the standardization of aseptic, antiseptic, and technical procedures in surgery has produced a notable decrease in the wound infection rate compared to historical controls, so now it is difficult to demonstrate significant differences in the results of clinical trials. Finally, the response to the fundamental question of "What do we propose to prevent and to what degree?" with which the antibiotic era began is either difficult to formulate or described ambiguously when referring to advanced procedures, such as endoprostheses, endoscopic retrograde cholangiography, or dental implants.

A clinical trial on the prevention of catheter-related sepsis using a new hub model.

BACKGROUND: Catheter hub contamination is being increasingly recognized as a source of catheter-related sepsis. The authors have investigated the efficacy of a new hub design in preventing endoluminal catheter contamination and catheter-related sepsis arising at the hub. METHODS: Adult surgical and intensive care patients requiring a subclavian catheter for at least 1 week were randomly assigned to receive catheters with standard connectors (control group, n=73) or equipped with a new hub model (new hub group, n=78). Skin, catheter tip, and hub cultures were performed at the time the catheter was withdrawn because therapy was terminated or because of suspicion of sepsis, in which case peripheral blood cultures were taken. RESULTS: Of the 151 patients included, 15 (10%) developed catheter-related sepsis. Catheters were more often withdrawn because suspicion of infection in the control group (42 vs. 19%, p<0.005). Catheter sepsis rate was higher in the control group (16 vs. 4%, p<0.01) because of the low rate of catheter sepsis arising at the hub observed in the new hub group (1 vs. 11%, p<0.01). The prevalence of culture-positive catheter hubs without associated bacteremia (colonization) was higher in the control group (18 vs. 5%, P<0.03). CONCLUSIONS: A new catheter hub has proved to be useful in preventing endoluminal bacterial colonization and catheter-related sepsis in subclavian lines inserted for a mean of 2 weeks.

Activation state of polymorphonuclear leukocytes in surgical patients: characterization of surface receptor expression.

BACKGROUND: We studied the expression of chemotactic, opsonic, and adherent receptors on the membranes of polymorphonuclear neutrophils (PMNs) from surgical patients because modulation of these receptors has been suggested in the control of critical PMN functions that directly or indirectly influence patient outcome. METHODS: Healthy subjects who had PMN adherence, chemotaxis, and receptor measurements were compared with preoperative surgical patients and those who were within 48 hours of an admission to an intensive care unit (surgical intensive care unit) because of an acute illness. RESULTS: The following receptor/cell pattern was found in control subjects, preoperative patients, and patients in the surgical intensive care unit, respectively: formyl peptide (13,000 vs 18,000 vs 22,000), CR3 (59,000 vs 105,000 vs 121,000), fibronectin (21,000 vs 20,000 vs 35,000), FcII gamma (9,000 vs 20,000 vs 25,000), C5a (347 vs 265 vs 250 mean channel number), and FcIIIR (64,000 vs 75,000 vs 26,000). This receptor pattern was partly correlated directly or indirectly with the acute-phase response, neutrophil adherence, and PMN chemotaxis from these subjects. CONCLUSIONS: The data suggest that there are alterations in the expression and modulation of PMN surface membrane receptors in patients with a "stable" disease process compared with those with an acute illness, which may affect critical PMN functions needed to combat bacterial infections.

Circulating and exudative polymorphonuclear neutrophil priming and oxidative capacity in anergic surgical patients.

OBJECTIVES: To examine the oxidative capacity of circulating and exudate polymorphonuclear neutrophils from reactive patients and anergic patients before surgery to determine why anergic patients have increased sepsis-related mortality once an infectious complication develops. DESIGN: Prospective in vitro patient study. SETTING: Tertiary care, major university teaching hospital. PARTICIPANTS: Surgical patients admitted for major elective gastrointestinal surgery. MAIN OUTCOME AND MEASURES: We used flow cytometry and the dye 2-7-dichlorofluorescein diacetate to measure hydrogen peroxide production of circulating and exudate polymorphonuclear neutrophils at baseline and after stimulation with Staphylococcus epidermidis. RESULTS: We found that polymorphonuclear neutrophils were primed in the intravascular space as evidenced by increased numbers of formyl-methionyl-leucyl-phenylalanine receptors, increased hydrogen peroxide production at baseline, and increased hydrogen peroxide production with stimulation. These results were more evident in the anergic patient. After exudation, anergic polymorphonuclear neutrophils lost most of their capacity to produce additional hydrogen peroxide. CONCLUSIONS: The data suggest that this intravascular priming adversely affected polymorphonuclear neutrophils during exudation, more marked in the anergic patient, and may contribute to the sepsis-related mortality of the anergic patients.

Altered neutrophil function following reperfusion of an ischemic myocutaneous flap.

The neutrophil has been implicated as a source of oxygen free radicals provoking the reperfusion injury in various ischemic organs. This provided the motivation to explore the pathophysiologic role of the neutrophil in a swine model of postischemic latissimus dorsi myocutaneous flaps. Neutrophil function, neutrophil sequestration, and the anatomic distribution of muscle injury were estimated following a 6- to 8-hour global ischemic insult. Neutrophil function as measured by phorbol myristate acetate-stimulated superoxide production was found to be enhanced on reperfusion of ischemic flaps (n = 17). Neutrophil sequestration estimated from the arterial-venous difference of flap blood (n = 12) demonstrated that postischemic flaps more avidly sequester neutrophils than nonischemic flaps. The anatomic distribution of muscle injury (n = 7) was predominantly localized to the proximal portion of the ischemic flap. The enhanced functional response exhibited by neutrophils reperfusing an ischemic myocutaneous flap supports an active neutrophil role in the mediation of reperfusion injury.

Critically ill anergic patients demonstrate polymorphonuclear neutrophil activation in the intravascular compartment with decreased cell delivery to inflammatory focci.

Skin test anergy, the failure to produce a delayed type hypersensitivity (DTH) response, is associated with an increase in infection-related complications and death usually due to multiple organ failure (MOF). Refractory intravascular activation of polymorphonuclear neutrophils (PMNs) has been implicated in the development of MOF. We studied 20 critically ill surgical patients with life threatening infections to determine if PMN intravascular activation was present and how this affected essential PMN functions such as exudation. The 11 anergic patients had a more intense inflammatory response to their infection. Plasma lactoferrin was 6.1 +/- 0.3 microgram/ml in anergic patients compared to 3.9 +/- 1.5 in reactive P less than 0.05, accompanied by reduced total primary (3.3 +/- 1.9 vs 4.7 +/- 2.1 micrograms/10(6) PMN P less than 0.01) and secondary (2.8 +/- 0.4 vs 5.0 +/- 0.9 microgram/10(6) PMN P less than 0.01) granule content, respectively. In vitro superoxide production following 100 ng/ml PMA stimulation was 0.44 +/- 0.1 in anergics vs 0.36 +/- 0.1 nmol/microgram PMN protein in reactivities, P less than 0.05. PMN chemotaxis was 8.2 +/- 0.6 PMNs/HPF in anergics compared to 10.2 +/- 1.6 PMNs/HPF in reactives P less than 0.05, accompanied by decreased PMN delivery to skin blister windows (3.2 +/- 1.4 vs 4.5 +/- 1.9 x 10(7) PMN/ml, respectively, P less than 0.05). We conclude that critically ill anergic surgical patients have increased intravascular PMN activation, which may contribute to oxygen-derived tissue damage in the vascular space, as well as a deficient delivery of effector cells in areas of bacterial invasion. This may lead to inability to clear the inflammatory signals which set up the vicious circle of MOF leading to death.

Anergic patients before elective surgery have enhanced nonspecific host-defense capacity.

Albeit anergy in patients before surgery is associated with an increase in septic-related complications and mortality, it is not clear whether this is due to a downregulated nonspecific host defense or a specific cellular immune defect. We studied polymorphonuclear leukocyte neutrophil (PMN) function in 14 patients who were admitted for elective surgery and compared them with 5 healthy controls. At admission, patients were classified according to their delayed-type hypersensitivity skin test response into reactive or anergic groups. In vivo PMN delivery to skin windows, the plasma lactoferrin level, serum and skin window fluid chemoattractant activity, and in vitro superoxide production were measured. Compared with reactive patients, anergic patients showed an increased cell delivery (8.7 x 10(6) PMNs per well vs 1.6 x 10(6) PMNs per well), an increased plasma lactoferrin level (4.4 +/- 1.5 mg/L vs 3.1 +/- 0.8 mg/L), an increased chemoattractant capacity of serum and skin window fluid (38 +/- 21 cells per high-power field vs 16.8 +/- 7.2 cells per high-power field), and an increased superoxide production. We concluded that nonspecific host defense, as reflected by PMNs, is enhanced in anergic patients before surgery and may not explain the increased susceptibility to infection.

In vitro polymorphonuclear neutrophil function in surgical patients does not correlate with anergy but with "activating" processes such as sepsis or trauma.

We studied 199 preoperative patients admitted for esophagogastric, gastric, colonic, or rectal resections, 132 patients with severe blunt trauma, 180 surgical intensive care unit patients with major sepsis, and 95 laboratory controls in order to clarify the role of polymorphonuclear neutrophil (PMN) adherence and chemotaxis to outcome. Patients were also stratified by the delayed-type hypersensitivity response to five ubiquitous antigens. PMN adherence and PMN chemotaxis were not different in preoperative reactive or anergic patients and were equal to the control values, whereas both reactive patients and anergic patients showed altered PMN function after trauma or sepsis. There was no difference in PMN adherence or chemotaxis between patients who died and those who lived. Multiple logistic regression analysis showed that patient age, delayed-type hypersensitivity, and admission serum albumin level, not PMN adherence or chemotaxis, were significantly related to septic mortality. We concluded that altered circulating PMN adherence and chemotaxis is seen in all patients after an "activation" event such as trauma or sepsis. This is a nonspecific immune alteration not related to specific immune events such as delayed-type hypersensitivity; it does not correlate with patient outcome and should not be used as a predictive variable.

Predicting mortality based on body composition analysis.

The role of the Nae/Ke ratio (the ratio of exchangeable sodium to exchangeable potassium) was examined as a nutritional marker in surgical patients in relation to anthropometrical and biochemical indexes by its ability to identify patients at risk for mortality after hospitalization. In 73 patients with sepsis and malnutrition (Training Group, Madrid) the following were determined: percentage of recent weight loss, triceps skin fold, midarm muscle circumference, serum albumin, serum transferrin, delayed hypersensitivity skin test response, total lymphocytes, and Nae/Ke ratio by multiple isotope dilution. The predictive power of Nae/Ke ratio was so strong (F = 105.1; p less than 0.00001) that it displaced anthropometric, biochemical, and immunologic variables from the linear equation derived from stepwise discriminant analysis using hospital mortality as the dependent variable. A theoretical curve of expected deaths was developed, based on an equation obtained by logistic regression analysis: Pr/death/ = 1/(1 + e[11.8-5.2 Nae/Ke]). Pre- and post-test probabilities on that curve allowed us to determine two cut-off values, Nae/Ke ratios of 1.5 and 2.5, which were markers for nonrisk and mortality, respectively. The model was tested in a heterogeneous data base of surgical patients (n = 417) in another hospital (Validation Group, Montreal). For patients exhibiting an abnormal Nae/Ke ratio (greater than 1.2) and a greater than 10% of probability of death, 54 deaths were expected and 53 observed (X2 = 1.8 NS). Two tests confirmed the basic agreement between the model and its performance, a G statistic of -0.704 and the area beneath the "receiver-operating-characteristic" (ROC) curve (Az = 0.904 + 0.0516 for the Madrid group vs. Az = 0.915 + 0.0349 for the Montreal group, NS). It was concluded from this analysis that, compared with the usual anthropometric measurements, the Nae/Ke ratio, if available, is the best method for identifying malnourished patients at risk of dying.

The anergic state as a predictor of pancreatic sepsis.

From 1984 to 1987, 187 patients with acute pancreatitis (AP) were studied. All patients were stratified according to Ranson's criteria upon admission and were followed up by performing a CT scan weekly. One hundred and thirty-eight patients had 3 or less Ranson's criteria (non-severe acute pancreatitis = NSAP) and 49 presented 4 or more (severe acute pancreatitis = SAP). Ninety-six percent of the patients with (p less than 0.0001). Of the 49 patients with SAP, 39 developed pancreatic or peripancreatic NSAP were reactive to skin tests on the third week, while 4% remained anergic necrosis and were operated. Twenty-two of these patients had positive cultures demonstrating the presence of bacteria in the tissue samples. One hundred percent of the infected patients remained anergic until surgery, while only 40% of those with negative cultures remained anergic (p less than 0.05). Mortality rate correlated well with skin test responses, being 31% in anergic patients while only 5% in reactive subjects. Sustained anergic state (AS), sequentially checked, is associated with a high incidence of pancreatic sepsis.