Assessment of panobacumab as adjunctive immunotherapy for the treatment of nosocomial Pseudomonas aeruginosa pneumonia.

The fully human anti-lipopolysaccharide (LPS) immunoglobulin M (IgM) monoclonal antibody panobacumab was developed as an adjunctive immunotherapy for the treatment of O11 serotype Pseudomonas aeruginosa infections. We evaluated the potential clinical efficacy of panobacumab in the treatment of nosocomial pneumonia. We performed a post-hoc analysis of a multicenter phase IIa trial (NCT00851435) designed to prospectively evaluate the safety and pharmacokinetics of panobacumab. Patients treated with panobacumab (n = 17), including 13 patients receiving the full treatment (three doses of 1.2 mg/kg), were compared to 14 patients who did not receive the antibody. Overall, the 17 patients receiving panobacumab were more ill. They were an average of 72 years old [interquartile range (IQR): 64-79] versus an average of 50 years old (IQR: 30-73) (p = 0.024) and had Acute Physiology and Chronic Health Evaluation II (APACHE II) scores of 17 (IQR: 16-22) versus 15 (IQR: 10-19) (p = 0.043). Adjunctive immunotherapy resulted in an improved clinical outcome in the group receiving the full three-course panobacumab treatment, with a resolution rate of 85 % (11/13) versus 64 % (9/14) (p = 0.048). The Kaplan-Meier survival curve showed a statistically significantly shorter time to clinical resolution in this group of patients (8.0 [IQR: 7.0-11.5] versus 18.5 [IQR: 8-30] days in those who did not receive the antibody; p = 0.004). Panobacumab adjunctive immunotherapy may improve clinical outcome in a shorter time if patients receive the full treatment (three doses). These preliminary results suggest that passive immunotherapy targeting LPS may be a complementary strategy for the treatment of nosocomial O11 P. aeruginosa pneumonia.

TICACOS international: A multi-center, randomized, prospective controlled study comparing tight calorie control versus Liberal calorie administration study.

Since the first TICACOS study, 3 additional studies have been published comparing a medical nutrition therapy guided by indirect calorimetry to a regimen prescribed on the basis of predictive equations. A recent guidelines document included a meta-analysis including these 4 papers and found a trend for improvement (OR 0.98-1.48) in favor of medical nutrition therapy guided by indirect calorimetry in terms of survival. The aim of our study was to perform a multicenter prospective, randomized, controlled non blinded study in critically patients to assess the added value for measuring daily resting energy expenditure as a guide for nutritional support. The primary objective was to decrease infectious rate of these critically ill patients. MATERIAL AND METHODS: This phase III, multi-center, randomized, controlled non blinded study was planned to include 580 newly-admitted, adult ventilated ICU patients that were planned to stay more than 48 h in the ICU departments. The nutritional support was aimed to meet 80-100% of energy requirement measured by indirect calorimetry. The calorie needs were determined by IC in the Study group and by an equation (20-25 kcal/kg ideal body weight/day) in the Control Group. The ICU staff was trained to strive to supply 80-100% of a patient's energy requirements through artificial nutrition, preferably enteral feeding. Primary endpoint was infection rate and secondary endpoints included other morbidities and mortality during ICU, at 90 and 180 days. Comparison between the study and the control group was performed using T test for equality of means (independent samples test). Correlations were performed using the Pearson correlation test. A p level of 0.05 or below was considered as significant. Cross tabs procedure used Chi-square test for testing differences in complication rates, length of stay and length of ventilation. Correlations between energy balances and complications was also be tested using one way analysis as well as ANOVA analysis between groups and within groups. Kaplan Meir curves assessed the proportion of surviving patients in the 2 groups. RESULTS: Seven centers with a calorimeter available participated to the study. Due to slow inclusion rate, the study was stopped after 6 years and after inclusion of 417 patients only. From the 417 intended to treat patients, 339 followed the protocol. There was no differences between control and study groups in terms of age, sex BMI, SOFA (7.1 ± 3.1 vs 7.4 ± 3.3) and APACHE II scores (22.4 ± 7.9 vs 22.2 ± 7.4). The rate of infection (40 vs 31), including pneumonia rate, need for surgery, dialysis requirement, length of ventilation, ICU length of stay, and hospital length of stay were not different between groups. Mortality (30 in the control vs 21 in the study group) was not significantly different between groups. The decreased mortality observed in the study group when added to previous studies may have a positive effect on the meta-analysis previously published. CONCLUSION: Tight Calorie Control guided by indirect calorimetry decreased the rate of infection and mortality but not significantly. This may be explained by the not relatively small sample size. There results together with the previous 4 prospective randomized studies, may improve the results of the meta-analysis exploring the effects of IC guided nutrition on mortality.

Toll-like receptor 4 modulation as a strategy to treat sepsis.

Despite a decrease in mortality over the last decade, sepsis remains the tenth leading causes of death in western countries and one of the most common cause of death in intensive care units. The recent discovery of Toll-like receptors and their downstream signalling pathways allowed us to better understand the pathophysiology of sepsis-related disorders. Particular attention has been paid to Toll-like receptor 4, the receptor for Gram-negative bacteria outer membrane lipopolysaccharide or endotoxin. Since most of the clinical trial targeting single inflammatory cytokine in the treatment of sepsis failed, therapeutic targeting of Toll-like receptor 4, because of its central role, looks promising. The purpose of this paper is to focus on the recent data of various drugs targeting TLR4 expression and pathway and their potential role as adjunctive therapy in severe sepsis and septic shock.

Adjunctive therapies for severe sepsis.

Severe sepsis-associated mortality may still be improved by earlier recognition, faster and adequate source control, and targeted resuscitation. Patients who may benefit from the administration of drotrecogin alfa (activated) are currently those at high risk of death, and other indications should be better defined by ongoing trials. Use of low-dose steroids for the treatment of severe sepsis must be re-clarified by new studies and should be restricted to patients with refractory septic shock. Trials exploring the role of natural anticoagulants and Toll-like receptor inhibitors are ongoing and should be completed in the coming 3 years. Future trials in severe sepsis should target more homogeneous populations with a well-defined focus of infection and severity, receiving appropriate standard of care, and the tested intervention should be administered in a timely fashion according to the expected host response.

Non-heart-beating donor, 10-year experience in a Belgian transplant center.

All over the world, transplant teams are looking for ways to increase and improve the donor pool. Non-heart-beating donation may increase the number of donors, even if some technical, logistical, and emotional problems are still encountered. The results obtained by our team should stimulate other centers to implement this kind of donation in their hospitals. Herein we have described our experience with non-heart-beating donation.

Predictors of clinicians' underuse of daily sedation interruption and sedation scales.

PURPOSE: The purpose of the study is to identify predictors of underuse of sedation scales and daily sedation interruption (DSI). METHODS: We surveyed all physicians and seven nurses in every Belgian intensive care unit (ICU), addressing practices and perceptions on guideline recommendations. Underuse was defined for sedation scales as use less than 3× per day and for DSI as never using it. Classification trees and logistic regressions identified predictors of underuse. RESULTS: Underuse of sedation scales and DSI was found for 16.6% and 32.5% of clinicians, respectively. Strongest predictors of underuse of sedation scales were agreeing that using them daily takes much time and being a physician (rather than a nurse). Further predictors were confidence in their ability to measure sedation levels without using scales, for physicians, and nurse/ICU bed ratios less than 1.98, for nurses. The strongest predictor of underuse of DSI among physicians was the perception that DSI impairs patients' comfort. Among nurses, lack of familiarity with DSI, region, and agreeing DSI should only be performed upon medical orders best predicted underuse. CONCLUSIONS: Workload considerations hamper utilization of sedation scales. Poor familiarity, for nurses, and negative perception of impact on patients' comfort, for physicians, both reduce DSI utilization. Targeting these obstacles is essential while designing quality improvement strategies to minimize sedative use.

Current surgical management of acute pancreatitis.

BACKGROUND: About 20% of the patients with acute pancreatitis may run a rapidly progressive or fulminant course resulting in the multiple organ dysfunction syndrome with or without accompanying sepsis. In this subset of patients, the mortality rate still ranges from less than 10% with sterile to over 30% with infected pancreatic necrosis. The goal of this review is to assess the available treatment strategies to allow the development of a formalized surgical approach to those patients. METHODS: A literature review of management of acute pancreatitis. RESULTS AND CONCLUSION: Over the past 20 years, there has been a substantial change in the surgical management of severe acute pancreatitis. This change has been away from a preventive surgery based on early major interventions towards a surgery of complications based increasingly on less aggressive options that take place at a later stage of the attack with specific criteria governing the timing of surgical therapy. Non-surgical options remain more than ever the cornerstone of management in many of these patients.

Antimicrobial therapy for intra-abdominal infections: guidelines from the Infectious Disease Advisory Board (IDAB).

Intra-abdominal infection is a common cause of severe sepsis in a hospital setting and remains associated with a significant morbidity, mortality and resource use. Early adequate surgery or drainage remain the cornerstones of intra-abdominal infection management and impact on patients outcome. Concomitant early and adequate empiric antimicrobial therapy further influences patients morbidity and mortality. Multiple empirical regimens have been proposed in this setting, but rarely supported by well designed, randomized-controlled studies. The current manuscript summarizes the recommendations of the Infection Disease Advisory Board on the management of intra-abdominal infections. Empiric antimicrobial therapy for the most common causes of abdominal infections is proposed. In addition, particular attention has been paid on antibiotic treatment duration.

[Traumatic perforation of the sigmoid colon: role of computed tomography]. / Perforation sigmoïdienne traumatique: intérêt du bilan tomodensitométrique.

The authors report a case of a delayed traumatic perforation of the sigmoid colon, presenting three days after a motor vehicle accident. A review of the literature is presented.

Strengths and limitations of industry vs. academic randomized controlled trials.

Clinical research has evolved substantially over the last two decades, but industry-sponsored research is still substantially superior to academic research in preparing, organizing and monitoring studies. Academics have to realize that conducting clinical research has become a real job with professionalism requirements. The primary objectives of research and development clearly differ between industry and academics. In the first case, new drug development is expected to generate profit, whereas in the latter case, research is aimed at understanding mechanisms of disease, promoting evidence-based medicine, and improving public health and care. However, a large number of clinical studies do not achieve their goals, and the reasons for failure may also differ between sponsored and academic studies. Industry and academics should develop better constructive partnerships and learn from each other. Academics should guide industry in study design and in investigator site selection, and academics should benefit from industry's expertise in improving monitoring and reporting processes. Finally, the existing database from former studies should be opened and shared with academics, to enable the exploration of additional scientific questions and the generation of new hypotheses. The two types of research should not be opposed, but should take the form of a constructive collaboration, increasing the chances of reaching each individual goal.

Transjugular intrahepatic portosystemic shunt approach and local thrombolysis for treatment of early posttransplant portal vein thrombosis.

Early portal vein thrombosis is a rare but severe posttransplant complication that may lead to graft and/or patient loss. Transjugular intrahepatic portosystemic shunting and local thrombolysis may represent an easy solution to this major complication of liver transplantation.

Transjugular intrahepatic portosystemic shunt after adult liver transplantation: experience in eight patients.

BACKGROUND: Transjugular intrahepatic portosystemic shunting (TIPS) has become an effective treatment for the complications of portal hypertension. We assessed the feasibility and outcome of TIPS in liver transplant recipients. METHODS: During the period from December 1992 to January 1998, eight adults presenting recurrent hepatitis C virus (five patients) and hepatitis B virus (one patient) infection, veno-occlusive disease (one patient), and secondary biliary cirrhosis (one patient) had TIPS because of refractory ascites (five patients), bleeding esophageal varices (one patient), refractory hepatic hydrothorax (one patient), retransplantation (two patients), and redo-biliary surgery (one patient). RESULTS: In two patients, the procedure was difficult due to cavo-caval implantation. Ascites, hydrothorax, and variceal bleeding were controlled in all patients. Moderate to severe encephalopathy developed in four patients; two patients had worsening of their existing encephalopathy. Three of five patients treated with cyclosporine needed a drastic dose reduction due to the development of severe side effects. No long-term survivor developed shunt stenosis or occlusion. Two patients did moderately well at 6 and 14 months, respectively; the former died due to chronic rejection while waiting for a retransplantation. Three did well at 14, 36, and 28 months, respectively; the latter patient died of liver failure 32 months after TIPS. One jaundiced patient died after 1.5 months due to necrotic pancreatitis. Two patients died after 4 and 8.5 months, respectively, due to liver failure; the latter was doing well until 7 months after TIPS. CONCLUSIONS: TIPS is feasible in transplant recipients in cases of decompensated allograft cirrhosis, of allograft veno-occlusive disease or when retransplantation or redo-biliary surgery are scheduled in the presence of portal hypertension. At transplantation, the surgeon should keep in mind the eventuality of a later TIPS procedure. Close immunosuppression monitoring is warranted because modified metabolization of cyclosporine (and probably tacrolimus) may cause serious side effects.

Hepatic sickling: an unusual cause of liver allograft dysfunction.

Orthotopic liver transplantation can be performed successfully in thalassemia. In this article, we describe a case of liver transplantation in a patient with sickle cell/beta-thalassemia complicated by liver sickling. Intrahepatic sickling must be considered in case of allograft dysfunction. This condition can easily be diagnosed by biochemical investigation and liver ultrasonography.

Conservative treatment of postsurgical lymphatic leaks with somatostatin-14.

Successful management of lymphatic leaks by continuous IV administration of somatostatin was first reported by Ulibarri and coworkers in Spain,(1) and more recently by authors from Italy(2) and Switzerland.(3) The present article reports the clinical history of two patients in whom postsurgical lymphatic leak was successfully treated after the administration of either somatostatin-14 alone (case 1) or combined somatostatin-14 and total parenteral nutrition (TPN; case 2). Although further pathophysiologic studies are needed for the elucidation of its mechanisms of action, somatostatin-14 seems to be an intriguing therapy against postsurgical lymphatic leaks that may make potentially risky transthoracic reoperation unnecessary.

Hemodynamic and metabolic effects of rapid correction of hypophosphatemia in patients with septic shock.

STUDY OBJECTIVE: To examine the hemodynamic and metabolic short-term effects of hypophosphatemia correction in patients with septic shock receiving catecholamine therapy. DESIGN: Prospective, single cohort study. SETTING: ICU, university hospital. PATIENTS: Ten patients with septic shock and hypophosphatemia below 2 mg/dL. INTERVENTIONS: Infusion of glucose-1-phosphate solution (20 mmol of elemental phosphorus) for 60 min. MEASUREMENTS AND RESULTS: Hemodynamic, oxygen-derived, acid-base, and electrolyte parameters before and immediately after phosphate infusion. Left ventricular stroke work index increased significantly (22%) from a mean low value of 24 +/- 10 g/m2 without changes in filling pressures. Systolic arterial pressure improved by 12%. Arterial pH improved slightly but significantly. Ionized calcium level slightly decreased within the normal range values. Other parameters remained unchanged. CONCLUSIONS: Severe hypophosphatemia may be considered as a superimposed cause of myocardial depression, inadequate peripheral vasodilatation, and acidosis in septic shock. A rapid correction of hypophosphatemia is well tolerated and may have both myocardial and vascular beneficial effects. The magnitude of the response, however, is variable and unpredictable on the basis of serum phosphorus levels.

Significance of pathologic oxygen supply dependency in critically ill patients: comparison between measured and calculated methods.

OBJECTIVE: oxygen supply dependency at normal or high oxygen delivery rate has been increasingly proposed as a hallmark and a risk factor in critical illnesses. We hypothesized that as far as an adequate oxygen delivery is provided, oxygen consumption, when determined by indirect calorimetry, is not dependent on oxygen delivery in critically ill patients whereas calculated oxygen consumption is associated with artefactual correlation of oxygen consumption and delivery. DESIGN: oxygen delivery, oxygen consumption and their relationship were analyzed prospectively. Metabolic data gained from both measured and calculated methods were obtained simultaneously before and after volume loading. SETTING: the study was completed in the intensive care unit as part of the management protocol of the patients. PATIENTS: 32 consecutive patients entered the study and were divided into 3 groups according to a clinical condition known to favour oxygen supply dependency: sepsis syndrome, adult respiratory distress syndrome and acute primary liver failure. INTERVENTION: the rise in oxygen delivery was obtained by colloid infusion (oxygen flux test) performed in hemodynamically and metabolically stable patients. All were mechanically ventilated. No change in therapy was allowed during the test. MEASUREMENTS AND RESULTS: oxygen consumption was simultaneously evaluated by calculation (Fick Principle) and direct measurement using indirect calorimetry. Oxygen delivery was derived from the cardiac output (thermodilution) and arterial content of oxygen. Oxygen supply dependency was considered while observing an increase in oxygen delivery greater than 45 ml/min.m2. Irrespective of patient's clinical diagnosis and outcome, measured oxygen uptake remained unaltered by volume infusion whereas both oxygen delivery and calculated oxygen consumption increased significantly. Arterial lactate level > 2 mmol/l and measured oxygen extraction ratio > 25% failed to identify oxygen supply dependency when measured data were considered. CONCLUSION: analysis of oxygen uptake, when measured by indirect calorimetry, failed to substantiate oxygen supply dependency in the vast majority of the critically ill patients irrespective of diagnosis and outcome. Mathematical coupling of shared variables accounted for the correlation between oxygen delivery and calculated oxygen consumption.

Evaluation of oxygen uptake and delivery in critically ill patients: a statistical reappraisal.

OBJECTIVE: The evaluation of oxygen consumption (VO2) and oxygen delivery (DO2) has gained increasing importance in the monitoring of critically ill patients. They can be obtained from either direct measurements or by indirect calculations based on the Fick principle. However the choice between these two approaches remains controversial. The aim of the study was to investigate whether these 2 methods provide similar results, and if not, to define the best one in terms of reproducibility. DESIGN: Oxygen delivery and oxygen consumption were prospectively analyzed in 171 consecutive critically ill patients. Metabolic data were obtained simultaneously. SETTING: The study was completed in the intensive care unit as part of the management of the patients studied. PATIENTS: A first "group" of 279 evaluations was carried out in 73 consecutive critically ill patients. The results were subsequently validated by 423 observations performed in the 98 following patients. INTERVENTIONS: Before and during each evaluation, the patients were kept in stable hemodynamic and metabolic conditions. All were mechanically ventilated. MEASUREMENTS AND RESULTS: VO2 was evaluated by calculation (Fick principle) and direct measurement using indirect calorimetry. Cardiac output was both measured by the thermodilution technique and calculated (Fick principle) and the data were used for the evaluation of the directly measured and indirectly calculated DO2. For both VO2 and DO2 the agreement between direct and indirect evaluations was not satisfactory. Differences as great as 55 ml/min.m2 and 267 ml/min.m2 between simultaneously measured and calculated VO2 and DO2 respectively may be expected. Finally, the indirect calculated methods were less reproducible than the measured ones. These observations resulted mainly from the cumulative effects of the random errors in the metabolic data entering into the calculation of VO2 and DO2. CONCLUSIONS: Our data suggested that the indirect calculation (Fick equation) and the direct measurement (indirect calorimetry, thermodilution) of both VO2 and DO2 did not provide similar results. Direct measurements are more reproducible methods and must be preferred.

Focal bowel wall changes detected with colour Doppler ultrasound: diagnostic value in acute non-diverticular diseases of the colon.

We performed a study to determine if colour Doppler findings may help to identify the cause of wall thickening in acute non-diverticular diseases of the colon. The study group included 66 patients admitted to the emergency department with a final diagnosis of infectious colitis (n=23), inflammatory colitis (n=10), ischaemic colitis (n=23) and malignant tumours (n=10). The following ultrasound features were assessed: maximal wall thickness, wall stratification, arterial flow in the colonic wall and arteriolar resistive index. Higher values of wall thickness were observed in malignant tumour (18.2+/-6.2 mm, p<0.001). Moderately thickened wall (6.6+/-1.3 mm, p< or =0.06), preserved stratification (90% versus 46% in the remainder of the study population) and lower resistive index (0.51+/-0.10, p< or =0.05) were significantly related to inflammatory colitis. Absence of arterial flow was more frequently observed in ischaemia (43% versus 12% in the remainder of the study population). In conclusion, despite some overlap, both ultrasound and colour Doppler features are helpful in the differential diagnosis of colonic thickening related to non-diverticular colonic lesions.