Marc Reynaert

Lenercept (p55 tumor necrosis factor receptor fusion protein) in severe sepsis and early septic shock: a randomized, double-blind, placebo-controlled, multicenter phase III trial with 1,342 patients.

ObjectivePhase III study to confirm a trend observed in a previous phase II study showing that a single dose of lenercept, human recombinant p55 tumor necrosis factor receptor-immunoglobulin G1 (TNFR55-IgG1) fusion protein, decreased mortality in patients with severe sepsis or early septic shock. DesignMulticenter, double-blind, phase III, placebo-controlled, randomized study. SettingA total of 108 community and university-affiliated hospitals in the United States (60), Canada (6) and Europe (42). PatientsA total of 1,342 patients were recruited who fulfilled the entry criteria within the 12-hr period preceding the study drug administration. InterventionAfter randomization, an intravenous dose of 0.125 mg/kg lenercept or placebo was given. The patient was monitored for up to 28 days, during which standard diagnostic, supportive, and therapeutic care was provided. Measurements and Main Results The primary outcome measure was 28-day all-cause mortality. Baseline characteristics were as follows: a total of 1,342 patients were randomized; 662 received lenercept and 680 received placebo. The mean age was 60.5 yrs (range, 17–96 yrs); 39% were female; 65% had medical admissions, 8% had scheduled surgical admissions, and 27% had unscheduled surgical admissions; 73% had severe sepsis without shock, and 27% had severe sepsis with early septic shock. Lenercept and placebo groups were similar at baseline with respect to demographic characteristics, simplified acute physiology score II-predicted mortality, profiles of clinical site of infection and microbiological documentation, number of dysfunctioning organs, and interleukin-6 (IL-6) plasma concentration. Lenercept pharmacokinetics were similar in severe sepsis and early septic shock patients. Tumor necrosis factor was bound in a stable manner to lenercept as reflected by the accumulation of total serum tumor necrosis factor &agr; concentrations. There were 369 deaths, 177 on lenercept (27% mortality) and 192 on placebo (28% mortality). A one-sided Cochran-Armitage test, stratified by geographic region and baseline, predicted 28-day all-cause mortality (simplified acute physiology score II), gave a p value of .141 (one-sided). Lenercept treatment had no effect on incidence or resolution of organ dysfunctions. There was no evidence that lenercept was detrimental in the overall population. ConclusionLenercept had no significant effect on mortality in the study population.

Skeletonizing en bloc esophagectomy for cancer.

ObjectiveTo evaluate the long-term outcome of patients with esophageal cancer after resection of the extraesophageal component of the neoplastic process en bloc with the esophageal tube. Summary Background DataOpinions are conflicting about the addition of extended resection of locoregional lymph nodes and soft tissue to removal of the esophageal tube. MethodsEsophagectomy performed en bloc with locoregional lymph nodes and resulting in a real skeletonization of the nonresectable anatomical structures adjacent to the esophagus was attempted in 324 patients. The esophagus was removed using a right thoracic (n = 208), transdiaphragmatic (n = 39), or left thoracic (n = 77) approach. Lymphadenectomy was performed in the upper abdomen and lower mediastinum in all patients. It was extended over the upper mediastinum when a right thoracic approach was used and up to the neck in 17 patients. Esophagectomy was carried out flush with the esophageal wall as soon as it became obvious that a macroscopically complete resection was not feasible. Neoplastic processes were classified according to completeness of the resection, depth of wall penetration, and lymph node involvement. ResultsSkeletonizing en bloc esophagectomy was feasible in 235 of the 324 patients (73%). The 5-year survival rate, including in-hospital deaths (5%), was 35% (324 patients); it was 64% in the 117 patients with an intramural neoplastic process versus 19% in the 207 patients having neoplastic tissue outside the esophageal wall or surgical margins (P < .0001). The latter 19% represented 12% of the whole series. The 5-year survival rate after skeletonizing en bloc esophagectomy was 49% (235 patients), 49% for squamous cell versus 47% for glandular carcinomas (P = .4599), 64% for patients with an intramural tumor versus 34% for those with extraesophageal neoplastic tissue (P < .0001), and 43% for patients with fewer than five metastatic nodes versus 11% for those with involvement of five or more lymph nodes (P = .0001). ConclusionsThe strategy of attempting skeletonizing en bloc esophagectomy in all patients offers long-term survival to one third of the patients with resectable extraesophageal neoplastic tissues. These patients represent 12% of the patients with esophageal cancer suitable for esophagectomy and 19% of those having neoplastic tissue outside the esophageal wall or surgical margins.

Noninvasive ventilation for acute respiratory failure: a prospective randomised placebo-controlled trial

The aim of the present study was to clarify whether the known effects of noninvasive positive-pressure ventilation (NPPV) in patients with respiratory failure are real or due to placebo effects and whether early application of NPPV in the emergency department leads to rapid improvement of the patients condition and outcome. A prospective randomised placebo-controlled study was conducted in 20 patients with severe acute respiratory failure (ARF) secondary to an acute exacerbation of chronic obstructive pulmonary disease (COPD) or acute pulmonary oedema, not improving under conventional medical therapy and on the edge of intubation. Patients received either conventional medical therapy plus two-level NPPV (bi-level NPPV) or conventional medical therapy plus “placebo” NPPV. The main outcome measures involved the need for endotracheal intubation in the bi-level NPPV arm and in the placebo arm after crossing over to active NPPV. Morbidity, length of stay, mortality and the effect of the ventilatory mode on clinical, arterial-blood gas parameters, and the sternocleidomastoid muscles electromyogram (EMG) activity were also measured. The 10 patients in the active NPPV group rapidly improved and none needed intubation. Placebo NPPV resulted in no change in the clinical condition of patients that continued to worsen and the 10 patients were crossed over to active NPPV. Three patients were intubated. No differences in terms of morbidity, length of stay or mortality between the two groups were observed. Active NPPV (but not placebo NPPV) led to a rapid and significant improvement in the clinical parameters, pH and the carbon dioxide tension in arterial blood and to a decrease in respiratory frequency and sternocleidomastoid EMG activity. Early application of bi-level noninvasive positive-pressure ventilation in patients with severe acute respiratory failure, due to chronic obstructive pulmonary disease and acute pulmonary oedema, leads to a rapid improvement in clinical status and blood gases. Noninvasive positive-pressure ventilation had no placebo effect.

Is early enteral nutrition in acute pancreatitis dangerous? About 20 patients fed by an endoscopically placed nasogastrojejunal tube.

Bowel rest during treatment of acute pancreatitis deprives the gut of nutrients and affects its structure and function. Enteral feeding is usually performed late in the course of acute pancreatitis and therefore cannot prevent intestinal barrier dysfunction and possible bacterial translocation. To assess the effect of early enteral nutrition we performed a prospective study on 21 patients (11 males/10 females) presenting with severe acute pancreatitis (13 biliary, 6 alcoholic, and 2 miscellaneous). Severity was established by a mean Ranson score of 3.57. All but one patient could be fed through a double-lumen nasogastrojejunal tube within 60 h after admission. No significant complication of the technique was observed. We conclude that early jejunal feeding can be used safely in severe acute pancreatitis. Further comparative studies are necessary to demonstrate any superiority to total parenteral nutrition.

Helium-oxygen versus air-oxygen noninvasive pressure support in decompensated chronic obstructive disease: A prospective, multicenter study.

ObjectiveTo study whether noninvasive pressure support ventilation (NIPSV) with helium/oxygen (He/oxygen), which can reduce dyspnea, Paco2, and work of breathing more than NIPSV with air/oxygen in decompensated chronic obstructive pulmonary disease, could have beneficial consequences on outcome and hospitalization costs. DesignProspective, randomized, multicenter study. SettingIntensive care units of three tertiary care university hospitals. PatientsAll patients with chronic obstructive pulmonary disease admitted to the intensive care units for NIPSV during a 24-month period. InterventionsPatients were randomized to NIPSV with air/oxygen or He/oxygen. NIPSV settings, number of daily trials, decision to intubate, and intensive care unit and hospital discharge criteria followed standard practice guidelines. ResultsA total of 123 patients (male/female ratio, 71:52; age, 71 ± 10 yrs, Acute Physiology and Chronic Health Evaluation II, 17 ± 4) were included. Intubation rate (air/oxygen 20% vs. He/oxygen 13%) and length of stay in the intensive care unit (air/oxygen 6.2 ± 5.6 vs. He/oxygen 5.1 ± 4 days) were comparable. The post–intensive care unit hospital stay was lower with He/oxygen (air/oxygen 19 ± 12 vs. He/oxygen 13 ± 6 days, p < .002). Cost of NIPSV gases was higher with He/oxygen, but total hospitalization costs were lower by

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

3,348 per patient with He/oxygen. No complications were associated with the use of He/oxygen. ConclusionHe/oxygen did not significantly reduce intubation rate or intensive care unit stay, but hospital stay was shorter and total costs were lower. He/oxygen NIPSV can be safely administered and could prove to be a cost-effective strategy.

Prospective Evaluation of Thoracic-duct Drainage in the Treatment of Respiratory-failure Complicating Severe Acute-pancreatitis

ObjectiveOxygen 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 fas 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.DesignOxygen 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.SettingThe study was completed in the intensive care unit as part of the management protocol of the patients.Patients32 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.InterventionThe 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 resultsOxygen 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 patients 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.ConclusionAnalysis 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.

Transjugular intrahepatic portosystemic shunt and liver transplantation

Thoracic duct drainage (TDD) may be of value for removing toxic substances released by the inflamed pancreas and which are responsible for lung damage. We have prospectively assessed the efficacy of TDD in improving pulmonary gas exchange in 12 patients with severe acute pancreatitis (SAP) complicated by persistent respiratory failure despite standard conservative treatment including peritoneal dialysis in 8 patients. In group A were 6 patients (mean Ranson score=7.3) with adult respiratory distress syndrome (ARDS) and in group B were 6 hypoxemic patients (mean Ranson score=6.6) judged to be at risk of developing ARDS. The duration of TDD ranged from 3 to 10 days and the total amount of drained lymph (L) varied from 770 to 15 600 ml. Immunoreactive trypsin levels were significantly higher in L when compared to blood in both groups. Leukocyte myeloperoxidases in L (normal value < than 332±82 ng/ml in plasma) were increased in 5 of 5 group A patients (830±317 ng/ml) and in 3 of 6 patients in group B (671±467 ng/ml). After TDD pulmonary gas exchange as measured by median PaO2/FiO2 (mmHg) improved from 148±60 to 285±42 in group A and from 192±37 to 330±42 in group B (p<0.05). All patients were weaned after ventilation for a mean of 8 days in group A and 4 days in group B. All patients survived apart from 1 group B patient who died of sepsis on day 34. These data suggest that TDD, by allowing removal of potential mediators of lung injury is of major therapeutic value in ARDS complicating SAP. This approach may also prevent further respiratory impairment in susceptible patients.

High serum levels of secretory IgA in liver disease

Transjugular intrahepatic portosystemic stent shunting (TIPSS) appears to be an attractive, nonsurgical procedure to overcome complications of end-stage liver disease. During the period August 1992 to February 1995, 23 adults who had previously undergone TIPSS received liver transplants. These patients were compared to 36 cirrhotic patients, grafted during the same time period, in relation to the implantation technique, the intraoperative use of blood products, and the length of their hospital stay. These groups were comparable for previous right upper quadrant surgery, splanchnic vein modifications, and Child-Pugh classification. Liver transplantation was performed electively in all TIPSS patients. Ten patients (43.4%) presented with a significant shunt stenosis at a median follow-up time of 4.5 months (range 2.5 to 30 months). At transplantation 8 of the 23 TIPSS patients (34.8%) had specific TIPSS-related modifications i.e., extrahepatic portal vein aneurysm formation (n=2), dislocation of the distal end of the stent into the inferior vena cava (n=4) or into the main portal vein trunk (n=1), bilioportal fistula (n=1), and pronounced phlebitis of the inferior vena cava and hepatic veins due to redilation of shunt stenosis (n=4). The intraoperative blood product requirement at transplantation was similar in the 23 TIPSS-patients and in the 36 cirrhotic patients who received transplants without the TIPSS procedure during the same time period [median 800 ml (range 0–20300 ml) vs median 620 ml (range 0–7600 ml), respectively]. There was also no difference between the two groups in length of hospital stay [median 18 days (range 0–34 days) vs median 19 days (range 0–66 days), respectively]. We conclude that TIPSS plays an important role in the management of life-threatening complications of end-stage liver disease arising in potential liver transplant candidates. TIPSS should be considered as a temporary, effective bridge to elective transplantation and not as a means to lower the blood product requirement at transplantation. Specific TIPSS-related modifications should be recognized early by the transplant surgeon in order to adapt the technique of graft implantation.

High serum levels of secretory IgA in liver disease: possible liver origin of the circulating secretory component.

Patients with liver disease frequently display unexplained elevations of serum secretory IgA (sIgA). The sIgA levels in various liver diseases were compared to various biochemical or clinical parameters. Patients with primary biliary cirrhosis, biliary tract obstruction, or acute hepatitis displayed highest sIgA levels. In chronic parenchymal liver disease sIgA levels correlated strongly with serum alkaline phosphatase (r=0.79), leucine aminopeptidase (r=0.83), and direct bilirubin levels (r=0.63), but not with prothrombin time, aminopyrine breath test, or presence of portacaval shunting. In acute hepatitis sIgA correlated best with serum glutamic oxaloacetic transaminase (r=0.69) but not with bilirubin; in four patients with fulminant hepatitis, sIgA fell rapidly together with all liver enzymes and prothrombin time; it rose quickly again in one patient when parenchymal regeneration occurred. These results suggest a hepatobiliary origin of the serum sIgA in liver disease. In acute hepatitis the persistence of hepatocytes seems necessary for maintaining high serum sIgA levels, suggesting a possible hepatocyte origin of the secretory component.