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Biomedical subjects

J F Dhainaut

Publications and source records attributed to J F Dhainaut.

At least 19 recordsLinked to original sources
PubMed1995

CDP571, a humanized antibody to human tumor necrosis factor-alpha: safety, pharmacokinetics, immune response, and influence of the antibody on cytokine concentrations in patients with septic shock. CPD571 Sepsis Study Group.

OBJECTIVES: To determine the safety of a "humanized" antibody to human anti-tumor necrosis factor-alpha (TNF-alpha) in patients with septic shock, and to examine the pharmacokinetics, immune response, and influence of the antibody on cytokine concentrations in this patient group. DESIGN: Prospective, randomized, placebo-controlled, phase II multicenter clinical trial, with escalating doses of a fully humanized anti-TNF-alpha antibody (CDP571). SETTING: Seven academic intensive care units in Europe. PATIENTS: Forty-two patients with rapidly evolving septic shock who received CDP571 in addition to standard supportive care. INTERVENTIONS: Patients received intravenously either placebo or one of four single doses of CDP571: 0.1, 0.3, 1.0, or 3.0 mg/kg. MEASUREMENTS AND MAIN RESULTS: The humanized anti-TNF-alpha antibody was well tolerated. The overall all-cause 28-day mortality rate was 62%. Mortality rate was similar in the placebo and treatment groups, except that all six patients who received 0.3 mg/kg of CDP571 died within 7 days. This outcome, which was not dose-related, is consistent with the poorer prognostic characteristics of this group at baseline. The peak CDP571 concentrations and area under the curve increased proportionately with the dose. The low level of the immune response detected had little effect on the ability of circulating CDP571 to bind TNF-alpha and on the pharmacokinetics of the antibody. An abrupt reduction in circulating TNF-alpha concentration was observed 30 mins after CDP571 administration at all active dosage levels. While interleukin-1 beta and interleukin-6 plasma concentrations decreased with time in all dosage groups, these cytokine concentrations decreased more rapidly during the initial 24 hrs in the treatment groups than in the placebo group. CONCLUSIONS: The humanized anti-TNF-alpha antibody, CDP571, is well tolerated and able to cause a dose-dependent reduction in circulating TNF-alpha concentrations in patients with septic shock. Further studies are needed to determine the efficacy of this antibody to improve the survival rates of critically ill patients with severe sepsis.

APACHE↗
PubMed1995

Effect of inhaled nitric oxide on right ventricular function in adult respiratory distress syndrome.

To determine whether inhaled nitric oxide (NO) affects pulmonary circulation, thereby improving right ventricular (RV) function in adult respiratory distress syndrome (ARDS), we studied 13 patients with both a lung injury severity score of 2.5 or more and a mean pulmonary artery pressure higher than 30 mm Hg. RV function was assessed by a thermodilution technique using a pulmonary artery catheter equipped with a rapid response thermistor before and 15 min after initiation of inhalation of NO (5 ppm). At baseline, stroke volumes were in a normal range (46 +/- 14 ml/m2), with a RV dilation (end-diastolic volume = 142 +/- 36 ml/m2). Inhaled NO was followed by an improvement in arterial oxygenation (PaO2/FIO2 = 103 +/- 47 versus 142 +/- 63, p < 0.05) and a drop in pulmonary artery pressure (36.1 +/- 4.5 versus 31.3 +/- 6.1 mm Hg, p < 0.01); stroke volumes and heart rates did not change. The resulting fall in pulmonary vascular resistance (211 +/- 43 versus 180 +/- 59 dyn-s/cm5, p < 0.05) was associated with an increase in RV, ejection fractions (32 +/- 5 versus 36 +/- 6%, p < 0.05), a trend toward decreased RV end-systolic (96 +/- 25 versus 85 +/- 19 ml/m2, NS) and end-diastolic (142 +/- 36 versus 131 +/- 27 ml/m2, NS) volumes, and a decrease in right atrial pressures (10.9 +/- 2.9 versus 9.6 +/- 3.2 mm Hg, p < 0.05). No relationship was seen between the improvement in arterial oxygenation and the decrease in pulmonary vascular resistance.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗
PubMed1995

Should mechanical ventilation be optimized to blood gases, lung mechanics, or thoracic CT scan?

This study was aimed at providing data for optimization of mechanical ventilation in patients with acute respiratory distress syndrome (ARDS). The effects of ventilation with positive end-expiratory pressure (PEEP) titrated to blood gases were studied by thoracic computed tomographic (CT) scans and lung mechanics measurements in eight patients. CT density histograms at end-expiration were used to investigate the effects of PEEP on three differently aerated zones. Static pressure-volume (P-V) curves were used to determine the deflection point above which baro-volotrauma (a combination of barotrauma and volotrauma) may occur. Peak pressures, plateau pressures, and lung volumes measured by Respitrace were compared with the deflection point. CT scan showed that PEEP increased "normally aerated" areas, decreased "nonaerated" areas, and did not change "poorly aerated" zones. No correlations were found between CT scan and either PaO2 or mechanical data. Pressure at the deflection point was lower than the usually recommended 35 to 40 cm H2O for peak pressure in four patients (range, 28 to 32 cm H2O). With regard to plateau pressures, only one patient was ventilated above the deflection point. However, monitoring of volumes showed that these four patients had an end-inspiratory volume above this point. We conclude that mechanical ventilation may be initially adjusted on the basis of blood gas values and then optimized on the basis of lung mechanics to limit the risk of baro-volotrauma.

Adolescent↗
PubMed1994

Recombinant human interleukin 1 receptor antagonist in the treatment of patients with sepsis syndrome. Results from a randomized, double-blind, placebo-controlled trial. Phase III rhIL-1ra Sepsis Syndrome Study Group.

OBJECTIVE: To further define the safety and efficacy of recombinant human interleukin 1 receptor antagonist (rhIL-1ra) in the treatment of sepsis syndrome. STUDY DESIGN: Randomized, double-blind, placebo-controlled, multicenter, multinational clinical trial. POPULATION: A total of 893 patients with sepsis syndrome received an intravenous loading dose of rhIL-1ra, 100 mg, or placebo followed by a continuous 72-hour intravenous infusion of rhIL-1ra (1.0 or 2.0 mg/kg per hour) or placebo. OUTCOME MEASURE: Twenty-eight-day all-cause mortality. RESULTS: There was not a significant increase in survival time for rhIL-1ra treatment compared with placebo among all patients who received the study medication (n = 893; generalized Wilcoxon statistic, P = .22) or among patients with shock at study entry (n = 713; generalized Wilcoxon statistic, P = .23), the two primary efficacy analyses specified a priori for this trial. Results from secondary analyses suggest an increase in survival time with rhIL-1ra treatment among patients with dysfunction of one or more organs (n = 563; linear dose-response, P = .009). Retrospective analysis demonstrated an increase in survival time with rhIL-1ra treatment among patients with a predicted risk of mortality of 24% or greater (n = 580; linear dose-response, P = .005) as well as among patients with both dysfunction of one or more organs and a predicted risk of mortality of 24% or greater (n = 411; linear dose-response, P = .002). CONCLUSIONS: There was not a statistically significant increase in survival time for rhIL-1ra treatment compared with placebo among all patients who received the study medication or among patients with shock at study entry. Secondary and retrospective analyses of efficacy suggest that treatment with rhIL-1ra results in a dose-related increase in survival time among patients with sepsis who have organ dysfunction and/or a predicted risk of mortality of 24% or greater.

Adult↗
PubMed1994

Accuracy assessment for three fiberoptic pulmonary artery catheters for SvO2 monitoring.

OBJECTIVE: To compare values of SvO2 obtained by reflectance spectrophotometry continuous monitoring with those obtained from blood samples measurements by transmission spectrophotometry (Co-Oximetry). DESIGN: Values of SvO2 recorded by three pulmonary artery catheters for continuous monitoring, SAT1, SAT2 and Oximetrix3 (OX3), were compared in a prospective manner to those measured on blood samples by a Co-Oximeter, using the statistical analysis of Bland and Altman. SETTING: Adult intensive care unit in an University Hospital. PATIENTS: 37 patients admitted for acute respiratory failure and/or shock who required hemodynamic monitoring. MAIN RESULTS: The bias (average under- or overestimation) was small for all comparative measurements: +1.3, -0.2 and +1.0 sat% for SAT1, SAT2 and OX3, respectively. However, limits of agreement were only acceptable for SAT2 (-8.3 to +7.9 sat%) and OX3 (-6.7 to +8.6 sat%), but not for SAT1 (-23.3 to +25.9 sat%). No significant drift during 24 h was found with the three catheters. However, in vitro calibration was only found acceptable for SAT2 and OX3. The results were not influenced by the numbers of wavelengths of the device (2 for SAT1 and SAT2, and 3 for OX3) nor did they correlate with any of the hemodynamic and biochemical variables tested. CONCLUSION: For usual monitoring in the ICU, SAT2 and OX3, gave SvO2 values which are in acceptable agreement with SvO2 measured on blood samples by Co-Oximetry.

Aged↗
PubMed1994

Value of elementary, combined, and modeled hemodynamic variables.

PURPOSE: It has been well recognized that the usefulness of the clinical examination and simple hemodynamic variables in the critically ill is limited. Modelization for hemodynamic analysis may improve the diagnostic performance by a systematic and multivariate analysis. This requires a rigorous formalization that may otherwise expand the usefulness of hemodynamic data, both as predictors and as therapeutic targets. Our study was designed to test the value of a model for assessing the pathophysiology of circulatory disorders and for establishing the diagnosis. METHODS: We tested all available variables using survival as the end point. A population of 223 patients (652 measurements) with compromised circulatory status was studied. We evaluated traditional variables: (1) morphological and physical data, (2) elementary right heart catheterization data, and (3) usually calculated variables, versus (4) new modeled variables. These new modeled variables were derived from a previously validated computer program for hemodynamic evaluation. They expressed differences between observed hemodynamic performance and estimated needs. RESULTS: Among traditional variables, major prognostic factors were: (1) in all patients, lactate level elevation, physical signs of hypoperfusion, and a decreased systemic arterial pressure; (2) in septic patients, a high PaO2/SaO2 ratio; (3) in nonseptic patients, low left ventricle work indices. In all cases, modeled hemodynamic variables assessing performance-needs adequacy enhanced the prognostic value of hemodynamic monitoring. CONCLUSIONS: Compared with traditional variables, modeled variables were found of greater interest to quantify pathophysiology of shock. These results enabled us to validate the initial step of the hemodynamic reasonning formalization and to develop "new" diagnostic criteria that more closely fit the interrelationship between pathophysiology, diagnosis, and prognosis.

Algorithms↗
PubMed1994

Extracorporeal carbon dioxide removal technique improves oxygenation without causing overinflation.

Extracorporeal CO2 removal combined with low frequency positive pressure ventilation (ECCO2R-LFPPV) improves gas exchange and decreases peak pressures, respiratory rates, and tidal volumes in animals and in humans. Recent evidence suggests that pulmonary barotrauma results from lung overinflation rather than from high pressures. This study was to test the hypothesis whether ECCO2R-LFPPV could improve gas exchange without causing lung overinflation, despite the use of higher levels of PEEP, when compared with conventional mechanical ventilation. Eleven patients with severe adult respiratory distress syndrome (ARDS) who failed to respond to different modes of mechanical ventilation were treated with ECCO2R-LFPPV. Risk of pulmonary barotrauma was evaluated by static pressure-volume (P-V) curves and dynamic changes in volumes monitored by respiratory inductive plethysmography (Respitrace). ECCO2R-LFPPV PaO2/FIO2 increased from 79 +/- 21 to 207 +/- 108 (p = 0.003). Risk of barotrauma, as shown by the shape of the P-V curve, was present in all patients receiving mechanical ventilation even though most of them were treated with permissive hypoventilation. By contrast, no evidence of persistent lung overinflation could be detected by either static P-V curves or dynamic measurements in nine of 11 patients who were treated by ECCO2R-LFPPV. The two remaining patients had severe airway obstruction because of bleeding, and they remained ventilated with persistent risk of barotrauma. We conclude that ECCO2R-LFPPV improves gas exchange without causing lung overinflation in a majority of patients with ARDS.

Adolescent↗
PubMed1994

Lack of oxygen supply dependency in patients with severe sepsis. A study of oxygen delivery increased by military antishock trouser and dobutamine.

BACKGROUND: During severe sepsis, the existence of a pathologic oxygen supply dependency remains controversial. STUDY OBJECTIVE: To evaluate the relationship between oxygen delivery (DO2) and oxygen consumption (VO2) during severe sepsis and to compare, in this respect, survivors and nonsurvivors and patients with normal or increased concentration of plasma lactate. STUDY DESIGN: Cohort analytic study. SETTING: Three European ICUs in university hospitals. PATIENTS: Seventeen mechanically ventilated patients with severe sepsis (six with high blood lactate levels) studied within the first day of diagnosis. INTERVENTIONS AND MEASUREMENTS: Pulmonary elimination of carbon dioxide, or carbon dioxide production (VCO2) and VO2 were measured by indirect calorimetry before and after two interventions designed to increase DO2 (calculated from the Fick equation): inflation of a military antishock trouser (MAST) and infusion of dobutamine. RESULTS: During MAST inflation, DO2 increased by 19% in patients with a normal concentration of plasma lactate (p < 0.01), but remained unchanged in patients with high lactate levels. During dobutamine infusion, DO2 increased in both groups by 16% (p < 0.01) and 20% (p < 0.05), respectively. In both groups, we found that the VO2 and VCO2 were not affected by either the MAST or the dobutamine-induced increase in DO2. There was no difference between survivors and nonsurvivors. CONCLUSION: There was no evidence of a pathologic oxygen supply dependency in patients with severe sepsis, even in those who had an elevated concentration of plasma lactate and in those who ultimately died. These results do not favor the conclusion that maximizing DO2 is a primary therapeutic objective in such patients.

Acute Disease↗
PubMed1994

Platelet-activating factor receptor antagonist BN 52021 in the treatment of severe sepsis: a randomized, double-blind, placebo-controlled, multicenter clinical trial. BN 52021 Sepsis Study Group.

OBJECTIVE: To evaluate the safety and efficacy of a natural platelet-activating factor receptor antagonist, BN 52021 (Ginkgolide B), in the treatment of patients with sepsis syndrome. DESIGN: Prospective, randomized, placebo-controlled, double-blind, phase III, multicenter clinical trial. SETTING: Twenty-one academic medical center intensive care units in France. PATIENTS: Two hundred sixty-two patients with sepsis syndrome who received standard supportive care and antimicrobial therapy, in addition to the administration of platelet-activating factor receptor antagonist or placebo. INTERVENTIONS: Patients received either a 120-mg dose of platelet-activating factor receptor antagonist intravenously every 12 hrs over a 4-day period or placebo. MAIN OUTCOME MEASUREMENTS: All patients were evaluated for 28-day, all-cause mortality. RESULTS: The 28-day mortality rate was 51% for the placebo group and 42% for the platelet-activating factor receptor antagonist group (p = .17). However, the efficacy of platelet-activating factor receptor antagonist was significantly greater in patients with Gram-negative sepsis (test for interaction, p = .03). In a separate analysis of patients with and without Gram-negative sepsis, the 28-day mortality rate was 57% for the patients receiving placebo (30 deaths of 53 patients) and 33% for patients receiving platelet-activating factor receptor antagonist (22 deaths of 67 patients; p = .01). Platelet-activating factor receptor antagonist also significantly (p = .01) reduced the mortality rate among patients with Gram-negative sepsis who were in shock at entry into the study (mortality rate was 65% for placebo vs. 37% for platelet-activating factor receptor antagonist) and among patients > 60 yrs of age (mortality rate was 74% for placebo vs. 31% for platelet-activating factor receptor antagonist). A Cox proportional-hazards model identified five independent prognostic factors: a) adequacy of antibiotic therapy; b) severity of illness; c) renal failure; d) hematologic failure; and e) hepatic failure at study entry. When the Gram-negative sepsis population was stratified by age and these five prognostic factors were controlled for, the relative risk of death of the platelet-activating factor receptor antagonist group was 0.61 (0.34 to 1.08, 95% confidence interval; p = .09). This risk corresponds with an adjusted reduction in mortality rate of 39% for patients receiving platelet-activating factor receptor antagonist. No differences in mortality rates were found between the placebo and the platelet-activating factor receptor antagonist groups in the absence of Gram-negative sepsis. There were no differences in adverse events between the placebo and the treated groups. CONCLUSION: The studied platelet-activating factor receptor antagonist (BN 52021) seems to be a safe and promising treatment for patients with severe Gram-negative sepsis.

APACHE↗