Jean François Dhainaut

Symptoms of anxiety and depression in family members of intensive care unit patients: Ethical hypothesis regarding decision-making capacity

ObjectiveAnxiety and depression may have a major impact on a person’s ability to make decisions. Characterization of symptoms that reflect anxiety and depression in family members visiting intensive care patients should be of major relevance to the ethics of involving family members in decision-making, particularly about end-of-life issues. DesignProspective multicenter study. SettingForty-three French intensive care units (37 adult and six pediatric); each unit included 15 patients admitted for longer than 2 days. PatientsSix hundred thirty-seven patients and 920 family members. InterventionsIntensive care unit characteristics and data on the patient and family members were collected. Family members completed the Hospital Anxiety and Depression Scale to allow evaluation of the prevalence and potential factors associated with symptoms of anxiety and depression. Measurements and Main ResultsOf 920 Hospital Anxiety and Depression Scale questionnaires that were completed by family members, all items were completed in 836 questionnaires, which formed the basis for this study. The prevalence of symptoms of anxiety and depression in family members was 69.1% and 35.4%, respectively. Symptoms of anxiety or depression were present in 72.7% of family members and 84% of spouses. Factors associated with symptoms of anxiety in a multivariate model included patient-related factors (absence of chronic disease), family-related factors (spouse, female gender, desire for professional psychological help, help being received by general practitioner), and caregiver-related factors (absence of regular physician and nurse meetings, absence of a room used only for meetings with family members). The multivariate model also identified three groups of factors associated with symptoms of depression: patient-related (age), family-related (spouse, female gender, not of French descent), and caregiver-related (no waiting room, perceived contradictions in the information provided by caregivers). ConclusionsMore than two-thirds of family members visiting patients in the intensive care unit suffer from symptoms of anxiety or depression. Involvement of anxious or depressed family members in end-of-life decisions should be carefully discussed.

Compliance with triage to intensive care recommendations.

Design Recommendations for triage to intensive care units (ICUs) have been issued but not evaluated. Setting In this prospective, multicenter study, all patients granted or refused admission to 26 ICUs affiliated with the French Society for Critical Care were included during a 1-month period. Characteristics of participating ICUs and patients, circumstances of triage, and description of the triage decision with particular attention to compliance with published recommendations were recorded. Results During the study period, 1,009 patients were and 283 were not admitted to the participating ICUs. Refused patients were more likely to be older than 65 yrs (odds ratio [OR], 3.53; confidence interval [CI], 1.98–5.32) and to have a poor chronic health status (OR, 3.09; CI, 2.05–4.67). An admission diagnosis of acute respiratory or renal failure, shock, or coma was associated with admission, whereas chronic severe respiratory and heart failure or metastatic disease without hope of remission were associated with refusal (OR, 2.24; CI, 1.38–3.64). Only four (range, 0–8) of the 20 recommendations for triage to ICU were observed; a full unit and triage over the phone were associated with significantly poorer compliance with recommendations (0 [0–2] vs. 6 [2–9], p = .0003; and 1 [0–6] vs. 6 [1–9], p < .0001; respectively). Conclusion Recommendations for triage to intensive care are rarely observed, particularly when the unit is full or triage is done over the phone. These recommendations may need to be redesigned to improve their practicability under real-life conditions, with special attention to phone triage and triaging to a full unit.

The clinical evaluation committee in a large multicenter phase 3 trial of drotrecogin alfa (activated) in patients with severe sepsis (PROWESS): role, methodology, and results.

ObjectiveIn the multinational PROWESS trial, drotrecogin alfa (activated) significantly reduced mortality rate in patients with severe sepsis compared with placebo. The use of large multiple-center trials can potentially complicate interpretation of results in severe sepsis populations because of variability in medical attitudes and practices and the frequency of confounding events such as protocol violations. The objective of this study was to perform a blinded, critical, integrated review of data from the 1,690 severe sepsis patients from 164 medical centers enrolled in the PROWESS trial using a Clinical Evaluation Committee. DesignBlinded, critical, integrated review of data. SettingParticipating sites. PatientsThe 1,690 severe sepsis patients from 164 medical centers enrolled in the PROWESS trial. InterventionsWe performed analyses of the optimal cohort, defined as patients who had full compliance with the protocol, had evidence of an infection, and received adequate anti-infective therapy. We also performed other analyses, including significant underlying disorders, life support measures, and causes of death. Measurements and Main ResultsThe optimal cohort of 81.4% of the intention-to-treat population [drotrecogin alfa (activated), n = 695; placebo, n = 680] had similar baseline severity of illness between the two groups, a similar pharmacodynamic effect, and a relative risk of death estimate consistent with that observed in the overall PROWESS trial (0.83, 95% confidence interval 0.69–0.99 vs. 0.806, 95% confidence interval 0.69–0.94). A beneficial effect of drotrecogin alfa (activated) similarly was observed in patients with significant underlying disorders (0.73, 95% confidence interval 0.57–0.93) who were more severely ill and had a higher percentage of patients forgoing life-sustaining therapy. In contrast with the original investigator determinations, a benefit associated with drotrecogin alfa (activated) treatment in urinary tract infection adjudicated by the Clinical Evaluation Committee was observed. ConclusionsThe survival benefit associated with drotrecogin alfa (activated) use was consistent with the results of the overall trial regardless of whether patients met criteria of the optimal cohort or had a significant underlying disorder.

Recombinant tissue factor pathway inhibitor in severe community-acquired pneumonia: a randomized trial.

RATIONALE Severe community-acquired pneumonia (sCAP) is a leading cause of death worldwide. Adjunctive therapies for sCAP are needed to further improve outcome. A systemic inhibitor of coagulation, tifacogin (recombinant human tissue factor pathway inhibitor) seemed to provide mortality benefit in the sCAP subgroup of a previous sepsis trial. OBJECTIVES Evaluate the impact of adjunctive tifacogin on mortality in patients with sCAP. METHODS A multicenter, randomized, placebo-controlled, double-blind, three-arm study was conducted from July 2005 to June 2008 at 188 centers in North and South America, Europe, South Africa, Asia, Australia, and New Zealand. Adults with sCAP were randomized to receive a continuous intravenous infusion of tifacogin 0.025 mg/kg/h, tifacogin 0.075 mg/kg/h, or matching placebo over 96 hours. MEASUREMENTS AND MAIN RESULTS Severity-adjusted 28-day all-cause mortality. Of 2,138 randomized patients, 946, 238, and 918 received tifacogin 0.025 mg/kg/h, tifacogin 0.075 mg/kg/h, and placebo, respectively. Tifacogin 0.075 mg/kg/h was discontinued after the first interim analysis according to prespecified futility criterion. The 28-day all-cause mortality rates were similar between the 0.025 mg/kg/h (18%) and placebo groups (17.9%) (P = 0.56). Greater reduction in prothrombin fragment 1+2 and thrombin antithrombin complexes levels relative to baseline throughout the first 96 hours was found with tifacogin 0.025 mg/kg/h than with placebo. The incidence of adverse events and serious adverse events were comparable between the tifacogin 0.025 mg/kg/h and placebo groups. CONCLUSIONS Tifacogin showed no mortality benefit in patients with sCAP despite evidence of biologic activity.

Outcome of patients with systemic rheumatic disease admitted to medical intensive care units.

The outcome of patients admitted to intensive care units is known to be influenced by such factors as age, previous health status, severity of disease, and diagnosis. To estimate the outcome of such patients with systemic rheumatic diseases and to determine if the severity of these diseases unfavourably influences the prognosis at the time of admission to a medical intensive care unit, the clinical courses of all patients with systemic rheumatic disease admitted to two medical intensive care units between January 1978 and December 1988 were studied retrospectively. Sixty nine patients with systemic lupus erythematosus (n = 16), necrotising vasculitis (n = 19), rheumatoid arthritis (n = 19), and other systemic rheumatic diseases (n = 15) were included. The mean (SD) age on admission into the medical intensive care unit was 53 (17) years and the mean simplified acute physiological score was 12 (5.5). The principal diagnoses on admission were infectious complications (29/69 patients) and acute exacerbation of the systemic rheumatic disease (19/69 patients). The death rate in the medical intensive care unit was 33% (23/69 patients) and was similar to that of a non-selected population with comparable simplified acute physiological score. The death rate in hospital was 42% (29/69 patients). Infection was the main cause of death in the medical intensive care unit (19/23 patients) and the infection was mainly acquired in the unit. Only the simplified acute physiological score on admission was a statistically significant prognostic factor: the simplified acute physiological score in patients who died was 15 (5.2) v 9.9 (4.7) for survivors. Long term outcome analysis showed that 83% (33/40 patients) of patients were still alive after admission to the medical intensive care unit with a follow up time between two months and nine years (mean 38 months). The death rate was relatively high and was mainly due to nosocomial infections. It was not different, however, from that of nonselected patients and the long term prognosis was highly favourable. This shows that the complications are often reversible, particularly infectious applications, and justifies admission to the medical intensive care unit of this group of patients.

Left ventricular contractility using isovolumic phase indices during PEEP in ARDS patients.

The effects of incremental increases in PEEP during mechanical ventilation on left ventricular (LV) contractility before and after intravascular volume expansion (IVE) were studied in 10 patients treated for ARDS. A pulmonary artery (PA) catheter, a LV catheter-tip mi-cromanometer, and an esophageal balloon catheter were inserted in these patients. We measured transmura) right atria) and PA pressures, transmural LV end-diastolic and systemic arterial pressures, the first derivative of LV pressure (LV dP/dt), the ratio of LV dP/dt at transmural developed LV pressure (dP/dt/DPt) with DPt = 5, 10, 40 mm Hg, cardiac index (CI) at every level of PEEP and after IVE at the highest PEEP. Stepwise increases in PEEP (from 0–20 cm H2O) were associated with progressive fall in CI whereas heart rate remained unchanged. Transmural right atrial and PA pressures did not change; transmural LV end-diastolic and systemic arterial pressures and peak dP/dt decreased significantly with PEEP, except for dP/dt/dPt. IVE reversed this fall in CI and peak dP/dt. Whereas transmural LV enddiastolic pressure rose markedly.We conclude that the observed fall in LV performance during PEEP is not the result of a depressed LV contractility because PEEP does not induce a decrease in dP/dt/DPt, the least sensitive to change in preload isovolumic phase indices of contractility.

Introduction to the Fourth Margaux Conference on Critical Illness: Acute lung injury - Understanding the mechanisms of injury and repair

Acute lung injury (ALI) and its most severe form, adult respiratory distress syndrome (ARDS), represent a significant healthcare burden. They result from an inflammatory process initiated by any of a number of potential systemic and/or pulmonary insults that result in heterogeneous disruption of the capillary– endothelial interface. The increased permeability of this barrier, which causes leakage of protein-rich fluid from the capillaries into the lungs, and the increased risk of ventilatory-acquired pneumonia both favor the movement of microorganisms from the lungs into the circulation, which may lead to the initiation of a systemic inflammatory response, sepsis, and death. Studies in experimental models indicate that neutrophils accumulate in the lungs in the early stages of ALI and increase the amounts of proinflammatory cytokines in the lungs. In addition, apoptosis of neutrophils is impaired in ALI, exacerbating the inflammatory processes. Inflammation in the alveoli is further promoted by the extrinsic procoagulant tissue factor–factor VIIa complex, which leads to fibrin deposition and reduced fibrinolytic activity caused by the inhibition of urokinase plasminogen activator and downstream inhibition of locally produced plasmin. Build up of liquid in the alveoli and pulmonary fibrosis lead to impaired gas exchange and alveolar collapse. Unless the alveoli are successfully recruited, pulmonary dysfunction can lead to additional organ dysfunction and, ultimately, death. This publication begins with a series of articles by Martin, Downey, Abraham, Pugin, and Moss, who discuss the role of neutrophils in ALI. Idell, Aird, Ruf, Levi, and Russell go on to describe the procoagulant and proinflammatory environment of the lung, including the pathways surrounding fibrin deposition, the heterogeneity of endothelial cells and their role in signaling of coagulation proteases, coagulation and fibrinolysis in the lung during endotoxemia and pneumonia, and finally, the genetic factors surrounding predisposition to intravascular and intraalveolar coagulation. The next series of articles, by Sznajder, Thompson, Dhainaut, Barbas, and Villar, focus on the resolution of ALI. Solutions discussed include the use of mechanical ventilation to resolve alveolar edema, treatment with glucocorticoids to modulate the immune response, transforming growth factortherapy to mediate cell regulation, optimal recruitment maneuvers, and the role of genomics in improved selection of therapies for individual patients. Following on, Rubenfeld, Rouby, Vincent, Gattinoni, and Angus report on the epidemiology of ALI and acute respiratory failure, the use of computed tomography in assessing lung aeration, the rationale for ventilator settings in ALI/ARDS, and suggested improvements for trial design in ALI. The publication concludes with articles by Brower, Derdak, Lewis, Laterre, and Falke, who look to the future of treatments for ALI/ARDS including the following: lung protective ventilation strategies to avoid the onset of ventilator-associated lung injury; high-frequency oscillatory ventilation in ARDS patients; the role of exogenous surfactant in ALI; anticoagulant therapy; and selective pulmonary vasodilation in ARDS. We hope that this supplement provides a comprehensive overview of ALI, from pathophysiology and epidemiology to developments in care and future treatment strategies. We thank Eli Lilly and Company for its gracious support of this meeting and all participants for their valuable contributions. Jean-François Dhainaut, MD, PhD Roy G. Brower, MD James A. Russell, MD Presented, in part, at the Margaux Conference on Critical Illness, Cabo da Roca in Sintra, Portugal, November 13–17, 2002. Copyright