Can C-reactive protein, procalcitonin and mid-regional pro-atrial natriuretic peptide measurements guide choice of in-patient or out-patient care in acute pyelonephritis? Biomarkers In Sepsis (BIS) multicentre study.

Whereas C-reactive protein (CRP), procalcitonin (PCT) and mid-regional pro-atrial natriuretic peptide (ANP) may be of use at the bedside in the management of adult patients with infectious disorders, their usefulness has not been established in the setting of acute pyelonephritis. To assess the effectiveness of CRP, PCT and ANP measurements in guiding emergency physicians' decisions whether to admit to hospital patients with acute pyelonephritis, we conducted a multicentre, prospective, observational study in 12 emergency departments in France; 582 consecutive patients were included. The reference standard for admission was defined by experts' advice combined with necessity of admission or death during the 28-day follow-up. Baseline CRP, PCT and ANP were measured and their accuracy in identifying the necessity of admission was analysed using area under curves (AUC) of receiver-operating characteristic (ROC) plots. According to the reference standard, 126 (22%) patients required admission. ANP (AUC 0.75, 95% CI 0.69-0.80) and PCT (AUC 0.75, 95% CI 0.71-0.80) more accurately predicted this than did CRP (AUC 0.69, 95% CI 0.64-0.74). The positive and negative likelihood ratios for each biomarker remained clinically irrelevant whatever the threshold. Our results did not support the use of these markers to help physicians in deciding about admission of patients experiencing acute pyelonephritis in daily practice.

Treatment effects of drotrecogin alfa (activated) in patients with severe sepsis with or without overt disseminated intravascular coagulation.

Disseminated intravascular coagulation (DIC) is a serious condition associated with sepsis. Clinical management of DIC is hampered by lack of clear diagnostic criteria. The International Society on Thrombosis and Haemostasis (ISTH) has proposed a diagnostic scoring algorithm for overt DIC based on routine laboratory tests. The objective was to assess a modified version of the ISTH scoring system and determine the effect of drotrecogin alfa (activated) (DrotAA, recombinant human activated protein C) on patients with DIC. The large database from the PROWESS clinical trial in severe sepsis was retrospectively used to assess a modified ISTH scoring system. Baseline characteristics and treatment effects of DrotAA were evaluated. At baseline, 29% (454/1568) of patients had overt DIC. Overt DIC was a strong predictor of mortality, independent of APACHE II score and age. Placebo-treated patients with overt DIC had higher mortality than patients without (43 vs. 27%). DrotAA-treated patients with overt DIC had a trend towards greater relative risk reduction in mortality than patients without (29 vs. 18%, P = 0.261) but both groups had greater relative risk reduction than placebo-treated patients. Serious bleeding rates during DrotAA infusion in patients with and without overt DIC were slightly increased (P = 0.498), compared with placebo, while clinically overt thrombotic events during the 28-day period were slightly reduced (P = 0.144). Modified ISTH overt DIC scoring may be useful as an independent assessment for identifying severe sepsis patients at high risk of death with a favorable risk/benefit profile for DrotAA treatment. Patients without overt DIC also received significant treatment benefit.

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.

A multi-centre, double-blind, placebo-controlled study of liposomal prostaglandin E1 (TLC C-53) in patients with acute respiratory distress syndrome.

OBJECTIVE: To evaluate the safety of liposomal PGE1 (TLC C-53) in patients with acute respiratory distress syndrome (ARDS), and determine its efficacy in improving oxygenation and reducing ventilator dependency. DESIGN: A multi-centre, randomized, double-blind, placebo-controlled clinical study. SETTING: Thirty-one hospitals in six European countries. PATIENTS: One hundred two patients with ARDS. INTERVENTIONS: Patients were randomized in a 2:1 ratio to receive infusions of either the study drug TLC C-53 or placebo. Infusions were given over 60 min every 6 h for 7 days. The dose of study drug started at 0.6 microg/kg per h, rising over 24 h to a maximum dose of 1.8 microg/kg per h. MEASUREMENTS AND MAIN RESULTS: Seventy patients received the study drug and 32 placebo. Sixty-nine patients (47 treatment, 22 placebo) completed the study protocol. Patients were monitored for changes in the PaO2/FIO2 ratio, changes in lung compliance, time to off-ventilator and 28-day mortality, in addition to basic haematological and haemodynamic parameters. There were no significant differences in demographics and baseline characteristics between the two groups. There were no differences in the time to off-ventilation (16 days with treatment, 16.6 days with placebo, p=0.94) or in 28-day mortality (30% with treatment, 28% with placebo, p=0.78). There was a difference in the time to achieve a PaO2/FIO2 ratio above 300 in favour of TLC C-53 (10.3 versus 26.5 days) but this was not statistically significant (p=0.23). CONCLUSIONS: TLC C-53 was generally well-tolerated but failed to reduce mortality or duration of mechanical ventilation.

French intensivists do not apply American recommendations regarding decisions to forgo life-sustaining therapy.

OBJECTIVE: Recommendations for making and implementing decisions to forgo life-sustaining therapy in intensive care units have been developed in the United States, but the extent that they are realized in practice has yet to be measured. DESIGN: Prospective, multicenter, 4-wk study. For each patient with an implemented decision to forgo life-sustaining therapy, the deliberation and decision implementation procedures were recorded. SETTING: French intensive care units. PATIENTS: All consecutive patients admitted to 26 French intensive care units. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 1,009 patients admitted, 208 died in the intensive care unit. A decision to forgo life-sustaining therapy was implemented in 105 patients. The number of supportive treatments forgone was 2.3 +/- 1.7 per patient. Decisions to forgo sustaining therapy were preceded by 3.5 +/- 2.5 deliberation sessions. Proxies were informed of the deliberations in 62 (59.1%) cases but participated in only 18 (17.1%) decisions. The patient's perception of his or her quality of life was rarely evaluated (11.5%), and only rarely did the decision involve evaluating the patient's wishes (7.6%), the patient's religious values (7.6%), or the cost of treatment (7.6%). Factors most frequently evaluated were medical team advice (95.3%), predicted reversibility of acute disease (90.5%), underlying disease severity (83.9%), and the patient's quality of life as evaluated by caregivers (80.1%). CONCLUSIONS: A decision to withhold or withdraw life-sustaining therapy was implemented for half the patients who died in the French intensive care units studied. In many cases, the decision was taken without regard for one or more factors identified as relevant in U.S. guidelines.

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

OBJECTIVE: Anxiety 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. DESIGN: Prospective multicenter study. SETTING: Forty-three French intensive care units (37 adult and six pediatric); each unit included 15 patients admitted for longer than 2 days. PATIENTS: Six hundred thirty-seven patients and 920 family members. INTERVENTIONS: Intensive 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 RESULTS: Of 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). CONCLUSIONS: More 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.

Mitochondrial membrane potential and apoptosis peripheral blood monocytes in severe human sepsis.

UNLABELLED: Reduced mitochondrial membrane potential (Delta(Psi)m), which is considered as an initial and irreversible step towards apoptosis, as well as cell death regulating proteins, such as Fas, Hsp70, or Bcl-2, may play an important role in sepsis. We studied the relationship between sepsis severity and peripheral blood monocyte Delta(Psi)m, cell death (necrosis and apoptosis), soluble Fas ligand, Hsp70, and Bcl-2 expression over time in 18 patients with sepsis, and compared these data with those of a group of 17 healthy control subjects. All measurements were performed within 3 d of the onset of severe sepsis (T1), then 7 to 10 d later (T2), and finally at hospital discharge (T3). Delta(Psi)m was expressed as the percent monocytes with altered Delta(Psi)m (%Delta(Psi)m). Patients with sepsis had greater %Delta(Psi)m at T1 and T2 but not at T3 (14.6 +/- 2.6% and 15.9 +/- 2%, respectively, versus control 6.6 +/- 0.2%, p < 0.01). Septic patients exhibited greater cell death in their monocytes and had greater Hsp70 expression only at T1. Bcl-2 levels were similar in septic and control subjects. Comparing survivors with non-survivors of sepsis, nonsurvivors had a greater %Delta(Psi)m at T1 (26.4 +/- 5.3% versus 10.1 +/- 2.7%, p < 0.01) and a significant decrease in Bcl-2 expression, whereas no difference was found in Hsp70 levels. These results indicate that mitochondrial dysfunction and subsequent cell death occur in severe sepsis and suggest that %Delta(Psi)m is a marker of severity in human sepsis. KEYWORDS: mitochondria; apoptosis; sepsis; heat-shock protein 70; proto-oncogene protein c-Bcl-2

Hepatic response to sepsis: interaction between coagulation and inflammatory processes.

OBJECTIVES: a) To review the hepatic response to sepsis and to establish how this response contributes to coagulation and inflammatory processes; b) to review the physiologic and biochemical mechanisms that suggest hepatic dysfunction may occur during sepsis, enhance procoagulant and proinflammatory activities, and participate in the potential evolution to multiple organ dysfunction syndrome. DATA SOURCES: A summary of published medical literature from MEDLINE search files and published reviews on liver function in experimental and human sepsis. DATA SUMMARY: In sepsis, the liver plays a major role in host defense mechanisms. Kupffer cells are responsible for bacterial scavenging, bacterial products inactivation, and inflammatory mediators clearance and production. Hepatocytes, via receptors for many proinflammatory cytokines, modify their metabolic pathway toward gluconeogenesis, amino-acid uptake, and increased synthesis of coagulant and complement factors and protease inhibitors. The acute-phase protein (APP) response also contributes to the procoagulant state, especially by enhancing the inhibition of protein C (alpha1-antitrypsin and alpha2-macroglobulin) and by decreasing liver synthesis of protein C and antithrombin (negative APPs). Elevated C-reactive protein levels (positive APPs) promote the expression of tissue factor by mononuclear cells. Increased liver production of thrombin-activatable fibrinolytic inhibitor (positive APPs) enhances fibrinolysis inhibition. Conversely, such hepatic inflammatory and coagulation processes in sepsis may alter the function of this organ. Indeed, the liver can be injured by activated Kupffer cells that release chemokines, attract blood neutrophils into the liver, and activate them. Neutrophils up-regulate their surface adhesion molecules, tissue factor, and Kupffer cells, whereas tissue factor pathway inhibitor and thrombomodulin are almost undetectable in endothelial cells. This may lead to microcirculatory disturbances, fibrin deposition, hepatocyte injury, endotoxin and bacteria spillover, and multiple organ failure. CONCLUSIONS: In sepsis, the liver participates in host defense and tissue repair through hepatic cell cross-talk that controls most of the coagulation and inflammatory processes. When this control is not adequate, a secondary hepatic dysfunction may occur and may sometimes lead to bacterial products spillover, enhanced procoagulant and inflammatory processes, and in turn, multiple organ failure and death.

Activated protein C versus protein C in severe sepsis.

OBJECTIVE: To delineate critical differences between activated protein C (APC) and its precursor, protein C, with regard to plasma levels in health and in severe sepsis, and to discuss the implications of these differences as they relate to treatment strategies in patients with severe sepsis. DATA SOURCE/STUDY SELECTION: Published literature including abstracts, manuscripts, and review articles reporting studies in both experimental animal models and humans that provide an understanding of the relationship and the critical differences between circulating levels of APC and protein C. DATA EXTRACTION AND SYNTHESIS: The protein C pathway represents one of the major regulatory systems of hemostasis, exhibiting antithrombotic, profibrinolytic and anti-inflammatory properties. This pathway also plays a critical role in the pathophysiology of severe sepsis. Central to this pathway is the vitamin K-dependent serine protease, APC, and its precursor, protein C. The conversion of protein C to APC is dependent on the complex of thrombin and thrombomodulin, an integral endothelial surface receptor. The conversion of protein C to APC is further augmented by another endothelial surface protein, the endothelial protein C receptor. There are limited published data on APC levels in health and disease, probably due to the complexity of the assay methodology for measuring APC and the absence of commercially available diagnostic kits. In animals and humans with normal functioning endothelium, circulating levels of APC (1-3 ng/mL) are positively correlated with protein C (4000-5000 ng/mL) concentration and the amount of thrombin generated. In patients with severe sepsis, there is a generalized endothelial dysfunction, contributing to multiple organ failure with increased morbidity and mortality. Persistently low protein C levels are related to poor prognosis. Key to understanding the treatment strategy with APC or protein C is knowledge of the functional status of the endothelium and, specifically, whether the microvasculature in patients with severe sepsis can support the conversion of protein C to APC. To date, only APC (drotrecogin alfa [activated]) has been shown to reduce mortality in severe sepsis in a large, phase 3, placebo-controlled, double-blind international trial. In contrast, no data, other than open-label case studies, are available for evaluation of the effects of protein C in the treatment of severe sepsis. CONCLUSION: The limited data available indicate that lower levels of protein C in sepsis occur in the absence of appreciable conversion to APC. These observations indicate that treatment with APC may be more efficacious than protein C in severe sepsis, where generalized endothelial dysfunction may impair conversion of protein C to APC. Additional research is required to confirm these observations.

Exhaled and nasal nitric oxide as a marker of pneumonia in ventilated patients.

Because inflammation stimulates the expression of inducible nitric oxide (NO) synthase (iNOS) with an associated increased local NO production, we hypothesized that patients with pneumonia would have increased excretion of NO into their airways. To test this hypothesis, NO was measured in the exhaled air and from the nasal cavities of 49 consecutively intubated and mechanically ventilated patients in our ICU. After excluding NO gas contamination in the inspiratory circuit, nasal NO and end-expiratory and mean exhaled tracheal NO levels and plasma nitrate concentrations were measured using a fast response chemiluminescence analyzer. Twenty-one patients (43%) presented with infectious pneumonia. End- expiratory exhaled NO concentrations were significantly higher in patients with pneumonia as compared with patients without pneumonia (5.9 +/- 1 ppb versus 3.2 +/- 0.5 ppb, p < 0.01). Similarly, mean nasal NO was higher in patients with pneumonia (1039 +/- 138 ppb versus 367 +/- 58 ppb, p = 0.003). Plasma nitrate levels did not differ between patient groups. Threshold values of tracheal or nasal NO were defined and subsequently validated in 60 other patients. Positive and negative values of a maximal tracheal level > 5 ppb for pneumonia were 74% and 89%, respectively. Thus tracheal and nasal NO levels may be of help in distinguishing patients with acute pneumonia from other causes. Furthermore, because these differences in airway NO levels were not paralleled in blood nitrite concentrations, we conclude that pneumonia per se is not associated with systemic NO production.

Efficacy and safety of recombinant human activated protein C for severe sepsis.

BACKGROUND: Drotrecogin alfa (activated), or recombinant human activated protein C, has antithrombotic, antiinflammatory, and profibrinolytic properties. In a previous study, drotrecogin alfa activated produced dose-dependent reductions in the levels of markers of coagulation and inflammation in patients with severe sepsis. In this phase 3 trial, we assessed whether treatment with drotrecogin alfa activated reduced the rate of death from any cause among patients with severe sepsis. METHODS: We conducted a randomized, double-blind, placebo-controlled, multicenter trial. Patients with systemic inflammation and organ failure due to acute infection were enrolled and assigned to receive an intravenous infusion of either placebo or drotrecogin alfa activated (24 microg per kilogram of body weight per hour) for a total duration of 96 hours. The prospectively defined primary end point was death from any cause and was assessed 28 days after the start of the infusion. Patients were monitored for adverse events; changes in vital signs, laboratory variables, and the results of microbiologic cultures; and the development of neutralizing antibodies against activated protein C. RESULTS: A total of 1690 randomized patients were treated (840 in the placebo group and 850 in the drotrecogin alfa activated group). The mortality rate was 30.8 percent in the placebo group and 24.7 percent in the drotrecogin alfa activated group. On the basis of the prospectively defined primary analysis, treatment with drotrecogin alfa activated was associated with a reduction in the relative risk of death of 19.4 percent (95 percent confidence interval, 6.6 to 30.5) and an absolute reduction in the risk of death of 6.1 percent (P=0.005). The incidence of serious bleeding was higher in the drotrecogin alfa activated group than in the placebo group (3.5 percent vs. 2.0 percent, P=0.06). CONCLUSIONS: Treatment with drotrecogin alfa activated significantly reduces mortality in patients with severe sepsis and may be associated with an increased risk of bleeding.

Meeting the needs of intensive care unit patient families: a multicenter study.

Intensive care unit (ICU) caregivers should seek to develop collaborative relationships with their patients' family members, based on an open exchange of information and aimed at helping family members cope with their distress and allowing them to speak for the patient if necessary. We conducted a prospective multicenter study of family member satisfaction evaluated using the Critical Care Family Needs Inventory. Forty-three French ICUs participated in the study. ICU characteristics, patient and family member demographics, and data on satisfaction were collected. Factors associated with satisfaction were identified using a Poisson regression model. A total of 637 patients were included in the study, and 920 family members completed the questionnaire. Seven predictors of family satisfaction were found: one family-related factor, namely, family of French descent and six caregiver-related factors, namely, no perceived contradictions in information given by caregivers; information provided by a junior physician; patient to nurse ratio

NF-kappaB expression in mononuclear cells of patients with sepsis resembles that observed in lipopolysaccharide tolerance.

The expression of NF-kappaB was studied in freshly isolated peripheral blood mononuclear cells (PBMC) of patients with severe sepsis and major trauma. The expression of p65p50 heterodimer, the active form of NF-kappaB, was significantly reduced for all patients as compared with control subjects. The p50p50 homodimer, an inhibitory form of NF-kappaB, was reduced in the survivors of sepsis and in patients with trauma. Subsequent in vitro stimulation of PBMC with lipopolysaccharide (LPS) did not induce further NF-kappaB nuclear translocation: the survivors of sepsis and trauma patients showed low expression of both p65p50 and p50p50, whereas nonsurvivors of sepsis showed a predominance of the inactive homodimer and a low p65p50/p50p50 ratio when compared with control subjects. In the later group of patients there was a reverse correlation between plasma IL-10 levels and the p65p50/p50p50 ratio after in vitro LPS stimulation (r = -0.8, p = 0.04). The reduced expression of nuclear NF-kappaB was not due to its inhibition by IkappaBalpha, as very low expression of IkappaBalpha, as well as low levels of p65 and p50 were found in the cytoplasm of PBMC from patients with sepsis and trauma when compared with control subjects. These results demonstrate that upon LPS activation, PBMC of patients with systemic inflammatory response syndrome show patterns of NF-kappaB expression that resemble those reported during LPS tolerance: global down-regulation of NF-kappaB in survivors of sepsis and trauma patients and the presence of large amounts of the inactive homodimer in the nonsurvivors of sepsis.

Association of PEEP with two different inflation volumes in ARDS patients: effects on passive lung deflation and alveolar recruitment.

OBJECTIVE: To assess the effects of the association of positive end-expiratory pressure (PEEP) with different inflation volumes (V(T)'s) on passive lung deflation and alveolar recruitment in ARDS patients. DESIGN: Clinical study using PEEP with two different V(T)'s and analyzing whether passive lung deflation and alveolar recruitment (Vrec) depend on end-inspired (EILV) or end-expired (EELV) lung volume in mechanically ventilated ARDS patients. SETTING: Medical intensive care unit in a university hospital. PATIENTS AND PARTICIPANTS: Six mechanically ventilated consecutive supine patients with ARDS. INTERVENTIONS: Time-course of thoracic volume decay during passive expiration and Vrec were investigated in six ARDS patients ventilated on PEEP with baseline V(T) (V(T),b) and 0.5V(T) (0.5V(T),b), and on zero PEEP (ZEEP) with V(T),b. Time constants of the fast (tau1) and slow (tau2) emptying compartments, as well as resistances and elastances were also determined. MEASUREMENTS AND RESULTS: (a) the biexponential model best fitted the volume decay in all instances. The fast compartment was responsible for 84+/-7 (0.5V(T),b) and 86+/-5% (V(T),b) on PEEP vs 81+/-6% (V(T),b) on ZEEP (P:ns) of the exhaled V(T), with tau1 of 0.50+/-0.13 and 0.58+/-0.17 s vs 0.35+/-0.11 s, respectively; (b) only tau1 for V(T),b on PEEP differed significantly (P < 0.02) from the one on ZEEP, suggesting a slower initial emptying; (c) for the same PEEP, Vrec was higher with a higher volume (V(T)b) than at a lesser one (0.5V(T),b), reflecting the higher V(T). CONCLUSIONS: In mechanically ventilated ARDS patients: (a) the behavior of airway resistance seems to depend on the degree of the prevailing lung distension; (b) alveolar recruitment appears to be more important when higher tidal volumes are used during mechanical ventilation on PEEP; (c) PEEP changes the mechanical properties of the respiratory system fast-emptying compartment.