Intrarenal urothelium proliferation: an unexpected early event following ischemic injury.

Identification of renal cell progenitors and recognition of the events contributing to cell regeneration following ischemia-reperfusion injury (IRI) are a major challenge. In a mouse model of unilateral renal IRI, we demonstrated that the first cells to proliferate within injured kidneys were urothelial cells expressing the progenitor cell marker cytokeratin 14. A systematic cutting of the injured kidney revealed that these urothelial cells were located in the deep cortex at the corticomedullary junction in the vicinity of lobar vessels. Contrary to multilayered bladder urothelium, these intrarenal urothelial cells located in the upper part of the medulla constitute a monolayered barrier and express among uroplakins only uroplakin III. However, like bladder progenitors, intrarenal urothelial cells proliferated through a FGF receptor-2 (FGFR2)-mediated process. They strongly expressed FGFR2 and proliferated in vivo after recombinant FGF7 administration to control mice. In addition, IRI led to FGFR phosphorylation together with the selective upregulation of FGF7 and FGF2. Conversely, by day 2 following IRI, renal urothelial cell proliferation was significantly inhibited by FGFR2 antisense oligonucleotide administration into an intrarenal urinary space. Of notice, no significant migration of these early dividing urothelial cells was detected in the cortex within 7 days following IRI. Thus our data show that following IRI, proliferation of urothelial cells is mediated by the FGFR2 pathway and precedes tubular cell proliferation, indicating a particular sensitivity of this structure to changes caused by the ischemic process.

Multifocal community-acquired necrotizing fasciitis caused by a Panton-Valentine leukocidin-producing methicillin-sensitive Staphylococcus aureus.

We describe a rare case of multifocal necrotizing fasciitis (NF) complicating a single vaccine injection. Injection of hepatitis B vaccine of a 16-year-old immunocompetent woman developed into rapidly spreading multifocal NF of the right arm and the thighs, with septic shock. Treatment with antimicrobial therapy and surgical debridements allowed amputation to be avoided with a favourable outcome. The etiological agent was a methicillin-sensitive Staphylococcus aureus (MSSA) isolate harboring the Panton-Valentine leukocidin (PVL) and five enterotoxins. PVL has recently been reported in large series of methicillin-resistant SA cases and has been associated with necrotizing infections. Some strains of MSSA could harbor PVL and enterotoxins. PCR investigation is not frequent but could improve the understanding of the mechanisms of lesions. This case is in keeping with the increasing incidence of MSSA harboring PVL and enterotoxins with multifocal dissemination NF and emphasizes the necessary precautions for skin decontamination before vaccine injection.

[Pharmacokinetic evaluation of linezolid in patients with major thermal injuries]. / Pharmacocinétique du linézolide chez des patients souffrant de brûlures sévères.

The aims of this multicentre open-label study was to evaluate the pharmacokinetics of linezolid in patients with burn injury above 20 % BSA and to compare them with healthy volunteers, matched in age, sex and weight. After a single 600 mg IV dose of linezolid, multiple blood and urine samples were taken from subjects, in order to determine linezolid concentrations, using a HPLC assay. C(max) and volume of distribution at steady state were not different between the two groups. Values describing clearance were altered in burns, leading to a reduction by half in AUC in these patients (42.5 versus 98.1 mghL(-1)). The enhancement of clearance was due to which of non renal clearance (323+/-191 versus 80.4+/-27.5 mLmin(-1)). We conclude that pharmacokinetics of linezolid are altered in burn patients, in a magnitude sufficient that linezolid concentration may be subtherapeutic in some patients and we suggest that the dosage interval may need to be decreased in this patient population.

Effects of candidaemia on outcome of burns.

AIM: To evaluate the diversity and antifungal susceptibilities of Candida isolates from wounds and blood of burn victims, and the associated mortality rates compared with those of controls without candidaemia. METHODS: We performed a nested case-control study within a database of clinical data for all patients admitted to our burn unit from January 2001 to December 2005. Each candidaemic patient was compared with two matched controls. Bloodstream cultures were performed if the core temperature was >39 degrees C, and three sites were cultured weekly for fungal identification (burn wound, pharynx, urinary tract). RESULTS: At least one episode of candidaemia was diagnosed among 20 of 851 persons admitted during the study period. Isolates in bloodstream infection were Candida albicans (65%), C. parapsilosis (25%) and C. tropicalis (10%). The median time between admission and onset of candidaemia was greater with C. albicans infection (42.6+/-31 days) than with infection by other yeasts (18+/-12 days). Candidaemia was associated with more extensive burn and longer duration of hospital stay but with similar mortality, compared with controls. CONCLUSION: Candidaemia in burn cases is mostly due to fluconazole-susceptible C. albicans and is not associated with increased mortality.

Pharmacokinetic evaluation of linezolid in patients with major thermal injuries.

AIMS: To evaluate the pharmacokinetics of linezolid following its administration in patients with major thermal injuries and in a group of healthy volunteers. METHODS: In an open-label, multicentre design with two parallel groups, a group of patients with major thermal injuries (>20% body area) and a group of age-, sex- and weight-matched healthy volunteers, subjects received a single 600 mg intravenous dose of linezolid. Serial blood and urine collections were made and the concentrations of linezolid in these samples were determined by HPLC. Non-compartmental analyses were used to describe the pharmacokinetic disposition of linezolid. RESULTS: C(max) concentrations and the volume of distribution at steady state (V(ss)) were not statistically different (P > 0.05) between the two groups of subjects. In contrast, values describing clearance [elimination rate constant (k(el)), t(1/2) and mean residence time (MRT)] were significantly different (P < 0.05) in patients with thermal injuries compared with volunteers, which lead to an approximate reduction by half in AUC(0-infinity) from 98.1 mg.h/L (volunteers) to 42.5 mg.h/L (patients). Although renal clearance was similar in the two groups (24.7 +/- 23 versus 30.6 +/- 14.3 mL/min; P = 0.156), non-renal clearance was substantially increased (323 +/- 191 versus 80.4 +/- 27.5 mL/min) in the patients with thermal injuries, though this difference did not achieve statistical significance (P = 0.063). CONCLUSIONS: The pharmacokinetics of linezolid are altered in patients with major thermal injuries, mainly as a result of increased non-renal clearance. These changes are of sufficient magnitude that linezolid concentrations may be sub-therapeutic in some patients and we suggest that the dosage interval may need to be decreased in this patient population.

Case report: cytomegalovirus primoinfection may be associated with severe outcome in burns.

We report two cases of severe cytomegalovirus (CMV) primoinfection in seriously burned patients. The infection may have contributed to both patients' fatal outcome. This underlines the importance of research in viral aetiology, especially with regard to CMV, when immunodeficient patients - as burn patients are - develop unexplained fever. We propose a monitoring and a prevention strategy for CMV in the most severely burned patients. The prevention strategy involves the use of skin allografts and blood products in seronegative patients. CMV infection should not be underestimated in severely burned patients.

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.

[Does Doppler analysis of hepatic venous flow predict increased right atrial pressure and right ventricular dysfunction?]. / L'analyse doppler du flux des veines sus-hépatiques permet-elle de prédire le niveau de pression auriculaire droite au cours de l'infarctus du ventricule droit?

The aim of this study was to test the hypothesis that Doppler study of hepatic venous flow, reflecting right atrial pressures and right ventricular dysfunction, allows prediction of increased right atrial pressure and right ventricular dysfunction in patients with right ventricular infarction. The authors studied 30 patients (27 men, mean age 54 +/- 12 years) in sinus rhythm with acute inferior myocardial infarction who underwent right heart catheterisation and Doppler echocardiography including recording of regurgitant and hepatic vein flow within 48 hours of hospital admission. Hepatic venous flow was used to measure peak velocity and velocity time integrals (VTI) of the systolic (S), diastolic (D) and atrial (a) contraction waves. The fraction of systolic filling was calculated: VTI S/VTI S + VTI D. The pressure half-time of pulmonary regurgitant flow (PHT IP) was also measured. Using haemodynamic criteria (non-compliant right atrial pressure wave form or right ventricular end diastolic pressure/pulmonary capillary pressure > or = 0.8), patients were divided into two groups: Group 1: right ventricular infarction (VD+, N = 22). Group 2: no right ventricular infarction (VD-, N = 8). No correlation was observed between Doppler parameters of hepatic venous flow and haemodynamic data, in particular right atrial pressure and pressure wave form. Moreover, no statistically significant difference was observed between the two groups with respect to the Doppler parameters derived from hepatic venous flow. On the other hand, the results confirmed good diagnostic performance of Doppler analysis of pulmonary regurgitant flow: sensitivity 80%, specificity 83%, positive predictive value 94%, negative predictive value 55%. The authors conclude that, in patients with acute inferior wall infarction, Doppler analysis of hepatic venous flow does not allow assessment of right atrial pressure or of ischaemic right ventricular dysfunction.

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.

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.

[Physiopathological basis of the treatment of heart failure]. / Bases physiopathologiques du traitement de l'insuffisance cardiaque.

Therapeutic advances have changed the mode of presentation of cardiac failure over the last decades: the main cause, nowadays, is myocardial ischaemia. The modern treatment of cardiac failure is based on relatively simple physiopathological mechanisms which take into account the different aspects of cardiac physiology: a pump, a muscle, a coronary circulation supplying oxygen to the myocardium, an automatic contraction. The concept of vasodilatation and the blocking of vasoconstrictive systems introduced during the 70s is the basis of modern treatment of cardiac failure which involves angiotensin converting enzyme inhibitors and, increasingly, betablockers. In the near future, with earlier treatment of cardiac failure, the stimulation of vasodilator systems could become a new therapeutic strategy. Early detection of ischaemia and its complications with the aim of limiting the loss of cardiac myocytes is a priority for slowing the progression of cardiac failure. The prevention of cardiac failure also depends on educating cardiologists to treat rapidly the factors predisposing to or prolonging episodes of even mild cardiac failure.

Heparin-induced thrombocytopenia with thrombotic complications during prophylactic treatment with low-molecular-weight heparin.

Heparin-induced thrombocytopenia is very uncommon with low-molecular-weight heparin, especially when given for prophylaxis of venous thromboembolism. In two of the four published cases, with thrombotic complications, thrombocytopenia may have been related to cross-reactivity between unfractionated heparin and low-molecular-weight heparin. We report one patient who received low-molecular-weight heparin for prophylaxis against venous thromboembolism without any previous injection of unfractionated heparin, and experienced thrombocytopenia with thrombotic complications. Heparin-induced thrombocytopenia was confirmed by several laboratory assays. This observation emphasizes the need for platelet count monitoring during low-molecular-weight heparin therapy.