Aldosterone and Vascular Mineralocorticoid Receptors in Murine Endotoxic and Human Septic Shock.

OBJECTIVES: Vascular mineralocorticoid receptors play a role in vascular tone and blood pressure regulation, might participate in the pathophysiology of circulatory failure during sepsis, and represent a potential therapeutic target in this disease. We aimed to study the effects of mineralocorticoids and the involvement of vascular mineralocorticoid receptors in murine endotoxic and human septic shock. DESIGN: Experimental study. SETTING: Translational investigation including animal research and in vitro experiments using human vascular cells and plasma from septic patients. SUBJECTS: Adult male C57Black 6 mice, adult patients with septic shock. INTERVENTIONS: Mice were injected with lipopolysaccharide and/or aldosterone. Human endothelial and smooth muscle cells were treated with pro-inflammatory cytokines with or without aldosterone, nuclear factor-κB inhibitor BAY 11-7082, or plasma from septic patients. MEASUREMENTS AND MAIN RESULTS: Aldosterone improved 5-day survival, invasive arterial pressure, and in vivo and ex vivo arterial response to phenylephrine at 18 hours after induction of murine endotoxic shock. Both α1-adrenoceptor and mineralocorticoid receptor expressions studied in mouse aortas were down-regulated at 6 and 18 hours in endotoxemic mice and restored in aldosterone-treated mice. Furthermore, tumor necrosis factor-α decreased both mineralocorticoid receptor and α1-adrenoceptor expressions within 5 hours in human vascular cells in a nuclear factor-κB pathway-dependent manner. Mineralocorticoid receptor expression was also blunted in human cells treated with plasma from septic patients. CONCLUSION: We found a beneficial effect of mineralocorticoids on survival, blood pressure, and vascular reactivity, associated with a restoration of α1-adrenoceptor expression in endotoxic shock. Furthermore, blunted vascular mineralocorticoid receptor expression might participate in hemodynamic failure during sepsis.

Sulfenic Acid Modification of Endothelin B Receptor is Responsible for the Benefit of a Nonsteroidal Mineralocorticoid Receptor Antagonist in Renal Ischemia.

AKI is associated with high mortality rates and the development of CKD. Ischemia/reperfusion (IR) is an important cause of AKI. Unfortunately, there is no available pharmacologic approach to prevent or limit renal IR injury in common clinical practice. Renal IR is characterized by diminished nitric oxide bioavailability and reduced renal blood flow; however, the mechanisms leading to these alterations are poorly understood. In a rat model of renal IR, we investigated whether the administration of the novel nonsteroidal mineralocorticoid receptor (MR) antagonist BR-4628 can prevent or treat the renal dysfunction and tubular injury induced by IR. Renal injury induced by ischemia was associated with increased oxidant damage, which led to a cysteine sulfenic acid modification in endothelin B receptor and consequently decreased endothelial nitric oxide synthase activation. These modifications were efficiently prevented by nonsteroidal MR antagonism. Furthermore, we demonstrated that the protective effect of BR-4628 against IR was lost when a selective endothelin B receptor antagonist was coadministered. These data describe a new mechanism for reduced endothelial nitric oxide synthase activation during renal IR that can be blocked by MR antagonism with BR-4628.

Prognosis of Very Elderly Patients after Intensive Care.

Elderly patients (over age 85) are increasingly treated in Intensive Care Units (ICU), despite doctors' reluctance to accept these frail patients. There are only few studies describing the relevance of treatments for this group of patients in ICU. One of these studies defined an age of 85 or over as the essential admittance criterion. Exclusion criteriwere low autonomy before admittance or an inability to answer the phone. Epidemiological data, history, lifestyle, and autonomy (ADL score of six items) were recorded during admission to the ICU and by phone interviews six months later. Eight French ICUs included 239 patients aged over 85. The most common diagnostics were non-cardiogenic lung disease (36%), severe sepsis/septic shock (29%), and acute pulmonary oedem (28%). Twenty-three percent of patients were dependent at the time of their admission. Seventy-one percent of patients were still alive when released from ICU, and 52% were still alive after 6 months. Among the patients which were non-dependent before hospitalization, 17% became dependent. The only prognostic criterifound were the SAPS II score on admission and the place of residence before admission (nursing home or family environment had poor prognosis). Although the prognosis of these elderly patients was good after hospitalization in ICU, it should be noted that the population was carefully selected as having few comorbidities or dependence. No triage critericould be suggested.

When a Ventilator Takes Autonomous Decisions without Seeking Approbation nor Warning Clinicians: A Case Series.

BACKGROUND: Complexity and functions of automated medical devices used to support life (eg, ventilators, dialysis machines, monitors, insulin pump with continuous blood glucose monitoring system, etc.) increase over time. Until recently, devices were partially automated by very simple feedback loops, with no or few software dependence (such as the simplest home thermostat). For the last two decades, devices have been increasingly driven by complex algorithms devoted to improve patient's treatment and monitoring as well as users experience. METHODS: We report the unexpected and inappropriate operation of two recent ventilators, associated to potential harmful consequences. We provide both a description of the clinical situations (five ICU patients, archetypal situations) and a test bench analysis. RESULTS: While set in volume mode, these ventilators activated an algorithm dedicated to limit airway pressure when an increase in airway resistance occurred. In such situations, a pressure-like mode was activated (with decelerating inspiratory flow and set pressure, with target of volume). The main consequences observed were that the tidal volume was no longer guaranteed or delivered and that the pressure limitation operated by the algorithm prevented the airway pressure from reaching the high-pressure alarm threshold. CONCLUSION: This led to the silent takeover of commands by the ventilator without clinicians or nurses being aware of it and without any warnings or alarms emission adapted to the severity of the event. Generally speaking, such an algorithm questions the place of automation and its limit when users are not aware of its presence as well as the need for regulation and additional tests before its implementation. Intensivists and respiratory care specialists should remain vigilant regarding the risk of rare but critical events related to unexpected functioning or insufficiently tested equipment during the pre-clinical development phases. They should not neglect misunderstood critical events without having performed sufficient investigations.

Homocitrulline as marker of protein carbamylation in hemodialyzed patients.

BACKGROUND: Homocitrulline (HCit) is a carbamylation-derived product (CDP) that has been identified as a valuable biomarker of morbidity and mortality in patients with chronic kidney disease (CKD). The aim of this study was to determine whether initiation of hemodialysis therapy (HD) could induce variations of HCit concentrations in CKD patients. METHODS: Serum HCit concentrations were determined by LC-MS/MS in CKD patients (n=108) just before (M0) and six months (M6) after the initiation of HD therapy. RESULTS: Mean HCit concentrations reached 1000µmol/mol Lysine before initiation of HD therapy and decreased by 50% within 6months after HD onset. HCit concentrations remained stable over time as assessed during a 24-months follow-up period. HCit was mostly found in its protein-bound form in HD patients. HCit concentrations obtained at M0 were positively correlated with urea (r=0.58) and carbamylated hemoglobin (r=0.41), and are likely to be promising predictive markers of mortality. However, no correlations were found between HCit concentrations and Kt/V values, suggesting that HCit is not a marker of HD efficiency. CONCLUSION: HCit concentrations reflect the intensity of protein carbamylation and are stable over time during HD treatment, making HCit a reliable biomarker in the follow-up of CKD patients.

Is there a need for a national or a global apheresis registry?

Indications for apheresis may vary and more than 45 different diagnoses have been reported from various countries. New devices are being developed and, in the beginning their clinical implications and use are limited to detect rare but important side effects. However, to achieve more reliable information on the effects and side effects we need more extensive sampling of data. Collection of such data is considered a safety and quality issue in several countries. However, data is still limited and little is known about therapeutic apheresis practised around the world including the incidence and pattern of adverse events. The establishment of national registries and analyses of data on a global level therefore seems important. Thus the World Apheresis Association (WAA) has initiated a global apheresis registry for therapeutic procedures and collection of e.g., stem cells. The WAA registry is Internet based and the site is at www.iml.umu.se/medicin. A login code to test the registry is needed (AL61TMS). This report deals with the aim of a global registry as well as some comparative data regarding findings of the Canadian, French and Swedish registries.

Sirolimus-induced thrombotic microangiopathy is associated with decreased expression of vascular endothelial growth factor in kidneys.

The aim of this study was to examine the clinical characteristics, the histological features and the renal expression of vascular endothelial growth factor (VEGF) of five patients with sirolimus-associated thrombotic microangiopathy (TMA). Sirolimus-induced TMA occurs preferentially in kidneys with concomitant endothelial injury: it was observed in three patients with acute cellular rejection on calcineurin inhibitor-free regimen, in one patient with chronic graft rejection on a calcineurin inhibitor-free protocol and in one patient with chronic calcineurin inhibitor nephrotoxicity. We found that renal VEGF expression during sirolimus-induced TMA was significantly lower than VEGF expression in normal transplanted kidneys (p < 0.01). Decreased expression of VEGF seems to be a consequence of sirolimus treatment since (i) analysis of two biopsies performed after the switch of sirolimus to calcineurin inhibitor showed reappearance of VEGF expression, (ii) no decreased expression of VEGF was found in five kidneys with classical TMA and, (iii) an increased expression of VEGF was observed in seven kidneys with acute cellular rejection on a sirolimus-free immunosuppressive regimen (p < 0.01). The potential role of sirolimus-induced downregulation of VEGF as a predisposing factor to the development of TMA is discussed.