Olivier Lesur

Effects of Fluid Resuscitation With Colloids vs Crystalloids on Mortality in Critically Ill Patients Presenting With Hypovolemic Shock The CRISTAL Randomized Trial

IMPORTANCE Evidence supporting the choice of intravenous colloid vs crystalloid solutions for management of hypovolemic shock remains unclear. OBJECTIVE To test whether use of colloids compared with crystalloids for fluid resuscitation alters mortality in patients admitted to the intensive care unit (ICU) with hypovolemic shock. DESIGN, SETTING, AND PARTICIPANTS A multicenter, randomized clinical trial stratified by case mix (sepsis, trauma, or hypovolemic shock without sepsis or trauma). Therapy in the Colloids Versus Crystalloids for the Resuscitation of the Critically Ill (CRISTAL) trial was open label but outcome assessment was blinded to treatment assignment. Recruitment began in February 2003 and ended in August 2012 of 2857 sequential ICU patients treated at 57 ICUs in France, Belgium, North Africa, and Canada; follow-up ended in November 2012. INTERVENTIONS Colloids (n = 1414; gelatins, dextrans, hydroxyethyl starches, or 4% or 20% of albumin) or crystalloids (n = 1443; isotonic or hypertonic saline or Ringer lactate solution) for all fluid interventions other than fluid maintenance throughout the ICU stay. MAIN OUTCOMES AND MEASURES The primary outcome was death within 28 days. Secondary outcomes included 90-day mortality; and days alive and not receiving renal replacement therapy, mechanical ventilation, or vasopressor therapy. RESULTS Within 28 days, there were 359 deaths (25.4%) in colloids group vs 390 deaths (27.0%) in crystalloids group (relative risk [RR], 0.96 [95% CI, 0.88 to 1.04]; P = .26). Within 90 days, there were 434 deaths (30.7%) in colloids group vs 493 deaths (34.2%) in crystalloids group (RR, 0.92 [95% CI, 0.86 to 0.99]; P = .03). Renal replacement therapy was used in 156 (11.0%) in colloids group vs 181 (12.5%) in crystalloids group (RR, 0.93 [95% CI, 0.83 to 1.03]; P = .19). There were more days alive without mechanical ventilation in the colloids group vs the crystalloids group by 7 days (mean: 2.1 vs 1.8 days, respectively; mean difference, 0.30 [95% CI, 0.09 to 0.48] days; P = .01) and by 28 days (mean: 14.6 vs 13.5 days; mean difference, 1.10 [95% CI, 0.14 to 2.06] days; P = .01) and alive without vasopressor therapy by 7 days (mean: 5.0 vs 4.7 days; mean difference, 0.30 [95% CI, -0.03 to 0.50] days; P = .04) and by 28 days (mean: 16.2 vs 15.2 days; mean difference, 1.04 [95% CI, -0.04 to 2.10] days; P = .03). CONCLUSIONS AND RELEVANCE Among ICU patients with hypovolemia, the use of colloids vs crystalloids did not result in a significant difference in 28-day mortality. Although 90-day mortality was lower among patients receiving colloids, this finding should be considered exploratory and requires further study before reaching conclusions about efficacy. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00318942.

Impact of Emergency Colectomy on Survival of Patients With Fulminant Clostridium difficile Colitis During an Epidemic Caused by a Hypervirulent Strain

Objectives:To determine whether emergency colectomy reduces mortality in patients with fulminant Clostridium difficile-associated disease (CDAD), and to identify subgroups of patients more likely to benefit from the procedure. Summary Background Data:Many hospitals in Quebec, Canada, have noted since 2003 a dramatic increase in CDAD incidence and in the proportion of cases severe enough to require intensive care unit (ICU) admission. The decision to perform an emergency colectomy remains largely empirical. Methods:Retrospective observational cohort study of 165 cases of CDAD that required ICU admission or prolongation of ICU stay between January 2003 and June 2005 in 2 tertiary care hospitals of Quebec. Multivariate analysis was performed through logistic regression; adjusted odds ratios (AOR) and their 95% confidence intervals (CI) were calculated. The primary outcome was mortality within 30 days of ICU admission. Results:Eighty-seven (53%) cases resulted in death within 30 days of ICU admission, almost half (38 of 87, 44%) within 48 hours of ICU admission. The independent predictors of 30-day mortality were: leukocytosis ≥50 × 109/L (AOR, 18.6; 95% CI, 3.7–94.7), lactate ≥5 mmol/L (AOR, 12.4; 95% CI, 2.4–63.7), age ≥75 years (AOR, 6.5; 95% CI, 1.7–24.3), immunosuppression (AOR, 7.9; 95% CI, 2.3–27.2) and shock requiring vasopressors (AOR, 3.4; 95% CI, 1.3–8.7). After adjustment for these confounders, patients who had an emergency colectomy were less likely to die (AOR, 0.22; 95% CI, 0.07–0.67, P = 0.008) than those treated medically. Colectomy seemed more beneficial in patients aged 65 years or more, in those immunocompetent, those with a leukocytosis ≥20 × 109/L or lactate between 2.2 and 4.9 mmol/L. Conclusion:Emergency colectomy reduces mortality in some patients with fulminant CDAD.

Innate immunosenescence: effect of aging on cells and receptors of the innate immune system in humans.

Components of the innate immune response, including neutrophils and macrophages, are the first line of defense against infections. Their role is to initiate an inflammatory response, phagocyte and kill pathogens, recruit natural killer cells (NK), and facilitate the maturation and migration of dendritic cells that will initiate the adaptive immune response. Extraordinary advances have been made in the last decade on the knowledge of the receptors and mechanisms used by cells of the innate immunity not only to sense and eliminate the pathogen but also to communicate each other and collaborate with cells of adaptive immunity to mount an effective immune response. The analysis of innate immunity in elderly humans has evidenced that aging has a profound impact on the phenotype and functions of these cells. Thus altered expression and/or function of innate immunity receptors and signal transduction leading to defective activation and decreased chemotaxis, phagocytosis and intracellular killing of pathogens have been described. The phenotype and function of NK cells from elderly individuals show significant changes that are compatible with remodeling of the different NK subsets, with a decrease in the CD56bright subpopulation and accumulation of the CD56dim cells, in particular those differentiated NK cells that co-express CD57, as well as a decreased expression of activating natural cytotoxicity receptors. These alterations can be responsible of the decreased production of cytokines and the lower per-cell cytotoxicity observed in the elderly. Considering the relevance of these cells in the initiation of the immune response, the possibility to reactivate the function of innate immune cells should be considered in order to improve the response to pathogens and to vaccination in the elderly.

Signal transduction and functional changes in neutrophils with aging.

It is well known that the immune response decreases during aging, leading to a higher susceptibility to infections, cancers and autoimmune disorders. Most widely studied have been alterations in the adaptive immune response. Recently, the role of the innate immune response as a first‐line defence against bacterial invasion and as a modulator of the adaptive immune response has become more widely recognized. One of the most important cell components of the innate response is neutrophils and it is therefore important to elucidate their function during aging. With aging there is an alteration of the receptor‐driven functions of human neutrophils, such as superoxide anion production, chemotaxis and apoptosis. One of the alterations underlying these functional changes is a decrease in signalling elicited by specific receptors. Alterations were also found in the neutrophil membrane lipid rafts. These alterations in neutrophil functions and signal transduction that occur during aging might contribute to the significant increase in infections in old age.

Treatment of adult respiratory distress syndrome: plea for rescue therapy of the alveolar epithelium

Although much has been learned about the mechanisms leading to acute lung injury, mortality—which is mainly related to sepsis or associated non-pulmonary organ dysfunction1—remains high (around 50%) in patients with adult respiratory distress syndrome (ARDS).2-4 Many new therapeutic approaches aiming to control the inflammatory response accompanying ARDS have been evaluated.5 However, these treatments have had no impact on the mortality stemming from the disease.5 The lack of success with these new interventions is probably multifactorial.6 One possible explanation is that the appropriate patient population had not been enrolled for study.7 In this regard, it is also probably unrealistic to hope that a single treatment will modify the evolution of all ARDS patients who represent a heterogeneous population with very different severities of lung injury. Thus, it is unlikely that the efficacious treatment of patients with mild lung injury will be as efficient in patients with severe lung injury. Most of the treatments tested recently were targeted to control the inflammatory response.5 Although the development of lung injury is mainly dependent on aggression of endothelial cells by inflammatory cells,8 its severity and recovery also depend on epithelial cell function.9 In fact, the predominant pathological finding in acute lung injury is diffuse alveolar epithelial damage.10 11 Furthermore, physiologically it has been shown that the structure and function of the alveolar epithelium are important determinants of lung injury.12Finally, the alveolar epithelium is also the site of alveolar fluid reabsorption and plays a major role in the development of lung fibrosis associated with ARDS.13-15 Treatments aimed at improving epithelial function might therefore become one of the key elements to accelerate recovery and decrease the mortality of patients with ARDS. In this review we will emphasise the importance of modulating two …

Endotoxin-induced myocardial dysfunction: effects of macrophage migration inhibitory factor neutralization.

The pathophysiology of sepsis-induced myocardial dysfunction still remains controversial. Macrophage migration inhibitory factor (MIF) has recently been identified as a cardiac-derived myocardial depressant factor in septic shock. Putative mechanisms by which MIF affects cardiac function are unknown. In an investigation of possible mechanisms of action, a rat model of endotoxin toxicity was designed using intraperitoneal (I/P) injection of lipopolysaccharides (LPS) with or without coinfusion of neutralizing anti-MIF or isotypic-matched antibodies. Echocardiographic evaluation revealed that MIF neutralization reversed endotoxin-induced myocardial dysfunction at 24 hours after injection. RNase protection assay (RPA) and Western blot established that MIF neutralization prevented LPS-induced mRNA expression and production of heart-derived inflammatory paracrine and autocrine cytokines such as IL-1s and IL-6. Moreover, MIF immunoneutralization increased heart Bcl-2/Bax protein ratio and suppressed endotoxin-induced release of mitochondrial cytochrome-c, as demonstrated by Western blotting. Inhibition of mitochondrial loss of cytochrome-c decreased in heart caspase-3 activity at 6 and 24 hours after injection. MIF neutralization also restored the LPS-induced deficient nuclear translocation of phospho-Akt and consequently the expression of the heart survival nuclear factor GATA-4. The restoration of the translocation/expression of survival factors by MIF inhibition resulted in lowered endotoxin-induced DNA fragmentation at 24 hours, a hallmark of downstream cardiomyocyte apoptosis. Our data indicate that early inactivation of MIF significantly reverses the imbalance of proapoptotic to prosurvival pathways and reduces acute inflammation of the heart thereby improving myocardial dysfunction induced by endotoxin.

The D-dopachrome tautomerase (DDT) gene product is a cytokine and functional homolog of macrophage migration inhibitory factor (MIF)

Macrophage migration inhibitory factor (MIF) is a pivotal regulator of the immune response. Neutralization or genetic deletion of MIF does not completely abrogate activation responses, however, and deletion of the MIF receptor, CD74, produces a more pronounced phenotype than MIF deficiency. We hypothesized that these observations may be explained by a second MIF-like ligand, and we considered a probable candidate to be the protein encoded by the homologous, D-dopachrome tautomerase (D-DT) gene. We show that recombinant D-DT protein binds CD74 with high affinity, leading to activation of ERK1/2 MAP kinase and downstream proinflammatory pathways. Circulating D-DT levels correlate with disease severity in sepsis or malignancy, and the specific immunoneutralization of D-DT protects mice from lethal endotoxemia by reducing the expression of downstream effector cytokines. These data indicate that D-DT is a MIF-like cytokine with an overlapping spectrum of activities that are important for our understanding of MIF-dependent physiology and pathology.

Impairment of SHP-1 down-regulation in the lipid rafts of human neutrophils under GM-CSF stimulation contributes to their age-related, altered functions

It has been shown that the functions and the rescue from apoptosis by proinflammatory mediators of polymorphonuclear leukocytes (PMN) tend to diminish with aging. Here, we investigated the role of protein tyrosine phosphatases (PTP), especially Src homology domain‐containing protein tyrosine phosphatase‐1 (SHP‐1), in the age‐related, altered PMN functions under granulocyte macrophage‐colony stimulating factor (GM‐CSF) stimulation. The inhibition of PTP suggested a differential effect of GM‐CSF on phosphatase activity in modulating PMN functions with aging. The down‐regulation of phosphatase activity of immunopurified SHP‐1 from lipid rafts of PMN of young donors was found significantly altered at 1 min of stimulation with aging. In young donors, SHP‐1 is displaced from lipid rafts at 1 min of stimulation, whereas in the elderly, SHP‐1 is constantly present. We assessed in PMN lipid rafts the phosphorylation of tyrosine and serine residues of SHP‐1, which regulates its activity. We observed an alteration in the phosphorylation of tyrosine and serine residues of SHP‐1 in PMN of elderly subjects, suggesting that GM‐CSF was unable to inhibit SHP‐1 activity by serine phosphorylation. GM‐CSF activates Lyn rapidly, and we found alterations in its activation and translocation to the lipid rafts with aging. We also demonstrate that SHP‐1 in the PMN of elderly is constantly recruited to Lyn, which cannot be relieved by GM‐CSF. In contrast, in the young, the resting recruitment could be relieved by GM‐CSF. Our results suggest an alteration of the SHP‐1 modulation by GM‐CSF in lipid rafts of PMN with aging. These alterations could contribute to the decreased GM‐CSF effects on PMN.

Aging and neutrophils: there is still much to do.

Human neutrophils are activated by a wide array of compounds through their receptors. This elicits their classical functions, such as chemotaxis, phagocytosis, and the production of reactive oxygen species (ROS). Upon stimulation, neutrophils also produce lipid and immune mediators and can present antigen through the major histocompatibility complex I (MHC-I). The age-related impairment of the classical functions of neutrophils is well described, but experimental evidence showing alterations in the production of mediators and antigen presentation with aging are lacking. This review highlights the role of neutrophils in age-related pathologies such as Alzheimers disease, atherosclerosis, cancer, and autoimmune diseases. Furthermore, we discuss how aging potentially affects the production and release of mediators by human neutrophils in ways that may contribute to the development of these pathologies.

Sepsis, leukocytes, and nitric oxide (NO): an intricate affair.

Sepsis is exceedingly burdensome for hospital intensive care unit caregivers, and its incidence, as well as sepsis-related deaths, is increasing steadily. Sepsis is characterized by a robust increase in NO production throughout the organism that is driven by iNOS. Moreover, NO is an important factor in the development of septic shock and is synthesized by NOS, an enzyme expressed by a variety of cells, including vascular endothelium, macrophages, and neutrophils. However, the effects of NO on leukocyte functions, and the underlying mechanisms, are relatively unknown. Thus, the present review focuses on the effects of NO and its derivatives on cells of the immune system. Experimental evidences discussed herein show that NO induces posttranslational modifications of key proteins in targeted processes with the potential of deterring cellular physiology. Consequently, the manipulation of NO distribution in septic patients, used in conjunction with conventional treatments aimed at restoring normal immune functions, may represent a valuable therapeutic strategy.