Jérôme Pugin

University of Geneva, Genève, Geneva, Switzerland

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Publications (149)779.99 Total impact

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    ABSTRACT: A systemic anticoagulation is often required to prevent circuit and filter clotting in ICU patients undergoing continuous renal replacement therapy (CRRT). A regional citrate-based anticoagulation (RCA) does not induce a systemic anticoagulation and prolongs the filter lifespan, but metabolic side-effects have been associated with this therapy. We conducted a randomized controlled trial with patients requiring CRRT to determine whether RCA using a balanced predilution replacement fluid is more effective than heparin in terms of renal replacement delivered dose and safety profile. One hundred and three patients with AKI requiring CRRT were included. The patients were randomized to either CRRT with RCA or heparin anticoagulation. Primary endpoints were effective daily delivered RRT dose during the first 3 days of CRRT and filter lifespan. Secondary endpoints were 28-day and 90-day survival and severe metabolic complications and bleeding disorders. Median CRRT duration was 3.0 (2-6) days. Effective delivered daily RRT doses were 29 ± 3 and 27 ± 5 mL/kg/hr in the RCA and heparin groups, respectively (p = 0.005). Filter lifespans were 49 ± 29 versus 28 ± 23 hrs in the RCA and heparin groups (p = 0.004). Survival rates at 28 and 90 days were 80-74% in the RCA and 74-73% in the heparin group. Electrolytes and acid-base disturbances were uncommon and transient in patients treated with RCA. These results show that RCA is superior to heparin-based anticoagulation in terms of delivered RRT dose and filter life span and is a safe and feasible method. This does not translate into an improvement in short term survival. ClinicalTrials.gov NCT01269112 . Registered 3rd January 2011.
    Critical care (London, England) 12/2015; 19(1):822. DOI:10.1186/s13054-015-0822-z
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    ABSTRACT: Whilst augmented renal clearance (ARC) is associated with reduced β-lactam plasma concentrations, its impact on clinical outcomes is unclear. This single-centre prospective, observational, cohort study included non-pregnant, critically ill patients aged 18–60 years with presumed severe infection treated with imipenem, meropenem, piperacillin/tazobactam or cefepime and with creatinine clearance (CLCr) ≥60 mL/min. Peak, intermediate and trough levels of β-lactams were drawn on Days 1–3 and 5. Concentrations were deemed ‘subthreshold’ if they did not meet EUCAST-defined non-species-related breakpoints. Primary and secondary endpoints were clinical response 28 days after inclusion, and ARC prevalence (CLCr ≥ 130 mL/min) and subthreshold and undetectable concentrations, respectively. Logistic regression was used to evaluate associations between ARC, antibiotic concentrations and clinical failure. From 2010 to 2013, 100 patients were enrolled (mean age, 45 years; median CLCr at inclusion, 144.1 mL/min). ARC was present in 64 (64%) of the patients. Most patients received imipenem/cilastatin (54%). Moreover, 86% and 27% of patients had at least one subthreshold or undetectable trough level, respectively. Among imipenem and piperacillin trough levels, 77% and 61% were subthreshold, respectively, but intermediate levels of both antibiotics were largely above threshold. ARC strongly predicted undetectable trough concentrations (OR = 3.3, 95% CI 1.11–9.94). A link between ARC and clinical failure (18/98; 18%) was not observed. ARC and subthreshold β-lactam antibiotic concentrations were widespread but were not associated with clinical failure. Larger studies are necessary to determine whether standard dosing regimens in the presence of ARC impact negatively on clinical outcome and antibiotic resistance.
    International Journal of Antimicrobial Agents 01/2015; 45(4). DOI:10.1016/j.ijantimicag.2014.12.017 · 4.26 Impact Factor
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    Jérôme Pugin
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    ABSTRACT: Adrenomedullin is a vasodilatory polypeptide with pleiotropic effects secreted by various organs. Adrenomedullin is produced first as a prepropeptide, and then cleaved into mature adrenomedullin and mid-regional proadrenomedullin. Whereas levels of the latter have been shown to correlate with severity of sepsis and carry prognostic value, adrenomedullin plays a role in vascular tone homeostasis. In the previous issue of Critical Care, the infusion of exogenous adrenomedullin is suggested to protect against increased lung endothelial permeability and end-organ dysfunction in a model of pneumococcal pneumonia in mechanically ventilated mice, possibly by stabilizing vascular endothelia. Since adrenomedullin is a strong vasodilatory molecule, further studies are needed to evaluate its potential as a future treatment of sepsis.
    Critical care (London, England) 06/2014; 18(3):152. DOI:10.1186/cc13924
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    ABSTRACT: The spread of microorganisms in hospitals is an important public health threat, and yet few studies have assessed how human microbial communities (microbiota) evolve in the hospital setting. Studies conducted so far have mainly focused on a limited number of bacterial species, mostly pathogenic ones and primarily during outbreaks. We explored the bacterial community diversity of the microbiota from oral and respiratory samples of intubated patients hospitalized in the intensive care unit and we discuss the technical challenges that may arise while using culture-independent approaches to study these types of samples.
    Frontiers in Cellular and Infection Microbiology 05/2014; 4:65. DOI:10.3389/fcimb.2014.00065 · 2.62 Impact Factor
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    ABSTRACT: Inflammation is mediated mainly by leukocytes which express both toll-like receptor 4 (TLR4) and Fc gamma receptors (FcγR). Dysregulated activation of leukocytes via exogenous and endogenous ligands of TLR4 results in a large number of inflammatory disorders that underlie a variety of human diseases. Thus, differentially blocking inflammatory cells while sparing structural cells, which are FcγR negative, represents an elegant strategy when targeting the underlying causes of human diseases. Here, we report a novel tethering mechanism of the Fv and Fc portions of anti-TLR4 blocking antibodies that achieves increased potency on inflammatory cells. In the presence of ligand, e.g., lipopolysaccharide (LPS), TLR4 trafficks into glycolipoprotein microdomains, forming concentrated protein platforms that include FcγRs. This clustering produces a microenvironment allowing anti-TLR4 antibodies to co-engage TLR4 and FcγRs, increasing their avidity and thus substantially increasing their inhibitory potency. Tethering of antibodies to both TLR4 and FcγRs proves valuable at ameliorating inflammation in vivo. This novel mechanism of action therefore has the potential to enable selective intervention of relevant cell types in TLR4-driven diseases.
    Journal of Biological Chemistry 04/2014; 289(22). DOI:10.1074/jbc.M113.537936 · 4.60 Impact Factor
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    ABSTRACT: Background Infections are a leading cause of death in patients with advanced cirrhosis, but there are relatively few data on the epidemiology of infection in intensive care unit (ICU) patients with cirrhosis. AimsWe used data from the Extended Prevalence of Infection in Intensive Care (EPIC) II one-day point-prevalence study to better define the characteristics of infection in these patients. Methods We compared characteristics, including occurrence and types of infections in non-cirrhotic and cirrhotic patients who had not undergone liver transplantation. ResultsThe EPIC II database includes 13,796 adult patients from 1,265 ICUs: 410 of the patients had cirrhosis. The prevalence of infection was higher in cirrhotic than in non-cirrhotic patients (59 vs. 51%, p<0.01). The lungs were the most common site of infection in all patients, but abdominal infections were more common in cirrhotic than in non-cirrhotic patients (30 vs. 19%, p<0.01). Infected cirrhotic patients more often had Gram-positive (56 vs. 47%, p<0.05) isolates than did infected non-cirrhotic patients. Methicillin-resistant Staphylococcus aureus (MRSA) was more frequent in cirrhotic patients. The hospital mortality rate of cirrhotic patients was 42%, compared to 24% in the non-cirrhotic population (p<0.001). Severe sepsis and septic shock were associated with higher in-hospital mortality rates in cirrhotic than in non-cirrhotic patients (41% and 71% vs. 30% and 49%, respectively, p<0.05). Conclusions Infection is more common in cirrhotic than in non-cirrhotic ICU patients and more commonly due to Gram-positive organisms, including MRSA. Infection in patients with cirrhosis was associated with higher mortality rates than in non-cirrhotic patients.This article is protected by copyright. All rights reserved.
    Liver international: official journal of the International Association for the Study of the Liver 03/2014; DOI:10.1111/liv.12520 · 4.41 Impact Factor
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    ABSTRACT: Fibroblast growth factor 21 (FGF21) is a key regulator in glucose and lipid metabolism and its plasma levels have been showed to be increased in humans in different situations such as type 2 diabetes, obesity and nonalcoholic fatty liver disease but also in animal models of sepsis and pancreatitis. FGF21 is considered as a pharmacological candidate in conditions associated with insulin resistance. The aim of this study was to compare FGF21 plasma levels in patients with sepsis, in patients with a systemic inflammatory response syndrome (SIRS), and in healthy controls. We measured FGF21 plasma concentrations in 22 patients with established sepsis, in 11 with SIRS, and in 12 healthy volunteers. Here, we show that FGF21 levels were significantly higher in plasma from patients with sepsis and SIRS in comparison to healthy controls. Also, FGF21 levels were significantly higher in patients with sepsis than in those with noninfectious SIRS. FGF21 plasma levels measured at study entry correlated positively with the APACHE II score, but not with procalcitonin levels, nor with C-reactive protein, classical markers of sepsis. Plasma concentrations of FGF21 peaked near the onset of shock and rapidly decreased with clinical improvement. Taken together, these results indicate that circulating levels of FGF21 are increased in patients presenting sepsis and SIRS and suggest a role of FGF21 in inflammation. Further studies are needed to explore the potential role of FGF21 in sepsis as a potential therapeutic target.
    09/2013; 2(3). DOI:10.1530/EC-13-0040
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    Clinical Therapeutics 08/2013; 35(8):e79. DOI:10.1016/j.clinthera.2013.07.227 · 2.59 Impact Factor
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    ABSTRACT: In the context of worldwide increasing antimicrobial resistance, good antimicrobial prescribing in more needed than ever; unfortunately, information available to clinicians often are insufficient to rely on. Biomarkers might provide help for decision-making and improve antibiotic management. The purpose of this expert panel review was to examine currently available literature on the potential role of biomarkers to improve antimicrobial prescribing, by answering three questions: 1) Which are the biomarkers available for this purpose?; 2) What is their potential role in the initiation of antibiotic therapy?; and 3) What is their role in the decision to stop antibiotic therapy? To answer these questions, studies reviewed were limited to recent clinical studies (<15 years), involving a substantial number of patients (>50) and restricted to controlled trials and meta-analyses for answering questions 2 and 3. With regard to the first question concerning routinely available biomarkers, which might be useful for antibiotic management of acute infections, these are currently limited to C-reactive protein (CRP) and procalcitonin (PCT). Other promising biomarkers that may prove useful in the near future but need to undergo more extensive clinical testing include sTREM-1, SuPAr, ProADM, and presepsine. New approaches to biomarkers of infections include point-of-care testing and genomics.
    07/2013; 3(1):22. DOI:10.1186/2110-5820-3-22
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    ABSTRACT: Biomarker-guided initiation of antibiotic therapy has been studied in four conditions: acute pancreatitis, lower respiratory tract infection (LRTI), meningitis, and sepsis in the ICU. In pancreatitis with suspected infected necrosis, initiating antibiotics best relies on fine-needle aspiration and demonstration of infected material. We suggest that PCT be measured to help predict infection; however, available data are insufficient to decide on initiating antibiotics based on PCT levels. In adult patients suspected of community-acquired LRTI, we suggest withholding antibiotic therapy when the serum PCT level is low (<0.25 ng/mL); in patients having nosocomial LRTI, data are insufficient to recommend initiating therapy based on a single PCT level or even repeated measurements. For children with suspected bacterial meningitis, we recommend using a decision rule as an aid to therapeutic decisions, such as the Bacterial Meningitis Score or the Meningitest(R); a single PCT level >=0.5 ng/mL also may be used, but false-negatives may occur. In adults with suspected bacterial meningitis, we suggest integrating serum PCT measurements in a clinical decision rule to help distinguish between viral and bacterial meningitis, using a 0.5 ng/mL threshold. For ICU patients suspected of community-acquired infection, we do not recommend using a threshold serum PCT value to help the decision to initiate antibiotic therapy; data are insufficient to recommend using PCT serum kinetics for the decision to initiate antibiotic therapy in patients suspected of ICU-acquired infection. In children, CRP can probably be used to help discontinue therapy, although the evidence is limited. In adults, antibiotic discontinuation can be based on an algorithm using repeated PCT measurements. In non-immunocompromised out- or in- patients treated for RTI, antibiotics can be discontinued if the PCT level at day 3 is < 0.25 ng/mL or has decreased by >80-90%, whether or not microbiological documentation has been obtained. For ICU patients who have nonbacteremic sepsis from a known site of infection, antibiotics can be stopped if the PCT level at day 3 is < 0.5 ng/mL or has decreased by >80% relative to the highest level recorded, irrespective of the severity of the infectious episode; in bacteremic patients, a minimal duration of therapy of 5 days is recommended.
    07/2013; 3(1):21. DOI:10.1186/2110-5820-3-21
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    06/2013; 2(1). DOI:10.1186/2047-2994-2-S1-P125
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    ABSTRACT: OBJECTIVE:: A hallmark of sepsis and severe systemic inflammatory response syndrome (SIRS) is the massive recruitment of immature neutrophils from the bone marrow into the circulation (left shift, band forms). Their capacity to participate in innate defense against bacteria is ill defined. We aimed at comparing various innate immune functions of mature vs. immature neutrophils circulating during sepsis and SIRS. DESIGN:: Prospective, observational cohort study. SETTING:: Tertiary level ICU and associated research laboratory. PATIENTS:: Thirty-three ICU patients with sepsis; 12 ICUs with SIRS; 32 healthy volunteers. INTERVENTIONS:: Twenty milliliters of whole heparinized blood was used for in vitro studies including neutrophil viability and apoptosis, surface expression of CD16, Toll-like receptors (1) 4 and TLR2, CD14, MD-2, HLA-DP,-DQ and -DR, and CXCR2, chemotaxis, phagocytosis, bacterial killing, and tumor necrosis factor (TNF)-α/interleukin (IL)-10 baseline intracellular cytokine levels. MEASUREMENTS AND MAIN RESULTS:: Immature neutrophils were capable of mediating important innate immune functions such as bacterial phagocytosis and killing via the production of reactive oxygen species, although less efficiently than mature neutrophils. Immature neutrophils had a longer life span and resistance to spontaneous apoptosis, and could mature ex vivo. They expressed lower levels of receptors for bacterial molecules such as CD14 and MD-2 and migrated less efficiently than mature granulocytes. Immature neutrophils had higher basal intracellular TNF-α/IL-10 ratio than that of mature neutrophils, suggesting a proinflammatory phenotype. No significant differences were observed between immature neutrophils isolated from patients with sepsis and those from patients with severe SIRS. CONCLUSIONS:: Despite their "immaturity", band forms are capable of mediating crucial innate immune functions during severe infections and sepsis. Their fate and capacity to mature in vivo remain to be determined.
    Critical care medicine 01/2013; DOI:10.1097/CCM.0b013e318274647d · 6.15 Impact Factor
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    ABSTRACT: BACKGROUND: Experimentally, erythropoietin (EPO) has nephroprotective as well as immunomodulatory properties when administered after ischemic renal injury. We tested the hypothesis that different doses of recombinant human EPO administered to patients after cardiac surgery would minimize kidney lesions and the systemic inflammatory response, thereby decreasing acute kidney injury (AKI) incidence. METHODS: In this double-blinded randomized control study, 80 patients admitted to the ICU post-cardiac surgery were randomized by computer to receive intravenously isotonic saline (n = 40) versus alpha-Epoetin (n = 40): either 40000 IU (n = 20) or 20000 IU (n = 20). The study lasted one year. The primary outcome was the change in urinary NGAL concentration from baseline and 48 h after EPO injection. Creatinine, cystatine C and urinary NGAL levels were measured on the day of randomization and 2--4 days after EPO injection. To assess acute inflammatory response, serum cytokines (IL6 and IL8) were measured at randomization and four days after r-HuEPO injection. Patients and care-takers were blinded for the assignment. RESULTS: No patient was excluded after randomization. Patient groups did not differ in terms of age, gender, comorbidities and renal function at randomization. The rate of AKI assessed by AKIN criteria was 22.5% in our population. EPO treatment did not significantly modify the difference in uNGAl between 48 hours and randomization compared to placebo [2.5 ng/ml (-17.3; 22.5) vs 0.7 ng/ml (-31.77; 25.15), p = 0.77] and the incidence of AKI was similar. Inflammatory cytokines levels were not influenced by EPO treatment. Mortality and hospital stays were similar between the groups and no adverse event was recorded. CONCLUSION: In this randomized-controlled trial, alpha-Epoetin administrated after cardiac surgery, although safe, demonstrated neither nephroprotective nor anti-inflammatory properties.Trial registration numberNCT00676234.
    BMC Nephrology 10/2012; 13(1):132. DOI:10.1186/1471-2369-13-132 · 1.52 Impact Factor
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    Néphrologie & Thérapeutique 09/2012; 8(5):333. DOI:10.1016/j.nephro.2012.07.277 · 0.55 Impact Factor
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    Jérôme Pugin
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    ABSTRACT: Systemic inflammation is very prevalent among critically ill patients, particularly those with extensive tissue injury. Although downstream mediators (cytokines) and effector cells (phagocytes) have been identified, proximal mediators originating from injured tissues remained elusive. Alarmins ("danger signals") released by necrotic/injured cells have been identified recently and certainly play a role in triggering local and systemic inflammation in critically ill patients. The most promising alarmin candidates are of mitochondrial origin, i.e. mitochondrial DNA and the chemotactic factor fMet-Leu-Phe (fMLP). ATP also is released from necrotic tissues and stimulates the assembly of the inflammasome, leading to the production of proinflammatory cytokines, such as interleukin (IL)-1SZ. The identification of novel alarmins opens new therapeutic avenues for the treatment of severe SIRS, and SIRS-dependent organ dysfunction.
    07/2012; 2(1):27. DOI:10.1186/2110-5820-2-27
  • Carolyn S Calfee, Jérôme Pugin
    American Journal of Respiratory and Critical Care Medicine 07/2012; 186(1):2-4. DOI:10.1164/rccm.201205-0854ED · 11.99 Impact Factor
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    ABSTRACT: Recognition of microbial molecules by mammalian host receptors is essential to mount an immune response. Hexaacylated LPS is the prototypic example of a bacterial molecule recognized by the receptor complex TLR4/MD-2 with its lipid A moiety, whereas bacterial lipopeptides are recognized by TLR2. Here we show that a series of synthetic triacylated lipid A-like molecules are weak Toll-like receptor (TLR) agonists (mainly TLR2 agonists) but very potent TLR4/MD-2 antagonists (submicromolar range). Not only do they block human cell responses to LPS but also to whole gram-negative bacteria, and they inhibit the phagocytosis of gram-negative bacteria. These compounds may represent promising immunomodulatory agents.
    Journal of Biological Chemistry 03/2012; 287(20):16121-31. DOI:10.1074/jbc.M112.348383 · 4.60 Impact Factor

Publication Stats

8k Citations
779.99 Total Impact Points

Institutions

  • 1992–2015
    • University of Geneva
      • • Division of Intensive Care
      • • Department of Microbiology and Molecular Medicine (MIMOL)
      • • Division of Nephrology
      • • Division of Gastroenterology and Hepatology
      • • Division of Anaesthesiology
      Genève, Geneva, Switzerland
  • 2004–2011
    • Hôpitaux Universitaires de Genève
      • • Service des soins intensifs
      • • Service de néphrologie
      Genève, Geneva, Switzerland
    • University of Alabama at Birmingham
      • Department of Medicine
      Birmingham, AL, United States
  • 2001
    • University of California, San Francisco
      • Cardiovascular Research Institute
      San Francisco, CA, United States
  • 2000
    • University of Vienna
      Wien, Vienna, Austria
  • 1994
    • Minneapolis Veterans Affairs Hospital
      Minneapolis, Minnesota, United States
    • The Rockefeller University
      New York, New York, United States
  • 1993–1994
    • The Scripps Research Institute
      • Department of Molecular and Experimental Medicine
      La Jolla, California, United States