Jean-Daniel Chiche

The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3)

IMPORTANCE Definitions of sepsis and septic shock were last revised in 2001. Considerable advances have since been made into the pathobiology (changes in organ function, morphology, cell biology, biochemistry, immunology, and circulation), management, and epidemiology of sepsis, suggesting the need for reexamination. OBJECTIVE To evaluate and, as needed, update definitions for sepsis and septic shock. PROCESS A task force (n = 19) with expertise in sepsis pathobiology, clinical trials, and epidemiology was convened by the Society of Critical Care Medicine and the European Society of Intensive Care Medicine. Definitions and clinical criteria were generated through meetings, Delphi processes, analysis of electronic health record databases, and voting, followed by circulation to international professional societies, requesting peer review and endorsement (by 31 societies listed in the Acknowledgment). KEY FINDINGS FROM EVIDENCE SYNTHESIS Limitations of previous definitions included an excessive focus on inflammation, the misleading model that sepsis follows a continuum through severe sepsis to shock, and inadequate specificity and sensitivity of the systemic inflammatory response syndrome (SIRS) criteria. Multiple definitions and terminologies are currently in use for sepsis, septic shock, and organ dysfunction, leading to discrepancies in reported incidence and observed mortality. The task force concluded the term severe sepsis was redundant. RECOMMENDATIONS Sepsis should be defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. For clinical operationalization, organ dysfunction can be represented by an increase in the Sequential [Sepsis-related] Organ Failure Assessment (SOFA) score of 2 points or more, which is associated with an in-hospital mortality greater than 10%. Septic shock should be defined as a subset of sepsis in which particularly profound circulatory, cellular, and metabolic abnormalities are associated with a greater risk of mortality than with sepsis alone. Patients with septic shock can be clinically identified by a vasopressor requirement to maintain a mean arterial pressure of 65 mm Hg or greater and serum lactate level greater than 2 mmol/L (>18 mg/dL) in the absence of hypovolemia. This combination is associated with hospital mortality rates greater than 40%. In out-of-hospital, emergency department, or general hospital ward settings, adult patients with suspected infection can be rapidly identified as being more likely to have poor outcomes typical of sepsis if they have at least 2 of the following clinical criteria that together constitute a new bedside clinical score termed quickSOFA (qSOFA): respiratory rate of 22/min or greater, altered mentation, or systolic blood pressure of 100 mm Hg or less. CONCLUSIONS AND RELEVANCE These updated definitions and clinical criteria should replace previous definitions, offer greater consistency for epidemiologic studies and clinical trials, and facilitate earlier recognition and more timely management of patients with sepsis or at risk of developing sepsis.

Reversible myocardial dysfunction in survivors of out-of-hospital cardiac arrest ☆

OBJECTIVES The aim of the study was to assess the hemodynamic status of survivors of out-of-hospital cardiac arrest (OHCA). BACKGROUND The global prognosis after successfully resuscitated patients with OHCA remains poor. Clinical studies describing the hemodynamic status of survivors of OHCA and its impact on prognosis are lacking. METHODS Among 165 consecutive patients admitted after successful resuscitation from OHCA, 73 required invasive monitoring because of hemodynamic instability, defined as hypotension requiring vasoactive drugs, during the first 72 h. Clinical features and data from invasive monitoring were analyzed. RESULTS Hemodynamic instability occurred at a median time of 6.8 h (range 4.3 to 7.3) after OHCA. The initial cardiac index (CI) and filling pressures were low. Then, the CI rapidly increased 24 h after the onset of OHCA, independent of filling pressures and inotropic agents (2.05 [1.43 to 2.90] 8 h vs. 3.19 l/min per m(2) [2.67 to 4.20] 24 h after OHCA; p < 0.001). Despite a significant improvement in CI at 24 h, a superimposed vasodilation delayed the discontinuation of vasoactive drugs. No improvement in CI at 24 h was noted in 14 patients who subsequently died of multiorgan failure. Hemodynamic status was not predictive of the neurologic outcome. CONCLUSIONS In survivors of OHCA, hemodynamic instability requiring administration of vasoactive drugs is frequent and appears several hours after hospital admission. It is characterized by a low CI that is reversible in most cases within 24 h, suggesting post-resuscitation myocardial dysfunction. Early death by multiorgan failure is associated with a persistent low CI at 24 h.

High frequency oscillatory ventilation compared with conventional mechanical ventilation in adult respiratory distress syndrome: a randomized controlled trial [ISRCTN24242669].

IntroductionTo compare the safety and efficacy of high frequency oscillatory ventilation (HFOV) with conventional mechanical ventilation (CV) for early intervention in adult respiratory distress syndrome (ARDS), a multi-centre randomized trial in four intensive care units was conducted.MethodsPatients with ARDS were randomized to receive either HFOV or CV. In both treatment arms a priority was given to maintain lung volume while minimizing peak pressures. CV ventilation strategy was aimed at reducing tidal volumes. In the HFOV group, an open lung strategy was used. Respiratory and circulatory parameters were recorded and clinical outcome was determined at 30 days of follow up.ResultsThe study was prematurely stopped. Thirty-seven patients received HFOV and 24 patients CV (average APACHE II score 21 and 20, oxygenation index 25 and 18 and duration of mechanical ventilation prior to randomization 2.1 and 1.5 days, respectively). There were no statistically significant differences in survival without supplemental oxygen or on ventilator, mortality, therapy failure, or crossover. Adjustment by a priori defined baseline characteristics showed an odds ratio of 0.80 (95% CI 0.22–2.97) for survival without oxygen or on ventilator, and an odds ratio for mortality of 1.15 (95% CI 0.43–3.10) for HFOV compared with CV. The response of the oxygenation index (OI) to treatment did not differentiate between survival and death. In the HFOV group the OI response was significantly higher than in the CV group between the first and the second day. A post hoc analysis suggested that there was a relatively better treatment effect of HFOV compared with CV in patients with a higher baseline OI.ConclusionNo significant differences were observed, but this trial only had power to detect major differences in survival without oxygen or on ventilator. In patients with ARDS and higher baseline OI, however, there might be a treatment benefit of HFOV over CV. More research is needed to establish the efficacy of HFOV in the treatment of ARDS. We suggest that future studies are designed to allow for informative analysis in patients with higher OI.

Surviving Sepsis Campaign: association between performance metrics and outcomes in a 7.5-year study.

Purpose:To determine the association between compliance with the Surviving Sepsis Campaign (SSC) performance bundles and mortality. Design:Compliance with the SSC performance bundles, which are based on the 2004 SSC guidelines, was measured in 29,470 subjects entered into the SSC database from January 1, 2005, through June 30, 2012. Compliance was defined as evidence that all bundle elements were achieved. Setting:Two hundred eighteen community, academic, and tertiary care hospitals in the United States, South America, and Europe. Patients:Patients from the emergency department, medical and surgical wards, and ICU who met diagnosis criteria for severe sepsis and septic shock. Methods:A multifaceted, collaborative change intervention aimed at facilitating adoption of the SSC resuscitation and management bundles was introduced. Compliance with the SSC bundles and associated mortality rate was the primary outcome variable. Results:Overall lower mortality was observed in high (29.0%) versus low (38.6%) resuscitation bundle compliance sites (p < 0.001) and between high (33.4%) and low (32.3%) management bundle compliance sites (p = 0.039). Hospital mortality rates dropped 0.7% per site for every three months (quarter) of participation (p < 0.001). Hospital and intensive care unit length of stay decreased 4% (95% CI: 1% - 7%; p = 0.012) for every 10% increase in site compliance with the resuscitation bundle. Conclusions:This analysis demonstrates that increased compliance with sepsis performance bundles was associated with a 25% relative risk reduction in mortality rate. Every 10% increase in compliance and additional quarter of participation in the SSC initiative was associated with a significant decrease in the odds ratio for hospital mortality. These results demonstrate that performance metrics can drive change in clinical behavior, improve quality of care, and may decrease mortality in patients with severe sepsis and septic shock.

Temporal changes in management and outcome of septic shock in patients with malignancies in the intensive care unit.

Objective:Septic shock is a severe, often terminal, complication of malignancy. For patients without malignancy, outcome from septic shock has improved with new advances in care. We wished to explore whether outcome from septic shock has similarly improved for cancer patients, with regard to implementation of recent adjuvant therapies. Design:An 8-yr retrospective observational study. Setting:A 24-bed medical intensive care unit in a university hospital. Patients:Patients were 238 consecutive cancer patients (solid tumors or hematologic malignancies) with septic shock admitted to the intensive care unit within two consecutive 4-yr periods: 1998–2001 and 2002–2005. Interventions:None. Measurements and Main Results:Septic shock occurred in 90 patients in 1998–2001 and 148 in 2002–2005. Management of septic shock between the two periods mostly differed by emergence of adjuvant therapies of sepsis (mainly low-dose glucocorticoids) and intensive insulin therapy and a more frequent use of renal replacement therapy in the recent period. Short-term survival rates were significantly higher during 2002–2005 compared with the previous 4-yr period: 28-day, intensive care unit, and hospital survival rates were 47.3% vs. 27.8% (p = .003), 41.2% vs. 26.7% (p = .02), and 36.5% vs. 21.1% (p = .01), respectively. After adjustment, intensive care unit admission between 2002 and 2005 was an independent favorable prognostic factor for short-term outcome. Improved survival was mainly observed in patients who did not require renal replacement therapy during their stay in the intensive care unit (hospital survival 65% in 2002–2005 vs. 21.4% in 1998–2001, p < .001). Conclusions:Improved outcome in critically ill cancer patients extended to the subgroup of patients with septic shock. This might be ascribed both to a better selection of patients and to improvements in the care and management, including new therapeutic strategies for sepsis.

Sp110 Localizes to the PML-Sp100 Nuclear Body and May Function as a Nuclear Hormone Receptor Transcriptional Coactivator

ABSTRACT The nuclear body is a multiprotein complex that may have a role in the regulation of gene transcription. This structure is disrupted in a variety of human disorders including acute promyelocytic leukemia and viral infections, suggesting that alterations in the nuclear body may have an important role in the pathogenesis of these diseases. In this study, we identified a cDNA encoding a leukocyte-specific nuclear body component designated Sp110. The N-terminal portion of Sp110 was homologous to two previously characterized components of the nuclear body (Sp100 and Sp140). The C-terminal region of Sp110 was homologous to the transcription intermediary factor 1 (TIF1) family of proteins. High levels of Sp110 mRNA were detected in human peripheral blood leukocytes and spleen but not in other tissues. The levels of Sp110 mRNA and protein in the human promyelocytic leukemia cell line NB4 increased following treatment with all-trans retinoic acid (ATRA), and Sp110 localized to PML-Sp100 nuclear bodies in ATRA-treated NB4 cells. Because of the structural similarities between Sp110 and TIF1 proteins, the effect of Sp110 on gene transcription was examined. An Sp110 DNA-binding domain fusion protein activated transcription of a reporter gene in transfected mammalian cells. In addition, Sp110 produced a marked increase in ATRA-mediated expression of a reporter gene containing a retinoic acid response element. Taken together, the results of this study demonstrate that Sp110 is a member of the Sp100/Sp140 family of nuclear body components and that Sp110 may function as a nuclear hormone receptor transcriptional coactivator. The predominant expression of Sp110 in leukocytes and the enhanced expression of Sp110 in NB4 cells treated with ATRA raise the possibility that Sp110 has a role in inducing differentiation of myeloid cells.

Comparison between Flotrac-Vigileo and Bioreactance, a totally noninvasive method for cardiac output monitoring

IntroductionThis study was designed to compare the clinical acceptability of two cardiac output (CO) monitoring systems: a pulse wave contour-based system (FloTrac-Vigileo) and a bioreactance-based system (NICOM), using continuous thermodilution (PAC-CCO) as a reference method.MethodsConsecutive patients, requiring PAC-CCO monitoring following cardiac surgery, were also monitored by the two other devices. CO values obtained simultaneously by the three systems were recorded continuously on a minute-by-minute basis.ResultsContinuous recording was performed on 29 patients, providing 12,099 simultaneous measurements for each device (417 ± 107 per patient). In stable conditions, correlations of NICOM and Vigileo with PAC-CCO were 0.77 and 0.69, respectively. The bias was -0.01 ± 0.84 for NICOM and -0.01 ± 0.81 for Vigileo (NS). NICOM relative error was less than 30% in 94% of the patients and less than 20% in 79% vs. 91% and 79% for the Vigileo, respectively (NS). The variability of measurements around the trend line (precision) was not different between the three methods: 8 ± 3%, 8 ± 4% and 8 ± 3% for PAC-CCO, NICOM and Vigileo, respectively. CO changes were 7.2 minutes faster with Vigileo and 6.9 minutes faster with NICOM (P < 0.05 both systems vs. PAC-CCO, NS). Amplitude of changes was not significantly different than thermodilution. Finally, the sensitivity and specificity for predicting significant CO changes were 0.91 and 0.95 respectively for the NICOM and 0.86 and 0.92 respectively for the Vigileo.ConclusionsThis study showed that the NICOM and Vigileo devices have similar monitoring capabilities in post-operative cardiac surgery patients.

Transforming growth factor-β: A mediator of cell regulation in acute respiratory distress syndrome

ObjectiveTo review recent advances in the use of transforming growth factor (TGF)-&bgr; in acute lung injury and to apply this knowledge to understanding the pathophysiology of this syndrome. Data Sources and Study SelectionPublished research and review articles in the English language related to the role of TGF-&bgr; in acute lung injury. Data Extraction and SynthesisThe cytokine TGF-&bgr; plays a critical role in the resolution of tissue injury in multiple organs, including the lung. Following injury, TGF-&bgr; has been most thoroughly evaluated during the late phases of tissue repair, where it plays a critical role in the development of pulmonary fibrosis. In contrast, recent animal studies showed that expression levels of several TGF-&bgr;-inducible genes were dramatically increased as early as 2 days after the induction of injury. The integrin &agr;v&bgr;6 activates latent TGF-&bgr; in the lungs. Mice lacking this integrin were completely protected from pulmonary edema in a model of bleomycin-induced acute lung injury. Pharmacologic inhibition of TGF-&bgr; also protected wild-type mice from pulmonary edema induced by bleomycin or Escherichia coli endotoxin. Similar findings also have been reported in patients in a clinical study evaluating TGF-&bgr; in the bronchoalveolar lavage fluid during the course of acute respiratory distress syndrome (ARDS). Indeed, the bronchoalveolar lavage concentrations were dramatically increased as early as 1 day after the initiation of ARDS criteria and were correlated with decreases in the Pao2/Fio2 ratio, suggesting an important role for TGF-b1 in the development of ARDS in humans. ConclusionsThese studies suggest that TGF-&bgr; not only participates in the late phase of acute lung injury, but also might be active early in acute lung injury and potentially could contribute to the development of pulmonary edema. Integrin-mediated local activation of TGF-&bgr; is critical to the development of pulmonary edema in ARDS, and blocking TGF-&bgr; or its activation could be an effective treatment for this disorder.

Importance of hemostatic gene polymorphisms for susceptibility to and outcome of severe sepsis

Individuals vary considerably in their susceptibility to infection and in their ability to recover from apparently similar infectious processes. These differences can be partially explained by polymorphisms of the genes encoding proteins involved in mediating and controlling the innate immune response, the inflammatory cascade, coagulation, and fibrinolysis. It is evident from experimental studies that dysregulation of the coagulation system, which is characteristic of the pathophysiology of septic shock (a procoagulant and antifibrinolytic state), contributes to systemic inflammation and death in sepsis. Several genetic variations in proteins that increase coagulation or impair anticoagulation and fibrinolysis have been described. Thus, polymorphisms have been reported in prothrombin, fibrinogen, factor V, tissue factor, endothelial protein C receptor, and plasminogen activator inhibitor-1 genes. Some of them are associated with an increased risk of pulmonary emboli, acute myocardial infarction, stroke, and severe sepsis. Hence, the deletion polymorphism (4G) within the promoter region of the plasminogen activator inhibitor-1 gene leads to impaired fibrinolysis and influences the severity and outcome of meningococcal disease and the susceptibility to severe sepsis and multiple organ failure after trauma. The factor V Leiden mutation is associated with thrombotic events and has been reported to exacerbate purpura fulminans in meningococcal infection. Surprisingly, this genetic variant seems to provide a survival advantage in severe sepsis, underlying the extreme complexity of the interaction between inflammation and coagulation. The study of genetic polymorphisms might provide important insights into the pathogenesis of severe sepsis and could make it possible to identify individuals who are at risk of developing or dying of severe infections. As genetic associations are discovered, medical practice can become more preemptive, using the predictive ability of genetics to anticipate disease and recommend therapy.

Pneumothorax During Laparoscopic Fundoplication: Diagnosis and Treatment with Positive End-Expiratory Pressure

Pneumothorax can develop during laparoscopy, particularly during laparoscopic fundoplication, since the left parietal pleura is exposed and can be torn during dissection in the diaphragmatic hiatus.Such an event will result in specific pathophysiologic changes, since CO2, under pressure in the abdominal cavity, will pass into the pleural space. The aim of this study was to document the pathophysiologic changes induced by pneumothorax, and to evaluate the benefit of positive end-expiratory pressure (PEEP) to treat pneumothorax. Forty-six ASA physical status I and II patients scheduled for laparoscopic fundoplication were monitored extensively; heart rate, mean arterial pressure, endtidal CO2 (PETCO2), oxygen saturation of hemoglobin (SpO2), minute ventilation, tidal volume, dynamic total lung thorax compliance, and airway pressures were recorded. In 25 patients, oxygen uptake, CO2 elimination and arterial blood gases were also measured. Pneumothorax was diagnosed in seven patients. It resulted in the following pathophysiologic changes: decrease in total lung thorax compliance, increase in airway pressures, and increase in CO2 absorption. Consequently, PaCO2 and PETCO2 also increased. SpO2, however, remained normal. The use of PEEP largely corrected these respiratory changes. None of these pneumothoraces required drainage. These data suggest that pneumothorax is common during laparoscopic fundoplication. Early diagnosis is possible by simultaneous monitoring of PETCO2, total lung thorax compliance, and airway pressures. Finally, treatment with PEEP provides an alternative to chest tube placement when pneumothorax is secondary to passage of peritoneal CO2 into the interpleural space. (Anesth Analg 1995;81:993-1000)