Ignacio Martin-Loeches

Empiric Antibiotic Treatment Reduces Mortality in Severe Sepsis and Septic Shock From the First Hour: Results From a Guideline-Based Performance Improvement Program*

Objectives:Compelling evidence has shown that aggressive resuscitation bundles, adequate source control, appropriate antibiotic therapy, and organ support are cornerstone for the success in the treatment of patients with sepsis. Delay in the initiation of appropriate antibiotic therapy has been recognized as a risk factor for mortality. To perform a retrospective analysis on the Surviving Sepsis Campaign database to evaluate the relationship between timing of antibiotic administration and mortality. Design:Retrospective analysis of a large dataset collected prospectively for the Surviving Sepsis Campaign. Setting:One hundred sixty-five ICUs in Europe, the United States, and South America. Patients:A total of 28,150 patients with severe sepsis and septic shock, from January 2005 through February 2010, were evaluated. Interventions:Antibiotic administration and hospital mortality. Measurements and Main Results:A total of 17,990 patients received antibiotics after sepsis identification and were included in the analysis. In-hospital mortality was 29.7% for the cohort as a whole. There was a statically significant increase in the probability of death associated with the number of hours of delay for first antibiotic administration. Hospital mortality adjusted for severity (sepsis severity score), ICU admission source (emergency department, ward, vs ICU), and geographic region increased steadily after 1 hour of time to antibiotic administration. Results were similar in patients with severe sepsis and septic shock, regardless of the number of organ failure. Conclusions:The results of the analysis of this large population of patients with severe sepsis and septic shock demonstrate that delay in first antibiotic administration was associated with increased in-hospital mortality. In addition, there was a linear increase in the risk of mortality for each hour delay in antibiotic administration. These results underscore the importance of early identification and treatment of septic patients in the hospital setting.

Th1 and Th17 hypercytokinemia as early host response signature in severe pandemic influenza.

IntroductionHuman host immune response following infection with the new variant of A/H1N1 pandemic influenza virus (nvH1N1) is poorly understood. We utilize here systemic cytokine and antibody levels in evaluating differences in early immune response in both mild and severe patients infected with nvH1N1.MethodsWe profiled 29 cytokines and chemokines and evaluated the haemagglutination inhibition activity as quantitative and qualitative measurements of host immune responses in serum obtained during the first five days after symptoms onset, in two cohorts of nvH1N1 infected patients. Severe patients required hospitalization (n = 20), due to respiratory insufficiency (10 of them were admitted to the intensive care unit), while mild patients had exclusively flu-like symptoms (n = 15). A group of healthy donors was included as control (n = 15). Differences in levels of mediators between groups were assessed by using the non parametric U-Mann Whitney test. Association between variables was determined by calculating the Spearman correlation coefficient. Viral load was performed in serum by using real-time PCR targeting the neuraminidase gene.ResultsIncreased levels of innate-immunity mediators (IP-10, MCP-1, MIP-1β), and the absence of anti-nvH1N1 antibodies, characterized the early response to nvH1N1 infection in both hospitalized and mild patients. High systemic levels of type-II interferon (IFN-γ) and also of a group of mediators involved in the development of T-helper 17 (IL-8, IL-9, IL-17, IL-6) and T-helper 1 (TNF-α, IL-15, IL-12p70) responses were exclusively found in hospitalized patients. IL-15, IL-12p70, IL-6 constituted a hallmark of critical illness in our study. A significant inverse association was found between IL-6, IL-8 and PaO2 in critical patients.ConclusionsWhile infection with the nvH1N1 induces a typical innate response in both mild and severe patients, severe disease with respiratory involvement is characterized by early secretion of Th17 and Th1 cytokines usually associated with cell mediated immunity but also commonly linked to the pathogenesis of autoimmune/inflammatory diseases. The exact role of Th1 and Th17 mediators in the evolution of nvH1N1 mild and severe disease merits further investigation as to the detrimental or beneficial role these cytokines play in severe illness.

Assessment of the worldwide burden of critical illness: the Intensive Care Over Nations (ICON) audit

BACKGROUND Global epidemiological data regarding outcomes for patients in intensive care units (ICUs) are scarce, but are important in understanding the worldwide burden of critical illness. We, therefore, did an international audit of ICU patients worldwide and assessed variations between hospitals and countries in terms of ICU mortality. METHODS 730 participating centres in 84 countries prospectively collected data on all adult (>16 years) patients admitted to their ICU between May 8 and May 18, 2012, except those admitted for fewer than 24 h for routine postoperative monitoring. Participation was voluntary. Data were collected daily for a maximum of 28 days in the ICU and patients were followed up for outcome data until death or hospital discharge. In-hospital death was analysed using multilevel logistic regression with three levels: patient, hospital, and country. FINDINGS 10,069 patients were included from ICUs in Europe (5445 patients; 54·1%), Asia (1928; 19·2%), the Americas (1723; 17·1%), Oceania (439; 4·4%), the Middle East (393; 3·9%), and Africa (141; 1·4%). Overall, 2973 patients (29·5%) had sepsis on admission or during the ICU stay. ICU mortality rates were 16·2% (95% CI 15·5-16·9) across the whole population and 25·8% (24·2-27·4) in patients with sepsis. Hospital mortality rates were 22·4% (21·6-23·2) in the whole population and 35·3% (33·5-37·1) in patients with sepsis. Using a multilevel analysis, the unconditional model suggested significant between-country variations (var=0·19, p=0·002) and between-hospital variations (var=0·43, p<0·0001) in the individual risk of in-hospital death. There was a stepwise increase in the adjusted risk of in-hospital death according to decrease in global national income. INTERPRETATION This large database highlights that sepsis remains a major health problem worldwide, associated with high mortality rates in all countries. Our findings also show a significant association between the risk of death and the global national income and suggest that ICU organisation has an important effect on risk of death. FUNDING None.

Spectrum of practice in the diagnosis of nosocomial pneumonia in patients requiring mechanical ventilation in European intensive care units.

Objectives:Information on clinical practice regarding the diagnosis of pneumonia in European intensive care units is limited. The aim of this study was to describe the spectrum of actual diagnostic practices in a large sample of European intensive care units. Design:Prospective, observational, multicenter study. Setting:Twenty-seven intensive care units of nine European countries. Patients:Consecutive patients requiring invasive mechanical ventilation for an admission diagnosis of pneumonia or receiving mechanical ventilation for >48 hrs irrespective of admission diagnosis. Interventions:None. Measurements and Main Results:A total of 2,436 patients were evaluated; 827 were admitted with or developed nosocomial pneumonia (hospital-acquired pneumonia [HAP], 27.1%; ventilator-associated pneumonia [VAP], 56.2%; very early onset VAP, 16.7%). Mean age was 59.4 ± 18.1 yrs, 65.0% were men, and mean admission Simplified Acute Physiology Score II was 46.7 ± 17.1. Worsening oxygenation (76.8%), purulent/changing respiratory secretions (72.1%), and new temperature elevation (69.2%) were the most frequent clinical signs of nosocomial pneumonia. Etiological diagnosis was based on noninvasive respiratory specimens in 74.8% of episodes. Bronchoscopy was performed in 23.3% of episodes. Bronchoscopy performance, after adjustment by severity of illness, age, and type of hospital, were predicted by worsening oxygenation (odds ratio 2.03; 95% confidence interval, 1.27–3.24) and male sex (odds ratio 1.77; 95% confidence interval, 1.19–2.65). Definite cause was documented in 69.5% of nosocomial pneumonia cases. The most common isolates were Staphylococcus aureus (16.3% methicillin-sensitive S. aureus and 16.0% methicillin-resistant S. aureus), Pseudomonas aeruginosa (23.1%), and Acinetobacter baumannii (19.1%). Presence of nosocomial pneumonia significantly prolonged mean length of mechanical ventilation (10.3 days, p < .05) and mean intensive care unit length of stay (12.2 days, p < .05) in intensive care unit survivors. Mortality rate was 37.7% for nosocomial pneumonia vs. 31.6% for patients without pneumonia (p < .05). Conclusions:Etiological diagnosis of nosocomial pneumonia in a large sample of European intensive care units was based mainly on noninvasive techniques. However, there was high variability in bronchoscopy use between the participating intensive care units.

Host adaptive immunity deficiency in severe pandemic influenza

IntroductionPandemic A/H1N1/2009 influenza causes severe lower respiratory complications in rare cases. The association between host immune responses and clinical outcome in severe cases is unknown.MethodsWe utilized gene expression, cytokine profiles and generation of antibody responses following hospitalization in 19 critically ill patients with primary pandemic A/H1N1/2009 influenza pneumonia for identifying host immune responses associated with clinical outcome. Ingenuity pathway analysis 8.5 (IPA) (Ingenuity Systems, Redwood City, CA) was used to select, annotate and visualize genes by function and pathway (gene ontology). IPA analysis identified those canonical pathways differentially expressed (P < 0.05) between comparison groups. Hierarchical clustering of those genes differentially expressed between groups by IPA analysis was performed using BRB-Array Tools v.3.8.1.ResultsThe majority of patients were characterized by the presence of comorbidities and the absence of immunosuppressive conditions. pH1N1 specific antibody production was observed around day 9 from disease onset and defined an early period of innate immune response and a late period of adaptive immune response to the virus. The most severe patients (n = 12) showed persistence of viral secretion. Seven of the most severe patients died. During the late phase, the most severe patient group had impaired expression of a number of genes participating in adaptive immune responses when compared to less severe patients. These genes were involved in antigen presentation, B-cell development, T-helper cell differentiation, CD28, granzyme B signaling, apoptosis and protein ubiquitination. Patients with the poorest outcomes were characterized by proinflammatory hypercytokinemia, along with elevated levels of immunosuppressory cytokines (interleukin (IL)-10 and IL-1ra) in serum.ConclusionsOur findings suggest an impaired development of adaptive immunity in the most severe cases of pandemic influenza, leading to an unremitting cycle of viral replication and innate cytokine-chemokine release. Interruption of this deleterious cycle may improve disease outcome.

Community-acquired respiratory coinfection in critically ill patients with pandemic 2009 influenza A(H1N1) virus.

BACKGROUND Little is known about the impact of community-acquired respiratory coinfection in patients with pandemic 2009 influenza A(H1N1) virus infection. METHODS This was a prospective, observational, multicenter study conducted in 148 Spanish ICUs. RESULTS Severe respiratory syndrome was present in 645 ICU patients. Coinfection occurred in 113 (17.5%) of patients. Streptococcus pneumoniae (in 62 patients [54.8%]) was identified as the most prevalent bacteria. Patients with coinfection at ICU admission were older (47.5±15.7 vs 43.8±14.2 years, P<.05) and presented a higher APACHE (Acute Physiology and Chronic Health Evaluation) II score (16.1±7.3 vs 13.3±7.1, P<.05) and Sequential Organ Failure Assessment (SOFA) score (7.0±3.8 vs 5.2±3.5, P<.05). No differences in comorbidities were observed. Patients who had coinfection required vasopressors (63.7% vs 39.3%, P<.05) and invasive mechanical ventilation (69% vs 58.5%, P<.05) more frequently. ICU length of stay was 3 days longer in patients who had coinfection than in patients who did not (11 [interquartile range, 5-23] vs 8 [interquartile range 4-17], P=.01). Coinfection was associated with increased ICU mortality (26.2% vs 15.5%; OR, 1.94; 95% CI, 1.21-3.09), but Cox regression analysis adjusted by potential confounders did not confirm a significant association between coinfection and ICU mortality. CONCLUSIONS During the 2009 pandemics, the role played by bacterial coinfection in bringing patients to the ICU was not clear, S pneumoniae being the most common pathogen. This work provides clear evidence that bacterial coinfection is a contributor to increased consumption of health resources by critical patients infected with the virus and is the virus that causes critical illness in the vast majority of cases.

Impact of obesity in patients infected with 2009 influenza A(H1N1).

OBJECTIVE A large proportion of patients infected with 2009 influenza A(H1N1) (A[H1N1]) are obese. Obesity has been proposed as a risk factor influencing outcome in these patients. However, its role remains unclear. We evaluate the outcome of patients who are obese and infected with A(H1N1) in the ICU, determining whether obesity is a risk factor for mortality. METHODS This was a prospective, observational, and multicenter study performed in 144 ICUs in Spain. Data were obtained from the Grupo de Trabajo en Enfermedades Infecciosas de la Sociedad Española de Medicina Intensiva, Crítica y Unidades Coronarias (GTEI/SEMICYUC) registry. Adult patients with A(H1N1) that was confirmed by real-time polymerase chain reaction were included in the analysis. Patients who were obese (BMI > 30) were compared with patients who were nonobese. Cox regression analysis was used to determine adjusted mortality. Differences of P < .05 were considered significant. RESULTS In January 2010, the GTEI/SEMICYUC registry had complete records for 416 patients. One hundred and fifty patients (36.1%) were obese, of whom 67 (44.7%) were morbidly obese (BMI > 40). Mechanical ventilation (MV) was more frequently applied in patients who were obese (64% vs 52.4%, P < .01) Patients with obesity remained on MV longer than patients who were nonobese (6.5 ± 10.3 days vs 9.3 ± 9.7 days, P = .02), had longer ICU length of stay (10.8 ± 12.1 days vs 13.7 ± 11.7 days, P = .03), and had longer hospitalization (18.2 ± 14.6 days vs 22.2 ± 16.5 days, P = .02). Mortality adjusted by severity and potential confounders identified that obesity was not significantly associated with ICU mortality (hazard ratio, 1.1; 95% CI, 0.69-1.75; P = .68). CONCLUSIONS In our cohort, patients who were obese and infected with A(H1N1) did not have increased mortality. However, there was an association between obesity and higher ICU resource consumption.

Interleukin-6 Is a Potential Biomarker for Severe Pandemic H1N1 Influenza A Infection

Pandemic H1N1 influenza A (H1N1pdm) is currently a dominant circulating influenza strain worldwide. Severe cases of H1N1pdm infection are characterized by prolonged activation of the immune response, yet the specific role of inflammatory mediators in disease is poorly understood. The inflammatory cytokine IL-6 has been implicated in both seasonal and severe pandemic H1N1 influenza A (H1N1pdm) infection. Here, we investigated the role of IL-6 in severe H1N1pdm infection. We found IL-6 to be an important feature of the host response in both humans and mice infected with H1N1pdm. Elevated levels of IL-6 were associated with severe disease in patients hospitalized with H1N1pdm infection. Notably, serum IL-6 levels associated strongly with the requirement of critical care admission and were predictive of fatal outcome. In C57BL/6J, BALB/cJ, and B6129SF2/J mice, infection with A/Mexico/4108/2009 (H1N1pdm) consistently triggered severe disease and increased IL-6 levels in both lung and serum. Furthermore, in our lethal C57BL/6J mouse model of H1N1pdm infection, global gene expression analysis indicated a pronounced IL-6 associated inflammatory response. Subsequently, we examined disease and outcome in IL-6 deficient mice infected with H1N1pdm. No significant differences in survival, weight loss, viral load, or pathology were observed between IL-6 deficient and wild-type mice following infection. Taken together, our findings suggest IL-6 may be a potential disease severity biomarker, but may not be a suitable therapeutic target in cases of severe H1N1pdm infection due to our mouse data.

Determinants of prescription and choice of empirical therapy for hospital-acquired and ventilator-associated pneumonia

The objectives of this study were to assess the determinants of empirical antibiotic choice, prescription patterns and outcomes in patients with hospital-acquired pneumonia (HAP)/ventilator-associated pneumonia (VAP) in Europe. We performed a prospective, observational cohort study in 27 intensive care units (ICUs) from nine European countries. 100 consecutive patients on mechanical ventilation for HAP, on mechanical ventilation >48 h or with VAP were enrolled per ICU. Admission category, sickness severity and Acinetobacter spp. prevalence >10% in pneumonia episodes determined antibiotic empirical choice. Trauma patients were more often prescribed non-anti-Pseudomonas cephalosporins (OR 2.68, 95% CI 1.50–4.78). Surgical patients received less aminoglycosides (OR 0.26, 95% CI 0.14–0.49). A significant correlation (p<0.01) was found between Simplified Acute Physiology Score II score and carbapenem prescription. Basal Acinetobacter spp. prevalence >10% dramatically increased the prescription of carbapenems (OR 3.5, 95% CI 2.0–6.1) and colistin (OR 115.7, 95% CI 6.9–1,930.9). Appropriate empirical antibiotics decreased ICU length of stay by 6 days (26.3±19.8 days versus 32.8±29.4 days; p = 0.04). The antibiotics that were prescribed most were carbapenems, piperacillin/tazobactam and quinolones. Median (interquartile range) duration of antibiotic therapy was 9 (6–12) days. Anti-methicillin-resistant Staphylococcus aureus agents were prescribed in 38.4% of VAP episodes. Admission category, sickness severity and basal Acinetobacter prevalence >10% in pneumonia episodes were the major determinants of antibiotic choice at the bedside. Across Europe, carbapenems were the antibiotic most prescribed for HAP/VAP.

Bacteremia is an independent risk factor for mortality in nosocomial pneumonia: a prospective and observational multicenter study

IntroductionSince positive blood cultures are uncommon in patients with nosocomial pneumonia (NP), the responsible pathogens are usually isolated from respiratory samples. Studies on bacteremia associated with hospital-acquired pneumonia (HAP) have reported fatality rates of up to 50%. The purpose of the study is to compare risk factors, pathogens and outcomes between bacteremic nosocomial pneumonia (B-NP) and nonbacteremic nosocomial pneumonia (NB-NP) episodes.MethodsThis is a prospective, observational and multicenter study (27 intensive care units in nine European countries). Consecutive patients requiring invasive mechanical ventilation for an admission diagnosis of pneumonia or on mechanical ventilation for > 48 hours irrespective of admission diagnosis were recruited.ResultsA total of 2,436 patients were evaluated; 689 intubated patients presented with NP, 224 of them developed HAP and 465 developed ventilation-acquired pneumonia. Blood samples were extracted in 479 (69.5%) patients, 70 (14.6%) being positive. B-NP patients had higher Simplified Acute Physiology Score (SAPS) II score (51.5 ± 19.8 vs. 46.6 ± 17.5, P = 0.03) and were more frequently medical patients (77.1% vs. 60.4%, P = 0.01). Mortality in the intensive care unit was higher in B-NP patients compared with NB-NP patients (57.1% vs. 33%, P < 0.001). B-NP patients had a more prolonged mean intensive care unit length of stay after pneumonia onset than NB-NP patients (28.5 ± 30.6 vs. 20.5 ± 17.1 days, P = 0.03). Logistic regression analysis confirmed that medical patients (odds ratio (OR) = 5.72, 95% confidence interval (CI) = 1.93 to 16.99, P = 0.002), methicillin-resistant Staphylococcus aureus (MRSA) etiology (OR = 3.42, 95% CI = 1.57 to 5.81, P = 0.01), Acinetobacter baumannii etiology (OR = 4.78, 95% CI = 2.46 to 9.29, P < 0.001) and days of mechanical ventilation (OR = 1.02, 95% CI = 1.01 to 1.03, P < 0.001) were independently associated with B-NP episodes. Bacteremia (OR = 2.01, 95% CI = 1.22 to 3.55, P = 0.008), diagnostic category (medical patients (OR = 3.71, 95% CI = 2.01 to 6.95, P = 0.02) and surgical patients (OR = 2.32, 95% CI = 1.10 to 4.97, P = 0.03)) and higher SAPS II score (OR = 1.02, 95% CI = 1.01 to 1.03, P = 0.008) were independent risk factors for mortality.ConclusionsB-NP episodes are more frequent in patients with medical admission, MRSA and A. baumannii etiology and prolonged mechanical ventilation, and are independently associated with higher mortality rates.