Estudo comparativo de pacientes sobreviventes e não sobreviventes com sepse em um hospital universitário

rsbmt Revista da Sociedade Brasileira de Medicina Tropical Rev. Soc. Bras. Med. Trop. 0037-8682 1678-9849 Sociedade Brasileira de Medicina Tropical - SBMT Uberaba, MG, Brazil Para determinar parâmetros associados à evolução da sepse, foi realizado estudo retrospectivo de 5 anos em um hospital universitário. Foram avaliados 104 pacientes consecutivos com sepse, sendo 55,8% homens. A mortalidade foi de 68,3%, associada à idade elevada (p<0,05). Doenças crônicas associadas e sítio de infecção não relacionados ao prognóstico. Identificação de bactérias gram-positivos foi mais frequente em sobreviventes (p<0,05) e não detecção do germe foi associada à mortalidade (p<0,01). O uso apropriado de antibióticos (germe sensível a pelo menos uma droga administrada) foi associado à sobrevida (p<0,0001) enquanto uso inapropriado (p<0,05) ou empírico (p<0,01) foi mais freqüente em não sobreviventes. No diagnóstico, leucocitose foi a principal (54,8%) alteração no leucograma. Na evolução, leucograma normal foi associado à sobrevida (p<0,01) e leucocitose à mortalidade (p<0,05). Em conclusão, a mortalidade foi associada à ausência de detecção do germe, leucocitose na evolução da sepse e uso inapropriado ou empírico de antibióticos. O tratamento baseado em evidências e direcionado para fatores de risco que podem ser modificados deve melhorar o prognóstico do paciente com sepse. ARTIGO ARTICLE Comparative study of survivor and nonsurvivor sepsis patients in a university hospital Estudo comparativo de pacientes sobreviventes e não sobreviventes com sepse em um hospital universitário Aline Pâmela Vieira de OliveiraI; Cristina Hueb BarataII; Eddie Fernando Candido MurtaIII; Beatriz Martins Tavares-MurtaI IDiscipline of Pharmacology, Department of Biological Sciences, Federal University of Triângulo Mineiro, Uberaba, MG IIDiscipline of Infectious Diseases, Department of Medical Clinics, Federal University of Triângulo Mineiro, Uberaba, MG IIIDiscipline of Gynecology and Obstetrics, Federal University of Triângulo Mineiro, Uberaba, MG Address to ABSTRACT To determine parameters associated with the evolution of sepsis, a five-year retrospective study was conducted in a university hospital. One hundred and four consecutive sepsis patients were evaluated, of whom 55.8% were men. The mortality was 68.3% and was associated with older age (p<0.05). Chronic comorbidities and infection site were not associated with prognosis. Gram-positive bacteria were more frequently identified in survivors (p<0.05), while non-detection of the germ was associated with mortality (p<0.01). Appropriate use of antibiotics (germ sensitive to at least one drug administered) was associated with survival (p<0.0001) while inappropriate use (p<0.05) or empirical use (p<0.01) were more frequent in nonsurvivors. Leukocytosis was the main abnormality (54.8%) detected on diagnosis, from the leukocyte count. During the evolution, normal leukocyte count was associated with survival (p<0.01) and leukocytosis with mortality (p<0.05). In conclusion, mortality was associated with nondetection of the pathogen, leukocytosis during the evolution of the sepsis and inappropriate or empirical use of antimicrobials. Evidence-based treatment that is directed towards modifiable risk factors might improve the prognosis for sepsis patients. Key-words: Sepsis. Prognosis. Antimicrobials. Risk factors. RESUMO Para determinar parâmetros associados à evolução da sepse, foi realizado estudo retrospectivo de 5 anos em um hospital universitário. Foram avaliados 104 pacientes consecutivos com sepse, sendo 55,8% homens. A mortalidade foi de 68,3%, associada à idade elevada (p<0,05). Doenças crônicas associadas e sítio de infecção não relacionados ao prognóstico. Identificação de bactérias gram-positivos foi mais frequente em sobreviventes (p<0,05) e não detecção do germe foi associada à mortalidade (p<0,01). O uso apropriado de antibióticos (germe sensível a pelo menos uma droga administrada) foi associado à sobrevida (p<0,0001) enquanto uso inapropriado (p<0,05) ou empírico (p<0,01) foi mais freqüente em não sobreviventes. No diagnóstico, leucocitose foi a principal (54,8%) alteração no leucograma. Na evolução, leucograma normal foi associado à sobrevida (p<0,01) e leucocitose à mortalidade (p<0,05). Em conclusão, a mortalidade foi associada à ausência de detecção do germe, leucocitose na evolução da sepse e uso inapropriado ou empírico de antibióticos. O tratamento baseado em evidências e direcionado para fatores de risco que podem ser modificados deve melhorar o prognóstico do paciente com sepse. Palavras-chaves: Sepse. Prognóstico. Antimicrobianos. Fatores de risco. Sepsis is a major challenge in medicine. It is a complex clinical syndrome resulting from a damaging host response to infection7. In the United States, over 700,000 patients per year develop sepsis with an unsatisfactorily high mortality rate, which is reported to range from 30 to 70%, despite the best available therapeutic interventions and supportive care21. Sepsis represents a substantial high-cost healthcare burden1 and there is limited epidemiological information about the demography of sepsis or about the temporal changes in its incidence and outcome. The occurrence of sepsis in the United States from 1979 to 2000 using a nationally representative sample showed that the incidence and number of sepsis-related deaths increased, despite a decline in the overall in-hospital mortality among sepsis patients17. Sepsis is especially common among the elderly: mortality due to sepsis increases with age, from 10% among children to 38.4% among those over 85 years old. It is likely to increase substantially as the population ages2. Neutrophils constitute the first line in the host defense against microorganisms, and they are recruited to inflammatory sites by chemoattractants, particularly chemokines19. Once migrated, these leukocytes are able to display phagocytic activity and to generate large amounts of reactive oxygen and nitrogen species, such as hydrogen peroxide and nitric oxide, which are crucial products for the microbicidal activity of these cells16. It has been demonstrated that neutrophil migration in sepsis patients is significantly lower in nonsurvivors than in survivors, in comparison with control volunteers24. Since neutrophils appear to play a crucial role in controlling the infectious process, it can be hypothesized that neutropenia might aggravate infections and sepsis. Many studies have analyzed risk factors for mortality among sepsis patients. However, great variability can be noted, considering the heterogeneity of patients, geographic location and hospital type3. In the present study, we aimed to recognize the profile of sepsis patients in our university hospital and to specifically determine factors that might influence the occurrence of prognosis disparities. We sought to examine these relationships with respect to age, gender, skin color, chronic comorbid conditions, white blood cell count, source of infection, causal organisms and use of antibiotics. PATIENTS AND METHODS Patients. This retrospective study enrolled 104 consecutive patients who developed sepsis in the tertiary teaching hospital of the Federal University of Triângulo Mineiro, southeastern Brazil, during a five-year period from January 2001 to November 2005. The patients who were enrolled presented clinical and/or laboratory variables that fulfilled the criteria for sepsis at its different stages of severity5. The study was approved by the Human Subjects Institutional Committee of the Federal University of Triângulo Mineiro. Measurements. For each patient, general and specific characteristics concerning the infection and its management were collected from the medical records. These included age, gender, skin color, source of infection, causal organisms, chronic comorbid conditions and use of antimicrobials. In addition, white blood cell count was determined at two time points: upon diagnosis and within the clinical course of the sepsis, at a time close to the patient’s recovery or death. In accordance with these characteristics, the patients were further analyzed in two groups: survivors and nonsurvivors. Evaluation of use of antimicrobials. For the purposes of this investigation, the use of antimicrobials was evaluated according to the use of drugs to which documented pathogens were sensitive, as assessed by an antibiogram. Antimicrobial treatment was considered appropriate when the germ was sensitive to at least one drug used and inappropriate antimicrobial treatment included those in which none of the antibiotics used was germ-sensitive as well as drugs that were not tested by an antibiogram. Empirical use of antibiotics was considered to consist of treatment without identifying any pathogen. Data analysis. The data were analyzed using the Prism 3 and GraphPad InStat software. Categorical variables were compared using the chi-square test. Median ages were compared using the Mann-Whitney test. The significance level was established at p<0.05 (two-tailed). RESULTS One hundred and four sepsis patients, of mean age ± SD of 51.5 ± 17.8 years (range: 21-91), were enrolled in this study. There were 58 (55.8%) men and 46 (44.2%) women, and 70 (67.3%) were white and 34 (32.7%) were nonwhite. In all cases, the patients developed sepsis at the hospital and the median length (and range) of hospital stay was four days (0-64) in the intensive care unit and 19 days (0-128) in noncritical care units, starting from the day of sepsis diagnosis. The overall mortality was 68.3%, consisting of 35 men (60.3% of the male population) and 36 women (78.3% of the female population) (p=0.082, chi-square test). The age (median; range) was greater for nonsurvivors (54; 22-91 years) than for survivors (42; 21-81 years) (p<0.01, Mann-Whitney test). The mortality rate was similar for white (68.6%) and nonwhite (67.6%) patients. The patients were distributed according to their chronic comorbid conditions (Table 1). Considering all the sepsis patients, 44 (42.3%) had AIDS, diabetes or cancer and 29 (27.9%) presented other chronic diseases (Chagas disease, pulmonary obstructive disease or renal failure), while in 31 (29.8%) cases no comorbidities were reported. No statistical differences in chronic conditions were detected according to gender (data not shown). Table 1 shows the distribution of survivors and nonsurvivors according to comorbidities, without differences between the groups. The most (36.5%) frequent source of infection was respiratory, either alone (n=16, 15.4%) or in association with other infectious sites (n=22, 21.1%), followed by genitourinary sites (7.7%). In 44 (42.3%) patients, the source of infection was considered to have an unknown origin (Table 2). Sepsis patients in whom the infection site was in the respiratory tract presented 76.3% mortality and, considering gender, 87.5% of such women died compared with 68.2% men (p=0.25, chi-square test). Table 2 shows that survivors and nonsurvivors did not significantly differ in relation to the source of infection, although respiratory foci reached greater frequency among nonsurvivors than among survivors. Microorganisms were recovered from blood cultures from 76 (73.1%) patients but in 28 (26.9%) cases, no pathogen was detected. Table 3 shows that there was a similar frequency of gram-positive organisms and polymicrobial sepsis, while gram-negative organisms corresponded to lesser cases. In one case, fungi were detected associated with Gram-positive pathogens. The two groups differed in relation to causative organisms. Gram-positive pathogens were significantly more often recovered from survivor patients, while in the nonsurvivor group, the causative microorganism was more frequently not detected (Table 3). Concerning the use of antimicrobials, 26.9% of the patients were treated empirically. Among patients with documented infection, appropriate antibiotic use was observed in 60.6% cases, including 24 (23%) patients in whom the germ was sensitive to all the antibiotics used. Inappropriate use was observed in relation to 13 (12.5%) patients. The data in Table 4 show that antibiotic use was highly associated with prognosis. Appropriate use of antimicrobials was associated with survival (p<0.0001), while inappropriate or empirical treatment was more frequent among nonsurvivor patients (p<0.05 and p<0.01, respectively) (chi-square test). White blood cell counts were analyzed at two time points: upon diagnosis and at a time close to the patient’s recovery or death. Around one third of the patients presented normal leukocyte counts, and leukocytosis was the main abnormality detected (Table 5). Although abnormalities (leukopenia or leukocytosis) did not differ between survivors and nonsurvivors upon diagnosis, they were more frequent in the nonsurvivor group when analyzed at a time point during the evolution. Statistical significance was detected for leukocytosis, while a normal white blood cell count was significantly associated with survival (Table 5). DISCUSSION Sepsis patients are a heterogeneous group of patients with great variability in underlying illnesses, infection sites and etiological agents. This highlights the importance of identifying clinical and laboratory variables among sepsis patients that may be useful in predicting outcomes. In this retrospective five-year study, we found 104 patients with the criteria for a diagnosis of sepsis. It is possible that this number represents underreporting, since physicians caring for sepsis patients recognize the difficulty of defining and diagnosing sepsis and are aware that they often misdiagnose such patients20. Previous reports on high mortality among sepsis patients are also valid in relation to our hospital. Hospital mortality due to sepsis has ranged from 25% to 80% over the last few decades3. The median length of stay in the intensive care unit was similar to that reported for a Swedish university hospital15 and shorter than in previous data2. Furthermore, the median hospital stay was similar to findings from larger epidemiological studies2. The mean length of hospital stay has been decreasing and the rate of discharge to nonacute medical care facilities has been increasing17. A number of patients were treated outside the critical care unit, in part because of the reduced number of available beds and in part because of the criteria for sepsis severity. Since critical care units maintain the best supportive care, we could not rule out that this might have contributed towards mortality. Our study population was constituted mainly by white persons and men. The occurrence of sepsis in the United States from 1979 to 2000 was more common among men and nonwhite persons17. These individuals are considered to be at increased risk of sepsis12 17 while others have explain the lower mortality among women in terms of differences in age, comorbidity and infection site2. We found a higher frequency of mortality among women, which could be partially explained by the association with respiratory site. Other studies have found increased mortality among women, associated with hospital-acquired pneumonia9. We found that around 42% of the patients had AIDS, diabetes or cancer, which was in agreement with other studies2, but the presence of chronic diseases was not associated with mortality. These underlying disorders may alter the overall immune response, even though the coagulation and inflammatory response to infection is not altered11. Clinical trials on antisepsis agents often exclude the very elderly, HIV-positive individuals and patients with malignancies because they are at higher risk of death and less likely to respond to treatment. Nonetheless, a large cohort study evaluating 192,980 patients with severe sepsis found that such patients constituted a large proportion of the sepsis population and that their exclusion would compromise the external validity of the study2. The respiratory tract, followed by genitourinary sources, was the most frequent infection site, which was in agreement with larger epidemiological studies2 23. In line with our findings, other studies have found a great frequency of unspecified sites2. We observed a mortality rate of more than 70% among patients with respiratory foci as the source of infection, and this is considered to be an independent factor associated with mortality8 10, whereas urosepsis is rarely fatal8. The infection site and nature of the organism are considered to have a significant impact on survival from sepsis8. In our study, gram-positive organisms or polymicrobial sepsis were mainly observed, and gram-positive pathogens were associated with survival. A large retrospective study found that gram-positive bacteria have become the predominant pathogen since 1987, and that these are an increasingly common cause of sepsis17. Gram-negative bacilli were mainly responsible for bloodstream infections in cancer patients26, and were associated with a mortality rate higher than for infection with gram-positive organisms8. The use of antibiotics with specific activity against identified pathogens was associated with survival, but inappropriate or empirical antimicrobial treatment was associated with greater hospital mortality. These findings serve to alert clinicians towards prioritizing blood cultures and identifying causal organisms. A recent study has encouraged modification of prescribing habits such as reductions in prescribing broad-spectrum antibacterial drugs22. Our findings agree with others in that antimicrobial regimens that lack activity against identified microorganisms are associated with mortality among sepsis patients13 14. One hypothesis has postulated that sepsis moves through different phases, such that enhanced inflammation alternates with immunosuppression. Considering that the criteria for sepsis include high or low white blood cell counts and that this could indicate hyperinflammation or immunosuppression respectively, we sought to determine whether such alterations could be predictive for the prognosis. It was noted that at least one third of the patients had normal white blood cell counts on diagnosis. Leukocytosis and leukopenia detected during the evolution were more frequent in nonsurvivors: leukocytosis was associated with mortality and normal white blood cell counts were associated with survival. A recent study using mice that were subjected to sepsis by means of cecal ligature and puncture showed that animals that died during the evolution of the disease could present evidence of either immunosuppression or immunostimulation27. The role of neutrophils in the development of multiple organ failure due to sepsis has been recently reviewed6. Perhaps what is of greater pathophysiological importance in causing severe sepsis is not the number of circulating neutrophils, but that these cells are not functionally active25. We have reported that blood neutrophils obtained from sepsis patients failed to respond in vitro to chemotactic stimuli and that this unresponsiveness was associated with death24. The mechanism involved was found to result from signal receptor desensitization mediated by continuous and excessive chemotactic receptor activation4. Moreover, it was found among breast cancer patients who underwent chemotherapy that a reduction in neutrophil migration was evident among patients who developed episodes of infection18. Considering recent trials with novel antisepsis therapies, it will be important to delineate the risk factors that reflect septic processes that are potentially modifiable, from those that are not2. We have found that nonidentified pathogens and empirical use of antibiotics were associated with worse outcome and risk factors that could be changed. In conclusion, this study reinforces the notion that sepsis treatment should be guided by evidence-based information, in accordance with the patient population characteristics and the microbiology profile of each institution, in a process directed towards improving the outcomes for sepsis patients. Address to: Profª Beatriz Martins Tavares Murta Department of Biological Sciences/UFTM Praça Manoel Terra 330 38015-050, Uberaba, MG Tel: [phone] e-mail: [e-mail] Recebido para publicação em: 12/03/07 Aceito em: 15/01/2008 Research support by FAPEMIG (Fundação de Amparo à Pesquisa do Estado de Minas Gerais). 1. Adrie C, Alberti C, Chaix-Couturier C, Azoulay E, Lassence A, Cohen Y, Meshaka P, Cheval C, Thuong M, Troché G, Garrouste-Orgeas M, Timsit J-F. Epidemiology and economic evaluation of severe sepsis in France: age, severity, infection site, and place of acquisition (community, hospital, or intensive care unit) as determinant of workload and cost. Journal of Critical Care 20: 46-58, 2005. Epidemiology and economic evaluation of severe sepsis in France: age, severity, infection site, and place of acquisition (community, hospital, or intensive care unit) as determinant of workload and cost Journal of Critical Care 2005 46 58 20 Adrie C Alberti C Chaix-Couturier C Azoulay E Lassence A Cohen Y Meshaka P Cheval C Thuong M Troché G Garrouste-Orgeas M Timsit J-F 2. Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis in the United States: Analysis of incidence, outcome and associated costs of care. Critical Care Medicine 29: 1303-1310, 2001. Epidemiology of severe sepsis in the United States: Analysis of incidence, outcome and associated costs of care Critical Care Medicine 2001 1303 1310 29 Angus DC Linde-Zwirble WT Lidicker J Clermont G Carcillo J Pinsky MR 3. Angus DC, Wax RS. Epidemiology of sepsis: An update. Critical Care Medicine 29: 109-116, 2001. Epidemiology of sepsis: An update Critical Care Medicine 2001 109 116 29 Angus DC Wax RS 4. Arraes SM, Freitas MS, Silva SV, Paula Neto H, Alves-Filho JC, Martins MA, Basile-Filho A, Tavares-Murta BM, Barja-Fidalgo C, Cunha FQ. Impaired neutrophil chemotaxis in sepsis associates with GRK expression and inhibition of actin assembly and tyrosine phosphorylation. Blood 108: 2906-2913, 2006. Impaired neutrophil chemotaxis in sepsis associates with GRK expression and inhibition of actin assembly and tyrosine phosphorylation Blood 2006 2906 2913 108 Arraes SM Freitas MS Silva SV Paula Neto H Alves-Filho JC Martins MA Basile-Filho A Tavares-Murta BM Barja-Fidalgo C Cunha FQ 5. Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, Schein RM, Sibbald WJ. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Members of the American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference Committee. Critical Care Medicine 20: 864-874, 1992. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis: Members of the American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference Committee Critical Care Medicine 1992 864 874 20 Bone RC Balk RA Cerra FB Dellinger RP Fein AM Knaus WA Schein RM Sibbald WJ 6. Brown KA, Brain SD, Pearson JD, Edgeworth JD, Lewis SM, Treacher DF. Neutrophils in development of multiple organ failure in sepsis. Lancet 368: 157-169, 2006. Neutrophils in development of multiple organ failure in sepsis Lancet 2006 157 169 368 Brown KA Brain SD Pearson JD Edgeworth JD Lewis SM Treacher DF 7. Cohen J. The immunopathogenesis of sepsis. Nature 420: 885-891, 2002. The immunopathogenesis of sepsis Nature 2002 885 891 420 Cohen J 8. Cohen J, Cristofaro P, Carlet J, Opal S. New method of classifying infections in critically ill patients. Critical Care Medicine 32: 1510-1526, 2004. New method of classifying infections in critically ill patients Critical Care Medicine 2004 1510 1526 32 Cohen J Cristofaro P Carlet J Opal S 9. Crabtree TD, Pelletier SJ, Gleason TG, Pruett TL, Sawyer RG. Gender-dependent differences in outcome after the treatment of infection in hospitalized patients. Journal of the American Medical Association 282: 2143-2148, 1999. Gender-dependent differences in outcome after the treatment of infection in hospitalized patients Journal of the American Medical Association 1999 2143 2148 282 Crabtree TD Pelletier SJ Gleason TG Pruett TL Sawyer RG 10. De Miguel-Yanes JM, Andueza-Lillo JA, Gonzalez-Ramallo VJ, Pastor L, Munoz J. Failure to implement evidence-based clinical guidelines for sepsis at the ED. American Journal of Emergency Medicine 24: 553-559, 2006. Failure to implement evidence-based clinical guidelines for sepsis at the ED American Journal of Emergency Medicine 2006 553 559 24 De Miguel-Yanes JM Andueza-Lillo JA Gonzalez-Ramallo VJ Pastor L Munoz J 11. Dhainaut JF, Claessens YE, Janes J, Nelson DR. Underlying disorders and their impact on the host response to infection. Clinical Infectious Diseases 41: 481-489, 2005. Underlying disorders and their impact on the host response to infection Clinical Infectious Diseases 2005 481 489 41 Dhainaut JF Claessens YE Janes J Nelson DR 12. Esper AM, Moss M, Lewis CA, Nisbet R, Mannino DM, Martin GS. The role of infection and comorbidity: Factors that influence disparities in sepsis. Critical Care Medicine 34: 2576-2582, 2006. The role of infection and comorbidity: Factors that influence disparities in sepsis Critical Care Medicine 2006 2576 2582 34 Esper AM Moss M Lewis CA Nisbet R Mannino DM Martin GS 13. Garnacho-Montero J, Garcia-Garmendia JL, Barrero-Almodovar AF, Jimenez-Jimenez FJ, Perez-Paredes C, Ortiz-Leyba C. Impact of adequate empiric antibiotic therapy on the outcome of patients admitted to the intensive care unit with sepsis. Critical Care Medicine 31: 2742-2751, 2003. Impact of adequate empiric antibiotic therapy on the outcome of patients admitted to the intensive care unit with sepsis Critical Care Medicine 2003 2742 2751 31 Garnacho-Montero J Garcia-Garmendia JL Barrero-Almodovar AF Jimenez-Jimenez FJ Perez-Paredes C Ortiz-Leyba C 14. Harbarth S, Garbino J, Pugin J, Romand JA, Lew D, Pittet D. Inappropriate initial antimicrobial therapy and its effect on survival in a clinical trial of immunomodulating therapy for severe sepsis. American Journal of Medicine 115: 529-535, 2003. Inappropriate initial antimicrobial therapy and its effect on survival in a clinical trial of immunomodulating therapy for severe sepsis American Journal of Medicine 2003 529 535 115 Harbarth S Garbino J Pugin J Romand JA Lew D Pittet D 15. Jacobson S, Johansson G, Winso O. Primary sepsis in a university hospital in northern Sweden: A retrospective study. Acta Anaesthesiologica Scandinavica 48: 960-967, 2004. Primary sepsis in a university hospital in northern Sweden: A retrospective study Acta Anaesthesiologica Scandinavica 2004 960 967 48 Jacobson S Johansson G Winso O 16. Malawista SE, Montgomery RR, van Blaricom G. Evidence for reactive nitrogen intermediates in killing of staphylococci by human neutrophil cytoplasts. A new microbicidal pathway for polymorphonuclear leukocytes. Journal of Clinical Investigation 90: 631-636, 1992. Evidence for reactive nitrogen intermediates in killing of staphylococci by human neutrophil cytoplasts: A new microbicidal pathway for polymorphonuclear leukocytes Journal of Clinical Investigation 1992 631 636 90 Malawista SE Montgomery RR van Blaricom G 17. Martin GS, Mannino DM, Eaton S, Moss M. The epidemiology of sepsis in the United States from 1979 through 2000. The New England Journal of Medicine 348: 1546-1554, 2003. The epidemiology of sepsis in the United States from 1979 through 2000 The New England Journal of Medicine 2003 1546 1554 348 Martin GS Mannino DM Eaton S Moss M 18. Mendonça MAO, Cunha FQ, Murta EFC, Tavares-Murta BM. Failure of neutrophil chemotactic function in breast cancer patients treated with chemotherapy. Cancer Chemotherapy and Pharmacology 57: 663-670, 2006. Failure of neutrophil chemotactic function in breast cancer patients treated with chemotherapy Cancer Chemotherapy and Pharmacology 2006 663 670 57 Mendonça MAO Cunha FQ Murta EFC Tavares-Murta BM 19. Moser B, Wolf M, Walz A, Loetscher P. Chemokines: multiple levels of leukocyte migration control. Trends in Immunology 25: 75-84, 2004. Chemokines: multiple levels of leukocyte migration control Trends in Immunology 2004 75 84 25 Moser B Wolf M Walz A Loetscher P 20. Poeze M, Ramsay G, Gerlach H, Rubulotta F, Levy M. An international sepsis survey: a study of doctors knowledge and perception about sepsis. Critical Care 8: 409-413, 2004 An international sepsis survey: a study of doctor’s knowledge and perception about sepsis Critical Care 2004 409 413 8 Poeze M Ramsay G Gerlach H Rubulotta F Levy M 21. Riedemann NC, Guo R-F, Ward PA. The enigma of sepsis. Journal of Clinical Investigation 112: 460-467, 2003. The enigma of sepsis Journal of Clinical Investigation 2003 460 467 112 Riedemann NC Guo R-F Ward PA 22. Sarkar P, Gould IM. Antimicrobial agents are societal drugs: how should this influence prescribing? Drugs 66: 893-901, 2006. Antimicrobial agents are societal drugs: how should this influence prescribing? Drugs 2006 893 901 66 Sarkar P Gould IM 23. Strehlow MC, Emond SD, Shapiro NI, Pelletier AJ, Camargo Jr CA. National study of emergency department visits for sepsis. Annals of Emergency Medicine 48: 326-331, 2006. National study of emergency department visits for sepsis Annals of Emergency Medicine 2006 326 331 48 Strehlow MC Emond SD Shapiro NI Pelletier AJ Camargo Jr CA 24. Tavares-Murta BM, Zaparolli M, Ferreira RB, Silva-Vergara ML, Oliveira CHB, Murta EFC, Ferreira SH, Cunha FQ. Failure of neutrophil chemotactic function in septic patients. Critical Care Medicine 30: 1056-1061, 2002. Failure of neutrophil chemotactic function in septic patients Critical Care Medicine 2002 1056 1061 30 Tavares-Murta BM Zaparolli M Ferreira RB Silva-Vergara ML Oliveira CHB Murta EFC Ferreira SH Cunha FQ 25. Tsuda Y, Takahashi H, Kobayashi M, Hanafusa T, Herndon DN, Suzuki F. Three different neutrophil subsets exhibited in mice with different susceptibilities to infection by methicillin-resistant Staphylococcus aureus. Immunity 21: 215-226, 2004. Three different neutrophil subsets exhibited in mice with different susceptibilities to infection by methicillin-resistant Staphylococcus aureus Immunity 2004 215 226 21 Tsuda Y Takahashi H Kobayashi M Hanafusa T Herndon DN Suzuki F 26. Velasco E, Byington R, Martins CAS, Schirmer M, Dias LMC, Gonçalves VMSC. Comparative study of clinical characteristics of neutropenic and non-neutropenic adult cancer patients with bloodstream infections. European Journal of Clinical Microbiology & Infectious Diseases 25: 1-7, 2006. Comparative study of clinical characteristics of neutropenic and non-neutropenic adult cancer patients with bloodstream infections European Journal of Clinical Microbiology & Infectious Diseases 2006 1 7 25 Velasco E Byington R Martins CAS Schirmer M Dias LMC Gonçalves VMSC 27. Xiao H, Siddiqui J, Remick DG. Mechanisms of mortality in early and late sepsis. Infection and Immunity 74: 5227-5235, 2006. Mechanisms of mortality in early and late sepsis Infection and Immunity 2006 5227 5235 74 Xiao H Siddiqui J Remick DG