© 2003 American Thoracic Society
Current Epidemiology of Septic ShockThe CUB-Réa NetworkService de Réanimation Médicale, Hôpital Raymond Poincaré, Assistance Publique Hôpitaux de Paris, Garches; Service de Biostatistique et Informatique Médicale, Hôpital Ambroise Paré, Assistance Publique Hôpitaux de Paris, Boulogne; Service de Réanimation Médicale, Hôpital Saint Antoine, Assistance Publique Hôpitaux de Paris, Paris; and INSERM U444, Paris, France Correspondence and requests for reprints should be addressed to Djillali Annane, M.D., Ph.D., Service de Réanimation Médicale, Hôpital Raymond Poincaré, Faculté de Médecine Paris Ile de France Ouest, Université de Versaille Saint Quentinen-Yvelinnes, 104, Boulevard Raymond Poincaré, 92380 Garches, France. E-mail: djillali.annane{at}rpc.ap-hop-paris.fr
To update the epidemiology of septic shock we analyzed clinical, microbiologic, and outcome variables from 100,554 intensive care unit admissions on the Collège des Utilisateurs de Bases de données en Réanimation (CUB-Réa) database, collected from 22 hospitals over a 8-year period, 1993 to 2000. The overall frequency of septic shock was 8.2 per 100 admissions (i.e., 8,251 stays). It increased from 7.0 (in 1993) to 9.7 per 100 admissions (in 2000). The distribution analysis of the sites of infection and of the types of pathogens showed an increase in the rate of pulmonary infection (p = 0.001) and of multiresistant bacteria-related septic shock (p = 0.001). The crude mortality was 60.1% and declined from 62.1% (in 1993) to 55.9 (in 2000) (p = 0.001). As compared with matched intensive care unit admissions without sepsis, the excess risk of death due to septic shock was 25.7 (95% confidence interval, 24.0–27.3) and the matched odds ratio of death was 3.9 (95% confidence interval, 3.5–4.3). The frequency of septic shock is increasing with more multiresistant strains. Its crude mortality rate is decreasing, but patients with septic shock still have a high excess risk of death than critically ill patients who are nonseptic.
Key Words: sepsis • epidemiologic studies • case–control studies • intensive care unit • outcome Sepsis is present when there is clinical suspicion of infection, combined with evidence of systemic inflammation, usually defined by two or more of the following criteria: fever or hypothermia, leukocytosis or leukopenia, tachycardia, and tachypnea (1, 2). Septic shock has sepsis combined with hypotension that is refractory to fluid replacement. Most recent epidemiologic data on septic shock come from surveys conducted in the end of the eighties or the beginning of the nineties or are extrapolated from control groups of randomized trials. In the United States, in 1993, the entity "septicemia" represented the 13th leading cause of death, with an age-adjusted death rate of 7.9 per 100,000 population (3). Some authorities estimate that, in 1993, the hospital incidence of severe sepsis was two cases per 100 admissions with patients in intensive care units (ICUs) accounting for 59% of cases and that septic shock was present at onset of sepsis syndrome in 25% of patients (4). The most recent data were obtained from 1995 state hospital discharge records from seven states. This large observational cohort study provided national estimates of 751,000 cases of severe sepsis, i.e., 3.0 cases per 1,000 population and 2.26 cases per 100 hospital discharges (5). The overall hospital mortality was 28.6%. The authors estimated that, in 1995, severe sepsis accounted for 9.3% of all deaths in the United States. In France, in 1993, the mean attack rate of severe sepsis was estimated at 6.3 per 100 ICU admissions and the mortality rate at 56% (6). A number of factors may be associated with mortality in severe sepsis and septic shock, e.g., age, severity of patient's underlying disease, number of organ system dysfunction, severity of illness, hypothermia, thrombocytopenia, lactic acidosis, multiple sources of infection, positive blood stream, type of organism (6), and endocrine function (7). At the dawn of the third millennium, apart from early appropriate antibiotic therapy and source control (8), numerous efforts are still needed to develop specific treatment for septic shock (9). Recent Phase III trials suggested survival benefit from human recombinant activated protein C in patients with severe sepsis and at least one organ dysfunction (10) and from low-dose steroids in patients with septic shock with presumed adrenal dysfunction (11). Several characteristics of septic shock like the site of infection and the type of organisms have significantly changed over time (12). As these factors determine the antibiotic therapy that must be promptly initiated, there is an urgent need to update clinical and microbiologic characteristics of septic shock. Therefore, we analyzed (1) the annual frequency of septic shock treated in adult ICUs from 1993 to 2000, (2) clinical and microbiologic patterns, (3) interventions, (4) attributable mortality risk, and (5) factors affecting ICU mortality.
The Database The database included data from 35 ICUs in Paris and its suburb and has been described elsewhere (13, 14) (APPENDIX 1). Data were extracted for the 100,554 admissions to the 22 ICUs participating in the database since 1993. According to French regulation, the CUB-Réa project was approved by the Comité National Informatique et Liberté.
Data
Analyses
Frequency of Septic Shock In the 22 ICUs population (n = 100,554), the overall frequency of septic shock was 8.2 per 100 ICU admissions (n = 8,251). Its annual frequency significantly (p < 0.001) increased from 7.0 in 1993 to 9.7 per 100 ICU admissions in 2000 (Figure 1) . When considering, only first admission similar rates were observed, e.g., 8.8 and 9.7 per 100 ICU admissions in 1999 and 2000, respectively.
Clinical and Microbiologic Patterns Demographic characteristics. Table 1 compares the demographic characteristics of the 8,251 ICU stays with septic shock with those of the population without septic shock in the same 22 ICUs. The septic shock subset comprised older patients, a greater proportion of males, patients having underlying disease with presumably reduced life expectancy (Figure 2) , or having immune depression, and a lower proportion of medical patients, or patients coming from the community. Finally, the septic shock subset represented more severely ill patients, i.e., higher SAPS II and higher crude mortality, than the general ICU population.
Site of infection and type of pathogens. The lung was the primary source of infection, followed by the abdomen, and the urinary tract (see Table E1 in the online supplement). Although the proportion of lung infection–related septic shock significantly increased from 1993 to 2000 (p < 10-4), the percentage of septic shock due to urinary tract infection has significantly decreased (p < 10-4), and the proportion of abdominal sepsis remained rather unchanged. In about one fourth of the population, there are multiple sites of infection accounting for septic shock. The relative frequency of positive blood cultures in the septic shock population was about one third and increased with time. The proportion of septic shock from an unknown source of infection significantly decreased with time (p = 0.001) but still remained about one fifth. The proportion of septic shock with unidentified pathogen decreased with time (p < 10-4) but still remained about one third. The percentage of polymicrobial infection (p < 10-4) as well as the proportion of multiresistant bacteria, like Pseudomonas (p < 10-4) and methicillin-resistant Staphylococci (p < 10-4), has significantly increased with time.
Interventions and Outcome
Outcomes
ICU length of stay. The ICU length of stay was on average 15.2 days (median 8 days) and significantly increased since 1997 (p = 0.0001). However, this trend was mainly observed among nonsurvivors (see Table E2 in the online supplement).
Septic Shock–related Mortality
Matched comparison with ICU stays with nonseptic shock. To further refine the estimate of mortality related to septic shock, we compared 2,350 ICU stays with septic shock with 2,350 ICU stays with nonseptic shock (Table 4) . The control patients were in cardiogenic, hemorrhagic, and neurogenic shock in 43, 33, and 17% of cases, respectively. Septic shock admissions were still more likely to have immune deficiency and a need for mechanical ventilation, vasopressor therapy, renal replacement therapy, or a right-heart catheter. Finally, they had a higher mortality rate. Septic shock was associated with a matched excess risk of death in the ICU of 11.6 (95% confidence interval, 9.0–14.1). The matched risk ratio was 1.26 (95% confidence interval, 1.2–1.3), and the matched OR was 1.8 (95% confidence interval, 1.6–2.0). Septic shock remained significantly associated with death in the ICU with an OR of dying of 1.3 (95% confidence interval 1.1 to 1.5) after adjusting on other prognostic variables (ARDS, respiratory support, hemodynamic support, and renal replacement therapy) (see Table E4 in the online supplement).
As compared with the latest published large study on epidemiology of severe sepis (5), the current study provided important additional information. First, this study focused on septic shock patients admitted to the ICU and used a common definition for septic shock (2). Second, this is the first large longitudinal study that covers almost all the nineties, whereas the study by Angus and coworkers was restricted to data from 1995. Finally, the current study provides more detailed information on demographic data and comorbidities, sites and types of infection, types of pathogens, and interventions. To avoid bias related to the addition of data from new ICUs, we restricted the analyses to the data from the 22 ICUs that contributed to the database since its initiation in 1993. This analysis of the CUB-Réa database showed a significant increase in the annual frequency of septic shock treated in the ICUs over the 8-year period 1993 to 2000. In 2000, the mean attack rate of septic shock was 9.7 per 100 ICU admissions. Analyses of data from the whole database (35 units) showed slightly lower annual frequencies, a similar trend with time, and a mean attack rate of septic shock for 2000 of 8.8 per 100 ICU admissions. The annual frequency of septic shock of 6.9 per 100 ICU admissions observed in 1995 in our study is very consistent with the 10% incidence in the ICU of severe sepsis reported for the same year by Angus and coworkers (5), given that septic shock is a subset of severe sepsis. Similarly, the frequency of septic shock of 7.0 per 100 ICU admissions observed for 1993 is also consistent with a previous French cohort study, which reported an incidence of confirmed severe sepsis of 6.3 per 100 ICU admission (6). The mean SAPS II value of 56 and the crude hospital mortality of 59% observed suggested that the authors were reporting data for septic shock rather than severe sepsis. The observed increase in the frequency of septic shock with time might have been explained by change in ICU admission decisions with the less sick patients not being admitted anymore, as suggested by the increase in mean SAPS II values. However, the proportion of patients with comorbidities did not dramatically change with time, and even the proportion of patients with the McCabe score above 0 significantly decreased from 49.8 per 100 ICU admissions in 1993 to 42.4 in 2000. In addition, the size of units were constant (apart for 1999 when two units merged into a new one), and the number of stays increased. Thus, it seems very unlikely that the observed increase in septic shock frequency was related to changes in ICU admission decisions. This study confirms that, as compared with the general ICU population, the septic shock subset is made of older patients, a higher proportion of patients with previous diseases reducing life expectancy or having immune deficiency, and a higher proportion of surgical patients (5, 6, 20). This study also confirms that the lung is the primary source of infection, whereas the number of urinary tract infection–related shocks has considerably decreased (5, 6, 12, 20, 21). In addition, the proportion of Pseudomonas and Staphylococcus resistant to methicillin-related septic shock has dramatically increased with time, to reach a worrying proportion of one fifth to one fourth of cases in 2000. This result is in keeping with previous findings in European ICUs (22) and might result from the high "antibiotic pressure" in ICUs (23). By contrast, septic shock crude mortality and adjusted mortality decreased during the 8-year period from 63 (in 1,993) to 58% (in 2000). This absolute 5% reduction in mortality represented almost 60 additional rescued patients a year. This drop in mortality might result from more aggressive diagnostic testing, as suggested by the reduction in the proportion of unknown source of infection, and by more aggressive therapies. In the last decade, the Société de Réanimation de Langue Française has made tremendous efforts to standardize the care of the critically ill patients, notably to manage septic shock. Guidelines were established for fluid resuscitation, the use of catecholamines, and for renal replacement therapy (24–26). Whether these efforts explain the observed reduction in mortality with time remains speculative. Interestingly, after stratification on quartiles of SAPS II, we observed that the reduction in mortality mainly occurred in the two lower strata (SAPS II under 54), whereas in the upper fourth (SAPS II over 72) mortality remained constant about 90%. This study allowed the estimation that infection-related shock was associated with an excess risk of death of 25.7% when compared with matched critically ill patients without sepsis, and with an excess risk of death of 11.6% when compared with patients with nonseptic shock. Given, the high frequency of multiresistant strains, this excess risk of death of patients with septic shock is in keeping with previous reports (27–30). As compared with the "general" ICU patients and with patients with nonseptic shock, patients with septic shock required more frequent mechanical ventilation, vasopressor therapy, renal replacement therapy, and heavier daily workload. In addition, the use of the life-supporting therapies increased with time in the treatment of septic shock, suggesting a more aggressive management. Notably, fewer pulmonary artery catheters were used with time, probably resulting from the impact of the worrisome report of increased risk of death associated with their use in critically ill patients (31) and the increasing use of noninvasive tools. Nonetheless, as compared with their use in matched nonseptic shock, pulmonary artery catheters are still more frequently used in septic shock.
Study Limitations As far as the matching procedures are concerned, the time to onset of septic shock was not available for all patients, preventing the selection of control patients on minimal duration of exposure. The reason for ICU admission was "shock" in about one third of septic shock stays and "infection" in about 35%. We must acknowledge that only one reason for admission was entered in the database and that there were no recommendation for coding this variable. Nonetheless, the introduction in multivariate analysis of the reason for admission ("shock" or "infection") did not lower the strength of the relation between septic shock and death (data not shown). When we restricted the analysis to the pairs being stayed in the ICU at least two days, or even 10 days, the matched OR of death remains about 4 and over 3, respectively. In addition, in pairing, for lack of witnesses, one drew aside the most seriously ill patients and therefore the excess of risk may be underestimated. An interesting although costly alternative to the use of sampling and statistical methods is the appropriateness evaluation protocol, where experts conclude on explicit criteria whether each day of stay or even death for patients with septic shock is related to septic shock. In conclusion, septic shock is more and more frequent in the ICU. Its crude mortality rate remains about 60%, and its attributable mortality risk is about 25%. The physicians who care for patients with septic shock must take into account a high likelihood for the patient to have (1) comorbidity that affects life expectancy or immune suppression, (2) multiresistant bacteria involved, and (3) need for life-support therapies.2
DATABASE CHARACTERISTICS Briefly, in 1992 on the initiative of the Société de Réanimation de Langue Française, the CUB-Réa network was set up among intensivists of hospitals in Paris and its suburbs. Initially made of by 22 ICUs the number of participating centers increased up to 30 in 1996 and 35 in 1999. The number of beds per unit ranged from 8 to 20, for a total of nearly 500 beds. Among these, two-thirds belong to teaching hospitals (60.4% of stays in 2000), whereas four are surgical ICUs (10.0% of stays in 2000). Each year, about 20,000 stays are added to the database. In 2000, the mean SAPS II was 37.1, mean length of stay was 7.4 days, whereas ICU and hospital death rate were 17.3 and 21.2%, respectively, giving a mean standardized mobility ratio of 0.78. A steering committee meets every month. The Steering Committee has established a house-style book, is responsible for quality controls, training of ICUs' representatives, and the follow-up of the database. A representative of each ICU has been trained and follows yearly updating courses. A common set of data and thesauri have been defined. All data are recorded prospectively in each unit with standardized database software, whereas methods of coding are harmonized through yearly meetings. Quality assurance procedures, including a computer program operating fifty rules dedicated to consistency between diagnoses and procedures, are applied both to local data within each unit and to data in the common database. Quality controls involving 25 units assessed the reliability of this database of case mix and outcome information (13), showing, for instance, that evaluation of severity of illness, as assessed by SAPS II was highly reproducible (intraclass correlation coefficient = 0.89).  coefficients measuring agreement for patient sex, type of admission, and outcome were 0.99, 0.78, and 0.97, respectively, whereas reliability of the McCabe and Jackson classification appeared moderate ( = 0.51, when considering modality "nonfatal comorbidity" vs. "other"). Agreement was 89% ( = 0.76) for the coding of cardiovascular failure, 79% ( = 0.56) for respiratory failure, and 90% for renal failure (- = 0.58). Agreement was even higher when considering organ support. The intraclass correlation coefficients for length of stay and total workload were 0.99 and 0.96, respectively. Quality controls were again performed during the year 2000 and confirmed overall reliability of the data, notably showing good agreement for septic shock (90%, = 0.67) and excellent ones for comorbidities such as hematologic malignancy ( = 0.76), cancer ( = 0.81), or human immunodeficiency virus–related disease ( = 0.93).
THE CUB-Réa NETWORK Members of CUB-Réa database are (*indicates ICUs participating in the database since 1993): F. Jardin, B. Page (Hôpital Ambroise Paré*), J. P. Bedos, P. Guezennec (Hôpital André Mignot*), F. Brivet (Hôpital Antoine Béclère*), Y. Cohen, J. Ph. Fosse (Hôpital Avicenne*), Cl. Gibert (Hôpital Bichat*), B. Regnier, Ph. Auburtin (Hôpital Bichat*), Ch. Richard, J. Depré-Vassal (Hôpital Bicêtre*), J. Labrousse, E. Guerot (Hôpital Boucicaut*), J. Y. Fagon (Hôpital Européen Georges Pompidou*), J. F. Dhainaut, A. Cariou (Hôpital Cochin*), F. Fraisse, G. Moret (Hôpital Delafontaine), P. Kalfon (Hôpital Diaconesses), F. Blin (Hôpital Gonesse*), F. Lemaire, Ch. BrunBuisson (Hôpital Henri Mondor*), A. Rabbat (Hôpital Hotel Dieu*), G. Nitenberg, F. Blot (Institut Gustave Roussy), J. L. Pourriat, R. Gauzit (Hôpital Jean Verdier*), F. Baud, D. Goldgran-Toledano (Hôpital Lariboisière*), D. Dreyfuss (Hôpital Louis Mourier*), A. Tenaillon (Hôpital Louise Michel), J. L. Pallot, E. Obadia (Hôpital Montreuil), J. M. Coulaud, L. Donetti (Hôpital Montfermeil), H. Bismuth (Hôpital Paul Brousse), T. Similowski (Hôpital Pitié-Salpétrière), F. Bolgert (Hôpital Pitié-Salpétrière, H. Outin (MICU, Hôpital Poissy/St. Germain), J. P. Terville (SICU, Hôpital Poissy/St. Germain), Ph. Gajdos, M. C. Jars-Guincestre (Hôpital Raymond Poincaré*), F. Hilpert, P. Manet (Hôpital Robert Ballanger*), G. Offenstadt, B. Guidet (Hôpital Saint-Antoine*), J. Carlet, B. Misset (Hôpital Saint-Joseph), J. R. Le Gall, G. Leleu (MICU, Hôpital Saint-Louis*), L. Jacob (SICU, Hôpital Saint-Louis*), C. Mayaud, A. Parrot (Hôpital Tenon), G. Bleichner, H. Mentec (Hôpital Victor Dupouy*).
Supported by Assistance Publique—Hôpitaux de Paris, Paris, France (to CUB-Réa database). This article has an online supplement, which is accessible from this issue's table of contents online at www.atsjournals.org Received in original form January 31, 2002; accepted in final form May 7, 2003
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ABSTRACT
METHODS
2 statistics were used for comparisons of continuous and nominal variables, respectively. The changes from 1993 to 2000 for relevant variables were analyzed by analysis of variance with the contrasts method and by Pearson 
uvre et évaluation d'une base de données commune aux services de réanimation d'Ile-de-France. Rev Epidémiol Santé Publique 1998;46:226–237.
