In recent years, our knowledge of the characteristics of patients who are admitted to critical care with sepsis, severe sepsis, or septic shock has greatly advanced thanks to the findings of numerous observational studies 123456. There is wide variation in the incidence of sepsis and severe sepsis in the intensive care unit (ICU) setting, with reported rates ranging from 20% to 80%, and reported mortality of 20% to 50% 123456. Septic shock, defined as a state of acute circulatory failure characterized by persistent hypotension unexplained by other causes, despite adequate fluid resuscitation 7, affects between 10% and 30% of patients managed in the ICU 1348910, and its incidence is increasing 3. Mortality from septic shock in the ICU is estimated to range between 45% and 63% in observational studies 3, but is reportedly declining over time 3. These differences between reports are largely related to the definitions used to define infection 4911, the different phases of sepsis 712, and organ dysfunction 101314.

In recent decades, several epidemiological studies have been published focusing on sepsis and reporting data from ICUs in France (either partially or entirely) 4811151617. The only French study to date to have included exclusively patients with septic shock was published by Annane et al. 3 almost 10 years ago, with data collected between 1993 and 2000. The authors of all these studies have themselves acknowledged their limitations, which include: short inclusion periods 48111516 that preclude any evaluation of the impact of seasons; the heterogeneity of the patients included 48111618; short follow-up (for example, 2 weeks) 16; and use of a database using ICD definitions, with the inherent risk of wrong diagnostic codes, particularly since the codes were not standardized 3. Despite these limiting factors, the data from French ICUs is sufficiently robust to allow comparison with data from other countries. The overall frequency of septic shock was 8.2 per 100 admissions (in 2000), and crude mortality in the ICU was 60.1%, declining from 62.1% in 1993 to 55.9% in 2000 3.

However, all these French observational studies were performed and reported before the publication of the Surviving Sepsis Campaign 719, and before the publication of French national guidelines for the management of sepsis published jointly by the two French scientific societies in critical care (Société de Réanimation de Langue Française (French-language society of intensive care, SRLF, and Société Française d'Anesthésie Réanimation) in 2006 2021. Reports from other countries suggest that compliance with these guidelines can have a positive impact on mortality 2223.

The objective of this study was to collect up-to-date epidemiological data from real-life practice in France on septic shock, to describe the survival probabilities at 3, 7, and 28 days after an initial episode of septic shock and to identify prognostic factors from these recent data.

In this large-scale, multicenter study of septic shock in French ICUs, we observed an incidence of 13.5%, and death rates of 39.5%, 42%, and 48.7% at ICU discharge, 28 days, and hospital discharge, respectively. Our findings represent the most recent data on incidence and mortality of septic shock from France, using a standardized definition of septic shock 35 combined with hypoperfusion criteria, as defined in the PROWESS-SHOCK study 24. Over the period 1993 to 2000, the overall incidence of septic shock in France was reported to be on average 8.2 per 100 admissions 3, with the authors reporting an increase over the period from 7.0 in 1993 to 9.7 per 100 admissions in 2000. Mean mortality over the same period was 60.1%, with a decreasing trend from 62.1% in 1993 to 55.9% in 2000. The increasing incidence and high mortality observed by Annane et al. was partially explained by the increasing age of patients admitted to the ICU over the period under study, with ever more co-morbidities, particularly immunosuppression.

Recent studies from various countries around the world have reported mortality rates from 35% to 59% (in-hospital or at 30 days) 5681836, albeit with study populations that were more heterogeneous than that included in our study. Our results are especially important in that they were prospectively collected in a broad mix of ICUs in a contemporary period over 18 months, after the publication of several major trials related to treatment of sepsis likely to have influenced management 373839. In these recent interventional studies, the hospital mortality rates reported in the control group ranged from 46.5% to 69% and from 30.5% to 60% in the treatment groups 3739. The 28-day mortality was also different in these recent interventional studies, reportedly ranging from 24% to 61% in the control group, and from 24.7% to 55% in the treatment group. The difference was explained by the inclusion and exclusion criteria, and the severity at inclusion, which may not have accurately reflected 'real life' patient populations.

In recent years, several sets of guidelines have been issued and updated on the management of sepsis in the setting of intensive care 1923. In addition, national guidelines have been issued in France jointly by the two French scientific societies in critical care (Société de Réanimation de Langue Française (French-language society of intensive care, SRLF, and Société Française d'Anesthésie Réanimation) in 2006 2021. The implementation of these recommendations in practice has favorably influenced patient prognosis, as reported in several studies, particularly due to earlier recognition of the severity of disease, followed by consistent, multidisciplinary management 22234041. Other authors have reported a reduction in mortality in-hospital or at 28 days, after the rigorous implementation of such guidelines 4142. Our data show that mortality in the ICU decreased by approximately 17% between 2000 3 and the period 2009 to 2011 (inclusion period of our study), for patients with septic shock and comparable severity at admission (mean SAPS II score of 56 in the study by Annane et al. vs. 58 in our study). These data suggest that management has improved over the last decade, and undoubtedly, the publication of international clinical practice guidelines for management contributed to this trend, although a recent study by Leone et al. showed that there is still room for considerable improvement before guidelines are fully implemented 43.

Conversely, overall hospital mortality only decreased by around 10% over the same period, after initial ICU stays of 15.2 days on average in the report by Annane et al. 3 versus 9 days in our study. This suggests that despite earlier recognition and management, with likely more appropriate therapy, the effectiveness of post-ICU care of septic shock patients remains suboptimal 44. It is possible that certain patients expressed their desire not to be resuscitated or re-admitted to ICU, or that a decision to limit or withdraw therapy may have been made by physicians. Such factors could also explain the reduced mortality benefit that we observed during the ICU stay. Padkin et al. reported post-ICU mortality of 12.3%, corresponding to 18% of patients discharged alive from the ICU but who subsequently died before being discharged from the hospital 36. Inappropriately early discharge 45 or discharge to an unsuitable follow-up ward because of excessive workload could also be contributing factors 4546.

The independent prognostic factors for time to mortality right censored at day 28 identified in our study were age, immunosuppression, SOFA score, and Knaus score C/D. Conversely, we observed that urinary tract infection as the origin of sepsis had a protective effect. In a similar population, Annane et al. showed that age, severity of illness, characteristics of infection, and life-support therapy were associated with ICU mortality 3. However, in our study, life-support therapy was not included in the multivariate analysis, as it is a time-dependent variable with no adjustment for the updated SOFA value, and this could introduce an indication bias. The prognostic factors for death in septic shock patients reported in the literature vary widely according to the type of statistical analysis (uni- or multivariate), the primary endpoint (28-day, ICU, or in-hospital mortality), and the inclusion criteria of the studies.

The rate of documented infection varies from 52% to 90% in the literature, while in our study infection with an identified microorganism was documented in nearly 60% of septic shock cases. As regards the site of infection responsible for septic shock, the most common locations were pulmonary (48.5%), abdominal (17.6%), and urinary tract (9.5%), as reported in previous studies 3681647. Our results show that gram-negative organisms currently account for a majority of infections, as reported in other studies 6816. However, in our study, we did not observe the germ responsible for infection to be associated with 28-day mortality. This corroborates findings from another recent French study that included over 4,000 episodes of severe sepsis in 3,588 patients 48.

Early appropriate antibiotic therapy is of capital importance in the management of sepsis, as reported by several authors 4049. In our study, all patients in whom the causative microorganism was identified by antibiogram were classified according to whether they received appropriate antimicrobial therapy or not. However, it is noteworthy that in our study, antibiotic therapy (appropriate or inappropriate) was not shown to be significantly associated with time to death, right censored at 28 days, which reflects findings by other authors 50. It is more probable that the severity, mirrored by the level of organ dysfunction at the time of the shock, and expressed by the SOFA score, is a major determinant of mortality in septic shock patients. Therefore, an organ dysfunction score should be measured at inclusion in sepsis studies, as it can be used for stratification of patients and for adjustment when assessing outcome 38. In addition to these variables, others factors not measured in our study may also influence outcome in patients with septic shock and thus help refine prognostic prediction. For example, cytokine levels or other markers of inflammation may have a role to play, as suggested by a recent expert panel 7.

This study has several strengths. Diagnosis of septic shock was prospective and used standard criteria similar to those used in most clinical trials in this clinical setting. The sites included both university teaching hospitals and general (non-academic) hospitals of various sizes. Accrual was over a relatively long but contemporary time period, with prospective inclusion of all consecutive patients and practically no loss to follow-up. The population was homogeneous, comprising only patients with septic shock, and not a mix of sepsis, severe sepsis, and septic shock as in many published studies. The large sample size yields narrow confidence intervals around the estimates of mortality and made it possible to include a considerable number of variables in the regression analysis. Participating sites entered study data directly into a specially designed software programme, and data were of a high standard thanks to extensive data checking at the time of data entry by the clinical research assistants. Similarly, data were monitored, verified, and analyzed by a highly-qualified, central coordinating center (INSERM CIE 1).

Conversely, a few limitations of this study deserve to be underlined, and include the lack of detailed pre-ICU-admission data (for example, fluid challenge, exact time of onset of signs of sepsis). The majority of known prognostic factors were included in our analysis, but we cannot exclude that other variables not recorded in our study (for example, biomarkers) may have influenced outcome. Since selection of the investigating sites was on a voluntary basis, there is a possibility that only the most motivated centers participated, and results should not be extrapolated to other contexts. Furthermore, the fact that several participating sites were also participating in the Prowess-Shock study may have influenced prescriptions of drotrecogin alpha in our study. Lastly, the population of this study is mainly composed of medical patients (almost 84%) and therefore, results cannot be extrapolated to the entire population of ICU patients in France.

In summary, our results show that a large-scale cohort of septic shock patients is feasible using simplified computer-based data collection, and shows that mortality among this patient group is still very high. This can be explained by the fact that patients with septic shock admitted to the ICU are generally older, with more co-morbidities, a worse previous state of health, and requiring more life-support therapies. These observations may be useful for quality improvement of the care provided to patients at risk of, or with confirmed septic shock, for the design of future clinical studies and for healthcare decision-makers.

• This is the first large-scale epidemiological study performed in France since the publication of the Surviving Sepsis Campaign recommendations and of French national guidelines for the management of septic shock.

• Mortality in the ICU among patients admitted for septic shock is declining, or rather, death occurs at a later stage. In-hospital mortality has remained constant for many years, likely due to better initial management.

• The older age, greater dependency, and more frequent co-morbidities among ICU patients admitted for septic shock probably also explain why overall mortality has remained stable over time.

• Mortality at 28 days after an initial episode of septic shock in the ICU was 42% in this prospective, multicenter, cohort study from 14 ICUs in 10 public hospitals in France. Main factors significantly associated with time to death, right censored at 28 days were age, Knaus, and SOFA scores.

ICU: Intensive Care Unit; IQR: interquartile range; SAPS II: Simplified Acute Physiological Score II; SD: standard deviation; SOFA: Sepsis-related Organ Failure Assessment.

The authors declare that they have no competing interests.

Study conception and design: JPQ, CB, AP; Data acquisition: All authors; Study coordination: VC, JC, GL, PP, AN; Statistical analysis: JPQ, CB, AP; Drafting of the manuscript: JPQ, CB, AP, FG, JCN; Critical revision of the manuscript: All; Final approval of the manuscript for submission: All.