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Incidence and Impact of Organ Dysfunctions Associated With Sepsis^*

Bertrand Guidet, MD; Philippe Aegerter, MD, PhD; Remy Gauzit, MD; Patrick Meshaka, MD; Didier Dreyfuss, MD; on behalf of the CUB-Réa Study Group

^* From CUB-Réa (Dr. Guidet), Service de Réanimation Médicale, Hôpital Saint-Antoine, Paris; Biostatitique (Dr. Aegerter), Hôpital Ambroise Paré, Paris; Service de Réanimation (Dr. Gauzit), Hôpital Jean Verdier, Bondy; Laboratoire Eli-Lilly (Dr. Meshaka), Suresnes; and Service de Réanimation Médicale (Dr. Dreyfuss), Hôpital Louis Mourier, Colombes, France.

Correspondence to: Bertrand Guidet, MD, Service de Réanimation Médicale, Hôpital Saint-Antoine, 184, rue du Faubourg Saint-Antoine, 75012 Paris, France; e-mail: bertrand.guidet{at}sat.ap-hop-paris.fr

	Abstract

TOP Abstract Introduction Materials and Methods Results Discussion Conclusions Appendix References

 
Objective: To study the incidence and severity of organ dysfunction associated with sepsis.

Design: Comprehensive review of prospectively collected data from intensive care patients hospitalized between 1997 and 2001.

Setting: Thirty-five ICUs in nonuniversity and university hospitals located in the Paris area.

Patients: All patients hospitalized in the ICU for > 24 h meeting the criteria for severe sepsis (SS), either with only one organ dysfunction present during the ICU stay (SS1; n = 5,675) or with at least two organ dysfunction present during the ICU stay (SS2; n = 12,598), were compared to all other patients hospitalized for > 24 h in the ICU over the same time period (n = 47,637).

Interventions: None.

Measurements and main results: We collected information on demographic characteristics, type of admission, underlying disease, organ dysfunction, organ support, McCabe and Charlson-Deyo scores, simplified acute physiology score II, length of stay, and outcome. The incidence of SS was 27.7% (8.6% for SS1 and 19.1 for SS2). Compared with non-SS patients, those with SS were significantly older, were more frequently men, required organ support more frequently, had higher severity scores, and stayed longer in the ICU and hospital. Respiratory and cardiovascular dysfunction and fungal infection were strong independent risk factors for death in SS patients, with 5.64-fold, 4.35-fold, and 2.0-fold increased risks, respectively. SS2 is significantly different from SS1: older age, more surgical stays and admission from external transfer, greater number of organ supports, site of infection (less pulmonary and urinary tract infections, and more abdominal and cardiovascular infections), type of bacteria (more methicillin-resistant Staphylococcus aureus, Pseudomonas, and fungus), ICU length of stay (20.4 d vs 11.6 d), hospital length of stay (33 d vs 27.9 d), ICU mortality (42.7% vs 5.5%), and hospital mortality (49% vs 11.3%).

Conclusions: Our study identifies a subgroup of patients with an ICU stay > 24 h and SS with at least two organ dysfunctions. This group of patients requires special attention since their ICU mortality is > 40% and they occupy almost 40% of all ICU beds.

Key Words: epidemiology • infection • intensive care • organ failure • scoring systems • severe sepsis

	Introduction

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Severe sepsis (SS) is generally defined as sepsis with acute organ failure.¹ It is a major cause of concern for intensive care physicians.² Several recent epidemiologic studies³⁴⁵⁶ have reported an incidence of 51 to 95 cases of SS per 100,000 in the population. The incidence was 300 per 100,000 in a single study⁷ in the United States reporting approximately 2,000 episodes of SS occurring daily, with at least 600 related deaths. As new effective therapeutic agents are becoming available,⁸ it is important that epidemiologic data be updated in order to better understand the incidence and pathophysiology of the disease and to plan the rational treatment of patients in the future. We have previously reported from the Collège des Utilisateurs de Bases de données en Réanimation (CUB-Réa) ICU database on the epidemiology of septic shock in Paris and its suburbs and found that during the study period from 1993 to 2000, the frequency of SS had increased with more multiresistant strains and the mortality had decreased. However, patients with SS had a high excess risk of death when compared to critically ill nonseptic patients.⁹

In the present study, we focused our study on a specific group of patients most likely to benefit from the new therapies for SS,⁸¹⁰ ie, those hospitalized in ICU for > 24 h and those having at least two organ dysfunctions present during the ICU stay (SS2). The results were compared to those obtained in ICU patients with SS with only one organ dysfunction present during the ICU stay (SS1) and patients with no SS (SS0). We hypothesize that SS2 patients might have an intermediate severity between SS1, a subgroup of patients not severe enough to be good candidates for new expensive drugs, and patients with SS with a mortality close to 60% in a nonselected population.⁹

	Materials and Methods

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Data Sources
The period of our study focused on the years 1997 to 2001, inclusive. There were 35 participating ICUs (23 located in teaching hospitals and 12 located in nonuniversity hospitals) housing 464 beds.

Patients
We analyzed all patients hospitalized in the ICU for > 24 h from January 1997 to December 2001. Three populations were studied: SS0, SS1, and SS2. SS patients (SS1 or SS2) were patients in whom the database code indicated respiratory, cardiovascular, neurologic, GI, urinary, skin, or blood infection ^{(Appendix 1)} and at least one organ dysfunction with or without organ support ^{(Appendix 2)}. A patient with scheduled surgery with mechanical ventilation during the postoperative period did not qualify for respiratory dysfunction since he did not have a diagnosis of respiratory failure. So, a patient might have organ dysfunction without organ support, but organ support does not by itself indicate organ dysfunction. We consider community-acquired SS and nosocomial SS altogether.

Data Collection
Besides administrative ICU data, the following patient information was recorded: demographic characteristics, category of admission (medical, scheduled surgery, unscheduled surgery), type of admission (external transfer or other), underlying disease, organ or system dysfunction, organ support, comorbidity as assessed by the McCabe and Jackson score¹¹ and the Charlson-Deyo score,¹² mortality risk as assessed by the simplified acute physiology score (SAPS) II measured 24 h after ICU admission,¹³ length of ICU and hospital stay, and status (survival or death) when discharged from the ICU and hospital. There are no missing data for the ICU stays (length of stay, SAPS II, mortality) since all stays are included in the French diagnosis-related group system with specific checking procedures for the hospital level and in the administrative center. Due to informatics constraints, two ICUs did not provide hospital mortality data; however, their ICU mortality rates were not significantly different from the others. Globally, for the whole database, the hospital mortality information for 1,783 stays is missing.

Data Collection and Quality Control of Data
CUB-Réa is financed by Assistance Publique-Hôpitaux de Paris (AP-HP). CUB-Réa has a steering committee composed of nine medical doctors and a database administrator (P.A.). The steering committee is charged with defining the minimum data set, item definitions, participation requirements, coding rules, annual activity report, and data audit. Standard information, both administrative and medical in nature, is collected locally. Data are gathered prospectively for all patients hospitalized in the ICUs and are transmitted anonymously to the administrative center to be recorded in a relational database. All ICU stays are referred to the hospital diagnosis-related group. Each hospital controls the completeness of coding, so there are no missing patients or information regarding ICU stay characteristics. In order to participate in the CUB-Réa, units must meet several criteria: a firm commitment to the study; a physician in charge of collecting and validating the data in each unit; acceptance of external control; and provision of information on staffing and equipment.

Data were collected in each ICU using a standardized form and a computer program. Before exporting the data to the operating center, a trained data collector in each ICU checked the completeness and the quality of information. The operating center reformatted data before entering them into the database. Logical checks were performed for missing data and to find inconsistencies, especially regarding clinical diagnosis, date, and severity scores. In 1996, quality control was performed on the 1995 database by blindly reviewing 215 randomly selected records. The reliability of the database was confirmed on the basis of the interrater reproducibility measured by the coefficient for categorical variables and the intraclass correlation coefficient for continuous variables.¹⁴ For instance, evaluation of severity of illness, as assessed by the SAPS II, was highly reproducible (intraclass correlation coefficient = 0.89). However, the reliability of the McCabe and Jackson classification appeared moderate ( = 0.51). Quality assessments were again performed during year 2000 on 260 stays and confirmed the overall reliability of the data, notably showing good agreement for organ support: circulatory support, = 0.71; respiratory support, = 0.95; and renal support, = 0.84. The agreement for the diagnosis of infection was lower: = 0.618 for bacterial pneumonia to = 0.907 for peritonitis, while = 0.633 for SS. The CUB-Réa database has already been used to study specific situations such as cost-effectiveness ratio, SS, or systemic candidiasis.⁹¹⁵¹⁶

Statistical Analysis
Categorical variables were compared using the Pearson ² test, and continuous variables were measured using the Student t test. Because of skewness, length of stay was log-transformed before comparison. Potential risk factors for death in the ICU and in-hospital were first studied using univariate analyses. Then variables associated with p < 0.2 were used for multivariate modeling. More generally, each model-building process followed the same steps: univariate test of the relation with death, exploratory analysis of the form of the relationship with death for continuous variables by additive models, development of multivariate models by stepwise procedures, and test of interactions. At last, a Box-Tidwell transformation was performed to take into account nonlinearity of the logit and to improve calibration. Goodness of fit was assessed by the Hosmer-Lemeshow ² C statistic. All tests were two tailed, and p < 0.01 was considered significant in multivariate models to take into account multiple comparisons. Data were analyzed using statistical software (SAS Institute; Cary, NC).

	Results

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Incidence of SS
Among 96,193 ICU admissions from 1997 to 2001 in the Paris area, SS was reported in 20,963 (21.4 per 100 admissions) cases overall. Among 65,910 ICU stays > 24 h, SS was reported in 18,273 cases (27.7 per 100 ICU stays > 24 h. The incidence of SS (SS1 plus SS2) increased over time from 17.2 per 100 ICU admissions (3,043 of 17,657) in 1997 to 18.7 per 100 admissions (3,824 of 20,444) in 2001 (p < 0.0001). SS2 occurred in 12,598 cases, giving a 13.1 per 100 admissions incidence rate when considering all ICU stays and 19.1 per 100 ICU stays > 24 h. Likewise, the incidence of SS2 increased over time from 11.9 per 100 admissions (2,092 of 17,657) in 1997 to 13.0 per 100 admissions (2,652 of 20,444) in 2001 (p < 0.001).

When considering all ICU admissions and calculating the incidence of SS2 by bed and year, rates were very close in university housing (5.6 patients per bed per year) and nonuniversity housing (5.9 patients per bed per year). The incidence of SS2 was twofold higher in patients admitted for unscheduled surgery than in those admitted for scheduled surgery or on medical grounds (p < 0.001). It was also higher in patients admitted to surgical ICU than in those admitted to medical or medicosurgical ICUs (p < 0.001). The incidences of SS1 and SS2 were similar in small ICUs (10 to 12 beds) and large ICUs (> 16 beds), and lower than in medium-sized ICUs. The incidence of SS1 as well as of SS2 increased with age, with an incidence of 20.5% in patients < 50 years old, rising to 32.2% in patients > 75 years old (p < 0.001). However, this was observed only in patients without associated comorbidities (ie, Charlson-Deyo score = 0; Fig 1 ).

View larger version (15K): [in this window] [in a new window] [Download PPT slide]   Figure 1. Incidence of SS2 according to age and Deyo-Charlson comorbidity score (Incid. Ch = 0 indicates no comorbidity; Incid. Ch = 1 indicates minor comorbidity; Incid.Ch = 2 indicates major comorbidity). Age*10 indicates age decile.

View larger version (16K): [in this window] [in a new window] [Download PPT slide]   Figure 2. ICU mortality rate of SS according to age and Deyo-Charlson comorbidity score (ICU Mort. Ch = 0 indicates ; ICU Mort. Ch = 1 indicates ; ICU Mort. Ch 2 indicates . Age*10 indicates age decile.

	Discussion

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Epidemiologic studies of SS are difficult to compare, not only because their results are influenced by their date of implementation and the type of ICU analyzed, but also because SS is a highly heterogeneous condition.² In 1992, a consensus conference of the American College of Chest Physicians and the Society of Critical Care Medicine attempted to clarify the pathology by defining various sepsis stages of increasing severity, from systemic inflammatory response syndrome (SIRS, including fever or hypothermia, leukocytosis or leukopenia, tachycardia, and tachypnea or a supranormal minute ventilation), to sepsis (SIRS with confirmed or suspected infection), SS (sepsis with organ failure), and septic shock.¹ This conference has been updated in 2001.¹⁷ However, the value of this definition has been debated.¹⁸ Apart from the fact that the diagnostic criteria of SIRS are difficult to apply,¹⁹ the concept of SIRS is questioned, notably because of its sensitivity.²⁰ Thus, in a large epidemiologic study,²¹ one fifth of infections did not fulfill SIRS criteria. Moreover, the American College of Chest Physicians/Society of Critical Care Medicine definition excludes patients without documented infection. In comparison, the definition of SS used in the present study was more inclusive and closer to the "real life," as we did not use the item SIRS and we included patients with infection, regardless of whether it was documented or not. We also included patients in whom SS was present at ICU admission or developed during their ICU stay. It must be acknowledged that considering the nature of our database and the retrospective nature of our study, the causal (or temporal) relationship between organ dysfunction and infection is unavailable, inducing a possible overestimation of the reported incidences of SS. In one study,²¹ 18% of patients did not meet case definition criteria at the time of ICU admission but did meet them within the first week of ICU admission. All these reasons may explain why the incidence of SS reported in our study (21.8%) is higher than that reported in other studies.⁵⁶ Considering the number of ICU beds encompassed in our database and the total number of ICU beds in France, we can estimate that there are approximately 54,000 cases of SS annually in France, with one case in ICU per 1,000 inhabitants. An incidence of approximately three cases of SS in hospital per 1,000 inhabitants was reported in the United States.² Explaining this difference is difficult, but it must be pointed out that the US data took into account all hospital cases of SS and > 40% of the patients were treated outside the ICU.²

The increased prevalence of patients with transplantation and AIDS, the greater ability to sustain critically ill patients by improved techniques, and the increased use of immunosuppressive therapies and invasive devices¹ may explain the rising incidence of SS in French ICUs between 1997 and 2001. At the same time, the rate of mortality tended to decrease. This result, all the more remarkable since the incidence of SS2 also increased between 1997 and 2001, and the lack of specific therapies for SS at the time of the study, suggest that basic supportive measures have improved and are beneficial (ie, early goal-directed therapy, tight glucose control, and low-dose steroids). Thus, the overall 37.8% hospital mortality rate of SS patients was in the lower range of those reported in prior epidemiologic studies^{2151719202122232425} of SS, 20 to 66%.

As compared with ICU patients without SS, ICU patients with SS had a longer length of stay, a higher requirement for organ support, and a higher mortality rate. Similar data were obtained in a study performed in German ICU²⁵: the mean length of stay of patients hospitalized for > 24 h was approximately 6 days; that of SS patients was 17 days in the ICU and 33 days in the hospital, as compared to 7 days, 18 days, and 32 days in French ICUs, respectively.

We confirm that the lung is the most frequent site of infection, followed by the abdomen,²⁶ and that infection of the urinary tract was independently associated with a reduced risk of mortality.¹⁹²⁰ As in the study by Rangel-Frausto et al,²⁸ the number of positive blood culture results increased with the severity of the sepsis syndrome. Infection was not documented in approximately 40% of cases. This rate of negative culture, higher than reported in older studies,¹⁹²¹ may be due to the increase in empiric antimicrobial therapy in patients with suspected sepsis. In contrast to an earlier study,²⁰ in which Escherichia coli was the most common microorganism, we found that S aureus, followed by Gram-negative Pseudomonas species, were most frequent. A meta-analysis²⁶ of sepsis studies indicated that Gram-positive organisms have become more common in the more recent studies. Whereas bacteria, except Pseudomonas, did favorably influence outcome, fungal infection was independently associated with mortality, as previously suggested.¹²²⁷

The majority of SS patients had two organ failures, a change from an earlier US study² in which most patients had only one organ failure. Severity scores, the number of organs supported, length of stay, and mortality were dependent on the number of organ failures. This result underlines the fact that it is the cumulative burden of organ failure that leads to death, the average risk of death increasing by 15 to 20 percentage points with failure of each additional organ.²⁸ Interestingly, whereas age did not influence the incidence of patients with one organ failure, we showed that the incidence of patients with two organ failures was higher in patients > 50 years old. We confirm that cardiovascular, renal, and neurologic failures are independent risk factors of ICU death.²⁹ Pulmonary dysfunction was the most common organ failure; its odds ratio for predicting ICU death was the highest. Among the two comorbidity indexes used in the present study, the Charlson-Deyo score, which takes into account the number but also the severity of comorbidities, and the McCabe and Jackson classification, only the former was shown to be a significant independent predictor of death. Moreover, a Charlson-Deyo score of 2 predicted mortality with a higher odds ratio than the SAPS II score, originally established as an outcome prediction score. The lower predictive value of the SAPS II score for mortality may be due to the fact that it was measured using data from a single time point, 24 h after ICU entry, regardless of the timing of sepsis occurrence.³¹

Although the CUB-Réa database was not specifically designed for SS patients, we believe that our results give a current and representative picture of SS in French ICUs, as the analysis was performed recently, over a long period of time, in both nonuniversity and university French ICUs, and in a large number of patients. We did not exclude patients usually excluded in clinical trials receiving therapeutic interventions, such as the very elderly, patients with HIV infection, and patients with malignancies. However, it is noteworthy that we restricted our study to sepsis in the ICU, which may differ from sepsis in hospital, due in part to a higher incidence of nosocomial infections in the former.²⁰ We also excluded serious inflammatory conditions not caused by infection, such as trauma or pancreatitis.³² Finally, patients who died within the first 24-h period were not analyzed. We reproduce results very close to those reported in the placebo group enrolled in the Phase III Recombinant Human Activated Protein C Worldwide Evaluation of Severe Sepsis trial.³⁷

	Conclusions

TOP Abstract Introduction Materials and Methods Results Discussion Conclusions Appendix References

 
SS is a condition occurring with increasing frequency, but with a mortality rate tending to stabilize or even decrease. In the ICU, it is the condition associated with the longest length of stay, the highest requirement for organ support, and the highest mortality rate. Its severity depends on the number of organ failures. Septic patients with at least two organ dysfunctions should probably be considered separately from patients with only one organ dysfunction when designing clinical trials on therapeutic intervention.

	Appendix

TOP Abstract Introduction Materials and Methods Results Discussion Conclusions Appendix References

 
Infection Site Categories With Corresponding Sites Used in the CUB-Réa Database
Pulmonary:
Pneumonia (J15.9, J12.9, J17.2, J17.3, J69.0), purulent pleural effusion (J86.9), pulmonary abscess (J85.2), sinusitis (J32.9), epiglottis (J05.1).

Cardiovascular:
Mediastinitis (J85.3), endocarditis (I33.0), infectious pericarditis (I30.1), myocarditis (I40.0).

Neurologic:
Meningitis and encephalitis (G0.1,G04.9, G05.0, G00.9), cerebral abscess (G06.0).

Abdominal:
Peritonitis (K65.0, K35.0, K65.1), angiocholitis (K83.0), cholecystitis (K80.0), liver abscess (K75.0).

Cutaneous:
Cellulites (L03.9), gangrene (A48.0), arthritis (M00.9), osteomyelitis (M86.1).

Urinary Tract:
Acute pyelonephritis (N39.0), renal abscess (N15.1, N13.6), prostatitis (N41.0).

Blood Infection:
Positive blood culture result (A40.0 to A41.9).

International Classification of Diseases, Tenth Revision Codes and Omega Codes Used for Defining Organ Dysfunction and Organ Support
Respiratory Dysfunction:
Diagnosis, acute respiratory insufficiency (J96.0), ARDS (J80); procedures, invasive or noninvasive mechanical ventilation (with or without respiratory dysfunction).

Cardiovascular Dysfunction:
Diagnosis, shock (R57.8); procedures, use of vasoactive agents.

Renal dysfunction:
Diagnosis, acute renal insufficiency (N17.0,N17.1, N17.2, N17.9); procedures, use of dialysis or hemofiltration (with our without renal dysfunction).

Neurologic Dysfunction:
Diagnosis, coma (R40.2).

Hematologic Dysfunction:
Diagnosis, symptomatic disseminated intravascular coagulation (D65).

Metabolic Dysfunction:
Diagnosis, lactic acidosis (E87.2).

Members of the CUB-Réa Study Group
F. Jardin, B. Page (Hôpital Ambroise Paré); J.P. Bedos (Hôpital André Mignot); F. Brivet (Hôpital Antoine Béclère); Y. Cohen, JPh. Fosse (Hôpital Avicenne); Cl. Gibert (Hôpital Bichat); B. Regnier (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. Brun-Buisson (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 (MICU, Hôpital Saint-Louis); L. Jacob (SICU, Hôpital Saint-Louis); C. Mayaud, A. Parrot (Hôpital Tenon); and G. Bleichner, H. Mentec (Hôpital Victor Dupouy).

	Footnotes

 
Abbreviations: AP-HP = Assistance Publique-Hôpitaux de Paris; CUB-Réa = Collège des Utilisateurs de Bases de données en Réanimation; MRSA = methicillin-resistant Staphylococcus aureus; SAPS = simplified acute physiology score; SIRS = systemic inflammatory response syndrome; SS = severe sepsis; SS0 = no septic shock; SS1 = one organ dysfunction present during the ICU stay; SS2 = at least two organ dysfunctions present during the ICU stay

Presented in part at fourteenth ESICM meeting, Geneva, Switzerland, 2001 (O 233).

Investigators participating in the CUB-Réa Study Group are listed in ^{Appendix 3}.

This study was funded in part by Eli Lilly. CUB-Réa is supported by AP-HP.

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