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Septic shock, a sepsis-induced circulatory insufficiency, occurs in 10–20% of intensive care unit (ICU) patients, is associated with a high mortality rate (30–50%), associates an activation of inflammation and hemostatic systems leading to microcirculatory anomalies such as disseminated intravascular coagulation (DIC) [1], which impact on mortality prediction is not clear [2].

DIC diagnosis is based on the combination of a DIC-promoting condition with laboratory parameters for ongoing intravascular coagulation [3]. The overt DIC score of the DIC subcommittee of the International Society on Thrombosis and Haemostasis (ISTH) contains as laboratory parameters platelet count, prothrombin time, fibrinogen level and a fibrin-related marker (FRM) [3], which type has not been specified, even if the many validation studies performed hereafter have all employed D-dimers [4].

Among available FRMs for routine clinical practice are D-dimers (DDi) and fibrin monomers (FM): theoretically, FM or soluble fibrin would more closely reflect intravascular acute fibrin formation than DDi, which may also detect acutely formed crosslinked fibrin as well as plasmin-mediated proteolytic fragments of extravascular fibrin deposits [4].

A previous study performed in a clinically heterogeneous cohort of 331 ICU patients (12.1% with a septic shock) showed that the use of FM antigen instead of DDi may enhance the prognostic power of the ISTH overt DIC score [5], with some prognostic impact on the mortality rate at day 28.

The Haemostasis Impact in Septic Shock (HISS) project hypothesis was that hemostasis parameters investigated early in patients with septic shock may be related to mortality and may allow categorization of patients according to their prognosis as they enter ICU. The present study is the continuation of our first results from the HISS project [6], this second sub-study being focused on early FM, DDi and the related ISTH overt DIC scores values. The study was approved by our Local Ethics Committee and was conducted in our 1200-bed university hospital which contains a single 26-bed ICU.

Consecutive patients entering the ICU (1 January 2008 to 1 January 2010) were considered for potential inclusion. Inclusion criteria was acute septic shock defined as described [5], exclusion criteria being an age <18 years old or a septic shock developing after ICU admission [5]. The diagnosis was adjudicated by an internal medical group containing an epidemiologist, an internist, an infectiologist and a microbiologist. Patients were treated according to available recommendations. We were limited to 350 patients for cost reasons.

The patients were monitored for 90 days after ICU admission. Survival at day 90 was the primary outcome criteria with subsequent categorization in survivors and non-survivors. In patients who left the hospital alive, this was checked by contacting the patient, the family and their general practitioner. The major source of bias in prospective cohort studies, loss to follow-up, was eliminated (no loss to follow-up). Ascertainment and interviewer bias are unlikely because of the primary outcome criteria.

Laboratory parameters were assayed at ICU admission, blindly to the patients’ clinical status and to the overt DIC scores values. Coagulation tests were performed on the STA-R® analyzer using commercially available reagents from Stago, Asnières, France: STA®– Neoplastine® CI Plus for the prothrombin time, STA®– Fibrinogen kit (Clauss’ method) for fibrinogen plasma levels. DDi plasma concentrations were assayed using an immuno-turbidimetric method (STA®– Liatest® D-Di), as were soluble fibrin monomer complexes concentrations (STA®– Liatest® FM). This assay uses the F405 [7] monoclonal antibody coated on latex microparticles: the recognized epitope was the alpha-chain N-terminal region exposed upon removal of the A peptide from the Aalpha-chain, F405 binding to the alpha-chain N-terminal oligo-peptide of fibrin (GPRVVERHQ) [7].

ISTH DIC scores were calculated as described [3]. For FRM DDi ≤ 0.5 mg L−1 = 0 and FM ≤ 5 mg L−1 = 0, according to data obtained in normal controls in our previous work [6]. The cut-off values separating moderate increases (attributed points: 2) from strong increases (attributed points: 3) were experimentally determined as the ones separating survivors from non-survivors in a plot comparing the DDi or FM centile values (Q-Q plot). In case of a systematic shift in the distributions between the two groups, the plot systematically diverges from the x = y line after a threshold value. These threshold values were as follows: DDi 4 mg L−1; FM 10 mg L−1. Two DIC scores, ranging from 0 to 8, were systematically calculated: using DDi -DIC score DDi- or using FM -DIC score FM-. A total score ≥ 5 indicated a positive overt DIC [3].

The concordance between the values of the two DIC scores was estimated by calculation of Kappa coefficient and its 95% confidence interval (CI). Survival analysis was performed to provide estimates of death probability within 90 days. Survival times were calculated from the admission to the ICU to death or censure. Event rates were estimated using the Kaplan–Meier method and comparison between groups was performed with the log-rank test. The hazard ratio (HR) and two-sided 95%CI was calculated with the use of a Cox proportional hazards model. Risk proportionality hypothesis was verified. Areas under receiver-operating characteristic curves (AUC) evaluating the ability of each variable to predict death by the end of the 90th day were calculated and compared using a non-parametric approach [8].

Screening 547 consecutive patients entering ICU for acute shock finally led to the inclusion of 350 patients whose septic status was ascertained by a positive culture: median age 70 years, interquartile range (IR) 17, range 19–94 years, 203 males (58%) and 147 females. The median follow-up time was 90 days, range 1–90 days. The following infections were assessed: community- or hospital-acquired pneumonia (n =166); an upper urinary tract infection (n = 55); generalized skin disease with secondary infection (n = 11); meningitis (n = 3); and surgical patients with perforations leading to abdominal sepsis (n = 115). A risk factor for hospital mortality was characterized 68 patients (19.4%): chronic hepatic insufficiency (n = 5); chronic renal insufficiency (n = 6); chronic respiratory insufficiency (n = 22); hematological neoplasia or immunosuppressive medication (n = 17); neurologic insufficiency (n = 5); diabetes mellitus (n = 9); and alcohol abuse (n = 4). A total of 165 patients died within 90 days of admission (47.1%).

The HR value for non-survival was 1.53, 95%CI (1.3–1.8), χ2 26.4, P < 0.0001 for DDi after log transformation and was 1.53, (1.3–1.7), χ2 56.1, P < 0.001 for FM after log transformation.

The Kappa coefficient value between the two DIC scores was 0.58, 95% CI (0.5–0.7), indicating a moderate to substantial agreement. The DIC score DDi values were globally higher than the DIC score FM values (P < 0.0001), mainly for DIC score FM values lower than five. Patients with a null (DIC score DDi minus DIC score FM) difference constituting the reference group, those with a negative difference had a trend for a higher non-survival risk [HR 1.55, 95% CI (0.8–3), χ2 1.64, P = 0.20] and those with a positive difference had a lower non-survival risk [HR 0.42, 95% CI (0.3–0.7), χ2 12.6, P = 0.0004].

DIC score DDi values predicted non-survival: HR 1.48, 95%CI (1.3–1.7), χ2 45.4, P < 0.0001 for each DIC score unit increase. A similar aspect was evidenced for DIC score FM values: HR 1.41, 95%CI (1.3–1.5), χ2 57.4, P < 0.0001.

Patients with a positive overt DIC score were at higher risk of death: respectively, HR 2.45, 95%CI (1.8–3.3), χ2 32.6, P < 0.001 (log-rank test: χ2 43.8, P < 0.0001) using DDi and HR 2.84, 95% CI (2.1–3.9), χ2 43.8, P < 0.001 (log-rank test: χ2 50.5, P < 0.0001) using FM.

Non-survival risks in patients categorized according to their DIC scores were calculated (Table 1). DIC score DDi categories did not indicate significant risks in spite of progressively increasing HR values. Increasing DIC score FM values were strikingly associated with increasing non-survival risks. Figure 1 depicts mortality rates vs. increasing scores. For values ≥ 4, a linear and parallel relationship is evidenced between increasing scores and mortality rates. The relationship linearity was broken for DIC scores ≤ 3; the very few observations with DIC score DDi values lower than three generating confusion. Increasing values of the individual absolute difference between DIC score DDi and DIC score FM were associated with decreasing mortality rates (P = 0.0005).

Table 1.   Risks for non-survival between disseminated intravascular coagulation (DIC) scores categorized according to their values, using D-dimers (DIC score DDi) or fibrin monomers (DIC score FM) as the fibrin generation marker. HR: hazard ratio; 95% CI: 95% confidence interval
ValueNNon-survivorsχ2HR95% CIP
DIC score DDi
 032 1  
 11200.0010.0000–101470.974
 23954.5950.170.032–0.860.032
 375250.9450.490.116–2.060.329
 496430.1690.740.180–3.070.681
 581490.0281.130.274–4.640.867
 639270.1881.370.327–5.780.665
 715131.1922.290.517–10.20.275
 8111.0493.520.317–39.10.306
DIC score FM
 0304 1  
 133102.1222.370.743–7.550.145
 24190.9631.800.555–5.880.326
 358235.5643.591.24–10.380.0183
 460319.0984.971.75–14.10.0026
 5774713.6886.882.48–19.10.0002
 6332518.57510.23.55–29.5< 0.0001
 7171519.79412.34.07–37.1< 0.0001
 8117.33120.92.32–1880.0068
image

Figure 1.  Mortality rates according to the value of the disseminated intravascular coagulation (DIC) score using D-dimers (DIC score DDi) or using fibrin monomers (DIC score FM), and according to the individual value of the difference between the DIC score DDi value and the DIC score FM value. The number of patients associated with each DIC score value is given at the top of each bar.

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AUCs were 0.659 (95% CI 0.60–0.72) for DDi and 0.720 (0.67–0.77) for FM, which demonstrated a higher predictive ability (P = 0.0284). AUCs corresponding to DIC score DDi and DIC score FM were 0.701 (95% CI 0.65–0.76) and 0.729 (0.68–0.78), respectively, P = 0.132. The global ability of these four parameters to predict death was moderate: a non-survivor patient would on average have higher DDi, FM, DIC score DDI or DIC score FM values than 66%, 72%, 70%, or 73% of the survivors, respectively.

In patients investigated as they entered ICU with septic shock, a DIC-promoting condition, DDi and FM values, but also a positive overt DIC score calculated using DDi or FM, were associated with a poor 90-day outcome. Calculating DIC scores, the higher threshold for FRM was eight times the upper limit of normal for DDi, similar to previous studies, but only two times the upper limit of normal for FM. This probably explains the low number of patients with low scores using DDi, comparatively to using FM, and also the uncertainty of the relationship between DIC scores and mortality rates for low DIC scores. Threshold values had, however, both been chosen as the best one indicating a shift between mortality and survival. The relationship between the individual difference between the two scores and mortality rates may indicate that the more patients initially generate DDi over FM, the less mortality is likely. The acute fibrinolytic response in DIC being the release of plasminogen activators PAI-1 increase being delayed [4], this may point to a positive effect of an initially enhanced plasmin generation potential, which may protect the microcirculation from fibrin deposits. Some specific investigations are warranted.

The choice of the fibrin-related marker between D-dimers and fibrin monomers, performed using commercially-available reagents based on the same general analytical principle driven on the same automated analyser, impacted on the clinical meaning of the ISTH overt DIC score for values lower than 4. A significant gradual increase of the risk of death was finally evidenced for increasing values of the DIC score FM, the relationship being lost for low values of the DIC score DDi. This statistically significant difference may thus have limited clinical relevance. DDi are widely available in laboratories near ICUs on a 24-h basis and introducing another FRM beside the one currently used for venous thromboembolism exclusion may induce some organizational difficulties. A prospective multicentric careful evaluation is thus warranted and other disorders favoring DIC have to be considered.

Addendum

  1. Top of page
  2. Addendum
  3. Acknowledgements
  4. Disclosure of conflict of interest
  5. References

J.-C. Gris, G. Lissalde-Lavigne and J.-Y. Lefrant designed the study. J.-Y. Lefrant coordinated the management of the patients and gathered the medical data. J.-C. Gris, É. Cochery-Nouvellon and G. Lissalde-Lavigne gathered the biological data. J.-L. Faillie analyzed the data and gave statistical expertise. J.-C. Gris and J.-Y. Lefrant drafted the manuscript. All authors critically reviewed the manuscript.

Acknowledgements

  1. Top of page
  2. Addendum
  3. Acknowledgements
  4. Disclosure of conflict of interest
  5. References

The authors are grateful to the practitioners who recommended their septic shock patients to the medical staff of the central ICU. They thank A. Berthier, D. Aleksan and K. Carrière, Stago, for their support and help. They would also like to thank the research staff of the ‘Direction de la Recherche Clinique et de l’Innovation’ of the University Hospital of Nîmes: S. Clément, C. Meyzonnier, S. Granier, B. Lafont, H. Obert, H. Léal, O. Albert. They thank C. Suehs for her help in English editing. This study was directly supported by a specific technical grant obtained from Stago, Asnières France and by an internal grant of the Clinical Research Committee of the University Hospital of Nîmes. The funders of the study were not involved in the initiation of the study, in the study design, in the data collection, in the analyzes of the results and in their interpretation, or in the writing of the manuscript.

Disclosure of conflict of interest

  1. Top of page
  2. Addendum
  3. Acknowledgements
  4. Disclosure of conflict of interest
  5. References

J.-C. Gris and J.-Y. Lefrant received speakers’ honoraria from Stago. The other authors state that they have no conflict of interest.

References

  1. Top of page
  2. Addendum
  3. Acknowledgements
  4. Disclosure of conflict of interest
  5. References
  • 1
    Amaral A, Opal SM, Vincent JL. Coagulation in sepsis. Intensive Care Med 2004; 30: 103240.
  • 2
    Wada H, Wakita Y, Nakase T. Outcome prediction of dissemination intravascular coagulation in relation to the score when treatment was begun. Thromb Haemost 1995; 78: 84852.
  • 3
    Taylor FBJr, Toh CH, Hoots WK, Wada H, Levi M. Towards definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation. Thromb Haemost 2001; 86: 132730.
  • 4
    Levi M, Meijers JC. DIC: which laboratory tests are more useful. Blood Rev 2011; 25: 337.
  • 5
    Dempfle CE, Wurst M, Smolinski M, Lorenz S, Osika A, Olenik D, Fiedler F, Borggrefe M. Use of soluble fibrin antigen instead of D-dimer as fibrin-related marker may enhance the prognostic power of the ISTH overt DIC score. Thromb Haemost 2004; 91: 8128.
  • 6
    Lissalde-Lavigne G, Combescure C, Muller L, Bengler C, Raillard A, Lefrant JY, Gris JC. Simple coagulation tests improve survival prediction in patients with septic shock. J Thromb Haemost 2008; 6: 64553.
  • 7
    Hamano A, Tanaka S, Takeda Y, Umeda M, Sakata Y. A novel monoclonal antibody to fibrin monomer and soluble fibrin for the detection of soluble fibrin in plasma. Clin Chim Acta 2002; 318: 2532.
  • 8
    Hanley JA, McNeil BJ. The meaning and use of the area under a receiver operating characteristic (ROC) curve. Radiology 1982; 143: 2936.