Nationwide registry of sepsis patients in Japan focused on disseminated intravascular coagulation 2011–2013

Sepsis is a syndrome with physiologic, pathologic, and biochemical abnormalities induced by infection. Sepsis can induce the dysregulation of systemic coagulation and fibrinolytic systems, resulting in disseminated intravascular coagulation (DIC), which is associated with a high mortality rate. Although there is no international consensus on available treatments for sepsis-induced DIC, DIC diagnosis and treatment are commonly performed in Japanese clinical settings. Therefore, clinical data related to sepsis-induced DIC diagnosis and treatment can be obtained from Japanese clinical settings. We performed a retrospective nationwide observational study (Japan Septic Disseminated Intravascular Coagulation [J-SEPTIC DIC] study) to collect data regarding characteristics of sepsis patients in Japan, with a focus on coagulofibrinolytic dysregulation and DIC treatment received by each patient. The J-SEPTIC DIC study collected information for a total of 3,195 patients with severe sepsis and septic shock and is the largest data set in Japan on DIC diagnosis and treatment in clinical settings.


Background & Summary
Sepsis is a syndrome with physiologic, pathologic, and biochemical abnormalities induced by infection and resulting in life-threatening organ dysfunction 1,2 . A global epidemiological report estimated that 31.5 million people are affected by sepsis and 19.4 million people are affected by severe sepsis each year, with a potential 5.3 million deaths worldwide from sepsis each year 3 .
Disseminated intravascular coagulation (DIC) is induced by the dysregulation of systemic coagulation and fibrinolytic systems in sepsis and septic shock 2,4,5 . Sepsis-induced DIC causes the development of microthrombi, which cause tissue hypoperfusion and result in multiple organ failure; sepsis-induced DIC is thus associated with a high mortality rate 2,4,5 . However, because appropriate treatments for sepsisinduced DIC have not been widely studied, there is no international consensus on available treatments for sepsis-induced DIC 6,7 , and in many countries specific treatment for sepsis-induced DIC in clinical settings is not provided 8 . On the other hand, in Japanese clinical settings, DIC diagnosis using scoring systems are generalized in sepsis management 9 . Furthermore, recombinant thrombomodulin, antithrombin and other anticoagulants are approved as DIC treatment drugs and are frequently used in patients with sepsis-induced DIC 10,11 . Therefore, clinical data related to the treatment of sepsisinduced DIC can be collected from clinical settings in Japan.

Methods
The J-SEPTIC DIC study was conducted in 42 intensive care units (ICUs) of 40 institutions throughout Japan (Table 1 and Fig. 1) and was approved by the institutional review boards of each hospital. The boards waived the requirement for informed consent, due to the retrospective design.
We retrospectively reviewed data of consecutive patients who were admitted to the ICUs of participating institutions to be treated for severe sepsis or septic shock between January 2011 and December 2013. Severe sepsis and septic shock were defined based on the International Sepsis Definitions Conference criteria 21 . We excluded patients who were &lt; 16 years old, or patients who developed severe sepsis or septic shock after their ICU admission.
The following data were collected: age; sex; body weight; admission route to the ICU; pre-existing organ dysfunction; pre-existing hemostatic disorder; Acute Physiology and Chronic Health Evaluation (APACHE) II score; 22 Sequential Organ Failure Assessment (SOFA) score 23 (days 1, 3, and 7); systemic inflammatory response syndrome (SIRS) score 24 (days 1, 3, and 7); primary infection site; blood culture results; microorganisms responsible for the sepsis; daily results from laboratory tests during the first week after ICU admission; lactate levels (days 1, 3, and 7); administration of drugs, including immunoglobulins, and low-dose steroids, during the first week after ICU admission; therapeutic interventions, including surgical interventions at the infection site, renal replacement therapy, renal replacement therapy for nonrenal indications, polymyxin B direct hemoperfusion, extracorporeal membrane oxygenation, and intraaortic balloon pumping, during the first week after ICU admission; and outcomes in the hospital.
The following data related to DIC diagnosis and treatment were also collected: systemic inflammatory response syndrome score; daily results from laboratory tests, which included platelets counts, prothrombin time/international normalized ratio, fibrinogen level, and antithrombin activity; D-dimer levels; fibrin/fibrinogen degradation product levels during the first week after ICU admission; administration of anti-DIC drugs, which included antithrombin, recombinant thrombomodulin, protease inhibitors and heparinoids, and other anticoagulants during the first week after ICU admission; and transfusion amounts and bleeding complications during the first week after ICU admission.
Finally, the following data related to the institutions and ICUs were collected: characteristics of institutions and ICUs (general ICU or emergency ICU); management policy of the ICU (closed or open); number of beds in the ICU; reagents of fibrin/fibrinogen degradation products and D-dimer measurements.

Data Records
A single data set resulted from the present study. This data set contains information of the 3,195 patients with severe sepsis or septic shock in 42 ICUs over 3 years. The information of the institution and the ICU where each patient was admitted is described in the same line as the patient's information (Data Citation 1). Blanks in the data set indicate missing data. In the present study, all laboratory results were measured according to clinical necessity. Therefore, many missing data were included in the data set. Furthermore, some variables were not available due to death or discharge.
Detailed information on variable specifications is included in a Read_me file (Data Citation 1).

Technical Validation
The present study was a retrospective design. Information of eligible patients was collected in each participating institute and reported to the principal institute (Hokkaido University Hospital) by one investigator per institution. Collected data were assessed by expert emergency and critical care physicians; if outliers in each variable and contradictions within data were detected, data were validated with each investigator in each hospital. The outliers and contradictions were judged by the expert emergency and critical care physicians. Data were finalized and fully anonymized on September 8, 2015.