Clinical outcomes and prognostic factors of patients with sepsis caused by intra-abdominal infection in the intensive care unit: A post-hoc analysis of a prospective cohort study in Korea

Abstract

Background: Sepsis is the most common cause of death in hospitals, and intra-abdominal infection (IAI) accounts for a large portion of the causes of sepsis. We investigated the clinical outcomes and factors influencing mortality of patients with sepsis due to IAI.

Methods: This post-hoc analysis of a prospective cohort study included 2,126 patients with sepsis who visited 16 tertiary care hospitals in Korea (September 2019–February 2020). The analysis included 219 patients aged > 19 years who were admitted to intensive care units owing to sepsis caused by IAI.

Results: The incidence of septic shock was 47% and was significantly higher in the non-survivor group (58.7% vs 42.3%, p=0.028). The overall 28-day mortality was 28.8%. In multivariate logistic regression, after adjusting for age, sex, Charlson comorbidity index, and lactic acid, only coagulatory dysfunction (p=0.001, odds ratio: 2.78 [1.47­–5.23]) was independently associated, and after adjusting for each risk factor, only simplified acute physiology score III (p=0.014) and continuous renal replacement therapy (p<0.001) were independently associated with higher 28-day mortality.

Conclusions: Considering the independent risk factors influencing 28-day mortality, more intensive care may be needed for patients with coagulopathy than for patients with other organ dysfunctions caused by IAI.

Introduction

Sepsis is an uncontrolled reaction of the host to infection, which can be potentially life-threatening. Accurate calculation of the global burden of sepsis is difficult. A recent study has reported approximately 48.9 million cases and 11 million sepsis-related deaths in 2017. This accounts for nearly 20% of all deaths worldwide, and sepsis is the most common cause of death in hospitals in the United States [1, 2]. Sepsis is a major public health issue, and the costs for treating sepsis in hospitals have increased, exceeding US $24 billion per year [2, 3]. Likewise, the incidence of sepsis and the treatment costs in Korea have steadily increased, particularly among older adults.

Intra-abdominal infection (IAI) is defined as an inflammatory reaction to bacteria and their toxins in the peritoneum, resulting in a purulent exudate in the peritoneal cavity [4–7]. Among all the causes of sepsis, IAI is reportedly the second most common cause, with a relatively high mortality rate of nearly 30.0% [8–10]. In particular, most sepsis cases in surgical intensive care units (ICUs) are caused by IAI. Source control and antibiotic use are essential in the treatment of these patients. Various forms of IAIs may exist, including those in the hepatobiliary tract, stomach, small bowel, and colon. In addition, there are differences in mortality and clinical outcomes according to the type of organ, degree of anatomical disruption, and duration of IAI [4, 6, 8]. Treatment of IAI can be difficult because the spectrum of infection is wide compared with that of other infection causes and source control, wherein drainage or surgical treatment is often required.

However, studies on the clinical outcomes and impact of organ dysfunction in patients with sepsis due to IAI are limited. Therefore, the primary objective of our study was to investigate the clinical outcomes and the factors affecting the mortality in patients with sepsis due to IAI. The secondary objective was to determine the impact of organ dysfunction on mortality rates.

Materials And Methods

Results

Discussion

Despite the increased incidence of sepsis and septic shock, recent studies have consistently shown a decrease in sepsis mortality over time, owing to advances in medical technology [1, 13]. However, the overall in-hospital mortality rate due to sepsis was quite high at 29.0% in some recent studies in Korea [9, 14]. Similarly, our study showed that the overall in-hospital mortality rate with sepsis was 28.1%, and the mortality rate for sepsis caused by IAI was 23.3%. Moreover, the mortality rate of all patients with sepsis treated in the ICU and the mortality rate of patients treated for sepsis due to IAI in the ICU were even higher at 35.1% and 28.8%, respectively.

There have been many studies on tools for predicting the progress and prognosis of the disease, which are still underway [15–17]. One of the most important factors affecting the mortality and clinical outcomes in sepsis is comorbidity, and the CCI can quantify a patient's comorbidity. In this time of aging populations, the CCI of patients is increasing. The CCI is widely used as a tool to predict the mortality rate of patients with sepsis due to IAI and determine their prognosis in advance [14, 18, 19]. In our study, the mean CCI in the non-survivor group was higher than that in the survivor group, with significant differences (5.9 ± 3.0 vs. 5.1 ± 2.3, p = 0.011). In addition, CCI (p = 0.039, OR = 1.13 [1.00–1.26]) was an independent risk factor for mortality prediction in the univariate logistic regression analysis.

Multicenter research and efforts are being conducted worldwide to improve the clinical outcomes of patients with sepsis. For instance, the Surviving Sepsis Campaign released new guidelines for the treatment of sepsis and a new updated “Hour-1 bundle” for sepsis treatment [20, 21]. Immediate resuscitation, initial early screening, antibiotic treatment, and source control are imperative to reduce the social burden and improve patient outcomes [14]. In addition, initial lactate levels and initial SOFA scores can be used to predict clinical progress and prognosis of sepsis. A large number of studies have already shown that, the higher the initial lactate level and initial SOFA score, the higher the mortality rate in patients with sepsis [22, 23]. In our study, initial lactate level and SOFA score were also independent risk factors in predicting the mortality rate in patients with sepsis caused by IAI (p < 0.001).

Many studies have shown that patients with septic shock have higher mortality rates than those without septic shock [9, 24, 25]. There were more patients with septic shock in the non-survivor group, and the study of predicting risk factors can interpret that patients with septic shock have a 1.94 times higher risk of mortality than those without septic shock (p = 0.029).

In the treatment of patients with sepsis due to IAI, the usage of antibiotics and source control is very important. Adequate and swift antibiotic administration and coverage from the time of recognition of sepsis are vital [26–29]. Although no significant difference was noted, the non-survivor group showed a tendency of delayed antibiotic administration in our study compared with that in the survivor group (217.5 ± 422.8 min vs. 171.4 ± 238.8 min, p = 0.495). Sepsis caused by IAI due to biliary sepsis, intestinal perforation, postoperative leakage, and intra-abdominal abscess can be controlled using open laparotomy, percutaneous transhepatic biliary drainage, and percutaneous catheter drainage insertion. Ultimately, the prognosis of patients with sepsis depends on the source controls, and the faster the source control, the lower is the mortality rate [30, 31]. Our study showed a significantly higher number of survivors in the source control group (46.8% vs. 27.0%, p = 0.007). In addition, patients who did not perform source control have a 2.38-fold higher association with mortality than patients who did (p = 0.008, OR = 2.38 [1.26 ~ 4.51]).

In several studies on IAI, E. coli and K. pneumoniae were the most common gram-negative causative pathogens. In gram-positive pathogens, most of them were E. faecalis and E. faecium [5, 8]. In our study, the same pathogens were detected and the proportion was similar, as previously mentioned. The mortality rate was higher in patients whose causative pathogens were not identified. However, there was no significant difference in our study (p = 0.087). Additionally, some studies on IAI have shown that MDR is an independent risk factor for mortality [5, 8, 32]. However, the impact of MDR on mortality was not significant in our study (p = 0.136).

Organ dysfunction is a useful prognostic indicator for mortality in patients with sepsis, and the mortality rate increases significantly as the number of organ dysfunctions increases [33–35]. In one study by Takeshi et al., patients with three (23.5%) and four or more organ dysfunctions (38.9%) had over two and four times the ICU mortality rates, respectively, compared with that of single organ dysfunction (8.9%). In addition, the hazard ratios were 1.6, 2.0, and 2.7 in 2-, 3-, and 4 or more organ dysfunctions, respectively, showing an increasing trend as the number of organ dysfunctions increases [33]. In our study, the mortality rate was more than two-fold higher in patients with three organ dysfunctions (55.6%) and four or more organ dysfunctions (50.0%) than that of patients with single organ dysfunction (24.7%). The ORs were also 4.07 (p < 0.001) and 2.76 (p = 0.028) in patients with three and four or more organ dysfunctions, respectively. Similarly, the dysfunction of three or more organs in our study could be considered as an independent risk factor for mortality.

The impact of each organ dysfunction on mortality and the proportion of organ dysfunction occurring in patients with sepsis varies between the studies. In addition, in several studies of organ dysfunction in patients with sepsis, the most frequent cause of respiratory and cardiovascular system dysfunction is organ dysfunction [13, 33]. In contrast to the above-mentioned studies, respiration (36.5%), renal (36.1%), coagulation (34.2%), cardiovascular (25.6%), CNS (19.6%), and liver (18.3%) were observed in patients with sepsis caused by IAI in our study. And in patients with sepsis, respiratory and cardiovascular dysfunctions have a higher mortality rate than other organ dysfunctions [13, 33–35]. By contrast, our study showed the mortality rate of each organ dysfunction was highest in patients with CNS dysfunction (44.2%, p = 0.013), followed by coagulation (44.0%, p < 0.001), renal dysfunction (38.0%, p = 0.024), respiration (37.5%, p = 0.03), cardiovascular dysfunction (35.7%, p = 0.183), and liver dysfunction (27.5%, p = 0.845).

Microvascular thrombosis and ischemia are the most important processes in sepsis, causing tissue damage and multiple organ dysfunctions [36, 37]. In addition, the coagulation cascade may be abrogated owing to the aberrant expression of cytokines and tissue factors in response to systemic inflammation. As the coagulation system is deranged, sepsis-induced coagulopathy occurs, and manifestations of bleeding increase [36–38]. Coagulopathy in patients with sepsis is highly associated with mortality [39, 40]. Moreover, after adjusting for age, sex, CCI, and lactic acid level, coagulatory dysfunction (p < 0.001, OR = 2.99 [1.63–5.48]) had the greatest impact on mortality among the organ dysfunctions in our study.

This study has several limitations. First, this was a retrospective study based on medical records conducted in multiple institutions. Each hospital differed in its treatment policy, level, and system, including its facilities. As this study did not only focus on sepsis caused by IAI, the data may also be inadequate. To overcome these limitations, a prospective study of patients with sepsis caused by IAIs may be needed.

Conclusions

In our study, CCI, septic shock, initial lactate level, initial SOFA score, SAPS 3 score, acute kidney injury with CRRT, source control, and the number of dysfunctional organs were found to be independent risk factors affecting 28-day mortality. Among the organ dysfunctions in sepsis caused by IAI, coagulopathy was found to be an independent risk factor for 28-day mortality. Therefore, more intensive care may be needed because the prognosis could be worse in patients with coagulopathy than in those with other organ dysfunctions due to IAI.

Abbreviations

Intra-abdominal infection (IAI), intensive care units (ICUs), Korean Sepsis Alliance (KSA), Korea Disease Control and Prevention Agency (KDCA), Sequential Organ Failure Assessment (SOFA), body mass index (BMI), Charlson comorbidity index (CCI), simplified acute physiology score III (SAPS 3), multidrug resistance (MDR), odds ratios (ORs), continuous renal replacement therapy (CRRT), central nervous system (CNS)

Declarations

Ethics approval and consent to participate

This study was conducted according to the guidelines of the Declaration of Helsinki. The study was approved by the Institutional Review Board of Asan Medical Center (approval number 2018-0675). And this study also approved by the Institutional Review Boards of all participating hospitals; Chonnam national university hospital (approval number CNUH2029075), Chungnam national university hospital (approval number 2019-11-048-001), Daegu Catholic University Medical Center (approval number CR-18-163-L), Hallym University Sacred heart hospital (approval number 2018-09-004), Hanyang University Guri Hospital (approval number 2020-08-015), Inje University Sanggye Paik Hospital (approval number 2018-08-014), Jeju National University Hospital (approval number 2018-06-012), Jeonbuk national university hospital (approval number CUH 2018-10-027), Kangwon national university hospital (approval number 2018-08-004-001), Korea University Anam Hospital (approval number 2 0 1 9 A N 0 0 2 7), Pusan National University Yangsan Hospital (approval number 05–2019–092), Samsung Medical Center (approval number 2018-05-108), Seoul National University Bundang Hospital (approval number B-1810-500-402), Seoul national university hospital (approval number H-1808-135-967), Ulsan university hospital (approval number UUH 2018-08-003).

Data were collected and analyzed in an ethical manner while protecting the patients' right to privacy. The requirement for informed consent was waived owing to the non-interventional, observational characteristics by the Institutional Review Boards (IRB) of all participating hospitals; Asan Medical Center Institutional Review Board (approval number 2018-0675), Chonnam national university hospital (approval number CNUH2029075), Chungnam national university hospital (approval number 2019-11-048-001), Daegu Catholic University Medical Center (approval number CR-18-163-L), Hallym University Sacred heart hospital (approval number 2018-09-004), Hanyang University Guri Hospital (approval number 2020-08-015), Inje University Sanggye Paik Hospital (approval number 2018-08-014), Jeju National University Hospital (approval number 2018-06-012), Jeonbuk national university hospital (approval number CUH 2018-10-027), Kangwon national university hospital (approval number 2018-08-004-001), Korea University Anam Hospital (approval number 2 0 1 9 A N 0 0 2 7), Pusan National University Yangsan Hospital (approval number 05–2019–092), Samsung Medical Center (approval number 2018-05-108), Seoul National University Bundang Hospital (approval number B-1810-500-402), Seoul national university hospital (approval number H-1808-135-967), Ulsan university hospital (approval number UUH 2018-08-003).

Consent for publication

Not applicable.

Availability of Data and Materials

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests

All authors declare that they have no competing interests. 

Funding

This work was supported by the Research Program funded by the Korea Disease Control and Prevention Agency (fund code 2020E280700).

Author contributions

CH analyzed and interpreted the patient data regarding sepsis patients. JW and HJ reviewed the literature and contributed to manuscript drafting. All authors read and approved the final manuscript.

Acknowledgements

Not applicable.

References

1. Rudd KE, Johnson SC, Agesa KM, Shackelford KA, Tsoi D, Kievlan DR, et al. Global, regional, and national sepsis incidence and mortality, 1990–2017: analysis for the Global Burden of Disease Study. Lancet 2020; 395:200–11. https://doi.org/10.1016/S0140-6736 (19) 32989–7.
2. Liu V, Escobar GJ, Greene JD, Soule J, Whippy A, Angus DC, et al. Hospital deaths in patients with sepsis from 2 independent cohorts. JAMA 2014; 312:90–2. https://doi.org/10.1001/jama.2014.5804.
3. Martin AB, Hartman M, Benson J, Catlin A, National Health Expenditure Accounts Team. National health spending in 2014: faster growth driven by coverage expansion and prescription drug spending. Health Aff (Millwood) 2016; 35:150–60. https://doi.org/10.1377/hlthaff.2015.1194.
4. Lopez N, Kobayashi L, Coimbra R. A comprehensive review of abdominal infections. World J Emerg Surg 2011; 6:7. https://doi.org/10.1186/1749-7922-6-7.
5. Sartelli M, Chichom-Mefire A, Labricciosa FM, Hardcastle T, Abu-Zidan FM, Adesunkanmi AK, et al. The management of intra-abdominal infections from a global perspective: 2017 WSES guidelines for management of intra-abdominal infections. World J Emerg Surg 2017; 12:29. https://doi.org/10.1186/s13017-017-0141-6.
6. Solomkin JS, Mazuski JE, Bradley JS, Rodvold KA, Goldstein EJ, Baron EJ, et al. Diagnosis and management of complicated intra-abdominal infection in adults and children: guidelines by the Surgical Infection Society and the Infectious Diseases Society of America. Clin Infect Dis 2010; 50:133–64. https://doi.org/10.1086/649554.
7. Wittmann DH, Schein M, Condon RE. Management of secondary peritonitis. Ann Surg 1996; 224:10–8. https://doi.org/10.1097/00000658-199607000-00003.
8. Blot S, Antonelli M, Arvaniti K, Blot K, Creagh-Brown B, de Lange D, et al. Epidemiology of intra-abdominal infection and sepsis in critically ill patients: “AbSeS”, a multinational observational cohort study and ESICM Trials Group Project. Intensive Care Med 2019; 45:1703–17. https://doi.org/10.1007/s00134-019-05819-3.
9. Jeon K, Na SJ, Oh DK, Park S, Choi EY, Kim SC, et al. Characteristics, management and clinical outcomes of patients with sepsis: a multicenter cohort study in Korea. Acute Crit Care 2019; 34:179–91. https://doi.org/10.4266/acc.2019.00514.
10. Oh SY, Cho S, Kim GH, Jang EJ, Choi S, Lee H, et al. Incidence and outcomes of sepsis in Korea: a nationwide cohort study from 2007 to 2016. Crit Care Med 2019; 47:e993–8. https://doi.org/10.1097/CCM.0000000000004041.
11. Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al. The third international consensus definitions for sepsis and septic shock (sepsis-3). JAMA 2016; 315:801–10. https://doi.org/10.1001/jama.2016.0287.
12. Magiorakos AP, Srinivasan A, Carey RB, Carmeli Y, Falagas ME, Giske CG, et al. Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance. Clin Microbiol Infect 2012; 18:268–81. https://doi.org/10.1111/j.1469-0691.2011.03570.x.
13. Pedersen PB, Henriksen DP, Brabrand M, Lassen AT. Prevalence of organ failure and mortality among patients in the emergency department: a population-based cohort study. BMJ Open 2019; 9:e032692. https://doi.org/10.1136/bmjopen-2019-032692.
14. Kim J, Kim K, Lee H, Ahn S. Epidemiology of sepsis in Korea: a population-based study of incidence, mortality, cost and risk factors for death in sepsis. Clin Exp Emerg Med 2019; 6:49–63. https://doi.org/10.15441/ceem.18.007.
15. Balcan B, Olgun Ş, Torlak F, Sağmen SB, Eryüksel E, Karakurt S. Determination of factors affecting mortality of patients with sepsis in a tertiary intensive care unit. Turk Thorac J 2015; 16:128–32. https://doi.org/10.5152/ttd.2015.4510.
16. Kassyap CK, Abraham SV, Krishnan SV, Palatty BU, Rajeev PC. Factors affecting early treatment goals of sepsis patients presenting to the emergency department. Indian J Crit Care Med 2018; 22:797–800. https://doi.org/10.4103/ijccm.IJCCM_27_18.
17. Ruiz-Mesa JD, Marquez-Gomez I, Sena G, Buonaiuto VA, Mora-Ordoñez J, Salido M, et al. Factors associated with severe sepsis or septic shock in complicated pyelonephritis. Medicine 2017; 96:e8371. https://doi.org/10.1097/MD.0000000000008371.
18. Emami-Razavi SH, Mohammadi A, Alibakhshi A, Jalali M, Ghajarzadeh M. Incidence of post-operative sepsis and role of Charlson co-morbidity score for predicting postoperative sepsis. Acta Med Iran 2016; 54:318–22.
19. Sinapidis D, Kosmas V, Vittoros V, Koutelidakis IM, Pantazi A, Stefos A, et al. Progression into sepsis: an individualized process varying by the interaction of comorbidities with the underlying infection. BMC Infect Dis 2018; 18:242. https://doi.org/10.1186/s12879-018-3156-z.
20. Lavallée JF, Gray TA, Dumville J, Russell W, Cullum N. The effects of care bundles on patient outcomes: a systematic review and meta-analysis. Implement Sci 2017; 12:142. https://doi.org/10.1186/s13012-017-0670-0.
21. Teles F, Rodrigues WG, Alves MGTC, Albuquerque CFT, Bastos SMO, Mota MFA et al. Impact of a sepsis bundle in wards of a tertiary hospital. J Intensive Care 2017; 5:45. https://doi.org/10.1186/s40560-017-0231-2.
22. Freund Y, Lemachatti N, Krastinova E, Van Laer M, Claessens YE, Avondo A, et al. Prognostic accuracy of sepsis-3 criteria for in-hospital mortality among patients with suspected infection presenting to the emergency department. JAMA 2017; 317:301–8. https://doi.org/10.1001/jama.2016.20329.
23. Lie KC, Lau CY, Van Vinh Chau N, West TE, Limmathurotsakul D, for Southeast Asia Infectious Disease Clinical Research Network. Utility of SOFA score, management and outcomes of sepsis in Southeast Asia: a multinational multicenter prospective observational study. J Intensive Care 2018; 6:9. https://doi.org/10.1186/s40560-018-0279-7.
24. Grozdanovski K, Milenkovic Z, Demiri I, Spasovska K. Prediction of outcome from community-acquired severe sepsis and septic shock in tertiary-care university hospital in a developing country. Crit Care Res Pract 2012; 2012:182324. https://doi.org/10.1155/2012/182324.
25. Mačiulienė A, Maleckas A, Kriščiukaitis A, Mačiulis V, Vencius J, Macas A. Predictors of 30- day in-hospital mortality in patients undergoing urgent abdominal surgery due to acute peritonitis complicated with sepsis. Med Sci Monit 2019; 25:6331–40. https://doi.org/10.12659/MSM.915435.
26. Ferrer R, Martin-Loeches I, Phillips G, Osborn TM, Townsend S, Dellinger RP, et al. Empiric antibiotic treatment reduces mortality in severe sepsis and septic shock from the first hour: results from a guideline-based performance improvement program. Crit Care Med 2014; 42:1749–55. https://doi.org/10.1097/CCM.0000000000000330.
27. Micek ST, Welch EC, Khan J, Pervez M, Doherty JA, Reichley RM, et al. Empiric combination antibiotic therapy is associated with improved outcome against sepsis due to gram-negative bacteria: a retrospective analysis. Antimicrob Agents Chemother 2010; 54:1742–8. https://doi.org/10.1128/AAC.01365-09.
28. Kumar A, Ellis P, Arabi Y, Roberts D, Light B, Parrillo JE, et al. Initiation of inappropriate antimicrobial therapy results in a fivefold reduction of survival in human septic shock. Chest 2009; 136:1237–48. https://doi.org/10.1378/chest.09-0087.
29. Kumar A, Roberts D, Wood KE, Light B, Parrillo JE, Sharma S, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med 2006; 34:1589–96. https://doi.org/10.1097/01.CCM.0000217961.75225.E9.
30. Bloos F, Thomas-Rüddel D, Rüddel H, Engel C, Schwarzkopf D, Marshall JC, et al. Impact of compliance with infection management guidelines on outcome in patients with severe sepsis: a prospective observational multi-center study. Crit Care 2014; 18:R42. https://doi.org/10.1186/cc13755.
31. Azuhata T, Kinoshita K, Kawano D, Komatsu T, Sakurai A, Chiba Y, et al. Time from admission to initiation of surgery for source control is a critical determinant of survival in patients with gastrointestinal perforation with associated septic shock. Crit Care 2014; 18:R87. https://doi.org/10.1186/cc13854.
32. Silva-Nunes J, Cardoso T. Intra-abdominal infections: the role of different classifications on the selection of the best antibiotic treatment. BMC Infect Dis 2019; 19:980. https://doi.org/10.1186/s12879-019-4604-0.
33. Umegaki T, Ikai H, Imanaka Y. The impact of acute organ dysfunction on patients’ mortality with severe sepsis. J Anaesthesiol Clin Pharmacol 2011; 27:180–4. https://doi.org/10.4103/0970-9185.81816.
34. Lone NI, Walsh TS. Impact of intensive care unit organ failures on mortality during the five years after a critical illness. Am J Respir Crit Care Med 2012; 186:640–7. https://doi.org/10.1164/rccm.201201-0059OC.
35. Nfor TK, Walsh TS, Prescott RJ. The impact of organ failures and their relationship with outcome in intensive care: analysis of a prospective multicentre database of adult admissions. Anaesthesia 2006; 61:731–8. https://doi.org/10.1111/j.1365-2044.2006.04707.x.
36. Levi M, van der Poll T. Coagulation and sepsis. Thromb Res 2017; 149:38–44. https://doi.org/10.1016/j.thromres.2016.11.007.
37. Iba T, Levi M, Levy JH. Sepsis- induced coagulopathy and disseminated intravascular coagulation. Semin Thromb Hemost 2020; 46:89–95. https://doi.org/10.1055/s-0039-1694995.
38. Iba T, Levy JH, Warkentin TE, Thachil J, van der Poll T, Levi M, et al. Diagnosis and management of sepsis-induced coagulopathy and disseminated intravascular coagulation. J Thromb Haemost 2019; 17:1989–94. https://doi.org/10.1111/jth.14578.
39. Lyons PG, Micek ST, Hampton N, Kollef MH. Sepsis- associated coagulopathy severity predicts hospital mortality. Crit Care Med 2018; 46:736–42. https://doi.org/10.1097/CCM.0000000000002997.
40. Semeraro N, Ammollo CT, Semeraro F, Colucci M. Sepsis, thrombosis and organ dysfunction. Thromb Res 2012; 129:290–5. https://doi.org/10.1016/j.thromres.2011.10.013.