Features of Development and Course of Disseminated Intravascular Coagulation Syndrome During Surgical Interventions in Children with Oncological Diseases

Coagulopathy always accompanies blood loss, and its transformation into disseminated intravascular coagulation syndrome (DIC) is associated with increased morbidity and mortality.

Objective: to characterize the features of the development and course of DIC during bleeding, as well as identify the main predictors of its formation during surgical interventions in children with oncological diseases.

Material and Methods. A retrospective study of children under 18 years of age with oncological pathology who received surgical treatment for the period from 2017 to 2019 years. Children who received blood transfusion and hemostatic therapy with intraoperative bleeding were selected. The resulting cohort (n=207) was divided into two groups using the modified ISTH assessment system: children with DIC (n=59), without DIC (n=148). Demographic, clinical, and laboratory factors were compared between groups. The final model of multivariate logistic regression included signs that were before the development of DIC on the second day after the operation and were selected as a result of univariate analysis (P<0.05), had less than 10% missing data and were clinically plausible. The prediction accuracy of the multivariate model was checked by analyzing the area under the ROC curve.

Results. DIC was found to develop often in children with cancer during surgical operations in the retroperitoneal space (OR=2.09 [1.07; 4.05]; P=0.03) and liver (OR=3.86 [1.72; 8.67]; P=0.001). Multiple organ failure (MOF) was more severe and was represented by pulmonary, hepatic and renal failure in the group with identified DIC. The development of MOF was accompanied by a decrease in tissue perfusion and an increase in D-dimer. The probability of detecting acute thrombosis after surgery was 4.5 times higher in the group of patients with DIC than in the group without DIC (OR=4.5 [1.4; 14.3]; P=0.01). 90-daily survival was 84.41±6.49% [71.69%; 97.13%] in the group of patients with DIC, and 96.22±3.12 [90.1%; 100%] in the group without DIC. Multivariate analysis showed that age less than 8 years, platelet count less than 150X109/l, hypocalcemia less than 1 mmol/l and the period of intraoperative critical hypotension for more than 25 minutes are predictors of the development of DIC after surgery. ROC analysis showed excellent quality of the obtained predictive model (AUC=0,94 [0,9; 0,97]).

Conclusion. In children with oncological diseases, in the presence of bleeding, coagulopathy in the postoperative period is transformed into a DIC-syndrome, proceeding clinically with the development of organ failure. Age less than 8 years, platelet count less than 150X109/l, hypocalcemia less than 1 mmol/L and a period of intraoperative critical hypotension of more than 25 minutes are predictors of the development of DIC. The extreme expression of the «organ» type DIC is the progression of thrombotic syndrome to life threatening complications, which reduces the 90-day survival by 12%.

1. Halmin M, Chiesa F Vasan SK, Wikman A, Norda R, Rostgaard K., Pedersen O.B., Erikstrup Ch., Nielsen K.R., Titlestad K., Ullum H., Hjalgrim H., Edgren G. Epidemiology of Massive Transfusion: A Binational Study From Sweden and Denmark. Crit Care Med. 2016; 44 (3): 468477. DOI: 10.1097/CCM.0000000000001410.

2. Ramirez M. Multiple organ dysfunction syndrome. Curr Probl Pediatr Adolesc Health Care. 2013; 43 (10): 273-7. DOI: 10.1016/j.cppeds.2013.10.003.

3. Halmin M., Chiesa F., Vasan S.K., Wikman A., Norda R., Rostgaard K., Birger O., Pedersen V, Erikstrup Ch., Nielsen K.R., Titlestad K., Ullum H., Hjalgrim H., Edgren G.. Epidemiology of Massive Transfusion: A Binational Study From Sweden and Denmark. Crit Care Med. 2016; 44 (3): 468-477. DOI: 10.1097/CCM.0000000000001410. PMID: 26901542

4. Saito S, Uchino S, Hayakawa M, Yamakawa K, Kudo D, Iizuka Y., Sanui M., Takimoto K., Mayumi T., Sasabuchi Y. Japan Septic Disseminated Intravascular Coagulation (JSEPTIC DIC)study group. Epidemiology of disseminated intravascular coagulation in sepsis and validation of scoring systems. J Crit Care. 2019; 50: 23-30. DOI: 10.1016/j.jcrc.2018.11.009. Epub 2018 Nov 14.

5. Hernandez-Ramirez O., Sanchez-Hurtado L.A., Ferrer-Burgos G., Gue-vara-GarciaH., Garcia-GuillenFJ., Namendys-Silva SA. Incidence of disseminated intravascular coagulation in critically ill cancer patients. J Intensive Care Soc. 2019; 20 (3): NP17-NP18. DOI: 10.1177/1751143719840262. Epub 2019 Apr 15.

6. Levi M., Si vapalaratnam S. Disseminated intravascular coagulation: an update on pathogenesis and diagnosis. Expert Rev Hematol. 2018; 11 (8): 663-672. DOI: 10.1080/17474086.2018.1500173. Epub 2018 Jul 20.

7. Levi M., Toh C.H., Thachil J., Watson H.G. Guidelines for the diagnosis and management of disseminated intravascular coagulation. British Committee for Standards in Haematology. Br J Haematol. 2009; 145 (1): 24-33. DOI: 10.1111/j.1365-2141.2009.07600.x. Epub 2009 Feb 12.

8. Wada H, Matsumoto T, Hatada T. Diagnostic criteria and laboratory tests for disseminated intravascular coagulation. Expert Rev Hematol. 2012; 5 (6): 643-652. DOI: 10.1586/ehm.12.57.

9. Kulikov A.V., Shifman E.M., Bulanov A.YU., Zabolotskih I.B., Sinkov S.V Intensive therapy of acute hemostatic disorders in obstetrics (DIC-syndrome). Clinical recommendations (treatment protocols). Anestesiol. i Reanimatol. 2017; 62 (5): 399-406 [In Russ.]. DOI: 10.18821/0201-7563-2017-62-5-399-406

10. Goobie S.M., Haas T. Perioperative bleeding management in pediatric patients. Curr Opin Anaesthesiol. 2016; 29 (3): 352-358. DOI: 10.1097/ACO.0000000000000308.

11. Gando S. Microvascular thrombosis and multiple organ dysfunction syndrome. Crit Care Med. 2010; 38 (2 Suppl): S35-42. DOI: 10.1097/CCM.0b013e3181c9e31d.

12. Kawasaki T., Shime N., Straney L., Bellomo R., MacLaren G., Pilcher D., Schlapbach L.J. Paediatric sequential organ failure assessment score (pSOFA): a plea for the world-wide collaboration for consensus. Intensive Care Med. 2018; 44 (6): 995-997. DOI: 10.1007/s00134-018-5188-7. Epub 2018 Apr 27.

13. Sarganas G., Schaffrath Rosario A., Berger S., Neuhauser H.K. An unambiguous definition of pediatric hypotension is still lacking: Gaps between two percentile-based definitions and Pediatric Advanced Life Support/Advanced Trauma Life Support guidelines. J Trauma Acute Care Surg. 2019; 86 (3): 448-453. DOI: 10.1097/TA.0000000000002139.

14. Maw G, Furyk C. Pediatric Massive Transfusion: A Systematic Review. Pediatr Emerg Care. 2018 Aug; 34 (8): 594-598. DOI: 10.1097/PEC.0000000000001570

15. Oh G.J., Sutherland S.M. Perioperative fluid management and postoperative hyponatremia in children. Pediatr Nephrol. 2016 Jan; 31 (1): 53-60. DOI: 10.1007/s00467-015-3081-y. Epub 2015 Mar 18.

16. Lison S., Weiss G., Spannagl M., Heindl B. Postoperative changes in procoagulant factors after major surgery. Blood Coagul Fibrinolysis. 2011; 22 (3): 190-196. DOI: 10.1097/MBC.0b013e328343f7be.

17. Byuk S.K., Hyun Y.Ch., Seung M.R., Myung Ch.K., Woong J, Sung H.P., Lee Ch.M., Kim W.Y. The Prevalence and Significance of Overt Disseminated Intravascular Coagulation in Patients with Septic Shock in the Emergency Department According to the Third International Consensus Definition. Korean J Crit Care Med. 2016; 31 (4): 334-341 DOI: 10.4266/kjccm.2016.00339

18. Wada H., Matsumoto T., Suzuki K., Imai H., Katayama N., Iba T., Mat-sumoto M. Differences and similarities between disseminated intravascular coagulation and thrombotic microangiopathy. Thromb J. 2018; 16: 14. DOI: 10.1186/s12959-018-0168-2.eCollection 2018.

19. Levi M. Pathogenesis and diagnosis of disseminated intravascular coagulation. Int J Lab Hematol. 2018; 40 Suppl 1: 15-20. DOI: 10.1111/ijlh.12830.

20. Disma N., Mameli L., Pistorio A., Davidson A., Barabino P, Locatelli B.G., Sonzogni V., Montobbio G. A novel balanced isotonic sodium solution vs normal saline during major surgery in children up to 36 months: a multicenter RCT. Paediatr Anaesth. 2014; 24 (9): 980-986. DOI: 10.1111/pan.12439. Epub 2014 May 14.

21. Aleksandrovich Yu.S., Vorontsova N.Yu., Grebennikov V.A., Diordiev A.V., Zhirkova Yu.V., Kochkin V.S., Lazarev V.V., LekmanovA.U., Ma-tinyanN.V., PshenisnovK.V., Stepanenko S.M., TSypinL.E., Shchukin V.V., Khamin I.G. Recommendations for infusion-transfusion therapy in children during surgery. Vestnik anesteziologii i reanimato-logii.2018; 15 (2): 68-84 [In Russ.]. DOI: 10.21292/2078-5658-2018-15-2-68-84

22. Giancarelli A., Birrer K.L., Alban R.F, Hobbs B.P, Liu-DeRyke X. Hypocalcemia in trauma patients receiving massive transfusion. J Surg Res. 2016; 202 (1): 182-187. DOI: 10.1016/j.jss.2015.12.036. Epub 2015 Dec 30.

23. Ho K.M., Pavey W. Applying the cell-based coagulation model in the management of critical bleeding. Anaesth Intensive Care. 2017; 45 (2): 166-176. DOI: 10.1177/0310057X1704500206

24. Gando S. Hemostasis and thrombosis in trauma patients. Semin Thromb Hemost. 2015; 41 (1): 26-34. DOI: 10.1055/s-0034-1398378. Epub 2015 Jan 20.

25. Chang J.C. Disseminated intravascular coagulation: is it fact or fancy? Blood Coagul Fibrinolysis. 2018; 29 (3): 330-337. DOI: 10.1097/MbC.0000000000000727.

26. Deppe A.C., Weber C., Zimmermann J., Kuhn E. W., Slottosch I., Liako-poulos O.J., Choi Y.H., Wahlers T. Point-of-care thromboelastog-raphy/thromboelastometry-based coagulation management in cardiac surgery: a meta-analysis of 8332 patients. J Surg Res. 2016; 203 (2): 424-433. DOI: 10.1016/j.jss.2016.03.008. Epub 2016 Mar 26.

27. Francis R.C.E, Theurl I., Maegele M., Graw J.A. Point-of-Care diagnostics of coagulation in the management of bleeding and transfusion in trauma patients. Curr Opin Anaesthesiol. 2020 Feb 4. DOI: 10.1097/ACO.0000000000000836.

28. Dias J.D., Sauaia A., Achneck H.E., Hartmann J., Moore E.E. Throm-boelastography-guided therapy improves patient blood management and certain clinical outcomes in elective cardiac and liver surgery and emergency resuscitation: A systematic review and analysis. J Thromb Haemost. 2019; 17 (6): 984-994. DOI: 10.1111/jth.14447. Epub 2019 May 13.

29. FominskiyE., Nepomniashchikh V.A., Lomivorotov V.V., MonacoF, Vi-tiello C., Zangrillo A., Landoni G. Efficacy and Safety of Fibrinogen Concentrate in Surgical Patients: A Meta-Analysis of Randomized Controlled Trials. J Cardiothorac Vasc Anesth. 2016; 30 (5): 1196-1204. DOI: 10.1053/j.jvca.2016.04.015. Epub 2016 Apr 16.

30. Ranucci M., Baryshnikova E., Pistuddi V, Menicanti L., Frigiola A. for the Surgical and Clinical Outcome REsearch (SCORE)Group The effectiveness of 10 years of interventions to control postoperative bleeding in adult cardiac surgery. Interact Cardiovasc Thorac Surg. 2017; 24 (2): 196-202. DOI: 10.1093/icvts/ivw339.

31. Bhardwaj N. Perioperative fluid therapy and intraoperative blood loss in children. Indian J Anaesth. 2019; 63 (9): 729-736. DOI: 10.4103/ija.IJA_493_19

32. Ding X.F., Yang Z.Y., Xu Z.T., L.-F. Li, Yuan B., Guo L.-N., Wang L.-X., ZhuX., Sun T.-W. Early goal-directed and lactate-guided therapy in adult patients with severe sepsis and septic shock: a meta-analysis of randomized controlled trials. J Transl Med. 2018; 16 (1): 331. Published 2018 Nov 29. DOI: 10.1186/s12967-018-1700-7

33. DengQ.W., Tan W.C., Zhao B.C., Wen S.H., Shen J.T., Xu M. Is goal-directed fluid therapy based on dynamic variables alone sufficient to improve clinical outcomes among patients undergoing surgery? A meta-analysis. Crit Care. 2018; 22 (1): 298. Published 2018 Nov 14. DOI: 10.1186/s13054-018-2251-2

34. Osawa E.A., Rhodes A., Landoni G., Galas FR., Fukushima J.T., Park C.H., Clarice H. L., Almeida J.P., Nakamura R.E., Strabelli T.M.V., Pi-leggi B., Leme A., Fominskiy E., Sakr Y., Lima M., Franco R., Chan R., Piccion, M., Mendes P, Menezes S., Bruno T., Gaiotto F, Lisboa L., Dal-lan L., Hueb A., Pomerantzeff P, Kalil Filho R., Jatene F, Auler Junior J.O.C., HajjarL.A. Effect of Perioperative Goal-Directed Hemodynamic Resuscitation Therapy on Outcomes Following Cardiac Surgery: A Randomized Clinical Trial and Systematic Review. Crit Care Med. 2016; 44 (4): 724-733. DOI: 10.1097/CCM.0000000000001479.

35. GerentA.R.M, Almeida J.P., Fominskiy E., Landoni G.,Queiroz de Oliveira G., Itala Rizk S., Tizue Fukushima J., Marques Simoes C., Ribeiro U.Jr3, Lee Park C., Ely Nakamura R., Alves Franco R., Ines Candido P.,Tavares C. R., Camara L., dos Santos Rocha Ferreira G., Pinto Ma-rinho de Almeida E., Filho R. K., Barbosa Gomes Galas FR., Abrahao Hajjar L. Effect of postoperative goal-directed therapy in cancer patients undergoing high-risk surgery: a randomized clinical trial and meta-analysis. Crit Care. 2018; 22 (1): 133. Published 2018 May 23. DOI: 10.1186/s13054-018-2055-4

36. Somonova O.V., Madzhuga A.V, Elizarova A.L. Thrombosis and thromboembolism in oncology. A modern view of the problem. Zlo-kachestvennye opukholi. 2014; (3): 172-176 [In Russ.]. DOI: 10.18027/2224-5057-2014-3-172-176

37. Mishenina S.V, Madonov P.G., Bajkalov G.I., Leontev S.G., Zotov S.P. Oral thrombolysis in venous thrombosis (clinical trial). Tromboz, ge-mostaz i reologiya. 2019. 4 (80): 54-67 [In Russ.]. DOI: 10.25555/THR.2019.4.0900