Concise Critical Appraisal: Early Hemostatic Management of Disseminated Intravascular Coagulopathy

Inflammation and coagulation pathobiology play a significant role in the development of multiorgan failure occurring with sepsis. Inflammation induced by an infection can lead to endothelial injury, which subsequently promotes coagulation and downregulates fibrinolysis, leading to end-organ damage. Thrombocytopenia-associated multiple organ failure (TAMOF), an inflammatory phenotype associated with thrombotic microangiopathy occurring in some children with sepsis, can present as a spectrum of syndromes, including disseminated intravascular coagulopathy (DIC), and carries a high mortality rate.¹ Treatment of DIC in septic pediatric patients with platelets, coagulation factors (either in plasma or as individual factors), or anticoagulants is controversial and typically is recommended only after the patient develops active bleeding or clinically significant thromboses.² El-Nawawy et al sought to determine whether early hemostatic intervention can prevent the development of DIC and improve outcomes.³
 
This is a prospective interventional open-label randomized clinical trial involving children with severe sepsis or septic shock admitted to a single pediatric intensive care unit (PICU). Patients not already diagnosed with overt DIC were placed in one of two groups. Group 1 received standard of care management of sepsis plus an additional 15mL/kg of fresh frozen plasma, low-dose unfractionated heparin at 5 IU/kg/hr for 24 hours, and tranexamic acid (an antifibrinolytic agent) at 15mg/kg every 8 hours for 24 hours immediately after initial assessment. Group 2 received standard of care management only. The determination of overt DIC versus nonovert DIC was based on the International Society on Thrombosis and Haemostasis DIC scoring system. The primary outcome measured was the development of overt DIC. Secondary outcomes included mortality, shock reversal time, PICU length of stay, development of complications, and occurrence of bleeding events.
 
Forty patients were recruited for each group. The two groups’ demographics were mostly comparable, although Group 2 had significantly more girls than Group 1. Initial Pediatric Index of Mortality 2 scores, Pediatric Logistic Organ Dysfunction scores, inotropic scores, and Glasgow Coma Scale scores were comparable between the two groups. The number of patients who progressed to overt DIC was significantly higher in Group 2, as was the number of complications. The time to progression to DIC was significantly lower in Group 2. More notably, Group 1 had a statistically higher survival rate (90% vs. 50%) than Group 2. It should be noted that Group 2 had shorter shock reversal time, shorter PICU length of stay, and fewer ventilator days, although the authors claim these differences may be explained by the increased deaths in Group 2. There was no statistical difference in bleeding events between the two groups. Interestingly, outside of the initial plasma given to Group 1, the two groups’ receipt of blood products during the course of their PICU stay was the same. It should be noted that the percentage of subjects who developed DIC and those who developed DIC and died appears to be higher than in other reports.^1,4
 
Inflammation and coagulation defects are inexorably tied together in pediatric sepsis. Additionally, the presence of overt DIC, a severe derangement in coagulation, carries a higher mortality rate in both adults and children, and studies looking at the use of therapeutic anti- and procoagulants have not demonstrated benefit.⁵ This study is novel in its approach of treating all pediatric patients with severe sepsis or septic shock early, before DIC develops, with therapies that address each component of DIC—fresh frozen plasma to replace consumed coagulation factors, heparin to prevent microthrombi from forming, and tranexamic acid to halt excessive fibrinolysis. More research is needed to confirm these positive results and to determine the efficacy of using these therapies in other manifestations of TAMOF.

Author of this installment of Concise Critical Appraisal:
 
Daniel E. Sloniewsky, MD, FCCM, is an associate professor in the Division of Pediatric Critical Care Medicine in the Department of Pediatrics at Stony Brook Long Island Children’s Hospital. Dr. Sloniewsky is an editor of Concise Critical Appraisal.

References

1. Carcillo JA, Berg RA, Wessel D, et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Collaborative Pediatric Critical Care Research Network. A multicenter network assessment of three inflammation phenotypes in pediatric sepsis-induced multiple organ failure. Pediatr Crit Care Med. 2019 Dec;20(12):1137-1146. http://doi.org/10.1097/PCC.0000000000002105
2. Levi M, Toh CH, Thachil J, Watson, HG. Guidelines for the diagnosis and management of disseminated intravascular coagulation. British Committee for Standards in Haematology. Br J Haematol. 2009 Apr;145(1):24-33. https://pubmed.ncbi.nlm.nih.gov/19222477/
3. El-Nawawy AA, Elshinawy MI, Khater DM, et al. Outcome of early hemostatic intervention in children with sepsis and nonovert disseminated intravascular coagulation admitted to PICU: a randomized controlled trial. Pediatr Crit Care Med. 2020 Oct 12. Online ahead of print. http://doi.org/10.1097/PCC.0000000000002578
4. Kutko MC, Calarco MP, Flaherty MB, et al. Mortality rates in pediatric septic shock with and without multiple organ system failure. Pediatr Crit Care Med. 2003 Jul;4(3):333-337. http://doi.org/10.1097/01.PCC.0000074266.10576.9B
5. Khemani RG, Bart RD, Alonzo TA, Hatzakis G, Hallam D, Newth CJL. Disseminated intravascular coagulation score is associated with mortality for children with shock. Intensive Care Med. 2009 Feb;35(2):327-333. https://pubmed.ncbi.nlm.nih.gov/18802683/