Patient Blood Management for Massive Obstetric Hemorrhage

Post Partum Hemorrhage Clinical Trial

Official title:

ROTEM Guided and Hemostatic Drugs Algorithms vs Standard Coagulation Test and Hemocomponent for Massive Obstetric Hemorrhage

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03784794
• Other study ID #: 099/21012018/MEDCRITICAHENM
• Status: Completed
• Phase: N/A
• Start date: November 1, 2018
• Est. completion date: December 30, 2020

Study information

• Verified date: June 2021
• Source: Grupo Mexicano para el Estudio de la Medicina Intensiva
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Obstetric Hemorrhage continues to be the first cause of maternal morbidity and mortality around the world especially in middle to low income countriesThe blood components are high value resources; however, its use has been shown to be a risk factor of known complications. The aim of the study is to compare two algorithms of coagulation management in massive obstetric hemorrhage Methods A randomized prospective trial single center two arms study in patients with severe obstetric hemorrhage (PPH > 1000) 2 different transfusion protocols one guided by thromboelastometry and hemostatic drugs (protrombine complex concentrate and fibrinogen concentrate) and the second guided by standard coagulation test and hemocomponents. Sample is calculated to known variance, Analyses are intention-to-treat without imputation, with outcomes will be performed between groups using mixed-effects two level regression models. For binary outcomes, a logistic model will be used and results presented as adjusted odds ratios (ORs) alongside 95% confidence intervals (CIs). Count data will be analysed using Poisson multilevel or negative binomial models.

Primary Outcome Parameter:

Compare between the two protocols:

Number of allogeneic blood products transfused intra-op, within 24h after screening and in-hospital (RBC, Platelets and FFP; separate and overall)

Secondary Outcome Parameter:

Analysis of mortality, lenth of stay admission to the ICU, hysterectomy surgical reintervencion, Transfuse associated circulatory overload, Transfusion associated Acute lung injury, health associated infection will be measured as secondary outcome.

Description:

Introduction Obstetric Hemorrhage continues to be the first cause of maternal morbidity and mortality around the world especially in middle to low income countries. Copying trauma transfusion therapies now a days algorithms have been developing for 2.1.1 transfusion in massive obstetric hemorrhage. Blood products, play an essential role in the management of these patients, either during resuscitation or definitive treatment. Early transfusion, defined as that required in the first 24 hours after admission, it is required in about 5% that enters the hospital and about 3% comes to require massive transfusion. The blood components are high value resources; however, its use has been shown to be a risk factor for infectious transfusion related immunomodulation, and noninfectious complications (TRALI, TACO), development of systemic inflammatory response, multiple organ failure and death. A liberal transfusion policy can further introduce the risk of a patient who is already committed.

Patient blood management is an evidence-based, multidisciplinary approach to optimizing the care of patients who might need transfusion. PBM encompasses all aspects of patient evaluation and clinical management surrounding the transfusion decision-making process, including the application of appropriate indications, as well as minimization of blood loss and optimization of patient red cell mass.

The aim of the study is to compare two algorithms of coagulation management in massive obstetric hemorrhage Methods A randomized prospective trial single center two arms study in patients with severe obstetric hemorrhage (PPH > 1000) 2 different transfusion protocols one guided by thromboelastometry and hemostatic drugs (protrombine complex concentrate and fibrinogen concentrate) and the second guided by standard coagulation test and hemocomponents.

Randomization for the patients will be made for every obstetric patient that enters the obstetric ward for attention of partum, and will be asked to sign consent, and the patients will be selected for each group of the study. Only does that have severe PPH will be entering the protocol with the algorithm for management previously selected. Demographic caracteristics will include Ethnicity, Body weight (KG), body height (CM) and BMI at hospital admission, Previous deliveries, Previous Caesarean section, Pre-eclampsia during pregnancy, History of obstetric hemorrhage, History of other kind of hemorrhage, Onset of labor (spontaneous, induced, no labor) Multiple gestation (singleton, twins, triplet) Reported cause of obstetric hemorrhage (placenta previa, placenta accreta, placenta abruption, retained placenta, uterine atony, trauma, surgical bleeding Mode of delivery (spontaneous vaginal, instrumental vaginal , elective Caesarean section, non-elective Caesarean section) Baseline Hb, Hct, Plt count, Fibrinogen (Clauss), PT/INR, PTT (at hospital admission) Estimated blood loss at study entry (ML).

Treatment algorithms are evidence based and the management of coagulopathy is based on treat first what kills fist (ATLS proposal)

Group A:

THROMBOELASTOMETRY-GUIDED ALGORITHM FIBRINOGEN CONCENTRATE FIBTEM A5 < 12 MM AND EXTEM A5 < 40 MM FIBTEM A5 = 9-11 MM → 2 G FIBRINOGEN CONC. (25 MG/KG); FIBTEM A5 = 4-8 MM → 4 G FIBRINOGEN CONC. (50 MG/KG); FIBTEM A5 < 4 MM → 6 G FIBRINOGEN CONC. (75 MG/KG) GOAL: FIBTEM A5: 12-16 MM PLATELETS EXTEM A5 < 40 MM AND FIBTEM A5 ≥ 12 MM EXTEM A5 < 40 MM → 1 PLATELET POOL OR APHERESIS; EXTEM A5 < 30 MM → 2 PLATELET POOL OR APHERESIS GOAL: EXTEM A5: 40-50 MM PROTROMBIN COMPLEX CONCENTRATE EXTEM CT > 80 SEC AND FIBTEM A5 ≥ 8 MM 4F-PCC 20 IU/KG (F II, VII, IX and X) GOAL: EXTEM CT ≤ 80 SEC NO INTERVENTION FIBTEM A5 ≥ 12 MM AND EXTEM A5 ≥ 40 MM AND EXTEM CT > 80 SEC NO FIBRINOGEN, CRYO, PLATELETS, 4-PCC, FFP; TRANSFUSE RBC IF Hb < 7 G/DL GOAL: Hb > 7.5 G/DL

Group B RATIO / STANDRAD LAB TEST-GUIDED ALGORITHM CRYOPRECIPITATE FIBRINOGEN (CLAUSS) < 250 MG/DL FIB 200-250 MG/DL → CRYOS, PACK OF 10 (25 MG/KG); FIB 100-200 MG/DL → CRYOS, PACK OF 20 (50 MG/KG); FIB < 100 MG/DL → CRYOS, PACK OF 30 (75 MG/KG) GOAL: FIB > 250 MG/DL PLATELETS PLATELET COUNT < 100/µL PLT < 100/µL → 1 PLATELET POOL OR APHERESIS; PLT > 50/µL → 2 PLATELET POOL OR APHERESIS GOAL: PLT COUNT > 100/µL FRESH FROZEN PLASMA TP AND/OR TTP PATHOLOGICAL INR, 2.0-4.0 → FFP 20 ML/KG GOAL: TP AND TTP NORMAL AND INR < 2.0 NO LAB RESULTS AVAILABLE TRANSFUSE RED BLOOD CELLS IF Hb < 7 G/DL; GIVE 1 UNIT FFP EVERY 2 UNITS OF RBC TRANSFUSED GOAL: Hb > 7.5 G/DL Statistical analysis Sample is calculated to known variance. The investigators calculated that 100 women will be needed to provide 80% power at the two-sided 5% level to detect a difference of total allogeneic units between groups. With a total of 100 patients 50 in each arm, with a first revision of results after recruiting 50 patients (25 in each arm). Analyses are intention-to-treat without imputation, with outcomes will be performed between groups using mixed-effects two level regression models. For binary outcomes, a logistic model will be used and results presented as adjusted odds ratios (ORs) alongside 95% confidence intervals (CIs). For continuous outcomes, a linear regression model will be performed and results presented as difference in adjusted means (arm A vs arm B) alongside 95% CIs. Count data will be analysed using Poisson multilevel or negative binomial models if over-dispersion is evident and presented as incident rate ratios (IRRs).

Objectives

Primary Outcome Parameter:

Compare between the two protocols:

Number of allogeneic blood products transfused intra-op, within 24h after screening and in-hospital (RBC, Platelets and FFP; separate and overall)

Secondary Outcome Parameter:

Compare between the two arms Number of packs of Cryo (pack of 5 ~ 1 G Fibrinogen), Fibrinogen Concentrate (G), and PCC (500 UI) administered intra-op, within 24h after screening and in-hospital Incidence ≥ 5 U RBC transfused (first 24h after screening) Incidence ≥ 10 U RBC transfused (first 24h after screening) Incidence of RBC, Platelets, FFP, Cryo, Fibrinogen Concentrate, and PCC transfusion/administration (intra-op, first 24h and in-hospital) Total volume of blood products and coagulation factor concentrates transfused/administered (intra-op, first 24h and in-hospital) Infusion: Crystalloid (ML) and Colloids (Type; ML) intra-op and within 24h after screening Overall estimated blood loss (EBL, ML) Time to bleeding control (time from study entry to last hemostatic intervention/transfusion) Incidence of coagulopathy (detected by thromboelastometry or standard coagulation laboratory tests) Incidence of hysterectomy Incidence of re-surgery Incidence of TACO Incidence of TRALI Incidence of surgical site infection or sepsis Incidence of ICU admission Length of stay (LOS) at ICU and hospital In-hospital mortality First post-op Hb, Hct, Plt count, Fibrinogen (Clauss), PT, INR, PTT (recovery room or ICU) Last Hb, Hct, Plt count, Fibrinogen (Clauss), PT, INR, PTT before discharge from hospital Total acquisition costs of allogeneic blood products and coagulation factor concentrates HYPOTHESIS. The algorithm guided by ROTEM plus the use of hemostatic drugs, are more efficient for the reversion of coagulopathy due to obstetric hemorrhage, than the standard treatment group, decrases the risk of development known complications, decreases the need of blood transfusions, decreases morbidity and mortality associated to PPH, length of stay, admissions to the intensive care unit and days of mechanical ventilation. Without a significant increase in costs.

RELEVANCE AND EXPECTATIONS To offer a safe alternative in the treatment of severe obstetric hemorrhage, which reduces the risk of transfusion associated complications,

Recruitment information / eligibility

• Status: Completed
• Enrollment: 100
• Est. completion date: December 30, 2020
• Est. primary completion date: November 30, 2020
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years to 45 Years

Eligibility

Inclusion Criteria:

Patients with severe obstetric hemorrhage of any cause

Exclusion Criteria:

obstetric hemorrhage patients derived from other hospitals Patients with less than 1000 ml of estimated blood loss those who do not want to participate in the study

Related Conditions & MeSH terms

• Disseminated Intravascular Coagulation
• Fibrinogen; Deficiency, Acquired
• Fibrinogenolysis; Hemorrhage
• Hemorrhage
• Massive Hemorrhage
• Post Partum Hemorrhage
• Postpartum Hemorrhage
• Transfusion Related Complication

Intervention

Diagnostic Test:
• Thromboelastometry
devices generate output by transducing changes in the viscoelastic strength of a small sample of clotting blood (300 µl) to which a constant rotational force is applied. These point of care devices allow visual assessment of blood coagulation from clot formation, through propagation, and stabilization, until clot dissolution. Computer analysis of the output allows sophisticated clot formation/dissolution kinetics and clot strength data to be generated
• Standard Coagulation Test
coagulation tests, such as the prothrombin time (PT), activated partial thromboplastin time (aPTT), and thrombin time (TT), to assess blood clotting function in patients. Clauss Fibrinogen.

Drug:
• Fibrinogen Concentrate Human
To treat acquired fribinogen deficiency investigators will treat with the following doses FIBTEM A5 = 9-11 MM a 2 G FIBRINOGEN CONC. (25 MG/KG); FIBTEM A5 = 4-8 MM a 4 G FIBRINOGEN CONC. (50 MG/KG); FIBTEM A5 < 4 MM a 6 G FIBRINOGEN CONC. (75 MG/KG)
• Prothrombin Complex Concentrates
to treat acquired factor deficiency investigators will treat as follows PROTROMBIN COMPLEX CONCENTRATE EXTEM CT > 80 SEC AND FIBTEM A5 = 8 MM 4F-PCC 20 IU/KG (F II, VII, IX and X) GOAL: EXTEM CT = 80 SEC

Other:
• Platelets
PLATELETS EXTEM A5 < 40 MM AND FIBTEM A5 = 12 MM EXTEM A5 < 40 MM ? 1 PLATELET POOL OR APHERESIS; EXTEM A5 < 30 MM ? 2 PLATELET POOL OR APHERESIS GOAL: EXTEM A5: 40-50 MM or PLATELET COUNT < 100/µL PLT < 100/µL ? 1 PLATELET POOL OR APHERESIS; PLT > 50/µL ? 2 PLATELET POOL OR APHERESIS GOAL: PLT COUNT > 100/µL
• Red Blood Cells
Transfuce Red Blood Cells if Hemoglobine levels < 7 G/DL; 1 unit of FFP for every unit of RBC Transfused GOAL: Hb > 7.5 G/DL
• Fresh Frozen Plasma
FRESH FROZEN PLASMA TP AND/OR TTP PATHOLOGICAL INR, 2.0-4.0 ? FFP 20 ML/KG GOAL: TP AND TTP NORMAL AND INR < 2.0
• cryoprecipitates
FIBRINOGEN (CLAUSS) < 250 MG/DL FIB 200-250 MG/DL ? CRYOS, PACK OF 10 (25 MG/KG); FIB 100-200 MG/DL ? CRYOS, PACK OF 20 (50 MG/KG); FIB < 100 MG/DL ? CRYOS, PACK OF 30 (75 MG/KG) GOAL: FIB > 250 MG/DL

Locations

Country	Name	City	State
Mexico	Hospital de Especialidades Del Niño Y La Mujer	Querétaro City	Queretaro

Sponsors (2)

Lead Sponsor	Collaborator
Angel Augusto Perez Calatayud	Grupo Mexicano para el Estudio de la Medicina Intensiva

Country where clinical trial is conducted

Mexico, 

References & Publications (12)

Baksaas-Aasen K, Van Dieren S, Balvers K, Juffermans NP, Næss PA, Rourke C, Eaglestone S, Ostrowski SR, Stensballe J, Stanworth S, Maegele M, Goslings JC, Johansson PI, Brohi K, Gaarder C; TACTIC/INTRN collaborators. Data-driven Development of ROTEM and TEG Algorithms for the Management of Trauma Hemorrhage: A Prospective Observational Multicenter Study. Ann Surg. 2019 Dec;270(6):1178-1185. doi: 10.1097/SLA.0000000000002825. — View Citation

Collins PW, Cannings-John R, Bruynseels D, Mallaiah S, Dick J, Elton C, Weeks AD, Sanders J, Aawar N, Townson J, Hood K, Hall JE, Collis RE. Viscoelastometric-guided early fibrinogen concentrate replacement during postpartum haemorrhage: OBS2, a double-blind randomized controlled trial. Br J Anaesth. 2017 Sep 1;119(3):411-421. doi: 10.1093/bja/aex181. — View Citation

Collins PW, Lilley G, Bruynseels D, Laurent DB, Cannings-John R, Precious E, Hamlyn V, Sanders J, Alikhan R, Rayment R, Rees A, Kaye A, Hall JE, Paranjothy S, Weeks A, Collis RE. Fibrin-based clot formation as an early and rapid biomarker for progression of postpartum hemorrhage: a prospective study. Blood. 2014 Sep 11;124(11):1727-36. doi: 10.1182/blood-2014-04-567891. Epub 2014 Jul 14. — View Citation

Hagemo JS, Christiaans SC, Stanworth SJ, Brohi K, Johansson PI, Goslings JC, Naess PA, Gaarder C. Detection of acute traumatic coagulopathy and massive transfusion requirements by means of rotational thromboelastometry: an international prospective validation study. Crit Care. 2015 Mar 23;19:97. doi: 10.1186/s13054-015-0823-y. — View Citation

Mace H, Lightfoot N, McCluskey S, Selby R, Roy D, Timoumi T, Karkouti K. Validity of Thromboelastometry for Rapid Assessment of Fibrinogen Levels in Heparinized Samples During Cardiac Surgery: A Retrospective, Single-center, Observational Study. J Cardiothorac Vasc Anesth. 2016 Jan;30(1):90-5. doi: 10.1053/j.jvca.2015.04.030. Epub 2015 May 5. — View Citation

Mallaiah S, Barclay P, Harrod I, Chevannes C, Bhalla A. Introduction of an algorithm for ROTEM-guided fibrinogen concentrate administration in major obstetric haemorrhage. Anaesthesia. 2015 Feb;70(2):166-75. doi: 10.1111/anae.12859. Epub 2014 Oct 7. Erratum in: Anaesthesia. 2015 Nov;70(11):1334. — View Citation

Mallaiah S, Chevannes C, McNamara H, Barclay P. A reply. Anaesthesia. 2015 Jun;70(6):760-1. doi: 10.1111/anae.13128. — View Citation

Olde Engberink RH, Kuiper GJ, Wetzels RJ, Nelemans PJ, Lance MD, Beckers EA, Henskens YM. Rapid and correct prediction of thrombocytopenia and hypofibrinogenemia with rotational thromboelastometry in cardiac surgery. J Cardiothorac Vasc Anesth. 2014 Apr;28(2):210-6. doi: 10.1053/j.jvca.2013.12.004. — View Citation

Pérez-Calatayud ÁA, Briones-Garduño JC, Rojas-Arellano ML. [Use of thromboelastography and thromboelastometry for the rational and opportune transfusion of hemoderivatives in obstetric hemorrhage]. Ginecol Obstet Mex. 2015 Sep;83(9):569-77. Review. Spanis — View Citation

Snegovskikh D, Souza D, Walton Z, Dai F, Rachler R, Garay A, Snegovskikh VV, Braveman FR, Norwitz ER. Point-of-care viscoelastic testing improves the outcome of pregnancies complicated by severe postpartum hemorrhage. J Clin Anesth. 2018 Feb;44:50-56. doi: 10.1016/j.jclinane.2017.10.003. Epub 2017 Nov 7. Erratum in: J Clin Anesth. 2018 Apr 15;48:8. — View Citation

Song JG, Jeong SM, Jun IG, Lee HM, Hwang GS. Five-minute parameter of thromboelastometry is sufficient to detect thrombocytopenia and hypofibrinogenaemia in patients undergoing liver transplantation. Br J Anaesth. 2014 Feb;112(2):290-7. doi: 10.1093/bja/aet325. Epub 2013 Sep 24. — View Citation

Wikkelsø AJ, Edwards HM, Afshari A, Stensballe J, Langhoff-Roos J, Albrechtsen C, Ekelund K, Hanke G, Secher EL, Sharif HF, Pedersen LM, Troelstrup A, Lauenborg J, Mitchell AU, Fuhrmann L, Svare J, Madsen MG, Bødker B, Møller AM; FIB-PPH trial group. Pre-emptive treatment with fibrinogen concentrate for postpartum haemorrhage: randomized controlled trial. Br J Anaesth. 2015 Apr;114(4):623-33. doi: 10.1093/bja/aeu444. Epub 2015 Jan 13. — View Citation

* Note: There are 12 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Blood products transfused	Number of allogeneic blood products transfused intra-op, within 24h after screening and in-hospital (RBC, Platelets and FFP; separate and overall)	24 hrs
Secondary	Number of hemocomponents or fibrinogen concentrates needed to treat hypofibrinogenemia	Number of packs of Cryo (pack of 5 ~ 1 G Fibrinogen), Fibrinogen Concentrate (G), and PCC (500 UI) administered intra-operating	day 0 to day 15
Secondary	Incidence of Red Blood Cells transfusion (RBC)	Incidence = 5 U RBC transfused	day 0 to day 15
Secondary	Incidence of Massive Red Blood Cells transfusion (RBC)	Incidence = 10 U RBC transfused (first 24h after screening)	day 0 to day 15
Secondary	estimated blood loss	Overall estimated blood loss (EBL, ML)	day 0 to day 15
Secondary	Time to bleeding control	time from study entry to last hemostatic intervention/transfusion	24 hrs
Secondary	Incidence of coagulopathy	detected by thromboelastometry or standard coagulation laboratory tests	day 0 to day 15
Secondary	Incidence of hysterectomy	number of obstetric hysterectomy for bleeding control	day 0 to day 15
Secondary	Incidence of re-surgery	number of procedures necessary for bleeding control	day 0 to day 15
Secondary	Incidence of Transfused associated circulatory overload	number of patients with transfused associated circulatory overload	day 0 to day 15
Secondary	Incidence of surgical site infection or sepsis	number of patients that developed health care related infections or sepsis	day 0 to day 15
Secondary	Incidence of ICU admission	number of patients that require admission to the ICU for complications related to hipovolemic shock	day 0 to day 15
Secondary	In-hospital mortality	number of deaths	day 0 to day 15