Thromboelastometry-identified Haemostatic Changes in Isolated Traumatic Brain Injury (THROMBIN)

The Influence of Thromboelastometry-identified Haemostatic Changes on Haemorrhagic Progression of Intracranial Injury and Clinical Outcome in Patients With Isolated Traumatic Brain Injury

A prospective open-label case-control study will be performed aiming to assess the utility of thromboelastometry (ROTEM) for identification of hemostatic changes, goal-directed coagulation management, and prognosis of intracranial hemorrhagic injury progression as well as clinical outcome in patients with isolated traumatic brain injury. Patients undergoing craniotomy to treat traumatic brain injury will be enrolled. All patients will undergo standard perioperative coagulation analysis (APTT, PT, INR, fibrinogen levels, platelet count), whereas ROTEM-guided group will additionally be tested with ROTEM. "Cases" will be managed according to a ROTEM-based algorithm, and "Controls" will be treated as usual (based on clinical judging). Comparative analysis of acquired demographic, clinical and laboratory data will be performed. The investigators believe that ROTEM results could provide better insight into perioperative coagulation changes, be beneficial to patient blood management, and result in better outcome.

Study Overview

• Status: Completed
• Conditions: Bleeding; Brain Injuries, Traumatic; Coagulation Disorder
• Intervention / Treatment: Other: Thromboelastometry-guided haemostatic treatment

Detailed Description

Aim of the study:

To assess the utility of thromboelastometry for identification of hemostatic changes, goal-directed coagulation management, and prognosis of intracranial hemorrhagic injury progression as well as clinical outcome in patients with isolated traumatic brain injury.

Objectives:

To evaluate perioperative prevalence and characteristics of thromboelastometry identified coagulopathy in neurosurgical patients with isolated traumatic brain injury; To assess the correlation between routine laboratory test results and thromboelastometric findings; To evaluate the influence of thromboelastometric findings and goal-directed coagulation management on the progression of intracranial hemorrhagic injury; To evaluate the utility of thromboelastometry for goal-directed coagulation management, and its possible influence on clinical outcome.

Study background:

Traumatic brain injury still accounts for a considerable proportion of preventable deaths worldwide. The prevalence of coagulation derangements among patients with traumatic brain injury (TBI) is high and approximates 30 % (1,2). The main hypothesis explaining the development of coagulopathy in the absence of massive bleeding is extensive release of tissue factor from the damaged brain tissue and subsequent over-activation of coagulation leading to consumption of coagulation substrates. The presence of coagulopathy in the setting of TBI is associated with high risk of intracranial hemorrhagic insult progression and death (3,4). Many authors investigating coagulopathy associated with traumatic brain injury have used routine coagulation tests, such as APTT, PT, INR, fibrinogen levels. However, those tests do not reflect the overall clot quality and reflect only separate parts of the coagulation process.

Craniotomy for traumatic brain injury is an urgent high-risk procedure presenting a serious challenge for the anesthesiology team. Significant, diffuse bleeding is not infrequent, and the spectrum of neurosurgical hemostatic options is limited. Moreover, even small amounts of intracranial blood may be life-threatening. Therefore the maintenance of optimal physiologic clotting capacity is crucial. Literature data investigating the use of ROTEM in TBI patients is still limited (5,6).

The investigators believe that thromboelastometry could provide novel insights into the dynamic coagulation changes of TBI patients. Moreover, it could serve as a clinical tool for targeted coagulation management in the perioperative period of patients undergoing craniotomies for intracranial traumatic hematomas, and prove beneficial for patient outcome.

Materials and methods:

A prospective open-label case-control study will be performed. Adult isolated traumatic brain injury patients undergoing craniotomy and will be enrolled. Required sample size was calculated based on the average number of craniotomies performed to treat traumatic brain injury during the past five years in a tertiary neurosurgical centre. The investigators plan to enroll 70 patients into the ROTEM-guided group (Cases), and 70 patients into the conventional therapy group (Controls). All patients will undergo standard coagulation analysis (APTT, PT, INR, fibrinogen levels, platelet count) preoperatively, and 3 days postoperatively, whereas ROTEM-guided group patients will additionally be tested with ROTEM (EXTEM, INTEM, FIBTEM, APTEM). Coagulation management decisions in the ROTEM-guided group will be made according to a ROTEM-based algorithm for goal-directed hemostatic therapy. Conventional therapy group will be treated as usual. Perioperative demographic, clinical and laboratory data of study patients will be registered. Early neurological state (on postoperative days 1,2,3,7, and until discharge) will be assessed according to the Glasgow coma scale. Late neurological outcome (6 and 12 months postoperatively) will be assessed according to Glasgow outcome scale. Comparative analysis of Case and Control groups will be performed. Perioperative prevalence and characteristics of coagulopathy in neurosurgical patients with isolated traumatic brain injury will be estimated. Correlation between routine laboratory test results and thromboelastometric findings will be assessed. The influence of thromboelastometric findings and goal-directed coagulation management on the progression of intracranial hemorrhagic injury will be assessed. The influence of goal-directed coagulation management on clinical outcome will be evaluated.

Anticipated scientific and clinical benefits:

The investigators believe that ROTEM results could provide better insight into perioperative coagulation changes, be beneficial to patient blood management, and result in better outcome.

• Study Type: Interventional
• Enrollment (Actual): 142
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Lithuania
  • Kaunas, Lithuania, LT-50009
    • Hospital of Lithuanian University of Health Sciences

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Isolated traumatic brain injury (within 48 hours) (AIS head >= 3)
• Urgent craniotomy is necessary
• A written informed consent is acquired from the patient or his/her representative

Exclusion Criteria:

• Refusal / inability to acquire an informed consent
• Significant trauma to other body regions (AIS other regions >= 3)
• Data on significant chronic hepatic or hematologic illness
• Use of oral anticoagulants or antiplatelet agents
• Pregnancy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Conventional therapy; Intraoperative haemostatic treatment is based on conventional coagulation assays.
Active Comparator: Goal-directed therapy; Thromboelastometry-guided haemostatic treatment is provided intraoperatively.	Other: Thromboelastometry-guided haemostatic treatment; Administration of blood products and/or procoagulants is based on thromboelastometric assays.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mortality	Mortality of patients in both groups	30 days
Early neurological state according to Glasgow coma scale	Glasgow coma scale (GCS) is used to objectively assess the level of consciousness after neurological injury according to best eye (range 1 to 4), verbal (range 1 to 5) and motor (range 1 to 6) response of the patient. Eye, verbal and motor scores are summed to give the total Glasgow coma score (range 3 to 15). The lowest possible GCS (the sum) is 3 (deep coma or death), while the highest is 15 (fully awake person).	30 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Coagulation abnormalities on conventional coagulation assays and ROTEM	The number of patients with abnormal results of PT (prothrombin time), INR (international normalized ratio), APTT (activated partial thromboplastin time), fibrinogen concentration, platelet count and/or any abnormal thromboelastometric (ROTEM) parameter	72 hours
Progressive hemorrhagic injury	Evidence of new or increased intracranial hemorrhagic injury	30 days
Clinical outcome according to Glasgow outcome score	The Glasgow Outcome Score (GOS) is used to divide patients with traumatic brain injury into groups (range 1 to 5) that allow standardised descriptions of the objective degree of recovery as follows: Death; Persistent vegetative state - Severe damage with prolonged state of unresponsiveness and a lack of higher mental functions; Severe disability - Severe injury with permanent need for help with daily living; Moderate disability - No need for assistance in everyday life, employment is possible but may require special equipment; Low disability - Light damage with minor neurological and psychological deficits	Up to 1 year

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Correlation between conventional coagulation assays and ROTEM parameters	The number of cases with corresponding results (both abnormal (or normal) conventional coagulation assays and ROTEM parameters) vs. the number of cases with conflicting results (abnormal (or normal) conventional coagulation assays, but normal (or abnormal) ROTEM parameters); Correlation between PT and EXTEM CT (thromboelastometric measure of clotting time in the extrinsic coagulation pathway); Correlation between APTT and INTEM CT (thromboelastometric measure of clotting time in the intrinsic coagulation pathway); Correlation between fibrinogen concentration and FIBTEM MCF (thromboelastometric measure of maximum clot firmness in the fibrinogen polymerisation assay); Correlation between platelet count and EXTEM MCF (thromboelastometric measure of maximum clot firmness in the extrinsic coagulation pathway); Correlation between platelet count and INTEM MCF (thromboelastometric measure of maximum clot firmness in the intrinsic coagulation pathway)	72 hours

Collaborators and Investigators

• Sponsor: Lithuanian University of Health Sciences

Publications and helpful links

General Publications

• Wafaisade A, Lefering R, Tjardes T, Wutzler S, Simanski C, Paffrath T, Fischer P, Bouillon B, Maegele M; Trauma Registry of DGU. Acute coagulopathy in isolated blunt traumatic brain injury. Neurocrit Care. 2010 Apr;12(2):211-9. doi: 10.1007/s12028-009-9281-1.
• Harhangi BS, Kompanje EJ, Leebeek FW, Maas AI. Coagulation disorders after traumatic brain injury. Acta Neurochir (Wien). 2008 Feb;150(2):165-75; discussion 175. doi: 10.1007/s00701-007-1475-8. Epub 2008 Jan 2.
• Maegele M. Coagulopathy after traumatic brain injury: incidence, pathogenesis, and treatment options. Transfusion. 2013 Jan;53 Suppl 1:28S-37S. doi: 10.1111/trf.12033.
• de Oliveira Manoel AL, Neto AC, Veigas PV, Rizoli S. Traumatic brain injury associated coagulopathy. Neurocrit Care. 2015 Feb;22(1):34-44. doi: 10.1007/s12028-014-0026-4.
• Brazinova A, Majdan M, Leitgeb J, Trimmel H, Mauritz W; Austrian Working Group on Improvement of Early TBI Care. Factors that may improve outcomes of early traumatic brain injury care: prospective multicenter study in Austria. Scand J Trauma Resusc Emerg Med. 2015 Jul 16;23:53. doi: 10.1186/s13049-015-0133-z.
• Schochl H, Solomon C, Traintinger S, Nienaber U, Tacacs-Tolnai A, Windhofer C, Bahrami S, Voelckel W. Thromboelastometric (ROTEM) findings in patients suffering from isolated severe traumatic brain injury. J Neurotrauma. 2011 Oct;28(10):2033-41. doi: 10.1089/neu.2010.1744. Epub 2011 Sep 23.

Study record dates

Study Major Dates

• Study Start (Actual): August 21, 2018
• Primary Completion (Actual): August 30, 2020
• Study Completion (Actual): December 31, 2020

Study Registration Dates

• First Submitted: July 13, 2018
• First Submitted That Met QC Criteria: July 31, 2018
• First Posted (Actual): August 6, 2018

Study Record Updates

• Last Update Posted (Actual): April 6, 2021
• Last Update Submitted That Met QC Criteria: April 5, 2021
• Last Verified: April 1, 2021

More Information

Terms related to this study

• Keywords: Traumatic brain injury; Craniotomy; Goal-directed treatment; Thromboelastometry
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Hematologic Diseases; Hemorrhagic Disorders; Craniocerebral Trauma; Trauma, Nervous System; Hemostatic Disorders; Blood Coagulation Disorders; Brain Injuries; Wounds and Injuries; Brain Injuries, Traumatic; Coagulants; Hemostatics
• Other Study ID Numbers: v2

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No