Point-of-care Management of Coagulopathy in Lung Transplantation

June 30, 2020 updated by: Durila Miroslav MUDr. Ph.D., University Hospital, Motol

Point-of-care (POC) Approach to Management of Coagulopathy in Lung Transplantation Versus Standard Approach and Their Effect on Primary Graft Dysfunction (PGD), Randomized Controlled Study

Pulmonary transplantation is a very demanding surgical procedure, often accompanied by coagulopathy and severe perioperative bleeding. The most common complication that develops within the first 72 hours after surgery is primary graft dysfunction (PGD), up to 30% in the most severe form. The etiology of PGD is multifactorial. One of the causes may be the amount of perioperative blood loss. Intravascular volume is normally maintained by the administration of crystalloid and colloid solutions and fresh frozen plasma, which is also used to treat coagulopathy, however it is administered at the discretion of the anaesthetist and his experience, practically meaning ,,blindly". In the field of the allogeneous ischemic organ, these substitution solutions essentially become another allogeneous material and can cause undesired immunomodulation and contribute to the development of PGD. In our prospective randomized trial (120 patients), two patient groups will be investigated. In the first group, the coagulopathy and perioperative blood loss will be treated by the current standard approach, by ,,blind" administration of fresh frozen plasma, crystalloids and colloids. In the second group, the cause of coagulopathy will be diagnosed and treated according to the point-of-care (POC) results of ROTEM, PFA 200 and Multiplate. A colloidal solution of 5% albumin will be used to replace the circulating volume and maintain the oncotic pressure. Investigators assume that the POC management of coagulopathy and bleeding in the second group will lead to a reduction in perioperative bleeding, to reduced administration of infusion solutions, and thus to a reduction of the incidence of PGD.

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

Detailed Description

Introduction and project description:

Primary graft dysfunction (PGD) in lung transplant patients is described as acute pulmonary damage occurring early in lung transplantation (in the first 72 hours) (1, 2), sometimes referred to as ischemia - reperfusion injury (1). It is characterized by non-cardiac pulmonary edema and diffuse alveolar damage. Clinically, it is manifested by varying degrees of hypoxemia, along with diffuse infiltrates in the X-ray of the lung. There are more theories that try to explain the cause of PGD. A number of factors such as cold organ ischemia, mechanical irritation during organ reperfusion, immunological, inflammatory, microbiological factors, and many others associated with lung transplantation (2, 3) may play a roll. Depending on the severity of the clinical symptoms and the severity of X-ray findings according to International Society of Heart and Lung Transplantation (ISHLT) there are three types of PGD. The incidence of PGD in its worst form (Grade 3) in early post-transplantation period is being reported to be present in up to 30% and between 10-25% within 24-72 hours after organ reperfusion. Lighter forms of PGD (1st and 2nd degree) occur much more frequently (2,3). Lung affected by PGD is characteristically edematous and the gas exchange is significantly impaired due to damage to the endothelial barrier integrity of the vessels and the epithelial barrier of the lung tissue. The presence of PGD significantly increases the morbidity and mortality of patients and significantly prolongs the time spent in invasive mechanical ventilation, generally prolongs the time spent in intensive care unit and is a significant risk factor for development of chronic rejection of the transplanted lung (2,3).

Lung transplantation is a demanding surgical procedure often associated with the development of coagulopathy and significant bleeding, especially when extracorporeal membrane oxygenation (ECMO) is used perioperatively, which is practically used in the most cases. Blood loss is replaced by the administration of crystalloid and colloid solutions in order to maintain normovolemia and by administering FFP, which is also used to treat coagulopathy, despite the fact that the International Normalized Ratio (INR) of blood plasma is 1.5-1.6. These preparations are administered according to the anesthesiologist's experience and practically ,,blindly". However, their administration in patient significantly immunocompromised may mean a risk of immunomodulation and thus a deterioration of PGD. In addition, the administration of blood plasma is generally associated with higher morbidity and mortality of patients (1).

On the other hand, point-of-care (POC) monitoring of the hemocoagulation state using rotational thromboelastometry (ROTEM) and subsequent targeted coagulopathy therapy during the perioperative period and traumatic life threatening bleeding resulted in decreased bleeding intensity and consumption of transfusion products and this approach led to a reduction in morbidity and mortality of these patients (2,3).

Also, methods for evaluating primary haemostasis such as PFA 200 (platelet function analyzer) and aggregometry-Multiplate can be used as POC methods in the operating room, especially for the diagnosis of coagulopathy accompanying the use of ECMO, especially for the diagnosis of von Willebrand's disease (PFA 200) or for the diagnosis of thrombocytopathy (Multiplate) (1-4).

All methods ROTEM, PFA 200 and Multiplate are used to predict bleeding in cardiac surgery and hepatic transplantation, and targeted therapy based on their results is associated with a reduction in blood transfusion (FFP, platelets, erythrocytes) administration, reduced bleeding and reduced morbidity and mortality (5-7).

Therefore, it can reasonably be assumed that a similar positive benefit of this POC approach can be expected even in patients undergoing lung transplantation.

In this prospective controlled randomized study of 120 lung transplant patients, investigators want to compare the incidence of PGD between a group of patients treated by standard ,,blind" approach and a ,,new" POC approach. Investigators assume that in a group where diagnosis and therapy of coagulopathy and bleeding will be managed based on the results of the ROTEM, PFA 200 and Multiplate tests, the clot strength will be increased and this will lead to reduced perioperative blood loss, reduced administration of infusion solutions and FFP and this will subsequently lead to reduced incidence of PGD.

Hypothesis:

Point-of-care approach to diagnosis of perioperative coagulopathy with ROTEM, PFA 200 and Multiplate and its subsequent aimed therapy will improve blood clot and thus will reduce blood loss, fluid infusion, blood transfusion and subsequently the incidence of PGD.

Methodology:

Patients undergoing bilateral lung transplantation (120 patients) will be randomized into 2 groups using computerised generator of random numbers. The study protocol will be registered in the Clinical Research Database and a clinical trial number (CTN) will be obtained and written informed consent will be obtained from patients before lung transplantation.

The first group of existing ,,standard care" - the approach to bleeding patient will be based on clinical experience of the anaesthetist, practically meaning administering crystalloids, colloids (hydroxyethyl starch or gelatin), fresh frozen plasma and erythrocytes to restore normovolemia and platelets, fibrinogen, prothrombin complex concentrate, von Willebrand factor, tranexamic acid, all products giving ,,blindly" when it comes to diagnosis and treatment of coagulopathy.

The second group of ,,point-of-care" approach to the diagnosis and treatment of perioperative bleeding and coagulopathy will be conducted on the basis of the results of the POC methods ROTEM, PFA 200 and Multiplate (prothrombin complex concentrate, fibrinogen, platelets, von Willebrand factor, tranexamic acid). A solution of 5% albumin and erythrocytes (to keep haemoglobin level over 100 g/l as it is critical for normal primary haemostasis) will be used to keep normal circulating volume and to compensate for perioperative blood loss.

Blood samples will obtained and analysed by ROTEM, PFA 200 and Multiplate, as well as the level and function of von Willebrand factor (multimers assay, ristocetin cofactor and collagen binding assay) will be performed in all patients:

  1. before lung transplantation, upon patient arrival to hospital before surgery (as a control)
  2. after lung transplantation, during admission of patient to postoperative intensive care unit
  3. in the ,,POC" group also in the operating room (ROTEM, Multiplate and PFA 200) during surgery

The PGD score will be evaluated post-operatively and in the following way: severity of PGD is defined in four degrees and is evaluated using partial arterial oxygen pressure (PaO2) and inspired fraction of oxygen ratio (FiO2) ratio and simultaneously evaluating X-ray finding of the lungs as soon as possible after reperfusion (time 0) and after 48 and 72 hours after lung reperfusion.

  • Grade 0 - PaO2/FiO2 ratio of any value but no pulmonary edema on chest X-ray
  • Grade 1 - PaO2/FiO2 > 300 and presence of pulmonary edema on chest X-ray
  • Grade 2 - PaO2/FiO2 200 - 300 and and presence of pulmonary edema on chest X-ray
  • Grade 3 - PaO2/FiO2 < 200 and presence of pulmonary edema on chest X-ray or patients in need of postoperative ECMO support or nitric oxide therapy

To exclude the possible thrombotic complication of any of these approaches, each patient will be screened ultrasonographically for venous thrombosis 72 hours postoperatively (vena poplitea, vena femoralis, vena jugularis, and vena subclavia bilat) and thrombotic complications will compared between groups.

Also other parameters will be compared between groups:

  • clot strength and whole coagulation profile before and after surgery using ROTEM, PFA 200 and Multiplate and evaluation of the functional level of von Willebrand factor. Correlation of coagulation profile with blood loss in the operating room and postoperative blood loss will be also assessed.
  • amount of perioperative blood loss in the operating room at the end of surgery and 24 hours after surgery (blood loss will measured as amount of blood in the suction container in operating room and as amount of blood in the chest drain in ICU postoperatively)
  • number of transfusion products administered in operating room and in postoperative ICU
  • duration of invasive and noninvasive mechanical ventilation and time to extubation (hours), duration of stay in the postoperative ICU and overall in hospital before discharge home (days)
  • morbidity of patients (SOFA score at 24, 48 and 72 hours after lung transplantation), morbidity and mortality among patients in 30, 90 and 365 days
  • incidence of lung graft rejection during whole period of hospitalisation

Time schedule: 4 years During the 3-years period recruitment of patients will be done and in the 4-th year data will be analysed and published in valuable journals.

Investigators expect a lower consumption of blood transfusion products and infusion solutions in the POC group.

In case of lower PGD incidence in the POC group investigators expect shorter time of mechanical ventilation, a shorter period of hospitalization at the postoperative ICU and in the hospital overall and a lower incidence of pulmonary graft rejection.

Investigators expect lower morbidity and mortality of patients in the POC group.

Investigators also believe that the POC approach will reduce the total hospitalisation costs.

Study Type

Observational

Enrollment (Actual)

67

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Czechia
      • Prague, Czechia, 150 06
        • Unoversity Hospital Motol, Department of Anaesthesiology and Intensive Care

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years to 78 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Probability Sample

Study Population

Patients over 18 years old who are indicated for bilateral lung transplantation with diagnosis of interstitial pulmonary fibrosis, cystic fibrosis, chronic obstructive pulmonary disease, exogenous allergic alveolitis.

Description

Inclusion Criteria:

  • Patients over 18 years
  • Indicated for bilateral lung transplantation with diagnosis of interstitial pulmonary fibrosis, cystic fibrosis, chronic obstructive pulmonary disease, exogenous allergic alveolitis

Exclusion Criteria:

  • Patients requiring plasmapheresis before lung transplantation
  • Patients waiting for lung transplantation on ECMO (ECMO used as bridging to surgery)
  • Patients undergoing simultaneous lung and heart transplantation

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Other
  • Time Perspectives: Prospective

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
Standard management of coagulopathy
The first group of existing ,,standard care" - the approach to bleeding patient will be based on clinical experience of the anaesthetist, practically meaning administering crystalloids, colloids (hydroxyethyl starch or gelatin), fresh frozen plasma and erythrocytes to restore normovolemia and platelets, fibrinogen, prothrombin complex concentrate, von Willebrand factor, tranexamic acid, all products giving ,,blindly" when it comes to diagnosis and treatment of coagulopathy.
Other: Fresh frozen plasma
Fresh frozen plasma will be used according to anaesthetist ,,blind,, decision
POC management of coagulopathy
group of ,,point-of-care" approach to the diagnosis and treatment of perioperative bleeding and coagulopathy will be conducted on the basis of the results of the POC methods ROTEM, PFA 200 and Multiplate (prothrombin complex concentrate, fibrinogen, platelets, von Willebrand factor, tranexamic acid). A solution of 5% albumin and erythrocytes (to keep haemoglobin level over 100 g/l as it is critical for normal primary haemostasis) will be used to keep normal circulating volume and to compensate for perioperative blood loss.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Compare the incidence of PGD in the group of patients with POC approach to treatment of coagulopathy versus existing standard ,,blind" approach to treatment of coagulopathy
Time Frame: 3 years
in percentage
3 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Compare the the amount of perioperative blood loss
Time Frame: 3 years
in milliliters
3 years
Compare the consumption of transfusion products between groups
Time Frame: 3 years
in units
3 years
Compare the incidence of thrombotic complications between groups
Time Frame: 3 years
yes/no
3 years
Compare the length of invasive mechanical ventilation
Time Frame: 3 years
in hours
3 years
Compare morbidity and mortality between investigated groups (30, 90 and 365 days)
Time Frame: 3 years
yes/no
3 years
Compare incidence of lung graft rejection
Time Frame: 3 years
yes/no
3 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University Hospital, Motol

Investigators

  • Principal Investigator: Miroslav Durila, assoc.prof., University Hospital, Motol

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

January 1, 2018

Primary Completion (Actual)

June 30, 2020

Study Completion (Actual)

June 30, 2020

Study Registration Dates

First Submitted

June 30, 2018

First Submitted That Met QC Criteria

July 16, 2018

First Posted (Actual)

July 26, 2018

Study Record Updates

Last Update Posted (Actual)

July 2, 2020

Last Update Submitted That Met QC Criteria

June 30, 2020

Last Verified

June 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • NV19-06-00471

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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