Clinical trial NCT03598907: Point-of-care Management of Coagulopathy in Lung Transplantation
Official title: 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
Study type: OBSERVATIONAL
Overall status: TERMINATED
Conditions: Lung Transplantation
Keywords: point of care
coagulopathy
lung transplantation
primary graft dysfunction
Lead sponsor: University Hospital, Motol
Sponsor class: OTHER
First posted: 2018-07-26
Enrollment: 100
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: OTHER
Time perspective: PROSPECTIVE
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.

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Perioperative Blood Loss
timeFrame: From the beginning of surgery to 24 hours postoperatively
Secondary outcomes:
Other outcomes:
measure: Primary Graft Dysfunction (PGD)
timeFrame: After surgery at 0 hours
measure: Primary Graft Dysfunction (PGD)
timeFrame: After surgry at 24 hours
measure: Primary Graft Dysfunction (PGD)
timeFrame: After surgry at 48 hours
measure: Primary Graft Dysfunction (PGD)
timeFrame: After surgry at 72 hours
Locations:
city: Prague
country: Czechia
facility: University Hospital Motol, Department of Anaesthesiology and Intensive Care
Study officials:
affiliation: University Hospital, Motol
name: Miroslav Durila, assoc.prof.
role: PRINCIPAL_INVESTIGATOR
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