RU2766350C1 - Method for prediction of thrombosis and bleeding in critical patients with covid-19 under conditions of ecmo - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to anesthesiology, resuscitation, and can be used for prediction of thrombosis and bleeding in critical patients with COVID-19 under conditions of extracorporeal membrane oxygenation (ECMO). Following parameters are determined: volume of heparinization with unfractionated heparin (IU/kg/h), activated partial thromboplastin time (sec), activity level of antithrombin-III (%), concentration of nitrogen oxide (mcmol/l), concentration of malondialdehyde (nmol/ml), concentration of angiotensin-converting enzyme (ACE units), total antioxidant status (mmol/l). Measured values are assigned points in accordance with Table 1. Obtained points are summed up. If the total score is 7 to 10, a low degree of risk of thrombosis and bleeding is predicted. If the total score is from 11 to 16 inclusive, the average degree is stated. If the total score is from 17 to 21 inclusive, the high degree is observed.

EFFECT: method enables to predict the risk of thrombosis or bleeding in critical patients with COVID-19 undergoing an ECMO procedure, based on an assessment of a number of laboratory values, which enables to establish the probability of life-threatening complications for the purpose of timely implementation of preventive and therapeutic measures.

1 cl, 4 tbl, 3 ex

Description

The invention relates to medicine, namely to anesthesiology and resuscitation, and can be used to predict thrombosis and bleeding in critically ill patients with COVID-19 under ECMO conditions.

From the prior art methods for assessing separately: the risk of thrombosis and the risk of bleeding.

In particular, there is a known method for predicting thromboembolic complications [patent RU 2621298], in which the vascular endothelial growth factor is determined and, based on the obtained value, the risk of thromboembolism is determined.

However, under conditions of a systemic inflammatory response caused by COVID-19 and mechanical injury of the vascular wall by large-diameter ECMO cannulas, this indicator loses its significance.

From the prior art, there are also known scales for determining the risk of bleeding, such as ISTH, HAS-BLED [euat.ru], which use, as a rule, clinical indicators for risk assessment without an emphasis on laboratory parameters, and also do not imply COVID-19 disease and the presence of EKM.

Closest to the claimed solution is a method for predicting a lethal outcome in resuscitation patients of a cardiac surgical profile [patent RU 2626674], which consists in calculating the integral index of the totality of hemostasis indicators in a group of patients similar in severity of the condition and the form of cannulation with patients diagnosed with COVID-19, based on the following measured parameters: K1 - the ratio of the number of platelets in the patient to the value of the lower limit of the reference interval; K2 - the ratio of antithrombin III activity in a patient to the value of the lower limit of the reference interval; K3 - the ratio of the content of fibrinogen in the patient to the value of the lower limit of the reference interval; K4 - the ratio of the content of fibrin monomer in the patient to the reference value; K5 is the ratio of the content of D-dimer in a patient to the reference value, and if the value of the integral index is below 10.0, a lethal outcome is predicted in resuscitation patients of a cardiosurgical profile.

The invention makes it possible to predict a lethal outcome in resuscitation patients of a cardiac surgical profile, however, it does not allow assessing the risk of life-threatening complications in patients with a new SARS-COV-2 coronavirus infection.

The technical problem is to develop a method for predictive risk assessment of complications caused by disorders in the hemostatic system in critically ill patients with COVID-19 undergoing extracorporeal membrane oxygenation.

The technical result to which the claimed invention is directed is the possibility of predicting the risk of thrombosis or bleeding in critically ill patients with COVID-19 undergoing extracorporeal membrane oxygenation, based on an assessment of laboratory parameters.

To achieve a technical result, the following indicators are determined in points in accordance with Table 1:

the volume of heparinization with unfractionated heparin based on body weight per hour (Heparin),

activated partial thromboplastin time (APTT),

the level of activity of antithrombin-III (AT3),

concentration of nitric oxide (NOx),

concentration of malondialdehyde (MDA),

concentration of angiotensin-converting enzyme (ACE),

total antioxidant status (TAS).

Table 1. Scoring of indicators of the blood coagulation system and the amount of anticoagulant therapy in accordance with the risk of an event of a thrombotic or hemorrhagic complication.

The scores obtained are summed up, and upon receipt of the score value from 7 to 10 inclusive, a low risk of thrombosis and bleeding is predicted, with a score of 11 to 16 inclusive - an average risk, with a score of 17 to 21 inclusive - a high risk.

The method allows to establish the probability of life-threatening complications for the purpose of timely implementation of preventive and therapeutic measures.

The technical result is achieved due to laboratory diagnosis of disorders of the hemostasis system, which consists in the study of blood serum. To assess the risk of bleeding and thrombosis in critically intensive care patients with COVID-19 under ECMO conditions, a significant set of indicators was used, including an assessment of the dosage of unfractionated heparin per body weight, since this anticoagulant is the drug of choice and is recommended for use in patients with COVID-19 when using ECMO [Interim Guidelines for Prevention, Diagnosis and Treatment of Novel Coronavirus Infection (COVID-19). Version 11(07.05.2021)], which allows to increase the accuracy of calculations; activated partial thromboplastin time, which is necessary to assess the state of the coagulation system of patients receiving anticoagulant therapy under ECMO conditions; the activity of antithrombin-III, which is necessary for evaluation in patients receiving unfractionated heparin, since antithrombin-III is one of the links in the mechanism of action of heparin, and also has athrombogenic properties; the concentration of nitric oxide, which is important for the systemic assessment of the state of the endothelium of the vascular wall in patients with COVID-19; malondialdehyde concentration, which is important for assessing oxidative stress in ECMO patients; the concentration of angiotensin-converting enzyme - to assess the functional state of the ACE-producing systems of the body, which are target organs in COVID-19; total antioxidant status, used as a marker of vascular wall endothelial injury, which is characteristic of the pathogenesis of thrombosis and bleeding in patients with COVID-19 under ECMO conditions, to assess the ability of the body's antioxidant system to cope with oxygen free radicals produced as a result of the ECMO circuit.

The proposed method is easy to implement and the ability to monitor patients with it throughout the entire period of hospitalization, which allows timely prediction of the development of thrombosis and bleeding.

The inventive method is implemented as follows.

In a specific embodiment of the invention, the volume of heparinization with unfractionated heparin (IU/kg/hour) is determined based on the amount of heparin (international units) received by the patient per hour, based on body weight; activated partial thromboplastin time (sec) is determined in blood plasma by the clotting method on an automatic coagulometer "CA 1500", Sysmex (Japan); the level of activity of antithrombin-III (%) is determined by the chromogenic method on an automatic coagulometer "CA 1500", Sysmex (Japan); the concentration of nitric oxide (μmol/l) is determined by the spectrophotometric method, according to which cadmium in the presence of zinc reduces nitrate to nitrite, the color intensity of the obtained products is measured on a SPECORD 40 spectrophotometer (Analytik Jena AG, Germany); the concentration of malonic dialdehyde (nmol/ml) is determined in the test with thiobarbituric acid (TBA) [Gavrilov V.B., Gavrilova A.R., Mazhul L.M. Analysis of methods for determining products of lipid peroxidation in blood serum according to the test with thiobarbituric acid. Question. honey. chemistry. 1987; 1: 118-22], the fluorescence intensity of butanol extracts, due to the presence of colored products of the TBA reaction, is measured on an LS 55 spectrofluorimeter (PerkinElmer, UK); the concentration of angiotensin-converting enzyme (ACE units) is estimated by spectrophotometric method on the biochemical analyzer "AU2700" (Beckman Coulter, USA); the total antioxidant status (mmol/l) is determined by the spectrophotometric method on an Olympus AU2700 biochemical analyzer (Beckman Coulter, USA).

This significant set of parameters was obtained from the results of treatment of 70 critically ill patients with COVID-19 under conditions of extracorporeal membrane oxygenation. The facts of complications of a thrombotic and hemorrhagic nature, including thrombosis of the elements of the extracorporeal circuit, were correlated with the parameters of the blood coagulation system and the dosage of unfractionated heparin obtained no earlier than 24 hours before the events, which made it possible to establish a relationship between changes in these indicators and complications and establish the relationship between them. To analyze the obtained data, mixed logistic regression models were used with the inclusion of a unique patient index as a variable, for which the random effects of predictors (heparin, APTT, antithrombin-3, NOx, MDA, ACE, TAS) of the risk of events (thrombotic and hemorrhagic) were evaluated. Based on the models obtained, the risk of events was assessed depending on the value of the predictor (heparin, APTT, antithrombin-3, NOx, MDA, ACE, TAS). Further, based on the predictions of the models, a comprehensive assessment of predictors was carried out, for which there was a minimal joint risk of developing hemorrhagic and thrombotic events.

The proposed method is confirmed by the following clinical examples.

Clinical example 1.

Patient R., 57 years old, was admitted on 04/17/2021, diagnosed with coronavirus infection caused by the COVID-19 virus, community-acquired bilateral polysegmental pneumonia, stage 2 respiratory failure, ECMO was connected on 04/20/2021, on the 5th day from the start of ECMO, laboratory diagnostics were scheduled : APTT - 22.2 sec, antithrombin-III - 71%, NOx - 14.99 µmol/l, MDA - 2.537 nmol/ml, ACE - 21.6 ACE units, TAS - 2.16 mmol/l, dosage calculated heparin - 5 IU/kg/h, which corresponded to 18 points and a high risk of thrombosis and bleeding. During the day, ultrasound revealed non-occlusive thrombosis of both internal jugular veins and the right common femoral vein.

Clinical example 2.

Patient Z., 56 y.o., was admitted on 03/24/2021, diagnosed with coronavirus infection caused by the COVID-19 virus, community-acquired bilateral polysegmental pneumonia, stage 2 respiratory failure, ECMO was connected on 03/29/2021, laboratory diagnostics were scheduled on the 1st day from the start of ECMO : APTT - 29.3 sec, antithrombin-III - 80%, NOx - 72.99 µmol/l, MDA - 2.904 nmol/ml, ACE - 55.7 ACE units, TAS - 1.09 mmol/l, dosage calculated heparin - 4.54 IU/kg/hour, which corresponded to 13 points and an average risk of thrombosis and bleeding. During the day there was bleeding from the nasal cavity with a volume of 20 cm ³ . The average degree of risk to clarify the prognosis requires additional research methods, for example, thromboelastometry.

Clinical example 3.

Patient Yu., 63 years old, was admitted on May 4, 2021, diagnosed with coronavirus infection caused by the COVID-19 virus, community-acquired bilateral polysegmental pneumonia, stage 2 respiratory failure, ECMO was connected on May 7, 2021, laboratory diagnostics were scheduled on the 1st day from the start of ECMO : APTT - 48.9 sec, antithrombin-III - 86%, NOx - 24.67 µmol/l, MDA - 4.734 nmol/ml, ACE - 69 ACE units, TAS - 1.44 mmol/l, calculated dosage of heparin - 11.49 IU/kg/h, which corresponded to 10 points and a low risk of thrombosis and bleeding. During the next day before discharge from the hospital, thrombosis and bleeding were not observed.

Claims (1)

A method for predicting thrombosis and bleeding in critically ill patients with COVID-19 under conditions of extracorporeal membrane oxygenation (ECMO), including determining the following parameters: heparinization volume with unfractionated heparin (ME/kg/h), activated partial thromboplastin time (sec), antithrombin activity level -III (%), nitric oxide concentration (µmol/l), malondialdehyde concentration (nmol/ml), angiotensin-converting enzyme concentration (ACE units), total antioxidant status (mmol/l), the measured values are assigned points in accordance with Table 1 , the scores obtained are summed up, and upon receipt of the value of the sum of points from 7 to 10 inclusive, a low degree of risk of thrombosis and bleeding is predicted, with a sum of points from 11 to 16 inclusive - an average degree, with a sum of points from 17 to 21 inclusive - a high degree.