What you learned from this study and how it contributes to patient outcomes/nursing etc.

Clinical and pathophysiologic aspects of
ECMO-associated hemorrhagic complications Konstantin A. PopugaevID1,2*, Sergey A. Bakharev2, Kirill V. Kiselev3, Alexander
S. Samoylov2, Nikolay M. Kruglykov2, Sergey A. Abudeev1, Sergey V. Zhuravel1, Aslan K. Shabanov1, Thomas Mueller4, Stephan A. Mayer5, Sergey S. Petrikov1
1 Department of Intensive Care, Sklifosovsky Research Institute of Emergency Medicine of the Moscow Healthcare Department, Moscow, Russia, 2 Department of Intensive Care, State Research Center—Burnasyan Federal Medical Biophysical Center of Federal Medical Biological Agency, Moscow, Russia,3 Department of Statistics and Cybernetics, Pirogov Russian National Research Medical University, Moscow,Russia, 4 Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany,5 Department of Neurology, Henry Ford Hospital, Detroit, MI, United States of America Stan.popugaev@yahoo.com

Abstract

Extracorporeal membrane oxygenation (ECMO) is increasingly used to treat severe cases of acute respiratory or cardiac failure. Hemorrhagic complications represent one of the most common complications during ECMO, and can be life threatening. The purpose of this study was to elucidate pathophysiological mechanisms of ECMO-associated hemorrhagic compli-cations and their impact on standard and viscoelastic coagulation tests. The study cohort included 27 patients treated with VV-ECMO or VA-ECMO. Hemostasis was evaluated using standard coagulation tests and viscoelastic parameters investigated with rotational throm-boelastometry. Anticoagulation and hemorrhagic complications were analyzed for up to seven days depending on ECMO duration. Hemorrhagic complications developed in 16(59%) patients. There were 102 discrete hemorrhagic episodes among 116 24-hour-inter-vals, of which 27% were considered to be clinically significant. The highest number of ECMO-associated hemorrhages occurred on the 2nd and 3rd day of treatment. Respiratory tract bleeding was the most common hemorrhagic complication, occurring in 62% of the 24- hour intervals. All 24-hours-intervals were divided into two groups: “with bleeding” and “with- out bleeding”. The probability of hemorrhage was significantly associated with abnormalities of four parameters: increased international normalized ratio (INR, sensitivity 71%, specificity 94%), increased prothrombin time (PT, sensitivity 90%, specificity 72%), decreased intrinsic pathway maximal clot firmness (MCFin, sensitivity 76%, specificity 89%), and increased extrinsic pathway clot formation time (CFTex, sensitivity 77%, specificity 87%). In conclu- sions, early ECMO-associated hemorrhagic complications are related to one traditional and two novel viscoelastic coagulation abnormalities: PT/INR elevation, reduced maximum clot firmness due to intrinsic pathway dysfunction (MCFin), and prolonged clot formation time due to extrinsic pathway dysfunction (CFTex). When managing hemostasis during ECMO,derangements in PT/INR, MCFin and CFTex should be focused on.PLOS ONE
PLOS ONE | https://doi.org/10.1371/journal.pone.0240117 October 13, 2020 1 / 13

OPEN ACCESS
Citation: Popugaev KA, Bakharev SA, Kiselev KV,
Samoylov AS, Kruglykov NM, Abudeev SA, et al.
(2020) Clinical and pathophysiologic aspects of
ECMO-associated hemorrhagic complications.
PLoS ONE 15(10): e0240117. https://doi.org/
10.1371/journal.pone.0240117
Editor: Hugo ten Cate, Maastricht University
Medical Center, NETHERLANDS
Received: April 2, 2020
Accepted: September 21, 2020
Published: October 13, 2020
Copyright: © 2020 Popugaev et al. This is an open
access article distributed under the terms of the
Creative Commons Attribution License, which
permits unrestricted use, distribution, and
reproduction in any medium, provided the original
author and source are credited.
Data Availability Statement: All relevant data are
within the paper and its Supporting Information
files.
Funding: There was no external funding for this
study. Laboratory examinations were part of the
institutional standard investigations for ECMO
patients. Thus, no funders had any role in study
design, data collection and analysis, decision to
publish, or preparation of the manuscript. The
authors received no specific funding for this work.

Extracorporeal membrane oxygenation (ECMO) is a technique increasingly used in the prac-tice of intensive therapy for extracorporeal gas exchange and/or circulatory support in patients with acute respiratory and/or cardiac failure, when conventional treatment modalities are inef-fective

[1]. Blood flow within an artificial extracorporeal circuit will lead to thromboembolic events and necessitates therapeutic anticoagulation. Obligatory use of anticoagulants, however,will increase the risk of hemorrhagic complications, including massive life-threatening bleed- ings

[2]. In critically ill patients, even before ECMO, many hemostatic disturbances can develop, which can be aggravated during ECMO. Therefore, prevention and correction of hemostatic disturbances during ECMO is important. The effectiveness of hemostasis manage- ment can often determine the clinical outcome in a patient in need of ECMO

[3].Traditional laboratory coagulation parameters assess separated parts of hemostasis in blood samples after centrifugation, which makes it difficult to evaluate the coagulation process as a whole

[4]. Global viscoelastic methods for assessing hemostasis, including thromboelastogra- phy (TEG) and rotational thromboelastometry (ROTEM), may offer important advantages to traditional clotting tests

[5]. TEG and ROTEM assess quantitative and qualitative aspects of whole blood coagulation, including clot formation, retraction, and lysis. Analysis of TEG and ROTEM data may allow intensivists to determine the mechanism of hemostatic disturbances and select a targeted therapy more accurately

[6].The purpose of this research was to better understand the pathophysiological mechanisms that underlie ECMO-associated hemorrhagic complications, and to identify traditional labora-tory coagulation and ROTEM parameters that might be useful to monitor to prevent such complications during ECMO.

Materials and methods

27 consecutive adult patients on ECMO were included into the study from June 2017 to April 2019 and all data were recorded prospectively. Inclusion criteria were age > 18 years on either veno-venous (VV) or veno-arterial (VA) ECMO, patients with proven brain death were excluded. All patients were treated at the Anesthesia, Intensive Care and ECMO Center of the State Research Center − Burnasyan Federal Medical Biophysical Center of the Federal Medical Biological Agency of Russia. The need for written patient consent was waived by the ethics committee of the hospital because laboratory investigations were conducted according to the local standard. The study was approved by the ethics committee of Burnasyan Federal Medical Biophysical Center (protocol #33, issued on 14.06.2017).
The principles of laboratory monitoring and patient management were standard, and cor-responded to national and international guidelines [7–12]. ECMO was performed using Rota-Flow or Cardiohelp devices (all Getinge, Rastatt, Germany). For both VV-ECMO and VA-ECMO a drainage cannula (21–25 Fr) was placed in the inferior vena cava via the femoral vein. For VV-ECMO the return cannula (17–21 Fr) was placed into the superior vena cava/right atrium via the right internal jugular vein. For VA-ECMO, the return cannula (19–23 Fr) was placed into the abdominal aorta via the femoral artery. A femoral distal perfusion cannula was placed in all VA-ECMO cases.
All patients received unfractionated heparin for anticoagulation. Immediately after cannu-lation all patients received a bolus of heparin of 50–100 U/kg, thereafter its dose was titrated using the activated clotting time (ACT), the activated partial thromboplastin time (aPTT), and the clotting time in the intrinsic thromboelastometry (INTEM) mode (CTin). Target values for ACT were 140–160 sec, for aPTT 45–55 sec, and for CTin 240–260 sec. APTT and ACT were monitored at least every 8 hours, CTin every 24 hours. Antithrombin III (AT-III),PLOS ONE
Clinical and pathophysiologic aspects of ECMO-associated hemorrhagic complications
PLOS ONE | https://doi.org/10.1371/journal.pone.0240117 October 13, 2020 2 / 13
Competing interests: All authors have declared
that no competing interests exist.

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