Traitement hémostatique basé sur la Thromboélastometrie Rotatoire (ROTEM) chez les Patients opérés en urgence en Chirurgie cardiovasculaire

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Thesis

Reference

Traitement hémostatique basé sur la Thromboélastometrie Rotatoire (ROTEM) chez les Patients opérés en urgence en Chirurgie

cardiovasculaire

SARTORIUS, Danielle Marie

Abstract

La première cause de mortalité au cours d'une intervention de chirurgie cardiovasculaire en urgence est l'hémorragie. Le diagnostic précoce des troubles de la crase rencontrés dans ce contexte est primordial afin de cibler un traitement rapide et efficace. La thromboélastometrie est un examen qui permet d'analyser rapidement les propriétés viscoélastiques du caillot sanguin, au bloc opératoire. Dans un premier temps les spécificités des troubles de l'hémostase rencontrés en chirurgie cardiovasculaire sont brièvement résumées. Ensuite, les méthodes d'analyse viscoélastique de la formation du caillot sanguin (thromboélastographie (ROTEM) et thromboélastometrie (TEG)) sont décrites. Finalement, nous rapportons l'expérience acquise au Hôpitaux Universitaires de Genève de l'utilisation de la thromboélastometrie au bloc opératoire et en particulier les résultats de l'implémentation d'un algorithme de gestion de l'hémostase au cours de la chirurgie cardiovasculaire pratiquée en urgence.

SARTORIUS, Danielle Marie. Traitement hémostatique basé sur la

Thromboélastometrie Rotatoire (ROTEM) chez les Patients opérés en urgence en Chirurgie cardiovasculaire . Thèse de doctorat : Univ. Genève, 2016, no. Méd. 10806

URN : urn:nbn:ch:unige-852530

DOI : 10.13097/archive-ouverte/unige:85253

Available at:

http://archive-ouverte.unige.ch/unige:85253

Disclaimer: layout of this document may differ from the published version.

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Volume 17 Issue 2 Apr - Jun 2014

1960 1970 1990

PMPM

IVS

LV

ALPM

Annals of Cardiac Anaesthesia • Volume 17 • Issue 2 • April-June 2014 • Pages 89-***

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Aims and Objectives: We assessed the clinical impact of goal‑directed coagulation management based on rotational thromboelastometry (ROTEM) in patients undergoing emergent cardiovascular surgical procedures.

Materials and Methods: Over a 2‑year period, data from 71 patients were collected prospectively and blood samples were obtained for coagulation testing. Administration of packed red blood cells (PRBC) and hemostatic products were guided by an algorithm using ROTEM‑derived information and hemoglobin level.

Based on the amount of PRBC transfused, two groups were considered: High bleeders (≥5 PRBC; HB) and low bleeders (<5 PRBC; LB). Data were analyzed using Chi‑square test, unpaired t‑test and analysis of variance as appropriate. Results: Pre‑operatively, the HB group (n = 31) was characterized by lower blood fibrinogen and decreased clot amplitude at ROTEM compared with the LB group (n = 40). Intraoperatively, larger amounts of fibrinogen, fresh frozen plasma and platelets were required to normalize the coagulation parameters in the HB group. Post‑operatively, the incidence of major thromboembolic and ischemic events did not differ between the two groups (<10%) and the observed in‑hospital mortality was significantly less than expected by the Physiological and Operative Severity Score for the enumeration of Mortality and Morbidity (POSSUM score, 22% vs. 35% in HB and 5% vs. 13% in LB group). Conclusions: ROTEM‑derived information is helpful to detect early coagulation abnormalities and to monitor the response to hemostatic therapy. Early goal‑directed management of coagulopathy may improve outcome after cardiovascular surgery.

Key words: Cardiovascular surgery; Postoperative bleeding; Rotational thromboelastometry

Goal‑directed hemostatic therapy using the rotational thromboelastometry

in patients requiring emergent cardiovascular surgery

Danièle Sartorius¹, Jean‑Luc Waeber¹, Gordana Pavlovic¹, Angela Frei¹, John Diaper¹, Patrick Myers², Tiziano Cassina³, Marc Licker^1,4

1Department of Anaesthesiology, Pharmacology and Intensive Care, ²Department of Cardiovascular Surgery, University Hospital, CH‑1211, Geneva, ³Department of Anesthesia and Intensive Care, Cardiocentro Ticino, CH‑6900 Lugano, Switzerland, ⁴Faculty of Medicine, University of Geneva, Geneva, Switzerland

Received: 07‑08‑13 Accepted: 27‑01‑14

ABSTRACT

acidosis and low ionized calcium.^[6] Although packed red blood cells (PRBC) improves tissue oxygen delivery and fresh frozen plasma (FFP) improves coagulation, homologous blood transfusion has been associated with an increased risk of mortality and a higher incidence of infection, thromboembolism, myocardial infarct, stroke and renal failure.^[2,4,7]

Unfortunately, conventional coagulation tests (CCTs) failed to characterize the multiple hemostatic abnormalities observed in surgical patients and they are further limited by their slow results and their poor correlation INTRODUCTION

Massive bleeding remains a leading cause of potentially preventable death after cardiovascular surgery.^[1] Surgical skills, extent of vascular injury and integrity of the hemostatic system all influence the volume of blood loss while the severity of anemia and the amount of blood transfusion are major determinants of postoperative outcome.^[2‑5]

Impaired hemostasis may develop in surgical patients, owing to dilution of coagulation factors, hypothermia, low hematocrit and hypoperfusion associated with metabolic

Address for correspondence: Prof. Marc Licker, Faculty of Medicine, University of Geneva, Rue Gabrielle‑Perret‑Gentil, CH‑1205, Geneva, Switzerland.

Department of Anesthesiology, Pharmacology and Intensive Care, University Hospital Geneva, CH‑1211, Geneva, Switzerland.

E‑mail: marc‑joseph.licker@hcuge.ch

Original Article

Access this article online Website: www.annals.in PMID:

***

DOI:

10.4103/0971‑9784.129829 Quick Response Code:

This article is accompanied by an invited commentary by Dr. Achal Dhir

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Sartorius, et al.: ROTEM‑guided hemostatic therapy in cardiovascular surgery

101 Annals of Cardiac Anaesthesia ^ Vol. 17:2 ^ Apr-Jun-2014

with transfusion requirements.^[8] Given the lack of a consensus in transfusion decision‑making, there is a wide variability in transfusion practices among different countries, hospitals and even health care providers within the same institution.^[9] Currently, several point‑of‑care (POC) devices have appeared in operating theatres, with the possibility to monitor the viscoelastic changes on whole blood, thereby evaluating all four phases of the cell‑based coagulation processes: Initiation, propagation, amplification and clot‑lysis.^[10] Among these POC monitors, the rotational thromboelastometry (ROTEM; Tem International GmbH, Munich, Germany) and thromboelastometry (TEG; Baintree, MA, USA) have been increasingly adopted in European and North American countries because of easy handling by the anesthetic team and rapid results leading to timely correction of coagulation abnormalities.^[11] Preliminary data suggest that management of perioperative coagulopathy based on ROTEM/TEG is associated with reduced blood products administration and may help clinicians to distinguish between surgical bleeding and severe coagulopathy.^[12]

Although using POC coagulation devices has been shown to improve the prediction of bleeding in various surgical settings, there is currently weak evidence on the risk and benefits of any transfusion policy guided by thromboelastometry and no report has specifically involved the emergency surgical settings.^[13‑15] We therefore conducted a cohort study to assess whether the implementation of an algorithm based on ROTEM parameters may effectively and safely reverse coagulation abnormalities in high‑risk bleeding patients undergoing emergent cardiovascular surgery.

MATERIALS AND METHODS

Patient selection and management

From January 2011 to December 2012, we included consecutive adult patients (>18 years) undergoing emergent cardiovascular procedures at the University Hospital of Geneva. During this period, thromboelastometry was routinely performed in the operating theater by nurses and physicians of the anesthesia department who had been trained to perform the ROTEM tests according to the manufacturer’s instructions. Only patients at high risk of bleeding were enrolled (ongoing post‑intervention bleeding, combined valve and coronary bypass surgery, clopidogrel treatment within 5 days before surgery). Pregnant patients and those with severe circulatory failure (requiring mechanical support) and severe sepsis (identified infection associated with dysfunction

involving at least one organ system) were excluded.

The study was approved by the institutional research ethics board and informed consent was waived given the emergency context, the routine practice of POC coagulation testing and the anonymized database.

An algorithm for perioperative coagulation management was implemented in our institution the preceding year [Figure 1]. Intraoperatively, forced airflow and fluid warming devices were routinely used to maintain normothermia and the blood ionized calcium concentration was kept above 1 mM/L. A restrictive transfusion strategy (hemoglobin level above 70‑80 g/L) was followed in euvolemic anesthetized patients whereas a hemoglobin level above 80‑90 g/L was targeted in patients with ongoing bleeding, ischemic heart disease and/or organ failure. All cardiac procedures were performed under cardiopulmonary bypass (CPB) with tranexamic acid (10 mg/kg in the priming fluid and 15 mg/kg slowly infused after anesthesia induction), unfractionated heparin (to achieve an activated clotting time [ACT] above 500 s) and protamine (titrated to normalize the ACT at the end of surgery).^[16]

Administration of blood products and hemostatic agents was guided by the results obtained with the ROTEM device that was checked every week by running standard quality control tests.

Measurements

Blood samples for ROTEM and CCTs were obtained as part of the routine management of surgical patients at high‑risk of bleeding at three time periods: Before surgery (preoperative), at the end of surgery (end surgery) and on the morning of the first postoperative day (POD1). Additional tests were performed at the discretion of the attending anesthesiologist. The CCTs included the international normalized ratio (INR), prothrombin time (Quick), partial thromboplastin time (PTT), fibrinogen concentration and the platelet count. The ROTEM analysis were performed on 300 μl citrated whole blood containing 20 μl 0.2 M calcium chloride and specific activators/inhibitors into a plastic cup to explore the whole spectrum of cell‑based clot formation:

The extrinsic and intrinsic coagulation pathways (EXTEM, using rabbit brain thromboplastin; INTEM using ellagic acid), fibrin based‑thromboelastometry (FIBTEM using cytochalasin to inhibit platelet’s contribution) and fibrinolysis (APTEM, using aprotinin). The motion of the rotational pin immersed in the blood sample was progressively limited by the generation of the fibrin filaments and changes in

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the viscoelastic properties of blood were graphically displayed over time. To characterize the initiation of fibrin strand formation, thrombin generation and lysis, several parameters were recorded: Clotting time (CT), alpha angle (α, rate of clot formation), clot amplitude after 15 min (CA15), maximum clot firmness (MCF) and clot formation time (CFT). As previously reported, ROTEM yields consistent values and reference ranges for the tests’ parameters have been determined in a multi‑center investigation.^[17]

Demographic and clinical data, incidence of pre‑operative anticoagulant/antiplatelet medications, type of surgery, intraoperative administration of fluids (crystalloids, colloids), blood transfusion products (PRBC, FFP, platelets concentrates (PC)) as well as other hemostatic agents (fibrinogen, tranexamic acid and activated recombinant factor VII [rFVIIa]) were all prospectively recorded on a dedicated case report form.

In addition, the electronic medical files were examined to report hospital and intensive care unit length of stay as well as major post‑operative complications (in‑hospital mortality, acute respiratory failure, infections, renal failure, thromboembolic events, myocardial infarct, and heart failure). Mortality was estimated from variables included in the Physiological and Operative Severity Score for the enumeration of Mortality and Morbidity (P‑POSSUM).^[18,19]

Study design

In this prospective cohort study, we divided the population sample in two groups depending on the number of PRBC being transfused: At least 5 units of PRBC (high bleeding, HB group) and <5 units PRBC (low bleeding, LB group). Given the inability to accurately measure blood loss, the number of PRBC units was used as a surrogate of excessive bleeding and the 5‑unit threshold has been previously shown to be an inflection point where mortality increased significantly.^[20]

Statistical analysis

Data are presented as means (± standard deviation), numbers and percentage as appropriate. Statistical calculations were performed with SPSS version 13.0 for Windows. Normally distributed data (Kolmogorov‑Smirnov test) were analyzed by the Student‑two tailed t‑test for unpaired samples and repeated measures analysis of variance. Data which were not normally distributed were analyzed by the Mann‑Whitney U‑test. For analysis of frequency, the X²‑test was used. In all tests, an a priori α‑error P < 0.05 was considered to be statistically significant.

RESULTS

During the study period, a total of 102 patients at high risk of bleeding underwent emergent cardiovascular

Figure 1: Algorithm for perioperative goal‑directed coagulation management. Physiological targets: Central temperature >35.5°C; pH >7.25; lactate <2.5 mm/L;

Ca++ >1.0 mm/L; Hb >70 g/L; fibrinogen >1.5 g/L; platelets >50,000/ml. Persistent hypocoagulation: Consider FXIII and/or recombinant activated FVII

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surgery. The ROTEM tests were not available in 31 of these patients, because the POC device was not available, or data were missing or the anesthesia personnel were too busy to perform these tests. Thus, complete data were obtained in 71 patients of whom 31 received >5 units of PRBC (HB group, 43.7%) and 40 received <5 units of PRBC (LB group, 54.3%). In the operating theater, ROTEM analyses were repeated several times from the time of anesthesia induction until the end of surgery (median values of 2 with interquartile range of 2‑3 per patient in both groups).

Patient’s pre‑operative clinical and surgical characteristics as well as baseline laboratory tests were similar in the two groups; except for a longer duration of surgery and a lower blood fibrinogen in the HB group compared with the LB group [Tables 1 and 2].

Pre‑operatively, CCTs (including fibrinogen) results were within the normal reference range, except a prolonged PTT in the two groups. At the end of surgery, hemoglobin concentration, platelet count, fibrinogen

level and Quick test were all similarly decreased in both groups compared with pre‑operative values; in contrast, blood lactate was increased in the HB group whereas it remained unchanged in the LB group.

At the start of surgery, the values of CT (EXTEM) and MCF (FIBTEM) were outside the normal range and several ROTEM parameters differed between the two groups: MCF (with EXTEM, FIBTEM and APTEM), CA15 (with EXTEM, INTEM, FIBTEM and APTEM) and CFT (with APTEM), were all significantly decreased in the HB group compared with the LB group [Table 3]. As shown in Figure 2, all these ROTEM‑derived data tended to shift toward normal values at the end of surgery and on POD1, with no difference between the two groups [Figure 2 and Table 2]. Intraoperatively, larger amounts of crystalloids, PRBCs, FFP, PC, protamine sulfate and fibrinogen were administered in the HB group compared with the LB group [Table 4]. In‑hospital mortality was higher in the HB group (22% vs. 5% in the LB group) although it was significantly lower than the predicted

Figure 2: Perioperative time course of rotational thromboelastometry‑derived parameters: Clotting time, clotting formation time and maximal clot firmness; specific assays for extrinsic activated test (EXTEM; a), intrinsic activated test (INTEM; b), fibrin clot obtained by platelet inhibition with cytochalasin (FIBTEM; c) and fibrinolysis (APTEM; d); POD1: Postoperative day 1

c b a

d

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mortality based on the POSSUM score (35% in the HB group and 13% in the LB group). The incidence of major complications was comparable in the two groups [Table 5]. Of note, the incidence of thromboembolic and ischemic events was <10% in both groups.

DISCUSSION

Early and aggressive management of coagulopathy is of vital importance in emergency surgical procedures.

The main findings of this prospective clinical trial are summarized as following: (1) Information derived from a ROTEM‑POC monitor was more helpful for anesthesiologists than CCTs to detect preoperative abnormalities in clot formation in surgical patients at high‑risk of bleeding, (2) implementation of a goal‑directed hemostatic protocol led to normalization of the ROTEM parameters at the end of surgery, (3) although patients with increased need of allogenic blood transfusion received larger amounts of hemostatic agents, the observed in‑hospital mortality was lower

than expected and the incidence of thromboembolic and ischemic events was similar than in patients receiving fewer PRBCs.

In cardiovascular surgery, transfusion of blood products is currently guided by clinical judgment and CCTs that often include activated PTT, prothrombin time (PT, Quick), platelet count and plasma fibrinogen.^[8,21] However, none of these tests were developed to predict bleeding or to guide coagulation management in the surgical setting, with the major limitations being the inability to identify coagulation factor deficiencies and the lack of real‑time monitoring of the hemostatic response to surgical trauma, fluid infusion and specific pro‑and anticoagulant treatment.^[22]

Table 1: Clinical and surgical data of patients at high risk of bleeding undergoing emergent cardiovascular surgery

Variables Patients

transfused with >5 units PRBC

n = 31

Patients transfused

with <5 units PRBC

n = 40

P value

Age (year) 68 (14) 63 (14) 0.076

BMI, kg/(m²)² 26.0 (4.5) 26.2 (4.6) 0.872

Gender (M/F) (%) 21 (68) / 10 (32) 32 (80) / 8 (20) 0.872

ASA score 3‑4 (n, %) 25 (81) 36 (90) 0.315

Comorbidities (n, %)

Renal failure 6 (19) 10 (26) 0.950

Coronary artery disease 12 (39) 15 (38) 0.976 Arterial hypertension 18 (58) 23 (59) 0.946

Diabetes mellitus 4 (13) 6 (15) 0.927

Arrhythmia 7 (23) 10 (25) 0.965

Hypercholesterolemia 13 (42) 12 (31) 0.326

Preoperative medications (n, %)

Aspirin 15 (48) 23 (59) 0.480

Clopidogrel 8 (26) 10 (26) 1.000

Vitamin K antagonists 2 (6.5) 6 (15) 0.452

Low molecular weight heparin 3 (10) 3 (8) 0.919 Unfractionated heparin 7 (23) 17 (44) 0.128 Type of surgery (n, %)

Combined cardiac surgery 2 (6) 1 (3) 0.791

CABGS 9 (29) 13 (33) 0.988

Valve surgery 11 (35) 8 (20) 0.233

Major vascular surgery 4 (13) 15 (38) 0.040 Re‑operation for bleeding 9 (29) 7 (18) 0.386 Surgical time (min) 294 (193) 182 (96) 0.006 ASA: American society of anesthesiology physical status classification, BMI: Body mass index, CABGS: Coronary artery bypass graft surgery, PRBC: Packed red blood cell

Table 2: Conventional laboratory tests in patients at high risk of bleeding undergoing emergent cardiovascular surgery

n = 31

n = 40

P value

Hemoglobin (N: 12‑17 g/dl)

Pre‑operative 10.9 (2.3) 11.9 (2.8) 0.096 End of surgery 9.2 (1.5)^† 9.0 (1.7)^† 0.751

POD1 9.8 (1.0)^† 9.9 (1.5)^† 0.904

Lactate (N: <2 mmol/l)

Pre‑operative 2.0 (2.5) 1.7 (2.3) 0.716

End of surgery 3.7 (2.9)^† 1.8 (1.6) 0.012

POD1 2.1 (1.1) 2.0 (1.6) 0.692

Creatinine (N: 40‑110 µmol/l)

Preoperative 103 (37) 124 (75) 0.324

End of surgery NA NA NA

POD1 135 (98) 135 (88) 0.993

INR (N: 0.9‑1.2)

Pre‑operative 1.2 (0.5) 1.3 (0.7) 0.768

End of surgery 1.4 (0.2) 1.5 (0.6) 0.745

POD1 1.5 (0.6) 1.6 (0.8) 0.915

PTT (N: 30‑40 s)

Pre‑operative 46 (22) 59 (61) 0.281

End of surgery 65 (36) 63 (41) 0.741

POD1 43 (29) 57 (37) 0.196

Quick (N: 70‑100%)

Pre‑operative 79 (20) 79 (22) 0.906

End of surgery 59 (17) 61 (19) 0.891

POD1 84 (13) 79 (17) 0.541

Fibrinogen (N: 2‑4 g/l)

Pre‑operative 3.4 (1.4) 4.5 (2.0) 0.037

End of surgery 1.9 (0.5)^† 2.1 (1.5)^† 0.679

POD1 4.8 (1.5)^† 4.5 (1.6) 0.589

Platelet count (N: 150‑350 G/L)

Preoperative 196 (98) 193 (79) 0.853

End of surgery 70 (35)^† 98 (59)^†

POD1 128 (74)^† 152 (76)^†

PRBC: Packed red blood cell, INR: International normalized ratio, NA: Not applicable, POD1: Postoperative day 1, PTT: Prothrombin time. ^†P < 0.05, compared with preoperative period

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Based on a 2‑year experience in POC‑supported coagulation management in elective major surgery, our team has developed and implemented a POC‑supported algorithm for goal‑directed hemostatic therapy using a transfusion trigger for PRBC and different procoagulant interventions (e.g., fibrinogen concentrates, FFPs, antifibrinolytic agents, protamine and rFVIIa). In the current study, we selectively focused on a group of patients scheduled for emergent cardiovascular surgical procedures and at high‑risk of bleeding.

These patients had multiple comorbidities and acquired coagulopathic disorders owing to major tissue trauma, CPB, large volume fluid resuscitation and antiplatelet/anticoagulant drug therapies. In previous reports,^[1,23‑25] major bleeding and allogenic blood transfusions have been identified as strong predictors of poor clinical outcome. In the current study, fourfold‑higher perioperative mortality was found in patients requiring five PRBC or more compared with those requiring <5 units, although both groups

presented similar clinical characteristics. These “high bleeders” underwent more stressful surgical procedures as reflected by the prolonged duration of surgery, a higher blood lactate concentrations and the need for a larger amount of fluid infusion compared with “low bleeders”. The lower than expected in‑hospital mortality (i.e., 22% vs. 35%) in these high‑risk surgical population could be attributed to timely perioperative medical management, particularly adherence to standardized clinical care bundles and also the application of an algorithm aimed to correct perioperative coagulation abnormalities and to minimize allogenic blood transfusion.^[26] Yet, no favorable impact has been demonstrated regarding early mortality and length of stay in intensive care unit, several studies indicate that target hemostatic management using ROTEM‑derived information leads to reduced transfusion of coagulation products and earlier re‑intervention in case of persistent bleeding associated with a normal clot formation.^[27,28]

Since the initial reports in 1987 by Tuman and Spiess,^[29‑32] at least 20 studies involving viscoelastic hemostatic assays such as ROTEM or TEG have been conducted, including more than 7500 cardiac surgical Table 3: Pre‑operative rotational thromboelastometric

tests in patients at high risk of bleeding undergoing emergent cardiovascular surgery

n = 31

n = 40

P value

EXTEM

CT (N: 42‑74 s) 85 (38) 74 (24) 0.148

CFT (N: 46‑148 s) 103 (35) 112 (51) 0.483 Alpha angle (N: 63‑81) 66 (12) 71 (10) 0.058

MCF (N: 50‑71 mm) 53 (9) 61 (10) 0.001

CA15 (N: 46‑67 mm) 47 (10) 56 (12) 0.003

INTEM

CT (N: 137‑240 s) 201 (64) 184 (68) 0.392 CFT (N: 40‑100 s) 162 (186) 117 (69) 0.211 Alpha angle (N: 71‑82) 66 (11) 68 (12) 0.618 MCF (N: 50‑72 mm) 54 (11) 59 (13) 0.100

CA15 (N: 47‑70 mm) 50 (11) 56 (12) 0.024

FIBTEM

CT (N: 43‑69 s) 74 (28) 86 (35) 0.112

CFT (N: ‑) 240 (160) 176 (106) 0.323

Alpha angle (N: ‑) 69 (9) 68 (15) 0.714

MCF (N: 9‑25 mm) 11 (4) 15 (8) 0.031

CA15 (N: 8‑22 mm) 11 (5) 14 (7) 0.053

APTEM

CT (N: ‑s) 97 (55) 88 (38) 0.479

CFT (N: ‑s) 165 (75) 112 (58) 0.002

Alpha angle (N: ‑) 65 (10) 68 (15) 0.215

MCF (N: ‑mm) 53 (9) 60 (12) 0.004

CA15 (N: ‑mm) 48 (10) 55 (15) 0.039

CT: Coagulation time, CFT: Clot formation time, MCF: Maximum clot firmness, CA15: Clot amplitude after 15 min, PRBC: Packed red blood cell

Table 4: Intraoperative administration of fluids and hemostatic agents in patients with high risk of bleeding undergoing emergent cardiovascular surgery

transfused with >5 units PRBC n = 31

Patients transfused with <5 units PRBC n = 40

P value

Crystalloids (ml) 3908 (1850) 3020 (1356) 0.029

Colloids (ml) 245 (412) 171 (306) 0.434

PRBC

N patients (%) 31 (100) 29 (73) 0.016

Volume (ml) 2577 (1247) 570 (376) <0.001

FFP

N patients (%) 25 (81) 17 (43) 0.002

Volume (ml) 1612 (1378) 378 (499) <0.001

PC

N patients (%) 26 (84) 13 (33) <0.001

Volume (ml) 1.8 (1.1) 0.6 (1.0) <0.001

Protamine sulfate

N patients (%) 22 (71) 15 (38) 0.008 Fibrinogen

N patients (%) 23 (74) 15 (38) 0.004

Dose (g) 3.7 (3.0) 1.2 (1.7) <0.001

raFVII

N patients (%) 2 (6) 2 (5) 1.000 Aminocaproic acid

N patients (%) 17 (55) 18 (45) 0.477

Dose (mg) 656 (709) 760 (907) 0.692

FFP: Fresh frozen plasma, PC: Platelet concentrate, PRBC: Packed red blood cell, raFVII: Recombinant activated factor VII

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patients.^[10,33‑35] Compared with CCTs, the viscoelastic hemostatic assays offer several advantages. Firstly, the POC tests are usually performed by trained anesthesia personnel in the operating theater and the turn‑around time is reduced to 10‑25 min instead of 90‑120 min with CCTs.^[12] Secondly, both ROTEM and TEG provide accurate assessment of the initiation, propagation and amplification of the clotting processes followed by fibrinolysis; both the intrinsic and extrinsic plasmatic pathways as well as the contribution of platelets corresponding to the cell‑based coagulation model are explored.^[36] Thirdly, in all clinical studies, viscoelastic hemostatic assays have been found superior to the CCTs in predicting subsequent bleeding and the need for reoperation.^[15,37‑40] Importantly, a Cochrane meta‑analysis of 9 randomized controlled trials found that ROTEM‑guided therapy resulted in lesser bleeding and reduced need for transfusing platelets and FFPs in patients undergoing liver transplantation or cardiac surgery.^[27] Finally, substituting or combining CCTs with TEG/ROTEM is a cost‑effective approach resulting in up to 50% cost savings in blood transfusion products in addition to sparing medical resources implicated in the treatment of transfusion‑related complications.^[41]

The current study confirms that fibrinogen is a key coagulation factor whose activity needs to be monitored and corrected during fluid resuscitation and surgery.^[42]

Pre‑operatively, the HB patients differed from the LB patients by their lower fibrinogen levels and weaker clot amplitude (MCF in EXTEM, FIBTEM and APTEM).

In agreement with our data, clot firmness and clot

amplitude (with EXTEM, INTEM and FIBTEM) have been found to best correlate with platelet function and fibrinogen levels.^[10,35,43] In one study involving liver transplantation, clot amplitude at 10 min exceeding 35 mm with EXTEM or exceeding 8 mm with FIBTEM was associated with efficient clot formation and a low probability of non‑surgical bleeding.^[44]

All preoperative abnormalities in ROTEM parameters reverted to normal at the end of surgery by adopting a goal‑directed hemostatic protocol. Consequently, larger amounts of fibrinogen, FFPs and platelets were needed in the HB group. Importantly, such hemostatic treatment was associated with lower than expected mortality (in both groups) and the three‑fold higher dose of fibrinogen in the HB group was not associated with an increased incidence of thromboembolic events. Interestingly, a decreased rate of thrombotic/thromboembolic events has even been reported by Gorlinger et al. after the implementation of a POC‑ROTEM algorithm using various coagulation factor concentrates in a large cohort of 3865 patients undergoing elective or emergent cardiovascular surgery (1.8% vs. 3.2%).^[45]

Several limitations of the study have to be acknowledged.

First, this study was performed at a single tertiary center and we analyzed a small sample of patients undergoing various procedures, with or without CPB; thus our results are not generalizable and they need to be replicated in other institutions and other surgical settings. Second, in its current version, the ROTEM device is not well suited to investigate platelet function;^[10,11] other POC device such as the Platelet Function Analyser (PFA‑100) and the multiple electrode platelet aggregometry (Multiplate™ Analyser) are now introduced in the perioperative field, enabling a quick and exhaustive assessment of platelet function and allowing individually guided therapy, particularly in the increasing number of patients taking antiplatelet drugs.^[36]

Third, we were unable to detect primary or secondary fibrinolysis since tranexamic acid was routinely administered in all cases requiring CPB. Finally, our ROTEM‑supported coagulation algorithm has not been validated previously; thus we are unable to identify the real impact of different hemostatic interventions that may contribute to improve outcome. Nevertheless, a strong body of knowledge support the benefit of a transfusion protocol in decreasing the need for transfusion.^[26] Other authors have emphasized the potential beneficial impact of replacing FFP with the administration of prothrombin complex concentrate and fibrinogen;^[45,46] however, there are few evidence‑based data and adverse events are likely underreported.^[47]

Table 5: Clinical outcome of patients at high risk of bleeding undergoing emergent cardiovascular surgery

transfused with >5 units PRBC n = 31

Patients transfused with <5 units PRBC n = 40

P

LOS in ICU (days) 9 (9) 8 (10) 0.497

LOS in hospital (days) 28 (21) 21 (19) 0.175

Mortality (%) 7 (22.6)* 2 (5.1) 0.036

Blood loss (>800 ml) (%) 6 (19) 5 (13) 0.516 Thrombo‑embolic event^#,^† (%) 2 (6) 2 (5) 1.000

Stroke (%) 3 (10) 0 (0) 0.079

Myocardial infarct (%) 3 (10) 0 (0) 0.079

Heart failure (%) 7 (23) 8 (21) 1.000

Arrhythmia (%) 13 (42) 13 (33) 0.462

ARDS (%) 0 (0) 3 (8) 0.251

Acute renal dysfunction* (%) 3 (10) 0 (0) 0.079

Infections^# (%) 7 (23) 3 (8) 0.092

PRBC: Packed red blood cell, LOS: Length of stay, ICU: Intensive care unit, ARDS: Acute respiratory distress syndrome. ^†Peripheral arterial and pulmonary embolism, venous thrombosis, *Post‑operative decrease in glomerular filtration rate >75%, ^#Pneumonia and wound infections

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CONCLUSION

We have demonstrated that, in contrast with CCTs, ROTEM derived parameters enable the clinicians to detect early coagulation defects and to normalize clot formation by implementing a goal‑directed hemostatic protocol with no increased risk of thromboembolic event. Given these favorable preliminary results, randomized controlled trials are required to ascertain the safety and effectiveness of specific hemostatic interventions based on POC‑coagulation devices.

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Cite this article as: Sartorius D, Waeber J, Pavlovic G, Frei A, Diaper J, Myers P, et al. Goal‑directed hemostatic therapy using the rotational thromboelastometry in patients requiring emergent cardiovascular surgery.

Ann Card Anaesth 2014;17:100‑8.

Source of Support: Nil, Conflict of Interest: None declared.

Invited Commentary

Point of care tests of coagulation – Have they come of age?

With astounding advances in the field of medicine, physicians are now able to manage patients who were considered inoperable a few years ago. Our cardiac surgical population is ever changing. Anesthesiologists are dealing with sicker and elderly patients who have multiple comorbidities and take newer antithrombotic and antiplatelet agents. When such patients are subjected to repeat, complex or emergency cardiac surgical procedures, perioperative bleeding takes the center stage. Acute blood loss leading to anemia and organ hypo‑perfusion is bad. Blood loss significant enough to trigger blood transfusion is even worse while a revisit to the operating room for bleeding is

worst. Vivacqua et al. showed that morbidity and mortality were lowest in patients who received no blood transfusion, higher for patients receiving blood transfusion but had no reoperation, higher still for those requiring reoperation but no blood transfusion, and highest among those who received blood transfusion and also a reoperation.^[1] To avoid indiscriminate use of allogeneic blood transfusion during severe perioperative bleeding, European Society of Anaesthesiology (ESA) guidelines^[2] strongly recommend the application of transfusion algorithms incorporating predefined intervention triggers to guide hemostatic intervention.

Perioperative bleeding is complex and multifactorial. In the majority of patients who were re‑explored for bleeding, the cause of bleeding was found to be surgical. Coagulopathy accounted for 23% of re‑explorations (coagulopathy alone in 13% while the combination of coagulopathy with surgical factors in another 10%).^[1] Defects in any stage of the hemostatic process (primary hemostasis, thrombin generation, clot formation, or fibrinolysis)