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Coagulation Derangements in Patients With Refractory Cardiac Arrest Treated With Extracorporeal Cardiopulmonary Resuscitation
ARTICLE IN PRESS Journal of Cardiothoracic and Vascular Anesthesia 000 (2018) 16
Contents lists available at ScienceDirect
Journal of Cardiothoracic and Vascular Anesthesia journal homepage: www.jcvaonline.com
Original Article
Coagulation Derangements in Patients With Refractory Cardiac Arrest Treated With Extracorporeal Cardiopulmonary Resuscitation D1X XLaura Ruggeri, D2X XMD, D3X XAnnalisa Franco, D4X XMD, D5X XAda Carla Alba, D6X XMD, D7X XRosalba Lembo, D8X XMSc, D9X XSamuele Frassoni, D10X XMSc, D1X XAnna Mara Scandroglio, D12X XMD, D13X XMaria Grazia Calabr o, D14X XMD, 1 D15X XAlberto ZangrilloD16X X, D17X XFederico PappalardoD18X X Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, Milan, Italy
Objective: Extracorporeal cardiopulmonary resuscitation (eCPR) with venoarterial extracorporeal membrane oxygenation (VA-ECMO) is gaining importance as a rescue therapy for refractory cardiac arrest. VA-ECMO, especially in the setting of eCPR, is plagued by hemorrhagic and thromboembolic complications. The authors’ aims were to describe the coagulation profile in refractory cardiac arrest and assess its prognostic role. Design: Single-center retrospective study. Setting: Cardiac surgical intensive care unit of a university hospital. Participants: One hundred eighty-eight patients treated with eCPR for intra-hospital and out-of-hospital refractory cardiac arrest, between 2008 and 2017. Interventions: The authors retrospectively analyzed data from the first blood sample drawn during cannulation for VA-ECMO to understand the association of coagulation parameters with survival to hospital discharge, number of blood components transfused, anticoagulation therapy, serum lactate levels, no-flow time, and low-flow time. Measurements and Main Results: Platelet count was 126 § 79 £ 109/L and in 17% of the population it was lower than 50 £ 109/L, prothrombin time was 3.22 § 4.01, activated partial thromboplastin time was 117 § 78 seconds, fibrinogen was 186 § 148 mg/dL, antithrombin was 47 § 16%, and D-dimer was 2-fold the normal upper limit in 95% of patients. Fifty percent of patients had a disseminated intravascular coagulation (DIC) score 6 (52% among out-of-hospital cardiac arrest, 33% among in-hospital cardiac arrest), according to the criteria of the Japanese Society on Thrombosis and Hemostasis (2016). The median DIC score was 5.5 points (interquartile range 4-8), significantly different between survivors and nonsurvivors (4 [3-6] v 6 [4-8], p = 0.007). Every DIC score point contributed to the mortality risk (OR 1.34, 95% CI 1.09-1.67, p = 0.006). Patients with overt DIC less frequently received anticoagulants (28.6% v 55.9%, p = 0.002), started anticoagulant therapy later (12 [10-23] v 8.5 [5-12] hours, p = 0.045), and received a larger quantity of blood products (11 [4-23] v 3 [0-8.5] units, p < 0.0001). Conclusion: Coagulation derangements are frequent in patients with refractory cardiac arrest and have important consequences for eCPR management for anticoagulant therapy and blood product transfusion. The presence of DIC diagnostic criteria should be considered among the prognostic factors in this population of patients. Ó 2018 Elsevier Inc. All rights reserved. Key Words: cardiac arrest; refractory cardiac arrest; disseminated intravascular coagulation; coagulation; extracorporeal cardiopulmonary resuscitation; extracorporeal membrane oxygenation
1
Address reprint requests to Federico Pappalardo, Associate Professor, Department of Anaesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, Via Olgettina 60, Milano, 20132 Italy. E-mail address: [email protected] (F. Pappalardo). https://doi.org/10.1053/j.jvca.2018.11.014 1053-0770/Ó 2018 Elsevier Inc. All rights reserved.
CARDIAC ARREST is a major health problem all over the world, as out-of-hospital cardiac arrest (OHCA) involves annually more than 420,000 people in the United States.1 Despite all the efforts to provide a better outcome to these
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patients through cardiopulmonary resuscitation, the survival rate is still very low, with approximately 10% of patients surviving for at least 30 days or to hospital discharge.1 Extracorporeal cardiopulmonary resuscitation (eCPR) plays an increasing role as rescue therapy for cardiac arrest with a better outcome compared to conventional cardiopulmonary resuscitation (CPR), when CPR is failing.24 Nevertheless, it is plagued by hemorrhagic and thromboembolic complications (38% and 21% of patients, respectively),5 which are more severe compared to venoarterial extracorporeal membrane oxygenation (VA-ECMO) alone, as numerous factors add to it (prolonged CPR, metabolic derangements, hypothermia). Coagulative dysfunctions are well described in patients resuscitated after cardiac arrest with return of spontaneous circulation (ROSC) through conventional CPR. However, no data about refractory cardiac arrest, nor eCPR approach, have been published, despite that coagulation is pivotal in this group of patients, owing to both the complications strictly related to extracorporeal membrane oxygenation (ECMO) and the coronary revascularization treatment, including antiplatelet drugs. In this retrospective study, the authors collected data about patients with refractory cardiac arrest before starting eCPR. The authors’ aim was, primarily, to describe the coagulation profile from the first blood sample drawn during cannulation and, secondly, to understand the association of coagulation parameters with survival to hospital discharge, number of blood components transfused, anticoagulation therapy, serum lactate levels, and no-flow time and low-flow time, considering the overall population and the subgroups of OHCA and intrahospital cardiac arrest (IHCA). Methods From 2008 to 2017, patients aged <75 years old with cardiac arrest refractory to advanced life support resuscitation (according to the current European Resuscitation Council Guidelines) were transferred to the authors’ intensive care unit under CPR by the local emergency medical service in case of OHCA or by the medical emergency team of the authors’ hospital in case of IHCA. In particular, patients were transferred in case of witnessed cardiac arrest, no-flow time <6 minutes and low-flow time <45 minutes, and EtCO2 >10 mmHg. Exclusion criteria were terminal malignancy, aortic dissection, peripheral arteriopathy, and severe aortic regurgitation. At hospital arrival, a rapid transesophageal echocardiographic assessment was performed to exclude any aortic pathologies (dissection or aneurysm rupture) or severe aortic regurgitation. Meanwhile, vascular accesses were obtained percutaneously, through the femoral artery and the femoral vein, under echographic guide. A ready-to-use preprimed heparin-free ECMO circuit was always available for emergency, and the perfusionist was available on call 24 hours a day. No anticoagulation was administered until bleeding was excluded and the coagulation profile was assessed fully; in cases of bleeding or high risk of bleeding, evaluated by clinical judgment, anticoagulant administration was deferred. Blood samples were collected at the time of cannulation. Coagulation parameters (prothrombin time international
normalized ratio (PT-INR), activated partial thromboplastin time, fibrinogen, antithrombin, D-dimer, full blood count) were tested. For disseminated intravascular coagulation (DIC) evaluation, the new criteria proposed by the Japanese Society on Thrombosis and Hemostasis were applied6 (Table 1). DIC was defined as a DIC score 6. Arterial blood gas analysis was performed as soon as available. Notes on clinical history, drugs, and time of no-flow and low-flow were taken. After the approval of the local ethical committee, data were collected in a dataset. In cases of coagulation values that resulted beyond the limits of laboratory detection, the following values were put in the dataset: 250 seconds for aPTT, 20 for PT-INR, and 40 mg/dL for fibrinogen. Patients receiving antiplatelets on top of acetylsalicylic acid and/or anticoagulant therapy were excluded from the analysis. Data were reported as counts and percentages for dichotomous and categorical variables, and as mean § standard deviation or median with interquartile range for continuous variables. Table 1 DIC Diagnostic Criteria DIC Diagnostic Criteria (Basic) Platelet count (£ 104/ml)
FDP (mg/mL)*
Fibrinogen (mg/dL) Prothrombin time INRy
Antithrombin (%) TAT, SF, or F1+2* Liver failurez DIC diagnosis
>12 8 < ¡ 12 5<¡8 5 30% decrease w/in 24 h <10 10 ¡ < 20 20 ¡ < 40 40 > 150 100 ¡ < 150 100 < 1.25 1.25 ¡ < 1.67 1.67 > 70 70 <2-fold of normal upper limit 2-fold of normal upper limit No Yes
0p 1p 2p 3p +1 p 0p 1p 2p 3p 0p 1p 2p 0p 1p 2p 0p 1p 0p 1p 0p ¡3 p 6 p
Modified from Asakura H, Takahashi H, Uchiyama T, et al. Proposal for new diagnostic criteria for DIC from the Japanese Society on Thrombosis and Hemostasis. Thromb J 2016;14:42. Abbreviations: DIC, disseminated intravascular coagulation; FDP, fibrin/ fibrinogen degradation products; INR, international normalized ratio; SF, soluble fibrin; TAT, thrombin-antithrombin complex; F1+2, prothrombin fragment 1+2. * For this retrospective study, FDP, TAT, SF, F1+2 were not available. The authors added 1 point when D-dimer was 2-fold the normal upper limit. y International sensitivity index of prothrombin time reagent use is close to 1.0 in our laboratory. z Liver failure was defined as “a prothrombin time activity of 40 % or an INR value of 1.5 owing to severe liver dysfunction seen within 8 weeks of onset of initial symptoms after liver impairment that develops in a normal liver or a liver that is thought to exhibit normal liver function” (acute liver failure) or “cirrhosis with a Child-Pugh classification of B or C (7 points)” (chronic liver failure) that may be viral or autoimmune in origin, drug-induced, or caused by circulatory failure.”
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A logistic regression model was developed to assess the association between the effect of DIC score and mortality. In the logistic regression, the DIC score is expressed as an odds ratio with 95% confidence interval. No multiple comparisons were made. Patients’ characteristics were compared using Student t test or Wilcoxon rank sum (Mann-Whitney) test, Fisher exact test or chi-square analysis. Correlation between variables was performed with Pearson’s test. Results From December 2008 to March 2017, 188 patients with refractory cardiac arrest were treated by the eCPR team in San Raffaele Hospital in Milan to undergo eCPR. The average age was 54 § 15 years. Five patients arrived severely hypothermic, being drowning (4 cases) or avalanche (1 case) victims. No-flow time was 6 § 9 minutes, while low-flow time was 61 § 31 minutes. In 25% of cases, cardiac arrest occurred in hospital, whereas in 75% of cases it occurred out of hospital. Hospital discharge survival rate was 12% in the overall population, 8% in OHCA, and 26% in IHCA, respectively (Fig 1). A ventricular assist device was implanted in 4 patients; among those, 1 survived until hospital discharge. Serum lactate levels were 17 § 9 mmol/L. Mean platelet count was 126 § 79 £ 109/L and in 17% of patients it was lower than 50 £ 109/L, PT-INR was 3.22 § 4.01, fibrinogen was 186 § 148 mg/dL, antithrombin was 47 § 16 %, D-dimer was increased 2-fold the normal upper limit in 95% of patients, and aPTT was 117 § 78 seconds. The median DIC score was 5.5 (interquartile range 4-8) (Table 2). Fifty percent of patients had DIC diagnosis criteria (57% among OHCA, 33% among IHCA). The DIC score was significantly higher in OHCA compared to IHCA (6 [4-8] v (4 [3-6], p = 0.003). The DIC score was significantly different between survivors and nonsurvivors (4 [3-6] v 6 [4-8], p = 0.007). Every DIC score point contributed to the mortality risk (odds ratio 1.35, 95% confidence interval 1.09-1.67, p = 0.006) (Fig 2). Anticoagulation was administered on average 15 § 18 hours after VA-ECMO implantation. Forty-four percent of patients received anticoagulants within the first 24 hours. DIC patients received anticoagulants less frequently (DIC patients 28.6%, no DIC patients 55.9%, p = 0.002), and started anticoagulant therapy later (12 [10-23] v 8.5 [5-12] hours, p = 0.045). Seventy-three percent of patients received blood products in the first 24 hours; median units transfused was 6 (1-17). DIC patients received a larger quantity of blood component transfusions (11 [4-23] v 3 [0-8.5] units, p < 0.0001). The correlations between serum lactate levels and DIC score, no-flow time and DIC score, and low-flow time and DIC score are presented in Figures 3, 4, and 5.
3
Selection criteria for eCPR: witnessed cardiac arrest no-flow time < 6 minutes low-flow time < 45 minutes etCO2 > 10mmHg Contraindications (at least one of the following): terminal malignancy aortic dissection peripheral arteriopathy severe aortic regurgitation
Patients treated with eCPR n=188 (OHCA 75%) (IHCA 25%)
30-days survival n=29 (10% of OHCA population) (32% of IHCA population)
Hospital discharge n=24 (8% of OHCA population) (26% of IHCA population) Fig 1. Patients’ flow. eCPR, extracorporeal cardiopulmonary resuscitation; OHCA, out of hospital cardiac arrest; IHCA, intra-hospital cardiac arrest.
Table 2 Coagulation Values in Overall Population Coagulation values (units of measurement) Platelet count (109/L) PT-INR Fibrinogen (mg/dL) Antithrombin (%) aPTT (s) DIC score (points)
126 § 79 3.22 § 4.01 186 § 148 47 § 16 117 § 78 5.5 § 2.5
NOTE: Data are presented as media and standard deviation. Abbreviations: aPTT, activated partial thromboplastin time; DIC, disseminated intravascular coagulation; PT-INR, prothrombin time international normalized ratio.
Discussion This retrospective study evaluated the coagulation profile in 188 patients with refractory cardiac arrest at the time of cannulation for eCPR.
Coagulation parameters were altered in most of the patients, with a considerable prevalence of DIC among this population and a prolonged average aPTT. The DIC score was significantly
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Fig 2. Patients’ number showed according to the DIC score and outcomes (survival, death and organ donation). DIC, disseminated intravascular coagulation.
Fig 5. Pearson’s test correlation between low-flow time and DIC score: 0.26 (p = 0.0012). DIC, disseminated intravascular coagulation.
Fig 3. Pearson’s test correlation between serum lactate levels and DIC score: 0.25 (p = 0.017). DIC, disseminated intravascular coagulation.
Fig 4. Pearson’s test correlation between no-flow time and DIC score: 0.23 (p = 0.0041). DIC, disseminated intravascular coagulation.
higher in nonsurvivors. Every DIC score point contributed to the mortality risk. eCPR management was different according to the DIC score, as DIC patients less frequently received anticoagulation in the first 24 hours and started anticoagulant therapy later. Moreover, DIC patients received a larger amount of
blood product transfusions. Surprisingly, the correlations between the DIC score and the lactate levels, the no-flow time, and the low-flow time were very weak, being the results of Pearson’s test 0.25 (p = 0.017), 0.23 (p = 0.0041), and 0.26 (p = 0.0012), respectively; thus those factors do not seem to account for the gravity of the coagulopathy. To the authors’ knowledge, this is the first description of the coagulation profile in patients with cardiac arrest refractory to advanced life support2 including an evaluation of the therapeutic implications. The timing of blood sample collection is a key advantage of this study, as the values are not influenced by the interaction between the patient and the ECMO circuit, thus representing the extreme consequence of the ischemic injury on the coagulation system. The authors’ results are consistent with the findings of changes in blood coagulation after cardiac arrest already described by other authors. Adrie et al.7 investigated the implication of the protein C anticoagulant pathway in 67 patients affected by OHCA having ROSC after a variable time. Patients had an activation of the inflammatory response (increased interleukin-6) and coagulation activity (thrombinantithrombin complex), reduced anticoagulation (antithrombin, protein C, and protein S), and activated or inhibited fibrinolysis. These abnormalities were more severe in patients who died from early refractory shock. Massive fibrin generation, especially in the first 24 hours after OHCA, was found by Gando et al.8 Increased levels of thrombin-antithrombin complexes were observed by Hostler et al. in a similar population.9 Wada et al. published data about DIC in OHCA patients with ROSC and found that 208 of 388 patients (54%) were in DIC status within 24 hours after cardiac arrest. In their study, DIC patients experienced a worse outcome compared to nonDIC patients, and DIC was found to be an independent predictor of mortality.10 Similarly, Kim et al. analyzed patients with ROSC after OHCA and found a prevalence of DIC of 33%; moreover, the DIC score was an independent predictor of poor outcome and early mortality risk.11 The prognostic value of the DIC score was confirmed by Ono et al., who studied 315 OHCA patients with successful ROSC and found that, except
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for fibrinogen level, all coagulation variables, fibrinolytic variables, and the DIC score were associated with neurological outcomes.12 Lee et al. confirmed these findings, studying 317 patients with cardiac arrest after ROSC: the DIC score was a significant predictor for poor neurologic outcome and 6-month mortality.13 In these studies, the prevalence of DIC and its connection with the prognosis are quite similar to those presented in the authors’ series; nevertheless, the clinical implication of coagulation impairment is dramatically different in the case of eCPR compared to standard treatment, with the no-/low-flow times, metabolic derangements, and pathophysiology of ECMO being far more severe. In the setting of eCPR, the consequence of coagulation derangements for bleeding and anticoagulation should be considered carefully because major bleeding and thrombotic complications are described frequently and life-threatening.5 Further studies should be dedicated to the interaction between the massive coagulation derangements and the antiplatelet therapy that part of these patients receive, with coronary occlusion as the reason for the cardiac arrest. While the platelet function after cardiac arrest will be the object of a future trial,14 the authors’ data described how not only the platelets but all the coagulation cascade is profoundly altered, leading, in most cases, to severe bleeding, with 73% of patients transfused with a high amount of blood products in the first 24 hours. Nevertheless, this series refers to a particular group of patients with nonresponsive cardiac arrest, although literature about patients who had ROSC seems to go in the same direction. Therefore, data to balance the hemorrhagic risk that some cardiac arrest patients present with the benefits of coronary revascularization are advocated, expecially in the setting of eCPR, where timing and management of percutaneous coronary intervention are not straighforward. Many authors suggest a possible implication of different coagulative profiles, for example a profibrinolytic or antifibrinolytic profile, in the prognosis of patients with cardiac arrest. Viersen et al. performed a rotational thromboelastometry (ROTEM) test at emergency department admission in 30 OHCA patients and found that a substantial portion of them (53%) developed hyperfibrinolysis in association with markers of hypoperfusion.15 Schochl et al. studied coagulation in 53 OHCA patients, through ROTEM in blood samples taken out of hospital: PTI, activated partial thromboplastin time, and EXTEM computed tomography revealed significant differences between ROSC and non-ROSC patients. Hyperfibrinolysis, according to ROTEM test results, was very common (35.8%).16 Wada et al. recently published that among DIC patients, hyperfibrinolysis was associated with a worse outcome and that lactate levels predicted hyperfibrinolysis.10 Interestingly, hyperfibrinolysis seemed to be the coagulative profile after unsuccessful resuscitation in organ donors after circulatory determination of death.17 According to these findings, evaluating the fibrinolytic profile could offer more detailed prognostic datum in cardiac arrest patients. Moreover, groups of patients with different coagulative profiles could be treated accordingly, as antifibrinolytic therapies could be considered in particular cases.18 Unfortunately, the authors cannot
5
speculate about the coagulation profile of patients involved in the study, because data were not available. Another important aspect is the pathophysiological interaction between the coagulopathy and the ECMO circuit.19 In fact, the contact of blood with the surfaces of the extracorporeal circuit causes platelets activation and release of coagulation factors, an activation of the complement system, and an inflammatory response. As a result, procoagulant as well as fibrinolytic and anticoagulant processes are described. These alterations could be even more pronounced in the presence of the severe coagulation impairment present before ECMO implantation, described by the authors’ results. This study had several limitations, being a retrospective singlecenter design. In fact, although dealing with a considerable number of patients treated with eCPR, the authors’ results need further confirmation through larger prospective studies. The DIC score was calculated using D-dimer values instead of fibrin/ fibrinogen degradation products, which could have given an even more precise point allocation. It was not possible to address the role of concomitant medication because of the emergency setting. Similarly, data on temperature at arrival were not available. The lack of data on the neurologic outcome was a strong limitation of this work. Nevertheless, this is the first description of coagulation derangements in patients with refractory cardiac arrest and reports implications for eCPR management. In conclusion, the data show that coagulation derangements are very frequent in patients with refractory cardiac arrest and have important consequences for the management of eCPR for anticoagulant therapy and blood product transfusion. The DIC score should be considered a prognostic factor in this population of patients. References 1 Gr€asner JT, Lefering R, Koster RW, et al. EuReCa ONE-27 Nations, ONE Europe, ONE Registry: A prospective one month analysis of out-of-hospital cardiac arrest outcomes in 27 countries in Europe. Resuscitation 2016;105:188–95. 2 Soar J, Callaway CW, Aibiki M, et al. Advanced life support: 2015 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science with Treatment Recommendations. Resuscitation 2015;95:71–120. 3 Chen YS, Lin JW, Yu HY, et al. Cardiopulmonary resuscitation with assisted extracorporeal life-support versus conventional cardiopulmonary resuscitation in adults with in-hospital cardiac arrest: An observational study and propensity analysis. Lancet 2008;372:554–61. 4 Kim SJ, Kim HJ, Lee HY, Ahn HS, Lee SW. Comparing extracorporeal cardiopulmonary resuscitation with conventional cardiopulmonary resuscitation: A meta-analysis. Resuscitation 2016;103:106–16. 5 Dennis M, McCanny P, D’Souza M, et al. Extracorporeal cardiopulmonary resuscitation for refractory cardiac arrest: A multicentre experience. Int J Cardiol 2017;231:131–6. 6 Asakura H, Takahashi H, Uchiyama T, et al. Proposal for new diagnostic criteria for DIC from the Japanese Society on Thrombosis and Hemostasis. Thromb J 2016;14:42. 7 Adrie C, Monchi M, Laurent I, et al. Coagulopathy after successful cardiopulmonary resuscitation following cardiac arrest: implication of the protein C anticoagulant pathway. J Am Coll Cardiol 2005;46:21–8. 8 Gando S, Kameue T, Nanzaki S, Nakanishi Y. Massive fibrin formation with consecutive impairment of fibrinolysis in patients with out-of-hospital cardiac arrest. Thromb Haemost 1997;77:278–82.
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9 Hostler D, Callaway CW, Newman DH, D’Cruz B. Thrombin-antithrombin appearance in out-of-hospital cardiac arrest. Prehosp Emerg Care 2007; 11:9–13. 10 Wada T, Gando S, Ono Y, et al. A disseminated intravascular coagulation with the fibrinolytic phenotype predicts the outcome of patients with out-of-hospital cardiac arrest. Thromb J 2016;14:43. 11 Kim J, Kim K, Lee JH, et al. Prognostic implication of initial coagulopathy in out-of-hospital cardiac arrest. Resuscitation 2013;84:48–53. 12 Ono Y, Hayakawa M, Maekawa K, et al. Fibrin/fibrinogen degradation products (FDP) at hospital admission predict neurological outcomes in outof-hospital cardiac arrest patients. Resuscitation 2017;111:62–7. 13 Lee DH, Lee BK, Jeung KW, et al. Disseminated intravascular coagulation is associated with the neurologic outcome of cardiac arrest survivors. Am J Emerg Med 2017;35:1617–23. 14 Skorko A, Thomas M, Mumford A, et al. Research protocol for platelets in out-of-hospital cardiac arrest: an observational, case-controlled, feasibility study to assess coagulation and platelet function abnormalities with
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ROTEM following out-of-hospital cardiac arrest (PoHCAR). BMJ Open 2017;7. Viersen VA, Greuters S, Korfage AR, et al. Hyperfibrinolysis in out of hospital cardiac arrest is associated with markers of hypoperfusion. Resuscitation 2012;83:1451–5. Sch€ochl H, Cadamuro J, Seidl S, et al. Hyperfibrinolysis is common in out-of-hospital cardiac arrest: Results from a prospective observational thromboelastometry study. Resuscitation 2013;84:454–9. Vendrell M, Hessheimer AJ, Ruiz A, et al. Coagulation profiles of unexpected DCDD donors do not indicate a role for exogenous fibrinolysis. Am J Transplant 2015;15:764–71. Buckley LF, Reardon DP, Camp PC, et al. Aminocaproic acid for the management of bleeding in patients on extracorporeal membrane oxygenation: Four adult case reports and a review of the literature. Heart Lung 2016;45:232–6. Weidman JL, Shook DC, Hilberath JN. Cardiac resuscitation and coagulation. Anesthesiology 2014;120:1009–14.
Contents lists available at ScienceDirect
Journal of Cardiothoracic and Vascular Anesthesia journal homepage: www.jcvaonline.com
Original Article
Coagulation Derangements in Patients With Refractory Cardiac Arrest Treated With Extracorporeal Cardiopulmonary Resuscitation D1X XLaura Ruggeri, D2X XMD, D3X XAnnalisa Franco, D4X XMD, D5X XAda Carla Alba, D6X XMD, D7X XRosalba Lembo, D8X XMSc, D9X XSamuele Frassoni, D10X XMSc, D1X XAnna Mara Scandroglio, D12X XMD, D13X XMaria Grazia Calabr o, D14X XMD, 1 D15X XAlberto ZangrilloD16X X, D17X XFederico PappalardoD18X X Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, Milan, Italy
Objective: Extracorporeal cardiopulmonary resuscitation (eCPR) with venoarterial extracorporeal membrane oxygenation (VA-ECMO) is gaining importance as a rescue therapy for refractory cardiac arrest. VA-ECMO, especially in the setting of eCPR, is plagued by hemorrhagic and thromboembolic complications. The authors’ aims were to describe the coagulation profile in refractory cardiac arrest and assess its prognostic role. Design: Single-center retrospective study. Setting: Cardiac surgical intensive care unit of a university hospital. Participants: One hundred eighty-eight patients treated with eCPR for intra-hospital and out-of-hospital refractory cardiac arrest, between 2008 and 2017. Interventions: The authors retrospectively analyzed data from the first blood sample drawn during cannulation for VA-ECMO to understand the association of coagulation parameters with survival to hospital discharge, number of blood components transfused, anticoagulation therapy, serum lactate levels, no-flow time, and low-flow time. Measurements and Main Results: Platelet count was 126 § 79 £ 109/L and in 17% of the population it was lower than 50 £ 109/L, prothrombin time was 3.22 § 4.01, activated partial thromboplastin time was 117 § 78 seconds, fibrinogen was 186 § 148 mg/dL, antithrombin was 47 § 16%, and D-dimer was 2-fold the normal upper limit in 95% of patients. Fifty percent of patients had a disseminated intravascular coagulation (DIC) score 6 (52% among out-of-hospital cardiac arrest, 33% among in-hospital cardiac arrest), according to the criteria of the Japanese Society on Thrombosis and Hemostasis (2016). The median DIC score was 5.5 points (interquartile range 4-8), significantly different between survivors and nonsurvivors (4 [3-6] v 6 [4-8], p = 0.007). Every DIC score point contributed to the mortality risk (OR 1.34, 95% CI 1.09-1.67, p = 0.006). Patients with overt DIC less frequently received anticoagulants (28.6% v 55.9%, p = 0.002), started anticoagulant therapy later (12 [10-23] v 8.5 [5-12] hours, p = 0.045), and received a larger quantity of blood products (11 [4-23] v 3 [0-8.5] units, p < 0.0001). Conclusion: Coagulation derangements are frequent in patients with refractory cardiac arrest and have important consequences for eCPR management for anticoagulant therapy and blood product transfusion. The presence of DIC diagnostic criteria should be considered among the prognostic factors in this population of patients. Ó 2018 Elsevier Inc. All rights reserved. Key Words: cardiac arrest; refractory cardiac arrest; disseminated intravascular coagulation; coagulation; extracorporeal cardiopulmonary resuscitation; extracorporeal membrane oxygenation
1
Address reprint requests to Federico Pappalardo, Associate Professor, Department of Anaesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, Via Olgettina 60, Milano, 20132 Italy. E-mail address: [email protected] (F. Pappalardo). https://doi.org/10.1053/j.jvca.2018.11.014 1053-0770/Ó 2018 Elsevier Inc. All rights reserved.
CARDIAC ARREST is a major health problem all over the world, as out-of-hospital cardiac arrest (OHCA) involves annually more than 420,000 people in the United States.1 Despite all the efforts to provide a better outcome to these
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patients through cardiopulmonary resuscitation, the survival rate is still very low, with approximately 10% of patients surviving for at least 30 days or to hospital discharge.1 Extracorporeal cardiopulmonary resuscitation (eCPR) plays an increasing role as rescue therapy for cardiac arrest with a better outcome compared to conventional cardiopulmonary resuscitation (CPR), when CPR is failing.24 Nevertheless, it is plagued by hemorrhagic and thromboembolic complications (38% and 21% of patients, respectively),5 which are more severe compared to venoarterial extracorporeal membrane oxygenation (VA-ECMO) alone, as numerous factors add to it (prolonged CPR, metabolic derangements, hypothermia). Coagulative dysfunctions are well described in patients resuscitated after cardiac arrest with return of spontaneous circulation (ROSC) through conventional CPR. However, no data about refractory cardiac arrest, nor eCPR approach, have been published, despite that coagulation is pivotal in this group of patients, owing to both the complications strictly related to extracorporeal membrane oxygenation (ECMO) and the coronary revascularization treatment, including antiplatelet drugs. In this retrospective study, the authors collected data about patients with refractory cardiac arrest before starting eCPR. The authors’ aim was, primarily, to describe the coagulation profile from the first blood sample drawn during cannulation and, secondly, to understand the association of coagulation parameters with survival to hospital discharge, number of blood components transfused, anticoagulation therapy, serum lactate levels, and no-flow time and low-flow time, considering the overall population and the subgroups of OHCA and intrahospital cardiac arrest (IHCA). Methods From 2008 to 2017, patients aged <75 years old with cardiac arrest refractory to advanced life support resuscitation (according to the current European Resuscitation Council Guidelines) were transferred to the authors’ intensive care unit under CPR by the local emergency medical service in case of OHCA or by the medical emergency team of the authors’ hospital in case of IHCA. In particular, patients were transferred in case of witnessed cardiac arrest, no-flow time <6 minutes and low-flow time <45 minutes, and EtCO2 >10 mmHg. Exclusion criteria were terminal malignancy, aortic dissection, peripheral arteriopathy, and severe aortic regurgitation. At hospital arrival, a rapid transesophageal echocardiographic assessment was performed to exclude any aortic pathologies (dissection or aneurysm rupture) or severe aortic regurgitation. Meanwhile, vascular accesses were obtained percutaneously, through the femoral artery and the femoral vein, under echographic guide. A ready-to-use preprimed heparin-free ECMO circuit was always available for emergency, and the perfusionist was available on call 24 hours a day. No anticoagulation was administered until bleeding was excluded and the coagulation profile was assessed fully; in cases of bleeding or high risk of bleeding, evaluated by clinical judgment, anticoagulant administration was deferred. Blood samples were collected at the time of cannulation. Coagulation parameters (prothrombin time international
normalized ratio (PT-INR), activated partial thromboplastin time, fibrinogen, antithrombin, D-dimer, full blood count) were tested. For disseminated intravascular coagulation (DIC) evaluation, the new criteria proposed by the Japanese Society on Thrombosis and Hemostasis were applied6 (Table 1). DIC was defined as a DIC score 6. Arterial blood gas analysis was performed as soon as available. Notes on clinical history, drugs, and time of no-flow and low-flow were taken. After the approval of the local ethical committee, data were collected in a dataset. In cases of coagulation values that resulted beyond the limits of laboratory detection, the following values were put in the dataset: 250 seconds for aPTT, 20 for PT-INR, and 40 mg/dL for fibrinogen. Patients receiving antiplatelets on top of acetylsalicylic acid and/or anticoagulant therapy were excluded from the analysis. Data were reported as counts and percentages for dichotomous and categorical variables, and as mean § standard deviation or median with interquartile range for continuous variables. Table 1 DIC Diagnostic Criteria DIC Diagnostic Criteria (Basic) Platelet count (£ 104/ml)
FDP (mg/mL)*
Fibrinogen (mg/dL) Prothrombin time INRy
Antithrombin (%) TAT, SF, or F1+2* Liver failurez DIC diagnosis
>12 8 < ¡ 12 5<¡8 5 30% decrease w/in 24 h <10 10 ¡ < 20 20 ¡ < 40 40 > 150 100 ¡ < 150 100 < 1.25 1.25 ¡ < 1.67 1.67 > 70 70 <2-fold of normal upper limit 2-fold of normal upper limit No Yes
0p 1p 2p 3p +1 p 0p 1p 2p 3p 0p 1p 2p 0p 1p 2p 0p 1p 0p 1p 0p ¡3 p 6 p
Modified from Asakura H, Takahashi H, Uchiyama T, et al. Proposal for new diagnostic criteria for DIC from the Japanese Society on Thrombosis and Hemostasis. Thromb J 2016;14:42. Abbreviations: DIC, disseminated intravascular coagulation; FDP, fibrin/ fibrinogen degradation products; INR, international normalized ratio; SF, soluble fibrin; TAT, thrombin-antithrombin complex; F1+2, prothrombin fragment 1+2. * For this retrospective study, FDP, TAT, SF, F1+2 were not available. The authors added 1 point when D-dimer was 2-fold the normal upper limit. y International sensitivity index of prothrombin time reagent use is close to 1.0 in our laboratory. z Liver failure was defined as “a prothrombin time activity of 40 % or an INR value of 1.5 owing to severe liver dysfunction seen within 8 weeks of onset of initial symptoms after liver impairment that develops in a normal liver or a liver that is thought to exhibit normal liver function” (acute liver failure) or “cirrhosis with a Child-Pugh classification of B or C (7 points)” (chronic liver failure) that may be viral or autoimmune in origin, drug-induced, or caused by circulatory failure.”
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A logistic regression model was developed to assess the association between the effect of DIC score and mortality. In the logistic regression, the DIC score is expressed as an odds ratio with 95% confidence interval. No multiple comparisons were made. Patients’ characteristics were compared using Student t test or Wilcoxon rank sum (Mann-Whitney) test, Fisher exact test or chi-square analysis. Correlation between variables was performed with Pearson’s test. Results From December 2008 to March 2017, 188 patients with refractory cardiac arrest were treated by the eCPR team in San Raffaele Hospital in Milan to undergo eCPR. The average age was 54 § 15 years. Five patients arrived severely hypothermic, being drowning (4 cases) or avalanche (1 case) victims. No-flow time was 6 § 9 minutes, while low-flow time was 61 § 31 minutes. In 25% of cases, cardiac arrest occurred in hospital, whereas in 75% of cases it occurred out of hospital. Hospital discharge survival rate was 12% in the overall population, 8% in OHCA, and 26% in IHCA, respectively (Fig 1). A ventricular assist device was implanted in 4 patients; among those, 1 survived until hospital discharge. Serum lactate levels were 17 § 9 mmol/L. Mean platelet count was 126 § 79 £ 109/L and in 17% of patients it was lower than 50 £ 109/L, PT-INR was 3.22 § 4.01, fibrinogen was 186 § 148 mg/dL, antithrombin was 47 § 16 %, D-dimer was increased 2-fold the normal upper limit in 95% of patients, and aPTT was 117 § 78 seconds. The median DIC score was 5.5 (interquartile range 4-8) (Table 2). Fifty percent of patients had DIC diagnosis criteria (57% among OHCA, 33% among IHCA). The DIC score was significantly higher in OHCA compared to IHCA (6 [4-8] v (4 [3-6], p = 0.003). The DIC score was significantly different between survivors and nonsurvivors (4 [3-6] v 6 [4-8], p = 0.007). Every DIC score point contributed to the mortality risk (odds ratio 1.35, 95% confidence interval 1.09-1.67, p = 0.006) (Fig 2). Anticoagulation was administered on average 15 § 18 hours after VA-ECMO implantation. Forty-four percent of patients received anticoagulants within the first 24 hours. DIC patients received anticoagulants less frequently (DIC patients 28.6%, no DIC patients 55.9%, p = 0.002), and started anticoagulant therapy later (12 [10-23] v 8.5 [5-12] hours, p = 0.045). Seventy-three percent of patients received blood products in the first 24 hours; median units transfused was 6 (1-17). DIC patients received a larger quantity of blood component transfusions (11 [4-23] v 3 [0-8.5] units, p < 0.0001). The correlations between serum lactate levels and DIC score, no-flow time and DIC score, and low-flow time and DIC score are presented in Figures 3, 4, and 5.
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Selection criteria for eCPR: witnessed cardiac arrest no-flow time < 6 minutes low-flow time < 45 minutes etCO2 > 10mmHg Contraindications (at least one of the following): terminal malignancy aortic dissection peripheral arteriopathy severe aortic regurgitation
Patients treated with eCPR n=188 (OHCA 75%) (IHCA 25%)
30-days survival n=29 (10% of OHCA population) (32% of IHCA population)
Hospital discharge n=24 (8% of OHCA population) (26% of IHCA population) Fig 1. Patients’ flow. eCPR, extracorporeal cardiopulmonary resuscitation; OHCA, out of hospital cardiac arrest; IHCA, intra-hospital cardiac arrest.
Table 2 Coagulation Values in Overall Population Coagulation values (units of measurement) Platelet count (109/L) PT-INR Fibrinogen (mg/dL) Antithrombin (%) aPTT (s) DIC score (points)
126 § 79 3.22 § 4.01 186 § 148 47 § 16 117 § 78 5.5 § 2.5
NOTE: Data are presented as media and standard deviation. Abbreviations: aPTT, activated partial thromboplastin time; DIC, disseminated intravascular coagulation; PT-INR, prothrombin time international normalized ratio.
Discussion This retrospective study evaluated the coagulation profile in 188 patients with refractory cardiac arrest at the time of cannulation for eCPR.
Coagulation parameters were altered in most of the patients, with a considerable prevalence of DIC among this population and a prolonged average aPTT. The DIC score was significantly
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Fig 2. Patients’ number showed according to the DIC score and outcomes (survival, death and organ donation). DIC, disseminated intravascular coagulation.
Fig 5. Pearson’s test correlation between low-flow time and DIC score: 0.26 (p = 0.0012). DIC, disseminated intravascular coagulation.
Fig 3. Pearson’s test correlation between serum lactate levels and DIC score: 0.25 (p = 0.017). DIC, disseminated intravascular coagulation.
Fig 4. Pearson’s test correlation between no-flow time and DIC score: 0.23 (p = 0.0041). DIC, disseminated intravascular coagulation.
higher in nonsurvivors. Every DIC score point contributed to the mortality risk. eCPR management was different according to the DIC score, as DIC patients less frequently received anticoagulation in the first 24 hours and started anticoagulant therapy later. Moreover, DIC patients received a larger amount of
blood product transfusions. Surprisingly, the correlations between the DIC score and the lactate levels, the no-flow time, and the low-flow time were very weak, being the results of Pearson’s test 0.25 (p = 0.017), 0.23 (p = 0.0041), and 0.26 (p = 0.0012), respectively; thus those factors do not seem to account for the gravity of the coagulopathy. To the authors’ knowledge, this is the first description of the coagulation profile in patients with cardiac arrest refractory to advanced life support2 including an evaluation of the therapeutic implications. The timing of blood sample collection is a key advantage of this study, as the values are not influenced by the interaction between the patient and the ECMO circuit, thus representing the extreme consequence of the ischemic injury on the coagulation system. The authors’ results are consistent with the findings of changes in blood coagulation after cardiac arrest already described by other authors. Adrie et al.7 investigated the implication of the protein C anticoagulant pathway in 67 patients affected by OHCA having ROSC after a variable time. Patients had an activation of the inflammatory response (increased interleukin-6) and coagulation activity (thrombinantithrombin complex), reduced anticoagulation (antithrombin, protein C, and protein S), and activated or inhibited fibrinolysis. These abnormalities were more severe in patients who died from early refractory shock. Massive fibrin generation, especially in the first 24 hours after OHCA, was found by Gando et al.8 Increased levels of thrombin-antithrombin complexes were observed by Hostler et al. in a similar population.9 Wada et al. published data about DIC in OHCA patients with ROSC and found that 208 of 388 patients (54%) were in DIC status within 24 hours after cardiac arrest. In their study, DIC patients experienced a worse outcome compared to nonDIC patients, and DIC was found to be an independent predictor of mortality.10 Similarly, Kim et al. analyzed patients with ROSC after OHCA and found a prevalence of DIC of 33%; moreover, the DIC score was an independent predictor of poor outcome and early mortality risk.11 The prognostic value of the DIC score was confirmed by Ono et al., who studied 315 OHCA patients with successful ROSC and found that, except
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for fibrinogen level, all coagulation variables, fibrinolytic variables, and the DIC score were associated with neurological outcomes.12 Lee et al. confirmed these findings, studying 317 patients with cardiac arrest after ROSC: the DIC score was a significant predictor for poor neurologic outcome and 6-month mortality.13 In these studies, the prevalence of DIC and its connection with the prognosis are quite similar to those presented in the authors’ series; nevertheless, the clinical implication of coagulation impairment is dramatically different in the case of eCPR compared to standard treatment, with the no-/low-flow times, metabolic derangements, and pathophysiology of ECMO being far more severe. In the setting of eCPR, the consequence of coagulation derangements for bleeding and anticoagulation should be considered carefully because major bleeding and thrombotic complications are described frequently and life-threatening.5 Further studies should be dedicated to the interaction between the massive coagulation derangements and the antiplatelet therapy that part of these patients receive, with coronary occlusion as the reason for the cardiac arrest. While the platelet function after cardiac arrest will be the object of a future trial,14 the authors’ data described how not only the platelets but all the coagulation cascade is profoundly altered, leading, in most cases, to severe bleeding, with 73% of patients transfused with a high amount of blood products in the first 24 hours. Nevertheless, this series refers to a particular group of patients with nonresponsive cardiac arrest, although literature about patients who had ROSC seems to go in the same direction. Therefore, data to balance the hemorrhagic risk that some cardiac arrest patients present with the benefits of coronary revascularization are advocated, expecially in the setting of eCPR, where timing and management of percutaneous coronary intervention are not straighforward. Many authors suggest a possible implication of different coagulative profiles, for example a profibrinolytic or antifibrinolytic profile, in the prognosis of patients with cardiac arrest. Viersen et al. performed a rotational thromboelastometry (ROTEM) test at emergency department admission in 30 OHCA patients and found that a substantial portion of them (53%) developed hyperfibrinolysis in association with markers of hypoperfusion.15 Schochl et al. studied coagulation in 53 OHCA patients, through ROTEM in blood samples taken out of hospital: PTI, activated partial thromboplastin time, and EXTEM computed tomography revealed significant differences between ROSC and non-ROSC patients. Hyperfibrinolysis, according to ROTEM test results, was very common (35.8%).16 Wada et al. recently published that among DIC patients, hyperfibrinolysis was associated with a worse outcome and that lactate levels predicted hyperfibrinolysis.10 Interestingly, hyperfibrinolysis seemed to be the coagulative profile after unsuccessful resuscitation in organ donors after circulatory determination of death.17 According to these findings, evaluating the fibrinolytic profile could offer more detailed prognostic datum in cardiac arrest patients. Moreover, groups of patients with different coagulative profiles could be treated accordingly, as antifibrinolytic therapies could be considered in particular cases.18 Unfortunately, the authors cannot
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speculate about the coagulation profile of patients involved in the study, because data were not available. Another important aspect is the pathophysiological interaction between the coagulopathy and the ECMO circuit.19 In fact, the contact of blood with the surfaces of the extracorporeal circuit causes platelets activation and release of coagulation factors, an activation of the complement system, and an inflammatory response. As a result, procoagulant as well as fibrinolytic and anticoagulant processes are described. These alterations could be even more pronounced in the presence of the severe coagulation impairment present before ECMO implantation, described by the authors’ results. This study had several limitations, being a retrospective singlecenter design. In fact, although dealing with a considerable number of patients treated with eCPR, the authors’ results need further confirmation through larger prospective studies. The DIC score was calculated using D-dimer values instead of fibrin/ fibrinogen degradation products, which could have given an even more precise point allocation. It was not possible to address the role of concomitant medication because of the emergency setting. Similarly, data on temperature at arrival were not available. The lack of data on the neurologic outcome was a strong limitation of this work. Nevertheless, this is the first description of coagulation derangements in patients with refractory cardiac arrest and reports implications for eCPR management. In conclusion, the data show that coagulation derangements are very frequent in patients with refractory cardiac arrest and have important consequences for the management of eCPR for anticoagulant therapy and blood product transfusion. The DIC score should be considered a prognostic factor in this population of patients. References 1 Gr€asner JT, Lefering R, Koster RW, et al. EuReCa ONE-27 Nations, ONE Europe, ONE Registry: A prospective one month analysis of out-of-hospital cardiac arrest outcomes in 27 countries in Europe. Resuscitation 2016;105:188–95. 2 Soar J, Callaway CW, Aibiki M, et al. Advanced life support: 2015 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science with Treatment Recommendations. Resuscitation 2015;95:71–120. 3 Chen YS, Lin JW, Yu HY, et al. Cardiopulmonary resuscitation with assisted extracorporeal life-support versus conventional cardiopulmonary resuscitation in adults with in-hospital cardiac arrest: An observational study and propensity analysis. Lancet 2008;372:554–61. 4 Kim SJ, Kim HJ, Lee HY, Ahn HS, Lee SW. Comparing extracorporeal cardiopulmonary resuscitation with conventional cardiopulmonary resuscitation: A meta-analysis. Resuscitation 2016;103:106–16. 5 Dennis M, McCanny P, D’Souza M, et al. Extracorporeal cardiopulmonary resuscitation for refractory cardiac arrest: A multicentre experience. Int J Cardiol 2017;231:131–6. 6 Asakura H, Takahashi H, Uchiyama T, et al. Proposal for new diagnostic criteria for DIC from the Japanese Society on Thrombosis and Hemostasis. Thromb J 2016;14:42. 7 Adrie C, Monchi M, Laurent I, et al. Coagulopathy after successful cardiopulmonary resuscitation following cardiac arrest: implication of the protein C anticoagulant pathway. J Am Coll Cardiol 2005;46:21–8. 8 Gando S, Kameue T, Nanzaki S, Nakanishi Y. Massive fibrin formation with consecutive impairment of fibrinolysis in patients with out-of-hospital cardiac arrest. Thromb Haemost 1997;77:278–82.
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9 Hostler D, Callaway CW, Newman DH, D’Cruz B. Thrombin-antithrombin appearance in out-of-hospital cardiac arrest. Prehosp Emerg Care 2007; 11:9–13. 10 Wada T, Gando S, Ono Y, et al. A disseminated intravascular coagulation with the fibrinolytic phenotype predicts the outcome of patients with out-of-hospital cardiac arrest. Thromb J 2016;14:43. 11 Kim J, Kim K, Lee JH, et al. Prognostic implication of initial coagulopathy in out-of-hospital cardiac arrest. Resuscitation 2013;84:48–53. 12 Ono Y, Hayakawa M, Maekawa K, et al. Fibrin/fibrinogen degradation products (FDP) at hospital admission predict neurological outcomes in outof-hospital cardiac arrest patients. Resuscitation 2017;111:62–7. 13 Lee DH, Lee BK, Jeung KW, et al. Disseminated intravascular coagulation is associated with the neurologic outcome of cardiac arrest survivors. Am J Emerg Med 2017;35:1617–23. 14 Skorko A, Thomas M, Mumford A, et al. Research protocol for platelets in out-of-hospital cardiac arrest: an observational, case-controlled, feasibility study to assess coagulation and platelet function abnormalities with
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ROTEM following out-of-hospital cardiac arrest (PoHCAR). BMJ Open 2017;7. Viersen VA, Greuters S, Korfage AR, et al. Hyperfibrinolysis in out of hospital cardiac arrest is associated with markers of hypoperfusion. Resuscitation 2012;83:1451–5. Sch€ochl H, Cadamuro J, Seidl S, et al. Hyperfibrinolysis is common in out-of-hospital cardiac arrest: Results from a prospective observational thromboelastometry study. Resuscitation 2013;84:454–9. Vendrell M, Hessheimer AJ, Ruiz A, et al. Coagulation profiles of unexpected DCDD donors do not indicate a role for exogenous fibrinolysis. Am J Transplant 2015;15:764–71. Buckley LF, Reardon DP, Camp PC, et al. Aminocaproic acid for the management of bleeding in patients on extracorporeal membrane oxygenation: Four adult case reports and a review of the literature. Heart Lung 2016;45:232–6. Weidman JL, Shook DC, Hilberath JN. Cardiac resuscitation and coagulation. Anesthesiology 2014;120:1009–14.