(Circulation. 1995;92:2572-2578.)
© 1995 American Heart Association, Inc.
Articles |
Activation of Blood Coagulation After Cardiac Arrest Is Not Balanced Adequately by Activation of Endogenous Fibrinolysis
Presented in part at the American Society of Anesthesiologists Annual Meeting, San Francisco, Calif, October 15-19, 1994, and at Resuscitation 94, Mainz, Germany, October 19-20, 1994.
From the Department of Anesthesia (B.W.B., J.M., H.B., T.B., E.M.), Clinical Laboratory at the Department of Surgery (M.A.), and the Department of Internal Medicine (P.P.N.), University of Heidelberg (Germany).
Correspondence to Bernd W. Böttiger, MD, DEAA, Department of Anesthesia, University of Heidelberg, Im Neuenheimer Feld 110, D-69120 Heidelberg, Germany.
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Abstract |
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Background Animal studies have demonstrated that hemostatic disorders occurring after cardiac arrest affect outcome. We investigated hemostatic changes during and after cardiopulmonary resuscitation (CPR) in humans.
Methods and Results The prospective study included 23 patients (29 to 86 years) who underwent out-of-hospital CPR for nontraumatic causes. Blood samples were drawn immediately and 15 and 30 minutes after initiation of CPR. In the case of restoration of spontaneous circulation (ROSC; n=7), additional blood samples were taken immediately, 30 minutes, and 2, 8, 24, 48, and 72 hours after ROSC. A marked activation of blood coagulation was found in all patients. The specific markers of activated blood coagulation and fibrin formation, thrombin-antithrombin complex (TAT; median during CPR, 260 µg/L; median after ROSC, 57 µg/L; normal range, 1.0 to 4.1 µg/L), and fibrin monomers (FM; median during CPR, 34.3 µg/mL; median after ROSC, 65.4 µg/mL; normal range, 0 to 3.6 µg/mL) were markedly increased during and in the early phase after CPR. When patients survived for 48 hours, TAT and FM values returned to the normal range. In most patients, the plasma levels of D-dimer, an indicator of endogenous fibrinolytic activity, were not markedly increased during CPR (median, <0.25 µg/mL; normal range, <0.25 µg/mL) but increased moderately after ROSC (median, 0.56 µg/mL). Levels of plasminogen activator inhibitor type 1 (normal range, 0.3 to 3.5 U/mL), a marker for endogenous inhibition of fibrinolytic activity, were moderately increased in most patients (median during CPR, 4.22 U/mL; median after ROSC, 8.08 U/mL).
Conclusions Our data clearly demonstrate that there is a marked activation of blood coagulation and fibrin formation after prolonged cardiac arrest and CPR in humans that is not balanced adequately by concomitant activation of endogenous fibrinolysis. These changes may contribute to reperfusion disorders, such as the cerebral "no-reflow" phenomenon, by inducing fibrin deposition and formation of microthrombi.
Key Words: cardiopulmonary resuscitation • circulation • coagulation • men • reperfusion
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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Changes indicating intravascular coagulation were found in the capillaries of the pulmonary and renal microcirculation in patients suffering from cardiac arrest who underwent CPR.1 In agreement with these observations, animal investigations demonstrated that there was a marked activation of blood coagulation after cardiac arrest and CPR.2 3 4 In addition, intravital microscopy showed the presence of microthrombi in cerebral vessels 5 to 10 minutes after cardiac arrest.5 Administration of heparin or thrombolytic agents before cardiac arrest leads to a significant increase in survival rate and neurological outcome in animals.6 7 8 We recently demonstrated in an animal model that a marked and significant improvement could be achieved in cerebral microcirculatory reperfusion after cardiac arrest by administration of thrombolytic treatment with heparin during CPR.9 This led us to hypothesize that activation of blood coagulation may play an important role in reperfusion after cardiac arrest in humans. The disseminated formation of microvascular fibrin and microthrombosis that follows the activation of blood coagulation without appropriate concomitant endogenous fibrinolysis may lead to general impairment of the microcirculatory blood flow during reperfusion. Therefore, treatment of these hemostatic disorders may be indicated. Increasing clinical experience with thrombolysis during CPR in patients suffering from fatal pulmonary embolism or myocardial infarction indicates that thrombolytic therapy may contribute to hemodynamic stabilization in these patients.10 11 12 In addition, several authors reported exceptionally good neurological outcome despite prolonged resuscitation when thrombolysis was carried out during CPR.10 11 12 Until now, no clinical investigation has examined the exact role of blood coagulation and fibrinolysis after cardiac arrest and during CPR in humans. Thus, the aim of our study was to investigate variables of coagulation and fibrinolysis during and after CPR in humans.
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Methods |
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Patients
After the Ethics Committee granted institutional approval, we included in this prospective study patients who underwent out-of-hospital CPR after cardiac arrest. Patients were numbered consecutively during the study period. When ROSC was accompanied by complete neurological recovery, written informed consent for the continuation of this study was obtained from the patient after detailed information was provided. Trauma patients and patients younger than 18 years of age were excluded. Patients who had been chronically treated with drugs that influence the hemostatic system, such as heparin, oral anticoagulants, or acetylsalicylic acid, had to be assessed retrospectively. To prevent a conflict of interest, an experienced physician joined the out-of-hospital emergency rescue team. This physician was exclusively responsible for blood sampling according to the study protocol.
During CPR, blood samples were taken immediately and 15 and 30 minutes after initiation of CPR. In the case of ROSC, additional blood samples were taken immediately and 30 minutes after, and 2, 8, 24, 48, and 72 hours after ROSC had been achieved. ROSC was defined according to the international standards in uniform reporting of data obtained from out-of-hospital cardiac arrest (Utstein style).13 In all patients, blood samples during CPR and immediately after ROSC were drawn from the external jugular vein through a separate 12-gauge venous cannula inserted opposite of the infusion site. In each case, we discarded the first 10 mL blood. After the subjects were admitted to the intensive care unit, blood samples were taken through a central venous line after the first 10 mL blood was discarded.
Samples were
taken into Vacutainer tubes (Boehringer Mannheim
Diagnostica GmbH) containing a mixture of citric acid,
theophylline, adenosine, and dipyridamole.
Immediately after sampling, the tubes were mixed carefully to avoid the
formation of foam and placed on a mixture of water and ice to ensure a
constant temperature of 4°C, which was controlled by a thermometer.
The tubes were centrifuged within 1 hour of collection at 3000
rpm (
1500g) for 15 minutes (4°C). The plasma was then
separated and stored as aliquots in plastic tubes at -70°C until it
was assayed for the hemostatic parameters. If the patient
died during CPR without ROSC, the underlying cause of cardiac arrest
was judged by the emergency medical doctor and discussed with the
experienced physician who joined the emergency team. The diagnosis was
always based on all available information, including an interview with
the general practitioner who treated the patient before the
arrest episode. In the case of ROSC, the diagnosis was available from
patient records.
Assays
Activation of the coagulation cascade was assessed by
sensitive
and specific dynamic molecular markers at various levels. We determined
the generation of thrombin by measuring the levels of TAT. FM formation
was used as a marker for the conversion of fibrinogen to fibrin.
Furthermore, we studied endogenous fibrinolytic activity by
measuring the levels of D-dimer. Endogenous
antifibrinolytic activity was assessed by determination of the levels
of PAI-1. TAT, FM, and PAI-1 were measured with an ELISA technique
based on the sandwich principle. Commercially available ELISA kits were
used. The ELISAs were performed in strict accordance with the test
manuals and the manufacturers' recommendations with the reagents
provided.
Concentrations of TAT, FM, and PAI-1 were calculated in relation to the reference curves, which were constructed from the reference standards. TAT levels were measured with the ELISA Enzygnost TAT micro (Behringwerke AG; normal range, 1.0 to 4.1 µg/L).14 Samples that yielded values outside the standard range covered by the test were diluted with standard TAT dilution plasma (maximum TAT level, >600 µg/L). FM values were obtained with the ELISA Enzymun-Test FM (Boehringer Mannheim) with a normal reference range of 0 to 3.6 µg/mL (preliminary reference value).15 Samples were diluted to FM levels of >96 µg/mL if necessary. PAI-1 was determined with the ELISA Berichrom PAI (Behringwerke AG), which has a normal reference range of 0.3 to 3.5 U/mL.16
D-Dimer measurements were made with a murine monoclonal antibody specific for the human D-dimer domain of cross-linked fibrin (Dade Dimertest Latex Assay, Baxter Diagnostics Inc). The normal range of this assay was <0.25 µg/mL. Higher levels of D-dimer in a sample were evaluated by serial dilutions of the plasma in Dimertest buffer up to a titer of >4 µg/mL. D-Dimer evaluation included a quality control that used positive and negative controls in each batch of tests according to the manufacturer's recommendations. This assay is specific for fibrin degradation products and does not cross-react with fibrinogen, factor Xa–cross-linked fibrinogen, or fibrinogen degradation products.17
All measurements were performed in duplicate, and the mean value was taken. All results were collected by use of "blinded" samples. To eliminate any hemodilution effect on the results, the hemoglobin concentration and hematocrit were measured in all blood samples.
Healthy Control Subjects
As control subjects, blood samples
were tested from eight
age-matched volunteers (three women, five men). To recognize
possible hemostatic changes caused by artificial activation of blood
coagulation or fibrinolysis resulting from inadequate
sampling procedures, we used the same sampling, storing, and laboratory
procedures in all volunteers and patients. The levels of TAT in control
volunteers ranged from 1.9 to 4.1 µg/L (median, 2.4 µg/L); the
levels of FM in control subjects ranged from <0.01 to 3.81 µg/mL
(median, 0.13 µg/mL). D-Dimer levels were not
detectable in control volunteers (all levels, <0.25 µg/mL). Levels
of PAI-1 ranged from 1.34 to 7.25 U/mL (median, 2.95 U/mL) in control
subjects.
Statistical Analysis
Because the individual courses of the
patients (duration of
cardiac arrest, CPR, and ROSC) varied to a great extent, the
recorded values from each patient are presented in Figs 1A
,
2A, 3A, and 4A. The correlation
between the duration of CPR and the
levels of activation products (TAT, FM, D-dimer, and
PAI-1) immediately after ROSC was evaluated by linear regression
analysis. To clarify whether coagulation parameters
correlated with the initial prognosis of the patient (ie, the
possibility to achieve ROSC), we compared the levels of TAT, FM,
D-dimer, and PAI-1 30 minutes after initiation of CPR
(T30) between patients with and without ROSC with the levels obtained
from control volunteers using the Kruskal-Wallis and Wilcoxon
tests. In the case of ROSC, the 30-minute CPR value was used for this
analysis if CPR lasted 30 minutes or more. If ROSC occurred
<30 minutes after initiation of CPR, we took the ROSC value that was
recorded close to 30 minutes after start of CPR. All data
representing group analysis are presented
as medians and ranges. A value of P<.05 was considered
statistically significant.
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Results |
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Of the 23 patients (8 women, 15 men; age, 29 to 86 years) included in our study, 7 (30%) could achieve ROSC after CPR procedures over a period of up to 90 minutes (see the Table
). Overall, a
total of 77 plasma samples were obtained. It was not possible to draw
blood from all patients at each time point during CPR. During CPR, one
blood sample was obtained in 7 patients, two samples in 6 patients, and
three samples in 8 patients (see Figs 1 through
4
). A T30 value
could
be obtained in 13 patients without ROSC and in all 7 patients with
ROSC. In all patients, the range of hemoglobin concentrations between
two consecutive blood samples during and immediately after CPR was
within ±10%, which indicates that dilutional effects did not occur in
the prehospital setting. One additional patient who suffered only
seconds of cardiac arrest and 1.5 minutes of CPR showed almost normal
TAT and FM values (data not shown).
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Activation of Blood Coagulation
Fig 1 shows
the results of the TAT measurements. The median TAT
level (normal range, 1.0 to 4.1 µg/L) during CPR was found to be 260
µg/L (range, 3.4 to >600 µg/L). Comparing the first and the last
individual TAT values during CPR in patients where more than one sample
was obtained (n=14), we observed an increase in TAT levels in all but 1
patient (Fig 1). The median TAT level after ROSC was 57
µg/L (range,
4.1 to >600 µg/L). TAT values decreased between 2 and 8 hours after
ROSC and reached the normal range within 24 to 48 hours in all patients
except patient 17. This patient suffered severe neurological damage,
including persistent generalized seizures beginning immediately after
ROSC. He developed a fulminant intravascular clotting syndrome, leading
to severe microcirculatory disorders at the whole body surface. TAT
levels 30 minutes after initiation of CPR (T30) were significantly
increased in patients with and without ROSC versus control subjects
(Fig 1; P<.01). The median of TAT levels at T30 in
patients
without ROSC was higher than that in patients with ROSC; this
difference, however, did not reach statistical significance (Fig
1).
Regression analysis revealed only moderate and insignificant
correlation between the duration of CPR and TAT levels immediately
after ROSC (r=.38; P=.40; Fig
5).
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The median FM level (normal range, 0 to 3.6
µg/mL) during CPR was
34.31 µg/mL (range, 0.37 to >96 µg/mL (Fig 2).
Comparing the first
and the last individual FM values during CPR in patients in whom more
than one sample was obtained (n=14), we observed an increase in FM
levels in all these patients (Fig 2). The median FM level after
ROSC
was 65.4 µg/mL (range, 1.23 to >96 µg/mL). In patients with ROSC,
the increase in FM levels persisted longer than the increase in TAT
levels (Figs 1 and 2). No significant
differences were found in FM
levels at T30 between patients with and without ROSC, but FM levels in
both groups were significantly increased compared with the values in
control volunteers (Fig 2; P<.01). There was no
significant
correlation between the duration of CPR and the FM levels immediately
after ROSC (r=.28; P=.55; Fig
5).
In general, the increases in TAT and FM levels indicate a marked activation of blood coagulation during and after CPR in patients with prolonged cardiac arrest. The only patient on chronic medication with the platelet antagonist acetylsalicylic acid (patient 18) showed only moderately increased TAT levels (3.4, 17, and 36 µg/L immediately and 15 and 30 minutes after initiation of CPR, respectively) and almost-normal FM levels (0.37, 2.47, and 6.93 µg/mL, respectively) during CPR.
Fibrinolysis
In contrast to the marked activation of blood
coagulation, we
could find only slight to moderate activation of endogenous
fibrinolysis. D-Dimer levels (normal,
<0.25 µg/mL) were not markedly increased during CPR in most patients
(median, <0.25 µg/mL; range, <0.25 to >4.0 µg/mL; Fig
3).
Comparing the first and last individual D-dimer values
during CPR in patients in whom more than one sample was obtained, we
observed an increase in D-dimer levels in 9 of the 14
patients (Fig 3). Moreover, moderate increases in
D-dimer
levels were found in most patients between 30 minutes and 8 hours after
ROSC (median after ROSC, 0.56 µg/mL; range, <0.25 to >4.0
µg/mL).
In one patient with increased D-dimer levels during CPR
(patient 22), subarachnoid hemorrhage was the estimated
diagnosis, which could explain elevated levels of D-dimer
associated with the underlying cause of cardiac arrest in this
patient.18 Interestingly, we measured a marked increase in
D-dimer immediately after the administration of
fibrinolytic agents for the treatment of acute myocardial infarction
(patient 13, from 1.5 to 3.0 µg/mL; patient 14, from 0.375 to >4
µg/mL; data not shown). Overall, D-dimer levels at T30
were increased versus D-dimer levels in control subjects
without reaching statistical significance (Fig 3;
Kruskal-Wallis test;
P=.83). There was no difference in T30 levels between
patients with and without ROSC (Fig 3). D-Dimer levels
immediately after ROSC in patients without thrombolytic
therapy correlated moderately with the duration of CPR
(r=.78; P=.07; Fig 5).
PAI-1 levels (normal range, 0.3 to 3.5 U/mL) were increased moderately
in most patients during CPR (median, 4.22 U/mL; range, 0.46 to 13.35
U/mL) and after ROSC (median, 8.08 U/mL; range, 0.91 to 27.2 U/mL; Fig
4), an indication of moderately increased endogenous
antifibrinolytic activity. When comparing the first and the last
individual PAI-1 values during CPR in patients in whom more than one
sample was obtained, we observed an increase in PAI-1 levels in 8
patients and a decrease in 5 patients (Fig 4). The difference
in PAI-1
levels between patients and control subjects at T30, however, did not
reach statistical significance (Fig 5; Kruskal-Wallis test;
P=.59). There was no correlation between the duration of
cardiac arrest and the PAI-1 values obtained immediately after ROSC in
patients without thrombolytic therapy (r=.06;
P=NS; Fig 5).
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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In this first study dealing with hemostatic disorders during and after CPR following prehospital cardiac arrest in humans, we found a marked activation of blood coagulation that was not balanced adequately by endogenous fibrinolytic activation. It is unlikely that artificial activation of blood coagulation influenced our results because we found normal-range values in all control volunteers and almost-normal values in one additional patient in whom the duration of cardiac arrest was only 20 seconds.
Activation of blood coagulation leads to thrombin generation, and the amount of thrombin generated correlates with the detectable concentrations of TAT.16 19 Soluble FM is found during thrombin-induced fibrinogen-to-fibrin conversion. Elevated levels of FM indicate increased thrombin generation and systemic fibrin formation.16 19 We measured TAT and FM levels and found both to be increased dramatically in most patients during CPR and in the early phase after ROSC. We observed a large range of TAT and FM levels among the patients; thus the question arises as to whether there is any correlation between the amount of TAT and FM coagulation activation and the duration of cardiac arrest or CPR, respectively. Although the duration of CPR could be determined exactly, it was impossible to determine the exact duration of cardiac arrest. These data were estimated retrospectively; hence, they are not precise enough to calculate correlations between coagulation activation and the duration of cardiac arrest. Regarding the duration of CPR, only a weak correlation was seen between TAT and FM values and the duration of CPR. Thus, the duration of CPR does not seem to be the only determinant of hemostatic disturbances after cardiac arrest. Several factors that we did not determine completely may have had substantial impact: the underlying disease, the duration of stasis and low-flow states,20 the amount of endogenously released and exogenously administered catecholamines,21 22 external electric defibrillation, and other currently unknown factors. In general, stasis of blood, increased levels of catecholamines, and endothelial cell damage are known sources of activation of the coagulation mechanisms,21 22 and all these phenomena occur during and after cardiac arrest.
Hemostatic disorders associated with activation of blood coagulation are frequently observed in critically ill patients suffering from severe trauma, sepsis, and thrombosis.19 23 24 Remarkably, in contrast to findings in those patients, we were unable to find adequate activation of the fibrinolytic system. In this study, the levels of D-dimer, the specific fibrin split product indicating fibrin-related plasmin activity,16 17 25 were not increased significantly during CPR. D-Dimer levels increased only moderately, and their peak was delayed after ROSC. Thus, the activation of blood coagulation was not balanced appropriately by endogenous fibrinolytic activity. In general, endogenous fibrinolysis may be impaired by either an increase in antifibrinolytic activity or a direct failure of the fibrinolytic system.19 Levels of PAI-1, the most important endogenous inhibitor of plasmin generation, were moderately increased. However, this does not entirely explain the observed imbalance. It must be considered that endogenous fibrinolytic activity depends on a relatively undisturbed function of the endothelium.26 After prolonged cardiac arrest, however, endothelial function is reduced by reperfusion injury.27 28 29 In addition, the most relevant portion of the endothelial cell surface is located in the microcirculation, and capillary reperfusion is known to be impaired ("no-reflow" phenomenon) after prolonged circulatory arrest.27 28 29 30 31 Thus, inappropriate activation of the fibrinolytic system after prolonged cardiocirculatory arrest may reflect reduced endothelial function and impaired microcirculatory reperfusion. D-Dimer levels started low but correlated moderately with the duration of cardiac arrest, which may reflect slow recovery of fibrinolytic endothelial cell function. Interestingly, D-dimer levels increased after initiation of thrombolytic therapy as an indication of fibrin formation preceding the administration of thrombolytics. These data are in agreement with animal studies. Latour et al4 reported a marked activation of Hageman factor, and Gaszynski2 3 described the development of disseminated intravascular clotting after cardiac arrest in rabbits. Endogenous fibrinolysis was not activated significantly, and the resuscitation procedures failed to restore normal hemostatic conditions.2 4
The observed hemostatic changes may lead to microcirculatory fibrin deposition during ischemia and reperfusion. It suggests that the use of exogenous thrombolytic therapy during reperfusion might be appropriate for rebalancing the hemostatic system. Increasing clinical experience with thrombolysis during CPR for the specific treatment of patients with pulmonary embolism or myocardial infarction as the underlying cause of cardiac arrest recently demonstrated the clinical feasibility and relevance of thrombolytic intervention during CPR.10 11 12
Our data do not support a strong correlation between activation of blood coagulation and initial success or failure of CPR procedures. This is not surprising, however, because, in contrast to experimental settings using previously healthy animals,6 7 8 activation of blood coagulation may not be the most relevant determinant regarding initial survival in the clinical setting. Resuscitation of the heart, associated disorders, and early institution of bystander CPR are known to be the most important factors with regard to the success of cardiocirculatory stabilization.32 For similar reasons, the extent of the activation of blood coagulation and the duration of initial survival may not correlate in the clinical situation. Activation of blood coagulation after cardiac arrest may be relevant, however, during microcirculatory reperfusion in the capillary beds of almost all organs and may be most relevant in cerebral reperfusion. There is evidence from animal studies that the neurological damage that follows cardiac arrest not only is due to anoxia during cardiac arrest but also may result from a combination of anoxia and the quantity of early cerebral microcirculatory reperfusion.27 28 29 30 31 Besides cerebral reoxygenation injury,29 activation of blood coagulation may lead to an impairment of cerebral reperfusion after cardiac arrest. Experimentally, a significant correlation has been demonstrated between the neurological outcome or survival rate and the amount of heparin or streptokinase administered before cardiac arrest.6 7 Safar et al33 observed an improved cerebral outcome after cardiac arrest using a combined postarrest treatment, including hypertensive reperfusion, heparin, and dextran. Besides the anticoagulatory effect of heparin, dextran is known to decrease platelet adhesiveness and promote endogenous fibrinolysis.34 Treatment with combined dextran and streptokinase reduced the duration of flat electroencephalogram periods and improved post–cardiac arrest cerebral blood flow.8 In addition, delayed hypoperfusion after cardiac arrest was found to be prevented by a platelet-activating factor antagonist.35 We recently demonstrated in cats that the administration of recombinant tissue-type plasminogen activator with heparin during reperfusion after cardiac arrest reduced the extent of nonreperfused areas of the cerebral microcirculation.9 Intravital and morphological microscopic findings of microthrombi in cerebral vessels after short periods of cardiac arrest agree with these findings.5 36 Therefore, the question arises as to whether the level of activated coagulation after cardiac arrest affects neurological outcome in humans. This question could not be answered by our data and thus should be addressed in further investigations.
In conclusion, our data demonstrate a marked activation of blood coagulation that is not balanced adequately by fibrinolysis after cardiac arrest in humans. These hemostatic changes may be important in the etiology of reperfusion disorders. Available results from animal studies suggest that our clinical observations may lead to new therapeutic strategies that focus on a general improvement in microcirculatory reperfusion by influencing and possibly rebalancing the hemostatic system.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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Dr Nawroth was supported by a Heisenberg fellowship from the Deutsche Forschungsgemeinschaft, Na. 138/3-1. We would like to thank the emergency staff of the German Red Cross (Heidelberg, Germany); Prof C. Herfarth, MD, and Dr U. Göhring (Department of Surgery, University of Heidelberg); the nursing staff in the intensive therapy unit (Department of Internal Medicine, University of Heidelberg); Prof W. Kübler, MD, and Dr U. Strasser (Department of Internal Medicine, University of Heidelberg); and all medical colleagues involved in the Heidelberg out-of-hospital emergency medical system (Departments of Surgery and Anesthesia, University of Heidelberg) for their kind support. In addition, we thank Dr H. Bauer (Department of Anesthesia, University of Heidelberg) for statistical advice.
Received January 26, 1995; revision received June 1, 1995; accepted June 4, 1995.
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