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Bedside coagulation monitoring in heparin-treated patients with active thromboembolic disease: A coronary care unit experience
Bedside coagulation monitoring in heparin-treated patients with active thromboembolic disease: A coronary experience
care unit
Patients with active venous and arterial thromboernbolic disorders are known to benefit from systemic anticoagulation with heparin. Clinical studies have shown, however, that therapeutic anticoagulation is rarely achieved rapidly and often is not maintained over time. Prolonged laboratory turnaround time of the activated partial thromboplastin time (aPTT) may contribute directly to these common problems. A total of 272 aPTT determinations were performed on 120 hepafin-treated patients admitted to the coronary care unit. The time from sample collection to data availabiflty was 126 + 84 minutes with standard laboratory aPTT testing. In contrast, a bedside coagulation device provtded an aPTT within 3 minutes (p < 0.001). Subtherapeutii aP’fl values (x85 seconds) were documented in 21% of all patients; in each, the heparin dose was changed and a repeat aPTT was required. In a separate study of 33 hepartnlzed patients randomized to either bedside or central laboratory aPTf testing (294 aPTT determinattons), the time to achieve a therapeutic state of systemic anticoagulatfon was 8.2 hours and 18.1 hours, respectively @ < 0.005). The time from aPTT determination to a decision regarding heparin titration adjustments was 14.5 minutes and 3 hours with bedside and laboratory testing, respectively @ < 0.001). Thus bedside,coagulation monitoring provides a convenient, rapid, and accurate assessment of systemic anticoagulation among heparin-treated patients with active thromboembolic disease in the coronary care unit. This technology warrants further clinical investigation. (AM HEART J 1994;128:719-23.)
Richard C. Becker, MD, James Cyr, RN, MS, CCRN, Steven P. Ball, RN Worcester, Muss.
Activated partial thromboplastin time (aPTT) is a widely used general screening test for assessing the integrity of the intrinsic and common pathways of coagulation. It is also the primary method of monitoring the anticoagulant effects of heparin therapy commonly used in the care of patients with venous and arterial thromboembolic disease states. Previous clinical studies have convincingly shown that a therapeutic state of systemic anticoagulation is a prerequisite for patient benefit when intravenous heparin is administered.1-3 They have also shown that adequate
From the Coronary Care Unit, Division of Cardiovascular Medicine, Thrombosis Research Center, University of Massachusetts Medical School. Received for publication June 21, 1993; accepted Jan. 20, 1994. Reprint requests: Richard C. Becker, MD, Thrombosis Research Center, Division of Cardiovascular Medicine, University of Massachusetts Medical School. Worcester, MA 01655. Copyright @ 1994 by Mosby-Year Book, Inc. 0002~3703/94/$3.00 + 0 4/l/67065
Jeanne M. Corrao, RN, MS, and
anticoagulation is rarely achieved rapidly, and in many instances if a therapeutic aPTT is achieved it is rarely maintained for the duration of treatment.4* 5 Because of the complex pharmacokinetics and pharmacodynamics of heparin,6 frequent aPTTs are required during the course of treatment to maximize an appropriate anticoagulant effect. In this regard, current laboratory methods have several shortcomings that may impact directly on the wide-scale challenge of achieving and maintaining therapeutic states of systemic anticoagulation in heparin-treated patients. One of the most serious is the potential for excessive time delays in the acquisition of information vital to patient care. Several years ago a portable whole-blood instrument was developed by Lucas et a1.7 for prothrombin time determinations. This instrument has subsequently been adapted for the determination of aPTTs. We assessed the instrument’s reliability in heparin-treated patients with active thromboembolic disease admitted to the coronary care unit of a major tertiary-care hospital and its 719
720
Becker et al.
ability to reduce the time delay for aPTT determinations and the time to achieve a therapeutic state of anticoagulation compared with standard laboratory methods. METHODS Consecutive patients admitted to the coronary care unit of the University of Massachusetts Medical Center between July and November 1992with active venous or arterial thromboembolic diseasereceiving a continuous intravenous infusion of heparin (Elkinns-Sinn, Cherry Hill, N. J.) were enrolled in the study. Blood sampleswere obtained by standard venipuncture or from an indwelling venous line. The blood was collected in a plastic syringe (Becton Dickinson and Co., Rutherford, N. J.) and transferred through an l&gauge needleto a test cartridge (bedsideaPTT) and a glasstube containing 0.38 mg/dl sodium citrate (standard laboratory aPTT). Turnaround time was defined as the time from sample acquisition to aPTT result availability. Transport time was defined asthe time from sampleacquisition to the time the samplewaslogged in by the central laboratory. The laboratory turnaround time was considered the time from log-in time to the time the results were entered into the hospital-wide laboratory test computer. A compositeof the two time intervals wasthe complete turnaround time. In a separatestudy of 33 heparinized patients, randomization to either bedsideor central laboratory aPTT testing was performed before treatment. All patients had aPTT determinations every 6 hours for 48 hours and heparin titration according to a standardized nomogram. An aPTT wasdetermined 4 hours after any changein heparin dosing. The studies were approved by the Committee for the Protection of Human Subjects in Clinical Research, University of MassachusettsMedical School. Standard laboratory aPTT determination.‘Blood sampleswere drawn into citrate tubes asdescribedpreviously. Care wastaken to fill each 5 ml tube completely. The sampleswere then mixed and centrifuged at 3000rpm at room temperature to obtain platelet-poor plasma. Activated partial thromboplastin time determinations were cakulated with an automated system (MLA 700, Medical Laboratory Automation, Pleasantville, N. Y.) after the manufacturer’s recommendations. In each, an aPTT reagent (activated FS) (American Dade, Aquada, Puerto Rico) was used (normal range 27.0 to 39.0 seconds). Bedside coagulation monitor. The Coaguchek Plus System (Boehringer Mannheim Diagnostics,Indianapolis, Ind., formerly Biotrack CoagulationMonitor, Ciba Corning Diagnostics, Medfield, Mass.) Biotrack 512 coagulation monitor is a battery-powered, portable laser photometer that usesa phospholipid (soybeanphosphatide) and an activator of intrinsic coagulation (bovine brain sulfatide) to determine the aPTT. Microliter samplesof capillary, arterial, or venous whole blood can be used. In the present study venous sampleswere usedin all cases;however, previous studies at our institution (unpublished data) have shown comparable results with each when meticulous attention to technique is observed.
American
October 1994 Heart Journal
In brief, a disposable plastic reagent cartridge was inserted into the instrument and allowed to warm. A drop of whole blood wasthen applied to the application well of the cartridge. The blood issubsequentlydrawn by capillary action through the reagent chamber, where it mixes with activator and phospholipid (Fig. 1). The laserphotometer, sensesvariations in light scatter from red blood cells, detecting the cessationof blood flow. The time from blood application to cessationof flow (clotting) is then converted mathematically to a plasmaequivalent aPTT. The conversion factor has been establishedpreviously by the manufacturer.8 (normal aPTT 31 seconds; range 21 to 41 seconds).All bedside tests were performed by coronary care unit nursestrained and certified by the central laboratory according to current guidelines. The time from aPTT determination to a decisionregarding heparin titration was charted prospectively on a bedsidedata sheet. Validation studies: Bedside coagulation monitor. A previous multicenter study coordinated at our institution of 319 anticoagulated patients compared aPTTs obtained from the Coaguchek Plus Biotrack 512 instrument and those determined by a conventional laboratory instrument.8 The correlation coefficient (0.83) wasnearly identical to the correlation coefficients observed when different laboratory aPTT reagents were compared. A recently completed validation study of 60 heparin-treated patients with unstable angina and acute myocardial infarction produced nearly identical correlation coefficients to those of the initial multicenter experience (unpublisheddata), even when thrombolytic therapy patients were included in the analysis.A high degreeof precision,asdemonstratedby low coefficients of variation, has been observedfor both within-day and between-day testing with the CoaguchekPlus Biotrack 512 monitor and normal controls.8 Quality control: Bedside coagulation monitor. On arrival in the laboratory each shipment of cartridges, which included a temperature sensorfor shipping condition verification, wasvalidated with lyophilized whole-blood quality controls. The individual cartridges were checked for dating and calibration on insertion into the monitor. The monitors themselveswere checkeddaily with bilevel quality control cartridges which simulateactual performanceof a test (timings, actions, measurements). Statistical analysis. Means r SD for the aPTT method groups were calculated. Repeated measuresanalysis of variance wasapplied to test for differences. In the time to therapeutic aPTT substudy, values were determined by interpolating (linearly) the aPTT measurementsto provide imputed hourly values. RESULTS A total of 272 aPTT determinations (mean 74.0 +- 28.3 seconds) were performed on 120 patients with active thromboembolic disease admitted to the coronary .care unit. In I2 patients the bedside aPTT was performed twice because of technical errors (inadequate sample volume). The time from sample collection to data availability for clinical decision
Volume 128, Number 4 American Heart Journal
Rmker cd al.
721
1. Disposableplastic reagent cartridge usedfor bedsideaPTT determinations in Boehringer Mannheim Biotrack 512 coagulation monitor.
Fig.
making (complete turnaround time) was 126 + 84 minutes (95 % CI 108 to 144 minutes) with standard laboratory aPTT testing and 3 minutes with the bedside coagulation monitor (p < 0.0001). The time from sample collection to arrival in the central laboratory (transport time) was 36 & 26 minutes (95% CI 24 to 42 minutes). Although this particular study was not designed to investigate the adequacy of heparinization achieved and maintained, 21% of patients participating were found to have subtherapeutic anticoagulation (aPTT < 65 seconds) when receiving a continuous intravenous heparin infusion. In each, an infusion adjustment and repeat aPTT was required. In the time-to-therapeutic-anticoagulation substudy, 264 aPTT determinations were performed on 33 heparin-treated patients. The median time required to achieve an aPTT of at least 65 seconds was 8.2 hours (25th percentile, 8.0; 75th percentile, 9.1) among patients randomized to bedside monitoring and 18.1 hours (8.4,29.5) in patients assigned to central laboratory aPTT testing (p 0.005). The time from aPTT determination to heparin titration adjustment averaged 14.5 minutes (range 1 to 20 minutes) with bedside testing and 3.0 hours (range 2.0 to 4.0 hours) with central laboratory testing (p < 0.001). Despite the rapid achievement of therapeutic systemic anticoagulation, subtherapeutic aPTTs were common in both groups during the study, suggesting that even a rapid bedside monitoring tool cannot compensate for suboptimal heparin dosing whether it be physician directed or, in this case, nomogram directed (Tables I and II).
DISCUSSION
Our study of heparin-treated patients admitted to the coronary care unit identified significant differences in aPTT determination time delays and differences in achieving a therapeutic state of systemic anticoagulation comparing standard central laboratory and bedside coagulation testing. Conceivably, the observed time delays could have been even greater had we included the time from data availability on the hospital-wide computer system to when the results prompted a clinical decision. Clearly, a nurse or physician would have to wait patiently by the computer for the results to appear to avoid additional time delay. This is not practical in a modern-day coronary or intensive care unit. Indeed, our experience (unpublished data) suggests that, on average, 30 minutes typically elapses between data availability on the computer and clinical decision making. In contrast, bedside testing allows prompt real-time decisions to be made. Furthermore, consistent with the findings of previous studies,4l 5 we found that, subtherapeutic anticoagulation was not an uncommon occurrence among patients receiving intravenous heparin, raising further concerns over delays in identifying inadequately treated patients and making timely adjustments. Bedside coagulation testing offered the clinician a rapid and reliable means of assessing anticoagulant response to heparin therapy. It is well known that commercial activated partial thromboplastin time reagents respond differently to heparin. g-11 Instrumentation i2-i4 collection tubes,‘” and blood volume16 may be iources of variability as
722
Becker et al.
American
October 1994 Heart Journal
Table I. aPTT values during the 48-hour study period: Time-to-therapeutic-anticoagulation substudy Study
groups*
Bedside Parameter
Time aPTT aPTT aPTT *Includes tp 0.005.
Median
to therapeutic aPTT (hr) 65-80 set (%) <65 set (% ) >80 set (%) all time points in 4%hour
25th
8.21 26.1 48.8 25.9
percentile
Laboratory 75th percentile
8.0 19.2 34.9 6.1
Median
25th
18.1 21.2 42.0 28.4
9.1 36.5 55.2 30.9
percentile
8.4 12.8 28.7 16.4
75th percentile
29.5 35.0 60.9 53.9
study period.
Table II. Duration and aPTT measurements:Time-to-therapeutic-anticoagulation substudy Study
groups*
Bedside Parameter
Duration (hr) aPTT <65 set aPTT 65-80 set aPTT >80 set Mean (set) aPTT <65 set aPTT >80 set *Includes
all
Median
25th
percentile
Laboratory 75th
Dercentile
Median
25th
percentile
75th percentile
23.2 11.8 10.1
10.1
32.1
18.0
12.9
8.8 2.1
21.0 15.8
10.2 15.2
6.3 10.5
33.4 20.0 20.9
55.8 100.2
53.7 87.1
58.8 110.2
58.5 100.5
54.9 92.9
58.9 114.7
time points in 4%hour study period.
well. The bedside coagulation device avoids these limitations and, in addition, the entire test is run by one person at the patient’s bedside, minimizing time delays and the potential for error. Heparin is the most commonly used anticoagulant in the treatment of patients with venous and arterial thromboembolic diseases. There is substantial evidence that a therapeutic state of systemic anticoagulation must be achieved and maintained to obtain maximum benefit while, at the same time, minimizing the likelihood of hemorrhagic complications.lw3s 17~I8 Our findings suggest that the routine use of standard laboratory aPTT testing is associated with marked delays in vital data acquisition. If heparin was less variable in its anticoagulant effects and easy to titrate, time delays in coagulation monitoring would have less of a clinical impact. On the contrary, it is widely appreciated that the pharmacokinetics of heparin are complex and its anticoagulant effects are difficult to predict with certainty.6 Frequent aPTT determinations are, therefore, required, particularly during the first 48 hours of intravenous heparin administration. A prolonged turnaround time for aPTT results in patients with active thromboembolic disorders may
translate directly into excessive delays in providing maximal care. This in turn could cause increased morbidity and mortality. We are currently exploring this area carefully. If confirmed, bedside coagulation monitoring would not only impact significantly on patient care but would likely influence medical cost as well. In conclusion, bedside aPTT testing with the Coaguchek Plus Biotrack 512 coagulation monitor provides a convenient, rapid, and accurate assessment of systemic anticoagulation in heparin-treated patients with active thromboembolic disease. Its use deserves further evaluation in the coronary care unit and other clinical settings. We thank the coronary care unit nursing staff for their support.
REFERENCES
1. H&a J, Hamilton WP, Kleiman N, Roberts R, Chaitman BR, Ross AM, for the Hart Investigators. A comparison between heparin and low-dose aspirin as adjunctive therapy with tissue plasminogen activator for acute myocardial infarction. N Engl J Med 1990;323:1433-7. 2. de Bono DP, Simoons ML, Tijssen J, Arnold AER, Betriv A, Bergersdijk C, Lopez-Bescos L, Mueller E, Pfisterer M, Vandewerf F, Zijlstra F, Verstraete M. Effect of early intravenous heparin on coronary patency, infarct size, and bleeding complications after alteplase thrombolysis: results of a ran-
Volume 128, Number 4 American HeaR Journal
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4.
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6. 7.
8.
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10.
demised double blind European Cooperative Study Group trial. Br Heart J 1992;67:122-8. Hull RD, Raskob GE, Hirsh J, Jay RM, Leclerc JR, Geerts WH. Continuous intravenous heparin compared with intermittent subcutaneous heparin in the initial treatment of proximal-vein thrombosis. N Engl J Med 1986,315:1109-14. Arnout J, Simoons M, de Bono D, Rapold HJ, Collen D, Verstraete M. Correlation between level of heparinization and patency of the infarct-related coronary artery after treatment of acute myocardial infarction with alteplase (rt-PA). J Am Co11 Cardiol 1992;20:513-9. Hsia J, Kleiman N, Aguirre F, Chaitman BR, Roberta R, Ross AM, for the Hart Investigators. Heparin-induced prolongation of partial thromboplastin time after thrombolysis: relation to coronary artery patency. J Am Co11 Cardiol 1992;20:31-5. Hirsh J. Henarin. N End J Med 1991:324:1565-74. Lucas FV, Duncan A, Jay R, Coleman R, Craft P, Ghan P, Winfrey L, Mungall DR, Hirsh J. A novel whole blood capillary technique for measuring the prothrombin time. Am J Clin Pathol 1987;88:442-6. Ansell J, Tiarks C, Hirsh J, McGehee W, Adler D, Weibert R. Measurement of the activated partial thromboplastin time from a capillary (fingerstick) sample of whole blood. Am J Clin Path01 1991;95:222-7. Bain B, Forster T, Sleigh B. Heparin and the activated partial thromboplastin time: a difference between the in vitro and in vivo effects and implications for the therapeutic range. Am J Clin Path01 1980;74:668-73. Barrowcliffe TW, Gray E. Studies of phospholipid reagents
Becker et al.
11. 12.
13. 14. 15.
16. 17.
18.
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used in coagulation II: factors influencing their sensitivity to heparin. Thromb Haemost 1981;46:634-7. Shapiro G, Huntzinger SW, Wilson JE. Variation among commercial activated partial thromboplastin time reagents in response to heparin. Am J Clin Path01 1977;67:477-80. Banez EI, Triplett DA, Koepke J. Laboratory monitoring of heparin therapy: the effect of different salts of heparin on the activated partial thromboplastin time. Am J Clin Path01 1980;74:569-74. Brandt JT, Triplett DA. Laboratory monitoring of heparin: effect of reagents and instruments on the activated partial thromboplastin time. Am J Clin Path01 1981;76(suppl):530-7. Owen J, Payne E, Carstairs K. Erroneous activated partial thromboplastin time. Ann Intern Med 1978;89:146-7. duP Heyns A, van den Berg DJ, Kleynhans PHJ, du Tort PW. Unsuitability of evacuated tubes for monitoring heparin therapy by activated partial thromboplastin time. ,I Clin Path01 1981;34:63-8. Peterson P, Gottfried E. The effects of inaccurate blood sample volume on prothrombin time and activated partial thromboplastin time. Thromb Haemost 1982;47:101-3. Bleich SD, Nichols TC, Schumacher RR, Cooke DH, Tate DA, Teichman SL. Effect of heparin on coronary arterial patency after thrombolysis with tissue plasminogen activator in acute myocardial infarction. Am J Cardiol 1990;66:1412-7. Basu D, Gallus A, Hirsh J, Cade J. A prospective study of the value of monitoring heparin treatment with the activated partial thromboplastin time. N Engl .J Med 1972;287:324-7.
care unit
Patients with active venous and arterial thromboernbolic disorders are known to benefit from systemic anticoagulation with heparin. Clinical studies have shown, however, that therapeutic anticoagulation is rarely achieved rapidly and often is not maintained over time. Prolonged laboratory turnaround time of the activated partial thromboplastin time (aPTT) may contribute directly to these common problems. A total of 272 aPTT determinations were performed on 120 hepafin-treated patients admitted to the coronary care unit. The time from sample collection to data availabiflty was 126 + 84 minutes with standard laboratory aPTT testing. In contrast, a bedside coagulation device provtded an aPTT within 3 minutes (p < 0.001). Subtherapeutii aP’fl values (x85 seconds) were documented in 21% of all patients; in each, the heparin dose was changed and a repeat aPTT was required. In a separate study of 33 hepartnlzed patients randomized to either bedside or central laboratory aPTf testing (294 aPTT determinattons), the time to achieve a therapeutic state of systemic anticoagulatfon was 8.2 hours and 18.1 hours, respectively @ < 0.005). The time from aPTT determination to a decision regarding heparin titration adjustments was 14.5 minutes and 3 hours with bedside and laboratory testing, respectively @ < 0.001). Thus bedside,coagulation monitoring provides a convenient, rapid, and accurate assessment of systemic anticoagulation among heparin-treated patients with active thromboembolic disease in the coronary care unit. This technology warrants further clinical investigation. (AM HEART J 1994;128:719-23.)
Richard C. Becker, MD, James Cyr, RN, MS, CCRN, Steven P. Ball, RN Worcester, Muss.
Activated partial thromboplastin time (aPTT) is a widely used general screening test for assessing the integrity of the intrinsic and common pathways of coagulation. It is also the primary method of monitoring the anticoagulant effects of heparin therapy commonly used in the care of patients with venous and arterial thromboembolic disease states. Previous clinical studies have convincingly shown that a therapeutic state of systemic anticoagulation is a prerequisite for patient benefit when intravenous heparin is administered.1-3 They have also shown that adequate
From the Coronary Care Unit, Division of Cardiovascular Medicine, Thrombosis Research Center, University of Massachusetts Medical School. Received for publication June 21, 1993; accepted Jan. 20, 1994. Reprint requests: Richard C. Becker, MD, Thrombosis Research Center, Division of Cardiovascular Medicine, University of Massachusetts Medical School. Worcester, MA 01655. Copyright @ 1994 by Mosby-Year Book, Inc. 0002~3703/94/$3.00 + 0 4/l/67065
Jeanne M. Corrao, RN, MS, and
anticoagulation is rarely achieved rapidly, and in many instances if a therapeutic aPTT is achieved it is rarely maintained for the duration of treatment.4* 5 Because of the complex pharmacokinetics and pharmacodynamics of heparin,6 frequent aPTTs are required during the course of treatment to maximize an appropriate anticoagulant effect. In this regard, current laboratory methods have several shortcomings that may impact directly on the wide-scale challenge of achieving and maintaining therapeutic states of systemic anticoagulation in heparin-treated patients. One of the most serious is the potential for excessive time delays in the acquisition of information vital to patient care. Several years ago a portable whole-blood instrument was developed by Lucas et a1.7 for prothrombin time determinations. This instrument has subsequently been adapted for the determination of aPTTs. We assessed the instrument’s reliability in heparin-treated patients with active thromboembolic disease admitted to the coronary care unit of a major tertiary-care hospital and its 719
720
Becker et al.
ability to reduce the time delay for aPTT determinations and the time to achieve a therapeutic state of anticoagulation compared with standard laboratory methods. METHODS Consecutive patients admitted to the coronary care unit of the University of Massachusetts Medical Center between July and November 1992with active venous or arterial thromboembolic diseasereceiving a continuous intravenous infusion of heparin (Elkinns-Sinn, Cherry Hill, N. J.) were enrolled in the study. Blood sampleswere obtained by standard venipuncture or from an indwelling venous line. The blood was collected in a plastic syringe (Becton Dickinson and Co., Rutherford, N. J.) and transferred through an l&gauge needleto a test cartridge (bedsideaPTT) and a glasstube containing 0.38 mg/dl sodium citrate (standard laboratory aPTT). Turnaround time was defined as the time from sample acquisition to aPTT result availability. Transport time was defined asthe time from sampleacquisition to the time the samplewaslogged in by the central laboratory. The laboratory turnaround time was considered the time from log-in time to the time the results were entered into the hospital-wide laboratory test computer. A compositeof the two time intervals wasthe complete turnaround time. In a separatestudy of 33 heparinized patients, randomization to either bedsideor central laboratory aPTT testing was performed before treatment. All patients had aPTT determinations every 6 hours for 48 hours and heparin titration according to a standardized nomogram. An aPTT wasdetermined 4 hours after any changein heparin dosing. The studies were approved by the Committee for the Protection of Human Subjects in Clinical Research, University of MassachusettsMedical School. Standard laboratory aPTT determination.‘Blood sampleswere drawn into citrate tubes asdescribedpreviously. Care wastaken to fill each 5 ml tube completely. The sampleswere then mixed and centrifuged at 3000rpm at room temperature to obtain platelet-poor plasma. Activated partial thromboplastin time determinations were cakulated with an automated system (MLA 700, Medical Laboratory Automation, Pleasantville, N. Y.) after the manufacturer’s recommendations. In each, an aPTT reagent (activated FS) (American Dade, Aquada, Puerto Rico) was used (normal range 27.0 to 39.0 seconds). Bedside coagulation monitor. The Coaguchek Plus System (Boehringer Mannheim Diagnostics,Indianapolis, Ind., formerly Biotrack CoagulationMonitor, Ciba Corning Diagnostics, Medfield, Mass.) Biotrack 512 coagulation monitor is a battery-powered, portable laser photometer that usesa phospholipid (soybeanphosphatide) and an activator of intrinsic coagulation (bovine brain sulfatide) to determine the aPTT. Microliter samplesof capillary, arterial, or venous whole blood can be used. In the present study venous sampleswere usedin all cases;however, previous studies at our institution (unpublished data) have shown comparable results with each when meticulous attention to technique is observed.
American
October 1994 Heart Journal
In brief, a disposable plastic reagent cartridge was inserted into the instrument and allowed to warm. A drop of whole blood wasthen applied to the application well of the cartridge. The blood issubsequentlydrawn by capillary action through the reagent chamber, where it mixes with activator and phospholipid (Fig. 1). The laserphotometer, sensesvariations in light scatter from red blood cells, detecting the cessationof blood flow. The time from blood application to cessationof flow (clotting) is then converted mathematically to a plasmaequivalent aPTT. The conversion factor has been establishedpreviously by the manufacturer.8 (normal aPTT 31 seconds; range 21 to 41 seconds).All bedside tests were performed by coronary care unit nursestrained and certified by the central laboratory according to current guidelines. The time from aPTT determination to a decisionregarding heparin titration was charted prospectively on a bedsidedata sheet. Validation studies: Bedside coagulation monitor. A previous multicenter study coordinated at our institution of 319 anticoagulated patients compared aPTTs obtained from the Coaguchek Plus Biotrack 512 instrument and those determined by a conventional laboratory instrument.8 The correlation coefficient (0.83) wasnearly identical to the correlation coefficients observed when different laboratory aPTT reagents were compared. A recently completed validation study of 60 heparin-treated patients with unstable angina and acute myocardial infarction produced nearly identical correlation coefficients to those of the initial multicenter experience (unpublisheddata), even when thrombolytic therapy patients were included in the analysis.A high degreeof precision,asdemonstratedby low coefficients of variation, has been observedfor both within-day and between-day testing with the CoaguchekPlus Biotrack 512 monitor and normal controls.8 Quality control: Bedside coagulation monitor. On arrival in the laboratory each shipment of cartridges, which included a temperature sensorfor shipping condition verification, wasvalidated with lyophilized whole-blood quality controls. The individual cartridges were checked for dating and calibration on insertion into the monitor. The monitors themselveswere checkeddaily with bilevel quality control cartridges which simulateactual performanceof a test (timings, actions, measurements). Statistical analysis. Means r SD for the aPTT method groups were calculated. Repeated measuresanalysis of variance wasapplied to test for differences. In the time to therapeutic aPTT substudy, values were determined by interpolating (linearly) the aPTT measurementsto provide imputed hourly values. RESULTS A total of 272 aPTT determinations (mean 74.0 +- 28.3 seconds) were performed on 120 patients with active thromboembolic disease admitted to the coronary .care unit. In I2 patients the bedside aPTT was performed twice because of technical errors (inadequate sample volume). The time from sample collection to data availability for clinical decision
Volume 128, Number 4 American Heart Journal
Rmker cd al.
721
1. Disposableplastic reagent cartridge usedfor bedsideaPTT determinations in Boehringer Mannheim Biotrack 512 coagulation monitor.
Fig.
making (complete turnaround time) was 126 + 84 minutes (95 % CI 108 to 144 minutes) with standard laboratory aPTT testing and 3 minutes with the bedside coagulation monitor (p < 0.0001). The time from sample collection to arrival in the central laboratory (transport time) was 36 & 26 minutes (95% CI 24 to 42 minutes). Although this particular study was not designed to investigate the adequacy of heparinization achieved and maintained, 21% of patients participating were found to have subtherapeutic anticoagulation (aPTT < 65 seconds) when receiving a continuous intravenous heparin infusion. In each, an infusion adjustment and repeat aPTT was required. In the time-to-therapeutic-anticoagulation substudy, 264 aPTT determinations were performed on 33 heparin-treated patients. The median time required to achieve an aPTT of at least 65 seconds was 8.2 hours (25th percentile, 8.0; 75th percentile, 9.1) among patients randomized to bedside monitoring and 18.1 hours (8.4,29.5) in patients assigned to central laboratory aPTT testing (p 0.005). The time from aPTT determination to heparin titration adjustment averaged 14.5 minutes (range 1 to 20 minutes) with bedside testing and 3.0 hours (range 2.0 to 4.0 hours) with central laboratory testing (p < 0.001). Despite the rapid achievement of therapeutic systemic anticoagulation, subtherapeutic aPTTs were common in both groups during the study, suggesting that even a rapid bedside monitoring tool cannot compensate for suboptimal heparin dosing whether it be physician directed or, in this case, nomogram directed (Tables I and II).
DISCUSSION
Our study of heparin-treated patients admitted to the coronary care unit identified significant differences in aPTT determination time delays and differences in achieving a therapeutic state of systemic anticoagulation comparing standard central laboratory and bedside coagulation testing. Conceivably, the observed time delays could have been even greater had we included the time from data availability on the hospital-wide computer system to when the results prompted a clinical decision. Clearly, a nurse or physician would have to wait patiently by the computer for the results to appear to avoid additional time delay. This is not practical in a modern-day coronary or intensive care unit. Indeed, our experience (unpublished data) suggests that, on average, 30 minutes typically elapses between data availability on the computer and clinical decision making. In contrast, bedside testing allows prompt real-time decisions to be made. Furthermore, consistent with the findings of previous studies,4l 5 we found that, subtherapeutic anticoagulation was not an uncommon occurrence among patients receiving intravenous heparin, raising further concerns over delays in identifying inadequately treated patients and making timely adjustments. Bedside coagulation testing offered the clinician a rapid and reliable means of assessing anticoagulant response to heparin therapy. It is well known that commercial activated partial thromboplastin time reagents respond differently to heparin. g-11 Instrumentation i2-i4 collection tubes,‘” and blood volume16 may be iources of variability as
722
Becker et al.
American
October 1994 Heart Journal
Table I. aPTT values during the 48-hour study period: Time-to-therapeutic-anticoagulation substudy Study
groups*
Bedside Parameter
Time aPTT aPTT aPTT *Includes tp 0.005.
Median
to therapeutic aPTT (hr) 65-80 set (%) <65 set (% ) >80 set (%) all time points in 4%hour
25th
8.21 26.1 48.8 25.9
percentile
Laboratory 75th percentile
8.0 19.2 34.9 6.1
Median
25th
18.1 21.2 42.0 28.4
9.1 36.5 55.2 30.9
percentile
8.4 12.8 28.7 16.4
75th percentile
29.5 35.0 60.9 53.9
study period.
Table II. Duration and aPTT measurements:Time-to-therapeutic-anticoagulation substudy Study
groups*
Bedside Parameter
Duration (hr) aPTT <65 set aPTT 65-80 set aPTT >80 set Mean (set) aPTT <65 set aPTT >80 set *Includes
all
Median
25th
percentile
Laboratory 75th
Dercentile
Median
25th
percentile
75th percentile
23.2 11.8 10.1
10.1
32.1
18.0
12.9
8.8 2.1
21.0 15.8
10.2 15.2
6.3 10.5
33.4 20.0 20.9
55.8 100.2
53.7 87.1
58.8 110.2
58.5 100.5
54.9 92.9
58.9 114.7
time points in 4%hour study period.
well. The bedside coagulation device avoids these limitations and, in addition, the entire test is run by one person at the patient’s bedside, minimizing time delays and the potential for error. Heparin is the most commonly used anticoagulant in the treatment of patients with venous and arterial thromboembolic diseases. There is substantial evidence that a therapeutic state of systemic anticoagulation must be achieved and maintained to obtain maximum benefit while, at the same time, minimizing the likelihood of hemorrhagic complications.lw3s 17~I8 Our findings suggest that the routine use of standard laboratory aPTT testing is associated with marked delays in vital data acquisition. If heparin was less variable in its anticoagulant effects and easy to titrate, time delays in coagulation monitoring would have less of a clinical impact. On the contrary, it is widely appreciated that the pharmacokinetics of heparin are complex and its anticoagulant effects are difficult to predict with certainty.6 Frequent aPTT determinations are, therefore, required, particularly during the first 48 hours of intravenous heparin administration. A prolonged turnaround time for aPTT results in patients with active thromboembolic disorders may
translate directly into excessive delays in providing maximal care. This in turn could cause increased morbidity and mortality. We are currently exploring this area carefully. If confirmed, bedside coagulation monitoring would not only impact significantly on patient care but would likely influence medical cost as well. In conclusion, bedside aPTT testing with the Coaguchek Plus Biotrack 512 coagulation monitor provides a convenient, rapid, and accurate assessment of systemic anticoagulation in heparin-treated patients with active thromboembolic disease. Its use deserves further evaluation in the coronary care unit and other clinical settings. We thank the coronary care unit nursing staff for their support.
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