Ann Thorac Surg 2004;77:973-976
© 2004 The Society of Thoracic Surgeons
Original article: cardiovascular
New technology, old standards: disparate activated clotting time measurements by the Hemochron Jr compared with the standard Hemochron
Christopher L. Aylsworth, PA-Ca*,
Faith Stefan, CCPa,
Karl Woitas, CCPa,
Randall H. Rieger, PhDb,
Martin LeBoutillier, III, MDa,
Verdi J. DiSesa, MDa
a The CardioVascular Center at The Chester County Hospital, West Chester, Pennsylvania, USA
b Department of Mathematics, West Chester University of Pennsylvania, West Chester, Pennsylvania, USA
Accepted for publication August 6, 2003.
* Address reprint requests to Mr Aylsworth, The CardioVascular Center at The Chester County Hospital, 701 East Marshall St, West Chester, PA 19380, USA
e-mail: caylsworth{at}cchosp.com
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Abstract
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BACKGROUND: Accurate control of the anticoagulation level is important for safe initiation of cardiopulmonary bypass. Using the Hemochron Jr., we consistently noted a higher than customary heparin dose required to achieve an activated clotting time (ACT) that, according to the literature and our quality standards, should be more than 480 seconds. This study was designed to determine whether there existed a significant difference in ACT values measured by the newer Hemochron Jr. and the older Hemochron 801 assay system.
METHODS: A total of 30 patients underwent cardiovascular surgical procedures requiring heparinization (300 U/kg). Multiple samples for measurement of the ACT were obtained from all patients before heparinization, after heparinization, during cardiopulmonary bypass, and after protamine administration. Arterial samples were collected, and ACT was determined simultaneously on the same sample using both Hemochron Jr. and Hemochron 801. Activated clotting time data were analyzed with a linear mixed model using an unstructured variance-covariance matrix.
RESULTS: Descriptive statistics on all heparinized patients revealed that the Hemochron Jr. yielded ACT results that on average were 121.28 seconds lower than the determination by the standard Hemochron 801 on the same sample of blood. This difference was -139.04 in on-pump cases and -90.51 in off-pump cases, primarily a function of the fact that higher heparin doses and therefore longer ACTs were used in patients having operations using the heart-lung machine. From the linear mixed model, the estimated average paired difference between the Hemochron Jr. and Hemochron 801 was found to be -86.03, yielding a highly significant test statistic (t28 = -6.18; p < 0.0001).
CONCLUSIONS: Lower ACT values determined by Hemochron Jr. are consistent with higher, clinically acceptable ACT values as measured by the Hemochron 801. These findings would suggest that safe levels of anticoagulation are determined in part by the specific assay used.
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Introduction
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Anticoagulation with heparin is a practical necessity for safe initiation of cardiopulmonary bypass. In this and other settings, the activated clotting time (ACT) is routinely used as a measure of anticoagulation after heparinization. Its introduction in the 1970s as a better means to determine a patient's level of anticoagulation demonstrated a poor correlation with actual heparin concentrations, but a reliable indicator of fibrin monomer formation in animal and pediatric models [1–3]. This mechanism for determining the level of anticoagulation translated into a more accurate way to avoid clot formation during cardiopulmonary bypass given the variability in dose-related heparin effects. Its superiority to rules using body surface area, or heparin concentration levels to gauge safe levels of anticoagulation, yielded less overall utilization of heparin and protamine, and ultimately decreased the incidence of transfusions by up to 30% [4–8]. Notably, the effects of hemodilution, hypothermia, and aprotinin use limit the celite ACT values [9–12]. These limitations and determinations of safe levels of anticoagulation were initially based on the measured ACTs determined by the Hemochron 801 assay system (Hemochron; International Technidyne, Inc, Edison, NJ).
At our institution we have used the newer Hemochron Jr. Signature (HJr; International Technidyne, Inc) routinely to monitor the ACT because of the fully automated process, thereby limiting the ability for user-dependent error or variance. We noted that after standard dosages of heparin, the ACT was lower than the quality standard of 480 seconds measured by the Hemochron, and additional heparin boluses were needed to achieve a therapeutic ACT. The HJr package insert admits an apparent 10% to 15% shorter time than celite-based ACTs and encourages institutions to determine their own safe levels for anticoagulation. Given the disparity between the ACT measured by the standard Hemochron and the HJr, we sought to determine whether a statistically significant difference existed between these two different measurements of ACT. This study was designed to compare these two assays performed on the same samples of blood from patients undergoing cardiac operations.
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Patients and methods
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A total of 173 arterial samples, before, during, and after reversal of anticoagulation with heparin, were drawn from 30 patients undergoing cardiovascular surgical intervention. Nineteen patients had surgery using cardiopulmonary bypass (109 samples), and 11 were done without bypass (64 samples). The Hemochron system used a celite-based ACT (HRFT CA510) with 12 mg of diatomaceous earth or a kaolin-based ACT (HRFT K-ACT) with 12 mg of kaolin for patients who received aprotinin. As recommended by the manufacturer, the user draws a 2-mL sample of blood, which is mixed with the activator by rotating and tapping the tube on a hard surface. The room temperature tubes are then heated by the machine to 37°C. The test is completed when the fibrin monomers slow movements of a foreign body within the sample. The HJr used the ACT+, a silica, kaolin, and phospholipid mixture not affected by aprotinin use. The cartridges are prewarmed by the machine to 37°C, and an automatic aspiration of a 15-µL sample of blood is done for evaluation. No shaking or mixing is required by the user. The test is completed when the formation of clot slows the movement of blood in a microcapillary tube below a preset rate, using electronic optical detection. All devices were calibrated daily by means of quality control tests from the manufacturer to ensure reliability. The ACT was determined in duplicate using both the standard Hemochron and simultaneously with the HJr. A minimum of three samples was drawn per patient, with each sample classified as a baseline or preheparin value, a heparinized value, or a postprotamine value. The number of samples varied from three to eight samples per patient dependent on the length of the procedure performed and number of additional heparin boluses required to achieve therapeutic anticoagulation.
Baseline or pre-ACTs were measured at the outset of the procedure before skin incision. Heparin was administered as a 300 U/kg intravenous bolus with additional boluses given to achieve an ACT in excess of 480 seconds as measured by the Hemochron. During the cardiovascular surgical procedure subsequent arterial samples were drawn to monitor the level of anticoagulation. Additional heparin was given as necessary to maintain an ACT above 480 seconds for on-pump cases and above 400 seconds for off-pump cases. After either discontinuation of cardiopulmonary bypass or completion of the proximal anastomoses in off-pump procedures, protamine was administered as a 1 mg/100 U of heparin infusion to achieve an ACT less than 200 seconds. All "post" values were recorded accordingly.
Figure 1 illustrates by means of a scatterplot the relationship between the mean HJr and the mean Hemochron for each heparinized patient. A Bland Altman analysis was also conducted [13, 14]. After verifying the assumption that the variances were independent of the subject means for both HJr and Hemochron, 95% limits of agreement for HJr - Hemochron were calculated. For each subject we plotted the difference between the means for the two methods against their average, including the 95% limits of agreement (Fig 2).
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Fig 2. Subject difference in activated clotting time (ACT) for Hemochron Jr minus Hemochron, against mean, including 95% limits of agreement, which is represented by the dashed line.
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Because the data are longitudinal and correlated, a linear mixed model was used to model the differences observed and to conduct tests of hypothesis [15–17]. This model is based on the traditional linear regression model with the added advantage that it takes into account the correlation between measurements within subjects. For these data, an unstructured variance-covariance matrix was chosen based on a plot of observations across time showing no discernible correlation pattern. The covariance structure allowed the correlation within each individual patient to be estimated without any constrictions. The specific null hypotheses of interest were (1) that the overall average difference in ACT was equal to zero and (2) that the overall average difference in ACT was equal between on-pump patients and off-pump patients. All hypothesis tests were based on least squares means from this model and were conducted at the nominal 
= 0.05 level.
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Results
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Tables 1 –3 display average means combining all measurements taken, without regard to within-subject correlation. Thus, these tables should be considered solely for descriptive purposes. Table 4 displays the regression variables from the linear mixed model. All statistical inferences (hypothesis tests and reported p values) are based on the results shown in Table 4.
In Figure 1, any points below the HJr = Hemochron line indicate subjects with an average HJr ACT lower than Hemochron. It is apparent from this scatterplot that HJr achieves a faster average ACT in 29 of the 30 patients during heparinization. This difference is large in many of the patients. As shown in Figure 2, using the Bland Altman procedure, the standard deviation of differences between single observations was found to be 143.82, leading to 95% limits of agreement of -420.87 and 142.88. Thus, a measurement by HJr is unlikely to exceed a measurement by Hemochron by more than 142.88 seconds or be less than 420.87 below.
The HJr recorded an ACT which averaged 121.28 (±12.07) seconds less than that determined by the Hemochron during full heparinization (Table 1), resulting in a highly significant average paired difference between HJr and Hemochron for the heparinized group (ß = -86.03; standard error of the mean, 13.91; t28 = -6.18; p < 0.0001). Table 2 compares time differences before heparin administration, during heparin administration, and after reversal. The average time differences were -31.43, -121.28, and -14.42 seconds, respectively. Table 3 further illustrates the average time difference in nonheparinized samples, stratified by pump status. For the heparinized samples (ß = -32.61; standard error of the mean, 27.82; t28 = -1.17; p = 0.2431) as well as nonheparinized samples (p = 0.8133), there was not a significant paired difference in ACT attributable to pump status.
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Comment
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The results of this study suggest that the ACT measured by the HJr is systematically lower that determined by the standard Hemochron. An ACT measured by the newer test is consistently approximately 86 seconds shorter than one measured by the original test on which the 480-seconds standard is based. For this reason and allowing for a margin of safety, we conclude that an ACT of 400 seconds as determined by the HJr is acceptable for the safe initiation of cardiopulmonary bypass. In addition to cost savings from achievement and reversal of supratherapeutic ACTs, benefits may also include a reduction in the incidence of transfusions from nonsurgical bleeding caused by excessive levels of anticoagulation. Also, from a quality control standpoint the HJr appears to offer an advantage by minimizing the effect of user-dependent preparation of samples.
The importance of adjusting standards to advances in pharmacology and technology is an old story in cardiac surgery. A related discussion and adjustment of standards occurred when aprotinin began to be used as a therapeutic adjunct. It was determined that this drug had an effect on standard measurements of ACT using celite, necessitating an alteration in the standard technique. The data from this study show clearly that the device used to determine ACT also should influence a clinician's determination of a safe level of anticoagulation. In this instance, the newer device to assay ACT produced results that differ significantly from its predecessor.
Cardiac surgery is exciting because it remains dynamic with new methods, techniques, drugs, and equipment introduced frequently. As new technology becomes available, it is important to reevaluate the basis for and methods by which original standards of practice were established.
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References
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Abstract
Introduction
