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Ann Thorac Surg 1996;61:795-799
© 1996 The Society of Thoracic Surgeons

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Original Articles: Cardiovascular

Response of Kaolin ACT to Heparin: Evaluation With an Automated Assay and Higher Heparin Doses

Departments of Anesthesiology, Internal Medicine, Pathology, and Surgery, Washington University School of Medicine, St. Louis, Missouri

Accepted for publication August 12, 1995.

	Abstract

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Background. Because previous reports suggest that the linear relationship between celite activated clotting time (ACT) values and heparin sodium is disrupted if values exceed 500 to 600 seconds, this study was designed to evaluate the relationship of kaolin activated clotting time (ACT) values to high in vitro heparin concentrations. In addition, the relationship of kaolin ACT to heparin concentration as determined manually was compared with that obtained with an automated heparin dose response assay.

Methods. Blood specimens were obtained prior to and after heparin administration from 41 cardiac surgical patients requiring cardiopulmonary bypass in this institutional human studies committee-approved study. Five ACT instruments were used to evaluate the response of kaolin ACT to manually added heparin at two anticoagulation levels: low range (ACT values of less than 500 seconds) and high range (ACT values of 500 seconds or greater). Specimens were also used to measure kaolin ACT values at three heparin concentrations with an automated heparin dose response assay (HDR) using a Hepcon instrument.

Results. A greater response of kaolin ACT to heparin was seen with high-range ACT values than low-range ACT values as illustrated by greater (p = 0.002) mean slope values (low range, 99 ± 30 s•U^-1•mL^-1; high range, 128 ± 50 s•U^-1•mL^-1). Good correlations were obtained between heparin concentration and either low- or high-range ACT values as demonstrated by mean correlation coefficients (low range, 0.992; high range, 0.982). The response of low-range kaolin ACT values to heparin was greater than that obtained with the automated heparin dose response assay as illustrated by greater (p = 0.005) mean slope values (low range, 99 +/30 s•U^-1•mL^-1; HDR, 82 ± 21 s•U^-1•mL^-1). Good correlations were observed for the relationship between heparin and ACT values obtained with the HDR assay (r = 0.998).

Conclusions. A variable response of kaolin ACT to heparin among patients was demonstrated in our study, especially when ACT values exceeded 500 seconds. We found that the response of kaolin ACT to higher heparin concentrations was acceptable for clinical monitoring based on good correlations obtained in individual patients. The HDR assay generally overestimates a patient's heparin requirements; most likely, this is due to a lower response of kaolin ACT to heparin concentration that is reflected by this assay. Because an exceptional correlation can be obtained between kaolin ACT values and heparin concentration using the assay, this automated assay can identify heparin-resistant patients who may need further treatment.

	Introduction

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Heparin sodium administration for cardiopulmonary bypass (CPB) can be based on either a fixed dosage schedule or the results of monitoring assays. One limitation of using fixed dosage schedules is the lack of confirmation that adequate anticoagulation has been achieved and maintained. To address this issue, the activated clotting time (ACT) is routinely determined to assess the adequacy of anticoagulation before and during CPB. On the basis of the substantial interpatient variability in the ACT response to heparin [1], use of a dose-response plot has been advocated to predict the heparin requirements of individual patients [2]. Accordingly, an automated heparin dose response assay (HDR; Medtronic HemoTec, Parker, CO) has been developed to project heparin requirements for a particular patient. Previous reports suggest that the linear relationship between celite ACT values and both heparin dose [1, 3] and concentration [4] is disrupted if values exceed 500 to 600 seconds. Therefore, this study was designed to evaluate the relationship between kaolin ACT values and high in vitro heparin concentrations and to compare the relationship of kaolin ACT to heparin concentration as determined manually with that obtained with the automated HDR assay.

For editorial comment, see 781.

	Material and Methods

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Enrollment and Intraoperative Management
Blood specimens from 41 adult patients undergoing cardiac operations requiring CPB were used in this institutional human studies committee-approved study. Exclusion criteria included administration of heparin preoperatively, intraoperative use of aprotinin, and emergency procedure. All patients were anesthetized with an opioid-based technique, and the anesthetic was supplemented with inhalational anesthetic agents, muscle relaxants, and benzodiazepines. Extracorporeal circulation was accomplished with a Bio-Medicus centrifugal pump (Bio-Medicus, Eden Prairie, MN) and a Bentley membrane oxygenator (Baxter Healthcare, Bentley Division, Irvine, CA), and systemic hypothermia was maintained at 28°C during cardioplegia. Systemic anticoagulation for CPB was accomplished with porcine heparin and was administered based on on-site measurements of heparin dose response, heparin concentration, and kaolin ACT using the Hepcon instrument (Medtronic HemoTec, Englewood, CO) as previously described [5]. After the patient was rewarmed to 37°C, extracorporeal circulation was discontinued and heparin, neutralized with protamine sulfate. The protamine dose was determined on the basis of the whole-blood heparin concentration measured prior to discontinuation of CPB (1.3 mg of protamine per milligram of residual heparin).

Coagulation Analysis Protocol
Single blood specimens obtained from radial or femoral artery catheters or both after removal of 6 dead-space volumes were used for coagulation analysis by on-site whole-blood assays. Blood specimens were obtained prior to and 10 minutes after systemic administration of heparin. Specimens were used to measure kaolin ACT values at various in vitro heparin concentrations with the HDR or manual titration. The automated assay was used to evaluate the response of kaolin ACT to three in vitro bovine heparin concentrations (0, 1.5, and 2.5 U/mL of heparin) using a Hepcon instrument. The manual titration technique involved addition of incrementally greater doses of porcine heparin to ACT cartridges followed by measurement of kaolin ACT using five separate automated clot timer instruments (Medtronic HemoTec). The concentrations of heparin required to prolong ACT values within the range of 0 to 500 seconds (low range) were estimated using results derived from the heparin dose response assay. Similarly, heparin was added manually to five ACT cartridges to prolong ACT values within the range of 500 to 1,000 seconds (high range) using manually obtained low-range results. Kaolin ACT values were also measured after systemic administration of a heparin dose that was projected by the heparin dose response assay to result in a kaolin ACT value of greater than 480 seconds. Kaolin ACT values obtained from both instruments (automated clot time and Hepcon) at each heparin concentration were expressed as the mean of duplicate measurements. Activated clotting time values that exceeded the detection limit of the instruments (999 seconds) were excluded from statistical analysis.

Statistical Analysis
Ordinary (nonweighted) least squares linear regression was used to estimate a linear relationship between kaolin ACT measurements and in vitro heparin concentration in each patient and over the series of patients; a p value of less than 0.05 was considered significant. To facilitate further statistical analysis, correlation coefficients were mathematically converted into Fisher's Z transformation values using the following formula: 0.5 x log [(1 + r)/(1 - r)]. Over the series of patients, slopes and Fisher's transformed correlation coefficient values were used to compare the response of kaolin ACT to heparin between low range (manual) and either high range (manual) or automated (HDR) measurements using paired Student's t test or signed rank test. Over the complete range of ACT values (up to 999 seconds), slope values were calculated using ad hoc transformed ACT values based on exponents of 0.95, 0.85, 0.75, 0.65, and 0.55 to evaluate whether this would improve the predictive capabilities of the regression model. The ACT values after heparin administration were summarized to evaluate whether the HDR assay adequately predicted the correct heparin dose.

	Results

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Relationship of ACT to In Vitro Heparin Concentration Among Patients and Within Individual Patients
Although a linear relationship between kaolin ACT values and in vitro heparin concentration (HC) (ACT = 64HC + 251) was demonstrated over the entire measurement range (0 to 999 seconds), there was variation in the response of kaolin ACT to heparin (r = 0.79) between patients. This variability was also demonstrated by a normal distribution of mean slope values (110 ± 38 s• U^-1•mL^-1) obtained from the series of patients (Fig 1). In contrast, an excellent relationship between kaolin ACT values and heparin concentration was evident in individual patients as demonstrated by the mean correlation coefficient value (0.98 ± 0.03) (Fig 2).

View larger version (44K): [in this window] [in a new window]   Fig 1. . Frequency distribution of regression slopes generated from linear relationship between kaolin activated clotting time (ACT) response to in vitro heparin dose (concentration). Frequency is expressed as number of patients in the series (n = 41). Linear regression slopes are expressed as seconds per unit of porcine heparin per milliliter of whole blood. Normal distribution curve was projected from the data and is plotted. (See text for complete description.)

View larger version (38K): [in this window] [in a new window]   Fig 2. . Linear relationship between kaolin activated clotting time (ACT) and in vitro heparin concentration in each patient. In vitro heparin concentration is expressed in units of porcine heparin per milliliter of whole blood. The linear regression relationship is plotted for each patient (n = 41), and patient number is designated in lower right corner of graph.

Relationship of ACT to In Vitro Heparin Concentration in Individual Patients: Comparison Between Automated and Manually Obtained Values for Low-Range ACT
The response of kaolin ACT to heparin dose with manually obtained low-range ACT values was greater than that obtained with the automated heparin dose response assay as illustrated by greater (p = 0.005) mean slope values (low range, 99 ± 30 s•U^-1•mL^-1; HDR, 82 +/21 s•U^-1•mL^-1). Accordingly, underestimation of kaolin ACT response or overestimation of heparin dose by the assay was confirmed after systemic administration of heparin by mean ACT values (592 ± 90 seconds) that exceeded the target ACT (480 seconds). Although the heparin dose response assay underestimated slope values, good correlations were observed for the relationship between heparin and ACT values obtained with the assay (r = 0.998).

	Comment

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
The practice of monitoring anticoagulation before and during CPB is based on the variable pharmacodynamic [6] characteristics of heparin before CPB, the variable pharmacokinetic [7] profile of heparin during CPB, and initial studies [8] that demonstrated a reduction in postoperative bleeding when ACT was used to monitor heparin therapy. Although the optimal ACT value for CPB is controversial [1, 2, 9, 10], values between 400 and 480 are commonly maintained. Strategies for optimal administration of heparin and protamine and the assessment of their effects on coagulation are currently being reevaluated in the cardiac surgical setting. The clinical impact of heparin and protamine dosing guided by in vitro testing has been reexamined in two recent clinical trials [5, 11]. Patients monitored with in vitro testing received more heparin and less protamine, had lower transfusion requirements, and exhibited less postoperative blood loss. These trials tailored the initial heparin dose for each patient on the basis of in vitro estimates of heparin response measured with either the HDR assay or the heparin response test (HRT; International Technidyne Inc, Edison, NJ), respectively.

Use of a dose-response plot has previously been advocated to predict the heparin requirements of individual patients before initiation of CPB [2], because there is substantial variability in the ACT response to heparin among patients [1]. Our current study confirms the variable response of kaolin ACT to heparin among patients, especially when ACT values exceed 500 seconds. Our data also show that the automated heparin dose response assay underestimates the response of kaolin ACT to heparin as demonstrated by lower mean slope values derived from the assay compared with manually obtained mean slope values. Accordingly, systemic administration of heparin on the basis of the heparin dose response assay estimates led to ACT values that exceeded 480 seconds in all but 1 patient in our series. This discrepancy may be due to reduced in vitro heparin activity in the automated assay secondary to decay from long-term storage [12] or may be related to the source of heparin used in the assay (bovine) versus the manual titration (porcine). It is established that there is considerable variability in heparin anticoagulant response that is related to the source of heparin (bovine lung versus porcine mucosa), the method of preparation, and the molecular weight distribution of various preparations [13].

Regulating heparin anticoagulation during CPB with only ACT measurements may be problematic because ACT values do not correlate with plasma heparin levels during CPB [3, 7, 14]. This may be due, at least in part, to the influence of CPB-related hypothermia and hemodilution on the ACT assay [3, 7, 14], the intrinsic variability of ACT measurements during anticoagulation, or activation or depression of platelet function [15]. Consequently, heparin concentrations can decline to less than 2 U/mL [7], which is lower than previously designated acceptable concentrations [15, 16], when heparin administration is guided by ACT-based protocols. More importantly, ACT anticoagulation protocols may lead to a consumptive state, as thrombin levels increase with time on CPB when heparin administration is based on these assays [17]. This limitation related to ACT monitoring may be overcome by using a system that not only provides ACT measurements but also accurately tracks heparin concentration both before and during CPB [7]. Accordingly, preliminary data indicate that maintenance of patient-specific heparin concentrations can preserve coagulation through enhanced inhibition of thrombin [18].

Reports [19, 20] of thromboembolic complications with use of aprotinin have stimulated additional interest in monitoring heparin anticoagulation during the perioperative period. Although celite ACT is prolonged by aprotinin, kaolin ACT is less affected [21]. The initial suggestion to maintain celite ACT greater than 750 seconds [22] has been supported by corresponding studies [23] showing that patients receive lower heparin doses and have lower heparin levels when the heparin dosing schedule is guided by celite ACT protocols in the setting of concurrent aprotinin administration. Current recommendations (package insert for aprotinin, Miles Inc) advise use of clotting assays that are unaffected by aprotinin. Stable heparin concentrations were maintained in patients receiving aprotinin when heparin administration was based on whole-blood heparin measurements in a recent evaluation [24]. This heparin dosing schedule also resulted in mean celite (1,309 ± 285 seconds) and kaolin (814 ± 204 seconds) ACT measurements that markedly exceeded ACT values previously recommended for CPB. However, whole-blood heparin concentration measurements do not reflect the biologic effect of heparin anticoagulation.

Previous reports suggest that the linear relationship between celite ACT values and both heparin dose [1, 3] and concentration [4] is disrupted if values exceed 500 to 600 seconds. Therefore, we pursued a formal evaluation of the relationship of kaolin ACT to higher heparin concentrations. In contrast to the variability seen between patients, our data demonstrate high correlations between kaolin ACT and heparin up to 1,000 seconds in individual patients (see Fig 2). Our data also reveal a greater response of kaolin ACT to heparin in the values greater than 500 seconds as demonstrated by greater mean slope values. This is not surprising, as other in vitro coagulation assays develop a logarithmic response to heparin as a particular threshold is reached [25]. Accordingly, an ad hoc transformation based on exponents (0.65 and 0.75) of measured ACT values improves the predictive capabilities of the regression model over the range of ACT values up to 1,000 seconds. Because ACT values greater than 500 seconds correlate extremely well with heparin concentration as demonstrated by mean correlation coefficients, the kaolin ACT assay can be used clinically to assess heparin anticoagulant effect at higher heparin concentrations.

In conclusion, there is significant variability in the response of kaolin ACT to heparin concentration among patients, which increases when ACT values exceed 500 seconds. In contrast to this interpatient variability, our data demonstrate an excellent correlation between kaolin ACT values and heparin concentration in individual patients up to ACT values of 1,000 seconds. Although the heparin dose response assay overestimates the dose of heparin needed to attain a target ACT value, higher correlations were observed between ACT values and heparin concentration using this assay. Therefore, the assay can be useful in identification of patients who have increased heparin requirements or who may benefit from transfusion of plasma to restore depleted antithrombin III levels. Because kaolin ACT values greater than 500 seconds correlate well with heparin concentration, these values accurately reflect the anticoagulant effect of higher heparin concentrations.

	Acknowledgments

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Supported in part by a research grant from Medtronic Hemotec.

	Footnotes

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Address reprint requests to Dr Despotis, Division of Cardiothoracic Anesthesiology, Department of Anesthesiology, Washington University School of Medicine, 660 S Euclid Ave, Box 8054, St. Louis, MO 63110.

	References

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 

1. Bull BS, Korpman RA, Huse WM, et al. Heparin therapy during extracorporeal circulation. I. Problems inherent in existing protocols. J Thorac Cardiovasc Surg 1975;69:674–84.[Abstract]
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3. Cohen J. Activated coagulation time method for control of heparin is reliable during cardiopulmonary bypass. Anesthesiology 1984;60:121–4.[Medline]
4. Stenbjerg S, Berg E, Albrechtsen OK. Heparin levels and activated clotting time (ACT) during open heart surgery. Scand J Haematol 1981;26:281–4.[Medline]
5. Despotis GJ, Joist JH, Hogue CW Jr, et al. The impact of heparin concentration and activated clotting time monitoring on blood conservation. A prospective, randomized evaluation in patients undergoing cardiac operations. J Thorac Cardiovasc Surg 1995;110:46–54.[Abstract/Free Full Text]
6. Esposito RA, Culliford AT, Colvin SB, et al. Heparin resistance during cardiopulmonary bypass. The role of heparin pretreatment. J Thorac Cardiovasc Surg 1983;85:346–53.[Medline]
7. Despotis GJ, Summerfield AL, Joist JH, et al. Comparison of activated coagulation time and whole blood heparin measurements to laboratory plasma anti-Xa heparin concentration in cardiac surgical patients. J Thorac Cardiovasc Surg 1994;104:1076–82.
8. Verska JJ. Control of heparinization by activated clotting time during bypass with improved postoperative hemostasis. Ann Thorac Surg 1977;24:170–3.[Abstract]
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12. Tunbridge LJ, Lloyd JV, Penhall RK, et al. Stability of diluted heparin sodium stored in plastic syringes. Am J Hosp Pharm 1981;38:1001–4.[Abstract]
13. Thomas DP, Barrowcliffe TW, Johnson EA. The influence of tissue source, salt and molecular weight on heparin activity. Scand J Haematol 1980;25:40–8.
14. Culliford AT, Gitel NS, Starr N, et al. Lack of correlation between activated clotting time and plasma heparin level during cardiopulmonary bypass. Ann Surg 1981;193:105–11.[Medline]
15. Gravlee GP. Anticoagulation for cardiopulmonary bypass. In: Gravlee GP, Davis RF, Utley JR, eds. Cardiopulmonary bypass: principles and Practice. Baltimore: Williams & Wilkins, 1993:340-80.
16. Jobes DR, Schwartz AJ, Ellison N, Andrews R, Ruffini RA, Ruffini JJ. Monitoring heparin anticoagulation and its neutralization. Ann Thorac Surg 1981;31:161–6.[Abstract]
17. Slaughter TF, Lebleu TH, Douglas JM, et al. Characterization of prothrombin activation during cardiac surgery by hemostatic molecular markers. Anesthesiology 1994;80:520–6.[Medline]
18. Despotis GJ, Joist JH, Hogue CW, et al. The effect of higher heparin concentrations on preservation of hemostasis in cardiac surgical patients. Anesthesiology 1995;83:91A.
19. Sundt TM III, Kouchoukos NT, Saffitz JE, Murphy SF, Wareing TH, Stahl DJ. Renal dysfunction and intravascular coagulation with aprotinin and hypothermic circulatory arrest. Ann Thorac Surg 1993;55:1418–24.[Abstract]
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24. Despotis GJ, Joist JH, Joiner-Maier D, et al. Effect of aprotinin on activated clotting time, whole blood and plasma heparin measurements. Ann Thorac Surg 1995;59:106–11.[Abstract/Free Full Text]
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