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J Thorac Cardiovasc Surg 1994;108:1076-1082
© 1994 Mosby, Inc.

CARDIOPULMONARY BYPASS, MYOCARDIAL MANAGEMENT, AND SUPPORT TECHNIQUES

Comparison of activated coagulation time and whole blood heparin measurements with laboratory plasma anti-Xa heparin concentration in patients having cardiac operations

St. Louis, Mo.

Supported in part by a research grant from Medtronic-Hemotec, Englewood, Colo.

Received for publication Dec. 23, 1993. Accepted for publication April 27, 1994. Address for reprints: George Despotis, MD, Division of Cardiothoracic Anesthesiology, Department of Anesthesiology, Box 8054, Washington University School of Medicine, 660 South Euclid Ave., St. Louis, MO 63110.

Abstract

Previous reports suggest that activated clotting times do not correlate with heparin concentration during cardiopulmonary bypass. This study was designed to compare whole blood heparin concentration and activated clotting time measurements with laboratory-based plasma heparin concentration. Sixty-two patients having cardiac operations requiring cardiopulmonary bypass were enrolled in this study. The study was conducted in two phases. In phase I of this trial, blood specimens were obtained from 30 patients before heparin administration and after each of three heparin doses (20, 80, and 150 U/kg). In phase II, blood specimens were obtained from 32 patients before heparin administration and 10 minutes after each of the following: heparin administration (250 or 300 U/kg), initiation of cardiopulmonary bypass, achievement of hypothermia, initiation of rewarming, and immediately before discontinuation of bypass. Blood specimens were used to measure activated clotting time (kaolin and celite), whole blood heparin concentration, and anti-factor Xa plasma heparin concentration. In phase I, activated clotting time (celite: r = 0.91; kaolin: r = 0.93) and whole blood heparin concentration (r = 0.98) measurements correlated well with plasma heparin concentration. After initiation of cardiopulmonary bypass (phase II), weak correlations for activated clotting time measurements (celite: r = 0.34; kaolin: r = 0.59) and a strong correlation for whole blood heparin concentration (r = 0.95) were evident when compared with plasma heparin concentration. During bypass, activated clotting time measurements also inversely correlated with temperature (celite: r = -0.21; kaolin: r = -0.19) and hematocrit (celite: r = -0.26; kaolin: r = -0.21). A weak correlation between activated clotting time measurements and plasma heparin concentration is evident during the cardiopulmonary bypass period, probably because of the influence of both reduced hematocrit and temperature on the activated clotting time assay. In contrast, whole blood heparin measurements correlate well with plasma heparin concentration before and during bypass. Further studies are needed to determine whether maintaining heparin levels during cardiopulmonary bypass by monitoring heparin concentration is more effective in preventing consumptive activation of the hemostatic system, reducing bleeding, and minimizing the use of blood products after cardiopulmonary bypass when compared with a protocol based on activated clotting time. (J THORAC CARDIOVASC SURG 1994;108:1076-82)

The activated clotting time (ACT) is routinely used to assess adequacy of anticoagulation before and during cardiopulmonary bypass (CPB). The ACT has also been used to estimate protamine dose required to reverse heparin and to evaluate heparin rebound in the postoperative setting. However, monitoring coagulation in the perioperative period exclusively with the ACT may be misleading because previous studies have illustrated that ACT values during CPB do not correlate well with plasma heparin level. ^1-5 The ACT assay has also been shown to be insensitive to low heparin concentrations, so that it is unsuitable for identifying patients with heparin rebound. ⁶

As previously described, an on-site hemostasis management system can provide ACT and heparin concentration measurements. ^7-12 Although this whole blood technology has been previously evaluated, a comparison of heparin concentration measurements between this automated protamine titration method and a standard laboratory assay has not been performed. Therefore, this study was designed to compare whole blood heparin concentration and ACT measurements with laboratory-based plasma anti-factor Xa heparin concentration to determine whether these on-site assays can accurately assess heparin concentration in the operative setting.

METHODS AND PATIENTS

Sixty-two adult patients scheduled for elective cardiac operations necessitating CPB were enrolled in this study. The study protocol was approved by the institutional human studies committee and informed consent was obtained from all patients. Exclusion criteria included intraoperative aprotinin administration and emergency procedures. All patients were anesthetized with an opioid-based technique, and the anesthetic was supplemented with inhalational anesthetic agents, muscle relaxants, and benzodiazepines. CPB was accomplished with a Bio-Medicus centripetal pump (Medtronic Bio-Medicus, Eden Prairie, Minn.), a Cobe membrane oxygenator (Cobe Laboratories, Inc., Lakewood, Colo.), and systemic hypothermia was maintained at 28° C during the operative interval involving cardioplegia administration. The CPB system was routinely primed with 2 L of electrolyte solution (Plasma-Lyte), 50 mEq of sodium bicarbonate, 25 gm of mannitol, and 5000 U of porcine heparin.

Systemic anticoagulation for CPB was accomplished with porcine heparin. To assess the correlation of on-site, whole blood determinations of heparin concentration and ACT with plasma heparin concentrations before and after initiation of CPB, the study was divided into two phases. Phase I of this trial was designed to evaluate correlations before CPB and consisted of 30 patients who had not received preoperative heparin. A total heparin dose of 250 U/kg body weight was administered in three divided doses after consecutive 15-minute periods: the initial dose was 20 U/kg, the second dose was an additional 80 U/kg, and this was followed by a final dose of 150 U/kg. Phase II of this trial was designed to assess assay correlations in 32 patients during CPB who had received one of two unfractionated heparin doses (250 or 300 U/kg) before CPB. Anticoagulation for CPB was monitored as per standard practice with the ACT (International Technidyne, Edison, N.J.); further doses of heparin were administered as needed to maintain an ACT of 480 seconds or more. After the patient was rewarmed to 37° C, extracorporeal circulation was discontinued and heparin was neutralized with protamine (0.8 mg of protamine per milligram of total heparin administered before and during CPB).

Single blood specimens obtained either from the CPB arterial cannula or from radial and/or femoral intraarterial catheters after removal of six dead space volumes were used for coagulation analysis by both routine laboratory and on-site, whole blood assays. In phase I, blood specimens (n = 4) were obtained 15 minutes before heparin administration and 10 minutes after each successive heparin dose (20, 80, and 150 U/kg). In phase II, blood specimens (n = 6) were obtained before heparin administration and 10 minutes after each of the following: heparin administration (A), initiation of CPB (B), achievement of hypothermia (C), initiation of rewarming (D), and immediately before discontinuation of CPB (E).

Blood specimens were divided into two aliquots. One aliquot was injected into a blue top Vacutainer tube (Becton Dickinson & Co., Rutherford, N.J.) (1/10 V, 0.129 mol/L sodium citrate), refrigerated, and transported to the laboratory for stat processing. After processing, a plasma aliquot of each blood specimen collected at each time period was labeled, frozen, and stored for later measurement of heparin concentration. Plasma heparin concentration was determined with an anti-factor Xa chromogenic substrate assay (Xa HC) as previously described. ¹³ A second aliquot was used during the operation to measure celite-activated ACT (HC ACT) using a Hemochron 801 instrument (International Technidyne, Edison, N.J.) and kaolin-activated ACT (HT ACT) using a Hepcon instrument (Medtronic Hemotec, Englewood, Colo.) in duplicate. ACT values obtained from both assays were expressed as the mean of duplicate measurements. This aliquot was also used to measure whole blood (WB) heparin concentration (HC) with an on-site protamine titration assay with the Hepcon instrument in duplicate. These replicate measurements to whole blood heparin concentration (WB HC1 and 2) were then used to determine mean whole blood heparin concentration values (WB HC). In addition, both hematocrit (Hct) and core temperature (Temp) values were quantified with each specimen collection. Hematocrit values were used to convert whole blood heparin concentration into plasma equivalent values with the following formula: plasma equivalent heparin concentration = whole blood HC x 100/100 - hematocrit.

Ordinary (nonweighted) least-squares linear regression was used to estimate a linear relationship between plasma antiXa heparin concentration measurements and on-site, whole blood assays with p < 0.05 considered statistically significant. ACT and whole blood heparin concentration were compared by analyzing the response of these assays to plasma anti-Xa heparin concentration before and during CPB by means of correlation coefficients, partial correlations, and bootstrap analysis. To assess the differential effects of hematocrit, temperature, and anti-Xa heparin concentration on the ACT assays, we examined the relationship of the ACT assays to these variables by means of multivariate Huber regression analysis.

RESULTS

Correlation between ACT, whole blood heparin concentration, and anti-Xa heparin concentration.
After administration of 20, 80 and 150 U/kg heparin doses, mean anti-Xa heparin concentrations during phase I were 0.3, 0.7 and 3.4 U/ml, respectively. In the pre-CPB period (phase I), ACT measurements (n = 182) from both assays and whole blood heparin concentration correlate well with laboratory-derived plasma anti-Xa heparin concentration (Table I). During the CPB interval (phase II), correlations between ACT measurements (n = 159) and anti-Xa heparin level are much weaker. In contrast, excellent correlations are apparent between whole blood heparin concentration and plasma anti-Xa heparin concentration during the CPB interval (Table I). Because whole blood heparin concentration results varied 20% of the time between replicate measurements, correlations were examined between each series of replicate heparin concentration measurements (WB HC1 and WB HC2) and anti-Xa heparin measurements. When compared with mean whole blood heparin concentration values (WB HC), replicate measurements of whole blood heparin concentration have similar correlations to anti-Xa heparin concentration. Excellent correlations for each series of replicate whole blood heparin concentration measurements are evident in both the pre-CPB (WB HC1: r = 0.98; WB HC2: r = 0.98) and CPB (WB HC1: r = 0.94; WB HC2: r = 0.94) phases of this trial. To correct for the influence of hematocrit, we converted whole blood heparin measurements to plasma equivalent values. As seen in Fig. 1, linear regression analysis of the relationship between plasma equivalent heparin concentration and plasma anti-Xa heparin concentration reveals a good linear fit (r ² = 0.92).

View larger version (24K): [in this window] [in a new window]   Fig. 1. Linear relationship of plasma equivalent Heparin Concentration (WB Heparin Conc) to anti-Xa plasma heparin concentration (Xa). Plasma equivalent heparin concentration expressed as units per millimeter of blood and derived from whole blood heparin concentration determined with an automated protamine titration method (Hepcon instrument) and represented as the mean of duplicate whole blood measurements. Plasma heparin concentration measured with a laboratory-based anti-Xa substrate assay.

Correlation between anti-Xa heparin concentra tion versus ACT and hematocrit.
During the CPB interval, a better correlation is evident between anti Xa heparin concentration and ACT values if hematocrit is included as a covariate in analysis. This is demonstrated by comparing the relationship between anti-Xa heparin concentration versus celite ACT (He mochron 801) and hematocrit (Xa = 0.19Hct x 0.002ACT - 2.49, r = 0.77) to the relationship between anti-Xa heparin concentration versus celite ACT (Xa = 0.002ACT x 1.46, r = 0.34). Similarly, a better correlation is also evident when the relationship between anti-Xa heparin concentration versus kaolin ACT and hematocrit (Xa = 0.16Hct x 0.004ACT - 2.54, r = 0.82) is compared with the relationship between anti-Xa heparin concentration versus kaolin ACT (Xa = 0.006ACT x 0.16, r = 0.59). The enhanced correlations between anti-Xa heparin concentration versus both ACT and hematocrit are predominantly related to the relationship between anti-Xa heparin concentration and hematocrit (Xa = 0.19Hct - 1.07, r = 0.70) during CPB.

Time course of physiologic and hematologic assay mean values.
Mean values for ACT, plasma equivalent heparin concentration, anti-Xa heparin concentration, hematocrit value, and core body temperature are displayed as a function of time in Fig. 2. The sharp decline in heparin levels between specimen collection points A and B reflects heparin decay and hemodilution after the initiation of CPB. Mean kaolin ACT values (Hepcon) approach the trigger (480 seconds) for administration of supplemental heparin only at the end of CPB. In contrast, mean celite ACT values (Hemochron 801) are above 480 seconds at all specimen collection points. The ability to predict the plasma heparin concentration at the end of CPB was also evaluated with a multivariate linear regression model. Although total CPB time (p = 0.006) and total heparin dose (p = 0.001) correlate with anti-Xa heparin concentration measured at the end of CPB, significant variability is evident in this linear relationship (r ² = 0.47).

View larger version (24K): [in this window] [in a new window]   Fig. 2. Time course of physiologic and hematologic mean values. Mean values for activated clotting time (ACT) expressed as seconds per 100 for both Hemochrin 801 (HC ACT) and Hepcon (HT ACT) assays. Plasma equivalent heparin concentration (WB HC) and anti-XA plasma heparin concentration (Xa HC) expressed as units per milliliter. Hematocrit (Hct) values expressed as percent divided by 10 (10%) and core body temperature (Temp) expressed as degrees centigrade divided by 10 (°C/10). Mean values for derived physiologic and hematologic variables are plotted as a function of time in minutes (mins). Phase II time points include prior to heparin administration and 10 minutes after each of the following: heparin administration (A), initiation of CPB (B), achievement of hypothermia (C), rewarming (D), and immediately before discontinuation of CPB (E).

Administration of blood and blood products is currently being reviewed with intense scrutiny as a consequence of increased awareness of the hazards of transfusion-related sequelae and cost-containment strategies. Consequently, strategies to optimize 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/protamine dosing guided by in vitro testing has been evaluated in previous clinical trials. ^14-17 These studies illustrate that coagulation monitoring protocols can reduce blood loss and transfusion in patients having cardiac operations. The improved clinical outcomes may have been due to better maintenence of therapeutic heparin concentration or subsequent optimal neutralization of heparin with protamine.

The ACT is routinely determined to assess the adequacy of anticoagulation before and during CPB. This practice is based on numerous studies that described a reduction in postoperative bleeding when the ACT was used to monitor heparin therapy. ^14,18,19 Maintenance of ACTsbetween 300 and 600 seconds ²⁰ was initially recommended because of a threefold to sixfold variation in heparin effect and a fourfold variation in heparin half-life. ²¹ Our data also demonstrate a significant variation in heparin half-life, because neither total heparin dose nor total time on CPB adequately predict anti-Xa heparin concentrations at the end of CPB. The minimum ACT of 300 seconds was initially based on the absence of detectable clots in the CPB oxygenator circuit above this value. ²² These authors ²² also initially recommended attaining a pre-CPB ACT of 480 seconds. On the basis of hematologic analysis, other authors recommended maintaining ACTs greater than 400 seconds. ²³ In contrast, others have not been able to determine a minimum ACT that defines adequacy of anticoagulation for CPB. ^5,24 Although it is controversial as to what is the optimal ACT for CPB, values between 400 and 480 seconds are commonly maintained.

Use of the ACT to regulate heparin anticoagulation during CPB may be problematic because previous studies have illustrated that ACTs during CPB do not correlate with plasma heparin levels. ^1-5,25 Similarly, our evaluation revealed weak correlations between ACT measurements and plasma heparin concentration during the CPB period. Previous studies have indicated that this may be due, at least in part, to the influence of CPB-related hypothermia and hemodilution on the ACT assay. ^1,3 This was confirmed in our evaluation, which demonstrated that both hypothermia and hemodilution affect ACT measurements. Other factors that may contribute to inconsistent ACT measurements include intrinsic variability of ACT measurements during anticoagulation, along with activation or depression of platelet function. ²⁶ Therefore, a particular heparin concentration, as defined by the target ACT before CPB, cannot be adequately maintained during CPB by means of ACT measurements. Instead, the use of heparin concentration assays to maintain a defined heparin level during CPB has been recommended by some authors. ^7,27 As previously described, the Hepcon instrument provides both ACT and heparin concentration measurements via an automated protamine titration method. ^7-12 Strong correlations between whole blood heparin concentration and anti-Xa plasma heparin concentration were obtained in both the pre-CPB and CPB phases of our trial. Therefore, our data indicate that this instrument provides rapid and accurate determination of heparin concentration.

Recent evaluations indicate that duration on CPB is the main predictor of nonsurgical blood loss after CPB. ^28,29 Patients with microvascular bleeding have lower platelet and coagulation factor levels because of a greater degree of consumption of these critical coagulation variables. ³⁰ Although consumption of clotting factors may be minimal for up to 2 hours during CPB if the ACT exceeds 400, ²³ ACT-based protocols do not suppress thrombin generation during CPB because concentrations of prothrombin fragment 1.2, thrombin/antithrombin complexes, and fibrin monomers increase with time on CPB. ³¹ Therefore, ACT-based anticoagulation protocols may contribute to a subclinical consumptive state especially in patients requiring prolonged use of CPB (>2 hours). Fig. 2 illustrates the decline in heparin concentration in our current ACT-based protocol. In patients with CPB times greater than 150 minutes, the decline in heparin concentration may reach a critical, subtherapeutic level and facilitate the consumption of coagulation factors. In our current series of patients who averaged approximately 2 hours on CPB (146 ± 55 minutes), plasma equivalent heparin concentration (1.86 ± 0.52 U/ml) fell below previously designated acceptable concentrations (2 U/ml) ^7,26 at the end of CPB. Higher heparin levels on CPB are associated with decreased collagen-mediated platelet aggregation ⁸ and decreased fibrinopeptide A levels during hypothermia even in patients who average 100 to 120 minutes on CPB. ⁹ Higher heparin concentrations may preserve the coagulation system during CPB by facilitating heparin cofactor II inactivation of thrombin. ³² Accordingly, by reducing activation of the coagulation system, maintenance of therapeutic heparin levels may preserve coagulation factors and platelets. Patients who have increased heparin needs because of prolonged use of CPB or preoperative heparin infusion may benefit the most by a system that guides the maintenance of a therapeutic heparin concentration. As previously described in patients who received higher heparin doses, postoperative bleeding is not increased if patients are monitored for heparin rebound in the postoperative period. ⁸

The ACT has been used to estimate protamine dose after CPB and to evaluate heparin rebound in the postoperative setting. Studies have illustrated that reduced doses of protamine for heparin neutralization after CPB can result in lower perioperative blood losses. ^14-16 Lower perioperative blood losses may be the result of reduced complement levels ^33,34 or reduced protamine-induced platelet inhibition ³⁵ associated with lower protamine doses. Because measurements derived with the Hepcon device more reliably reflect heparin concentration than ACT measurements, protamine dosing schedules based on these whole blood measurements may facilitate administration of lower protamine doses. Therefore, use of a hemostasis management system that evaluates both heparin concentration and heparin response (ACT) may result in the optimal administration of both heparin and protamine.

In conclusion, our data demonstrate that whole blood heparin measurements obtained via the Hepcon instrument correlate well with plasma heparin concentration before and during CPB. Although ACTs correlate with plasma anti-Xa heparin levels before CPB, our data confirm that a weak correlation exists during the CPB period. This may be, in part, due to the influence of both reduced hematocrit and temperature on the ACT assay during CPB. The Hepcon instrument can be used to accurately track heparin concentrations during the CPB period. Further prospective, randomized studies that include patients at high risk for bleeding are needed to determine if monitoring heparin concentration can more effectively prevent consumptive activation of the hemostatic system, reduce bleeding, and minimize use of blood products after CPB.

Footnotes

J THORAC CARDIOVASC SURG 1994;108:1076-82

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