Monitoring of heparin-induced anticoagulation with kaolin-activated clotting time in cardiac surgical patients treated with aprotinin.

High-dose aprotinin appears to enhance the anticoagulant effects of heparin, as documented by increases in the activated clotting times (ACTs) during cardiopulmonary bypass; hence, some authorities have advocated reducing the dose of heparin in patients treated with aprotinin. An in vitro study by our group suggested that the increase of the ACT in the presence of aprotinin and heparin may be due to the use of celite as surface activator. We compared celite and kaolin as surface activators for the measurement of the ACT in cardiac surgical patients treated with aprotinin and in patients given no aprotinin. This double-blind, randomized, placebo-controlled study included 30 patients, of whom 14 received aprotinin and 16 received a placebo. Before, during, and after cardiopulmonary bypass, the ACT was measured with two Hemochron 400 systems with 12 mg of either celite (C-ACT) or kaolin (K-ACT) used as surface activator and with one Hepcon HMS system (HR-ACT), which uses kaolin as activator. The latter also was used for measurement of the blood heparin concentration. The ACTs of blood without heparin did not differ between aprotinin and control patients. During anticoagulation with heparin and cardiopulmonary bypass, the average C-ACTs were 784 +/- 301 s (aprotinin) and 496 +/- 120 s (control) (P < .001); the K-ACTs were 502 +/- 131 s (aprotinin) and 458 +/- 101 s (control) (P > .05); the HR-ACTs were 406 +/- 87 s (aprotinin) and 423 +/- 82 s (control) (P > .05), which was consistently less than C-ACT and K-ACT.(ABSTRACT TRUNCATED AT 250 WORDS)     

Is the kaolin or celite activated clotting time affected by tranexamic acid?

BACKGROUND: During cardiopulmonary bypass, the activated clotting time is frequently used for determination of anticoagulation, and either Celite or kaolin are used as activators. If aprotinin is administered concomitantly, the Celite activated clotting time (C-ACT) becomes significantly higher than the kaolin activated clotting time (K-ACT). Therefore, insufficient anticoagulation using C-ACT in the presence of aprotinin is a major concern. Whether the application of tranexamic acid (TA), a pharmacologic alternative to aprotinin, has similar effects has not been studied before. METHODS: An in vitro study using the blood of healthy volunteers was performed. Both C-ACT and K-ACT were measured at baseline, after adding TA, and after adding TA and heparin. In addition, 30 patients undergoing primary cardiac operations had simultaneous measurements of C-ACT and K-ACT after skin-incision, 5 minutes after the application of heparin and TA, every 30 minutes during cardiopulmonary bypass, and 10 minutes after the application of protamine. RESULTS: In vitro, C-ACT and K-ACT correlated significantly at each measurement. Tranexamic acid had no influence on the activated clotting time. In vivo, C-ACT and K-ACT did not differ significantly, but at each time C-ACT tended to be greater than K-ACT (p = 0.086). The average difference between K-ACT and C-ACT was stable before and after the application of TA (p = 0.85) but the variability of the differences significantly increased during cardiopulmonary bypass (p < 0.001). CONCLUSIONS: Application of TA does not seem to differentially affect the mean C-ACT and K-ACT. No recommendation seems warranted to prefer one activator over the other in patients receiving TA.     

The plasma supplemented modified activated clotting time for monitoring of heparinization during cardiopulmonary bypass: a pilot investigation

The standard celite or kaolin activated clotting time (ACT) correlates poorly with heparin levels during cardiopulmonary bypass (CPB). We compared a modified kaolin ACT, in which plasma was supplemented, to a standard undiluted kaolin ACT for monitoring heparin levels during CPB. Fifteen patients undergoing normothermic CPB were enrolled in this prospective study. Heparin management was performed according to the Hepcon HMS results (Medtronic, Minneapolis, MN). The ACTs were performed with the ACT II device (Medtronic). Hepcon HMS calculations, standard kaolin ACTs, and plasma supplemented modified ACTs (mACTs), prepared by diluting blood samples 1:1 with human plasma (Behring, Marburg, Germany), were measured every 30 min during CPB. The data obtained were correlated to the plasma chromogenic anti-Xa activity as a reference assay for heparin levels. A total of 64 samples were evaluated. The chromogenic anti-Xa activity ranged from 0.2 to 5.5 IU/mL. The Hepcon HMS calculations ranged from 2.7-8.2 IU/mL of heparin, the standard ACT ranged from 424 to >999 s, and the mACT ranged from 210 to 801 s. The correlation to the chromogenic anti-Xa method was r = 0.43 for the standard kaolin ACT and r = 0.69 for the plasma mACT. The plasma mACT provided an improved correlation to chromogenically measured levels of anti-Xa activity during CPB. The improved correlation most likely results from a correction of the effects of the impairment of the coagulation system caused by hemodilution and consumption of procoagulants on extracorporeal surfaces. IMPLICATIONS: During cardiopulmonary bypass, the plasma modified kaolin activated clotting time (ACT) provides a better correlation with heparin levels than the standard kaolin ACT.     

Aprotinin does not prolong the Sonoclot aprotinin-insensitive activated clotting time

STUDY OBJECTIVE: To determine whether a new Sonoclot-based, aprotinin-insensitive activated clotting time (aiACT) assay yields stable results over a broad range of aprotinin concentrations. DESIGN: Prospective trial conducted on in vitro blood samples. SETTING: Tertiary-care teaching medical center. PARTICIPANTS: 19 healthy adult volunteers. INTERVENTIONS: Whole blood samples were collected from volunteers. Heparin (2 U/mL) and escalating concentrations of aprotinin of 160 to 500 kallikrein inhibitory units (KIU)/mL were added in vitro. MEASUREMENTS AND MAIN RESULTS: Celite ACT, kaolin ACT, and aiACT assays were completed. The aiACT showed stable activated clotting time (ACT) results on heparinized, noncitrated blood with added aprotinin (P = nonsignificant). In contrast, celite ACT and kaolin ACT were greatly prolonged when aprotinin was added to heparinized, noncitrated, and citrated blood (P < 0.05). The aiACT had consistent results at all aprotinin concentrations (P = nonsignificant). CONCLUSIONS: Aprotinin (160, 320, and 500 KIU/mL) significantly prolongs the ACT value with celite and kaolin activators but not with the aprotinin-insensitive activator.     

An investigation of a new activated clotting time "MAX-ACT" in patients undergoing extracorporeal circulation

Activated clotting time (ACT) is a test used in the operating room for monitoring heparin effect. However, ACT does not correlate with heparin levels because of its lack of specificity for heparin and its variability during hypothermia and hemodilution on cardiopulmonary bypass (CPB). A modified ACT using maximal activation of Factor XII, MAX-ACT (Actalyke MAX-ACT; Array Medical, Somerville, NJ), may be less variable and more closely related to heparin levels. We compared MAX-ACT with ACT in 27 patients undergoing CPB. We measured ACT, MAX-ACT, temperature, and hematocrit at six time points: baseline; postheparin; on CPB 30, 60, and 90 min; and postprotamine. Additionally, we assessed anti-Factor Xa heparin activity and antithrombin III activity at four of these six time points. With institution of CPB and hemodilution, MAX-ACT and ACT did not change significantly but had a tendency to increase, whereas concomitant heparin levels decreased (P = 0.065). Neither test correlated with heparin levels. ACT and MAX-ACT did not differ during normothermia but did during hypothermia, and ACT was significantly longer than MAX-ACT (P = 0.009). At the postheparin time point, ACT-heparin sensitivity (defined as [ACT postheparin - ACT baseline]/[heparin concentration postheparin - heparin concentration baseline]) was greater than MAX-ACT-heparin sensitivity (analogous calculation for MAX-ACT; 520 [266 - 9366] s. U(-1). mL(-1) vs 468 [203 - 8833] s. U(-1). mL(-1); P = 0.022). IMPLICATIONS: MAX-ACT (a new activated clotting time [ACT] test) uses more maximal clotting activation in vitro and, although it is less susceptible to increase because of hypothermia and hemodilution than ACT, lack of correlation with heparin levels remains a persistent limitation.     

Monitoring activated clotting time for combined heparin and aprotinin application: in vivo evaluation of a new aprotinin-insensitive test using Sonoclot.

OBJECTIVE: Kaolin-based activated clotting time assessed by HEMOCHRON (HkACT) is a clinical standard for heparin monitoring alone and combined with aprotinin during cardiopulmonary bypass (CPB). However, aprotinin is known to prolong not only celite-based but also kaolin-based activated clotting time. Overestimation of activated clotting times implies a potential hazardous risk of subtherapeutic heparin anticoagulation. Recently, a novel 'aprotinin-insensitive' activated clotting time test has been developed for the SONOCLOT analyzer (SaiACT). The aim of our study was to evaluate SaiACT in patients undergoing CPB in presence of heparin and aprotinin. METHODS: Blood samples were taken from 44 elective cardiac surgery patients at the following measurement time points: baseline (T0); before CPB after heparinization (T1 and T2); on CPB, before administration of aprotinin (T3); 15, 30, and 60 min on CPB after administration of aprotinin (T4, T5, and T6); after protamine infusion (T7). On each measurement time point, activated clotting time was assessed with HkACT and SaiACT, both in duplicate. Furthermore, the rate of factor Xa inhibition and antithrombin concentration were measured. Statistical analysis was done using Bland and Altman analysis, Pearson's correlation, and ANOVA with post hoc Bonferroni-Dunn correction. RESULTS: Monitoring anticoagulation with SaiACT showed reliable readings. Compared to the established HkACT, SaiACT values were lower at all measurement time points. On CPB but before administration of aprotinin (T3), SaiACT values (mean+/-SD) were 44+/-118 s lower compared to HkACT. However, the difference between the two measurement techniques increased significantly on CPB after aprotinin administration (T4-T6; 89+/-152 s, P=0.032). Correlation of ACT measurements with anti-Xa activity was unchanged for SaiACT before and after aprotinin administration (r2=0.473 and 0.487, respectively; P=0.794), but was lower for HkACT after aprotinin administration (r2=0.481 and 0.361, respectively; P=0.041). On CPB after administration of aprotinin, 96% of all ACT values were classified as therapeutic by HkACT, but only 86% of all values were classified therapeutic if ACT was determined by SaiACT. Test variability was comparable for SaiACT and HkACT. CONCLUSIONS: The use of SaiACT may result in more consistent heparin management that is less affected by aprotinin and a corresponding increase in heparin administration for patients receiving aprotinin.     

在体外及体外循环中抑肽酶对ACT的影响

选择健康献血员及心内直视手术病，观察抑肽酶对全血活化凝血时间的影响。结果：在体外肝素剂量与ＡＣＴ有显著线性相关。抑肽酶单狡应用并不使ＡＣＴ延，但与肝素合用可协同性延长ＡＣＴ值；在体外循环中抑肽酶延长ＡＣＴ的值更为显著，一般超过８００ｓ。结论：抑肽酶可与肝素协同性延长ＡＣＴ，体外循环中应用抑肽酶时应以ＡＣＴ大于８００ｓ作为肝素抗凝标准。     

The effects of aprotinin on thromboelastography with three different activators.

BACKGROUND: Thromboelastography is used for assessment of hemostasis. Adherence to thromboelastography-guided algorithms and aprotinin administration each decrease bleeding and blood product usage after cardiac surgery. Aprotinin, through inhibition of kallikrein, causes prolongation of the celite-activated clotting time and the activated partial thromboplastin ratio. The aim of this study was to assess the effects of aprotinin on the thromboelastography trace. METHODS: Three activators were used in the thromboelastography: celite (which is widely established), kaolin, and tissue factor. Assessment was performed on blood from volunteers and from patients before and after cardiac surgery. RESULTS: The tissue factor-activated thromboelastography trace was unaffected by the addition of aprotinin. When celite and kaolin were used as activators in the presence of aprotinin, the reaction time (time to clot formation) of the thromboelastography trace was prolonged (P < 0.0001) and the maximum amplitude (clot strength) was decreased (P < 0.05). With celite as an activator, the addition of aprotinin decreased (P < 0.05) the thromboelastography alpha angle (rate of clot extension). The reaction time of the celite-activated trace correlated with the activated partial thromboplastin ratio (P < 0.01). The reaction time of the tissue factor-activated trace correlated with the international normalized ratio (P < 0.01). CONCLUSION: The thromboelastography trace is altered in the presence of aprotinin when celite and kaolin are used as activators but not when tissue factor is the activator.     

Heparin monitoring during cardiopulmonary bypass surgery using the one-step point-of-care whole blood anti-factor-Xa clotting assay heptest-POC-Hi

The activated clotting time (ACT) generally used for monitoring heparinization during cardiopulmonary bypass (CPB) surgery does not specifically measure heparin anticoagulant activities. This may result in heparin over- or under-dose and subsequent severe adverse events. A new point-of-care whole blood clotting assay (Heptest POC-Hi [HPOCH]) for quantifying heparin anticoagulant activity specifically was compared with ACT and anti-factor Xa (anti-Xa) heparin plasma levels (Coatest heparin) in 125 patients undergoing CPB surgery. The analytical reliability of the HPOCH and the influence of preanalytical variables on assay results were also examined. The ACT and HPOCH clotting times determined throughout the entire observation period correlated closely (n=683; r = 0.80; p < .0001). Similarly, there was a significant linear correlation between HPOCH and Coatest anti-Xa levels (n=352; r = 0.87; p < .0001). Pre- and post-CBP values of HPOCH, ACT, and anti-Xa plasma levels correlated closely with each other (correlation coefficients between r = 0.90 and r = 0.99; p < .0001). During CPB, there was no significant relationship between ACT and whole blood or plasma heparin levels determined by HPOCH (n=157; r = 0.19) and the chromogenic anti-Xa assay (n=157; r = 0.04), respectively. In contrast, HPOCH and anti-Xa plasma levels correlated strongly during CPB (n=157; r = 0.57; p < .0001). However, bias analysis showed that the HPOCH and Coatest heparin could not be used interchangeably. The HPOCH was well reproducible and not influenced by aprotinin, hemodilution, or other factors affecting ACT. The HPOCH seems to be a promising new tool for specific on-site measurement of heparin activities in whole blood during CPB.     

CABG术中ACT、CR监测方法的比较

目的 冠状动脉旁路移植术(coronary artery bnypass graft,CABG)围术期常规监测激活凝血时间(activated clotting time,ACT)和纤维蛋白原(Fibrinogen,Fbg).通过使用Sonoclot凝血功能分析仪(sonoclot coagulation analyzer,SCA)与传统凝血检测的ACT(conventional ACTtest,C-ACT)和Fbg进行相关性分析,对CABG术中ACT、CR监测方法进行比较.方法　选择非体外循环(Off-pump)CABG患者18例(OP组),体外循环(cardiopulmonary bypass,CPB)CABG患者12例(CPB组),分别于诱导后(T_o)、首次给肝素(OP组0.8ms/ks,CPB组1.0mg/kg)后5min(T_1),追加肝素(OP组达1.5mg/kg,CPB组达3.0mg/kg)后5min(T_2),鱼精蛋白中和肝素后5 min(T_3)4个时间点,取中心静脉血同时测定C-ACT和SCA的3种ACT及CR.结果　①T_o点,SonACT、kACT、aiACT分别与C-ACT正相关,相关方程分别为:y=83.15+0.37×(R=0.438,P<0.05);y=71.33+0.43×(R=0.509,P<0.01);y=56.19+0.78×(R=0.790,P<0.01).sonCR、kCR、aiCR与术前Fbg正相关,相关方程分别为:y=1.16+0.09×(R=0.821,P<0.001);y=1.11+0.09x(R=0.773,P<0.001);y=1.50+0.06×(R=0.882,P<0.001 .②T_3点与T_o点相比,C-ACT差异有统计学意义(P<0.01).sonACT、kACT、aiACT差异均无统计学意义.③给予低剂量肝素0.8mg/kg和1.0mg/kg时,分别有39%和83%患者C-ACT大于300 s,而sonACT大于300s的例数达55%和95%,kACT则是55%和100%;CR的下降值(ACR)占基础值的百分比已达74%-76%和76%-83%.结论　①SCA3种ACT与C-ACT正相关性比较:aiACT>kACT>sonACT,aiACT相关性最好;CR与Fbg正相关性比较:aiCR>sonCR>kCR,aiCR相关性最好.②鱼精蛋白中和肝素后,SCA3种ACT比C-ACT恢复更好.③使用SCA与传统检测相比能够在低剂量肝素(0.8 mg/kg～1.0 mg/kg)时更敏感地监测ACT和CR.     

The Effects of Aprotinin on Thromboelastography with Three Different Activators

Background : Thromboelastography is used for assessment of hemostasis. Adherence to thromboelastography-guided algorithms and aprotinin administration each decrease bleeding and blood product usage after cardiac surgery. Aprotinin, through inhibition of kallikrein, causes prolongation of the celite-activated clotting time and the activated partial thromboplastin ratio. The aim of this study was to assess the effects of aprotinin on the thromboelastography trace.

Methods : Three activators were used in the thromboelastography: celite (which is widely established), kaolin, and tissue factor. Assessment was performed on blood from volunteers and from patients before and after cardiac surgery.

Results : The tissue factor-activated thromboelastography trace was unaffected by the addition of aprotinin. When celite and kaolin were used as activators in the presence of aprotinin, the reaction time (time to clot formation) of the thromboelastography trace was prolonged (P < 0.0001) and the maximum amplitude (clot strength) was decreased (P < 0.05). With celite as an activator, the addition of aprotinin decreased (P < 0.05) the thromboelastography [alpha] angle (rate of clot extension). The reaction time of the celite-activated trace correlated with the activated partial thromboplastin ratio (P < 0.01). The reaction time of the tissue factor-activated trace correlated with the international normalized ratio (P < 0.01).     

Aprotinin and hemostasis monitoring concerns during cardiac surgery

Aprotinin (Trasylol) is a serine protease inhibitor, isolated from bovine lung that initially was marketed for the treatment of pancreatitis. In the mid 1980s, reports of its ability to decrease hemorrhaging after cardiopulmonary bypass surgery introduced the drug to the realm of cardiac surgery. Unfortunately, its introduction into this arena was followed by the publication of multiple studies and case reports that blamed aprotinin for poor outcomes in the form of early graft closure. More than 17 years have passed since the initial article describing the use of aprotinin during cardiopulmonary bypass, and with time there has been a significant increase in scientific knowledge and clinical experience. Interestingly, modern literature does not support the dogma that aprotinin is a procoagulant. Aprotinin increases the activated partial thromboplastin time (aPTT), as well as the kaolin- and celite-activated clotting time (ACT), regardless of heparin. Aprotinin, because of its ability to inhibit kallikrein, has been found to decrease thrombin antithrombin III complexes, fibrin-split products, fibrinopeptide 1+2, prothrombin fragments, and all markers of thrombin formation. Some authors have suggested that it may have a synergistic effect with heparin to ensure graft patency. Anticoagulation monitoring during the use of aprotinin also has been developed based on early studies. Aprotinin administration does influence the results of various ACT tests, and consequently different methods of testing anticoagulation have been developed. Researchers have demonstrated that the celite ACT is not "artificially" prolonged in the presence of heparin and aprotinin, rather the kaolin ACT is "artificially" shortened. This article will review the scientific literature with regard to aprotinin's anticoagulatory effects and review the current recommendations for hemostasis monitoring during the use of aprotinin.     

Effects of heparin, haemodilution and aprotinin on kaolin-based activated clotting time: in vitro comparison of two different point of care devices

BACKGROUND: During cardiopulmonary bypass (CPB), measurement of kaolin-based activated clotting time (kACT) is a standard practice in monitoring heparin-induced anticoagulation. Despite the fact that the kACT test from the Sonoclot Analyzer (SkACT) has been commercially available for several years, no published data on the performance of SkACT are available. Thus, the aim of this in vitro study was to compare SkACT with an established kACT from Hemochron (HkACT). METHODS: Blood was withdrawn from 25 patients before elective cardiac surgery. SkACT and HkACT were measured in duplicate after in vitro administration of heparin (0, 1, 2 and 3 U/ml), calcium-free lactated Ringer's solution (25% and 50% haemodilution) and aprotinin (200 kIU/ml). RESULTS: A total of 600 duplicate kACT measurements were obtained from 25 cardiac surgery patients. Overall, mean bias +/- SD between SkACT and HkACT was 7 +/- 70 s (1.3% +/- 14.1%). Administration of heparin, haemodilution and aprotinin induced a comparable effect on both activated clotting time (ACT) tests. Mean bias ranged from -4 +/- 39 s (-1.7% +/- 12.9%) to 4 +/- 78 s (3.2% +/- 15.6%) for heparinzed blood samples after haemodilution or aprotinin application and increased after combined aprotinin administration and haemodilution. After haemodilution and administration of aprotinin, both ACT tests were less reliable for values >480 s in heparinized blood samples. CONCLUSION: Accuracy and performance of SkACT and HkACT were comparable after in vitro administration of heparin, aprotinin and haemodilution. Both ACT tests were considerably affected by aprotinin and haemodilution.     

In vitro effects of aprotinin on activated clotting time measured with different activators.

The effects in vitro of aprotinin on the activated clotting time measured with both celite- and kaolin-activated tubes were investigated in 21 consecutive patients requiring cardiopulmonary bypass. Four whole-blood samples (2 ml per sample) from each patient were tested simultaneously with Hemochron automated timing systems (International Technidyne Corp., Edison, N.J.) before, during, and after cardiopulmonary bypass. One tenth milliliter of either aprotinin (at a final concentration of 80, 120, or 180 KIU/ml) or saline solution was mixed in vitro with blood samples before determination of the activated clotting time. Aprotinin had no inhibitory effect on the activated clotting times of unheparinized blood. After heparin administration, aprotinin in the above concentrations prolonged the activated clotting times measured with celite-activated tubes by 47% to 71%, as compared with the measurements of the activated clotting time without the addition of aprotinin. The activated clotting times in kaolin-activated tubes were not increased, however, by the in vitro addition of aprotinin. Our in vitro results indicate that aprotinin in concentrations from 80 to 180 KIU/ml does not significantly enhance the inhibitory effects of heparin on the intrinsic coagulation system as evaluated by measurement of the activated clotting times in kaolin-activated tubes. The anticoagulation effect of heparin in patients receiving aprotinin infusion should be monitored with kaolin-activated instead of celite-activated tubes because the celite makes the measured activated clotting time unreliable in patients receiving aprotinin therapy. These in vitro results require confirmation in vivo in patients receiving aprotinin therapy.     

Activated clotting time (ACT) testing: analysis of reproducibility

Activated Clotting Time (ACT) has been the standard for monitoring heparin anticoagulation in cardiac surgery for three decades. Although a 10% coefficient of variation (CV) is the referenced standard for the test, no recent reports of precision are available. The precision of Hemochron FTCA510 (celite) and KACT (kaolin) ACT test tubes was evaluated using a retrospective analysis of results from both laboratory studies and routine clinical usage. Laboratory studies of reproducibility included analysis of the CV from repetitive testing using multiple lots of ACTs. Substrates used included 40 consecutive lots of control plasma and freshly heparinized donor blood. Across the lots of control plasma, the celite ACT yielded an average CV of 5.4% for the normal control level and 4.0% in the abnormal control level (range 3.6-9.7% and 2.7-6.3%, respectively). The KACT showed similar performance for the normal (mean = 4.5%, range 2.2-7.8%) and abnormal (mean = 3.8%, range 2.0-10.0%). These values, significantly less than 10%, reflect the combined variability of both the ACT tests and the lyophilized, single use vial, control material. Fresh whole blood samples exhibited improved ACT precision when compared to this artificial substrate. CVs for the celite ACT range from 0.6-6.0% at one unit heparin/ml blood to 2.4-11.6% at 5 units/ml where clotting times exceed 650 sec. The KACT showed even lower CVs at all heparin levels, with values of 2.4-7.0%. Clinical evaluations included samples (N = 56) collected from cardiac surgery patients with celite ACT values ranging to 744 sec. Duplicate values differed by an average of 7.5 sec or 1.8%. There was only one clinically significant difference in paired values; a 376 sec paired with a 406 sec, 400 sec being the clinical target time. This retrospective data analysis demonstrates that Hemochron ACT variability is significantly less than 10%.     

Heparin sensitivity test for patients requiring cardiopulmonary bypass

Anticoagulation for the open heart surgery patient undergoing cardiopulmonary bypass (CPB) is achieved with the use of heparin. The industry standard of activated clotting time (ACT) was used to measure the effect of heparin. The commonly acceptable target time of anticoagulation adequacy is 480 seconds or greater. Some patients, however, exhibit resistance to standard dosing of heparin and do not reach target anticoagulation time (480 seconds). Antithrombin III deficiency has been previously cited as the cause of heparin resistance. Early detection of heparin resistance (HR) may avoid both the delayed start of CPB and inadequate anticoagulation, if emergency bypass is required. An anticoagulation sensitivity test (AST) was developed by adding 12 units of porcine mucosa heparin to the ACT tube (International Technidyne, celite type). Before anticoagulation, 4 mL of blood was drawn from the patient arterial line. Following the manufacturer's instructions, 2 mL of blood was added to each tube (ACT-baseline and ACT-AST). Three minutes after anticoagulation with 4 mg heparin/kg body weight, a second sample (ACT-CPB) was taken to determine anticoagulation adequacy. The ACT times of each sample were recorded for 300 procedures occurring during 2004 and were retrospectively reviewed. Heparin resistance occurred in approximately 20% of the patients (n = 61). In 54 patients, heparin resistance was predicted by the ACT-AST. This was determined by the presence of an ACT-AST time and an ACT-CPB that were both < 480 seconds. The positive predictive value was 90%, with a false positive rate of 3%. Heparin resistance occurs in patients undergoing CPB. We describe a simple and reliable test to avoid the delays of assessing anticoagulation for CPB (90% positive predictive value). Depending on program guidelines, patients can be given additional heparin or antithrombin III derivatives to aid in anticoagulation. An additional ACT must be performed and reach target times before CPB initiation. Testing of patient blood before the time of incision for sensitivity to heparin is a way to avoid a delay that can be critical in the care of the patient. Commercial tests are available, but efficacy data are limited, and they lead to added inventory expense. This method of titrating a diluted heparin additive, mixed with patient blood in a familiar ACT test, has proven to be an inexpensive and reliable test to predict patient's sensitivity to heparin.     

Maintenance of blood heparin concentration rather than activated clotting time better preserves the coagulation system in hypothermic cardiopulmonary bypass

In cardiopulmonary bypass (CPB), despite heparin regimens in which the activated clotting time (ACT) is kept at more than 400 s, there is biochemical evidence of thrombin generation indicating activation of the coagulation system and increased fibrinolytic activity. Therefore, to reduce the coagulant activation has been one of the main issues in the improvement of CPB. The purpose of this study was to compare the heparin concentration with the ACT and to evaluate the effect of keeping higher heparin concentration on the coagulation and fibrinolytic systems during hypothermic CPB, employing moderate hypothermia (MHT) or deep hypothermic circulatory arrest (DHT). Heparin was either administered to maintain an ACT >400 s (ACT group) or to maintain a whole blood heparin concentration of 3 mg/kg (heparin group). At the lowest core temperature during CPB, the ACT and the heparinase ACT (unrelated to heparin concentration) were increased the most whereas the whole blood heparin concentration was less than half the initial concentration in both ACT groups of MHT and DHT. The thrombin-antithrombin III (TAT) content just after CPB in both MHT and DHT was significantly lower in the heparin group than in the ACT group. In conclusion, ACT does not reflect the whole blood heparin concentration during hypothermic CPB. Furthermore, maintenance of the higher heparin concentration during hypothermic CPB may suppress the activation of the coagulation system via thrombin inhibition. That effect was more remarkable in deep hypothermic CPB. Therefore, we believe that anticoagulation management during hypothermic CPB should be based on the maintenance of the higher blood heparin concentration.     

Anticoagulation for cardiac surgery in patients receiving preoperative heparin: use of the high-dose thrombin time

Patients receiving heparin infusions have an attenuated activated clotting time (ACT) response to heparin given for cardiopulmonary bypass (CPB). We compared patients receiving preoperative heparin (Group H) to those not receiving heparin (REF group) with respect to ACT, high-dose thrombin time (HiTT), and markers of thrombin generation during CPB. Sixty-five consecutive patients (33 Group H, 32 REF group) undergoing elective CPB were evaluated. ACT and HiTT were measured at multiple time points. Plasma levels of thrombin-antithrombin III complex and fibrin monomer were determined at baseline, during CPB, and after protamine administration. Transfusion requirements and postoperative blood loss were measured and compared. ACT values after heparinization increased less in Group H and were significantly lower than those in the REF group (P < 0.01). HiTT values did not differ significantly between the two groups. Blood loss and transfusion requirements were not significantly different between the two groups. Plasma levels of thrombin-antithrombin III complexes and fibrin monomer also did not differ between groups at any time, despite a lower ACT in Group H after heparinization and during CPB. Our data suggest that thrombin formation and activity are not enhanced in patients receiving heparin therapy, despite a diminished ACT response to heparin. The utility of ACT and the threshold values indicative of adequate anticoagulation for CPB are relatively undefined in patients receiving preoperative heparin. HiTT should be investigated as a safe and accurate monitor of anticoagulation for CPB in patients receiving preoperative heparin therapy. Implications: The diminished activated clotting time response to heparin, in patients receiving preoperative heparin therapy, poses difficulties when attempting to provide adequate anticoagulation for cardiopulmonary bypass. Current data suggest that heparin resistance is not observed when high-dose thrombin time is used to monitor anticoagulation and that a lower activated clotting time value in these patients may be safe.     

The in vitro effects of aprotinin on twelve different ACT tests

Aprotinin is frequently used during CPB to reduce post-operative bleeding and attenuate the inflammatory response. The level of anticoagulation in these patients is monitored by using various activated clotting time (ACT) tests, which are generally accepted as being altered by the presence of aprotinin in blood. Therefore, we have investigated the effect of aprotinin on several ACT tests using whole blood from CPB patients. With IRB approval, blood samples were collected from patients undergoing CPB before and after full heparinization (300 u/kg). Each blood sample was divided into two aliquots, and aprotinin was added to one of them to yield a final calculated concentration of 300 KIU/mL. Both aliquots were used simultaneously to perform the 12 ACT tests. A paired Student's t-test was performed on the data. Overall, test results from 9 of 12 devices were significantly increased by aprotinin. Of these, four were increased only when the sample was heparinized, three were elevated by both heparinized and unheparinized blood, and two were elevated only when the sample was unheparinized. Each affected test responded uniquely to aprotinin, producing ACT test results ranging from 12 to 51% above nonaprotinized values. Several tests that were affected by aprotinin using heparinized blood samples were unaffected using unheparinized blood samples. These data emphasizes the unique manner in which individual ACT tests respond to aprotinized blood samples and should be considered when developing institutional policy for anticoagulation of aprotinized patients.     

Heparin-coated Cardiopulmonary Bypass Circuits in Coronary Bypass Surgery

Abstract: Cardiopulmonary bypass (CPB) is a nonphysiologic environment for an organism. The damage of blood components may also lead to organ dysfunction, sometimes recognized as postperfusion syndrome. One possible way to diminish the risk of these complications would be to reduce the thorombogenicity and to improve the biocompatibility of the artificial surfaces by using a heparin-coated CPB circuit. In this study, we compared a heparin-coated CPB circuit with a noncoated CPB circuit in terms of biocompatibility in 20 patients undergoing elective coronary bypass surgery. We employed a Dura-flo II (n = 10) as a heparin-coated CPB circuit and a Univox IC (n = 10) as control subjects. Ten patients (Group C) were operated on using the heparin-coated CPB circuit. A total of 10 patients were given heparin in a reduced dose (2.0 mg/kg), and additional heparin was given if the activated clotting time (ACT) was below 400 s. The control group also included 10 patients (Group NC), who were operated on with noncoated devices. They received 2.5 mg/kg of heparin, and additional heparin was given if the ACT was below 450 s. All patients had normal coagulation parameters and did not receive blood transfusion. We measured complement activation levels (C3a, C4a), platelet count, thrombin-antithrombin III complex levels, D-dimer levels, and ACT during CPB and respiratory index postoperatively. The concentration of C3a in group NC was significantly higher than that in group C. Platelet reduction in group NC was significantly greater than that in group C. There were no significant differences in the remaining parameters between the 2 groups. We concluded that heparin-coated CPB circuits improved biocompatibility by reducing complement activation and platelet consumption and enabled us to reduce the dose of heparin required for systemic heparinization.