Heparin management protocol for cardiopulmonary bypass influences postoperative heparin rebound but not bleeding.

A group of 63 adult patients undergoing cardiac surgical procedures requiring cardiopulmonary bypass (CPB) were studied to examine the relationship between heparin doses administered and postoperative bleeding. Patients were randomly assigned either to receive heparin 200 U/kg and additional heparin as needed to reach and maintain an activated clotting time (ACT) greater than 400 s for CPB (group A, n = 30), or to receive heparin 400 U/kg and additional heparin as needed to reach and maintain a whole blood heparin concentration greater than 4.0 U/ml for CPB (group H, n = 33). Groups were compared for the amount of postoperative bleeding, heparin rebound, homologous transfusion requirements, and standard laboratory coagulation tests. In the last 33 patients studied, additional tests of platelet aggregation and plasma levels of beta thromboglobulin (BTG), antithrombin III, and several markers of fibrinolysis were measured and compared by group. The mean heparin dose was 28,000 +/- 4,800 U for group A and 57,000 +/- 10,700 U for group H (P less than 0.05 for group A vs. group H). At 8 and 24 h postoperatively, mediastinal drainage did not differ significantly between groups (mean 24-h drainage +/- SD = 901 +/- 414 ml in group A, 1035 +/- 501 ml in group H), nor did the incidence of transfusion with homologous blood products.(ABSTRACT TRUNCATED AT 250 WORDS)     

In vitro effect of fresh frozen plasma on the activated coagulation time in patients undergoing cardiopulmonary bypass

The in vitro effect of fresh frozen plasma (FFP) on the whole blood activated coagulation time (ACT) was examined in 18 patients undergoing cardiopulmonary bypass (CPB) during coronary artery bypass graft surgery. The addition of FFP to whole blood in vitro, after systemic heparinization, significantly prolonged the ACT from 451 +/- 21 seconds (mean +/- SE) to 572 +/- 41 seconds (P less than 0.05). There was no significant correlation between the plasma antithrombin III activity and the prolongation in ACT after systemic heparinization, with or without addition of FFP. The addition of FFP to whole blood in three of the six patients who exhibited heparin resistance (ACT less than 400 seconds after administration of 350 unit/kg heparin) did not prolong the ACT to greater than 400 seconds. These observations suggest that infusion of FFP will further prolong the ACT after heparin administration in most patients including some with initial heparin resistance.     

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.     

Heparin-coated cardiopulmonary bypass circuits reduce blood cell trauma. Experiments in the pig

Blood cell trauma and postoperative bleeding remain important problems in cardiopulmonary bypass (CPB). We compared heparin-coated with non-coated circuits in the pig. Twenty animals were perfused for 2 h at normothermia using membrane oxygenators (Bentley Bos 50). Two groups were studied. In the non-coated group (NC, n = 11) the CPB circuits used were without a heparin coating. This group had systemic heparinization of 400 IU/kg to maintain an ACT (activated clotting time) of over 400 s during CPB. In the coated group (C, n = 9), all surfaces exposed to blood in the CPB circuits were heparin-coated. This group had the heparin dose reduced to 25% (100 IU/kg) without further administration regardless of ACT. During CPB, group C displayed shorter ACT (per definition), higher platelet count, platelet adhesion and lower fibrinolysis and haemolysis (P less than 0.05) as compared to group NC. No thromboembolic events were detected during CPB. Three animals in group NC and 4 animals in group C were weaned from CPB and protaminized. Four hours postoperatively, the leucocyte consumption was two-fold greater and blood loss about four-fold greater in group NC as compared with group C (P less than 0.05). Perfusion with heparin-coated surfaces reduces blood cell trauma. The decreased postoperative blood loss observed in group C is probably explained by the reduced dosages of heparin and protamine.     

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.     

Increased fibrinolytic activity during surgery with cardiopulmonary bypass

We studied blood coagulation and fibrinolysis in 19 patients during surgery with cardiopulmonary bypass (CPB). CPB was performed with a rotating pump and a membrane oxygenator. Heparinization was achieved with heparin 3 mg.kg-1 and the ACT value was kept above 400 seconds throughout the CPB. Heparin was neutralized by protamine at a ratio of 1:1-1.5 of the total amount of heparin. Blood was collected four times from an indwelling arterial line. We obtained the first sample immediately after induction of anesthesia, the second sample before heparinization, the third sample before protamine administration, and the fourth sample at the end of the operation. FPA, FPB beta 15-42, alpha 2PI-Pl-C, D-dimer, and the t-PA activity were measured. A statistically significant elevation of FPA was observed during the operation. FPB beta 15-42, alpha 2PI-Pl-C, and the D-dimer rose significantly immediately after the beginning of the CPB and these elevations continued until the end of the operation. The t-PA activity was elevated significantly only during the CPB. In conclusion, the t-PA is released from the endothelial cells during CPB by some undetermined mechanism (primary fibrinolysis). Then, plasmin is generated by the t-PA and this dissolves the fibrin clots formed by thrombin before the beginning of the CPB (secondary fibrinolysis). Enhanced fibrinolytic activity before and after the CPB is physiological secondary fibrinolysis.     

An evaluation of the effects of a standard heparin dose on thrombin inhibition during cardiopulmonary bypass in neonates

We compared the adequacy of heparinization in neonates and older children undergoing cardiopulmonary bypass (CPB) by measuring heparin activity, thrombin formation, and thrombin activity. Ten neonates and 10 older children were administered 400 U/kg of heparin before CPB. Heparin anti-Xa activity, prothrombin fragment 1.2 (F1.2), and fibrinopeptide A (FPA) were measured at baseline, after 30 min on CPB, immediately post-CPB, and 3 and 24 h post-CPB. Heparin anti-Xa activity was significantly decreased during and immediately post-CPB in the neonatal group. F1.2 and FPA levels in neonates were significantly higher at baseline, decreased with the commencement of CPB, and increased to levels higher than those in older children after CPB. Our data show that with standard heparin doses, neonates exhibit less heparin anti-Xa activity during CPB. Higher baseline levels of F1.2 and FPA present in neonates indicate preoperative activation of their coagulation systems as compared with older children. Although F1.2 and FPA levels initially decrease with the commencement of CPB, probably representing hemodilution, the subsequent increase in these markers indicates significantly more thrombin formation and activity during and after CPB. These results raise the concern that 400 U/kg of heparin may not adequately suppress thrombin formation and activity in neonates undergoing CPB.     

Reducing hemostatic activation during cardiopulmonary bypass: a combined approach

Interventions such as heparin-coated circuits, epsilon-aminocaproic acid, and reduced shed blood reinfusion have shown mixed results when applied individually for limiting hemostatic activation during cardiopulmonary bypass (CPB). We compared coagulation and fibrinolytic activation during conventional CPB (control) (CTRL) using noncoated circuits, no antifibrinolytics, and open cardiotomy with a combined strategy (HAC) that used heparin-coated circuits, epsilon-aminocaproic acid, and closed cardiotomy. Blood samples were drawn before, during, and after CPB for primary coronary bypass grafting surgery from 9 CTRL patients and 10 HAC patients. Thrombin-antithrombin complex and fibrinopeptide A levels (markers of thrombin and fibrin generation) were reduced in the HAC versus CTRL group after 30 min of CPB (P < 0.05). Average tissue plasminogen activator (tPA) levels were significantly lower in the HAC group by 30 min on CPB (P < 0.05), resulting in preservation of plasminogen activator inhibitor (PAI)-1 during CPB (P < 0.05). D-Dimer, a measure of intravascular fibrin formation and removal, was reduced in the HAC group during and after CPB (P < 0.005). Overall, the combined strategy was associated with a reduction in CPB-induced increases in markers of thrombin generation, fibrin formation, tPA release, and fibrin degradation and better preservation of PAI-1. IMPLICATIONS: A combined approach during cardiopulmonary bypass (CPB) that uses heparin-coated circuits, epsilon-aminocaproic acid, and limited reinfusion of shed pericardial blood is associated with reduced activation of the coagulation and fibrinolytic systems that typically occurs during conventional CPB.     

Real time measurement of heparin concentration during cardiopulmonary bypass

BACKGROUND: A heparin/protamine titration system for measurement of heparin levels (Hepcon) is promising for efficient anticoagulation during cardiopulmonary bypass (CPB). METHODS: Fifty-seven patients subjected to CPB were divided into two groups, control (n = 24) and Hepcon groups (n = 33). The Hepcon group was further divided into three subgroups according to perfusion temperature. For the control group, conventional administration of an anticoagulant (300 IU/kg of heparin) and reversal protocol (heparin 1: protamine 1) was performed. For the Hepcon group, a heparin dose-response assay directed the initial dose of heparin. Hepcon also determined the dose of protamine by the titration. The initial dose of heparin in the control group (300 IU/kg) was statistically less than that of Hepcon group (360+/-80 IU/kg). RESULTS: In the Hepcon group, the sensitivity to heparin was correlated with coagulation time (r = -0.78) and antithrombin III levels (r = 0.70), and individual difference of sensitivity resulted in a wide range of dosage (160 to 490 IU/kg). A strong correlation was observed between plasma and whole blood concentration of heparin (r = 0.86). However, they did not correlate with ACT values. Perfusion temperature didn't affect the heparin level, but did the ACT value. In the Hepcon group, the dose of protamine was significantly less and adverse events were rare. CONCLUSIONS: In conclusion, whole blood heparin measurements correlated well with plasma heparin concentration. Protamine titration of heparin reduced the dose of protamine and decreased the chance of adverse reactions.     

Platelet involvement in the activated coagulation time of heparinized blood

The activated coagulation time (ACT), commonly used during cardiopulmonary bypass (CPB), is assumed to measure only differences in heparin levels. Studies were undertaken to determine whether platelet activation/inhibition might also influence the test. When either the platelet inhibitor prostacyclin or the platelet activator adenosine diphosphate (ADP) was added to healthy donor blood containing 2 IU of heparin per ml, there was significant prolongation of the ACT (prostacyclin: mean prolongation, 60.6%; ADP: mean prolongation, 52.3%). In blood taken from the extracorporeal circuit of ten CPB cases, the prolongation with the platelet inhibitor carbacyclin, a prostacyclin analogue, was infinite. It is concluded that the ACT as used during CPB must be interpreted as a measure of both platelet procoagulant activity and heparin activity. Furthermore, this dual sensitivity, while fortuitous, is probably advantageous; patients with hyporeactive platelets will automatically receive less heparin.     

Another point of view on the mechanism of thrombin generation during cardiopulmonary bypass: role of tissue factor pathway inhibitor

OBJECTIVE: To determine the role of tissue factor and tissue factor pathway inhibitor (TFPI) in coagulation activation during cardiopulmonary bypass (CPB). DESIGN: Prospective, observational study. SETTING: Operating room in a city hospital. PARTICIPANTS: Thirty-one patients undergoing cardiac surgery. MEASUREMENTS AND MAIN RESULTS: The plasma levels of tissue factor antigen (tissue factor), total and free TFPI, several markers of thrombin generation (prothrombin fragment F1+2, thrombin antithrombin complex, and fibrinopeptide A), and heparin concentration were measured. Blood samples were obtained after induction of anesthesia (baseline level), before and after CPB, and at the end of the surgery. Despite an average heparin concentration of 2.9 +/- 0.2 IU/ mL, markers of thrombin generation, fibrin formation and its degradation (D-dimer) were observed during CPB. Significant increases of total and free TFPI levels (p < 0.0001) were found during CPB associated with lower tissue factor concentration (p < 0.0001) compared with the baseline values. Heparin concentration correlated with levels of total TFPI (r2 = 0.613, p < 0.0001) and free TFPI (r2 = 0.689, p < 0.0001). Tissue factor concentration showed significant negative correlations with levels of total TFPI (r2 = 0.128, p = 0.0003) and free TFPI (r2 = 0.070, p = 0.0078). CONCLUSION: These data indicate that TFPI release by heparin probably has an important role in the suppression of the tissue factor-dependent coagulation pathway during CPB. These changes occur along with ongoing thrombin generation and its activation. Either insufficient prevention of thrombin generation by TFPI or indirect activation of the intrinsic coagulation pathway occurs during CPB.     

Heparin pretreatment does not alter heparin requirements during cardiopulmonary bypass

Heparin infusion may cause heparin resistance and may affectmonitoring by measurement of the activated coagulation time(ACT), making the assessment of anticoagulation difficult, withthe risk of over- or undertreatment, especially during cardiacsurgery. We studied two groups of patients undergoing cardiopulmonarybypass (CPB): patients on heparin infusions (group H) and heparin-naivecontrols (group C). All patients received heparin 300 IU kg^–1before CPB and a further dose of 5000 IU if the ACT 5 minafter commencing bypass was less than 400 s. Measurementsof ACT, heparin concentration, antithrombin-3, thrombin–antithrombincomplex, prothrombin fragment F₁₊₂ and D-dimers were made beforeand 5 and 20 min after start of CPB. A second dose of heparinwas given to eight out of 18 patients in group C and 10 outof 24 in group H. Antithrombin-3 in group H was significantlyless than in group C at 5 min [59 (14) vs 52 (9)%, P<0.05].ACT was significantly lower in group H than group C at 20 min[387 (64) vs 431 (67) s, P<0.05]. Despite ACTs of lessthan 400 s in both groups, no coagulation was seen, suggestingthat 300 IU kg^–1 heparin is a safe dose foranticoagulation in CPB even after heparin therapy. Br J Anaesth 2001; 87: 844–7     

Anticoagulation of children undergoing cardiopulmonary bypass is overestimated by current monitoring techniques

HYPOTHESIS: Children who undergo cardiopulmonary bypass (CPB) are proportionally more hemodiluted than adults who undergo CPB. Current methods of monitoring high-dose heparin sulfate anticoagulation are dependent on fibrinogen level. Because of the decreased fibrinogen levels in children, current methods of monitoring heparin anticoagulation overestimate their level of anticoagulation. DESIGN: Prospective controlled trial. MAIN OUTCOME MEASURE: Production of thrombin (adequacy of anticoagulation). METHODS: Children and adults undergoing cardiac surgery who received CPB were anticoagulated in the standard fashion as directed by activated clotting time (ACT) results. Each subject had blood sampled at baseline; heparinization; start of the CPB; CPB at 30, 60, and 90 minutes; and at termination of CPB. Samples were used to assess anticoagulation with the Heparin Management Test (less dependent on fibrinogen level than ACT). We also assessed 2 subclinical markers of thrombosis, thrombin-antithrombin complexes and prothrombin fragment F1.2; a marker of procoagulant reserve, fibrinogen; the natural antithrombotic, antithrombin; and heparin concentration. RESULTS: Ten children and 10 adults completed the study. Children had lower fibrinogen levels than adults throughout CPB (P<.05). All adults had both therapeutic ACT and Heparin Management Test levels measured throughout CPB. Although children had therapeutic ACT levels, their Heparin Management Test levels were subtherapeutic while undergoing CPB. The children had significantly higher thrombin-antithrombin complexes and prothrombin fragment F1.2 than adults, indicating ongoing thrombin production (P<.01). The increases in thrombin-antithrombin complexes and prothrombin fragment F1.2 in children were inversely proportional to their weight. CONCLUSIONS: Children undergoing CPB with heparin dosing adjusted to optimize the ACT manifest inadequate anticoagulation (ongoing thrombin formation). High-dose heparin anticoagulation therapy in children undergoing CPB should be directed by tests (like the Heparin Management Test) that are less dependent on fibrinogen level than ACT.     

Correlation of ACT as measured with three commercially available devices with circulating heparin level during cardiac surgery

Automated activated clotting time (ACT) is utilized as the primary means of assessing anticoagulation status for cardiopulmonary bypass (CPB) procedures. Influences on the clotting cascade during CPB such as hypothermia, hemodilution, and platelet dysfunction are known to affect ACT. The recently introduced Thrombolytic Assessment System (TAS) has been reported to be less sensitive to changes in hemodilution and hypothermia during CPB than more conventional ACT devices. This study evaluated the ability of TAS, and two other commercially available automated ACT systems, the HemoTec and Hemochron, to correlate with circulating heparin levels. Reference standards for circulating heparin were determined by inactivation of factor Xa assay. Nineteen patients undergoing moderate hypothermic CPB served as subjects for this investigation. Blood samples were obtained for study at four time periods: 1) baseline (control), 2) post heparin administration (300-400 U/kg) prior to CPB, 3) during CPB, and 4) post protamine. Study results demonstrated a high correlation between the HemoTec and Hemochron (r = 0.99), increased heparin dose response on CPB compared to pre-CPB activity (p < 0.05), and a significant (p < 0.05) negative correlation between devices and patient hematocrit during CPB. Additionally, device correlation with anti-Xa assay during collection periods 2 and 3 showed negative correlations in each of the three devices evaluated. We conclude that all automated devices tested demonstrated an inability to predict circulating heparin at levels necessary for CPB, and that these discrepancies become magnified during CPB procedures.     

The effect of temperature and aprotinin during cardiopulmonary bypass on three different methods of activated clotting time measurement

The activated clotting time (ACT) is used frequently for monitoring blood anticoagulant response with heparin before, during, and after cardiopulmonary bypass (CPB). Many cardiac procedures involving CPB require reduction of the patient's blood temperature and use of the serine protease inhibitor, aprotinin. Three different methods of ACT measurement were compared to show the effects of different CPB temperatures and the presence of aprotinin. A total of 42 patients were included in the study: 14 received CPB at 28 degrees C, 14 received CPB at 32 degrees C, and 14 normothermic (37 degrees C) CPB. Within each temperature group, seven received aprotinin. The ACT in each group of patients was measured by a celite activator (C-ACT), a kaolin activator (K-ACT), and a celite, kaolin and glass activator (MAX-ACT). All three methods of ACT measurement showed significant increases (p < .05) in clotting times at hypothermic CPB compared with normothermic groups. During heparinization the C-ACT was significantly increased (p < .05) in the presence of aprotinin. Comparability between the 3 ACT measurement methods showed a very high correlation between C-ACT and K-ACT clotting times (R2 = .8962), and slightly lower correlation between MAX-ACT and C-ACT (R2 = .7780), and MAX-ACT and K-ACT (R2 = .7827). All ACT measurements are affected by changes in blood temperature. The C-ACT measurement is prolonged with aprotinin, whereas the MAX-ACT and K-ACT method of measurement in the presence of aprotinin are not significantly altered. It appears that the MAX-ACT produces lower values and may necessitate additional heparin therapy for ACT target values considered safe during CPB. Further study is required from these additional findings.     

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.     

Fresh frozen plasma: a solution to heparin resistance during cardiopulmonary bypass

The reasons for the highly variable response of patients to heparin remain incompletely understood. Empirical maintenance of the activated clotting time (ACT) at levels of 400 to 480 seconds appears to be safe for cardiopulmonary bypass (CPB). For patients with ACT responses lower than predicted for initial heparin doses, titration with additional heparin has been customary. In 44 patients undergoing cardiopulmonary bypass, 20 patients were identified as having initial ACTs of 300 seconds or less after receiving 300 units per kilogram of heparin. In 11 of them, ACTs were titrated to 400 to 480 seconds with additional heparin. Nine were given 2 units of fresh frozen plasma shortly after institution of CPB. In this group, there was significant augmentation of the ACT immediately after infusion of plasma. No differences in total heparin dosages given during CPB were found between 24 control patients with initially acceptable ACTs and the group receiving fresh frozen plasma. In contrast, more heparin was necessary in the patients with a low ACT titrated with heparin alone. Data also indicated that protamine sulfate requirements were substantially lower after administration of plasma than were those in either the control or the heparin-titrated, low ACT group. Fresh frozen plasma appears to "normalize" the heparin-ACT dose-response curve in heparin-resistant patients and to lessen total heparin requirements during CPB.     

The relationship between hirudin and activated clotting time: implications for patients with heparin-induced thrombocytopenia undergoing cardiac surgery.

Anticoagulation with recombinant hirudin (r-hirudin) (Refludan) has been suggested as an alternative to heparin for patients with heparin-induced thrombocytopenia requiring cardiac surgery. We sought to develop a modified activated coagulation time (ACT) that would allow quantification of the levels of r-hirudin required during cardiopulmonary bypass (CPB). Twenty-one patients scheduled for elective cardiac surgical procedures requiring CPB were enrolled in this IRB-approved study. R-hirudin was added to blood specimens obtained before heparin administration (before CPB) and 30 min after heparin neutralization with protamine (after CPB) to result in concentrations of 0, 2, 4, 6, 7, or 8 microg/mL. Kaolin/ACT and complete blood count measurements were assayed in native specimens (first 10 patients, Phase I) or in specimens mixed with equal volumes of commercial normal plasma (second 11 patients, Phase II). In Phase I, good (r(2) = 0.83) linear relationships between ACT values and r-hirudin concentrations (< or =4 microg/mL) were observed in specimens obtained before CPB. However, ACT values were markedly prolonged (P < 0.0001) by r-hirudin in specimens obtained after CPB, with ACT values generally exceeding the ACT's detection limit (>999 s) at hirudin concentrations >2 microg/mL. In patient specimens mixed with normal plasma (Phase II), ACT/hirudin relationships (i.e., hirudin/ACT slope values obtained with hirudin concentration < or =4 microg/mL) in the post-CPB period (0.022 +/- 0.004 microg. mL(-1). s(-1)) were similar (P = 0.47) to those (0.019 +/- 0.004 microg. mL(-1). s(-1)) obtained in the pre-CPB period. Accordingly, a significant relationship between normal plasma-supplemented ACT values and predilution hirudin concentration was obtained in the post-CPB (hirudin = 0.039ACT - 4.34, r(2) = 0.91) period. Although our data demonstrate that the ACT test cannot be used to monitor hirudin during CPB, the addition of 50% normal plasma to post-CPB hemodiluted blood specimens yields a consistent linear relationship between hirudin concentration and ACT values up to a predilution concentration of 8 microg/mL. Plasma-modified ACT may be useful in monitoring hirudin anticoagulation during CPB. Implications: A modified activated clotting time test system that may be helpful in monitoring hirudin anticoagulation in patients with heparin-induced thrombocytopenia during cardiac surgery with cardiopulmonary bypass is described.     

The treatment of heparin resistance with Antithrombin III in cardiac surgery

PURPOSE: To report three patients who developed heparin resistance during cardiac surgery which was successfully managed with 1000 U Antithrombin III (AT III). CLINICAL FEATURES: We observed heparin resistance prior to cardiopulmonary bypass (CPB) in one patient and during the CPB in two patients. In the first patient who was scheduled for mitral valve replacement, although heparin was administered sequentially up to 500 U x kg(-1) prior the CPB, the ACT value was 354 sec. After 1,000 U ATIII were administered the ACT was 395 sec and CPB was initiated. The ACT remained between 496 and 599 sec throughout CPB and a total of 260 mg protamine sulfate was given. In the other two patients following 300 U x kg(-1) heparin, the ACT was up to 400 sec and CPB was initiated. During CPB, ACT were decreased 360 sec and 295 sec in patients II and III respectively. Although heparin was added 1,500 U, ACT increased to > or = 400 sec could not be achieved. In the second patient ATIII activity was found 10%. After the administration of 1,000 U ATIII, ATIII activity was found to be 67% 40 min later and ACT were increased up to 400 sec. There was no thrombosis within the extracorporeal circuit, additional heparin was not required, less protamine was administered (< or = 3 mg x kg(-1)) and no excessive postoperative bleeding was observed in all patients. CONCLUSION: We recommend that AT III supplementation should be considered to manage heparin resistance prior or during CPB in patients undergoing open heart surgery.     

Management of heparin resistance during cardiopulmonary bypass: the effect of five different anticoagulation strategies on hemostatic activation

OBJECTIVE: Attenuation of hemostatic activation is a central goal during CPB. However, this poses a problem in patients insensitive to heparin. The present investigation was performed to assess different strategies of managing patients with heparin resistance during CPB. DESIGN: A randomized, prospective clinical investigation. SETTING: A major European heart center. PARTICIPANTS: Five groups with 20 patients each were investigated. INTERVENTIONS: The groups were handled as follows: (1). maintenance of a target ACT, (2). maintenance of the target unfractionated heparin (UFH) level and supplementation of a UFH level-based strategy with (3). AT III, (4). the direct thrombin inhibitor r-hirudin, or (5). the short-acting platelet glycoprotein (GP) IIb/IIIa antagonist tirofiban. Platelet count and generation of contact factor XIIa, thrombin, and soluble fibrin were assessed. Samples were obtained before CPB and after CPB before protamine infusion. MEASUREMENTS AND MAIN RESULTS: There were no differences observed in the generation of factor XIIa. The UFH-based strategy and supplementation with AT III, r-hirudin, and tirofiban resulted in significantly reduced (p < 0.05) thrombin generation compared with ACT management. A significant reduction of fibrin formation was seen only in patients who received AT III, r-hirudin, or tirofiban supplementation to the UFH. The administration of tirofiban resulted in a significant preservation of the platelet count compared with the other groups. There were no significant differences in the postoperative blood loss. CONCLUSIONS: Activation of hemostasis during CPB in heparin-resistant patients most likely has to be attributed to stimulation of the tissue factor pathway. Even the sole use of high concentrations of UFH does not effectively inhibit this activation. Therefore, in these patients anticoagulation during CPB with UFH should be supplemented with either AT III, a short-acting direct thrombin inhibitor, or a short-acting platelet glycoprotein IIb/IIIa antagonist.