Clinical role of blood heparin level monitoring during open heart surgery

Protamine has been used for neutralizing heparin and its dosage is decided by the initial fixed dose of heparin. Adequate protamine neutralization is very important to reduce complications. To attenuate excess reactions, in particular, whole blood heparin concentration during and after cardiopulmonary bypass was measured using Hepcon®, and the efficacy of optimal protamine dose in open heart surgery was evaluated. Twenty patients were randomly divided into two comparable groups, P and C. In the C group, heparin was neutralized with an initial fixed dose of protamine, 1.67 mg protamine per milligram total heparin (n = 8). In the P group, protamine dose was determined for residual heparin concentration (n = 12). In the P group, blood heparin concentrations at 60 minutes after the establishment of cardiopulmonary bypass, just after cardiopulmonary bypass and first protamine administration were 2.35 ± 0.14, 2.31 ± 0.17 and 0.13 ± 0.08 U/ml, respectively. Concentrations reached zero with the second protamine administration. The requirement of transfusion (659 ± 224 vs. 1559 ± 323 ml, p = 0.0314), pulmonary vascular resistance index just after the protamine administration (190 ± 22 vs. 286 ± 18 dyne·s·cm^?5·m², p = 0.0137) and the IL-8 levels (just after protamine: 26.9 ± 5.1 vs. 43.5 ± 5.9 pg/ml, p = 0.0499, 12 hours after cardiopulmonary bypass: 37.1 ± 12.1 vs. 86.8 ± 20.0, p = 0.0435) in the P group were significantly lower than those in the C group. These data suggested that heparin level monitoring in whole blood may be useful to determine the optimal dose of protamine resulting in the decrease of a requirement of blood components in open heart surgery and attenuating in transient pulmonary hypertension and excess protamine-induced inflammatory reactions.     

Use of heparin-coated cardiopulmonary bypass circuit with low-dose heparin reduces postoperative bleeding.

Postoperative bleeding was examined in patients undergoing cardiopulmonary bypass with a heparin-coated circuit and low-dose heparin. Out of 150 patients who underwent cardiopulmonary bypass for longer than 90 minutes, 74 received a standard dose (300 IU/kg) of heparin with an uncoated circuit (group C) and 76 received a low-dose (150 IU/kg) of heparin with a heparin-coated circuit (group H). The coagulation and fibrinolytic systems were investigated in 24 patients. Re-opening of the chest due to bleeding was performed in 5 patients in group C (7%), but none of the patients in group H (p=0. 03). The median of blood loss in the first 12 hours after surgery was 292 ml in group C, and 216 ml in group H (p=0.006). There were no significant differences in the peak thrombin-antithrombin complex concentration between the two groups. The plasmin-alpha 2 plasmin inhibitor complex concentrations after protamine administration were 1.9 ng/ml (median) in group C and 1.1 ng/ml in group H (p=0.002). The use of heparin-coated cardiopulmonary bypass circuits with low-dose heparin suppressed the activation of fibrinolysis. This may explain the reduction in postoperative bleeding.     

Low-dose protamine based on heparin-protamine titration method reduces platelet dysfunction after cardiopulmonary bypass.

OBJECTIVE: The heparin-protamine titration method that uses the Hepcon hemostasis management system (Medtronic HemoTec Inc, Englewood, Colo) reduced blood loss in cardiac surgery in previous reports, but the mechanism is not fully understood. This study tests the hypothesis that reduced protamine administration preserves platelet function in human cardiac surgery. METHODS: Platelet count, alpha-granule secretion, and aggregation to thrombin before and after cardiopulmonary bypass in human beings were evaluated. In the control group (n = 14), a fixed dose of protamine (3 mg/kg) was administered. In the titration group (n = 20), protamine doses were based on the heparin concentration measured by the Hepcon system. RESULTS: Heparin concentrations before protamine administration were higher in the titration group (P =.0012), but protamine doses of patients in the titration group were markedly lower than those of the control group (P <.0001). During protamine infusion at a rate of 0.3 mg. kg(-1). min(-1), the percentage of granule membrane protein-140-positive platelets significantly increased in the control group compared with the titration group (18.8% +/- 8.6% vs 13.0% +/- 5.3%, P =.0188). After protamine administration, aggregation of washed platelets to thrombin recovered almost to the preoperative level in the titration group; however, it remained lower in the control group (20% +/- 20% vs 55% +/- 18%, P =.0009). CONCLUSION: Low-dose administration of protamine, based on a heparin-protamine titration method, restores not only the blood coagulation but also the platelet responses to thrombin and attenuates platelet alpha-granule secretion during heparin neutralization. Overdose of protamine activates platelets and may predispose patients to excessive bleeding after cardiac surgery.     

Effect of tranexamic acid on blood loss reduction after cardiopulmonary bypass

OBJECTIVE: We evaluated the effect of tranexamic acid on blood loss in patients undergoing elective cardiopulmonary bypass for coronary artery bypass surgery. METHODS: We randomly assigned 7 of 14 patients to a group receiving 50 mg/kg tranexamic acid before skin incision and after the start of cardiopulmonary bypass and the other 7 as controls. RESULTS: Intraoperative and postoperative blood loss was significantly (p = 0.025) reduced in the tranexamic acid group. A similar decrease in platelet count was observed during cardiopulmonary bypass in both groups. Antithrombin III was significantly (p = 0.013) decreased in both groups during cardiopulmonary bypass. Antithrombin III and thrombin-antithrombin III complexes were significantly (p = 0.001) increased after protamine administration. A significant (p = 0.010) decrease in alpha 2-plasmin inhibitor was noted at 5 and 60 minutes after the start of cardiopulmonary bypass in the tranexamic acid group. alpha 2-plasmin inhibitor-plasmin complexes were significantly (p = 0.001) increased after the start of cardiopulmonary bypass in both groups and were significantly (p = 0.012) decreased after protamine administration. alpha 2-plasmin inhibitor-plasmin complexes in the tranexamic acid group were significantly (p = 0.030) lower than in controls 60 minutes after the start of cardiopulmonary bypass, just prior to the end of cardiopulmonary bypass, and after protamine administration. CONCLUSIONS: These findings showed that tranexamic acid administration effectively prevented perioperative blood loss without thromboembolic complications and that tranexamic acid during cardiopulmonary bypass coordinates the anticoagulative effect of heparin and the antifibrinolytic effect of tranexamic acid.     

A prospective, randomized study of the effects of prostacyclin on platelets and blood loss during coronary bypass operations

A randomized, double-blind study was designed to evaluate the therapeutic effect and safety of prostacyclin (epoprostenol) in patients undergoing cardiopulmonary bypass. One hundred patients having isolated coronary bypass grafting received 300 units/kg of heparin and then either prostacyclin (12.5 ng/kg/min from heparinization until cardiopulmonary bypass, 25 ng/kg/min during bypass) or buffer/diluent in a similar manner. Standardized anesthetic, perfusion, and surgical techniques were used. Drug and placebo groups were similar in demographic data and bypass times, and there were no deaths. Activated coagulation time and platelet count were significantly higher during cardiopulmonary bypass in patients receiving prostacyclin. Platelet count remained significantly higher 24 hours after bypass in the active drug group. Immediately after operation, there was significantly less prolongation of bleeding time (1.3 versus 2.9 minutes; p = 0.009) in the patients receiving prostacyclin. Blood loss was significantly reduced during the first 4 hours postoperatively in the prostacyclin group (261 +/- 159 versus 347 +/- 197 ml; p = 0.02). There was no significant difference between the groups when total blood loss was compared (710 +/- 351 versus 869 +/- 498 ml; p = 0.07). Patients receiving prostacyclin required an average of 257 ml less blood transfused in the intensive care unit (p = 0.02). We conclude that the clinical impact of prostacyclin in patients undergoing coronary artery operations was demonstrable, but small. Prostacyclin may provide clinical benefits in patients undergoing cardiopulmonary bypass when there are contraindications to or other difficulties with blood transfusion. With prostacyclin, reduced heparin dose is possible and therefore reduced protamine requirement would offer a potential benefit of less cardiovascular depression immediately after bypass. However, the advantages offered by prostacyclin are not sufficient to recommend its routine use during cardiopulmonary bypass.     

Heparin dosing and monitoring for cardiopulmonary bypass. A comparison of techniques with measurement of subclinical plasma coagulation

Subclinical plasma coagulation during cardiopulmonary bypass has been associated with marked platelet and clotting factor consumption in monkeys. To better define subclinical coagulation in man, we measured plasma fibrinopeptide A concentrations before, during, and after cardiopulmonary bypass. Patients were assigned to one of three groups of heparin management: group 1 (n = 10)--initial heparin dose 300 IU/kg, with supplemental heparin if the activated coagulation time fell below 400 seconds; group 2 (n = 6)--initial heparin dose 250 IU/kg, with supplemental heparin if activated coagulation time was less than 400 seconds; and group 3 (n = 5)--initial heparin dose 350 to 400 IU/kg, with supplemental heparin if whole blood heparin concentration was less than or equal to 4.1 IU/ml. Activated coagulation time and heparin concentration were measured every 30 minutes during cardiopulmonary bypass, and fibrinopeptide A was measured at hypothermia, normothermia, and whenever activated coagulation time was less than 400 seconds. Quantitative and qualitative blood clotting competence was assessed after cardiopulmonary bypass, including mediastinal drainage for the first 24 hours. Fibrinopeptide A values were markedly elevated during cardiopulmonary bypass but were well below the levels present before and after cardiopulmonary bypass. Fibrinopeptide A correlated inversely with heparin concentration during cardiopulmonary bypass (r = -0.46, p = 0.03), but higher fibrinopeptide A levels during cardiopulmonary bypass did not correlate with post-cardiopulmonary bypass coagulopathy. Group 3 patients received the highest heparin doses (p less than 0.05) and had the greatest postoperative blood loss (p less than 0.05). Protamine dose and heparin concentration during cardiopulmonary bypass correlated best with postoperative mediastinal drainage. Our findings support the following conclusions: (1) compensated subclinical plasma coagulation activity occurs during cardiopulmonary bypass despite activated coagulation time greater than 400 seconds or heparin concentration greater than or equal to 4.1 IU/ml; (2) post-cardiopulmonary bypass mediastinal drainage correlates strongly with increased heparin concentration during cardiopulmonary bypass (p less than 0.05) and protamine dose (p less than 0.05); and (3) during cardiopulmonary bypass at both normothermia and hypothermia, activated coagulation times greater than 350 seconds result in acceptable fibrinopeptide A levels and post-cardiopulmonary bypass blood clotting.     

Heparin monitoring during cardiopulmonary bypass in congenital heart surgery

The Hepcon/HMS system automatically provides the activated clotting time and a whole blood heparin concentration. It also provides the adequate protamine dose by titration of protamine to heparin. 45 patients undergoing congenital heart surgery with cardiopulmonary bypass (CPB) were studied by the Hepcon/HMS device. We measured the heparin dose response before heparin administration, and the ration between the dose of protamine (ml) which was necessary for heparin neutralization at the termination of CPB and the dose of total heparin (ml) in each patient. The value of heparin dose response ranged 120-390 (mean 228) IU/kg. The ratio between protamine dose and heparin dose varied 0.11-0.99 (mean 0.55). There was a statistically significant correlation between the duration of CPB and this ratio (r = -0.51, n = 45, p = 0.0005). From the standpoint of variances in the value of heparin dose response, conventional way of the heparin administration according to the patient's body weight alone may cause inadequacy of anticoagulation during CPB. A dose of protamine determined by Hepcon device that is smaller than a conventional dose of protamine prevents inadvertent overdose and, therefore, can reduce the adverse effects excessive protamine has.     

Role of nitric oxide in a temperature dependent regulation of systemic vascular resistance in cardiopulmonary bypass.

OBJECTIVES: Nitric oxide is the most potent vasodilator among inflammation-mediated vasoactive substances. Tepid cardiopulmonary bypass has been known to maintain low vascular resistance and nitric oxide may also be involved. There has been no previous clinical study elucidating a role of nitric oxide in a temperature dependent regulation of systemic vascular resistance in cardiopulmonary bypass. METHODS: Thirty-one patients who underwent valvular surgery were randomly divided into two comparable groups; consisting of the hypothermic cardiopulmonary bypass (28 degrees C:14 patients) and the tepid cardiopulmonary bypass group (34 degrees C:17 patients). The serum levels of nitric oxide (NO(2)(-)+NO(3)(-)), prostaglandin E(2), bradykinin, 6-keto PGF1alpha, thromboxane B(2), endothelin-1, systemic vascular resistance index were measured before, 0, 12 and 24 h after cardiopulmonary bypass. RESULTS: The pattern of change in systemic vascular resistance index and nitric oxide during and after cardiopulmonary bypass were significantly different between the two groups (P=0.0008, P=0.02). The tepid group showed significantly lower levels of systemic vascular resistance index after cardiopulmonary bypass than the hypothermic group (0 h: 2278+/-735 vs. 4387+/-1289, 12 h: 1827+/-817 vs. 2817+/-1146 and 24 h: 1690+/-548 vs. 2761+/-641 dyne s cm(-5) m(2), P=0.0001, P=0.03, P=0. 0006). The nitric oxide levels were significantly higher at 0, 12 and 24 h after cardiopulmonary bypass in the tepid group than those in the hypothermic group (84.7+/-33.3 vs. 46.3+/-18.1, 69.8+/-31.1 vs. 40.1+/-17.5 and 80.1+/-38.5 vs. 39.1+/-15.6 micromol/l, P=0.008, P=0.03, P=0.01). The prostaglandin E(2) levels in the tepid group was significantly higher just after cardiopulmonary bypass than that in the hypothermic group (37.3+/-20.0 vs. 15.8+/-8.6 pg/ml, P=0.02). The bradykinin level in the hypothermic group was significantly higher just after cardiopulmonary bypass than that in the tepid group (2.40+/-0.32 vs. 1.85+/-0.21 log(10) (pg/ml), P=0.005). Only nitric oxide showed a significant negative correlation with the systemic vascular resistance index both during and after cardiopulmonary bypass (r=-0.60, P<0.0001) as compared with prostaglandin E(2) and bradykinin. CONCLUSIONS: These findings demonstrated that serum nitric oxide levels in tepid cardiopulmonary bypass were significantly higher than those in hypothermic cardiopulmonary bypass. Nitric oxide correlated with systemic vascular resistance. Thus, nitric oxide may play a pivotal role in a temperature dependent regulation of systemic vascular resistance in cardiopulmonary bypass.     

Reduction and elimination of systemic heparinization during cardiopulmonary bypass.

After extensive experimental evaluation, heparin-coated perfusion equipment was clinically evaluated with low or no systemic heparinization in three different groups of patients (n = 47). In group 1, resection of descending thoracic aortic aneurysms (n = 24) was performed with heparin-coated equipment used for left heart bypass (n = 12) or partial cardiopulmonary bypass (n = 12) for proximal unloading and distal protection (heparin 5000 IU, autotransfusion). All devices remained functional throughout the procedures and no systemic emboli were detected. The sole death (1 of 24, 4%) occurred in a patient with ruptured thoracoabdominal aortic aneurysm requiring operation in extremis. Paraparesis with spontaneous recovery occurred in one patient (1 of 24, 4%). In group 2, coronary artery revascularization randomized for low (activated clotting time greater than 180 seconds) versus full (activated clotting time greater than 480 seconds) systemic heparinization was prospectively analyzed in 22 patients. All patients recovered without sequelae, and no myocardial infarction was diagnosed. Low dose of heparin (8041 +/- 1270 IU versus 52,500 +/- 17,100 IU; p less than 0.0005) resulted in reduced protamine requirements (7875 +/- 1918 IU versus 31,400 +/- 14,000 IU; p less than 0.0005), reduced blood loss (831 +/- 373 ml versus 2345 +/- 1815 ml; p less than 0.01), reduced transfusion requirements of homologous blood products (281 +/- 415 ml versus 2731 +/- 2258 ml; p less than 0.001), and less patients transfused (5 of 12 versus 10 of 10; p less than 0.05). Lower D-dimer levels in the group perfused with low systemic heparinization (0.50 +/- 0.43 mg/L versus 1.08 +/- 0.59 mg/L; p less than 0.05) were attributed to the absence of cardiotomy suction in this group. In group 3, rewarming in accidental hypothermia by cardiopulmonary bypass was successfully performed without systemic heparinization in a patient with hypothermic cardiac arrest (23.3 degrees C) and intracranial trauma. We conclude that systemic heparinization for clinical cardiopulmonary bypass can be reduced and eliminated in selected patients if perfusion equipment with improved biocompatibility is used. Bypass-induced morbidity can be reduced.     

Comparison of two protocols for heparin neutralization by protamine after cardiopulmonary bypass

Twenty patients undergoing cardiac operations were randomly assigned to two protocols for heparin neutralization by protamine after cardiopulmonary bypass. In all patients protamine chloride was given at a ratio of 1 unit of protamine to 1 unit of injected heparin. In Group I (10 patients) all protamine was infused within 10 minutes after termination of cardiopulmonary bypass. Group II (10 patients) received 75% of the calculated protamine dose within 10 minutes after termination of bypass and the remainder after transfusion of all blood in the heart-lung machine. Plasma heparin levels were significantly lower in Group II 5 minutes after transfusion of all blood in the heart-lung machine and were 0.13 units/ml (standard deviation 0.04) in Group I and 0.06 units/ml (standard deviation 0.05) in Group II (p less than 0.001) 60 minutes after bypass. Activated partial thromboplastin time mirrored the changes in plasma heparin, whereas activated clotting time (Hemochron) was too insensitive to detect these low plasma heparin levels. We conclude that the two-dose protocol resulted in more complete heparin neutralization than the one-dose protocol.     

Use of heparin-bonded circuits in cardiopulmonary bypass improves clinical outcome

OBJECTIVE: The use of heparin-coated surfaces in cardiopulmonary bypass has been shown to decrease the inflammatory response imposed by the contact between blood and artificial surfaces. One would expect this reaction to improve clinical outcome. However, this has been difficult to verify. This investigation is based on an aggregation of two randomized studies from our institution and highlights possible effects of heparin coating on a number of clinically oriented parameters. DESIGN: Departmental analysis of patients subjected to coronary artery bypass surgery using heparin-coated circuits. Cardiopulmonary bypass was employed using either the Carmeda or Duraflo heparin coatings compared with a control. The systemic heparin dose was reduced in the heparin-coated groups (ACT > 250 s) vs control group patients (ACT > 480 s). The effects of heparin coating related to clinical outcome were studied. RESULTS: The use of heparin-coated circuits reduced the mean length of stay in hospital from 7.8 +/- 2.5 to 7.3 +/- 1.8 days (p = 0.040) and postoperative ventilation time from 9.7 +/- 9.2 to 8.2 +/- 8.5 h (p = 0.018), blood loss 8 h post surgery from 676 +/- 385 to 540 +/- 245 ml (p = 0.001), individual perioperative change of haemoglobin loss (p = 0.001), leukocyte count (p = 0.000) and creatinine elevation (p = 0.000), proportion of patients exposed to allogenous blood transfusions 39.2 vs 23.9% (p = 0.001), postoperative coagulation disturbances 4.4 vs 0.4% (p = 0.006), postoperative deviations from the normal postoperative course 47.2 vs 36.7% (p = 0.035), neurological deviations 9.4 vs 3.9% (p = 0.021) and atrial fibrillation 26.4 vs 18.0% (p = 0.041). No effects were found with respect to perioperative platelet count, postoperative fever reaction and 5-year survival. CONCLUSION: Based on several indicators, the use of heparin coating in cardiopulmonary bypass is associated with improved clinical results.     

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.     

Decreased blood loss after cardiopulmonary bypass using heparin-coated circuit and 50% reduction of heparin dose.

In a randomized, double-blind study of patients undergoing elective coronary artery grafting, the effect of heparin-coated circuit combined with 50% reduction of systemic heparin bolus was investigated. Ten patients comprised group HC (heparin-coated) and ten group C (controls). The mean total doses of heparin were 172 IU/kg in group HC and 416 IU/kg in group C and the respective protamine doses were 0.96 and 3.96 mg/kg (both p < 0.001). Activated clotting times during cardiopulmonary bypass were significantly shorter in group HC, and both intra- and postoperative bleeding was significantly less than in group C (7.7 vs. 11.7 ml/kg, p = 0.036, and 6.9 vs. 9.7 ml/kg, p = 0.004). Hemoglobin loss via the drains was 22.5 g in group HC and 43.7 g in group C (p < 0.005). Hemolysis at the end of bypass was significantly greater in group C. Apart from one perioperative myocardial infarction in group HC the postoperative course was uneventful. Use of a heparin-coated circuit is concluded to permit complication-free reduction of heparin and protamine doses and to decrease both intra- and postoperative bleeding, which may favorably influence the outcome of coronary artery grafting.     

The safety and efficacy of ten percent pentastarch as a cardiopulmonary bypass priming solution. A randomized clinical trial.

Ten percent pentastarch is a low-molecular-weight hydroxyethyl starch with greater oncotic pressure and shorter intravascular persistence than 6% hetastarch. To evaluate its safety and efficacy as a component of cardiopulmonary bypass priming solution, we prospectively studied 90 patients undergoing coronary artery bypass grafting or valve replacement necessitating cardiopulmonary bypass (bubble oxygenator and moderate systemic hypothermia). Sixty patients were randomized to receive 75 gm of either 10% pentastarch (group P) or 25% albumin (group A), and 30 patients received lactated Ringer's solution alone (group C). Intravascular colloid osmotic pressure during cardiopulmonary bypass was highest with either of the colloid primes (15-minute measurement: group P, 15.7 +/- 2.2 mm Hg (mean +/- standard deviation); group A, 15.2 +/- 2.0 mm Hg; group C, 11.3 +/- 1.7 mm Hg; p less than 0.05, groups P and A compared with group C). This was associated with a lower volume requirement during cardiopulmonary bypass to maintain the venous reservoir (group P, 333 +/- 318 ml; group A, 483 +/- 472 ml; group C, 1332 +/- 1013 ml; p less than 0.05, groups P and A compared with group C). Urine output during cardiopulmonary bypass was similar in each group. Net intraoperative fluid balance was lowest in the colloid groups (groups P and A, 5.7 +/- 1.4 L; group C, 6.9 +/- 1.3 L; p less than 0.05, groups P and A compared with group C). Cardiac index shortly after weaning from cardiopulmonary bypass was greatest in group P (group P, 3.2 +/- 0.9; group A, 2.8 +/- 0.8; group C, 2.7 +/- 0.6 dyne.sec.cm-5; p less than 0.05, group P compared with group C). Changes in alveolar-arterial oxygen gradients, shunt fraction, and effective compliance were similar in all groups. During cardiopulmonary bypass, pentastarch appeared to cause the greatest degree of hemodilution, as suggested by the lowest hemoglobin, factor VII and IX levels and platelet count. The activated partial thromboplastin time was significantly prolonged during and immediately after cardiopulmonary bypass in group P relative to groups A and C (p less than 0.05), although there were no significant differences in the activated clotting time before cardiopulmonary bypass, during cardiopulmonary bypass, or after heparin neutralization. As well, clinical indices of hemostasis, including mediastinal drainage, red cell, platelet, and fresh frozen plasma requirements, and reoperation for excessive postoperative bleeding, were similar. We conclude that pentastarch, when used in cardiopulmonary bypass prime, is as safe as either albumin or Ringer's solution alone.(ABSTRACT TRUNCATED AT 400 WORDS)     

Response to heparinization in adults and children undergoing cardiac operations.

The activated clotting time is an unreliable index of anticoagulation status during cardiopulmonary bypass procedures. However, modern instrumentation (Hemotec Hepcon HMS) now allows the monitoring of free heparin levels via automated protamine titration. In the present study, the standard procedure of anticoagulation at Killingbeck Hospital, Leeds, was investigated. Twenty-two pediatric patients and 20 adult patients undergoing open heart procedures involving cardiopulmonary bypass were given empirical doses of heparin (3 mg/kg body weight bolus), and activated clotting time was maintained at a level greater than 450 seconds using the Hemochron Timer. Heparin neutralization was performed at the termination of the bypass period using an empirical equivalent (3 mg/kg) of protamine sulfate. Mean free heparin concentration (+/- standard deviation) fell from 2.26 (+/- 0.45) mg/kg to 1.39 (+/- 0.34) mg/kg over the period 10 to 40 minutes on bypass in children. In adults, free heparin level declined from 2.56 (+/- 0.58) mg/kg to 1.81 (+/- 0.58) mg/kg over the same period. The biological half-life for heparin was 60 minutes in adults and 35 minutes in pediatric patients. Empirical protamine dosing resulted in excess protamine administration when compared with Hepcon titrated dose requirements: for children: median (range), 80 (12 to 350) versus 33 (12 to 97) mg, p less than 0.001; and for adults: 350 (200 to 500) versus 130 (61 to 237) mg, p less than 0.001. In conclusion, empirical heparin administration (3 mg/kg) does not result in "steady-state" anticoagulation during cardiopulmonary bypass, and empirical administration of protamine takes no account of interindividual differences in heparin sensitivity and biological half-life, which may be assessed using the Hepcon HMS.     

Prevention of heparin-induced thrombocytopenia during open heart surgery with iloprost (ZK36374)

Recurrent thrombocytopenia, thrombosis, or sudden death may develop in patients with heparin-induced thrombocytopenia who are reexposed to heparin. Three patients came to us in whom a diagnosis of heparin-induced thrombocytopenia had been made on the basis of clinical and serologic evidence; these patients required reexposure to heparin because of urgent cardiac surgery. Therefore, we evaluated the ability of iloprost (ZK36374), a new analogue of prostacyclin, to prevent heparin-dependent activation of platelets and thereby permit obligatory heparinization for safe extracorporeal circulation. Before operation, we demonstrated that iloprost prevented both heparin-dependent platelet aggregation and tritiated (3H)-serotonin release in vitro. Therefore a continuous infusion of iloprost was begun 1 hour before heparinization and was continued throughout cardiopulmonary bypass and for an additional 15 minutes after protamine administration. The mean platelet count of 130,000/microliters before operation remained stable, and no spontaneous platelet aggregation was observed in samples of platelet-rich plasma obtained before cardiopulmonary bypass but after heparin administration. Similarly, after heparin administration but before bypass, platelet responsiveness to adenosine diphosphate remained unchanged when compared with preoperative values. Plasma levels of platelet factor 4 increased from 26 +/- 1 ng/ml (mean +/- standard error) to 843 +/- 383 ng/ml after heparin administration but actually decreased throughout cardiopulmonary bypass to 52 +/- 25 ng/ml. Beta-thromboglobulin levels increased from 103 +/- 16 to 244 +/- 94 ng/ml with heparinization. The mean bleeding time was 10.5 minutes preoperatively and 13.3 minutes postoperatively. The mean amount of postoperative chest tube drainage (duration: 12 hours) was 432 +/- 67 ml. Thus, despite the confirmed presence of heparin-dependent platelet-activating factor in the plasma of these three patients, iloprost prevented heparin-induced platelet activation during cardiopulmonary bypass while preserving platelet function, as would be desired for postoperative hemostasis.     

Does tranexamic acid reduce desmopressin-induced hyperfibrinolysis?

OBJECTIVE: Desmopressin releases tissue-type plasminogen activator, which augments cardiopulmonary bypass--associated hyperfibrinolysis, causing excessive bleeding. Combined use of desmopressin with prior administration of the antifibrinolytic drug tranexamic acid may decrease fibrinolytic activity and might improve postoperative hemostasis. METHODS: This prospective randomized study was carried out with 100 patients undergoing coronary artery bypass operations between April 1999 and November 2000 in Gülhane Military Medical Academy. Patients were divided into 2 groups. Desmopressin (0.3 microg/kg) was administrated just after cardiopulmonary bypass and after protamine infusion in group 1 (n = 50). Both desmopressin and tranexamic acid (before the skin incision at a loading dose of 10 mg/kg over 30 minutes and followed by 12 hours of 1 mg.kg(-1).h(-1)) were administrated in group 2 (n = 50). RESULTS: Significantly less drainage was noted in group 2 (1010 +/- 49.9 mL vs 623 +/- 41.3 mL, P =.0001). Packed red blood cells were transfused at 2.1 +/- 0.5 units per patient in group 1 versus 0.9 +/- 0.3 units in group 2 (P =.0001). Fresh frozen plasma was transfused at 1.84 +/- 0.17 units per patient in group 1 versus 0.76 +/- 0.14 units in group 2 (P =.0001). Only 24% of patients in group 2 required donor blood or blood products compared with 74% of those in the isolated desmopressin group (group 1, P =.00001). Group 1 and group 2 findings were as follows: postoperative fibrinogen, 113 +/- 56.3 mg/dL versus 167 +/- 45.8 mg/dL (P =.0001); fibrin split product, 21.2 +/- 2.3 ng/mL versus 13.5 +/- 3.4 ng/mL (P =.0001); and postoperative hemoglobin level, 7.6 plus minus 1.2 g/dL versus 9.1 plus minus 1.2 g/dL (P =.0001). CONCLUSION: Tranexamic acid administration significantly reduces desmopressin and bypass-induced hyperfibrinolysis. Combined use of tranexamic acid and desmopressin decreases both postoperative blood loss and transfusion requirement.     

The influence of preoperative anticoagulation on heparin response during cardiopulmonary bypass.

The effect of preoperative anticoagulant therapy on intraoperative heparin response in patients undergoing cardiac operations was examined in a prospective study. The study included 45 patients with different preoperative anticoagulant treatments: 10 patients received treatment with phenprocoumon (a warfarin analogue) (group M), 12 patients received treatment with intravenous heparin (group Hiv), and 13 patients received treatment with subcutaneous heparin (group Hsc). The control group consisted of 10 patients who did not receive anticoagulant therapy before operation (group C). Preoperative antithrombin III activity was highest in group M (85% +/- 6%) and lowest in group Hiv (70% +/- 15%, p less than 0.05). The activated clotting time, determined 10 minutes after bolus injection of 250 IU (group M) or 375 IU heparin (all other groups), was 529 +/- 109 seconds in group C, greater than 1000 seconds in group M, 483 +/- 99 seconds in group Hsc, and 406 +/- 63 seconds in group Hiv (p less than 0.05). Heparin consumption during cardiopulmonary bypass varied between 4.6 +/- 1.4 IU/kg.min (group Hiv) and 2.6 +/- 0.9 IU/kg.min (group M) (p less than 0.05). Despite this increased heparin consumption, the patients who had received heparin before operation demonstrated increased activation of coagulation at the end of cardiopulmonary bypass (thrombin-antithrombin III complex, 19 +/- 4.1 ng/ml in group M and 61 +/- 7 ng/ml in group Hsc, p less than 0.05; cross-linked fibrin fragments, 257 +/- 92 ng/ml in group M and 875 +/- 152 ng/ml in group Hiv, p less than 0.05). Increased platelet activation was also found in patients with preoperative heparin therapy (beta-thromboglobulin at the end of cardiopulmonary bypass was 585 +/- 88 ng/ml in group M versus 1341 +/- 190 ng/ml in group Hsc, p less than 0.05). Drainage from the chest tube 24 hours after operation was 815 +/- 305 ml in group C, 644 +/- 238 ml in group M, 1133 +/- 503 ml in group Hsc, and 950 +/- 505 ml in group Hiv (p less than 0.05 for group M versus group Hsc). This study suggests that patients who receive heparin therapy before operation face a high risk of insufficient anticoagulation during cardiopulmonary bypass if standard heparin doses are used. Therefore, for patients who receive preoperative heparin therapy, a larger (500 IU/kg) initial bolus of heparin is recommended before cardiopulmonary bypass. On the other hand, patients who undergo preoperative treatment with phenprocoumon receive sufficient anticoagulative effect with a heparin bolus of 250 IU/kg.(ABSTRACT TRUNCATED AT 400 WORDS)     

Low-dose postoperative aprotinin reduces mediastinal drainage and blood product use in patients undergoing primary coronary artery bypass grafting who are taking aspirin: a prospective, randomized, double-blind, placebo-controlled trial

BACKGROUND: Although low-dose aprotinin administered after cardiopulmonary bypass has been reported to reduce mediastinal blood loss and blood product requirements in patients not taking aspirin, it is unknown whether low-dose postoperative aprotinin has any beneficial effects in patients undergoing coronary artery bypass operations who are at high risk of excessive postoperative bleeding and increased transfusion requirements because of aspirin use until just before the operation. METHODS: Fifty-five patients undergoing primary coronary artery operations with cardiopulmonary bypass who continued taking aspirin (150 mg/d) until the day before the operation were enrolled in a prospective, randomized, double-blind trial to receive a single dose of either placebo (n = 29) or 2 x 10(6) kallikrein inhibiting units of aprotinin (n = 26) at the time of sternal skin closure. RESULTS: Patients in the aprotinin group had a lower rate (28 +/- 18 vs 43 +/- 21 mL/h [mean +/- standard deviation], P <.005) and total volume of mediastinal drainage (955 +/- 615 vs 1570 +/- 955 mL, P <.007), as well as a shorter duration of mediastinal drain tube insertion (24.4 +/- 13.8 vs 31.3 +/- 16.5 hours, P <.05). In addition, a smaller proportion of patients receiving aprotinin required a blood product (31% vs 62%, P =.03), resulting in a reduction in the use of packed cells by 47% (P =.05), platelets by 77% (P =.01), fresh frozen plasma by 88% (P =.03), and total blood products by 68% (P =.01) in this group. CONCLUSIONS: These results suggest that postoperative administration of low-dose aprotinin in patients taking aspirin until just before primary coronary artery operations with cardiopulmonary bypass not only reduces the rate and total amount of postoperative mediastinal blood loss but also lowers postoperative blood product use.     

Beneficial effect of aspirin on renal function in patients with renal insufficiency postcardiac surgery

AIM: Renal function is one of the most important prognostic factors following cardiac surgery. Whether aspirin affects cardiopulmonary bypass related renal injury is investigated in this study. METHODS: Ninety-four patients with impaired renal function (creatinine = or >1.5 mg/dl) undergoing coronary artery bypass grafting (CABG) were categorized into 2 groups according to aspirin administration before surgery. Serum creatinine, urinary output and creatinine clearance along with other perioperative factors were compared between the 2 groups prior to surgery, 24 hours and 48 hours following cardiopulmonary bypass. RESULTS: Creatinine levels increased significantly in the second postoperative day only in the non-aspirin (control) group (3.7+/-1.6 vs 2.9+/-1.7 mg/dl, p=0.03). Aspirin (study) group had lower creatinine levels in day 1 (p=0.03) and day 2 (p=0.001). Furthermore, in the study group creatinine clearance was higher in day 1 (34.3+/-14.3 vs 30.9+/-13.1 ml/min, p=0.01) and in day 2 (32.6+/-13.8 vs 26.4+/-9.8 ml, p<0.0001). Creatinine levels at discharge were elevated compared to the preoperative levels in the control group (p=0.01). However, the study group had lower creatinine levels at discharge (2.6+/-1.4 vs 3.8+/-1.6 mg/dl, p<0.0001). Urinary output was higher in the study group in the first postoperative day compared to the control group (p=0.01). Postoperative bleeding was slightly increased in the study group compared to the control group (760+/-230 ml vs 530+/-210 ml, p=0.01). CONCLUSIONS: Continuation of aspirin administration until the day of surgery may have a protective effect against renal injury resulting from cardiopulmonary bypass, with only a negligible increase in bleeding. Possible explanations for this effect are antiplatelet activity of aspirin during cardiopulmonary bypass causing inhibition of vasoconstrictive agents like thromboxane, and improvement of renal perfusion by reducing blood viscosity.