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Asian Cardiovasc Thorac Ann 2004;12:47-52
© 2004 Asia Publishing EXchange Ltd

ORIGINAL CONTRIBUTION

Activated Clotting Time During Cardiopulmonary Bypass: Is Repetition Necessary During Open Heart Surgery?

Praveen Kumar Neema, MD, Prabhat Kumar Sinha, MD, Ramesh Chandra Rathod, MD

Department of Anaesthesiology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Kerala, India

For reprint information contact: Praveen Kumar Neema, MD Tel: 91 471 255 7321 Fax: 91 471 244 6433 Email: neema{at}sctimst.ac.in Department of Anaesthesiology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum – 695011, Kerala, India.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
We evaluated the need of activated clotting time monitoring and efficacy of heparinization protocol in 100 patients undergoing open heart surgery. Patients were anticoagulated with 300 or 400 units·kg-1 heparin, based on their heparin sensitivity assessed at 5 min by activated clotting time. One-third of the initial dose was repeated at 90 min and thereafter hourly until completion of cardiopulmonary bypass. Patients who attained an activated clotting time of > 350 seconds at 5 min were included. Activated clotting time was repeated every 30 min. A time of < 350 seconds or presence of clot in the surgical field/extracorporeal circuit was considered failure of the protocol. Cardiopulmonary bypass was performed using a membrane oxygenator, non-pulsatile flow, hypothermia and crystalloid/blood priming solution. At 5 min, 94 patients had activated clotting time of > 350 seconds, 6 were < 350 seconds. At predetermined time intervals of 30 min, up to 210 min, 406 activated clotting time measurements were above 400 seconds and 40 were between 350 and 400 seconds. No clot was observed in the surgical field or extracorporeal circuit. This anticoagulation protocol ensures adequate anticoagulation during hypothermic cardiopulmonary bypass. With this protocol, only one activated clotting time at 5 min after heparin administration is required and essential; subsequent monitoring is not necessary.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Heparin acts by binding and activating antithrombin III (AT III) as well as heparin cofactor II.1 The activated clotting time (ACT) is most commonly measured for monitoring the anticoagulation effect of unfractionated heparin during cardiopulmonary bypass (CPB).2 Heparin dosing in patients undergoing open heart surgical procedures has moved from the practice of empiric dosing to one of a structured approach of ACT monitoring. With this approach a considerable reduction in total heparin dose is witnessed in most patients. Current practice is to measure ACT at half-hourly intervals and maintain it at > 400 seconds or > 480 seconds throughout the conduct of CPB.3 However, there is concern about its limitations and controversy regarding overall usefulness during CPB.2 ACT is often criticized for its propensity to overestimate the anticoagulation response under conditions of hypothermia, hemodilution or aprotinin therapy.4,5 Using ACT alone during CPB, patients may be susceptible to developing consumptive coagulopathy marked by formation of thrombin antithrombin III complexes, fibrinopeptide A and prothrombin fragment 1.2 complexes.6 Inadequate anticoagulation can result in clotting in the pump circuit, end organ damage from systemic embolization from microscopic or macroscopic clots in the pump circuit or increased bleeding because of consumptive coagulopathy.

Prolongation of ACT and duration of heparin effect differs among patients after administration of a fixed dose of heparin; presumably, this variation is due to individuals’ sensitivity to heparin (pharmacodynamic diversity) and due to variations in its uptake and elimination (pharmacokinetic diversity). It is a common observation that ACT prolongation at 5 min following administration of 300 units·kg-1 of heparin varies from 300 seconds to > 500 seconds. Patient response to 300 units·kg-1 heparin can be categorized on the basis of ACT measured at 5 min as:

  1. normally sensitive, ACT of > 400 seconds;
  2. less sensitive, ACT between 350–400 seconds;
  3. resistant to heparin, ACT < 350 seconds.

We noted that if ACT at 5 min is > 400 seconds, and one-third of the initial dose, 100 units·kg-1, is repeated at 90 min and thereafter at every 60 min of bypass, the ACT measured at various time intervals of 30 min was always above 350 seconds. We hypothesize that if an ACT of > 400 seconds is achieved at 5 min after heparin administration and one-third of this dose (the dose needed to prolong ACT to > 400 seconds) is repeated at 90 min and subsequently at every 60 min, variability of duration of heparin effect among patients would cease to exist. In other words, duration of heparin effect would become uniform. An anticoagulation protocol considering patients’ heparin sensitivity, pharmacokinetics of heparin and effect of CPB on thrombin generation was structured. The present study was designed to evaluate the efficacy of this anticoagulation management protocol and its effect on the frequency of ACT monitoring.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
With the approval of the institutional review board and obtaining informed consent, one hundred patients of different age and both sexes undergoing various open heart surgical procedures were included in this study. No particular preoperative exclusion or inclusion criteria were defined. However, disorders known to interfere with heparin requirement during CPB were specifically questioned. These were:

  1. history of heparin therapy;
  2. presence of clot or myxoma in any cardiac chamber;
  3. renal dysfunction;
  4. liver dysfunction;
  5. history of subacute bacterial endocarditis;
  6. coagulopathy;
  7. presence of low cardiac output state or shock.

The study presented a fundamental shift from the routine approach of careful patient selection to one that allowed intersubject variability.

Anesthesia was induced with fentanyl 2–5 µg·kg-1, sleep dose of thiopentone (3–5 mg·kg-1) or intramuscular ketamine (6 mg·kg-1), and pancuronium (0.1 mg·kg-1); anesthesia was maintained with oxygen, nitrous oxide (N2O), isoflurane, fentanyl, pancuronium and midazolam. In cyanotic patients, N2O was not used. CPB was performed using a membrane oxygenator, non-pulsatile flow (1.5–2.4 L·min-1·m-2), hypothermia (22–32°C) and a crystalloid or crystalloid and blood priming solution to keep hematocrit above 25%. Aprotinin was not used in any study patient.

All patients were anticoagulated with 300 units·kg-1 of mucosal heparin (heparin sodium IP 5000 IU·mL-1, Gland Pharma Ltd, India) administered in a free-flowing central vein. All blood samples for ACT measurement were taken either from the central venous line (other than the one used for heparin administration) after withdrawal of 10 mL of blood and fluid from the connecting catheter or directly from the CPB circuit. Five min after heparin administration but before initiation of CPB, hemochron ACT (International Technidyne Corporation, Edison NJ, USA) was measured. Desired ACT was aimed at more than 400 seconds. Patients having ACT of less than 350 seconds were excluded from this study and their anticoagulation was maintained and monitored as per current recommendations. If ACT measured was found between 350–400 seconds, an additional dose of heparin, 100 units·kg-1, was administered. It was presumed that this additional dose would ensure an ACT of more than 400 seconds. In these patients, initial dose of heparin was considered as 400 units·kg-1. Further doses of heparin, one-third of initial dose, were given at 90 min and then every hour until completion of CPB. A repeat dose of heparin was not administered if CPB was expected to be terminated at or within 10 min of repeat dosing time. Hemochron ACT was measured every half-hour until the completion of CPB. Samples for ACT measurement were drawn just before administration of repeat dose of heparin. An ACT of less than 350 seconds or presence of clot in the surgical field or extracorporeal circuit (ECC) at any time in any study patient was considered a failure of the protocol. For all ACT measurements and further heparin dosing, initial heparin administration time was taken as the reference point.

After successful termination of CPB, anticoagulation was reversed with protamine, 1 mg for every 100 units of initial heparin, and ACT was measured after 10 min of heparin reversal. Additional protamine, 1 mg·kg-1, was administered if the surgical field was wet or ACT was > 130 seconds. Postoperatively, in the intensive care unit, chest drain was measured for 24 hours from the time of arrival.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Out of 100 consecutive patients, 6 patients were excluded from the study. Of the remaining 94 patients, 13 were on heparin therapy, 8 had prolonged prothrombin time (PT > 16/12) and 3 had renal dysfunction. Mild (30–32°C), moderate (26–30°C), and deep (22–26°C) hypothermic CPB was used in 4, 86 and 4 patients respectively. Patient characteristics, CPB data and postoperative chest drain are shown in Tables 1Go and 2Go.


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  		Table 1. Patient characteristics
 

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  		Table 2. CPB data and postoperative chest drain
 
ACT was measured in all patients at 5 min and thereafter at 30 min intervals in patients where CPB was continuing, and lastly 10 min after heparin reversal with protamine. At 5 min, out of 100 patients, in 75 patients ACT was > 400 seconds, in 19 patients it was between 350–400 seconds, and in 6 patients it was < 350 seconds. Overall, during the study, 40 observations were between 350–400 seconds; and all the remaining (406) measured ACT results were > 400 seconds. These results of ACT, measured at various time intervals of 30 min, are shown in Figure 1Go. Surgical field or ECC did not show clot in any patient during the study.



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  		Figure 1. ACT measurements at various time intervals.

 
ACT after protamine reversal was < 130 seconds in 90 patients and > 130 seconds in the remaining 4 patients. The surgical field was wet in 14 patients and they received additional protamine. Postoperative chest drain in patients operated for congenital heart disease ranged from 40–670 mL (median chest drain 100 mL) in CABG patients, it ranged from 100–890 mL (median chest drain 430 mL) whereas in valve replacement patients it was from 160–710 mL (median chest drain 300 mL). None of the study patients were re-explored for bleeding.

Of the 13 patients who were on heparin therapy, 9 showed normal sensitivity to heparin, whereas 4 showed less sensitivity. Of the three patients who had renal dysfunction, 2 showed normal sensitivity and 1 showed less sensitivity. Less sensitive patients received additional heparin as defined in the protocol. All these 16 patients showed an ACT of > 400 seconds during the study. Of 8 patients who had prolonged PT, 7 showed normal sensitivity and 1 showed less sensitivity and received additional heparin. All these patients showed an ACT of > 500 seconds during the study.

Of the 6 patients who were excluded from the study because of resistance to heparin, 1 patient was on heparin therapy and also had renal dysfunction, while in the remaining 5 patients, no apparent reason of heparin resistance could be ascertained.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Hattersley7 first described ACT measurement in 1966. However, until 1974, anticoagulation management during CPB was largely empirical. Later, Bull and coworkers assumed linear relationships between heparin doses used during CPB and ACT and recommended a structured approach of anticoagulation.8,9 Since then anticoagulation in a majority of patients’ the world over is monitored by ACT. Management based on ACT is subject to criticism due to two important reasons. Firstly, various clinical conditions common to CPB are known to influence ACT;3 secondly, the availability and usage of various ACT measurement methodologies – the manual ACT, the hemochron ACT and the hemotec ACT. Horkay and colleagues10 reported significantly higher hemochron ACT than hemotec ACT at five time points. They also found that the hemotec ACT was below the threshold value at all time points. In a comparative study hemotec ACT was found to be much more sensitive to heparin, when hemochron ACT rose into the range of 400–500 seconds, 10 of 12 hemotec ACTs exceeded 1000 seconds.3 The issue is further complicated by the fact that hemotec ACT cartridges are available with three different concentrations of kaolin to produce different sensitivities and dose response relationships to heparin. There is no guideline available in the literature regarding ACT range during CPB with a particular cartridge.

Bull and coworkers8 reported their clinical experience and observed that a clot does not form in the oxygenator circuit with an ACT exceeding 300 seconds. However, they also recommended attaining an ACT above 480 seconds before initiating CPB, suggesting that this particular value provides a safety margin over the minimum safe ACT of 300 seconds. Young and colleagues11 observed that an ACT above 400 seconds is safe. Gravlee and colleagues12 measured the activation of coagulation in humans and stated that ACTs’ greater than 350 seconds were not associated with any greater activation of coagulation. Dauchot and coworkers13 reported a mean ACT of 296 ± 51 seconds after rewarming during CPB, whereas Umlas and colleagues14 recommended heparin concentration monitoring during CPB and keeping a level between 2–4 units·mL-1. However, Nielsen and colleagues15 reported presence of clots in the surgical field as well as in the extracorporeal circuit of one patient despite maintenance of heparin concentration of > 4 units·mL-1 and concluded that this scenario could have been avoided by monitoring ACT. Based on these reports, we selected a minimum ACT value of 350 seconds to ensure the adequacy of this protocol as well as safety of the patients. In our study patients, no macroscopic clot was observed in the surgical field or ECC at any time during CPB. The lowest ACT observed with our protocol was 368 seconds.

It is well established that the key issue during CPB is adequate suppression of thrombin generation. Despite administration of high doses of heparin during CPB, accelerated thrombin and plasmin generation occurs and it increases with the duration of CPB as demonstrated by increasing concentrations of fibrinogen 1.2, thrombin antithrombin complexes, fibrin monomer and D dimer.16 Because of the accelerated generation of thrombin and plasmin there is consumption of labile coagulation factors and platelets.2 One can argue that adequate anticoagulation does not mean a particular ACT number or a particular heparin concentration. We believe that anticoagulation strategy during CPB should address:

  1. heparin sensitivity of the patient and its assessment (pharmacodynamics of heparin);
  2. half-life of heparin (pharmacokinetics of heparin);
  3. the effect of prolonged CPB on thrombin generation.

In our study, initial dosing was based on pharmacodynamics of heparin (patients’ response to 300 units·kg-1 heparin) assessed by ACT at 5 min. The subsequent dosing was based on pharmacokinetics (half-life) of heparin17 as well as the fact that prolonged CPB causes accelerated generation of thrombin and plasmin leading to consumption of labile coagulation factors. The half-life of heparin, with the usual doses administered during CPB, is dose dependent. In the volunteer study, reported by Olsson and co-workers,17 the half-life of heparin was found to be 126 ± 24 min with a heparin dose of 400 units·kg-1. However, the half-life for doses of 100 and 200 units·kg-1 were 61 ± 9 min and 93 ± 6 min respectively. Therefore, in our study, the first repeat dose of heparin was administered at 90 min. Despotis and colleagues4 compared both heparin levels as well as ACT values in 32 patients before and during CPB and observed a substantial decline in heparin concentration while mean ACT values either declined minimally (kaolin) or increased (celite). This decline in heparin concentration continued throughout the bypass period in patients who generally did not receive additional heparin since ACT values remained on average above the routine 400–480 seconds trigger. Thus, they observed that with ACT monitoring, heparin levels could decline to below 2 units·mL-1, which may be inadequate to suppress thrombin generation/activity.4 Nicholson and coworkers18 observed divergent values of ACT at similar concentrations and suggested that ACT is not as useful as once considered. It is obvious from the studies that anticoagulation assessment based on either ACT or heparin concentration monitoring may not reflect the true status of anticoagulation. In another study, Despotis and colleagues19 observed that patients whose heparin dosing was based on maintenance of patient specific heparin concentration received 25% more heparin during CPB compared with the group whose heparin dosing was based on ACT alone. When the perioperative blood requirements of both the groups were compared, the group whose heparin dosing was based on patient specific concentrations had substantial reductions in the number of non-red cell component requirements.19 Therefore, in our study, the subsequent doses of heparin were administered at 60 min intervals and the adequacy of anticoagulation was assessed by ACT monitoring at half-hour intervals.3

ACT at 5 min after initial dose of heparin (300 units·kg-1) administration, but before initiation of CPB, is a reflection of patients sensitivity to heparin. Based on their response to heparin at 5 min, as defined earlier in our study, 75% of patients were normally sensitive and showed an ACT of more than 400 seconds; 19% of patients were less sensitive (ACT between 350 and 400 seconds) and hence received additional heparin 100 units·kg-1 to ensure an ACT of > 400 seconds. Six percent of patients were resistant and excluded from the study. ACT measured at 30 min showed shift of a majority of the patients into the 400–500 seconds and > 500 seconds groups, evidently an effect of hemodilution and hypothermia.3 A similar trend continued during the remaining CPB period and by 150 min, none of the study patients showed an ACT of < 400 seconds. It is evident that at predetermined time points of 30 min intervals none of the patients were at risk of under-anticoagulation as measuredACT was always more than 350 seconds. If ACT is always more than 350 seconds with this protocol, is it necessary to monitor ACT? Our study clearly shows that in patients where hypothermic CPB is employed and an ACT of more than 400 seconds is ensured at 5 min after heparin administration but before initiation of CPB and one-third of initial dose is repeated at 90 min and subsequently at 60 min intervals, subsequent monitoring by ACT is not necessary. Metz and Keats have also questioned the need for ACT monitoring.20

Furthermore, the aim of the present study was not to evaluate its implications on cost containment in open heart surgical procedures. The cost of performing one ACT is merely one US dollar; however, its monitoring does need extra hands or causes distraction of the attending anesthetist. In the past, it was a routine practice to perform a plethora of laboratory tests in all patients presented for routine surgical procedures, however, it was realized later that only a few patients needed detailed laboratory work up. Our observations are similar, only a few patients who are resistant to heparin and are at risk of inadequate anticoagulation need frequent monitoring by ACT, the remaining patients do not need aggressive ACT monitoring and can be managed by the anticoagulation protocol evaluated in this study.

This study design may be criticized for inclusion of all types of patient viz., cyanotics, acyanotics, patients having congenital or acquired heart disease, renal dysfunction, prolonged PT and those on heparin therapy, etc. Nevertheless, these are the patients that normally constitute the cardiac surgical population. We believe anticoagulation protocol should be capable to ensure adequate anticoagulation in all these patients. With this protocol, even patients who were on heparin therapy or had renal dysfunction – the subset generally considered resistant to heparin – behaved similarly to other patients. However, due to their small number, no conclusion can be drawn and a further study with a large number of patients of this subset is needed to confirm or refute our hypothesis. The second important drawback may be finite CPB duration. What would happen if CPB time exceeds 4 hours? Whether the protocol would ensure adequate anticoagulation, the question remains unanswered as CPB did not exceeded 4 hours in any of our study patients. However, procedures needing CPB of more than 4 hours are rare nowadays. Furthermore, our study showed that ACT normalized after protamine administration in 95.7% patients. Fourteen patients needed additional protamine. The decision to give additional protamine was subjective and was based on the finding of the surgical field being wet or ACT being > 130 seconds. Several studies21,22 indicate that excess protamine and/or protamine-heparin complexes may have a direct detrimental effect on platelet function and this may explain, at least in part, why patients may bleed more with excessive protamine. Therefore, the dose of protamine chosen to reverse heparin was 1 mg for every 100 units of initial heparin, less than the recommended dose (1.3 mg for every 100 units of heparin) with an option to administer additional protamine in case of the surgical field being wet or ACT > 130 seconds. Hence, additional protamine was administered in 14 patients. We believe that the additional requirement of protamine is not because of over anticoagulation. In fact with this protocol 80 patients needed less protamine than the generally recommended dose. Moreover, in our study, postoperative chest drain is less than or comparable to the generally accepted levels for open heart surgical procedures.

In conclusion, the structured protocol, based on the pharmacology of heparin and effects of CPB on procoagulant load, ensures adequate anticoagulation during moderately hypothermic CPB. This protocol does ensure adequate anticoagulation with mild and deep hypothermic CPB. However, because of the small number of procedures performed in these categories, further study with a greater number of cases is necessary. With this protocol, one ACT at 5 min after heparin administration must be done to assess heparin sensitivity of the patient and to identify patients who are at a risk of inadequate anticoagulation. Subsequent monitoring during moderately hypothermic CPB by ACT is not essential.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Spiess BD, Silvay G. Overview of myocardial outcome: the interrelationships among coagulation, inflammation, and endothelium. J Cardiothorac Vasc Anesth 2000;14:2–5.[Medline]

  2. Despotis GJ, Joist JH. Anticoagulation and anticoagulation reversal with cardiac surgery involving cardiopulmonary bypass: an update. J Cardiothorac Vasc Anesth 1999;13:18–29.[Medline]

  3. Lesserson LS, Gravlee GP. Anticoagulation for cardiopulmonary bypass, in Gravlee GP (ed). Cardiopulmonary bypass Principles and Practice, Philadelphia, PA, Lippincott Williams and Wilkins 2000, pp 435–72.

  4. Despotis GJ, Summerfield AL, Joist JH, Goodnough LT, Santoro SA, Spitznagel E, et al. Comparison of activated coagulation time and whole blood heparin measurements with laboratory plasma anti-Xa heparin concentration in patients having cardiac operations. J Thorac Cardiovasc Surg 1994;108:1076–82.[Abstract/Free Full Text]

  5. Hunt BJ, Segal HC, Yacoub M. Guidelines for monitoring heparin by the activated clotting time when aprotinin is used during cardiopulmonary bypass. J Thorac Cardiovasc Surg 1992;104:211–2.[Medline]

  6. Shore-Lesserson L. Myocardial injury in cardiac surgery: the role of transfusion. J Cardiothorac Vasc Anesth 2000;14:11–4.[Medline]

  7. Hattersley PG. Activated coagulation time of whole blood. JAMA 1966;196:436–40.[Abstract/Free Full Text]

  8. Bull BS, Korpman RA, Huse WM, Briggs BD. Heparin therapy during extracorporeal circulation. I. Problems inherent in existing heparin protocols. J Thorac Cardiovasc Surg 1975;69:674–84.[Abstract]

  9. Bull BS, Huse WM, Brauer FS Korpman RA. Heparin therapy during extracorporeal circulation. II. The use of a dose response curve to individualize heparin and protamine doses. J Thorac Cardiovasc Surg 1975;69:685–9.[Abstract]

  10. Horkay F, Martin P, Rajah SM, Walker DR. Response to heparinization in adults and children undergoing cardiac operations. Ann Thorac Surg 1992;53:822–6.[Abstract]

  11. Young JA, Kisker CT, Doty DB. Adequate anticoagulation during cardiopulmonary bypass determined by activated clotting time and the appearance of fibrin monomer. Ann Thorac Surg 1978;26:231–40.[Abstract]

  12. Gravlee GP, Haddon WS, Rothberger HK, Mills SA, Rogers AT, Bean VE, et al. Heparin dosing and monitoring for cardiopulmonary bypass. A comparison of techniques with measurement of subclinical plasma coagulation. J Thorac Cardiovasc Surg 1990;99:518–27.[Abstract]

  13. Dauchot PJ, Berzina-Moettus L, Rabinovitch A, Ankeney JL. Activated coagulation and activated partial thromboplastin times in assessment and reversal of heparin-induced anticoagulation for cardiopulmonary bypass. Anesth Analg 1983;62:710–9.[Abstract/Free Full Text]

  14. Umlas J, Gauvin G, Taff R. Heparin monitoring and neutralization during cardiopulmonary bypass using a rapid plasma separator and a fluorometric assay. Ann Thorac Surg 1984;37:301–3.[Abstract]

  15. Nielsen LE, Bell WR, Borkon AM, Neill CA. Extensive thrombus formation with heparin resistance during extracorporeal circulation. A new presentation of familial antithrombin III deficiency. Arch Intern Med 1987;147:149–52.[Abstract/Free Full Text]

  16. Menges T, Wagner RM, Welters I, Ruwoldt R, Boldt J, Hempelmann G. The role of the protein C-thrombomodulin system and fibrinolysis during cardiovascular surgery: influence of acute preoperative plasmapheresis. J Cardiothorac Vasc Anesth 1996;10:482–9.[Medline]

  17. Olsson P, Lagergren H, Ek S. The elimination from plasma of intravenous heparin. An experimental study on dogs and humans. Acta Med Scand 1963;173:619–30.[Medline]

  18. Nicholson SC, Keeling DM, Sinclair ME, Evans RD. Heparin pretreatment does not alter heparin requirements during cardiopulmonary bypass. Br J Anaesth 2001;87:844–7.[Abstract/Free Full Text]

  19. Despotis GJ, Joist JH, Hogue CW, Alsoufiev A, Kater K, Goodnough LT, et al. The impact of heparin concentration and activated clotting time monitoring on blood conservation. A prospective randomized evaluation in patients undergoing cardiac operations. J Thorac Cardiovasc Surg 1995;110:46–54.[Abstract/Free Full Text]

  20. Metz S, Keats AS. Low activated clotting time during cardiopulmonary bypass does not increase postoperative bleeding. Ann Thorac Surg 1990;49:440–4.[Abstract]

  21. Moorman RM, Zapol WM, Lowenstein E. Neutralization of heparin anticoagulation, in Gravlee GP (ed). Cardiopulmonary bypass Principles and Practice, Baltimore, MD, Williams and Wilkins 1993, pp 381–2.

  22. Ammar T, Fisher CF. The effects of heparinase 1 and protamine on platelet activity. Anesthesiology 1997;86:1382–86.[Medline]





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