Heparin administration during extracorporeal circulation

Heparin administration during extracorporeal circulation Heparin rebound and postoperative bleeding The individual variations in heparin dose re;,ponse and heparin activity decay have indicated limitations or the protocols based on body surface area and weight of the patients. In the present study the heparin 11'1'1'1.1' and simpler clotting tests \I'ere monitored in a consecutive series of 7/ patients undergoing standard cardiac operations. The clotting tests used lI'ere the Celite activated clotting time (Celite ACT) and the whole blood activated recalcification time (BART). Forty-four patients received a loading dose of heparin, 3 mg. per kilogram, a maintenance dose of heparin, /.5 mg, per kilogram per hour, and 6 mg. of prolamine sulfate per kilogram at the termination of extra corporeal circulation (ECC) (Protocol l ). Twenty-seven patients received a similar initial dose, but the maintenance dose of heparin and the dosage or protamine sulfate lI'ere administered according to the measured heparin 11'1'1'/.1' (Protocol II). A significant difference lI'as .1'1'1'1I in the measured heparin levels (p < 0.0/), Celite ACT (p < 0.0/), and BART (p < 0.0/) in patients on Protocols / and II. Ten cf the 24 patients on Protocol I and none on Protocol II showed heparin rebound phenomenon, and blood loss in patients on Protocol I IVas significantly greater than that in patients on Protocol II, The SIl/(~Y clearly demonstrates that our protocol of heparin administration and control with simpler tests ensures safe hypocoagulation during ECC and efficient reversal at the end, with minimal postoperative blood loss.

Tej K. Kaul, F.R.C.S.,* Michael J. Crow, M.Sc.,* Somasundram M. Rajah, M.R.C.P.,* Philip B. Deverall, F.R.C.S.,** and David A. Watson, F.R.C.S.,* Leeds and London, England

Heparin is used extensively as an anticoagulant in clinical medicine. Its instant anticoagulant action and ready neutralization with protamine sulfate make it the anticoagulant of choice during extracorporeal circulation (ECC). Experience obtained over the past twenty years has led to the assumption that the control and reversal of heparin is a routine procedure predictable by simple empirical protocols based on body weight and surface area. The failure of these protocols resulting in either excessive or inadequate anticoagulation is often not recognized until the early postoperative period. At the end of perfusion. the hypocoagulable state encountered as a consequence of ECC may be accentuated From the Cardiac Research Unit. Leeds Regional Cardiothoracic Centre, Killingbeck Hospital. Leeds. and Guy's Hospital, London. England. Received for publication Dec, 29. 1978. Accepted for publication March 7. 1979. Address for reprints: Dr. S. M. Rajah. Consultant Haernatologist. Killingbeck Hospital, Leeds LSI4 6UQ. Yorkshire. U. K, *Killingbeck Hospital. **Guy's Hospital.

further by the fluctuations in heparin levels, which make it difficult to establish the cause of and to control postoperative bleeding. A simple and rapid method of measuring heparin levels would be valuable in this situation. This study was undertaken to ensure consistent and safe anticoagulation during ECC and adequate neutralization of heparin postoperatively.

Patients and method Clinical study. Heparin levels were monitored in a consecutive series of 7 I patients undergoing operation with ECC. The study was commenced by assigning the first 44 patients to Protocol I and subsequent patients to Protocol I!. The study was stopped with 27 patients in Protocol II, because a significant difference between protocols became apparent. The type of surgical procedure, age and weight of the patient, total heparin and protamine doses, and perfusion time for all patients are listed in Tables I and II. The extracorporeal circuit comprised a Pemco arterial pump with disposable bubble oxygenator, heat exchanger, cardiotomy reservoir, two Pall extracorporeal

0022-5223/79/070095+08$00.80/0 © 1979 The C. V, Mosby Co,

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PERFUSION TIME (MINSl

Fig. I. Heparin levels during cxtracorporeal circulation (ECC).

Table I. Surgical procedures done in patients in Protocols I and II Surgical procedure Mitral valve replacement Aortic valve replacement Multiple valve replacements Coronary artery bypass grafts Ventricular septal defects Atrial septal defects Tetralogy of Fallot Atrioventricular canal Pulmonary valvotomy Left ventricular aneurysm Transposition of great arteries Truncus arteriosus

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blood filters, and polyvinyl tubing. The oxygenator size, the volume of the extracorporeal circuit, and the composition of the perfusing fluid were determined by the patient's body surface area. The oxygenator selection criteria and the prime for all of the different patients are indicated in Table III. Heparin was added to all clear fluids, 30 mg. per liter in Protocol I and 15 mg. per liter in Protocol II, and to acid-citrate-dextrose (ACD) blood, 30 mg. per pint in both protocols. Heparin administration. All 44 patients in Protocol I underwent a standard procedure of heparinization. A loading dose of 3 mg. of heparin per kilogram of body weight was given prior to cannulation of the great vessels, and regular hourly maintenance doses of 1.5 mg. per kilogram were given for the duration of perfusion. At the end of perfusion, 6 mg. of protamine sul-

fate per kilogram of body weight was given and a coagulation screen carried out; if bleeding continued, a further dose, one quarter of the initial dose. was administered. The 27 patients in Protocol II also received a loading dose of 3 mg. of heparin per kilogram of body weight. Maintenance doses depended on the results of tests of heparin levels in the patient's blood. The dose of protamine sulfate at the end of perfusion was calculated according to the measured levels of heparin. Collection of blood samples. All blood samples were collected into plastic syringes from a cannula inserted into the patient's radial artery. In Protocol I, samples were collected at the following times: (I) prior to the loading dose of heparin; (2) 10 minutes after total body heparinization; (3) 10 minutes after the commencement of perfusion; (4) before and after maintenance doses; (5) at the end of perfusion; and (6) 10 minutes after infusion of protamine sulfate. Collection of samples of Protocol II was done as in Protocol I for the first three samples. The fourth sample was collected after 45 minutes on perfusion and at 25 minute intervals subsequently; the fifth sample, at the end of perfusion; and the sixth sample, 10 minutes following infusion of protamine sulfate. Laboratory methods. Coagulation tests. Three tests were used in both studies-the protamine sulfate neutralization test for heparin, the Celite activated clotting time (Celite ACT), and the blood activated recalcification time (BART). HEPARIN ASSAY (PROTAMINE NEUTRALIZAnON TEST). Heparin estimators are performed on platelet-

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Table II. Perfusion and patient data Protocol I

Protocol II 27

44

No, of patients Age (yr.)

)9/12 -67

Weight (Kg,) No of adults (> 14 yr.) No of children « 14 yr.) Total heparin dose (rng.) Total protamine dose (rng.) Heparin in prime (rng.) Time on perfusion (rnin.) Times between heparin given (rnin.) and commencing perfusion No, of patients given extra heparin

(29,6 mean) 7,5-81.5 (43,6 mean) 24 20 25-500 (231 mean) 70-600 (327 mean) 57-180 (127 mean) 19-165 (112 mean) 2-30 (13,7 mean)

5/12 -65

(31.4 mean) 3,8-84 (47.4 mean) 15 12 18-380 (182 mean) 40-600 (311 mean) 21-76 (66 mean) 42- 152 (104 mean) 2- 21 (II. 9 mean)

26 (59%)

13 (48%)

Table III. Criteria for oxygenator selection and prime Patient BSA Adult(>1.25M.") High blood prime Adult (> 1.25 M.") Low blood prime Children « I. 25 M." but >0.85 M.") Children (>0.30 M." and <0.85 M.") Infants «0.30 M." and <7 Kg.)

Type of oxygenator Bentley Q-IOO Bentley Q-IOO Bentley Q-11O Bentley Q- 110 Bentley Q-130

Priming fluids 2.0L. Hartmann 2.0 L. ACD blood 3.0 L. Hartmann 0.5 L. ACD blood 1.00 L. Hartmann 1.00 L. ACD blood 0.75 L. Hartmann 1.25 L. ACD blood 0.3 L. Hartmann 0.5 L. heparinized blood

Heparin level of priming fluid (Uclml.} 3.5-5.0 7.0-9.0 3.5-5.0 3.5-4.5 Only one case

Legend: BSA. Body surface area. ACD. Acid-citrate-dextrose.

poor plasma and subsequently corrected for hematocrit to give the concentration in whole blood by means of standard methods. I THE CELITE ACT. 2 Whole blood. 2 ml., was added to 12 mg. of Celite in a test tube at 37° C. and mixed thoroughly for 30 seconds. The tube was then placed in a water bath at 37° C. and tilted three times every minute, until fibrin strands were clearly visible. The stopwatch was started as the blood entered the tube and stopped at the first sign of clotting (Celite ACT normal range, 90 to 130 seconds). THE BART TEST. BART reagent,* 0.2 ml., was warmed in a test tube at 3r c. and 0.2 ml, of citrated whole blood was added. The reagents were mixed by inverting the tube three times, and the tube was then placed in a bath at 37° C. The tube was tilted three times every minute and examined for the first sign of a clot. The stopwatch was started on the addition of the blood and stopped at the first sign of a clot (BART time normal range, 85 to 125 seconds). Hemoglobin. hematocrit, platelet count, and plasma *B. D. Chemicals. Ltd .. London. England.

hemoglobin levels were determined during perfusion by standard methods. I HEPARIN REBOUND STUDY. Twenty-four patients in Protocol I and 20 patients in Protocol II were studied for evidence of heparin rebound after neutralization of heparin by protamine sulfate. Blood samples were collected from these patients 45 minutes after the end of perfusion and then hourly for the first 7 hours. The three coagulation tests were performed on each sample. The blood loss for the same period was accurately recorded. Any patient who bled excessively in the early postoperative period from any clearly demonstrable cause other than heparin was excluded from the rebound study. All patients had hemoglobin, hematocrit, platelet count, and fibrinogen levels" determined at regular intervals after perfusion. A coagulation screening was carried out in all patients postoperatively and consisted of prothrombin time, partial thromboplastin time, serum fibrinogen degradation products, fibrinogen estimation, and platelet count. Five milliliters of citrated blood and 2 ml , of nonanticoagulated blood were collected for each screening sample.

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Statistical analysis was performed by means of the coefficient of linear correlation. Significance testing between the two protocols was by use of Student's t test for unpaired data.

Results Comparison of Protocol I and Protocol II. The variation in heparin level during perfusion is shown in Fig. 1. Protocols I and II were identical at the initial stage. A significant difference (p < 0.05) between the protocols was apparent following administration of the

first maintenance dose. Protocol I patients showed higher values with a great variation. These differences increased with the duration of the perfusion. A similar pattern of change is seen with the Celite ACT test (Fig. 2) and the BART test (Fig. 3). In Protocol I, a steady rise in the level of heparin from a mean of 3.0 U. per milliliter at the beginning of perfusion to a mean of 4.8 U. per milliliter after 60 minutes on perfusion was demonstrated. In Protocol II, the change was from 3 to 3.6 U. per milliliter. A similar pattern of change was seen in the ACT and BART. The spread of the heparin

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levels in the patients in the two protocols is shown in Fig. 4. Each dot and cross represents the percent of Protocol I and II patients, respectively. attaining a corresponding heparin level during perfusion. The dots together indicate all Protocol I patients whose heparin levels ranged from 1.5 to 7 U. per milliliter during perfusion, and the crosses indicate all Protocol II patients whose heparin levels ranged from 2,0 to 4.5 U. per milliliter. Hence Protocol I patients had wider fluctuations in heparin levels than Protocol II patients,

Perfusion time and hypothermia below 25° C. (Fig. 5) did not significantly alter the heparin levels in Protocol I patients. Significantly higher levels of heparin were found in Protocol I adult patients who received a low blood prime than in the adults who received a high blood prime (p < 0.05). This difference was observed at the commencement of perfusion and became less marked after the first maintenance dose of heparin (Fig. 6). There was no significant difference in the mea-

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Table IV. Incidence of heparin rebound and postoperative blood loss Rebound

Protocol I No. of patients Blood loss (ml./Mt) Protocol II No. of patients Blood loss (mUM.")

I

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10 575*t

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surements of hemoglobin, hematocrit, platelet count, and plasma hemoglobin during perfusion in the two protocols. Rebound study. Ten of the 24 patients in Protocol I showed the heparin rebound phenomenon. None of the 20 patients in Protocol II showed rebound. Free heparin greater than 0.5 U. per milliliter was detected 2 to 4 hours after perfusion in the rebound group (Protocol I), although three patients had measurable amounts 6 hours after perfusion (Fig. 7). The maximum heparin levels encountered during rebound were around 1.0 U. per milliliter. The blood loss over the first 6 hours after perfusion showed a highly significant increase in the rebound Protocol I patients as compared to the nonrebound Protocol I patients (575 m!' per square meter in 6 hours, compared to 183 m!' per square meter in 6 hours [p < 0.001)). Protocol II patients showed a blood loss of 120 m!. per square meter in 6 hours (Table I V).

There was no significant difference in prothrombin time, partial thromboplastin time, fibrinogen degradation products, fibrinogen, and platelet count in the patients studied in Protocols I and II.

Discussion The heparin sensitivity and clearance rate (half-life of heparin) vary considerably from patient to patient during ECC. 5-, The amount of heparin required to produce arbitrary prolongation in the clotting time may vary threefold and the heparin degradation rate fourfold. These crucial variables of heparin therapy are not interrelated and predictable given the patient's age, weight, and body surface area. H The heparin requirement is also influenced by the urinary output of the patient. 6 A simple and reliable technique of monitoring the levels of heparin during ECC' is necessary to avoid microclot" or clot formation in the extracorporeal circuit": H. 9 and to achieve optimum neutralization with protamine sulfate' at the end of perfusion to prevent excessive postoperative bleeding. Several tests are available, including the Lee-White whole blood clotting time or its modifications, such as activated partial thromboplastin time and whole blood activated partial thromboplastin time. These tests have limitations, being insensitive in the presence of heparin. The protamine neutralization test is an accurate and reliable method of monitoring heparin level, but it requires technical expertise and is time consuming. The activated coagulation time (ACT) described b~ Hattersley" (1966) has been found to be a reliable method of monitoring heparin during bypass and has been

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I0 I

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Fig. 7. Mean heparin levels detected in 10 patients with heparin rebound 6 hours after perfusion. Parentheses indicate the number of patients with heparin rebound at any particular time. preferred owing to its accuracy, simplicity, and rapidity.": H Bull and associates" have demonstrated that an ACT greater than 300 seconds is necessary for optimum anticoagulation during bypass. Values of ACT between 180 and 300 seconds may produce contact activation, which may lead to clot formation, whereas values below 180 seconds are considered unsafe. Similarly, the BART test is less time consuming than is the protamine neutralization test." Values of BART of 300 seconds have been considered necessary for safe anticoagulation; although no evidence of clot formation in the extracorporeal circuit was noted when BART was maintained above 200 seconds;";" clot formation in the pericardial sac has been noted when BART fell below 300 seconds." We found a good correlation between the protamine neutralization (heparin levels), the Celite ACT (r = 0.76), and BART (r = 0.74) in our normal volunteers, indicating a good reliability of these clotting tests. As the protamine titration is time consuming and impractical for serial measurement during bypass, BART and Celite ACT can be used to control heparin administration during bypass and its neutralization at the end of ECC. The term heparin rebound implies reappearance of heparin in blood following its neutralization at the end of bypass. The reappearance of a state of hypocoagulability of blood after initial adequate neutralization occurs because of the escape of heparin into the extravascular compartment and its return via lymphatics and the thoracic duct several hours later. II In most studies heparin rebound has been reported to occur within 8 to 9 hours after neutralization, [2 although exceptionally it may occur as late as 18 hours after neutralization of heparin. [:l Since thrombocytopenia is a common occurrence following ECC, it is quite possible that heparin

sensitivity is enchanced." and bleeding may occur at lower heparin levels, as in our series. In our series patients with a wide age range and a variety of operations were studied. Patients in Protocol I showed higher levels of heparin and greater fluctuation in heparin levels; patients in Protocol II showed more uniformity in the levels of heparin, all of which were within the safe range. Ten patients in Protocol I showed rebound phenomenon with free unneutralized heparin, whereas none of the patients in Protocol II showed free heparin. Perfusion temperature has been reported to influence heparin degradation during ECC. Prolongation of clotting time, slow heparin degradation, and increased postoperative blood loss have been associated with hypothermia. t, [" However, in our study cooling did not significantly alter heparin levels in Protocol I patients. The duration of ECC also did not influence the levels of heparin in patients in Protocol I. Use of clear prime in adults resulted in significantly higher levels of heparin after the administration of the first dose, but there was no significant difference after the administration of the second dose. We have demonstrated that simple clotting tests can be used to achieve safe hypocoagulation during ECC. Further, a regimen (Protocol II) has been helpful in maintaining heparin levels within narrow limits and has helped to ensure adequate neutralization at the end of perfusion. We have not been able to show any real intraoperative advantage of Protocol II over Protocol I because of difficulties in measuring intraoperative blood loss. However, there was a significant reduction in postoperative bleeding and absence of heparin rebound in Protocol II patients. Our study suggests that our protocol of heparin administration may be effec-

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Kaul et al.

tively instituted with simple tests and will reduce the postoperative blood loss. We wish to thank Dr. A. Crew. Dr. J. Pandy. and Dr. R. Lane. Consultant Anesthetists. for active cooperation during the study. We wish to thank Mrs. J. Longley and Miss P. Robinson for preparation and typing of this manuscript. REFERENCES

2 3

4 5

6

Dacie JV. Lewis SM: Practical Haematology. ed 5. London. 1975. Churchill Livingstone Hattersley PG: Activated coagulation time of whole blood. JAMA 196:436-440. 1966 Reno W1. Rotman M. Grumbine FC, Dennis LH. Mohler ER: Evaluation of the BART test (a modification of the whole-blood activated recalcification time test) as a means of monitoring heparin therapy. Am J Clin Pathol 61:78-84. 1974 Martinek RG. Berry RE: Micromethod for the estimation of plasma fibrinogen. Clin Chem 11:10-16. 1965 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 dosage. J THORAC C.",RDIO\·ASC SL'RG 69:685689. 1975 Hill JD. Dontigny L. de Leva! MR. Mickle CH: A simple method of heparin management during prolonged extracorporeal circulation. Ann Thorac Surg 17:129-134. 1974

The Journal of Thoracic and Cardiovascular Surgery

7 Wright JS. Osborne JJ. Perkins. HA. Gcrbode F: Heparin levels during and after hypothermic perfusion. J Cardiovasc Surg 5:244-250. 1964 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 69:674-684. 1975 9 Friesen RH. Clement AJ: Individual responses to heparinization for extracorporeal circulation. J THORAC CARDIOVASC SURG 72:875-879. 1976 10 Jaberi M. Bell WR. Benson DW: Control of heparin therapy in open-heart surgery. J THORAC CARDIOVASC SLRG 67:133-141. 1974 II Schreiner R: Discussion of Nakamoto S. Holmes JH: Our experience in regional heparinization. Trans Am Soc Artif Intern Organs 4:36-41. 1958 12 Ellison N. Beatty CP. Blake DR. Wurzel HA. MacVaugh H III: Heparin rebound. Studies in patients and volunteers. J THORAC CARDIOVASC Sl.'RG 67:723-729. 1974 13 Hyun BH. Pence RE. Davila JC, Butcher 1. Custer RP: Heparin rebound phenomenon in extracorporeal circulation. Surg Gynecol Obstet 115:191-198. 1962 14 Pardanani OS. Roy C, Sen PK: Heparin rebound. A clinical study in cases of open heart surgery under cardiopulmonary bypass. Journal of postgraduate medicine. 16: 26-32. 1969

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