Management of postoperative heparin rebound following cardiopulmonary bypass

J

THORAC CARDIOVASC SURG

81:378-381, 1981

Management of postoperative heparin rebound following cardiopulmonary bypass Postoperative heparin rebound was investigated in 50 adult patients undergoing cardiopulmonary bypass with the use of the Hepcon heparin analyzer. Prior to bypass each patient received 2 mg/kg of heparin. During bypass, the activated clotting time (ACT) was utilized to assess the need for additional heparin to maintain the value between 300 and 400 seconds. The average amount of heparin given was 160 mg. Once cardiopulmonary bypass was terminated the Hepcon unit was employed to determine the actual amount of active circulating heparin and to calculate the dose of protamine sulfate. The average amount of protamine administered intraoperatively was 200 mg. The overall mean ratio of protamine-to-heparin was 1.25: I. Once hemostasis was achieved, no circulating heparin was measured with the Hepcon unit, and the ACT value had returned to its baseline, the incisions were closed and the patients were transferred to the intensive care unit. One hour later a blood sample was obtained and analyzed by the Hepcon unit for any heparin rebound. We found that 26 patients (52%) had circulating heparin and required an additional dose of protamine, averaging 70 mg. Drainage from the thoracotomy tubes averaged 400 cc in the first 24 hours, and a mean of 2 units of packed cells was infused. Three patients (6%) did not require any blood transfusions. The use of the Hepcon unit has produced a safe and expedient method of analyzing and neutralizing active circulating heparin in patients following cardiopulmonary bypass. It is a useful adjunct in blood conservation because it reduces excessive postoperative blood loss associated with heparin rebound.

Roque Pifarre , M.D., Ronald Babka, C.C.P., Henry J. Sullivan, M.D., Alvaro Montoya, M.D., Mamdouh Bakhos, M.D., and Adel El-Etr, M.D., Maywood and Hines, Ill.

T

he extensive and successful use of cardiopulmonary bypass has been enhanced through the use of heparin and the accurate and complete reversal of the heparin effect with protamine sulfate.!"' Following cardiopulmonary bypass, satisfactory hemostasis will not be accomplished if the reversal of the heparin effect is only temporary. The rate at which heparin is metabolized, the amount of protamine necessary for its reversal, and the patient's response to heparin are subject to wide individual variations. 5-8 The reappearance of hypocoagulability after adequate neutralization of heparin has been called "heparin rebound." After investigating this phenomenon, Gollub" concluded that the hypocoagulability was due to the reappearence of heparin in the circulating blood. From the Departments of Surgery and Anesthesia, Loyola University Medical Center, Maywood, Ill., and The Cardiopulmonary Surgical Section, Veterans Administration Hospital, Hines, Ill. Received for publication Jan. 24, 1980.

The activated clotting time (ACT), measured with a Hemochron, * provides an objective determination of the heparinization level prior to and during cardiopulmonary bypass. to, 11 At the conclusion of cardiopulmonary bypass it determines the patient's heparin level and the total dose of protamine necessary for the reversal of the heparin effect. To investigate further the phenomenon of heparin rebound, we have combined the use of the Hemochron with the Hepcon automatic heparin analyzer. t

Patients and methods Fifty adult patients subjected to cardiopulmonary bypass were studied. The perfusion apparatus consisted of the Sarns modular pump and the Harvey H-IOO oxygenator. A Pall 40 JL filter was placed on the arterial side of the circuit. The prime of the pump consisted of 2 L of lactated Ringer's solution, 5% dextrose, 44.6 mEq of sodium bicarbonate, and 25 gm of 50% dextrose. During bypass, 80 mEq of potassium chloride

Accepted for publication Aug. 18, 1980. Address for reprints: Roque Pifarre, M.D., 2160 S. First Ave., Maywood, Ill. 601S~

378

*International Technidyne Corp., Edison, N. J. tHepcon System A-IO, Henotics Inc., Englewood, Colo.

Volume81 Number 3 March, 1981

Heparin rebound after CPR

Table I. Mean data concerning heparin and

100

r =.5118

protamine

Total heparin dose (mg) Total heparin (mg/kg) Total protamine dose (mg) Total protamine (mg/kg) Ratio of protamine to heparin Total no. of pts. requiring protamine postop.

~ =.50 x-4

x

Variable

Mean

160 2.0 200

SD*

±37 ±0.3 ±80

Range

100-200 1.0-2.6 70-400

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80

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60

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1.25: I

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25 (52%)

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379

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Table II. Mean data concerning blood loss and blood replacement

__________EI Variation

Total blood loss in 24 hr (ml) Total blood loss (ml/kg) Total packed cells transfused in 24 hr (ml) Total packed cells (ml/kg)

20

SD*

Range

6.0 525

±200 ±4.5 ±324

200-1,000 2.2-17 0-1,000

6.1

±4.0

0-20

442

40

60

80

100

120

PERFUSION TIME (MIN,)

• Standard deviation.

and 20 units of regular insulin in 250 ml of 5% dextrose in water were administered in a slow drip manner. The pump flow rate was calculated at 2.2 L/m 2 of body surface area. The operative procedures consisted of six single aorta-coronary bypasses, 13 double bypasses, 19 triple bypasses, one quadruple bypass, one aortic valve replacement, four aortic valve replacements with bypasses, one mitral valve replacement, two mitral valve replacements with bypasses, one aortic and mitral valve replacement, one mitral valve commissurotomy, and one left ventricular aneurysm resection with a bypass. The mean age of the patients was 56 years. The average weight was 78 kg. The overall average perfusion time was 66 minutes. The ACT was measured with the Hemochron Model 400. Before bypass and after heparin neutralization, the circulating heparin levels were analyzed by the Hepcon heparin analyzer system. Prior to bypass the ACT of each patient was measured to achieve a baseline value. The heparin dose was calculated at 200 units/kg of body weight. The dose was administered into the right atrium of the heart by the surgeon prior to cannulation of the heart for cardiopulmonary bypass. During bypass the ACT value was maintained between 300 and 400 seconds. Once

Fig. 1. Correlation of postoperative protamine requirements to length of bypass.

bypass was discontinued, the protamine dose for heparin reversal was calculated with the use of the Hepcon analyzer system. The procedure is as follows: A 10 ml blood sample from an unheparinized line is withdrawn from the patient. Next, 1.5 cc of blood is injected into each of the four chambers of the testing cartridge. Each chamber contains a fixed amount of protamine sulfate, thromboplastin, and diluent. Once the cartridge is filled with blood and inserted into the Hepcon unit, air enters each chamber and percolates the blood. The bubbles counterflow within the chambers to maintain a constant blood level. Once a clot begins to develop in anyone of the chambers, the blood no longer will counterflow. The clot will be forced upward to a foam plug at the top of the chamber. A photocell in the unit will detect an increase in light transmission through the base of the chamber and register the amount of circulating heparin in units x 102/kg of body weight. The unit is placed in the neutralize mode and the amount of protamine required is computed at a preselected 1.1: 1 ratio of protamine to heparin. Fifteen minutes after the dose of protamine is administered, a second sample is withdrawn and analyzed to detect if additional protamine is needed. Following intraoperative heparin reversal and hemostasis, the incision is surgically closed and the patient is transferred to the intensive care unit. One hour postoperatively, a blood sample is withdrawn from the central venous pressure (CVP) lumen of the Swan-Ganz catheter and analyzed by the Hepcon unit to determine if any heparin has reappeared in the circulation.

The Journal of

Pifarre et al.

380

Thoracic and Cardiovascular Surgery

3 ~

700

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Fig. 2. Relationship between three methods of heparin neutralization and the amount of protamine given. 900 800

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Fig. 3. Relationship between three methods of heparin neutralization and the first 24 hour postoperative blood loss.

Since the CVP lumen is periodically flushed with heparin, 20 cc of blood is withdrawn prior to sampling to guard against a biased sample. Results The average ACT value prior to bypass was 130 seconds (range 88 to 168 seconds). During bypass the ACT was maintained between 300 and 400 seconds. Seven patients (14%) required additional heparin during bypass, the average amount being 50 mg. After protamine was administered following bypass, the ACT value averaged 3 seconds less than its baseline. Table I shows the amount of heparin and protamine administered. The total amount of heparin administered averaged 160 mg and varied from 100 to 200 mg. In relation to body weight, the mean dose of heparin given was 2.0 mg/kg and the range, from 1.0 to 2.6 mg/kg. The average amount of protamine given after bypass

was 200 mg (range 70 to 400 mg). Based upon the patient's weight, the amount of protamine administered was 2.7 mg/kg (range 1.5 to 5.0 mg/kg). The ratio of protamine to heparin averaged 1.25: 1 (range 0.6: I to 2.5: 1). In this study, 26 (52%) of the 50 patients required an additional dose of protamine 1 hour postoperatively, following adequate intraoperative heparin neutralization. An average of 70 mg of additional protamine (range 50 to 180 mg) was required to reverse rebounded circulating heparin. The total blood loss and blood transfused in the first 24 hours after operation is shown in Table II. The mean drainage from the thoracotomy tubes was 442 ml (range 200 to 1,000 ml). In relation to the patient's weight, the blood loss was 6.0 ml/kg (range 2.2 to 17 ml/kg). The average amount of packed cells transfused was 525 ml (range 0 to 100 ml). Three (6%) of the patients did not require postoperative blood transfusions. The amount of blood given per kilogram of body weight was 6.1 ml/kg (range 0 to 20 ml/kg). One patient in our study required surgical reexploration postoperatively following a double valve replacement. After intraoperative and postoperative heparin reversal was achieved, the drainage from the thoracotomy tubes averaged 200 to 300 ml/hr. The patient was returned to the operating room after the blood loss exceeded 1,000 rnl. In the operating room a specific bleeder was identified and controlled. The length of cardiopulmonary bypass influenced the amount of protamine required postoperatively. As seen in Fig. 1, a correlation coefficient of 0.512 was found by comparing the amount of postoperative protamine to the duration of cardiopulmonary bypass. The proportion of variance was 26%. Prior to this study, we 11 compared the use of the ACT for heparin neutralization to a standard protocol method. For the ACT method, a dose-response curve was utilized for the protamine dose as described by Bull and associates. 7 The standard protocol of heparin administration during bypass consisted of 3 mg/kg with 1.5 mg/kg every 45 minutes of bypass. The protomine dose was calculated at a protamine-to-heparin ratio of 1.5: 1. Fig. 2 compares the Hepcon system, the ACT method, and the standardized protocol with regard to the amount of protamine required after cardiopulmonary bypass. With the Hepcon system, the amount of protamine needed to achieve hemostasis was 40% (130 mg) lower than with the ACT method and 70% (451 mg) lower than with the standard protocol. The effect of the Hepcon system on 24 hour postoperative blood loss was similar, there being a 13% (60 ml) reduction when compared to the ACT method and a 50% (420

Volume 81

Heparin rebound after CPB

Number 3 March,1981

ml) reduction when compared to the standard protocol method (Fig. 3). Discussion The neutralization of heparin effect following cardiopulmonary bypass is accomplished with protamine sulfate." 4 Although dosages vary from institution to institution, various studies have demonstrated adequate reversal of heparin when I to 2 mg of protamine is administered for every milligram of heparin. 7, 11 However, the reappearance of heparin activity in the postoperative period has been blamed as the cause of postoperative bleeding." We demonstrated that from I to 5 hours after operation the plasma clotting times were abnormally elevated and were brought back to normal only after the addition of protamine. Although the exact reason for heparin rebound was not determined, the need for determining the exact dosage of protamine was pointed out. Previous studies noted that optimal reversal of heparin could be achieved by measuring the ACT. 10 However, the ACT method is not totally heparin specific and the possibility of giving an excess of protamine exists. 12 Excessive protamine has been known to cause transient anticoagulation. I:! These authors stated that protamine given at a level greater than 3 mg/kg behaved as an anti thromboplastin in reducing Factor VIII. Also, protamine toxicity has been reported previously in patients receiving an overdose.!" Symptoms of histamine release as well as changes in the electrocardiogram were reported. Therefore, the use of the automatic protamine titration unit was investigated in reversing the effect of heparin intraoperatively and I hour postoperatively. Unlike the ACT test, the heparin analysis unit is purely heparin specific. Blood injected into four chambers of a testing cartridge is mixed with different amounts of protamine and thromboplastin. The blood is percolated with air after the cartridge is inserted into the unit. After approximately I to 6 minutes, the blood will clot in one of the chambers that neutralizes the heparin. The unit will determine the amount of circulating heparin and calculate the dose of protamine needed to reverse it. Our results demonstrated that intraoperative neutralization of heparin was accomplished with a protamineto-heparin ratio of 1.25: I. In addition, 26 (52%) patients required an additional dose of protamine in the postoperative period, as previously described by Gollub." The average amount of protamine administered was 70 mg. We found that the amount of protamine given postoperatively correlated positively with the length of cardiopulmonary bypass (Fig. I), namely, the longer the duration of bypass the more protamine needed to reverse heparin rebound.

38 I

In conclusion, we would like to emphasize the need for postoperative evaluation of the reappearance of active circulating heparin in the blood. Preventing the so-called heparin rebound necessitates that more protamine be administered. The use of the heparin analyzer has brought a safe and expedient method of analyzing and neutralizing active circulating heparin in patients following cardiopulmonary bypass. It is a useful adjunct in blood conservation because it reduces excessive postoperative blood loss associated with heparin rebound. REFERENCES Estes JW: Kineticsof the antiocoagulanteffect of heparin. JAMA 212:1492-1495, 1970 2 Frick PG, and Brogli H: The mechanism of heparin rebound after extracorporeal circulation for open cardiac surgery. Surgery 59:721-726, 1966 3 Castenada AR: Must heparin be neutralized following open-heart operations? J THORAC CARDIOVASC SURG 52:716-724, 1966

4 Gans H, Castenada AR: Problems in hemostasis during open heart surgery. VII. Changes in fibrinogen concentration during and after cardiopulmonarybypass with particular reference to the effect of heparin neutralization on fibrinogen. Ann Surg 164:551-556, 1967 5 Gibbon JH Jr, Camishion R: Problems in hemostasis with extracorporeal apparatus. Ann NY Acad Sci 115: 195198, 1964

6 Gollub S: Unexplained bleeding in cardiothoracic operations. Ann NY Acad Sci 115:199-224, 1964 7 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 CARDIOVASC SURG 69:685689, 1975

8 Hattersley PG: Activated coagulation time of blood. JAMA 196:436-440, 1966 9 Gollub S: Heparin rebound in open heart surgery. Surg Gynecol Obstet 124:337-346, 1967 10 Mattox KL, Guinn GA, Rubio PA, Beall AC: Use of the activated clotting time in intraoperative heparin reversal for cardiopulmonary bypass. Ann Thorac Surg 19:634638, 1975

II Babka R, Colby C, EI Etr A, Pifarre R: Monitoring of intraoperative heparinization and blood loss following cardiopulmonary bypass surgery. J THORAC CARDIOVASC SURG 73:780-782, 1977 12 Hill AG, Lefrak EA: Monitoring heparin and protamine therapy during cardiopulmonary bypass. AMSECT Proc 6:8-13, 1978 13 Goldman BS, Joisen J, Austin WG: Cardiovascular effects of protamine sulfate. Ann Thorac Surg 7:459-471, 1969 14 Jaques LB: Protamine-antagonist to heparin. Can Med Assoc J 108:1291-1297, 1973