| Article Access Statistics|
| Viewed||13462 |
| Printed||156 |
| Emailed||1 |
| PDF Downloaded||0 |
| Comments ||[Add] |
Click on image for details.
|Year : 1979 | Volume
| Issue : 2 | Page : 70-74
Heparin rebound : A cause of bleeding following open heart surgery
SV Purandare, GB Parulkar, SR Panday, S Bhattacharya, Menna M Bhatt
Department of Cardio-vascular and Thoracic Surgery, Seth G. S. Medical College and K.E.M. Hospital, Bombay-400 012, India
S V Purandare
Department of Cardio-vascular and Thoracic Surgery, Seth G. S. Medical College and K.E.M. Hospital, Bombay-400 012
Source of Support: None, Conflict of Interest: None
Fifty patients undergoing open-heart surgery were studied. Twelve patients showed heparin rebound phenomenon in the postperfusion period and was one of the important factors responsible for bleeding after open-heart surgery. The clotting time came back to normal in all the cases after administration of extra protamine.
|How to cite this article:|
Purandare S V, Parulkar G B, Panday S R, Bhattacharya S, Bhatt MM. Heparin rebound : A cause of bleeding following open heart surgery. J Postgrad Med 1979;25:70-4
|How to cite this URL:|
Purandare S V, Parulkar G B, Panday S R, Bhattacharya S, Bhatt MM. Heparin rebound : A cause of bleeding following open heart surgery. J Postgrad Med [serial online] 1979 [cited 2023 Mar 21];25:70-4. Available from: https://www.jpgmonline.com/text.asp?1979/25/2/70/42111
| :: Introduction|| |
The introduction of extracorporeal circulation for open intra-cardiac operations faced a number of difficulties in the early years of its development. The foremost was the maintenance of blood in a fluid state during its extracorporeal circulation. An attempt was made by the early workers to maintain the fluidity of blood by using the defibrinating technique for obtaining incoagulable blood. But the danger of using this blood is apparent. The first real breakthrough came with the discovery of heparin by McLean.  Further work was carried out by Howell and Jolt (as quoted by Jorpes, 1964  ). Protamine and polybrene permitted neutralization of heparin.
This paper deals with our experience of the role heparin plays in postperfusion bleeding.
| :: Material And Method|| |
Fifty patients of either sex undergoing open intracardiac operations were studied. The age varied from 8 to 40 years. Heparin in a dose of 3 mg/kg. was administered to the patient before cannulation. Five mg% of heparin was added to the priming solution. Half the initial dose of heparin was administered in case the bypass was more than one hour. The heparin level was maintained between 3 and 5 mg% during perfusion. The heparin was neutralized at the end of bypass with a calculated dose of protamine sulphate.  The heparin-protamine titration was performed after 15 minutes of administration of protamine. A disposable bubble oxygenator was used during the entire period of study.
| :: Results|| |
[Table 1] summarizes the patients who showed heparin rebound. [Table 2] gives the level of circulating heparin and the amount of additional protamine required in the patients who showed heparin rebound.
| :: Discussion|| |
Excessive bleeding in the postperfusion period is not uncommon. The relative importance attributed to inadequate neutralization of heparin, thrombocytopenia, alteration of some blood clotting factors and fibrinolysis has varied in different studies. ,,
The phenomenon of "heparin rebound" has been considered to be the most common cause of bleeding in the postbypass period. The phenomenon is best defined as the reappearance of hypocoagulability of blood after adequate neutralization of heparin has been accomplished. Heparin is an indispensable anticoagulant in cardiopulmonary bypass procedures employing extracorporeal apparatus. The chelating agents such as ethylene diamine tetraacetic acid (EDTA) and citrate are unsuitable, since the degree of hypocalcemia required to prevent coagulation is incompatible with myocardial activity.  An inadequate neutralization results in prolonged time for closure of the incision, increased post-operative blood loss, increased morbidity and perhaps mortality.
Heparin rebound was observed in 12 patients during the course of the present study [Table 1]. It was detected as early as two hours after perfusion or as late as 18 hours post-operatively, after complete neutralization of heparin by protamine sulphate had been obtained. In all the instances the clotting time returned to normal on administration of a titrated dose of protamine. The amount of additional protamine required was 30-80 mg. A number of workers ,,, confirmed the presence of heparin rebound iii their patients and found no evidence of excess protamine interfering with blood clotting as suggested by Andersen and his coworkers.  Wright et al  in their study of heparin levels during and after hypothermic perfusion reported the presence of the rebound phenomenon in 5 out of 45 cases, although in only one instance it was considered likely to be of any significance. A point which needs to be emphasized is that unlike heparin which has both antithrombin and antithromboplastin activities, protamine sulphate being only antithromboplastic shows a considerably weaker anticoagulant effect. 
A number of reasons have been attributed to the reappearance of heparin in the circulation. It may be either due to reabsorption of heparin into the blood stream from extravascular depots in which it was stored during perfusion  or it may be due to the faster degradation of protamine.  Protamine is known to combine with plasma proteins, especially fibrinogen. Thus a competition for protamine between plasma proteins and heparin may arise as suggested by Rothnie and Kinmonth  The action of complex acidic phospholipid of blood may play a role in changing the equilibrium between heparin and protamine.  An alternative explanation is simply that the administered dose of protamine was not in fact sufficient and therefore no true heparin rebound phenomenon occurs. 
However efficiently designed an artificial heart-lung machine may be, the circulation it provides cannot be compared with that provided by the heart. As a result, blood gets sequestered in the poorly perfused areas. Tanaka and his co-workers  in studies in dogs reported that the heparinized blood gets sequestered in the different parts of the body within three to five minutes of the start of perfusion. The most likely organs where the blood gets trapped are the spleen, liver and splanchnic bed . , Large volumes of blood can also be pooled in the skin or the muscles.  After the perfusion is discontinued, some time elapses before the patient achieves hemodynamic equilibrium. It is during this period that the organs in which the blood is sequestered release it, thus bringing along with it unneutralized heparin.
Sharp and Eggleton  suggested that the dose of protamine be given on the basis of the initial dose given rather than on the titrated residual heparin at the end of perfusion. This would take care of the heparin in the extravascular fluid which returns to the circulation. We at this institute, give protamine on the basis of the total heparin (initial dose) administered. On an average, the amount of protamine required to neutralise the heparin works out to two and half times the amount of heparin given.
In an earlier study, Pardanani et al  have reported an interesting observation that by using protamine hydrochloride the incidence of heparin rebound and associated postperfusion bleeding is greatly reduced when compared to the group receiving protamine sulphate. Furthermore, a large amount of protamine is required in the protamine sulphate group as compared to protamine hydrochloride group in the post-operative period to control the rebound phenomenon. It has been suggested that protamine hydrochloride is a more stable salt compared to protamine sulphate.  We routinely use protamine sulphate to neutralize the effect of heparin in patients undergoing open-heart surgery.
| :: Conclusion|| |
Though an occasional patient bleeds excessively in the postperfusion period, as a result of alteration in the clotting factors, heparin rebound phenomenon is a major factor in postbypass bleeding. A prompt recognition of this effect by the heparin-protamine titration and immediate treatment with additional doses of protamine helps in avoiding excessive blood loss and minimizes blood transfusions.
| :: Acknowledgements|| |
We take this opportunity to thank Dr. C. K. Deshpande, M.D., F.R.C. Path. (Lond.), Dean, K.E.M. Hospital and Seth G. S. Medical College, Bombay, for permitting us to report the hospital material.
| :: References|| |
|1.||Allen, J. G.: "Extracorporeal Circulation", C. C. Thomas, Springfield, 1958. |
|2.||Amatuzio, D. S., Grande, F., Wada, S, and Hay, L. J.: A natural occurring lipid that neutralizes heparin activity in blood, J. Lab. Clin. Med., 56: 277-280, 1960. |
|3.||Andersen, M. N., Mandelow, M. and Alfano, G. A.: Experimental studies of heparin protamine activity with special reference to protamine inhibition of clotting. Surgery, 46: 1060-1068, 1959. |
|4.||Bentall, H. H. and Allwork, S. P.: Fibrinolysis and bleeding in open-heart surgery. Lancet, 1: 4-8, 1968. |
|5.||Bunker, J. P., Stetson, J. B,, Coe, R. C., Grillo, H. C. and Murphy, J.: Citric acid intoxication. J. Amer. Med. Assoc., 157: i.61.-1367, 1955. |
|6.||Clowes, G. H. A. Jr.: Extracorporeal maintenance of circulation and respiration. Physiol. Rev., 40: 826-897, 1960. |
|7.||Frick, P. G. and Brogli, H.: The mechanism of heparin rebound after extracorporeal circulation for open cardiac surgery. Surgery, 59: 721-726, 1966. |
|8.||Giannelli, S., Mahajan, D. R., Navarre, J. R. and Pratt, G. H.: Studies of blood volume changes during cardiopulmonary bypass in dogs. Ann. Surg., 152: 190-196, 1960. |
|9.||Hyun, B. H., Pence, R. E., Davila, J. C., Butcher, J. and Custer, R. P.: Heparin rebound phenomenon in extracorporeal circulation. Surg. Gynec. Obstet., 115: 1.91-198, 1962. |
|10.||Jorpes, J. E.: The early history of heparin, Ann. N.Y. Acad. Sci., 115: 392-398, 1964 |
|11.||Keats, A. S., Cooley, D. A. and Telford, J.: Relative antiheparin potency of polybrene and protamine in patients undergoing extracorporeal circulation. J. Thorac. Cardiovas. Surg., 38: 362-3M, 1959. |
|12.||McLean, J.: The thromboplastin action of heparin. Amer. J. Physiol., 41: 250-257, 1916. |
|13.||Neville, W. E., Kameya, S., Mustafa, O., Bloor, B. and Cloves, G. H. A.: Profound hypothermia and complete circulation interruption. Experimental, clinical and physiological observations. Arch. Surg., 82: 1.08-119, 1961. |
|14.||Pardanani, D. S., Roy, C. and Sen, P. K.: Heparin Rebound. A clinical study in cases of open-heart surgery under cardiolpulmonary bypass, J. Postgrad. Med., lti: 26-32, 1970. |
|15.||Pardanani, D, S. Roy, C. and Sen, P. K.: Comparative study of protamine hydrochloride and protamine sulphate for neutralization of circulating heparin after cardiopulmonary bypass for open heart surgery. Ind. J. Surg., 34: 148-151, 1972. |
|16.||Peden, J. C. Jr. and McFarland, J. A.: Use of the plasma thrombin time to assess the adequacy of i:c vivo neutralization of heparin: Comparative studies following operations employing extracorporeal circulation. Blood, 14: 1230-1236, 1959. |
|17.||Perkins, H. A., Osborn, J. J. and Gerbode, F.: The management of abnormal bleeding following extracorporeal circulation. Ann. Int. Med., 51: 658-667, 1959. |
|18.||Porter, J. M. and Silver, 0.: Alterations in fibrinolysis and coagulation associated with cardiopulmonary bypass. J. Thorac. Cardiovasc. Surgery, 56: 869-878, 1968. |
|19.||Rothnie, N. G. and Kinmonth, J. B.: Bleeding after perfusion for open-heart surgery. Importance of unneutralized heparin and its proper correction. Brit. Med. J. 1: 73-78, 1960. |
|20.||Rowen, H., Viles, P. and Ankeney, J. L.: The effect of total body perfusion upon cardiac output and vascular resistance. J. Thorac. Cardiovasc. Surg., 40: 529-535. 1960. |
|21.||Sharp, A. and Eggleton, M. J.: Haematology and the extracorporeal circulation. J. Clin. Path., 16: 551-557, 1963. |
|22.||Soloway, H. B . , Cornett, B. M., Dona - hoo, J. V. and Cox, S. P.: Differentiation of bleeding diatheses which occur following protamine correction of heparin anticoagulation. Amer. J. Clin. Path., 60: 188-191, 1973. |
|23.||Tanaka, T . , Hayashi, H . , Chiba, C . , Osawa, M., Shimizu, T., Iwamato, J., Hashimoto, A., Matsumura, C. and Sakakibara, S.: Extracorporeal circulation in dogs. Significant variation in the size of the spleen in response to various flow rates. J. Amer. Med. Assoc., 179: 708716, 1962. |
|24.||Wright, J. S., Osborn, J. J., Perkins, H. A. and Gerbode, F.: Heparin levels during and after hypothermic perfusion. J. Cardiovasc. Surg., 5: 244-250. 1964. |
[Table 1], [Table 2]