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Protamine-related perioperative complications in carotid endarterectomy
(Portuguese PDF version)

Jorge R. Ribas Timi¹, Jeferson F. Toregeani², Ian Gimenez Ribeiro^2, Marcio Miyamotto³

1. Associate professor, Universidade Federal do Paraná. Vascular Surgeon, Prof. Dr. Elias Abrão Division of Vascular Surgery, Curitiba, PR.
2. Resident physician, Prof. Dr. Elias Abrão Division of Vascular Surgery, Curitiba, PR.
3. Vascular surgeon, Prof. Dr. Elias Abrão Division of Vascular Surgery, Curitiba, PR.

*Project carried out at Prof. Dr. Elias Abrão Division of Vascular Surgery, Hospital Nossa Senhora das Graças and Hospital Universitário Cajuru da PUC-PR, Curitiba, PR.

Correspondence:
Jorge R. Ribas Timi
Rua Padre Agostinho, 1923/2601
CEP 80710-000 - Curitiba - PR
Brazil
Tel./Fax: +55 (41) 335.3233
E-mail: jorgetimi@terra.com.br

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ABSTRACT

Objective: Analysis of perioperative complications in carotid endarterectomy related to the use of protamine.

Patients and method: From January of 1996 to March of 2001, 215 carotid endarterectomies were performed. Of that total, 141 patients were male (65.6%), with a mean age of 68.9 years. The patients were divided into two groups. Group I consisted of 78 patients (36.3%) and Group II of 137 patients (63.7%). Heparin reversal was performed only on Group I. A comparison between the groups was performed concerning the following complications: bruises, transient ischemic attack, cerebrovascular accident, and death.

Results: Neurological complications occurred in 3.72% (five strokes and three transient ischemic attacks). Prevalence in Group I was 2.5% (one ischemic attack and one stroke) and in Group II was 4.37% (two ischemic attacks and four strokes) strokes. Postoperative hematoma occurred in 10.23% (Group I 10.25% vs. Group II 10.21%), therefore surgical drainage was needed in five patients, all of them from Group II. General mortality occurred in 1.8% (2.5% in Group I vs. 1.4% in Group II). One patient died because of an anaphylactic reaction related to protamine. There were no statistically significant differences between the two groups for this analysis.

Conclusion: In terms of perioperative complications from carotid endarterectomy, no statistically significant differences were found between patients who used protamine for heparin reversal and those patients who did not use the substance.

Key-words: carotid endarterectomy, cerebrovascular accident, protamines.
Palavras-chave: endarterectomia das carótidas, acidente vascular cerebral, protaminas.

J Vasc Br 2003;2(4):291-5

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Cerebrovascular accident (CVA) is the third leading cause of death in developed countries, with extracranial carotid disease being the most common cause. Surgical treatment of carotid stenosis (CS) for the prevention of CVA was performed successfully for the first time in 1954 by Eastcott et al.¹ Initially, the indication of carotid endarterectomy was based on results obtained from individual series and had low scientific evidence. It has only been during the last two decades, after large multicentric studies (NASCET, ACAS, ECST), that the real benefit of carotid endarterectomy for patients with carotid stenosis above 60-70% was proven.¹ However, the choice of surgical technique remains very personal, as each surgeon has his or her own preference. One of the divergences is in relation to whether or not a reversal of heparin with protamine should be performed.

Protamine, which was discovered in 1868 by Friedrick Miescher, is a cationic polypeptide with a low molecular weight (approximately 4500 Daltons).² It has 67% arginine in its molecular composition and is extracted from the gonads of salmon and certain other fish.³ The substance can also be found in the spermatozoid of humans and other animals. Protamine has two portions, one that functions as a mild anticoagulant and the other that joins with heparin². Its effect results from a simple ionic bonding; heparin has a negative charge and so the connection forms an inactive complex.²

DeLucia et al. studied the various types of protamine with electric charges between [+8] and [+21], demonstrating that protamines with a higher charge were more effective in the reversal of heparin. However, they also discovered that the higher charged protamines produced more side effects. ⁴ Hulin et al. developed a variant called [+18RGD] with a slightly lower charge [+3], and with the same neutralizing power. In addition, the adverse effects were significantly reduced.⁵

Until the 1980s, the adverse effects related to protamine were only observed in animal studies. It was only after Moorthy et al. published studies on the adverse reactions of protamine that greater emphasis was given to the possible complications related to its use^2,6,7 (Table 1). These effects occur with the greatest frequency in diabetic patients that use NPH insulin, vasectomized patients, patients with a previous allergy to fish (particularly salmon) and patients previously exposed to protamine.^8,9

Table 1- Adverse reactions related to the use of protamine

Peripheral vasodilatation (transient)

Reduced myocardial contractility

Inhibited platelet aggregation

Thrombocytopenia

Increase of Kaolin Partial Thromboplastin Time (KPTT)

Increase in time of prothrombin activation

Anaphylaxis

Transient pulmonary vasoconstriction

It is important to note that the use of protamine in high doses can cause anticoagulation due to its anticoagulant portion. Because of this, its use should always be equivalent to the volume of heparin that was infused. Thus, it forms a stable salt without anticoagulant activity.³

PATIENTS AND METHOD

In the period between January 1996 and March 2001, 215 patients who were submitted to carotid endarterectomy were analyzed in a nonrandomized retrospective study. Out of the total, 141 patients were males (65.6%), and their mean age was 68.9 years.

The patients were divided into two groups. Group I consisted of 78 patients (36.3%) who underwent treatment with protamine for heparin reversal. Group II consisted of 137 patients (63.7%) for which the heparin was not reversed.

The majority of the patients were symptomatic, and all were submitted to echo-color-Doppler as a preoperative examination. The arteriography, as well as the computed tomographic angiography and the magnetic resonance angiography, were performed on select cases.

Surgical indication was based on the results of large international multicentric studies (NASCET, ECST, ACAS, and VA trial). In general, patients that presented carotid stenosis above 70% were considered for surgery. The operations were performed by six different vascular surgeons with distinct surgical technique approaches (type of anesthesia, use of patch for arteriorrhaphy and use of drain).

Anesthesia with cervical blockage was used on 96 patients (44.65% of the total). General anesthesia was initially used in 108 patients (50.23%). In 11 patients, there was the need for conversion to general anesthesia for different reasons (Table 2). Preclamping anticoagulation was performed with 5,000 UI of endovenous heparin in all cases.

All of the procedures were performed using conventional techniques, except for two cases in which the eversion technique was used. Arteriorrhaphy was performed with the use of a bovine pericardial patch in 73.9% of the cases. Protamine was used on 78 patients (36.3%), generally for those who continued to have diffuse bleeding even after manual compression for hemostasis. Drainage with a Penrose drain was used on 128 patients (59.5%).

Table 2- Causes of conversion from cervical blockage to general anesthesia

Cause of conversion	n	%
Excessive preclamping sedation	1	1.04
Cough attack	2	2.08
Neurological deficit after clamping	8	8.33

In the postoperative stage, patients remained at the Intensive Care Unit for 24 hours. All patients were discharged with prescriptions for platelet antiaggregant drugs and were re-evaluated after 30 days.

The data obtained retrospectively was analyzed by the EPINFO statistical program (Division of Surveillance and Epidemiology - Center for Disease Control - Atlanta - Georgia - USA).

RESULTS

When the two groups were compared based on the surgical procedure utilized, there was a statically significant difference in terms of the type of anesthesia used and the use of the drain (Table 3).

Table 3- Association of surgical factors with the use of protamine

	GROUP I	GROUP II	P
	(reversal)	(non-reversal)
General anesthesia	34.6%	59.1%	0.0005
Cervical Blockage	60.2%	35.8%	0.0005
Conversion	5.12%	5.1%	0.99
Use of patch	69.2%	76.6%	0.23
Use of drain	72.9%	54%	0.028

In terms of neurological complications, there were one CVA in group I (1.28%) and four in group II (2.9%). In terms of the occurrence of transient ischemic attacks (TIA), there was one case in group I (1.28%) and two in group II (1.45%). Four deaths occurred in this series (two in each group), and one of the two deaths in group I was caused by an anaphylactic reaction to protamine (the first case in approximately 9,000 arterial procedures performed during the 30-year experience of our Division).

Cervical hematoma occurred in 22 out of the 215 patients (10.23%): eight cases in group I (10.25%), and 14 in group II (10.21%). There was a need for surgical drainage of the hematoma in five patients, all of whom were in group II (0% vs. 3.64%, P = 0.087). There was no statistically significant difference between groups I and II in relation to these analyzed parameters (Table 4).

Table 4- Complications

Complication	Total	Group I	Group II	P
	(n = 215)	(n = 78)	(n = 137)
CVA	5 (2.32%)	1 (1.28%)	4 (2.91%)	0.44
TIA	3 (1.39%)	1 (1.28%)	2 (1.45%)	0.91
Death	4 (1.86%)	2 (2.56%)	2 (1.45%)	0.56
Hematoma	22 (10.23%)	8 (10.25%)	14 (10.21)	0.99

DISCUSSION

Complications in carotid surgery are uncommon, given that the adequate surgical technique and the evolution in anesthetic and monitoring methods allow for a better control of the patient. However, serious complications such as CVA and death occurred with a frequency that varied between 3% and 6%, even in larger surgery divisions.^10,11

The occurrence of hematoma was practically the same in the two groups (10.25% vs. 10.21%). However, a literature review shows divergent reports. Many authors affirm that the incidence of hematomas increase significantly when protamine is not used.¹² Other authors state that there is no statistically significant difference between groups in which protamine is and is not used.¹¹ Even though the prevalence of hematoma was the same in the two groups analyzed in our series, the five large hematomas that needed surgical correction occurred exclusively in the group in which we did not use protamine (3.64%).

The occurrence of CVA in carotid endarterectomy due to the use of protamine was researched in various studies and the conclusions are divergent. In studies with cats, Piepras et al. demonstrated a higher patency after four hours of carotid endarterectomy when protamine was not used (100% vs. 30%).¹³

Chandler et al. carried out a similar study on dogs and found no statistically significant difference between the two groups (one in which heparin was reversed, and the other in which it was not reversed).¹⁴

Mauney et al.,¹¹ in a clinical study with 348 carotid endarterectomies, demonstrated that the incidence of CVA was significantly higher (P = 0.045) in the group in which protamine was used (2.6%) when compared to the group in which it was not used (0%). Treiman et al.¹⁵ analyzed 697 carotid endarterectomies and found evidence that the use of protamine significantly reduced the occurrence of cervical hematoma (1.2% vs. 6.5%, P = 0.0044) without increasing the occurrence of CVA.

Paradoxically, in our series, there was a higher incidence of neurological complications in the group in which heparin was not reversed by protamine, even though the difference was not statistically significant.

The incidence of mortality was higher in group I (2.56% vs. 1.45%), although it was not statistically significant. The two deaths that occurred in group II resulted from bronchopneumonia. In group I, there was a case of massive hemorrhage due to rupture of the suture line in the first postoperative day, which lead to the patient's death. The last case of death had a direct relationship with the use of protamine sulfate, causing an unexpected and intense anaphylactic reaction which lead to the patient's death. This patient had undergone carotid endarterectomy due to stenosis of over 80% in the left internal carotid. The procedure was performed under general anesthesia and with the use of a shunt, with bovine pericardial patch for closure. Even after a few minutes of compression, the patient still presented diffuse bleeding in the area of the incision, and, therefore, we decided to use protamine sulfate for heparin reversal. Approximately two minutes after the infusion, the patient presented signs of breathing difficulty with an increase in pulmonary resistance, a reduction in O2 saturation to 58%, and severe hypotension (Systolic Blood Pressure < 60 mmHg). Treatment was initiated with epinephrine, corticosteroids and endovenous fluids, but the case evolved to ventricular fibrillation and then death after various resuscitation attempts.

Anaphylaxis related to protamine is rare, however its consequences are disastrous. The prevalence of this complication in our division is of 0.011% if we consider all of the arterial procedures for which protamine was used. In medical literature worldwide, Gupta et al. analyzed 1,150 patients exposed to protamine and identified 11 cases of severe anaphylaxis (0.97%) with nine of these cases occurring in diabetic patients.³ All of these patients presented severe hypertension (Systolic Blood Pressure < 60 mmHg), and four patients suffered death (mortality rate of 36%).

The most common adverse effect of the use of protamine is hypotension after rapid infusion, which can be easily avoided by infusing the drug in a sterile solution with a continuous drip system for a period of over three minutes. Such an alteration generally occurs due to the degranulation of the mastocytes, which causes arteriolar vasodilatation. Other reactions include bronchoconstriction, increased mucus production, petechiae, urticaria and angioedema.^3,10 Anaphylactic reactions can also occur (type IIB) as a result of the direct activation of the mastocytes by the protamine or through the activation of the complement. The direct infusion into the aorta (or left chamber) significantly reduces the occurrence of complications, as, in this way, there is no first contact of the protamine with the mastocytes that are present in abundance in the pulmonary vascular bed.^2,15 However, even if hemodynamic alterations are avoided to a large extent with the infusion in the arterial circulation, an anaphylactic reaction can still occur.

Even in the cases in which the chance of anaphylaxis is small, certain precautions should be taken, principally in relation to the velocity of the infusion. It should be higher than three minutes to reduce the occurrence of hypotension, which is undesirable for this type of patient. The team should be prepared and attentive to a precocious diagnosis and the treatment of occasional complications. The use of protamine should be well evaluated for patients who have an increased risk of anaphylactic reactions, and if possible, it should be avoided.^16,17

REFERENCES

1. Haimovici H, Ascer E, Hollier LH, Strandness DE Jr, Towne JB. Haimovici's Vascular Surgery. 4th ed. UK: Blackwell Science; 1996. p. 913-37.

2. Horrow JC. Protamine: a review of its toxicity. Anesth Analg 1985;64:348-61.

3. Gupta SK, Veith FJ, Ascer E, et al. Anaphylactoid reactions to protamine: an often lethal complication in insulin-dependent diabetic patients undergoing vascular surgery. J Vasc Surg 1989;9:342-50.

4. DeLucia III A, Wakefield TW, Andrews PC, et al. Efficacy and toxicity of differently charged polycationic protamine-like peptides for heparin anticoagulant reversal. J Vasc Surg 1993;18:49-60.

5. Hulin MS, Wakefield TW, Andrews PC, et al. A novel protamine variant reversal of heparin anticoagulant in human blood in vitro. J Vasc Surg 1997;26:1043-8.

6. Dorman BH, Elliott BM, Spinale FG, et al. Protamine use during peripheral vascular surgery: a prospective randomized trial. J Vasc Surg 1995;22:248-56.

7. Moorthy SS, Pond W, Rowland RG. Severe circulatory shock following protamine (an anaphylactic reaction). Anesth Analg 1980;59:77-8.

8. Ellerhorst JA, Comstock JP, Nell LJ. Protamine antibody production in diabetic subjects treated with NPH insulin. Am J Med SCI 1990;299:298-301.

9. Levy JH, Schwieger IM, Zaidan JR, Faraj BA, Weitraub WS. Evaluation of patients at risk for Protamine reactions. J Thorac Cardiovasc Surg 1989;98:200-4.

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11. Mauney MC, Buchanan SA, Lawrence WA, et al. Stroke rate is markedly reduced after carotid endarterectomy by avoidance of protamine. J Vasc Surg 1995;22:264-70.

12. Treiman RL, Cossman DV, Foran RF, Levin PM, Cohen JL, Wagner WH. The influence of neutralizing heparin after carotid endarterectomy on postoperative stroke and wound hematoma. J Vasc Surg 1990;12:440-6.

13. Piepras DG, Sundt TM Jr, Didisheim P. Effect of anticoagulants and inhibitors of platelet aggregation on thrombotic occlusion of endarterectomized cat carotid arteries. Stroke 1976;7:248-54.

14. Chandler WF, Ercius MS, Ford JW. The effect of heparin reversal after carotid endarterectomy in the dog. A scanning electron microscopy study. J Neurosurg 1982;56:97-102.

15. Masone R, Oka Y, Hong YW, Santos H, Frater RW. Cardiovascular effects of right atrial injection of protamine sulfate compared to left atrial injection. Anesthesiology 1982;57:A6.

16. Bauer S. Thoughts on protamine toxicity. Anesth Analg 1985;64:1033.

17. Weiler JM, Freiman P, Sharath MD. Serious adverse reactions to protamine sulfate: are alternatives needed? J Allergy Clin Immunol 1985;75:297-303.