Y Arslan, A Tarhan, M Yilmaz, T Kehlibar, A Özler
allergy, cabg, protamine sulphate
Y Arslan, A Tarhan, M Yilmaz, T Kehlibar, A Özler. Life Threatening Protamine Reactions In Cardiac Surgery: Literature Review With A Case Report. The Internet Journal of Thoracic and Cardiovascular Surgery. 2004 Volume 7 Number 1.
Immunologic reactions to protamine sulfate during cardiac surgery are very rare. The frequency and outcome of such adverse reactions isunclear. We report a case of a severe anaphylactic reaction to protamine that occurred in a diabetic patient following the uneventful coronary artery bypass grafting operation. We also briefly review the mechanisms of this adverse reaction and emit some considerations on the management of this situation.
Introduction And Case Report
Protamine is a polycationic peptide that is mainly used to reverse the anticoagulant effects of heparin. Although protamine is a relatively safe drug, it is occasionally associated with a severe systemic reaction and significant morbidity and mortality (1).
A 75-year-old male, with a history of smoking and diabetes mellitus regulated with oral antidiabetics, with no allergy anamnesis, had unstabile angina pectoris. Coronary angiography revealed left main coronary stenosis %90, LAD proximal stenosis %70, Cx proximal stenosis %80, RCA %20 proximal stenosis but left dominancy present. Preoperative echocardiography ( LVIDd: 4,11 cm , LVIDs: 2,94 cm , EF: %67,2 with no valvular dysfunction). An elective CABG operation planned. The patient was transferred to the operating room. After median sternomy, LIMA and saphenous vein prepared, aortic an with stage venous canula cardiopulmonary bypass (CPB) was initiated, the patient was cooled to 28 C and antegrade K crystalloid cardioplegia (Plegisol) was administered through the ascending aorta with a large bore needle . Cx-saphenous vein, LAD- LIMA distal anastomoses were performed firstly and plegisol cardioplegia was given from saphenous vein. Under the same cross clamp period proximal anatomose (cx-Ao) was performed to the aorta. Total aortic cross-clamping time was 52 min. The patient was successfully weaned from CPB with no inotropic support. Total bypass time was 72 minutes. Heparin was reversed by a slow intravenous injection of 40,000 IU protamine sulfate.
Ten minutes after the complete administration of protamine, rapid right ventricular dilatation was observed. Mean systemic and pulmonary arterial pressure were 40 and 65 mmHg, respectively, without any electro-cardiographic alterations. The patient was heparinized fully. IABP planned but the patient had peripheral artery stenosis, femoral artery was severely calcified. The hemodynamics was tolerable after a support of volume infusion and inotropic drugs (adrenaline, dopamine, nitroglycerin) . The patient was transfered to post operative ICU. There was bleeding from the chest tubes, bleeding diatesis was suspected, ACT measured, it was over 500, 200 mg prednisolone infused, only half-dose of the necessary protamine was infused very slowly. 10 min after protamine again the patient responded with a marked blood pressure drop, and pulmonary hypertension simultaneously with global cardiac failure. We strongly suspected an anaphylactic reaction to protamine again and the patient was transfered to the operating room again. No cutaneous manifestations were present at any moment. Reexploration for bleeding was done and there wasn’t any surgical bleeding focus.
The hemodymamics was stabile with high dose inotropes but there was increased airway resistance and fall in PaO2. the ventilator support was given for 5 days and the patient was then extubated gradually. In the post operative echocardiography the left ventricular function was poor on the1st day (EF %25-%30 with globular hypochynesia, LVIDd:6.5cm LVIDs:5.5cm) with no valvular dysfunction. The patient was discharged from hospital in the 12th day of hospital stay. In the first month echocardiography EF: %50-60. And the clinical status was excellent.
Protamine is a basic polypeptide isolated from salmon sperm. It is used extensively to neutralize heparin following cardiac and vascular surgical procedures. Protamine is also used in the complexing of insulin to delay absorption and prolong duration of action. Protamine reverses the anticaoagulating effect of heparin, an acidic glycosaminoglycan, by a nonspecific acid-base interaction (polyanionic-polycationic interaction).
The incidence of adverse reactions has been reported as varying from 0.06 to 10.6% (2). It was reported reported in patients with fish allergy, in those previously exposed to protamine, principally diabetics who have received protamine zinc insulin. In addition, both vasectomised and infertile men have a theoretical risk of sensitivity via antibodies raised to protamine, contained in sperm released into the blood stream. Stewart first reported a 27 percent incidence of reactions following cardiac catheterization in insulins dependent diabetics who received neutral protamine Hagedorn (NPH) insulin preparations (3) but subsequent studies in cardiac surgical patients found a low incidence (4,5). Levy studied approximately 4,700 patients undergoing cardiac surgery with cardiopulmonary bypass and reported that the incidence of life-threatening reactions ranges from 0.6 to 2 percent in NPH insulin-dependent diabetics as compared to 0.06 percent in non-NPH-insulin-dependent diabetics (4,5).
The incidence of catastrophic reactions to protamine during cardiovascular surgery is reported to be 0.13% (6). Although the exact mechanisms by which protamine produces anaphylaxis are not completely understood, some possible mechanisms are described.
Protamine may act as an antigen and bind to the IgE antibodies. This process may lead to cross-linking with the antibody surfaces, which then initiates a process of cell degranulation. Adverse reactions may also be associated with the interaction between protamine and complement-fixing antiprotamine IgG antibodies. Protamine–heparin complexes activate the classical complement cascade with subsequent gener-ation of anaphylatoxins (7).
The spectrum of cardiovascular manifestations of protamine reactions in humans range from systemic vasodilation with increases in cardiac output, to acute pulmonary vasoconstriction and right ventricular dysfunction (4, 8).
Anaphylactoid responses to protamine are characterized by edema of the skin, mucosa, and viscera, decreased systemic vascular resistance, bronchospasm, and occasionally flushing. Catastrophic pulmonary vasoconstriction is accompanied by right ventricular dilation, pulmonary arterial hypertension, decreased left ventricular filling pressure, and systemic hypotension. This type of reaction appear to occur in patients with abnormal pulmonary hemodynamics (9).
Hypotension occurred when the increase in cardiac output was insufficient to offset the decreased peripheral resistance. A small reduction in left ventricle contractile activity is present only in patients with a decrease 10 mmHg in systemic blood pressure . However the precise mechanism that explains protamine-mediated systemic hypotension is unknown (10).
In vitro organ chambers and canine pulmonary artery studies indicate that protamine induces endothelium-dependent vasodilation, instead of a vasoconstriction, as previously documented (9). Heparin, in contrast to the systemic circulation, inhibits the endothelium-dependent vasodilation to protamine (11). However, this inhibitory effect can be overcome by higher doses of protamine, concluding that protamine complexed with heparin does not induce vasodilation. As in the systemic circulation, the precise mechanism is still unknown. Since the direct effect of protamine is vasodilation due to EDRF/NO release, it appears that this vasoconstriction may be secondary. It is possible that the protamine use for anticoagulation reversion causes release of thromboxane, which induces catastrophic pulmonary vasoconstriction (12). In the latest studies it was showed that protamin depresses the myocardial muscle contraction by inhibiting cellular mechanisms (13). Patients with impaired left ventricular funtion had a significant decrease in fractional shortening during and immediately after protamine (14).
Rapid injection of protamine increased cardiovascular effects . Recommendation for dosing is “no more than 50 mg of the drug is administered in any 10-min-period” (15).
We think that a major step in the surgical outcome of our patient was the decision to again administer protamine again. We thougt that we were dealing with protamine reactions but we had no change of giving protamine becouse the patient was bleeding heavyly (1500 cc/h). The mechanism of this cardiac failure supports the hypothesis of a direct effect of the heparin –protamine complexes on cardiac contractility (9).
Alternatives to protamine are available. Hexadimethrine bromide (poly-brene) was used before but is no longer available for clinical use and some heparinases are agents that have been used occasionally as reversal agents for heparin. Of all the pharmacologic alternatives for heparin reversal, rPF4 appears to be a most promising agent. In the absence of a safe and efficient agent for the reversal of heparin, when the risks of adverse reaction to protamine outweigh the risks of extensive bleeding, spontaneous reversal of heparin is allowed. Treatment of adverse responses to protamine is based on supporting the affected organs and reducing the effects of histamine.
Methylene blue is another durg that was suggested by some auothers to prevent and treat hemodynamic complications caused by the use of protamine after CPB. In patients who develop acute pulmonary hypertension and right heart failure, therapy attempts to reduce pulmonary artery pressure and maintain systemic pressure and right ventricular contractility (17). Vasodilators such as nitroglycerin and cyclic AMP-specific phosphodiesterase inhibitors (i.e., amrinone, milrinone, enoximone) may be useful. As a third-line therapy, alprostadil (PGE1 ) can be used but often infusion of a catecholamine with alpha-agonist properties (e.g., norepinephrine) through a left atrial catheter is needed (17). Lock also reported that heparin could reverse protamine-induced pulmonary hypertension by decreasing heparin-protamine complexes and stopping thromboxane release from macrophages, but this has not been confirmed (18). In our case we we exprienced that after reheparinizing the patient the hemodynamics recovered with inotropic support, we didn’t choose the cardiopulmonary bypass again becouse we thought that the systemic vascular resistance would drop much more.
Immunologic reactions to protamine have received little attention among clinicians. In view of our experience, we should like to suggest that anaphylactic reactions to protamine are uncommon but potentially life threating. Patients, who have had previous protamine injections during cardiovascular surgery, diabetics on protamine containing insulin, as well as patients with allergy to fish and vasectomised patients should perhaps be routinely tested for such sensitivity and be appropriately premedicated. Finally, when suspecting a severe adverse reaction to protamine, we estimate that heparin should not be reversed even with a greater risk of bleeding and subsequent reexploration. As protamin is being the only used alternative of heparin reversal in daily practice we have to approach this antity very carefully.
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