Successful management of IgE-mediated protamine allergy in cardiac surgery: bicentric case report

Abstract

Since the use of heparin reversed by protamine is the gold standard for anticoagulation during cardiopulmonary bypass (CPB), a documented allergy to protamine represents a serious challenge for cardiac anaesthesiologists. We report here a bicentric case report of two patients with documented IgE-mediated protamine allergy requiring redo cardiac surgery. Given the high hemorrhagic risk, a perioperative desensitization strategy was implemented to enable the use of protamine at CPB termination. The protocol was initially tested in outpatient care and demonstrated excellent tolerance. During surgery, standard heparin anticoagulation was used, followed by intraoperative desensitization to allow full heparin reversal. Protamine was hemodynamically well tolerated in both cases, and postoperative recovery was uneventful. To the best of our knowledge, this is the first description of a perioperative strategy designed to induce protamine tolerance in IgE-mediated protamine allergy during cardiac surgery with CPB. This management strategy appears particularly promising, as it offers a strategy that effectively minimises the risk of haemorrhagic complications.

Introduction

In conventional cardiac surgery, cardiopulmonary bypass (CPB) stands as a pivotal procedure. Since the use of heparin reversed by protamine is the gold standard for anticoagulation during CPB, a documented allergy to protamine represents a serious challenge for cardiac anaesthesiologists [1]. Although anaphylactic reactions to protamine are rare, they are associated with a significant increase in organ failure and mortality [2, 3]. Considering the risk of perioperative thrombosis and bleeding, no alternative provides a similar degree of both efficacy and safety [1]. In cases of IgE-mediated hypersensitivity reactions to an essential and non-substitutable medication, desensitization emerges as a compelling strategy, particularly well-documented for chemotherapies, humanised monoclonal antibodies, and aspirin [4]. In the context of confirmed IgE-mediated allergy to protamine, a desensitization protocol could thus enable the use of protamine during the perioperative period and reduce the haemorrhagic risk.

We present a case series involving two patients from two distinct university hospital centers (Hospices civils de Lyon and Centre hospitalo-universitaire Clermont-Ferrand) with confirmed IgE-mediated protamine hypersensitivity who underwent complex cardiac surgeries involving CPB. Both were successfully managed using perioperative desensitization protocols designed to allow safe administration of protamine.

Case presentations

Case 1

A 30-year-old woman with a complex medical history, including chronic obstructive pulmonary disease due to bronchiectasis, multiple drug allergies (including low-molecular-weight heparin and daptomycin), and previous cardiac surgeries, presented with recurrent endocarditis requiring orthotopic heart transplantation. During a previous surgery, she experienced a severe anaphylactic reaction to protamine characterized by vasoplegia, requiring high doses of vasopressors and temporary extracorporeal support. A tryptase level increased from 3.5 to 8.5 µg/L during the reaction, consistent with IgE-mediated hypersensitivity. Subsequent testing showed a weakly positive basophil activation test (negative control at 2%, positive control at 97%, and protamine at 6%), thus confirming the diagnosis of grade 3 IgE-mediated allergy to protamine.

Due to the high hemorrhagic risk associated with cardiac transplantation and reoperation, alternatives to protamine, including bivalirudin and unopposed heparin, were deemed too risky. A desensitization protocol was developed and trialed in outpatient care. Premedication included desloratadine 10 mg the evening before and the morning of the challenge. Protamine was administered incrementally, beginning at 0.012 mg and doubling every 15 min up to 18 mg over 180 min. No adverse reactions occurred.

Six weeks later, the patient underwent heart transplantation. The patient was premedicated with desloratadine 10 mg upon arrival, 1 h before induction. CPB was initiated with 5,000 of heparin during priming and an additional 300 IU/kg. The desensitization protocol began 15 min after the start of CPB. ACT was measured after each protamine injection into the CPB reservoir (slow injection over one minute). Two re-administrations of 2,500 IU of heparin were required during CPB (Fig. 1). Rotational thromboelastometry (ROTEM) after the fourth and eighth protamine doses confirmed adequate anticoagulation. Norepinephrine requirement remained unchanged (< 0.1 µg/kg/min) and no cutaneous reaction occurred throughout CPB. Before the final dose of protamine, tryptase was 3.5 µg/L and histamine was below 1nmol/L. No clot was observed in the oxygenator and pressures remained unchanged. After 150 min, the termination of CPB was achieved easily and a final protamine dose of 230 mg was given. ROTEM analysis indicated comparable clotting times between heparin-sensitive INTEM and heparinase-containing HEPTEM tests, excluding residual heparin. Satisfactory surgical haemostasis allowed rapid sternal closure and the patient was transferred to the intensive care unit (ICU). Postoperative bleeding was minimal (240 mL/24 h), and no transfusion was needed. The patient was extubated four hours after ICU admission and discharged from ICU on day 6.

Fig. 1.

A and B: Administration of protamine, activated clotting time, and transfusion during the whole procedures in case 1 (A) and case 2 (B). ACT: activated clotting time; CPB: cardiopulmonary bypass; ROTEM: rotational thromboelastometry

Case 2

A 75-year-old man with diabetes, chronic renal failure, COPD, severe pulmonary hypertension, atrial fibrillation, hepatic steatosis, and previous protamine-related cardiac arrest required redo aortic valve replacement due to prosthetic degeneration. He had a risk factor for a protamine allergy: he received human neuter protamine Hagedorn (NPH) insulin in 2011 during a diabetic decompensation. During his initial surgery in 2018, protamine administration led to sudden cardiac arrest. A tryptase level increased from 4.9 to 8.9 µg/L. Although specific IgE was negative, BAT confirmed strong basophil activation starting at 1 UAH/mL and remaining positive at higher concentrations (10 and 100 UAH/mL), surpassing the positive threshold of 5% and confirming the diagnosis of grade 4 IgE-mediated allergy to protamine.

Given his history and comorbidities, a desensitization approach was selected. Skin prick tests could not be performed due to the risk of severe anaphylaxis and the lack of a standardized protocol in the literature. Premedication included cetirizine 10 mg, montelukast 10 mg, and aspirin 325 mg daily for three days. Anesthesia induction was uncomplicated. CPB was initiated with 250 IU/kg of heparin (14,000 units). Protamine was administered every 10 min in increasing doses from 0.012 to 0.8 mg. The total CPB duration was 79 min. ACT values were within target range throughout, and no additional heparin was needed.

The final protamine administration was 60 mg over 45 min (initially 40 mg over 30 min, followed by an additional 20 mg over 15 min due to residual heparinization evidenced on ROTEM). No intraoperative anaphylaxis occurred. The patient was extubated 3 h after ICU admission, with no abnormal post operative bleeding. On post operative day 3 he developed acute right heart failure related to severe pulmonary hypertension during milrinone weaning, requiring reintubation. He recovered and was discharged home on day 14.

Discussion

These cases underscore the clinical complexity and risks associated with managing patients with IgE-mediated protamine allergy undergoing cardiac surgery. In such scenarios, perioperative desensitization to protamine may offer a valuable and feasible management strategy.

There are currently no established recommendations for managing CPB in patients with protamine allergy [1]. Protamine is the single FDA-recommended antidote to heparin leaving only two options for managing patients with IgE-mediated protamine allergy undergoing cardiac surgery: using heparin without antagonisation or an alternative anticoagulation treatment [1]. However, managing without reversal is rarely reported and has been associated with severe bleeding, as noted in a recent case [5]. Given the high bleeding risk of reoperative surgery, this approach was deemed unsafe. Alternatives anticoagulation treatment, such as bivalirudin and argatroban, present significant limitations. Bivalirudin has the broadest experience among patients undergoing cardiac surgery but managing CPB anticoagulation with bivalirudin is more complex and requires specialised expertise [6]. Bivalirudin has no antidote and may cause thrombus formation in CPB circuits, especially with stagnation [7]. Also, anticoagulation monitoring should be performed using ecarin clotting time (ECT), but this test is not commonly available. Alternatively, ACT can be used, albeit with lesser accuracy [8]. Argatroban, a direct thrombin inhibitor, is considered an alternative anticoagulant during cardiopulmonary bypass in patients with severe renal impairment; however, its unpredictable pharmacokinetics and association with significant bleeding risk limit its clinical applicability [9].

To the best of our knowledge, this is the first description of perioperative strategies designed to induce protamine tolerance for CPB. Both cases utilized structured protocols involving premedication and graded protamine administration, informed by previously published desensitization protocols [10]. Key elements contributing to safety included the use of BAT to confirm diagnosis, premedication to blunt mediator release, intraoperative desensitization with hemodynamic monitoring, and coagulation assessment using ROTEM and ACT. Tolerance induction thus allowed these two hypersensitive patients from two distinct centers to tolerate an indispensable and non-substitutable medication by gradually administering increasing doses until the full therapeutic dose was reached. Tolerance induction produces cellular and molecular modifications resulting in increased mast cell activation thresholds and the activation of regulatory/suppressor lymphocytes [4]. Tolerance induction is limited in time: tolerance is broken if the medication intake is interrupted, and the protocol must be restarted from the beginning [4]. In the current case report, desensitization had to be performed during CPB. Protamine injection is usually contraindicated during CPB but given the low doses of protamine during desensitization, the risk of clot formation appeared moderate, pending a tight monitoring of ACT, CPB pressures, and oxygenator visual control. It is also essential to ensure complete heparin reversal and to avoid heparin rebound, particularly since a 2-hour desensitization period is required before administering a new therapeutic dose of protamine. To limit the risk of heparin rebound, we monitored for residual heparin using ROTEM [1]. In Case 2, ROTEM analysis revealed residual anticoagulation, which was corrected with an additional 20 mg of protamine. Finally, perioperative protamine desensitization permitted safe administration in patients with confirmed IgE-mediated allergy. Its favorable safety profile suggests that future studies could explore prophylactic use in patients at anticipated risk, such as those treated with protamine-containing insulin.

Conclusion

Perioperative desensitization to protamine can allow safe administration in patients with confirmed IgE-mediated allergy undergoing high-risk cardiac surgery. This bicentric case report demonstrates the feasibility of this approach with appropriate multidisciplinary coordination, premedication, and intraoperative vigilance. In the absence of alternative reversal agents, desensitization provides a vital option for safe anticoagulation management.

Abbreviations

ACT

Activated clotting time

CPB

Cardiopulmonary bypass

PRBC

Packed red blood cells

ROTEM

Rotational thromboelastometry

Authors’ contributions

P.P. and M.C. wrote the main manuscript. B.B. drafted the desensitization protocol and reviewed the manuscript. M. J-L., M.P., J-L.F., L.S. and L.D. reviewed the manuscript and contributed to its improvement.

Funding

The authors have no financial, personal, or professional relationships that could be construed to have influenced the content or conclusions of this manuscript.

Data availability

All data generated or analysed during this study are included in this published article.

Declarations

Ethics approval and consent to participate

According to the policy of Hospices civils de Lyon and Centre hospitalo-universitaire Clermont-Ferrand ethical approval was not required for a case report. In France, the allocation and distribution of organs for transplantation are centrally managed by the French Biomedicine Agency under national legislation. In accordance with French law, the originating hospital of the donor organ cannot be disclosed. Organ donation in France is based on presumed consent: the national register of refusals is consulted and, if the individual is not listed, consent for organ donation is presumed. No organs or tissues were procured from prisoners or individuals under detention. All recipients provided informed consent for transplantation, and the procurement process complied with the Declaration of Helsinki and relevant national regulations.

Consent for publication

Written informed consent was obtained from both patients for publication of these case reports and accompanying clinical details.

Competing interests

The authors declare no competing interests.