Protamine is an FDA-approved drug for use in neutralizing the effect of unfractionated heparin. It is most commonly used to neutralize heparin-induced anticoagulation after separation from cardiopulmonary bypass. When appropriately dosed, this neutralization reduces the risk of postoperative bleeding. Protamine is also utilized to reverse the anticoagulation effects of unfractionated heparin in the setting of dialysis, invasive vascular procedures, and acute ischemic strokes. Finally, clinicians can use protamine for a partial reversal of low molecular weight heparins including enoxaparin, dalteparin, and tinzaparin, but the degree of reversal is unclear, and this use has not been FDA-approved. Currently, protamine is produced using recombinant technology, but it was originally isolated from salmon fish sperm. When first introduced, protamine was used to prolong the action of insulin preparations; adding it to the preparation prolonged the duration of action of the insulin and delayed insulin absorption.
Unfractionated heparin is a strongly anionic anticoagulant that, when exposed to the positive cationic arginine peptide of protamine, forms a salt aggregate. The salt aggregate that forms is inactive and has no anticoagulant properties. Protamine has a rapid onset of action, neutralizes unfractionated heparin within 5 minutes, and has a relatively short half-life of approximately 10 minutes. There is very little known about the metabolism of the heparin-protamine salt aggregate. Some studies have described the metabolism of the salt in the liver, while other studies have reported that the salt is metabolized and excreted by the kidneys. Care is necessary to administer the proper dose of protamine, as excessive doses, protamine has been shown to possess anticoagulation properties and may cause bleeding and increased transfusion requirements.
In the cardiac operating room setting protamine is typically administered intravenously as an infusion over 10 to 15 minutes; this slow infusion is intended to decrease the likelihood of side-effects that can occur if infused too rapidly. Many anesthesiologists in the cardiac operating room setting will administer a small bolus of protamine, often called a "test dose," to allow for early detection of adverse reactions including hemodynamic instability. Often, protamine is administered through a peripheral intravenous line rather than a central line, as studies have shown that protamine delivered through a central line can cause an increase in plasma histamine levels and a decrease in systemic vascular resistance. If no adverse reaction occurs, then the balance of the protamine dose is infused. Proper dosing of protamine to reverse heparin is controversial and varies in the medical literature. Protamine is packaged as an intravenous solution in a concentration of 10 milligrams/milliliter. To neutralize heparin, 1 to 1.5 mg of protamine gets injected per 100 units of heparin. Initial protamine treatment for dalteparin, tinzaparin, or enoxaparin overdosage is 1 mg protamine per 100 units of the low molecular weight heparin given. Follow up doses of protamine in the 0.5 mg range per 100 units can be given if bleeding continues 4 hours later. The efficacy of protamine reversing heparin can be assessed by measuring the activated clotting time or performing a thromboelastogram test. In clinical trials, hemodynamic changes and arterial oxygenation changes decreased with protamine infusion via the ascending aorta vs. a central venous line suggesting this may be the preferred route of administration.
The most common adverse effect associated with protamine administration includes an anaphylactic response consisting of systemic hypotension, pulmonary vasoconstriction, allergic reactions, pulmonary hypertension, bronchoconstriction, and bradycardia. The incidence of anaphylactic reactions ranges from 0.06% to 10.6%. There are also reports of liver and kidney tissue damage. Suspected anaphylactic responses to protamine receive treatment, in the same way, other perioperative anaphylactic reactions. Therapies include the use of albuterol, methylprednisolone, H1, and H2 antihistamines, vasopressin, norepinephrine, fluid administration, glucagon, and echocardiography to monitor cardiac function.
Excess protamine can also negatively impact platelet function, interfere with coagulation factors, and stimulate the breakdown of clot. The thinking is that protamine may potentiate fibrinolysis by decreasing thrombin concentrations.
Pulmonary hypertension is a potentially catastrophic adverse response to protamine administration; it is believed to be due to thromboxane A2 release. This release of thromboxane has been shown in studies to increase pulmonary vascular resistance by up to 10 times. This condition can have treatment with the use of a prostacyclin EI infusion. Some studies have suggested the protamine-induced pulmonary hypertension is preventable by continuing aspirin intake before surgery, as aspirin suppresses the production of thromboxanes through to its irreversible inactivation of the cyclooxygenase enzyme.
Hypotension from protamine infusion is thought to be due to intracellular calcium release and nitric oxide release. Prevention options include the use of antihistamines to suppress an allergic response and steroids to reduce any inflammatory response. Vasopressors are often used to counteract protamine-induced hypotension.
Patients with a history of past protamine exposure, vasectomy, fish allergies, and insulin-controlled diabetes are all at increased risk for an adverse reaction. The most common patient at risk for a protamine reaction is one who have had NPH insulin in the past. There are approximately 2.8 milligrams of protamine per 100 units of protamine zinc insulin and 0.5 milligrams or protamine per 100 units of isophane (NPH) insulin. Presumably, chronic exposure to low doses of protamine in a patient on these insulin preparations can cause the formation of antibodies to protamine.
Protamine should be given slowly, and patients should be monitored closely for anaphylaxis, rapid hypotension, or an increase in pulmonary artery pressures. Anaphylaxis can cause an increase in peak airway pressures along with hypotension, a rash, and wheezing or difficulty breathing. The presence of an arterial line for invasive blood pressure monitoring and/or a pulmonary artery catheter to monitor changes in pulmonary artery pressures is advantageous to recognize early negative sequelae from protamine administration. It is also imperative for the medical staff to have access to cardiovascular rescue drugs (vasoactive/inotropic drugs) and resuscitation equipment should an adverse reaction occur.
Protamine’s toxicity is thought to be due to its positive charge. It has been shown to cause a decrease in endothelial cell ATP production and progressive mitochondrial injury in bovine pulmonary endothelial cells. Protamine also has a toxic effect on myocardial cells that is postulated to be due to its positive charge affecting mitochondrial cells intracellularly. The theory is that the salt formed between protamine and heparin that effectively neutralizes the positively charged molecule of protamine offers some intracellular protection against toxicity.
The use of protamine requires an interprofessional team of healthcare professionals that includes physicians, nurses, and cardiac perfusionists. Without proper management and communication, the morbidity and mortality from protamine can be high. In cardiac surgery, protamine administration must be communicated to all members of the healthcare team, as protamine administration before separation from cardiopulmonary bypass can be fatal. Typically after separation from cardiopulmonary bypass, the cardiac surgeon asks for protamine to be given to reverse the effects of heparin. This request should be followed by closed-loop communication from the anesthesiologist that the protamine infusion has begun. This is to inform the cardiac perfusionists to stop all suction devices that drain into the cardiopulmonary bypass machine (to avoid introducing protamine into the cardiopulmonary bypass circuit in the event that the patient needs to be put back on cardiopulmonary bypass), as well as to inform the cardiac surgeon and nursing staff in the room to be vigilant for adverse reactions.
Protamine is useful in several different clinical scenarios in the hospital setting. The proper dosing and speed of infusion or injection of protamine to neutralize the anticoagulant effects of heparin should be appropriately followed. In other clinical situations, physicians and nursing should be extremely vigilant in monitoring patients for adverse reactions. Appropriate resources should be available to monitor and treat patients who experience adverse effects due to its administration. An understanding of the appropriate laboratory tests to follow during its administration is also critical to the safe use of protamine.
For decades since the start of cardiac surgery using cardiopulmonary bypass, investigators have studied the methods to provide a safe, efficient, and reproducible way of performing complex cardiac surgeries. Advances in cardiopulmonary bypass are the result of evidence-based randomized controlled trials, cohort studies, and anecdotal practice or consensus. After reviewing all available evidence, in 2018 The Society of Thoracic Surgeons, The Society of Cardiovascular Anesthesiologists, and The American Society of Extra-corporeal Technology released their clinical practice guidelines for anticoagulation during cardiopulmonary bypass. These guidelines discussed the use of heparin as the primary anticoagulant (bivalirudin if there are heparin contraindications) and protamine as the reversal agent. Though there are ongoing investigations into new medications for anticoagulation and reversal of such anticoagulation, the current gold standards for anticoagulation and reversal of anticoagulation for cardiac surgery continue to be heparin and protamine.
Protamine is a medication that requires the collaborative efforts of an interprofessional team, including clinicians, surgeons, anesthesiologists, nurse anesthetists, nursing, and pharmacists. As mentioned above, proper preparation, dosing, and protocol are necessary when using protamine, and each member of the team has the role to play in the bigger picture. Nursing should be monitoring along with anesthesia personnel. The pharmacist should have verified the planned dosing along with the heparin used for the procedure. Clinicians need to seek input and feedback from these other members so that the interprofessional team actually functions as such, not with everyone siloed into their own discipline. This approach will lead to proper protamine use and better patient outcomes. [Level V]
|||Carr JA,Silverman N, The heparin-protamine interaction. A review. The Journal of cardiovascular surgery. 1999 Oct; [PubMed PMID: 10596998]|
|||Holzmacher JL,Sarani B, Indications and Methods of Anticoagulation Reversal. The Surgical clinics of North America. 2017 Dec; [PubMed PMID: 29132510]|
|||Boer C,Meesters MI,Veerhoek D,Vonk ABA, Anticoagulant and side-effects of protamine in cardiac surgery: a narrative review. British journal of anaesthesia. 2018 May; [PubMed PMID: 29661409]|
|||Ranasinghe T,Mays T,Quedado J,Adcock A, Thrombolysis Following Heparin Reversal With Protamine Sulfate in Acute Ischemic Stroke: Case Series and Literature Review. Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association. 2019 Jul 17; [PubMed PMID: 31324409]|
|||Nybo M,Madsen JS, Serious anaphylactic reactions due to protamine sulfate: a systematic literature review. Basic [PubMed PMID: 18816305]|
|||Sokolowska E,Kalaska B,Miklosz J,Mogielnicki A, The toxicology of heparin reversal with protamine: past, present and future. Expert opinion on drug metabolism [PubMed PMID: 27223896]|
|||Stehle G,Wunder A,Sinn H,Schrenk HH,Friedrich EA,Dempfle CE,Maier-Borst W,Heene DL, Complexes of a modified low-molecular-weight heparin with protamine are predominantly cleared by a macrophage scavenger receptor-mediated process in rats. The Journal of surgical research. 1995 Feb [PubMed PMID: 7861773]|
|||DeLucia A 3rd,Wakefield TW,Kadell AM,Wrobleski SK,VanDort M,Stanley JC, Tissue distribution, circulating half-life, and excretion of intravenously administered protamine sulfate. ASAIO journal (American Society for Artificial Internal Organs : 1992). 1993 Jul-Sep [PubMed PMID: 8268631]|
|||Kimmel SE,Sekeres M,Berlin JA,Ellison N, Mortality and adverse events after protamine administration in patients undergoing cardiopulmonary bypass. Anesthesia and analgesia. 2002 Jun; [PubMed PMID: 12031996]|
|||Casthely PA,Goodman K,Fyman PN,Abrams LM,Aaron D, Hemodynamic changes after the administration of protamine. Anesthesia and analgesia. 1986 Jan [PubMed PMID: 3940472]|
|||Protamine Administration Via the Ascending Aorta May Prevent Cardiopulmonary Instability., Chaney MA,Devin Roberts J,Wroblewski K,Shahul S,Gaudet R,Jeevanandam V,, Journal of cardiothoracic and vascular anesthesia, 2016 Jun [PubMed PMID: 26948466]|
|||Morel DR,Lowenstein E,Nguyenduy T,Robinson DR,Repine JE,Chenoweth DE,Zapol WM, Acute pulmonary vasoconstriction and thromboxane release during protamine reversal of heparin anticoagulation in awake sheep. Evidence for the role of reactive oxygen metabolites following nonimmunological complement activation. Circulation research. 1988 May; [PubMed PMID: 3129208]|
|||Horiguchi T,Enzan K,Mitsuhata H,Murata M,Suzuki M, Heparin-protamine complexes cause pulmonary hypertension in goats. Anesthesiology. 1995 Oct [PubMed PMID: 7574058]|
|||Murase K,Naruse K,Kimura A,Okumura K,Hayakawa T,Sokabe M, Protamine augments stretch induced calcium increase in vascular endothelium. British journal of pharmacology. 2001 Dec; [PubMed PMID: 11724745]|
|||Pevni D,Gurevich J,Frolkis I,Keren G,Shapira I,Paz J,Kramer A,Locker C,Mohr R, Protamine induces vasorelaxation of human internal thoracic artery by endothelial NO-synthase pathway. The Annals of thoracic surgery. 2000 Dec; [PubMed PMID: 11156119]|
|||Weiler JM,Gellhaus MA,Carter JG,Meng RL,Benson PM,Hottel RA,Schillig KB,Vegh AB,Clarke WR, A prospective study of the risk of an immediate adverse reaction to protamine sulfate during cardiopulmonary bypass surgery. The Journal of allergy and clinical immunology. 1990 Apr; [PubMed PMID: 2182695]|
|||Srivastava V,Saravanan P,Abraham J,Au J, Successful on-pump coronary artery bypass without using protamine. The Annals of thoracic surgery. 2011 Feb; [PubMed PMID: 21256330]|
|||Knape JT,Schuller JL,de Haan P,de Jong AP,Bovill JG, An anaphylactic reaction to protamine in a patient allergic to fish. Anesthesiology. 1981 Sep; [PubMed PMID: 7270957]|
|||Wakefield TW,Hinshaw DB,Burger JM,Burkel WE,Stanley JC, Protamine-induced reductions of endothelial cell ATP. Surgery. 1989 Aug; [PubMed PMID: 2763036]|
|||Kossekova GP,Mitovska MI,Dancheva KI, Protamine inhibition of the oxidative phosphorylation in intact, cytochrome c-depleted and restored mitochondria. Acta biologica et medica Germanica. 1975; [PubMed PMID: 171893]|
|||Shore-Lesserson L,Baker RA,Ferraris VA,Greilich PE,Fitzgerald D,Roman P,Hammon JW, The Society of Thoracic Surgeons, The Society of Cardiovascular Anesthesiologists, and The American Society of ExtraCorporeal Technology: Clinical Practice Guidelines-Anticoagulation During Cardiopulmonary Bypass. Anesthesia and analgesia. 2018 Feb [PubMed PMID: 29346209]|
|||Bouraghda A,Gillois P,Albaladejo P, [Alternatives to heparin and protamine anticoagulation for cardiopulmonary bypass in cardiac surgery]. Canadian journal of anaesthesia = Journal canadien d'anesthesie. 2015 May [PubMed PMID: 25697279]|