How quickly does protamine work?
Protamine sulfate (protamine (protamines) s) has a rapid onset of action. Neutralization of heparin occurs within five minutes after intravenous administration.
How quickly does protamine reverse heparin?
Unfractionated Heparin As more time elapses from heparin administration, less protamine is necessary to reverse the anticoagulant effects. Administration of full dose protamine is indicated in patients who need reversal less than 60 minutes after bolus administration.
How does protamine sulfate work?
Mechanism. It is a highly cationic peptide that binds to either heparin or low molecular weight heparin (LMWH) to form a stable ion pair, which does not have anticoagulant activity. The ionic complex is then removed and broken down by the reticuloendothelial system.
What does protamine sulfate reverse?
Protamine sulfate is used to reverse the anticoagulant effects of heparin following cardiovascular surgical procedures. Systemic hypotension is not uncommon following administration of this drug.
What is the half life of protamine?
Conclusions: Protamine has a very short (approximately 5 minutes) half-life after a single 250-mg dose in adult patients. This short half-life could underlie recurrent anticoagulation after initial apparent reversal of heparin.
What happens if you give too much protamine?
Background and objective: Protamine is routinely administered following cardiopulmonary bypass in order to neutralize the effects of heparin. An excess of protamine can contribute to coagulopathy, hence predisposing to bleeding with associated morbidity and mortality.
When should protamine sulfate be given?
Protamine sulfate is used to counteract the anticoagulant effect of heparin: before surgery; after renal dialysis; after open-heart surgery; if excessive bleeding occurs and when an overdose has inadvertently been given.
How does protamine sulfate work against heparin?
Intravenous protamine sulphate can rapidly reverse the anticoagulant effects of heparin. Protamine sulphate is a basic protein derived from fish sperm that binds to heparin to form a stable salt. One milligram of protamine sulphate neutralizes approximately 100 units of heparin.
Is protamine sulfate a coagulant?
The anticoagulant activity of protamine has been attributed to inhibition of contact-activated and tissue factor–induced coagulation. Taken together, in addition to the well-known hemostatic action of protamine in reversing heparin-induced anticoagulation, excess protamine can potentially enhance bleeding tendency.
What is vitamin K the antidote for?
Vitamin K is an effective antidote for poisoning with a vitamin K antagonist. 42,43. There are 2 distinct enzymatic activities capable of reducing vitamin K1 quinone to the hydroquinone form.
Does vitamin K reverse heparin?
Vitamin K, and in emergency conditions, PCC, or FFP can be used for warfarin reversal, whereas protamine sul- fate reverses the effects of heparin completely. Fondaparinux and LMWH do not have effective reversal agents; however, protamine (for LMWH) and rFVIIa or activated PCC (for fon- daparinux) may have some value.
Does vitamin K reverse warfarin?
IV vitamin K has also been shown to be a safe and effective method of warfarin reversal. A dose finding study recommended 1 mg IV vitamin K for patients with an INR > 10.
How much protamine does it take to reverse Lovenox?
A second infusion of 0.5 mg protamine per 1 mg LOVENOX may be administered if the aPTT measured 2 to 4 hours after the first infusion remains prolonged....Time Since LOVENOX Dose.< 8 hours> 8 hours and ≤ 12 hours≥ 12 hours1mg protamine per 1mg enoxaparin0.5 mg protamine per 1mg enoxaparinmay not be required
How long does heparin stay in your system?
It happens to 10% of people with HIT. If you get it, your body will recover about 4 days after you stop taking heparin.
How much protamine do you need for ACT?
One milligram of protamine is enough to neutralize 1 mg heparin. This method can also be used to work with a target ACT, also adjusting the heparin dose.
Does protamine reverse LMWH?
Protamine is unable to completely reverse the anticoagulant effect of the low-molecular-weight heparins (LMWH), a fact of clinical importance given the rapid increase in use of LMWH in clinical practice.
How long does it take for Protamine Sulfate to work?
Protamine sulfate, which is administered by intravenous infusion, has an immediate onset and duration of action of about 2 hours.
How to dilute protamine sulphate?
Dilute 5 ml of protamine sulphate (10 mg/ml) 1 in 20 with barbitone buffer (p. 380), pH 7.4 to give 100 ml of a stock solution containing 500 μg/ml. Then make working solutions to cover the range of 0–500 μg/ml in 50 μg steps from the stock solution by dilution with buffer. The solutions keep indefinitely at 4°C.
What is the purpose of protamine sulfate?
Protamine. Protamine sulfate is used to reverse the anticoagulant effects of heparin following cardiovascular surgical procedures. Systemic hypotension is not uncommon following administration of this drug.
How many retrospective studies have been conducted on protamine sulfate?
Anaphylactic reactions to protamine sulfate during cardiac surgery have been systematically reviewed in a survey of nine retrospective studies and 16 prospective studies, of which only three of the latter were optimally designed as far as inclusion criteria, randomization, and description of symptoms were concerned; the incidence of anaphylactic reactions in the prospective studies was 0.69% and 0.19% in the retrospective studies [215M ].
How long does it take to administer protamine?
Typically, the drug is administered slowly over approximately 10 minutes. For unclear reasons, severe hypotensive, pulmonary vasoconstrictive, or anaphylactic/anaphylactoid reactions to protamine are uncommon in infants and children ( Seifert et al., 2003 ). Of these, hypotension is most frequent, occurring in between about 1.5% to 3% of protamine administrations. It is dependent on dosage and rate of administration, most likely caused by histamine release, usually fairly mild and transient, and responsive to volume replacement or calcium administration. Severe pulmonary vasoconstriction appears to be much less common than in adults, may be caused by complement activation or pulmonary thromboxane release (or both), and can be particularly problematic in patients with depressed contractile function ( Lowenstein et al., 1983 ).
Is protamine sulfate a complement?
Some reactions to protamine are complement mediated [ 19 ]. During a severe anaphylactoid reaction after intravenous administration of protamine sulfate in a 66-year-old man there was a parallel fall in circulating concentrations of complement C3 and C4 for 1 hour, with a nadir at 1.3 hours [ 20 ]. There were markedly increased concentrations of C3c and C3d soon after exposure, and they gradually fell to within the reference range within 6 and 22 hours respectively.
Does protamine sulfate reverse heparin?
Intravenous protamine sulphate can rapidly reverse the anticoagulant effects of heparin. Protamine sulphate is a basic protein derived from fish sperm that binds to heparin to form a stable salt. One milligram of protamine sulphate neutralizes approximately 100 units of heparin. Because the half-life of heparin is 60−90 min when given as an ...
How long does it take to administer protamine?
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.[10] 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. [3]
How long is a protamine drug evaluation?
A 1-year drug utilization evaluation of protamine in hospitalized patients to identify possible future roles of heparin and low molecular weight heparin reversal agents.
What is protamine used for?
Protamine is an FDA-approved drug for use in neutralizing the effect of unfractionated heparin. [1][2]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.[3] Protamine is also utilized to reverse the anticoagulation effects of unfractionated heparin in the setting of dialysis, invasive vascular procedures, and acute ischemic strokes.[4] 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.[2] Currently, protamine is produced using recombinant technology, but it was originally isolated from salmon fish sperm.[3] 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. [5][3]
What is the drug used to reverse and neutralize the anticoagulant effects of heparin?
Protamine is a medication used to reverse and neutralize the anticoagulant effects of heparin. Protamine is the specific antagonist that neutralizes heparin-induced anticoagulation. Protamine is a strongly alkaline (nearly two-thirds of the amino acid composition is arginine) polycationic low-molecular-weight protein found in salmon sperm that is also currently available in a recombinant form. This activity reviews indications, contraindications, mechanisms of action, adverse event profile, and other key elements of protamine use that are pertinent for members of the interprofessional team that manage the care of patients who require reversal of heparin.
How much protamine is given for heparin?
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. [11]
What are the adverse effects of protamine?
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%.[9] There are also reports of liver and kidney tissue damage.[6] 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.
Can protamine cause pulmonary hypertension?
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. [12][13] 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 its irreversible inactivation of the cyclooxygenase enzyme.
How long does it take for protamine to work?
The duration of action can persist up to 2 hours, depending on body temperature. The fate of the heparin-protein complex is unknown, but it appears to be partially degraded, with the release of heparin.
How much protamine should I take for dalteparin?
In general, protamine 1 mg IV for every 100 anti-Xa international units of dalteparin or tinzaparin is given. A second infusion of protamine 0.5 mg IV for every 100 anti-Xa international units of dalteparin or tinzaparin may be administered if the aPTT measured at 2 to 4 hours after the initial infusion remains prolonged. However, even with higher doses of protamine, the aPTT may remain more prolonged than would usually be found with protamine treatment following unfractionated heparin. In all cases, the anti-Xa activity is never completely neutralized (maximum 60% to 75%).
How many mg of a sulfate can you take?
Must individualize dosage; do not exceed 50 mg/dos e.
Is heparin a salt?
Heparin: (Contraindicated) Upon contact with heparin, protamine forms a salt, neutralizing the anticoagulant effect of both drugs. Protamine, a strongly basic compound, forms complexes with heparin sodium or heparin calcium, which are acidic compounds.
Does aPTT work with heparin?
However, even with higher doses of protamine, the aPTT may remain more prolonged than would usually be found with protamine treatment following unfractionated heparin. In all cases, the anti-Xa activity is never completely neutralized (maximum 60% to 75%).
Is protamine a risk factor for pulmonary hypertension?
Protamine administration has a risk of serious hypersensitivity reactions or anaphylaxis manifesting as severe hypotension, cardiovascular collapse, pulmonary edema, pulmonary vasoconstriction, and pulmonary hypertension. Risk factors for these events include high doses or overdose, rapid IV administration, previous exposure, repeated doses, and current or previous use of protamine-containing drugs (e.g., NPH insulin, protamine zinc insulin, and certain beta-blockers). Fish hypersensitivity, vasectomy, severe left ventricular dysfunction, and abnormal preoperative pulmonary hemodynamics may also be risk factors. Carefully consider the risks and benefits of use in patients with any of these risk factors. Administration requires a specialized care setting as vasopressors and resuscitation equipment should be immediately available in case of a severe reaction. Do not give protamine when bleeding occurs without prior heparin use.
Is protamine a serious drug?
Protamine administration has a risk of serious hypersensitivity reactions or anaphylaxis manifesting as severe hypotension, cardiovascular collapse, pulmonary edema, pulmonary vaso constriction, and pulmonary hypertension .
How to report Protamine side effects?
These are not all the possible side effects of Protamine. For more information, ask your doctor or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
What is the purpose of protamine?
Protamine is a prescription medicine used to treat the symptoms of Heparin Neutralization and to treat an overdose caused by Dalteparin, Tinzaparin and Enoxaparin. Protamine may be used alone or with other medications. Protamine belongs to a class of drugs called Antidotes, Other.
How long does it take for heparin to be neutralized?
Neutralization of heparin occurs within five minutes after intravenous administration. Although the metabolic fate of the heparin-protamine (protamines) complex has not been elucidated, it has been postulated that protamine sulfate (protamine (protamines) s) in the heparin-protamine (protamines) complex may be partially metabolized or may be attacked by fibrinolysin, thus freeing heparin.
How long does it take for heparin to bleed after surgery?
Hyperheparinemia or bleeding has been reported in experimental animals and in some patients 30 minutes to 18 hours after cardiac surgery (under cardiopulmonary bypass) in spite of complete neutralization of heparin by adequate doses of protamine sulfate (protamine (protamines) s) at the end of the operation.
How many units of heparin are neutralized by protamine sulfate?
Each mg of protamine sulfate (protamine (protamines) s) will neutralize approximately 90 USP units of heparin activity derived from beef lung tissue or about 115 USP units of heparin activity derived from porcine intestinal mucosa.
What are the side effects of Protamine?
Get medical help right away, if you have any of the symptoms listed above. The most common side effects of Protamine include: sudden fall in blood pressure, slow heart rate (bradycardia), pulmonary hypertension,
Can protamine cause a sudden drop in blood pressure?
Intravenous injections of protamine (protamines) may cause a sudden fall in blood pressure, bradycardia, pulmonary hypertension, dyspnea, or transitory flushing and a feeling of warmth. There have been reports of anaphylaxis that resulted in respiratory embarrassment (see PRECAUTIONS ).Other reported adverse reactions include systemic hypertension, nausea, vomiting and lassitude. Back pain has been reported rarely in conscious patients undergoing such procedures as cardiac catheterization. Because fatal reactions often resembling anaphylaxis have been reported after administration of protamine sulfate (protamine (protamines) s) , the drug should be given only when resuscitation techniques and treatment of anaphylactoid shock are readily available.
How long does protamine sulfate last?
Half-life. The half-life of protamine sulfate in healthy individual volunteers without heparin in the body was determined to be about a median 7.4 minutes (from a range of 5.9-9.3 minutes) 3.
What is the mechanism of action of protamine sulfate?
It is generally understood that, when administered as an antidote to heparin, protamine sulfate is a fairly strong basic protein that subsequently binds with strongly acidic heparin to produce a stable and inactive complex (salt) 9, 10, 7, 8. This inactive complex between protamine sulfate and heparin neutralizes ...
What is the effect of protamine sulfate on heparin?
This inactive complex between protamine sulfate and heparin neutralizes the anticoagulant effect of both solitary protamine and heparin 9, 10, 7, 8. In this way, protamine sulfate is used as an effective antidote to reverse the activity of heparin, and is useful for treating hemorrhage as a result of severe heparin or low-molecular weight heparin ...
How long does it take for protamine to neutralize?
Protamine concentrations were less than the limit of detection after twenty minutes or less, although the onset of action had been reported to appear within thirty to sixty seconds after intravenous administration 9, 10, 7, 8 It is, however, generally documented that the neutralization of heparin occurs within five minutes after the intravenous administration of protamine sulfate 9, 7, 8.
What are the side effects of protamine sulfate?
Administration of protamine sulfate intravenously could result in severe drop in blood pressure, dyspnea, bradycardia, pulmonary hypertension and anaphylaxis 9, 10, 7, 8. Systemic hypertension, nausea, vomiting and lassitude were also reported 9, 10, 7, 8. Overdosage of this drug may theoretically result in hemorrhage 9, 10, 7, 8.
Is protamine sulfate readily available?
Data regarding the protein binding of protamine sulfate is not readily available or accessible. Metabolism. The metabolic fate of the inactive heparin-protamine complex has not yet been formally elucidated 9, 10, 7, 8.
Does protamine sulfate affect XA?
Additionally, studies have also determined that protamine sulfate elicit s effects on the clotting factors human factor Xa and human antithrombin (AT) 10. In particular, it has been shown that protamine sulfate is capable of transforming and degrading factor Xa to inactive moieties, transforming Xa-AT complexes, promoting the digestive degradation of primary Xa-AT complexes to tertiary complexes, and ultimately promotes a reduction in total complex formulation via the hydrolysis of factor Xa moieties 10.
How is protamine sulfate determined?
Dose of protamine sulfate determined by dose of LMW heparin received, the time elapsed since the drug was given, and blood coagulation studies.
How much protamine sulfate is needed for blood loss?
Generally, 1 mg of protamine sulfate will neutralize no less than 100 units of heparin sodium.
How long after enoxaparin can you take protamine sulfate?
Protamine sulfate administration may not be required if >12 hours has elapsed since administration of enoxaparin.
How long does it take for heparin to be neutralized?
Neutralization of heparin occurs <5 minutes after IV administration.
How to treat protamine allergy?
Patients at risk for protamine allergy can be pretreated with corticosteroids and antihistamines. (See Actions.)
Is protamine sulfate needed for rebound?
Additional doses of protamine sulfate may be required in patients with heparin rebound (e.g., as may occur during extracorporeal circulation † in arterial and cardiac surgery or dialysis procedures) if indicated by coagulation studies. (See Effects on Hemostasis under Cautions.)
Can you use protamine for bleeding?
(See Sensitivity Reactions under Cautions.) Protamine should not be used for bleeding that occurs without prior exposure to heparin.
How long does it take to give protamine sulfate?
Protamine sulfate injection should be given by very slow intravenous injection over a 10-minute period in doses not to exceed 50 mg (see WARNINGS ). Protamine sulfate is intended for injection without further dilution; however, if further dilution is desired, D5-W or normal saline may be used.
How much protamine sulfate is lethal?
The median lethal dose of protamine sulfate is 50 mg/kg in mice. Serum concentrations of protamine sulfate are not clinically useful. Information is not available on the amount of drug in a single dose that is associated with overdosage or is likely to be life-threatening. Treatment.
How long after heparin is protamine sulfate given?
For example, if the protamine sulfate is administered 30 minutes after the heparin, one-half the usual dose may be sufficient.
What is USP injection?
Protamine Sulfate Injection, USP is indicated in the treatment of heparin overdosage.
What are the risks of protamine sulfate?
Risk factors include high dose or overdose, rapid administration (see WARNINGS and DOSAGE AND ADMINISTRATION ), repeated doses, previous administration of protamine, and current or previous use of protamine-containing drugs (N PH insulin, protamine zinc insulin, and certain beta-blockers). Allergy to fish, previous vasectomy, and severe left ventricular dysfunction and abnormal preoperative pulmonary hemodynamics also may be risk factors. In patients with any of these risk factors, the risk to benefit of administration of protamine sulfate should be carefully considered. Vasopressors and resuscitation equipment should be immediately available in case of a severe reaction to protamine. Protamine sulfate should not be given when bleeding occurs without prior heparin use.
Where do protamines occur?
They occur in the sperm of salmon and certain other species of fish. Protamine sulfate occurs ... Protamines are simple proteins of low molecular weight that are rich in arginine and strongly basic. They occur in the sperm of salmon and certain other species of fish.
Can protamine cause bradycardia?
The intravenous administration of protamine sulfate may cause a sudden fall in blood pressure and bradycardia. Other reactions include transitory flushing and feeling of warmth, dyspnea, nausea ... The intravenous administration of protamine sulfate may cause a sudden fall in blood pressure and bradycardia.
