BOXED WARNING
Protamine sulfate can cause severe hypotension, cardiovascular collapse, noncardiogenic pulmonary edema, catastrophic pulmonary vasoconstriction, and pulmonary hypertension. 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 (NPH 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.
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PROTAMINE SUMMARY
Protamines are simple proteins of low molecular weight that are rich in arginine and strongly basic.
Protamine Sulfate Injection, USP is indicated in the treatment of heparin overdosage.
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NEWS HIGHLIGHTS
Published Studies Related to Protamine
Pharmacokinetics and pharmacodynamics of insulin lispro protamine suspension
compared with insulin glargine and insulin detemir in type 2 diabetes. [2009] CONCLUSIONS: Following a single 0.8 U/kg dose in T2DM patients, ILPS, G, and D
Nocturnal glucose metabolism after bedtime injection of insulin glargine or
neutral protamine hagedorn insulin in patients with type 2 diabetes. [2008] morning... INTERPRETATION: Nocturnal variations of EGP and Rd explain the reduced
Can extra protamine eliminate heparin rebound following cardiopulmonary bypass
surgery? [2004] loss... CONCLUSIONS: Postoperative protamine infusion was able to almost totally abolish
Effects of differing rates of protamine reversal of heparin anticoagulation. [1996] changes were more likely to accompany rapid versus slow protamine administration... CONCLUSIONS: Significant declines in systemic VO2 and hemodynamic perturbations
Protamine use during peripheral vascular surgery: a prospective randomized trial. [1995] routine heparin reversal with protamine... CONCLUSIONS: Although protamine effectively reverses heparin anticoagulation, its
Clinical Trials Related to Protamine
Cardiac Surgery: In Vivo Titration of Protamine [Completed]
Safe use of cardiopulmonary bypass (CPB) requires massive doses of intravenous
unfractionated heparin. At end-CPB, residual heparin is neutralized with intravenous
injection of protamine sulfate. This prospective, randomized, controlled study will be
conducted in 82 voluntary subjects admitted for elective, first intention, cardiac surgery
requiring cardiopulmonary bypass. Each will be randomly assigned to one of two groups. The
control group will be submitted to a standard protamine infusion of 1. 3mg :100U of the total
heparin dose given during bypass. The test group will receive an infusion of protamine (over
15 minutes) until activated clotting time (ACT) values (determined every 3 minutes) depict a
plateau, sign that the optimal protamine to heparin ratio has been attained. The
investigators hypothesize this new in vivo titration method to be as efficient as the
standard protocol (adequacy of heparin neutralization, % heparin rebound, bleeding, and
transfusion), and potentially safer by its ability to prevent protamine overdose and its
deleterious impact on platelet function. 15
Principal Objective
Evaluate a new in vivo method of titration of protamine sulfate.
Secondary Objective
Evaluate the impact of this method on the adequacy of heparin neutralization by measuring:
1. platelet count
2. postoperative bleeding
3. transfusion exposure a
4. incidence of heparin rebound
Clinical Trial Comparing Heparin and Protamine Fixed and Titrated Doses in Cardiac Surgery With Cardiopulmonary Bypass [Completed]
There are currently several schemes described for anticoagulation with heparin and its
reversal with protamine during cardiac surgery with CPB. The oldest, and most used in our
routine environment, is the scheme of fixed doses, in which a bolus dose of heparin at the
start of CPB is established in IU/kg of body weight and the dose of protamine at the end of
CPB is calculated based on the initial dose of heparin administered.
These schemes do not take into account the variability inter-patients and can result in
overdose or sub-doses of one or both drugs.
The titration schedule of doses of heparin and protamine through the principle of
dose-response curve of Bull promotes individualization of dosage according to the response
of each patient. This scheme has been associated with an effective reversal of the effect of
heparin after CPB and with reduction of post-operatory bleeding and transfusion.
The restoration of a state of anticoagulation by heparin after its reversal by protamine is
called "rebound effect". It is a phenomenon explained by the recirculation of heparin stored
in the reticulum-endothelial system and connective tissue, or by free residual concentration
of heparin after clearance of protamine. This effect may be present for more than 6 hours of
post-operatory and may contribute to increase post-operatory bleeding.
Protamine in Cardiac Surgery and Haemostasis [Completed]
Protamine is used after Cardiopulmonary Bypass (CPB) to reverse the anticoagulant effects of
heparin and restore coagulation. Convincing evidence from in-vitro and in-vivo studies
suggest that an overdose of protamine has anticoagulant effects which might lead to bleeding
complications. Heparin levels usually decrease during cardiac surgery with CPB. Therefore, a
protamine regimen based on the initial heparin dose before CPB might lead to overdose of
protamine. In contrast, a protamine regimen based on the actual heparin concentration may
avoid this condition. The investigators compare both regimens of protamine dosing in
patients undergoing complex surgery with CPB and assess its effect on the amount of
protamine given, markers of the coagulation system, utilization of blood products and
perioperative blood loss.
Comparing Angiomax to Heparin With Protamine Reversal in Patients OPCAB [Completed]
The purpose of this study is to examine the safety and efficacy of Angiomax as an
alternative anticoagulant to heparin with protamine reversal in patients undergoing off-pump
coronary artery bypass graft surgery.
Comparison of Two Basal Insulins for Patients With Type 2 Diabetes (IOOY) [Completed]
The purpose of this study is to examine the effectiveness and safety of insulin lispro
protamine suspension (ILPS) as compared to insulin detemir as basal insulin therapy in
adults with type 2 diabetes. A gatekeeper strategy will be employed for sequentially testing
the secondary objectives.
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Page last updated: 2013-02-10
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