Indications And Clinical Uses: Used in the treatment of thrombophlebitis, phlebothrombosis, and cerebral, coronary, and retinal vessel thrombosis to prevent extension of clots and thromboembolic phenomena. Also used prophylactically to prevent the occurrence of thromboembolism, and to prevent clotting during dialysis and other surgical procedures, particularly vascular surgery.
When using in conjuction with dialysis machines or where heparin is added to glucose or saline it is most important that the pH is not less than 5 for heparin to act as an effective anticoagulant. Under pH 5 degradation sets in and with a pH around 4 or less there is very little activity. Likewise, with pH over 8.5 there will be some degradation. Recent work has indicated that early hemodialysis is of value in cases of multiple trauma.
Heparin has also been used as an anticoagulant in blood transfusion samples, particularly when the presence of citrates, oxalates, or fluorides might interfere with laboratory tests, such as electrolyte determination. Anti-inflammatory and diuretic activity have been obtained with heparin. However, these properties have not yet been put to any widespread clinical use.
Low Dose S.C. Heparin: For the prevention of serious venous thromboembolic complications in high risk surgical patients.
Contra-Indications: Hemophilia and severe clotting disorders; severe liver damage; shock; hypersensitivity to heparin. Active bleeding from a local lesion such as an acute ulcer or ulcerating carcinoma. Recent neurosurgery or spinal surgery.
Manufacturers’ Warnings In Clinical States: Administration of large doses of heparin should be delayed 4 hours postoperatively.
When any of the conditions mentioned under precautions are present the advantages of heparin therapy must be carefully weighed against the possibility of deleterious results.
Precautions: Purpura, and other blood dyscrasias with bleeding tendencies; active ulcerative diseases of the gastrointestinal tract; jaundice; subacute bacterial endocarditis; increased capillary fragility; threatened abortion; postoperative disease, following brain or spinal cord surgery. Malignant hypertension.
Heparin should be used with caution in the immediate postoperative period. Bleeding may be concealed, as in the case of hemothorax.
Pregnancy: Heparin should be used with caution in pregnancy although it does not cross the placental barrier and is the safest and most useful form of therapy in thromboembolic disorders of pregnancy.
For these reasons strict laboratory control of dosage is necessary. Heparin should be used with caution in patients with allergy. Patients on long term daily administration should be observed for the possible development of osteoporosis and spontaneous fractures of ribs and/or vertebrae.
Care must be taken where large doses of antibiotics and/or drugs containing amino groups are administered along with or prior to heparin administration.
Drugs such as codeine phosphate, pethidine HCl, streptomycin, erythromycin, kanamycin, neomycin, novobiocin, tetracyclines, ampicillin, penicillin G, polymyxin B, vancomycin, hydrocortisone sodium succinate, pentobarbitone, promazine HCl, vitamin B complex and vitamin C may complex with heparin. This complex may be reversible (heparin rebound) and may result in excess bleeding at the surgical site. Extra protamine sulfate may then be indicated.
Please also refer to the pH requirements in hemodialysis under indications.
Heparin has not been reported to interact pharmacologically in vivo with any other drugs. An increased bleeding tendency may be seen when heparin is used in combination with ethacrynic acid, ASA and dextran. Although digitalis, quinine, tetracycline, antihistamines, and nicotine have been stated to interfere with the anticoagulant activity of heparin, there is no substantial literature support for such interactions. The chemical interaction occurring between heparin and protamine is well known. This interaction is used clinically to antagonize the anticoagulant effect of heparin.
I.V. administered ethacrynic acid can cause gastrointestinal bleeding. However, a significantly higher incidence of gastrointestinal bleeding has been attributed to the concurrent use of i.v. ethacrynic acid and heparin. Furosemide may be a safer alternative when such diuretic therapy is indicated in the patient receiving heparin.
In a review article of heparin therapy, it was advocated that concurrent ASA administration be scrupulously avoided. While documentation to support this interaction is incomplete, it would be prudent to avoid concurrent therapy. ASA impairs the platelet release reaction and this platelet function defect combined with the anti-coagulant effect of heparin may produce a hemorrhagic tendency.
Limited data suggest that dextran and heparin may act synergistically when administered concurrently. Although the data are inadequate to document the clinical significance of this interaction, baseline laboratory measurements of anticoagulant activity should be obtained upon initiation of concurrent therapy as well as at frequent intervals during such therapy.
Adverse Reactions: Hemorrhage is the chief complication which may result from heparin therapy (see Overdose).
Hypersensitivity reactions, such as fever, skin eruptions, naso-pharyngeal congestion, bronchial asthma, anaphylactic shock, and osteoporosis, have been reported in some patients following heparin injection. Alopecia, effecting the entire scalp or confined to the temple, has been reported; the mechanism is unknown. Thrombocytopenia has also been described with heparin treatment.
Symptoms And Treatment Of Overdose: Symptoms and Treatment: Bleeding which may occur during therapy with heparin can usually be corrected by withdrawal. Clotting time should then return to normal in 30 to 60 minutes provided venous clotting time is not longer than 15 minutes when the infusion is interrupted. Should withdrawal of heparin fail to control bleeding, fresh, matched blood (not more than 3 days old) may be administered in quantities of 250 to 500 mL.
The most rapid means of counteracting the effects of heparin is i.v. administration of protamine sulfate. However, protamine is by itself an anticoagulant and, therefore, excess must be avoided. The amount of heparin neutralized by protamine varies with the organ from which it is derived, method of manufacture and specific activity of heparin. The amount of protamine required to neutralize 1 000 units of each lot of heparin used in the preparation of Hepalean is therefore accurately determined and is stated on the label as the number of mg of protamine sulfate required to neutralize 1 000 units.
Allowance should be made for the rapid removal of heparin from circulation. The rate of heparin removal from plasma is dose-dependent. However, it may be assumed that about 30 minutes after an i.v. injection, about 50% of the heparin is removed from circulation.
So the amount of protamine sulfate required to neutralize the heparin will be approximately half of that required for the original dose. For example if 1 000 units required 8.4 mg of protamine sulfate for neutralization, half an hour after i.v. administration of a 5 000 unit dose, the amount of protamine sulfate required will only be approximately:
5/2´8.4=21 mg Do not administer more than 50 mg protamine sulfate at any one time.
Dosage And Administration: I.M. injection (especially in the arm or thigh) and shallow s.c. injection are not recommended. The duration of effect is shortened and it is more likely to produce pain and hematoma.
Heparin activity is expressed in USP units and should be prescribed in units only.
The route of administration may be i.v. or s.c., depending upon the situation and the choice of the prescriber (see Table I). Adequate heparin-induced anti-coagulant therapy is present when the clotting time is elevated from 2 to 3 times normal as measured by the Lee-White method. Two types of dosage schedule are suggested: heparin may be administered i.v. in a dose of 5 000 USP units every 4 hours or in a dose of 10 000 USP units every 6 hours, depending upon the results of a whole blood clotting time test performed at the bedside just prior to each additional dose. If the clotting time is less than twice normal, the next dose is increased by one-third to one-half. If the clotting time is more than 2 1/2 times normal, the next dose is decreased by one-third to one-half. If the clotting time is between 2 and 2 1/2 times normal, the regular dose is repeated.
S.C. Injection Technique: Use of a 1 mL tuberculin syringe with a No. 25 or No. 26, 1/2 inch needle is recommended.
Disinfect area with alcohol then apply pressure between finger and thumb to the dermal fold until the injection site is blanched; insert the needle into the raised, blanched area. Reduce the pressure on the skin and inject slowly; withdraw the needle quickly and apply alcohol swab with pressure to the site of injection for 5 to 10 seconds to prevent loss of the heparin.
Low Dose S.C. Heparin: There is now good evidence that low dose herapin is effective in preventing serious venous thromboembolic complications in high risk surgical patients. The usually recommended dose is 5 000 units s.c. 2 hours before surgery and then 5 000 units given either 12 hourly or 8 hourly after surgery with the first dose given at approximately 12 hours after surgery. It is not necessary to monitor low dose prophylactic heparin.
Therapeutic Anticoagulant Action (Immediate and Short-term): The dose should be adjusted in keeping with the patient’s clotting time which should be determined just prior to the injection during the first day of treatment. It is also recommended that, in order to help regulate dosage, the clotting time be determined on the second and third day of treatment. (The recommended method is the Lee-White whole blood method.)
Anticoagulation is adequate when the clotting time is 2 to 3 times the normal value.
S.C. administration is usually employed for maintenance therapy after initial regulation.
Long-term Protective Anticoagulant Action: S.C. administration of 15 000 units every 12 hours is usually employed. Daily injections of 20 000 to 30 000 units have also been employed with success. After initial regulation the dosage should be adjusted according to weekly to monthly clotting time determinations. Anticoagulant therapy should not be terminated abruptly but should be gradually reduced over 3 to 4 days.
Deep Venous Thrombosis and Pulmonary Emoblism: Dosage of 20 000 units daily for 6 to 10 days has been of value.
Hemodialysis: (a) Multiple trauma: Recent literature has suggested the use of early hemodialysis in multiple trauma. (b) Chronic renal failure: The use of hemodialysis in this area has increased dramatically in recent years and may be in hospital or home dialysis.
It is most important to stress that the instructions for each equipment manufacturer’s unit must be followed scrupulously.
The following is merely intended as an overall summary of possible general procedures: 3 000 units of heparin is added to 1 000 mL of sterile saline as a dialyser flush prior to connection. Initial dosage: 5 000 units of heparin into the venous shunt or 2 500 units into the arterial fistula needle. With the shunt type the usual continuing dosage is 2 000 units per hour, with the fistula type, 1 500 units per hour by means of a suitable syringe and a pump to allow continuing infusion. Heparin reversal with protamine will be decided by the individual physician. Usually this is not done unless dialysis is being performed soon after surgery.
Coronary and Vascular Surgery: Patients undergoing total body perfusion for open heart surgery should receive an initial dose of not less than 150 units of heparin/kg. Frequently a dose of 300 units of heparin/kg is used for procedures estimated to last less than 60 minutes; or 400 units/kg for those estimated to last longer than 60 minutes.
Availability And Storage: Aqueous solutions, containing 1.0% benzyl alcohol as preservative, color coded labels: 1 000 USP units/mL in 10 or 30 mL vials; 10 000 USP units/mL in 5 mL vials; 25 000 USP units/mL in 2 mL vials. Cartons of 10 (2, 5, 10 and 30 mL).
Aqueous solution without preservative: 1 000 USP units/mL in 1 mL vial and 10 000 USP units/mL in 1 mL vial. Cartons of 100 (1 mL).
Source: Porcine intestinal mucosa.
HEPALEAN® Organon Teknika Heparin Sodium Anticoagulant