Protocol for Heparin Therapy of Burns ©
Original Method of Michael J. Saliba, Jr., MD
INTRODUCTION AND SCIENTIFIC RATIONALE
Burns are painful, coagulation-prone, blood-deficient, cellular-destructive thermal maladies that are difficult to treat, slow to heal, and usually have residual scars and contractures. The use of heparin according to this protocol has therapeutically altered the pathology of burns. Heparin maintained blood circulation, relieved burn pain, blanched erythema, reduced swelling, stopped cellular destruction; restored blood to deficient areas, enhanced healing, and resulted in smooth skin usually void of scars or contractures. Heparin’s multiple effects and mechanisms were evident:
1. Anticoagulative;
2. Antiinflammatory;
3. Neoangiogenic;
4. Tissue Restorative;
5. Collagen Regulating; and
6. Reepithelializing, through effects on
7. Dermal fibroblasts and
8. Smooth muscle cells.
The regression in burn pathology, progressive healing, and normal laboratory tests were indicators that the treatment methods and heparin doses were adequate. Moreover, use of this protocol reduced medical and surgical procedures, fluids, blood transfusions, hospital stay, and costs. This protocol, with minor variations, has been successfully used by doctors in the treatment of burned patients in the USA, India, Russia, China, Bulgaria, El Salvador, Brazil, Mexico, Haiti, Oman, South Korea, Nepal, Italy, Paraguay, Belgium, Peru, Chile, South Africa.
Sodium Aqueous Heparin Solution, USP for Injection, from porcine intestinal mucosa source, is the heparin recommended for use in human burn injuries. Standard commercial solutions of heparin can be obtained in multiple dose or single dose vials of 5000 IU/ml, 10,000 IU/ml, 20,000 IU/ml and 40,000 IU/ml. One milligram (1 mg) is equal to 100 International Units (IU). Sodium Aqueous Heparin Solution, USP, from animal lung tissue source produces acceptable, perhaps less effective, therapy for burns. Comparing the two heparins, porcine intestinal source heparin was less anti-coagulating, mg per mg, and significantly more effective than beef lung source heparin in preventing cellular destruction of ischemic tissue. The incidence of thrombocytopenia was favorably lower with the use of intestinal source heparin than with the use of lung source heparin.
ROUTES OF ADMINISTRATION AND FACTORS DETERMINING HEPARIN'S EFFECTS
The heparin is administered: (1.) Parenterally, infused intravenously, or injected subcutaneously into normal fat; (2.) Topically onto burn surfaces and into blisters, and; (3.) By inhalation. Heparin solution is never injected directly into burned tissue or below burned tissue. The 5000 IU/ml heparin solution is used for topical, inhalation, and intravenous administration. Higher concentrations are used for subcutaneous injection.
Heparin’s therapeutic effects in burns are related to, and have been dependent on:
•The time the treatment is started, at the earliest possible time;
•The dose and duration of heparin use, adequately large and sufficiently long;
•The site of the burns, with inhalation use for pulmonary involvement;
•The route of heparin administration, parenteral, topical and inhalation;
•The tissue and blood pH, with intravenous use early at acid pHs;
•The condition of the healing; progressive with diminishing doses;
•The laboratory tests, especially blood coagulation times, CBC, and urinalysis.
INITIAL CARE OF THE BURNED PATIENT
When the patient is seen on postburn Day 1, initiate standard burn therapy: establish a clear airway and intravenous lines, take blood for laboratory tests and a blood coagulation panel, obtain vital signs, insert an urinary catheter if necessary and do an urinalysis, take a brief history, perform a quick physical examination, evaluate the burn and its size, determine the patient’s lean body weight, and determine if heparin use is contraindicated. If heparin use is not contraindicated, begin topical and parenteral administration of heparin as soon as possible. First, relieve burn surface pain using heparin administered topically.
CONTRAINDICATIONS TO THE USE OF HEPARIN
The principal danger in the use of heparin is the potential to have bleeding if there is an open blood vessel. Heparin should not be administered to burned patients who also have trauma with active bleeding, a personal or a familial history of bleeding, an active peptic ulcer, a thrombocytopenia, or an allergy to heparin. Also, heparin is never injected into or below burned tissue, as such use could result in local bleeding.
USE AND PRECAUTIONS WITH HEPARIN ADMINISTRATION
Heparin can be administrated topically, parenterally, and by inhalation, starting promptly postburn or later. There are techniques and precautions to observe:
INTRAVENOUS Do not infuse large doses of heparin intravenously into burned patients if the heparin treatment is started 3 or more days postburn. In blood deficient burned tissue, there is characteristically a tissue acidosis present post-burn Day 1 to Day 3, and the tissue pH is in the acid range. In an acidosis, heparin has anti-inflammatory effects: combining, neutralizing, and inactivating most of the mediators of burn inflammation. These beneficial combination-neutralization-inactivation effects of heparin-with-mediators-of-inflammation are progressively reversed when the pH rises into the neutral or alkaline pH range. At neutral or in alkaline pHs, the mediators of inflammation are released and active, and the heparin is released and available to prevent the clotting of blood, so the potential for bleeding is increased.
SUBCUTANEOUS use of heparin can be started promptly postburn before heparin is used intravenously or, later, after intravenous use is stopped. Heparin is injected into fat once or twice a day in progressively diminishing doses that increase once daily blood clotting times to 2-3 times normal control times. Subcutaneous doses are progressively reduced as healing progresses, and subcutaneous heparin use is stopped the day coagulation times suddenly increase beyond 5 times normal blood coagulation time.
TOPICAL Heparin administration can be started and used at any stage in the course of treating a burn and it can be continued in diminishing amounts into final healing. Topical doses are progressively reduced as healing progresses. Topical dose is further reduced in highly vascular granulation tissue and in epithelializing areas that show a tendency to bleed if slightly traumatized. Topical Heparin use is discontinued in areas that bleed and when epithelialization is complete. Monitoring with coagulation times is not necessary because the administration of heparin topically on burn surfaces and into blisters does not increase systemic blood clotting times.
SUMMARY OF PROTOCOL PRECAUTIONS WITH HEPARIN USE
1. Do not administer heparin in burned patients who have contraindications to heparin use.
2. Do not use large doses of heparin intravenously after post-burn Day 3.
3. Subcutaneous injections into fat can be started postburn or within 1-2 weeks later and continued once or twice daily in diminishing amounts, using monitoring of coagulation times that are maintained at 2 to 4 times normal coagulation time. Subcutaneous use of heparin is discontinued when coagulations times exceed 5 times normal blood coagulation time.
4. Topical application of heparin in blisters is complete in 2 days. Topical use on burn surfaces can be started at any time and continued in diminishing amounts into the final healing.
5. Never inject heparin into or below burned tissue, as this could result in deep or superficial bleeding at the injection sites.
6.Stop parenteral use of heparin 24 to 36 hours before surgical procedures. Escarotomies and fasciotomies are exceptions but are usually not needed.
CLINICAL AND LABORATORY INDICATORS OF ADEQUATE AND SAFE DOSES OF HEPARIN
1. Relief, regression, abatement, and elimination of burn pathology signs and symptoms;
2. Progressive signs and symptoms of enhanced healing;
3. Appearance of heparin effects that accompany healing:
a. Inflammation is stopped — there is minimal or no pain, swelling, redness, active tissue destruction and the burned areas become smaller and drier;
b. Neoangiogenesis restores blood flow to burned ischemic areas;
c. Granulation tissue deposition and healing are accelerated; and
d. The new skin is smooth without scars and contractures.
4. Laboratory tests that are within normal safe values, notably coagulation times.
PREPARATION OF THE HEPARIN FOR TOPICAL USE
In a 5 or 10 ml syringe, place 2 to 8 milliliters of the 5000 IU/ml heparin solution taken from a 10 ml multiple dose vial containing 5000 IU/ml solution, and place a #30 gauge needle on the syringe. Or dilute the higher concentrations of heparin to 5000 IU/ml solution - To 1 ml of the 10,000, 20,000, or 40,000 IU/ml heparin solution, add 1, 3, or 7 ml of sterile water or physiological saline, and place a #30 gauge needle on the 5 or 10 ml syringe. To double the volume use a 20 ml syringe and double the components.
Precaution - to avoid excessive dilution of the heparin by the water: In preparing the dilution, always leave an airspace between the undiluted heparin in the syringe and the needle on the syringe which is inserted into the inverted water bottle above. While drawing the water down into the syringe, maintain an airspace, in order to prevent the spontaneous mixing and dilution of the heparin by the water in the bottle, which would result in a much lower than desired 5000 IU/ml concentration dilution of the heparin. After you have loaded the syringe, remove the #22-25 gauge needle and replace it with a #30 gauge needle.
TOPICAL HEPARIN TREATMENT METHOD FOR BURN SURFACES
Using the 5000 IU/ml heparin solution in the syringe, drip it onto the burn surface until
the entire burn surface is covered. Continue to drip heparin on the burn surface until the pain is relieved (usually in 1-2 minutes) and for a several minutes more. Then wait 5-10 minutes and repeat. Complete this cycle three to five times. In addition to relieving the pain, there will be a blanching of the initial burn erythema, if it was present. The pain usually will not return, or the pain will return in reduced amount and that pain will again be relieved by a lesser quantity of heparin solution. Total relief of pain and blanching of erythema, when present, are good indicators of an adequate initial topical heparin dose.
Repeat the topical treatment of burn surfaces twice more on Day 1, for a total of 3 treatments. Burn Day 1 total topical heparin dose is approximately 100,000 IU per 15% body surface area (BSA) burn size in three divided doses. Most of the heparin dose (perhaps 60 — 75 %) is used in the first application.
On Day 2 and beyond, administer the treatment twice (or for a few days 3 times) a day, using a diminishing quantity of heparin solution into final healing. The amount of heparin solution used topically daily is rapidly decreased as the burns heal until only a few drops are used in the final healing phase. Signs of healing will be evident. On Day 2, the burn surface will be smaller in size, drier, have minimal or no pain or swelling or erythema, and early revascularization may be observed in a few areas. Within a few days richly vascular granulation tissue will replace the burned tissue and mature until the burned areas are filled in up to the normal surface level. Then a thin (one cell thick) layer of epithelium (like shinny cellophane) will be seen spreading over the granulation tissue, from epithelial islands within the granulation tissue and from the periphery. The thin layer will mature into full thickness normal skin within 10-12 days. The resultant skin will be comfortable and smooth and, as a rule, void of scars and contractures. A surface itching sensation may be present for a limited time. The new skin may have variations in color because burn depth and repigmentation will be variable. The cosmetic results have been consistently and acceptably pleasant. Many onerous features of burn care are eliminated.
Patients with burns less than 10% of BSA size whom the therapist initially treats and then sends home Day 1, or later, can be given a syringe with a #30 gauge needle attached, containing 4 or 8 mls of 5000 IU/ml heparin solution for topical administration at home, two times more the first day and once the next day before returning to the burn therapist.
The treated burns may be covered with dry sterile non-adhering bandages, such as "telfa," taped to each other and to the normal skin at the burn edges, and sometimes a single layer of gauze may be loosely placed around the bandages. Dressings that stick to the burn surface should be removed using sterile water applied on top of the dressings in order to loosen the bandage so bandages may be removed without disturbing the healing. Later, when healing has progressed into the early reepithelializing stage, the burns may remain uncovered.
The topical use on burn surfaces and in blisters of heparin alone provide good therapy for burns that are less than 10% BSA size, and for small burns in children, when parenteral use of heparin is not practical. Topical use alone may provide good therapy for burned patients when heparin treatment is not started until a considerable number of days after the burn injury occurred.
TOPICAL BURN BLISTER TREATMENT USING HEPARIN
Using the #30 gauge needle on a syringe filled with 5000 IU/ml heparin solution, insert the needle into the blister and make a small hole that allows the burn fluid to drain. Then slowly insert heparin solution from the syringe into the blister. After the blister is filled and the solution begins to run out, continue injecting heparin solution. This creates a rinsing action. Fill up and rinse out the blister approximately 3 times. Repeat this cycle two to three times at 5 to 10 minute intervals. Leave heparin solution within the blister before you remove the needle for the final time. The pain in the blisters will be promptly relieved. The pain usually does not return, or the pain returns in much reduced amount, accompanied by a partial refilling of the blister with blister fluid. The pain can again be relieved by topical treatment with a smaller quantity of heparin. With heparin use, no narcotics are used, narcotic complications and addiction are eliminated, and burn patients are awake, alert, cheerful, and cooperate in their care. Many onerous features of burn care are eliminated.
Do not remove or debride the blisters. The collapsed blister functions as a natural skin graft. The blister rarely becomes infected. Healing progresses within and below the blister and no additional care is required. New smooth scar-free skin is evident when the very thin dried blister finally flakes off the surface.
Topical antibiotic ointments and creams are not routinely used nor have they been routinely needed with this protocol. Penicillin VK or erythromycin are the antibiotics routinely administered by the oral route if needed. Infection of the burns is less common with heparin use. Restoration of blood flow to the burn areas through heparin-mediated neoangiogenesis is one plausible reason. The heparin-induced neoangiogenesis with delivery by blood of the orally administered antibiotic to the burn site is another plausable mechanism. Heparin-mediated reduction in bacterial translocation from the intestinal tract with a reduction in sepsis and infection of the burn from within the body are collectively another plausible explanation and mechanisms.
Heparin use has simplified burn care by eliminating the need for daily baths to remove topical antibiotic creams, debridements of the burned tissue, and bandage changes. These improvements in care have reduced work and stress of patients, nurses, ancillary therapists, and doctors.
VARIATIONS IN TOPICAL TREATMENT
Dr. D.J. Mangus and coworkers in Northern California have used this protocol with the following two deviations: Infected skin areas were treated with an aqueous solution of culture-sensitive specific single antibiotic mixed with the 5000 IU/ml topical heparin solution and applied topically twice daily until the infection was eliminated. Follow-up cultures showed this treatment eliminated the bacterial pathogens and restricted bacterial growths to essential normal flora. For the few patients with proven sepsis, the culture-sensitive antibiotic was mixed with the parenteral heparin dose and administered by infusion twice daily at 12-hour intervals. Dr.Mangus treated patients with fungal infection with amphoteracin B solution mixed with the 5000 IU/ml heparin solution administered topically and parenterally. He obtained very favorable results in burned patients, ages 15 to 85, with deep 2nd and 3rd degree burns of 20% to 80% BSA size. Since heparin and the antibiotic were mixed and administered together, no statement could be made regarding the degree each agent contributed to the results.
Dr. K. M. Ramakrishnan and coworkers in India use this protocol with two variations: A larger volume of a lesser concentration of heparin solution is sometimes used topically, and antibiotics are routinely used topically on all burn patients, because the hot humid weather conditions in India warrant such use.
PARENTERAL USE OF HEPARIN IN THE TREATMENT OF BURNS
There is a formula to calculate the approximate Day 1 total heparin dose parenterally administered subcutaneously and intravenously: In general, give 400 IU of heparin, multiplied by the ideal lean body weight in kilograms, multiplied by the percent of severe (2nd and 3rd degree) burn size, divided by 15. Approximately 40% of this total dose is administered as an initial subcutaneous injection. The remainder is infused within the first 24 hours. Thus, a burned person of 70 kg lean weight with a 15% size (deep 2nd and 3rd degree) burn would be given: 400 (IU) x 70 (kg) x 15 (burn size %) divided by 15 which is a total of 28,000 IU of heparin administered parenterally postburn Day 1. The initial subcutaneous dose would be 28,000 x .40 or about 11,000 IU (roughly 10,000 IU). The total infused heparin day 1 dose would be roughly 18,000 IU in divided doses. Thus, a burned person of 60 kg ideal weight with a 24% size severe burn would be given: 400 (IU) x 60 (kg) x 24 (burn size) divided by 15 which is a total of about 38,000 IU of heparin, with the initial subcutaneous dose being about 15,000 IU, and the infused Day 1 dose would be roughly 23,000 IU.
Scald, hot water or steam burns are known to be less severe than burns caused by fire and smoke, with or without an initial explosion. Interestingly, the dose for scald type and fire type burns is the same for burns that are up to 15% size. Above 15% size, however, the fire type burns require the use of much more heparin than the scald type burns. In general, for scald type burns that are 2, 3, 4 or 5 times as large as 15% of body surface size (30%, 45%, 60% or 75% size), the total Day 1 heparin parenteral dose is merely 2, 3, 4 or 5 times as large, and the required dose of heparin is a simple mathematical progression. For example: a 70 kg person with a 60% size severe burn would require 400 IU x 70 (Kg) x 4 (60 divided by 15) or a total 112,000 IU of parenterally administered heparin Day 1.
However, the dose of heparin usually required for explosion, fire, and smoke burns is usually the square of the 15% size, up to 45% burn size, plus an additional amount of heparin that is 28,000 IU for every 15% increase in burn size above the 45% burn size. Thus, the 70 kg person with a 60% size severe explosion-fire-smoke burn could require 400 IU x 70 (kg) x 9 (3 squared or 9 for 45% size) plus 28,000 IU for one 15% size more than 45% size which equals a total parenteral Day 1 dose of 280,000 IU of heparin. The subcutaneous dose would be roughly 100,000 IU (2.5 ml of the 40,000 IU/ml) and the total infused doses at 4 hour intervals would approach 180,000 IU, of which perhaps 80,000 IU would be used with the first infusion to control the burn pain and blanch the burn erythema, if it were present. It is wise not to overtreat with heparin administered parenterally by intravenous infusion.
On postburn Day 1, admininister the calculated subcutaneous initial heparin dose using a #30 needle and a variable amount of the 20,000 IU/ml or 40,000 IU/ml heparin solution. This injection is into normal fat at a non-burned site. This will be the only subcutaneous injection of heparin the first day. After the injection, wait a few minutes to determine that there is no bleeding at the injection site.
Next, administer heparin parenterally by slow bolus infusion of the 5000 IU/ml solution using 5000 IU or more at a time through an intravenous line. Continue the heparin infusion until the deep burn pain is relieved and the initial burn erythema, if it is present, is blanched. The amount of heparin needed will vary. Relief of pain and blanching of burn erythema are good indicators of an adequate initial heparin dose. Day 1, evaluate the patient and the burn every 4 hours and treat with variable diminishing amounts of heparin as indicated. If pain, swelling or edema, or burn erythema are present, infuse more heparin in 5000 ml doses again. Relief of pain and other factors determine the dose. Beyond Day 1, evaluate at least every 8 hours and retreat as needed. Adequate dose are evident in clinical improvement and are accompanied by blood coagulation times that are normal or only 2-3 times longer than normal. When in doubt, to be safe, determine the laboratory coagulation time before administering the next parenteral dose. If the burn is clinically improved and if coagulation is elevated into the 3-4 times normal range, decrease the next dose given parenterally. Continue to decrease the dose. When coagulation times exceed 5 times normal, discontinue parenteral heparin administration.
After post burn day 3, discontinue infusions and use subcutaneous heparin once or twice a day, in a dose that maintains blood coagulation time at 2-3 times normal values. Subcutaneously administered doses are decreased as the burn progressively heals, and subcutaneous injections are discontinued when blood coagulation times, taken before the daily morning dose, increase to more then 5 times normal. Then only use heparin applied topically into final healing.
At 24 hours after starting treatment, the burn should be smaller in size by measurement, drier, and pain-free, with minimal local or general swelling or edema. There may be evidence of early revascularization. The amount of resuscitation fluid needed will be significantly less than the calculated need. There should be less or no need for surgical incisions, escarotomies and fasciectomies, or grafts. Hence little or no blood should be lost in surgery, and blood transfusions should not be needed.
No pain medicine, especially no narcotics such as morphine, dilaudid, demerol, or codeine has been needed when heparin is used. Heparin alone is all the pain medication that was required. Hence, there are no narcotic complications: no depressed respiration, no immobilized GI tract, no suppressed awareness, and no danger of addiction. Patients remain alert, active and cooperative in their care.
INHALATION TREATMENT WITH HEPARIN
Heparin solution in 5000 IU/ml concentration, using 1 or 2 ml of heparin can be placed in Intermittent Positive Pressure (IPPB) Respiratory Inhalation Machines and aerosolized and inhaled at four hour intervals, alternating every 2 hours with N-acetylcystine delivered by the IPPB machines. Large amount of heparin are used.
OTHER USES FOR HEPARIN AND HEPARIN-LIKE MEDICINES IN BURNS
•Heparin administered in minidose amounts injected subcutaneously is used to limit thromboses, thrombophebitis, and emboli;
•Heparin used in larger dose for infarctions including pulmonary emboli infarctions, in which heparin is the medicine of choice;
•Heparin used in large doses is used for disseminated intra-vascular coagulopathy syndrome, DIC. These uses of heparin are accepted medical practice.
•Sulcralfate is recommended orally three times daily for seriously burned patients. It has been used and there is evidence that it is useful in preventing and treating ulcers and in reducing gastrointestinal bleeding. The chemical formula of sulcralfate is so similar to heparin that it is essentially a semi-solid heparin;
•Dextran 70 or 110 solutions are ideal resuscitation fluids. Dextran is chemically a heparinoid, a synthetic heparin;
•If serious bleeding occurs with large doses of heparin, the heparin can be neutralized with Protamine Sulfate. 1 mg of protamine neutralizes 100 IU of heparin.
HEPARIN USE IN BURNS REDUCES PROCEDURES AND COSTS
Use of heparin reduces procedures and time in the hospital. The costs to treat burns with heparin added is often a tenth or less of the costs when heparin is not used.
Using only Sodium Aqueous Heparin Solution USP for injection (from porcine intestinal mucosa source), variable size syringes and needles, dry sterile non-adhering bandages, and tape, many simultaneously burned civilian individuals or military casualties could be efficiently and effectively treated at a thermal disaster site, or in isolated places, remote to medical facilities. The use of Heparin would promptly relieve the burn pain and there would be no need for narcotics, hence complications of narcotics would be avoided. Additionally, Heparin would initiate burn therapy, reduce morbidity and mortality, remove the chaos of the situation, and burned individuals would retain some capacity to perform critical military functions. The costs would be insignificant and the savings huge, especially if Heparin therapy was continued. Healing would be enhanced, and the new skin would be smooth and essentially void of scars and contractures.
