Burn Studies Using Heparin In Small Doses Only Inside the Burned Subjects’ Body 1941-1960

In 1941, Rigdon and Wilson found Sodium Aqueous Heparin Solution USP (heparin) had no ill effects on capillary permeability, inflammation, localization of leucocytes, or phagocytosis of staphylococci by leucocytes. Then studies of heparin administered parenterally in anti-coagulating doses produced significant favorable alteration in thermal burns in dogs, rabbits, and rats when tested by , McCleery et al,Parsons et al,Elrod et al, Brooks et al and Artz and Green. Compared with Controls, they found heparin: Maintained and Increased blood flow subjacent to the burn in 1.5 to 2 days in Heparin versus 5 to 7 days in Controls; Enhanced the speed and effectiveness of repair mechanisms in 5 days with Heparin to levels that required 9 days in Controls; reduced edema and onset of dry gangrene 2 days; Diminished tissue loss 12%; Improved renal function measured by BUN and Urinary volume; Increased intestinal blood flow; Healed burns up to 12 days sooner with Heparin versus Control; and Doubled survival time from 34.6 hours in Controls, compared to 72.2 hours in Heparin; All without harmful effects of Heparin compared with Controls.^2-7

These results in animals appeared in similar amount in 7 burned humans treated with similar anti-coagulating doses of heparin administered parenterally by Green and Artz.⁷

“Clinically, without Controls, the 7 patients treated with heparin seemed improved. The general appearance, color, sensorium, and sense of well-being seemed better. The urinary output was increased. No untoward side effects were noticed.”

In 1959, American Drs. Curtis Artz, MD, FACS and Byron Green MD, FACS injected small doses of heparin in the body of 7 burned humans and reported minimal benefits:

In 1963, Dr. Michael Saliba added large doses of heparin both on burn surfaces and within the body and produced major benefits.

Keller found in mast cells that histamine, serotonin, and proteolytic enzymes were combined with and neutralized by heparin at acidic pHs.⁸1 mg of histamine was combined with and inactivated by 400 IU of heparin. 1 mg of serotonin was combined with and inactivated by 1500 IU of heparin. No quantities were reported for proteolytic enzymes with heparin combinations. The combination-neutralizations at acidic pHs were reversed as the pH increased to neutral pH or into alkaline pHs, where at those pHs there was no combination-inactivation. Then, Dougherty and Dolewitz found heparin had strong antihistamine and anti-serotonin effects. They reported studies^9-10that found heparin produced therapy in life-threatening allergic reactions and the chronic weeping cellular-destructive inflammation of several skin diseases. The studies ^8-11and, a review of prior studies^1-7renewed research interest of heparin in burns. In theory, burns had pathology for which heparin potentially might provide therapy. The basis for the rationale was the research evidence that: Heparin had strong effects on 3 mediators of inflammation;^8-10Heparin had anti-sludging effect on blood which maintained blood circulation;⁶Heparin was the medicine of choice to prevent blood-clotting and to provide therapy for the multiple complications of blood clotting, namely emboli, infarctions, and DIC Syndrome; and, the pathology of burns involved all of those features.¹¹ New studies were initiated by Saliba^12,13and Saliba and Coworkers.^14-17

Clinical Studies in Burned Humans of Heparin Administered On Burn Surfaces and In Blisters (topical use) and also inside the body, infused by Vein and Deposited Into Fat Below Normal skin (parenteral or systemic use). And, Experiments in Burned Animals Using Larger Doses of Heparin Administered Only Parenterally, 1963 -1974.

Burn studies using Heparin in larger doses inside the body and on burn surfaces and in blisters 1963-present

Starting in 1963, the American Dr. MJ Saliba conceived and tested the hypothesis that larger than anti-coagulating doses of heparin administered both topically and parenterally should be effective in treating burned humans, because the pathology involved more than coagulating aspects, and the burns were directly accessible on the burn surface outside of the body, and indirectly accessible from inside the burned person’s body. The first studies published in the United States by Saliba without controls^12,13and the later ones with coworkers^14-17with controls^14,17and without controls^15,16reported good clinical results, and uncovered multiple additional heparin properties and effects. The heparin was added prior to any burn-related surgery.

Dr. Saliba reported the multiple beneficial effects of heparin from initial relief of pain, through the shortened enhanced healing with adequately restored tissues, into the final smooth skin consistently void of scars and contractures that resulted from continued topical administration of heparin in diminishing doses. There were no deaths.

Dr. Saliba then presented the studies, and worked as a heparin therapy consultant and coauthor in new studies with burn specialists in other countries. Dr. Saliba reported multiple beneficial heparin effects in addition to the anticoagulating - namely therapeutic antiinflammatory, neoangiogenic revascularizing, tissue restoring and regulating, and epithelializing effects. He was the first to describe neoangiogensis in ischemic tissues produced with heparin use; and the first to report the consistent smooth new skin usually void of scars and contracture that results with continued use of topically applied heparin in diminishing doses into final healing. Some heparin mechanisms were not initially stated because they were not known. In later burn and non-burn studies, researchers uncovered and documented the mechanisms by which heparin produced the effects. Saliba and coworkers treated over 1100 children and adults, from ages under 1 year to over age 82 years. He founded the Saliba Burns, Wounds, and Skin Problems Institute and the Saliba Burns Institute (SBI) Division.

Dr. Saliba worked with associated doctors in multiple burn centers in several dozen countries. Up to 2009, the benefits of adding heparin were documented in over 32,500 seriously burned patients in countries worldwide. The studies were reported in burn journals and presented in international burn meetings, conferences, symposiums and congresses. Doctors in various countries reported reduced costs of 50-90% in patients treated with heparin prior-to-surgery, compared to the previous costs in similarly burned and treated patient without heparin.

Saliba stated: "Heparin consistently relieves burn pain and other signs of inflammation. No pain medicines are needed and none, worldwide, have been used as a rule. Initial burn size is usually maximum size and thereafter the size and severity decreases. Fluid resuscitation needs are reduced to a half of usually. With the minimal swelling and reduced edema, escarotomy and fasciotomy incisions to relieve pressure in tissues are rarely needed. Blood loss is nil. Transfusions are uncommon. Revascularization and restored blood flow are regular features. Enhanced healing in approximately one-third usual time with smooth skin void of scars and contractures is the common result. With heparin added, medical and surgical procedures are reduced and simplified. The pathophysiology of thermal burn injuries involves:

(4) delayed and deficient restoration of collagen, smooth muscle cells, and dermal cells in the burn granulation tissue that results in

(5) delayed and imperfect production and regulation in the epithelialization phase of new skin cells that results in new skin often marred by scars and contractures.

Heparin is precise therapy for these pathological features of burns. Heparin's multiple therapeutic effects precisely matched and favorably altered, stopped, reversed, corrected the multiple pathological features of burn. The documented multiple therapeutic heparin effects are:

(4) Collagen, smooth muscle cell and dermal cell tissue restoring and regulating; and,

Heparin use first, when not contraindicated, is compatible with other therapeutic treatments, including surgery. The surgery is slightly delayed, in lesser quantity, under more favorable conditions that improve results, including more successful skin grafts. Use of heparin results in many benefits to the patient, doctors, nurses, ancillary therapists, and relatives, in a humane manner at greatly reduced costs which have been affordable in countries worldwide, including the economically underdeveloped ones.

Heparin is ideal for use in a single burned person or in the many persons simultaneously burned in the thermal disasters that are now commonly occurring in Peace, War, and Acts of Terrorism. Heparin sprayed on the burn surfaces and placed in blisters would promptly relieve the pain and initiate therapy at the site of a thermal disaster, as an emergency cost-effective treatment, for which there currently is no other suitable and workable therapy.”

Dr. John Kruggel MD, FACS, U.S. Plastic Surgeon. Earliest Coworker with Dr. Saliba of burned patients in hospitals in San Diego. A coauthor: Saliba, Dempsey, Kruggel JL “Large burns in humans: treatment with heparin. JAMA, 1973; 225:261-269. Dr. Kruggel treated half or more of the seriously burned patients in San Diego area using heparin until University of California San Diego (UCSD) Burn Center was opened.

“When I started my practice, I treated burns because they were within the realm of Plastic Surgery. Burn treatment then was difficult, unpleasant, and infection was a primary cause of death. 1/2 % Silver Nitrate Solution was used then to control infection. Silver nitrate produced good control of surface infection, but the staining ruined many hospital rooms, requiring room painting and new floor recovering. Next, Sulfamyalon treatment was used, which gave good control of burn site infection without staining, but caused severe ‘burning’ pain sensation in patients. Next, Silver sulfadiazine became the agent used to control infection, a use which continued for many years.

We still were in need of other modalities to limit other effects of burns. These included: Tissue swelling (edema), pain, histamine released in injured tissue causing further injury beyond the initial burn margins, and the blood clotting (thrombosis) in marginal areas of the burn. At this time Tangential Burn Surgical Excision was taking place which required removal of the burn tissue with much blood loss, and (it) created a site requiring early skin grafting. General anesthesia was needed for the painful multiple Tangential Excisions. The blood loss necessitated blood transfusions. The necessary skin graftings were problems.

In 1970, I attended a presentation at Sharp Memorial Hospital by Dr. Saliba on the uses of heparin in burn therapy. This gave me new pieces of burn treatment armament. I and Dr. Saliba treated burns at Sharp and Mercy Hospitals and presented and published our study results.

I observed the same treatment effects and results stated by Dr Saliba in his account of our work. Heparin seemed to solve some of the problems of platelet aggregation (slow blood flow), pain, swelling (edema), wound propagation and small vessel blood clots (thrombosis). Using heparin the care of major burns greater than 30% size with deep second and third degree severity became more manageable and there was less patient distress. Use of sulfa base creams and routine water baths were discontinued. Narcotic pain medicines were not needed. It was encouraging to observe reepithelialization (new skin formation) occurring on deep second and third degree burns. The size of the burn sites I grafted were decreased using heparin. The number of skin grafts performed decreased. From seeing a large number of deep second and third degree burns that were epithelializing (covered with new skin) made me feel that there was a stimulus from the heparin to create epithelial (skin) cells.

In retrospect and in light of all of the recent research on Stem Cells, abundant in adipose tissue, I think that research related to heparin stimulation of stem cells may be indicated.”

Dr. Donald J. Mangus, MD FACS Plastic Surgeon,Founder-Director of Chico CA Community Hospital Burn Center,

Dr. Mangus utilized Heparin Protocol in treating more than 250 patients. Worked with 4 MDs. in 2 hospitals and clinics. Gave heparin topically and by vein twice daily. For infections he mixed aqueous solutions. of culture-specific antibiotics with heparin placed on burns and into a vein twice a day. Which avoided use of messy and painful sulfa-based topical antibacterial creams; and made treated water baths with antimicrobials unnecessary. Benefits were similar to Drs Saliba and Kruggel's published study of 52 patients with large severe 2nd and 3rd degree burns. Dr. Mangus presented studies at Heparin in Burns Int’l Meeting, Feb. 1994, in San Diego, USA; and in 1st Russian American Burn Meeting, June 1997 in St. Petersburg and in Moscow, Russia. Heparin improved burn care, reduced mortality and procedures and enabled care of larger burns. With heparin days in hospital and costs were reduced 40%. Patients had few scars and contractures. "Heparin is a very effective burn medication. It frequently converted deep 2nd & 3rd degree burns into superficial 2nd degree severity burns, most of which healed with smooth new skin without skin grafting. I believe it is poor judgement not to consider the use of heparin topically and parenterally for its healing effects in the early treatment of burns and improved very good cosmetic and functional results in the last healing phase.”

“The heparin-treated patients were the most comfortable ones I ever treated. Every burn specialist should use heparin added to their burn treatment. I do not understand why my colleagues in the United States have not utilized heparin, where appropriate, when the benefits are so obvious and the results are so good.”

Dr. Daniel L. Traber PhD, Director of Research Studies, Shrine Burn Hospital for Crippled Children, Galveston, Texas.

Dr. DL Traber was an author on hundreds of medical studies of burned children and controlled studies of burned animals. His RN wife Lillian D. Traber was the Director of the Laboratory at the Galveston Shrine Burned Childrens Hospital. The Traber’s worked with medical researchers from within the United States and Foreign Countries who rotated through that Hospital for several decades. Their many studies were funded by grants from the Shriner’s Crippled Children Foundation Trust Fund for research and also funds from the National Institute of Health. Similar burn research studies were performed in the other 3 Shrine Burn Hospital for Children in Cincinnati, Boston, and Sacramento. The studies were published in prominent Journals and presented in the American Burn Association and International Society for Burn Injuries Inter’l Burn Meetings and Congresses. The Shrine Burn studies were the most numerous compared with all the other burn studies. In one ABA Intern’l Congress, 102 of the 252 studies were by authors associated with Shrine Burned Children hospitals.

In one series of burn studies, Dr. Traber’s and associated researchers in Galveston studied the effects of many medicines in controlled fatal smoke inhalation sheep (ovine) models in which a considerable amount of heparin was used to prevent blood clotting in the many monitoring tubes used to register various functions. In several studies the heparin was discovered to be more beneficial then the tested medicines. Then heparin alone was studied administered within the body or by inhalation in the burn model and produced significant results. The studies found heparin increased survival time, reduced lung burn damage and improved lung function. Studies in inhalation burns in children similarly improved lung function, reducing lung damage and lowered the mortality death rate.

The results in three studies are listed below, one in the ovine model and two in children treated by heparin inhalation. Those studies were the origin of heparin use by inhalation, which is widely accepted. Dr. R Mlcak was the Director of the Respiratory Care Department, Galveston Shrine Burn Hospital.

The Trabers were guest Plenary Session Speakers in 2 Saliba Burns Institute sponsored Heparin Effects in Burns Intern’l Symposiums, February 1994 in San Diego CA. and June 2000 in San Salvador, El Salvador. Dr. Ronald Mlcak (below) presented heparin administered by inhalation in burn studies in place of the Trabers, in 3 other SBI Heparin in Burns Intern’l Symposiums., in Las Vegas Nevada, Yokahoma Japan, and Shanghai China. View Traber Study

Ronald P. Mlcak PhD, RRT, FAARC, Director Respiratory Care, Shriners Hospital for Children, Galveston Burn Hospital and Associate Professor of Respiratory Care, School of Allied Health Science, University of Texas Medical Branch, Galveston, TX.

Along with three doctors, from 1990 to 2009 Dr. Mlcak researched adding heparin administered by Inhalation to treatment of thermally injured children with lung involvement.

Since 1990, has treated around 34 burned children per year, approximately 500 in total, age range from infant to 18 years with heparin administered only by inhalation.

Benefits include improved burn treatment, reduced procedures and mortality to about 11-12%, probably the lowest in the world. View Mlcak studies

John F. Hansbrough MD, FACS, General, Trauma, & Burn Surgeon. Dr Hansbrough, was a Professor in the University of California San Diego (UCSD) Department of Surgery and Director of the UCSD Burn Center in San Diego.

Although Dr Hansbrough had knowledge of the Heparin in Burns Protocol he did not add heparin topically or parenterally in treatment of burned clinical patients at the UCSD Hospital Burn Center. In his research laboratory at UCSD however, researchers performed a controlled study in 3^rd degree burned mice of heparin effect on the intestinal tract and the intestinal translocation of bacteria in which he is an author. That study found heparin preserved intestinal structure and reduced the movement of bacteria from inside the intestine through the wall into the body which would infect the body. He presented that important sentinel study as an invited Plenary Speaker at the Heparin Effects in Burns International Burn Meeting (the First Internationall Heparin Symposium) February 25, 1994, at the Marriot Hotel on San Diego Harbor, in San Diego. View Hansbrough Study