SUMMARY. Eight men and one woman, subjected to a propane gas explosion-fire, sustained 2nd- and 3rd-degree burns of 30-90% BSA size. In Hospital One (H1), four men with burns (40, 45, 83, and 90%; 65% av.) were treated promptly with large doses of heparin, administered topically and parenterally. The five patients with burns (30, 32, 35, 40, and 65%; 41% av.) treated at Hospital Two (H2) were not treated with heparin the first five days. The burn pain in patients at H1 was relieved by heparin; but, as a routine, four doses of pain medication were given on day 1. Without the use of heparin in the first five days, each H2 patient needed a significantly larger number of doses of pain medicine (av. 24 vs 4, p < 0.00001). Resuscitation fluids infused into H1 patients on days 1-3 were a significant 39-48% less than at H2 (p < 0.02). With heparin use, H1 patients had less swelling, no fasciectomies, earlier burn revascularization, and no bleeding. Without heparin, H2 patients had swelling, eight fasciectomies, and relatively avascular burns. Starting day 5, six 25,000 IU doses of heparin were topically applied, within 48 h, on the burns of each H2 patient. Their pains were relieved, pain medications were stopped, and revascularization resulted in minor surface bleeding by day 8, when topical use was discontinued and pain medications were restarted. Patients were given antibiotics. No skin grafts were performed. The skin was smooth without scars or contractures. Heparin shortened hospital stay: at H1 to 23 days (56% size av.); to 21 days at H2 (33%). A 5-day delay in using heparin increased hospital stay two weeks in comparable 40% patients. Burn treatment procedures and costs using heparin were much less.
Burn studies1-7 in humans and animals that tested large doses of heparin topically and parenterally produced significant therapeutic results. Relieved pain, enhanced healing, and smooth skin were findings. Fewer resuscitation fluids, fewer lung and intestinal complications, and fewer infections were reported.1-7 These burn studies and additional ones8-22 revealed, and other non-burn studies23-40 confirmed, that heparin had antiinflammatory,22-34 neoangiogenic,35-37 collagen-restoring,14 and epithelializing38,39 effects in addition to its anticoagulating effects. Smoke inhalation studies in sheep19,20 and a burn study in children21 found heparin used parenterally or by inhalation20,21 significantly reduced lung pathology.
Hundreds of burn victims were treated with heparin by burn specialists1-18,21 in several countries, without bleeding, the principal adverse heparin effect. No negative studies using heparin in burned humans were reported. Moreover, heparin simplified burn treatment and reduced costs. These alterations in treatment were advantageous ones for use in developing countries.
Therefore, after presentations of these heparin-use-in-burn studies and demonstrations of heparin’s effects on several burned patients in the hospital, this treatment was initiated at Hospital One (H1) in Tijuana, Mexico, in February 2000. The protocol41 had been utilized in the USA,1-7,9,21 India,8,10-14 Russia,15 El Salvador,16 Brazil,17 and Bulgaria.18 Other hospitals in Tijuana, a city of more than 3 million people, were not familiar with this treatment of burns using heparin.
A thermal disaster occurred on June 6, 2000. Ten people in one room were simultaneously thermally injured when they were subjected to a propane gas explosion and the fire and smoke in the room. Four victims, admitted to Hospital One (H1), were promptly treated with heparin. Five victims, sent to Hospital Two (H2), were not initially treated with heparin. This study reports the results.
The subjects
The nine men and one woman sustained burns that were 2nd-degree deep partial thickness and 3rd-degree deep full thickness burns (Table I, Figs. 1-9, photographs of patients [P] #2-10). The size of the burned body surface area (BSA), in percent of their total skin surface (%) was determined to be 2-90%. The man burned 2% was not hospitalized.
The four men at H1 (Table I, P #2-5) had total size mixed 2nd- and 3rd-degree burns of 40, 45, 83, and 90% size, an average 65%). 3rd-degree sizes were 10-80%. The average age was 29 yr. The average weight was 79 kg. The man burned 90% died on day 3.
At Hospital Two (H2), (Table I, P #6-10) the patients’ average total burn size was 41%. Their average age was 30 yr and weight was 67 kg. Patients #7-9 had mostly 2nd- degree burns of 30, 32, and 35%. The woman, P #6, had a mixed 40% burn. Patient #10 had a 65%s mixed burn. He died on day 9.
<% immagine "Table I","tab.jpg","Nine simultaneously burned patients burned treated with heparin therapy",230 %>The procedures
At H1 and H2, in the Emergency Department and Intensive Care Unit, standard burn treatment was started: intravenous lines and infused fluids (Table I), vital signs, blood oxygen monitoring and administration, cardiac monitoring, urinary catheter insertion, pain medication administration (Table 1), blood drawing for admission laboratory testing, and tetanus toxoid inoculation. Patient #5 at H1 and #10 at H2 were sedated, intubated, and ventilated.
The amount and frequency of pain medicine administered were sufficient to relieve pain (Table I). On admission and for one day each patient at H1 was given a total average four doses of Dipirona Magnesica. On admission and for five days, each patient at H2 was given a total average 24 doses of Dolac-Nubain.
No patient had an absolute contraindication to heparin uses, such as a personal or familial bleeding diathesis, a bleeding history, active bleeding or associated trauma with potential bleeding, an active intestinal ulcer, a thrombocytopenia, or a true allergy to heparin. As a safeguard against bleeding (1 mg of protamine neutralizes 100 IU of heparin), protamine sulphate was available; but none was used.
The four men men at H1 were administered intestinal source heparin according to protocol: in large doses both topically and intravenously burn days 1 to 3, during the initial burn acidosis period; then in lesser doses administered topically and subcutaneously for a variable number of days; then only topically, two or three times a day, in rapidly diminishing doses, until final healing (Table I). Heparin use was monitored by clinical signs: relief of pain and blanching of erythema; reduced swelling and oedema, decrease in burn size, drier burns, and revascularization. Parenteral doses were also monitored by partial thromboplastin time blood clotting times (PTT), which were maintained in the 1-3 times normal range. Subcutaneous injections were stopped when the daily PTT, tested before the heparin injection, exceeded 4 times normal. Topical dose was monitored and regulated: richly revascularized granulation tissue received progressively less heparin, and small areas with a tendency to bleed received no additional heparin. As an outpatient at H1, patient #1 had heparin topically applied to his 2%s burn once daily on day 8 and day 9.
<% immagine "Fig. 1","gr0000019.jpg","Patient #2 (R.F.), 32 yr, 40%.",230 %> <% immagine "Fig. 2","gr0000020.jpg","Patient #3 (A.S.), 19 yr, 45%.",230 %>For the first topical application, the heparin solution, in 5,000 IU/ml dilution, within a 10 ml syringe with a number 30 gauge needle attached, was slowly and evenly dripped or sprayed on open burn surfaces. Surfaces were retreated at 5 to 10 min intervals for 20 to 30 min. The number 30 gauge needle was introduced into each burn blister. A small opening was made in the blister so that the burn blister fluid would drain. The heparin solution within the syringe was introduced inside the blister through the needle of the syringe. Slowly the blister was repeatedly rinsed out with heparin solution, and finally a residual volume of heparin filled the blister space. Blisters were not removed. A few blisters that partially filled again with fluid were again rinsed out with the heparin solution, a second or a third time, the same day or the next day. No heparin was injected into burned tissue or below burned tissue.
<% immagine "Fig. 3","gr0000021.jpg","Patient #4 (E.A.), 31 yr, 83%.",230 %> <% immagine "Fig. 4","gr0000022.jpg","Patient #5.",230 %>At H2, no heparin was administered intravenously. At H2, two patients received a 2000 IU minidose of heparin subcutaneously daily as phophylaxis against thrombophlebitis: patient #6 for 6 days until transferred to H1; patient #10 for 8 days until he died. At H2, no heparin was applied topically until the evening of hospital day 5. Then, within 48 h, 150,000 IU was applied topically to each H2 patient in six 25,000 IU doses: once on day 5; three times on day 6; twice on day 7.
After a total 12,000 IU of heparin in minidoses had been given subcutaneously, and 150,000 IU had been applied topically, patient #6 was transferred on day 7 to H1. At H1, in the next 23 days, in diminishing amounts, an additional 1,300,000 IU of heparin was applied topically, and 230,000 IU was injected subcutaneously. She was sent home on day 30.
The nine burned patients were treated with antibiotics. The four patients at H1 were given 5,000,000 units of penicillin G by infusion IV every 6 h on days 1, 2, and 3, except patient #3 who did not receive it day 1. The man burned 83% was given penicillin orally on days 4 to 10. Then for a Pseudomonas infection, mainly on his left chest, on days 10-14 he received twice daily a topically applied solution of 0.5 g of aqueous cephalosporin mixed with 5 ml of 5000 IU/ml heparin solution. Bacterial culture testing showed a sensitivity to amikacin. Therefore, days 15-25, 0.5 grams of amikacin in aqueous solution was mixed with the 5 ml of 5000 IU/ml aqueous heparin solution and applied topically twice daily; and clindomycin was infused IV. At H2, patients received one or two broad spectrum antibiotics infused once or twice daily: patient #6 had cephalosporin; #7, 8, 9, dicloxicillin-gentamycin; #10, ampicillin-dicloxicillin.
<% immagine "Fig. 5","gr0000023.jpg","Patient #6 (C.V.), 35 yr, 40%.",230 %> <% immagine "Fig. 6","gr0000024.jpg","Patient #7 (A.N.), 17 yr, 30%.",230 %> <% immagine "Fig. 7","gr0000025.jpg","Patient #8 (C.A.P.), 34 yr, 32%.",230 %> <% immagine "Fig. 8","gr0000026.jpg","Patient #9 (A.S.), 30 yr, 35%.",230 %> <% immagine "Fig. 9","gr0000027.jpg","Patient #10.",230 %>At H1, water baths were avoided. No pain medicines were used after day 1. No intramuscular injections were given. Exercise was advocated. No skin grafts were performed on any patient at H1 or H2. Open method or non-adhering dry sterile dressings were used.
Statistical analyses were 2-sides Student tests (Table I lists values for t test, df, and p). The alpha level was 0.05, and a p value of > 0.05 but %lt; 0.10 was regarded as a statistical trend.
Figs. 1-9 are from colour photograph slides or prints with no enhancement.
There were no significant differences in age or weight of patients at H1 and H2 (Table I). The average total size of the burns of patients at H1 (65%) was 24%s larger than those at H2 (41%); but the size difference was not significant (p < 0.11). The average size of 2nd-degree burn was not significantly different, and in survivors it was the same (31%). The 3rd-degree burn in survivors at H1 was appreciably larger than at H2 (25.0% vs 1%, p < 0.06).
At H2 and H1, the first injection of pain medicine relieved the pain in each patient. At H1, 4 h later, heparin given topically and by infusion promptly relieved the superficial and deep burn pain. After heparin was started, none of the patients at H1 required pain medicine, but the additional doses ordered for day 1 were given by nurses as a matter of routine. At H2, without heparin, burn pain reoccurred and repeated doses were needed. The 24 average total doses of pain medicine administered in the first five days to the patients at H2 was significantly larger than the four doses given at H1 (p < 0.00001).
At H2, starting day 5, the pain of the five patients subsided when large doses of heparin were administered topically. Pain medicine was discontinued. The pain returned when topical heparin applications were stopped. Pain medication of necessity was resumed. At H1, on day 8, the man with the 2% burn reported his pain ceased when heparin was applied topically.
The resuscitation fluid volumes were analysed in infused ml per kg patient weight per percentage of burn size (ml/kg/%) per day (Table I). At H2, the average volume on day 1 of the five patients treated without heparin was 3.76, nearly the Parkland formula volume of 4. At H1, the day 1 fluid volume of the four patients treated with heparin was 2.17 average, a 42.3% lower volume than at H2 (p < 0.065). This was approximately half of the Parkland formula. The infused fluids on day 2 were 1.77 at H1, 39% lower, compared to 2.89 at H2, (p < 0.156). The fluids infused on day 3 at H1 were a 48% lower 1.16, compared to 2.23 at H2 (p < 0.043). The average ml/kg/% for 3 days at H1 was a significant 42.6% lower 1.70 compared to 2.96 at H2 (p < 0.02). Urinary output measured in ml per h average at H1 was 92 on day 1, 73 on day 2, and 42 on day 3. Urine volume at H2 was 128 ml/h on day 1, and 131 on day 2 and on day 3.
H1 patients #2-5 given heparin had less burn swelling and body swelling and no fasciectomies, compared to H2 patients #6-10 who received minidoses or no heparin. At H2, the man with 65%s burns, who received 40.832 ml of fluids the first three days, and the woman with 40%s burns who received 37,850 ml, each had 4 fasciectomies, a total of 8. At H1, the heparin-treated blisters did not become infected; and they required no further care. In time, new smooth epithelium was evident when the thin dry blister remnant flaked away.
Burn revascularization with heparin use was faster in H1 patients, and evident on day 2. Without heparin, burns of H2 patients on day 5 were still relatively avascular. Then, topical use of six 25,000 IU doses of heparin (150,000 IU total within 48 h) resulted in the revascularization of the ischaemic burns of three a patients, #7-9, at H2. Through inexperience, the dose was not reduced. The revascularization was such that on day 8 bleeding at a few sites resulted in a discontinuation of topical heparin use, also through inexperience. H1 patients had no bleeding problems with use of heparin in diminishing amounts. Comparing the burns of the two patients who died, #5 at H1, given large parenteral and topical heparin doses, had revascularization on day 2; but at H2, on day 8, the burns and fasciectomy sites of #10 were still relatively avascular following the limited only topical heparin use starting day 5 (Fig. 9). Patient #6, sent to H1, and given heparin subcutaneously and topically for 23 days, had her 40%s burns and 4 fasciectomy sites revascularized by day 8 and healed by day 38 (Fig. 5).
At H1, the comparable 40% burned patient, #2, treated topically and parenterally with heparin starting on day 1, required no fasciectomies; and he was sent home on day 15, 15 days earlier. A 5-day delay in starting heparin increased her hospital stay 2 weeks, fluid needs, and heparin needs. He received 53% less heparin (725,000 IU vs 1,542,000), and 53 or 58% less resuscitation fluid (18,000 ml total vs 37,850 or 1.76 ml/kg/% vs 4.18) than she. Interestingly, the average total IU of heparin used per day per % burn was nearly the same, 1208 and 1285 (Table I). Both patients had smooth skin with no scars or contractures.
The three H2 patients, #7-9, with 33% average mostly 2nd-degree burns, who after topical heparin use had notably accelerated healing, were sent home on day 21. They had no scars. Their cosmetic results, though good, were less good than those of patients #2-4, and #6 at H1.
The three H1 patients, #2-4, with average 56% total size and 25% 3rd-degree burns, given heparin intravenously, subcutaneously, and topically starting day 1, were sent home in 15, 27, and 23 days on average. They had no scars.
No skin grafts were performed on these thermal disaster involved patients. Re-epithelialization was nearly complete when patients were sent home. In the final phase of healing an itching sensation was sometimes present. Some hypo-pigmentation and hyperpigmentation areas were present.
Burns are painful maladies. The known suffering and sequelae of burn victims in a thermal disaster defies description. The treatment of many simultaneously burned humans has been difficult and onerous in the past. Use of the widely available and inexpensive medicine heparin in this study facilitated burn treatment. The significant relief of pain and the reduction in resuscitation fluids were beneficial effects when heparin was used. Other notable improvements when heparin was used were shortened revascularization time, reduction in swelling that obviated need for fasciectomies, reduced procedures, and shortened hospital time. Also noteworthy, the burn surface infection in patient #5 responded well to topical application of an acqueous solution of a culture-specific antibiotic mixed with heparin solution.7,42 The smooth skin found in this burn study and in previous ones42 using heparin was a pleasant improvement compared to the burn scars and contractures often found using other treatments. Importantly, the reduction in cost of this effective treatment was a major necessary beneficial consideration.
The findings in this study using heparin were similar to those in previous experimental and clinical burn studies that established the rationale and method of using heparin.1-21,41,42 Those prior studies reported that heparin relieved pain, reduced inflammation, prevented burn extension, enhanced revascularization, shortened healing, and resulted in healed skin that was smooth without scars or contractures. The heparin effects in past burn studies and in this one were similarly related to source, dose, time, pH, site, and duration.6 Mechanisms for heparin were demonstrated. Heparin was shown to reversibly inactivate many mediators of inflammation.23,24 It stimulated the migration of endothelial cells into ischaemic tissue, where they multipled to form new capillaries that restored blood flow.35-37
Heparin influenced the proliferation of dermal fibroblasts and aligning of their intracytoplasmic fibrils into regular parallel pattern that resulted in smooth skin.38,39 In scars, the distribution pattern was a chaotic clumping beneath the cell membrane. Heparin had therapeutic effects on pathology found in burns: intravascular stasis, thromboses, emboli, and disseminated coagulopathy. The initial large doses were partly a function of how much heparin was known to be needed to mediate these multiple functions.
In this study, the precautions taken to avoid bleeding, the potential principal adverse effect, were the same as those taken in previous studies.41,42 The heparin source was intestinal because it was found to be more antiinflammatory40 and less anticoagulating than lung.6 The initial large doses were rapidly reduced. Intravenous use was at acidic pHs on days 1-3 only. Subcutaneous use was while coagulation times were 1-3 times normal, and stopped when it exceeded 4 times normal. Topical use into final healing was in rapidly diminishing amounts.
Without heparin the burned patients had pain. With heparin use, patients had no pain. Burn size was not a factor (Table I). The pain in burns in 24% and with 34% 3rd-degree severity was relieved when heparin was started. The pain reappeared when heparin was stopped in patients at H2. The amount of 2nd-degree burns cannot be considered a factor, as the amount was not significantly different, and in survivors it was the same 31% (Table I). Without narcotics, the patients at H1 were more alert, awake, active, and able to eat and addiction and suppression of respiration and intestinal motility were avoided.
Revascularization of ischaemic burns was rapid in larger burns with the use of large doses of heparin both parenterally and topically starting on day 1, or with use of smaller doses of heparin used only topically in smaller burns starting on day 5. Richly revascularized healing tissue can bleed, however, with mild local trauma, as it did at H1. The potential bleeding problem was controlled by progressively decreasing the heparin dose, reducing it further in areas that were richly revascularized, and stopping heparin use in the small areas that started to bleed. This and prior studies found that heparin applied topically did not prolong systemic blood clotting times.
This study showed, as have previous ones,1-17,42 that heparin applied topically can be started at any time in burn healing and beneficially continued into final healing, and that smoother skin resulted. Starting heparin early resulted in much less total use of heparin.
Burn care in ten simultaneously burned patients was improved and simplified using heparin parenterally and topically. Heparin significantly relieved pain and reduced need for resuscitation fluids. Heparin enhanced revascularization, shortened healing, and resulted in smooth skin without scars or contractures. Heparin reduced procedures and the time patients were in the hospital. The cost of treating burns was greatly reduced using heparin. Heparin was shown to be a readily available, expediently administered, effective, and affordable treatment of multiple thermally injured patients in a burn disaster.
RESUME Neuf personnes ont été atteintes de brûlures de 2ème et 3ème degré dans une explosion de gaz de propane. Quatre patients, dans un hôpital, ont été traités avec des doses massives d’héparine administrées en manière topique et parentérale; les autre cinq patients, dans un autre hôpital, n’ont pas été traités avec l’héparine dans les premiers cinq jours après l’accident. Les Auteurs décrivent les avantages relatifs du traitement avec l’héparine: moins oedème, révascularisation plus précoce, absence de saignement, et la non nécessité de fasciectomies. Après cinq jours les patients non traités avec héparine ont reçu des doses d’héparine et leurs conditions se sont améliorées. Les Auteurs concluent que le traitement avec l’héparine des patients brûlés améliore la guérison et réduit notablement les coûts.