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The Use of Tannic Acid in the Local Treatment of Burn Wounds: Intriguing Old and New Perspectives  

Wounds 13(4):144-158, 2001. © 2001 Health Management Publications, Inc

Abstract and Introduction

Abstract

The use of tannic acid in the local treatment of burns is controversial. Although it became the therapy of choice shortly after its introduction in 1925 and most clinicians agreed upon its effectiveness, the tanning method was generally abandoned again halfway through the forties, as hepatotoxic effects were observed in both patients and experimental animals. However, a critical evaluation of early literature data shows that hepatic necrosis and impairment of liver function were not exclusively related to tannic acid treatment but also occurred in patients who were treated otherwise. Moreover, in those studies reporting adverse effects, tannic acid preparations of ill definition and poor quality were used often in extremely high concentrations. More recently, it has also become apparent that native pathophysiological phenomena, rather than tannic acid intoxication, underlie the liver damage seen in thermal injury. In this perspective, it is not surprising that the use of tannic acid as an adjuvant therapy for burn wounds has regained interest in present times. In particular, some preclinical and clinical studies indicate that highly purified tannic acids can provide a valuable tool to improve wound healing and to reduce scar tissue formation.

Introduction

A whole array of remedies has served in the local treatment of burns through the ages. In ancient Chinese texts, many decoctions of medicinal herbs were advocated for the "dispersal of heat and detoxication" of "fire poison."[1] Similarly, the Ayurveda contains references to the topical application to burn wounds of vegetable oils, powdered plant materials, honey, or mixtures thereof.[2] In his presidential address at the annual meeting of the American Burn Association in 1971, Moncrief[3] presented an overview of the developments in topical treatment of burns in the Western world. On this occasion, he recounted some noteworthy early milestones, such as: Hippocrates' recommendation to use swine's fat; the introduction in the 18th century of "Carron oil," a popular therapeutic containing linseed oil and lime water that continued to be used for over 200 years; and the appearance of boric lint and medicated paraffin at the end of the 19th and the beginning of the 20th century. Furthermore, Moncrief mentioned some recent progressions in this field through chemical escharotics and antibiotic agents, such as the aniline dyes, sulfonamide drugs, and penicillin, to eventually the adoption in burn therapy of silver sulfadiazine. The latter compound, together with cerium nitrate, which became available some years later,[4] has remained the topical treatment of choice until now.

The availability of increasingly adequate local therapeutics, in addition to advances in general care of burn patients and improved surgical techniques, have resulted in a gradual decrease of mortality due to burns. The work of Davidson[5] in the 1920s laid the foundation for this development, as it revolutionized the attitude of the medical profession toward the treatment of burns and was the impetus for further research in this field. He was one of the first who took pity on extensively burned patients and showed that their terrible suffering may be alleviated by better local therapeutic regimens, such as his tannic acid method of treatment. This method, which became immensely popular shortly after its introduction and has recently experienced a revival in interest, is the subject of this paper. The original method applied by Davidson as well as all later modifications will be reviewed. The arguments for and against the use of tannic acid, but in particular its alleged hepatotoxic effects, will also be elaborated upon and put in a historical perspective.

Tannins Used as Medicinal Agents: Structural Characteristics and Origin

Tannins comprise a large group of natural products widely distributed in the plant kingdom. They have a great structural diversity, but in general, two classes are distinguished, the hydrolyzable type and the condensed type.[6] Hydrolyzable tannins are esters of sugars, mainly glucose, and phenol carboxylic acids, such as gallic acid, hexahydroxydiphenic acid, or its stable dilactone ellagic acid. As their name infers, hydrolyzable tannins are readily degraded under hydrolytic conditions into these fundamental components. Hydrolyzable tannins are present in many different plant species but are found in particularly high concentrations in nutgalls growing on Rhus semialata (Chinese and Korean gallotannins) and Quercus infectoria (Aleppo or Turkish gallotannins), the seedpods of Caesalpinia spinosa (Tara tannins), and the fruits of Terminalia chebula.[7] The condensed tannins are much more resistant to decomposition and merely yield polymers or amorphous precipitates under the influence of acids. The basic monomer of condensed tannins is (epi)catechin, which is extended by the successive addition of similar units to form oligomers and polymers. Traditionally, important commercial sources of condensed tannins are the heartwood of Schinopsis lorentzii and S. balansae (Quebracho tannins), the bark and/or heartwood of Acacia catechu (Catechu tannins) and A. mollisima (Wattle or Mimosa tannins), and the bark of Rhizophora and Eucalyptus species.[8,9]

Although both types of tannin have been used to treat diseases in traditional medicine, the hydrolyzable tannins are generally considered as officinal in Europe and North America. They have been included in many pharmacopoeias, in the older editions in particular, and are specifically referred to as "acidum tannicum" or tannic acid.[10-13] Few accounts with respect to the use of condensed tannins originate from China, where plant extracts containing these tannins as their major constituents are also applied as medicinal agents for the treatment of burns.[14-16]

Introduction of Tannic Acid as a Topical Agent in Burn Treatment

Incidental accounts on the use of tannins and tannin-containing plants can be found here and there in the history of burn treatment. However, it is Davidson[5] who deserves the credit for introducing the tannic acid method of treatment that became the standard therapy for burn patients in subsequent years. It is his contribution to have developed one of the first therapies that significantly improved the treatment of thermal injury. The rationale behind Davidson's work was found in the toxin theory, one of the many theories that had by then evolved to explain the diverse pathophysiological phenomena observed in burn patients. This theory attributed the systemic reactions seen in these patients to the absorption of some toxic substance from the affected skin. It was, at that time, prevalent and most strongly supported by experimental evidence. Thus, already in 1905, Pfeifer[17] had reported the presence of a labile neurotoxic substance in the urine and serum of experimentally burned mice. This toxin was also found to induce necrosis of internal organs, in particular those of the gastrointestinal tract. Pfeiffer's observations were confirmed by many others, perhaps most convincingly by Robertson and Boyd in 1923.[18] These investigators grafted burned skin onto normal animals, which showed toxic manifestations within short notice. Likewise, injection of blood from burned animals into controls resulted in toxic effects in the latter. They isolated and characterized the toxin and found it to be composed of autolytic products of decomposed proteins. These experiments convinced Davidson of the necessity to prevent resorption of burn toxins into the circulation. To accomplish this objective, he used tannic acid, since it has the property to complex with all kinds of biomolecules and therefore "might be efficacious in precipitating poisonous materials in burned tissue."[5]

In his first publication on the subject, Davidson reviewed 25 case histories of burn patients treated with tannic acid. After some initial experiments with unfavorable outcomes in which he applied boric acid compresses to the tanned eschar in an attempt to remove it, Davidson successfully employed the open treatment method. Upon admission of the patient to the hospital, the burn wounds were dressed with sterile gauze and bandages and moistened with freshly prepared 2.5- to 5-percent aqueous solutions of tannic acid. The dressings were kept wet until a satisfactory coagulum had been formed, and the wounds had become insensitive to pain. At that moment, they were removed, and the burns were exposed to air. In few cases, in particular in facial burns, a 5-percent ointment with a petrolatum and lanolin base was used instead of the aqueous solutions.

In Davidson's experience, tannic acid was best suitable in the management of burns. It was superior to other therapeutic regimens, since it notably reduced the degree of toxemia as determined from clinical and physico-chemical observations and the lowered mortality rate. Tannic acid was also found to be advantageous in several other respects. The local protein-precipitating effects of tannic acid include relieving the pain, preventing the loss of plasma, and markedly limiting secondary infection. Furthermore, in nonfatal cases, a diminution in the amount of scar tissue formation was observed. This was believed to be an additional effect of the formed coagulum, which could provide "a scaffold for the growth of the young epithelial cells over the denuded surface."[5]

Experience with the Tannic Acid Method in the Anglo-Saxon World from the 1920s up to the Early 1940s

The tannic acid treatment of burns was adopted by many other clinicians, but in actual practice, only a few strictly adhered to Davidson's original method.[19] In the hands of others, it was soon modified to yield simpler or more efficacious treatment procedures. Beck and Powers[20] sprayed the burn frequently with a 2.5-percent aqueous solution until the wound surface was tanned. This became the standard method of treatment and was widely employed, although the concentrations of tannic acid used were liable to vary and ranged from 2 to 20 percent.[21-28] Other ways to apply tannic acid were also advocated, e.g., solved in physiological salt or Ringer's solution instead of water,[29] in the form of gels and/or ointments,[21,24,30-32] or as a bath.[33,34] Moreover, the use of a diverse array of additives was proposed. Hunt and Scott[35] used mixtures of tannic acid and collodion to strengthen the crust formed over the burn wound. To speed up the tanning process, Bettman[36,37] applied a 10-percent silver nitrate solution to the burn immediately after treatment with tannic acid. For protection against infection, antiseptics, such as perchloride of mercury,[25,26] dettol,[38] gentian violet,[28,30] acriflavine,[27,28] salicylic acid,[29] amyl-tricresol,[39] or hexyl-dichloro-resorcinol[31,32] were sometimes added.

These changes did not appear to influence the efficacy of tannic acid treatment, as the results in general remained satisfactory and confirmed those of Davidson. In agreement with Davidson, many authors stated that the use of tannic acid was a distinct advance in the treatment of cutaneous burns and found the care of patients relatively simple, since there was no longer distress from dressing changes. Similarly, based on clinical experience, they almost unanimously agreed upon such beneficial effects as rapid alleviation of pain, lessened infection, reduced local loss of body fluids, prosperous epithelization, relative absence of contractures, and diminished scar-tissue formation. But perhaps most important of all, good survival statistics were reported in several studies (Figure). Thus, in 1926, one year after the introduction of the tanning method, Bancroft and Rogers[40] observed a reduction in the number of deaths in patients treated with tannic acid in comparison to patients who had undergone debridement or were treated with an electric cradle; mortality rates were 22, 57, and 50 percent, respectively. Only patients treated by means of boric acid, picric acid, sodium carbonate, or magnesium sulfate, alone or in combination, had a lower mortality rate of 10 percent, but these were cases with burns of small total body surface areas requiring little therapy. In a follow-up study with 114 patients by the same authors, these preliminary findings could be confirmed.[41] In a series of 50 patients, Wilson[42] found the total number of death to be seven, of which only four (8%) were directly attributable to the injury. According to the author, this figure compared favorably with any that had been quoted from other methods. In a group of 114 patients treated with tannic acid, Beekman[43] observed a mortality rate of 14.9 percent, which was considerably lower than the death rate of 27.8 percent in the 320 patients treated otherwise. He also showed that the number of patients dying from the second to the tenth day, the period of toxemia, was strongly decreased in the tannic acid-treated group. Likewise, Davidson and Penberthy44 mentioned a drop in mortality in the period after thermal insult that was generally associated with the toxemic phase. Moreover, the results of nearly all studies carried out in subsequent years, up to the early forties, paralleled these initial observations.[24-26,45-51] In one publication only, an increase in the incidence of death after tannic acid treatment was noted, although this was no reason for the authors to reject this method since, as it was stated, it had numerous distinct advantages.[52]  

Figure.  

Comparative mortality rates of tannic acid and other methods of burn treatment as mentioned in the literature. Note that in many instances only a limited number of patients were available to establish the mortality rates, and those patients did not always represent uniformly distributed populations with respect to the severity of the burn injury or age. This is best exemplified by quoting Ollinger[105] who stated that "for the proper evaluation of the high mortality rate in the tannic acid-treated burn patients it is essential to keep in mind that merely the most severe cases were treated with tannic acid, a group which would anyhow have shown the highest number of death." Some authors used several alternatives for tannic acid. In those cases where no overall mortality rates could be calculated,[25,26,40,41] bars depict only one other treatment method: * debridement; † picric acid and dry air; ‡ picric acid (1924-1928). For the study by Fuchs and Lutzeyer,[101] a mean mortality rate of four different treatment regimens is depicted. The mortality rate of single alternative methods was, in some cases, much higher. Thus, the number of deaths in sulfonamide-treated children was identical to that of tannic acid-treated children.

The Role of Tannic Acid Therapy in Other Countries

The application of tannic acid to burn wounds has not been restricted to North America and the United Kingdom. Its effectiveness was also recognized in several other countries, such as France,[53] Spain,[54] Romania,[55] The Netherlands,[56] and Denmark.[57] However, in German-speaking countries in particular, many studies were performed to rate this new treatment regimen at its true value and to compare it with the current local therapy at that time of cod-liver oil.[58] With just one exception, which was a trial with severely burned patients of whom it was doubtful whether they would have survived or not under normal treatment,[59] the outcome of those studies were in line with the Anglo-Saxon literature data. Patients did clinically well,[60-66] and a reduction in mortality was observed.[67,68] It is striking to note that in most cases, these positive effects were obtained with Davidson's original method that was quite strictly adhered to. The only major modification that was propagated was the use of tannic acid ointments on a basis of glycerine,[66,69] lanolin, and petrolatum-based ointment[68,70,71] or other fatty oils.[72]

Objections Raised Toward the Tannic Acid Method of Burn Treatment

The tannic acid method was widely met with enthusiasm, and it came to assume a dominating position in the treatment of burn patients. Notwithstanding, this method could not satisfy all needs and had its limitations and disadvantages as may be expected in the case of an injury that was so difficult to treat and often demanded all of the clinician's skills to arrive at a positive outcome.

First, critics pointed out that this local therapeutic regimen did not consider specific measures to improve the general conditions of patients. The significance of such a systemic treatment, in particular fluid administration, had just become apparent with the work of Underhill and co-workers[73] and Blalock.[74] These authors demonstrated that the marked concentration of blood and lowering of blood pressure were due to the local loss of fluids and favored the suggestion that symptoms encountered in severely burned patients were due to this fluid loss rather than to the action of burn toxins.[75] Although from both clinical (vide supra) and experimental data[76,77] it could have been concluded that tanning may also improve the general condition of the patient by reducing the leakage of plasma from burn wounds, it was nevertheless feared that focusing mainly on the local treatment may incur the risk of distracting the attention from other systemic measures that could be beneficial to the patient's welfare.[78] In this respect, it was even suggested that the observed drop in the mortality rate could not be solely attributed to the introduction of tannic acid treatment but should, at least in part, be ascribed to the simultaneous advances in the general care of burn patients.[49,50,52,72,79,80]

Second, it was considered inappropriate by some to apply tannic acid to burns of the hands and face.[81-83] When used on the hands, tannic acid would form an inelastic eschar and prevent transudation, which could lead to edema formation, compression of the circulation, and finally necrosis of fingers or deformities of the hand. Tanning of facial burns may be detrimental in that, with the multiplicity of orifices in the vicinity, it was almost impossible to avoid infection. It could furthermore immobilize the eyelids, which may result in dehydration of the eyes and, consequently, inflammation and eventual loss of sight.

Third, it was put forward that tannic acid may destroy intact epithelium and in this way could inflict further damage, so that in some instances a second-degree burn is converted into a third-degree burn. With respect to this objection, considerable evidence both for and against has accumulated. In support of the belief that tannic acid damages epithelial cells, Taylor[79] noted that the viable epithelium stopped abruptly where the coagulum began. Ham[77] found a considerable thickness of dermis to be destroyed but only when the burned surface was denuded of epidermis prior to tanning. Similarly, Hirshfeld and associates[84] reported that in fresh wounds resulting from skin grafting, the dermis was destroyed to a great depth after application of tannic acid. The same authors observed a delay in epithelial regeneration and prolonged healing time, a finding that was confirmed by others.[80,83,85] The cause for these adverse effects on skin structure is not known exactly but might be related to the high acidity of the solutions[86] or the type of tannic acid used.[87] Opposed to this, a substantial body of evidence is available to refute the opinion that tannic acid is detrimental to epithelium. From the clinic, many reports on the prosperous healing of burn wounds have been issued (vide supra). In addition, Bancroft and Rogers,[40] looking into more detail to this aspect, found healthy skin to be apparently unaffected by tannic acid treatment. In microscopic examination of biopsies taken from one case, they also saw a thin layer of flat epithelium extending from the hair follicle and spreading out over the connective tissue. Likewise, Baltin[66] found the hair follicles and glands from which reepithelization may occur to be well preserved. Anagnostidis[88] did not observe any differences between tannic acid-treated and untreated burn wounds with respect to the microscopic wound characteristics and the healing process. Finally, Von Löhr and Zacher[58] examined the ability of tannic acid to fixate dead tissue in experimental burn wounds in animals and human operation material and showed the coagulating effect to be only superficial.

Fourth, the poor antibacterial capacity was assumed to be another negative aspect because it brought with it the risk of infections to spread under the eschar, thereby inducing further tissue damage.[58,82,83,89] The picture of heavily infected burn patients with profuse discharges and dressings soaked with odorous and often green pus was sometimes referred to as the "laudable pus days"[52] and was generally seen before the introduction of tannic acid treatment. This, however, was rarely encountered, though local foci of infection remained common. Thus, it was noted that in third-degree burns, there are a certain number of patients who develop infection,[41,85] and it was demonstrated that bacteria, in particular Streptococci, were present in burn wounds.[38,90] The insufficiency of tannic acid to prevent infection became particularly evident during the Second World War. While it was advocated by the Royal Navy as a first aid measure[91] and was considered to be the proper therapy in superficial burns by other war surgeons,[82,92] in more unfavorable situations it was far from adequate. For example, Porritt[93] reporting on the desert wars in the Middle East during the "Wavell," "Auchinleck," and "Alexander-Montgomery" periods found tanning in forward areas near the war front to be depressing in the extreme: Nine out of ten patients arrived in the hospital septic and in very poor general condition, and all that could be done for them was to remove the septic eschar. However, it should be noted that these battle casualty burns were, more frequently than not, serious and usually combined with other wounds, and transportation to the hospitals took, in general, several days or even more than a week. To overcome this particular problem of infection, several authors suggested the use of combined preparations of tannic acid and antiseptics (vide supra) or advocated the use of coagulating agents other than tannic acid, such as gentian violet, which had similar protein-precipitating properties but was a more potent bactericidal.[90]

However, none of these drawbacks associated with the use of tannic acid gave cause to reconsider its use on burn wounds. They were merely the reason for slight changes in the formulation or adaptations in the method of application. It was not until the late thirties and beginning of the forties, after reports on the potential hepatotoxic effects of tannic acid started to appear, that the opinion concerning the value of tannic acid treatment underwent a dramatic change.

Tannic Acid and Liver Necrosis

In 1938, Wilson, MacGregor, and Stewart[28] were the first to report on the occurrence of liver lesions in tannic acid-treated burn patients. Post-mortem examination in a series of 33 severely burned, fatal cases revealed a characteristic degeneration and necrosis of liver cells, which was much more intense than that seen in other organs. In its mildest form, it appeared as a fatty degeneration of the epithelial cells surrounding the veins in the central zone of the hepatic lobules but could, in more advanced examples, progress to a total destruction of the central zones in which only a narrow strip surrounding each portal tract showed surviving liver cells. In subsequent years, several other communications were published describing liver damage in burn patients who had some form of tannic acid therapy. Buis and Hartman[32] confirmed the findings by Wilson, et al.,[28] and, in addition, noted that the lesions in humans were identical to those found in experimentally burned animals treated with tannic acid jelly. Belt[94] reported histopathological changes that closely resembled those of yellow fever. McClure,[78] McClure and Lam,[31] and Duffin[95] observed the clinical signs of a marked jaundice and decreased liver function accompanied by central liver necrosis in some patients who failed to survive. Evidence of an impaired liver function has also been reported by others. Wolff, Elkinton and Rhoads,[96] as well as Abbott and Holden[97] found an elevation of blood bilirubin, impairment of glycogenesis and hippuric acid synthesis, and a decrease in prothrombin levels. However, none of these authors associated the phenomena seen in burn patients with the application of tannic acid but merely suggested it to be a consequence of toxemia and the circulation of burn toxins.

Only in 1942, Wells, Humphrey, and Coll[34] directly related the occurrence of liver damage to the tannic acid therapy. In their article in the New England Journal of Medicine, these authors described four patients who died three to five days after the injury, in the period which was generally associated with toxemia. In agreement with previous observations, on autopsy these patients exhibited central lobular liver necrosis as the outstanding feature or as the sole cause of death. Since the common denominator appeared to be the employment of tannic acid in these cases, the possible role of this constituent in the production of hepatic damage was further investigated. For this purpose, a series of experiments was performed in which rats were subcutaneously injected with different doses of tannic acid. This induced liver damage that was essentially similar to the lesions in humans and was proportional to the amount of tannic acid administered. Therefore, it was concluded that the liver damage seen in burn patients might be due to tannic acid poisoning and that it should be distinguished from the patient's toxemic phase, which resulted from the resorption of toxins from the burn wound.[34]

Following the experiments by Wells and coworkers, additional evidence was accumulated for the detrimental effects of tannic acid. The occurrence of hepatotoxic signs in tannic acid-treated burn patients was confirmed by several other clinicians.[50,51,98-102] The hepatotoxic signs were also related to the increase in the frequency of liver necrosis seen in fatal burns[103,104] and the comparable higher mortality rates as found in some late clinical trials (Figure 1).[101,105] Also, experimental data from animal studies provided further support for its harmfulness. Subcutaneous injection of tannic acid gave a disturbed liver function[106,107] and a fairly uniform and specific liver necrosis.[108-111] Intramuscular injections resulted in a slight, though definite, liver damage.[112] Intravenous injections produced severe liver lesions in mice[109,112] and more variable pathological changes in rabbits.[106] When tannic acid was applied to denuded skin surfaces, the amount of liver damage seemed to be dependent on the application form and the type of animal. An aqueous solution or an ointment usually produced hepatic necrosis in rats, whereas no lesions could be found when tannic acid was combined with silver nitrate.[108] Dogs treated with tannic acid jelly showed congestion, fatty degeneration, and myelinization of the liver but no central necrosis.[111] Application of tannic acid to denuded surfaces was lethal for mice but not for rats or rabbits.[107] Neither was liver damage, as measured by the Bromsulphalein test, seen in rabbits.[107] A comparable variation in the degree of liver damage was found when tannic acid was applied to experimentally induced burns. In guinea pigs there was only slight liver damage,[112] and burned dogs showed clinical jaundice and central liver necrosis in just a limited number of cases.[111] Conversely, varying degrees of liver damage were observed in goats and rabbits, although this was in no case as severe as after subcutaneous injection.[109]

Renewed Interest in the Use of Tannic Acid

As a consequence of these clinical and experimental observations, it became the dominating view for many years that deaths of liver necrosis were due to tannic acid; eventually, tannic acid treatment was generally abandoned. However, a few clinicians remained advocates of this therapy, especially in Germany.[113-117] In this country, the modest revival in interest in the use of tannic acid as an adjuvant therapy in the treatment of thermal injury started. It was first reintroduced in the early eighties by Hettich from Tübingen-University. By using a three-phased tanning procedure consisting of the subsequent application of solutions of Mercurochrome or iodine-povidone, tannic acid, and silver nitrate, he was able to conserve the burn wound and to delay primary excision.[118,119] This method had various advantages; the principle was that surgical debridement of the burned surface could be postponed and performed when the patient recovered from the first consequences related to the trauma. In addition, since second-degree burns were spontaneously reepithelized, less grafting material was needed, and if necessary, the newly formed epithelium could be used as autograft for large skin defects.

Subsequently, following Hettich's example, the application of tannic acid to burn wounds was resumed in some tentative studies in the Burn Centre of the Red Cross Hospital in Beverwijk, The Netherlands. Here tannic acid was no longer considered as the topical therapy of first choice, since newly available drugs, such as silver sulfadiazine and cerium nitrate, were better suitable in this respect, but it was valued for its potential superior long-term wound healing characteristics. The first indications for the beneficial effects on wound healing and scar tissue formation were obtained from animal experimental work. In a comparative burn wound model in the Yorkshire pig for the histopathological evaluation of local therapeutic regimens, tannic acid ointment was found to induce a durable, supple crust that did not obstruct the regular outgrowth of epithelium. Macroscopically, a striking diminution of the hyperemic zone was observed. Tannic acid-treated burns also showed fewer inflammatory signs as was established by microscopic investigations.[120,121] Further research provided evidence that tannic acid could be combined with other topical agents currently used in the clinic. Thus, combination with silver sulfadiazine in an alternating mode did not influence the physical qualities of the crust and resulted in a similar decrease of fibrosis and fibrovascular reactions in the wound bed.[122] In agreement with this, in a recent laboratory study, it was established that silver and cerium ions did not negatively interfere with the collagen cross-linking ability of tannic acid.[123]

The positive effects as seen in these experimental settings could be confirmed in a clinical trial with a limited number of patients. When applied to burn wounds after standard debridement and disinfection, tannic acid induced a supple crust within three days after the start of treatment, which remained intact for one to four weeks, depending on the area of the body treated and the involvement of joint regions. The wound healing was undisturbed, and no deepening of the burns was observed. In comparison with the universal silver sulfadiazine cream treatment, tannic acid-treated wounds demonstrated remarkably little granulation tissue.[124] Healed areas were covered with an epithelium with normal aspect, and the remaining scar was supple and not abnormally vulnerable. In seven out of nine patients, no hypertrophic scar formation was found, whereas in the other two patients, the hypertrophic area amounted to not more than 10 percent of the original tannic acid-treated region.[125]

Native pathophysiological phenomena, rather than tannic acid intoxication, induce the hepatic lesions seen in burn injury. In particular, the many clinical and experimental observations made in the forties were indicative for a potential hepatotoxic effect of tannic acid. Consequently, in general, this method of burn treatment is still considered as obsolete, although it has become apparent in the meantime that it might be beneficial when used as an additive therapeutic regimen under strictly controlled conditions. However, the assumed hepatotoxicity of tannic acid can be questioned when those early publications are analyzed in retrospect and with the knowledge acquired in recent years kept in mind.

For instance, references to pathological hepatic changes and impairment of liver function in burn patients are not restricted to the episode in which tannic acid therapy was widespread. Although not specifically emphasized as a characteristic feature, liver damage was already reported in papers that appeared prior to the introduction of tannic acid treatment. As early as 1898, Bardeen[126] reviewed in detail the lesions found at post-mortem examination in some fatal burn cases. Macroscopically, the chief gross change was a swelling of the liver. Microscopically, he noticed a parenchymatous swelling of the epithelium with focal areas in which there was marked vacuolization of the cell nucleus and some nuclear fragmentation, as well as a moderate congestion and capillary thrombosis. Likewise, Vogt[127] observed a fatty degeneration of liver epithelial cells and Kupffer cells along with an accumulation and degradation of white blood cells in the liver capillaries in burn patients who had died before 1925. Weiskotten[128] found no constant changes to be evident in the liver on gross examination, but microscopically he could detect foci of liver cell necrosis in two out of ten patients. Signs of liver injury were also mentioned by many authors during the tannic acid era in patients who were treated otherwise as well as shortly after cessation of local treatment with tannic acid. Reports on fatty changes, congestion and edema, and several forms of liver degeneration are relatively common.[50,103,104,129] Although possibly occurring less frequent, hepatic necrosis was observed in those patients as well. Zinck[130] found necrosis to occur in five out of twelve patients. Extensive burns involving approximately half of the total body surface, which led to a quick death, produced most striking damage to the central and intermediate parts of the hepatic lobules in this series of patients.[130] Baker[131] noted minimal degrees of necrosis to be present in four cases in which the burn itself may have been the cause. Moderate to severe necrosis, extending to more than a quarter or nearly one-half of the distance from the central vein to the periphery of the hepatic lobules, respectively, was also observed, but this was attributed to complications of the burns or other accessory factors, such as thrombosis and infection.[131] In addition, some degree of liver dysfunction in burn patients who were not treated with tannic acid could often be established by laboratory tests. Patients treated with gentian violet showed marked deviations from the normal in the dextrose tolerance test.[96,132] These alterations in liver function were comparable to those seen in tannic acid-treated patients.[96] Abnormalities in the serum bilirubin levels, the Bromsulphalein retention test, the hippuric acid conjugation test, and the cephalin flocculation test were shown after treatment with coagulating agents other than tannic acid or petrolatum gauze, with or without pressure dressing.[51] Using essentially similar test systems, James and coworkers[133] obtained comparable results. Furthermore, changes that were indicative for liver necrosis were found in the urine of burn patients treated with cod-liver ointment, indifferent ointment, or sterile dressings only.[101,102]

Similar to the results of human studies, histopathological and functional changes of the liver have been observed following experimentally induced thermal injuries in animals that did not receive tannic acid treatment. Thus, different levels of liver damage, ranging from serous inflammation, turbid distension, dissociation to fatty and parenchymatous degeneration, and even necrosis, were found in histological examinations in guinea pigs[114,115,134] and rabbits.[17] Impairment of hepatic functioning, as detected by a decreased clearance of the dye Rose Bengal, was also reported.[135]

Furthermore, in those studies evaluating the effects of tannic acid on the liver, the outcomes were not always univocal. The results obtained in at least two animal studies were contradictory to the general perception that tannic acid is hepatotoxic. Ahnefeld[114] noted a decrease in the incidence and severity of liver damage in experimentally burned guinea pigs treated with either a tannic acid spray or ointment in comparison with control animals. In experiments by the same author in which tannic acid was applied to artificial wounds after surgical removal of the skin, liver histology was essentially normal as well.[114] More recently, it was shown by Schölmerich and coworkers[136] that application of tannic acid to burned rats prevented some changes in liver morphology and metabolism. Animals treated one hour after burning showed no signs of ultrastructural changes in the liver cells, and blood urea concentrations were only slightly lowered or reached normal levels when animals were treated with tannic acid one hour or twenty-four hours after induction of the injury, respectively.

Additionally, it should be taken into account that the experimental design of those toxicity studies where a harmful effect of tannic acid was seen did not or only partly reflected clinical practice, which makes it difficult to extrapolate the findings. This difficulty of applying observations in animals directly to the human situation lies on the one hand in the differences in morphological and functional skin characteristics. Therefore, perhaps with exception of the pig model,[121] animal models for burn injury are, in general, not strictly comparable to human burns. Neither are the various denudation experiments[107,108,111] comparable in this respect. On the other hand, the dosages administered to animals as well as the mode of application of tannic acid also hampers comparison. The amounts of tannic acid given were often very high and exceeded, by far, the concentrations of the solutions applied on burn wounds. Likewise, absorption characteristics of subcutaneous, intramuscular, or intravenous injections are completely different from a topical administration to damaged skin.

However, it is not only this substantial body of evidence accumulated in the past that justifies the question of tannic acid being detrimental to the liver. Starting in the early sixties, it was gradually realized that hepatic failure was inextricably bound with the burn syndrome. The impetus for this change in the way of thinking has certainly been the fact that adequate tests became available to determine serum transaminase levels,[137] which facilitated the noninvasive diagnosis of liver damage in the course of time. With the aid of these enzyme assays, it was established that hepatocytes are subject to destruction in burn patients[138-146] and in experimentally burned animals.[147-153] Along with the results of these enzyme tests, more data were collected on the histopathology of the liver following thermal injury. At present, reports on different levels of liver damage, ranging from fatty changes, congestion, and edema, and several forms of liver degeneration to necrosis, are quite common.[117,141,147,150,153-157]

The experiments by the group of Allgöwer and Schoenenberger from the University of Basel in Switzerland have also been of significant importance in the conception that native pathophysiological phenomena, rather than tannic acid intoxication, underlie the liver damage seen in burn injuries. These researchers isolated and characterized a toxic macromolecular lipid-protein complex from burned mouse and human skin and from the serum of burn patients.[158-161] In various studies, the effects of this toxic complex on structural and metabolic parameters of the liver were extensively examined and compared with those observed after a controlled in-vivo burn injury. Using autoradiography, it was shown that 14C-labelled toxic complex accumulated in practically all organs with a significant preference for the liver.[162] Ultrastructural changes in the mitochondria of hepatocytes ranging from cristolysis, partial intramitochondrial vacuolization, and sometimes a total vacuolar destruction of mitochondria were found to occur both after toxin injection and experimental burn. The specificity of these alterations was proven by application of different doses of toxin, which resulted in a dose-dependent increase in destruction.[163,164] This damage to the mitochondria, where the cellular oxygenation chain is located, was reflected in liver metabolism studies, which demonstrated that several processes depending on ADP-rephosphorylation, such as gluconeogenesis, glycogen synthesis, and urea formation, were inhibited.[165]

Finally, it should be realized that the tannic acid preparations used in the thirties and forties for the local treatment of burn patients and in the early toxicity studies were ill defined and of low purity. This is reflected, in particular, in the pharmacopoeia descriptions of medicinal tannic acid of those days. In the Pharmacopoeia of the United States of America of 1926, it was described as "a tannin usually obtained from nutgall,"[13] not at all specifying the plant material from which the galls originated. Other pharmacopoeia were more explicit but still allowed various plant species to be used as a source of tannic acid. In the British and French pharmacopoeia, Turkish or Aleppo galls from several Quercus species were mentioned as sources of tannic acid.[10,12] However, according to commentaries on the pharmacopoeia of Germany and Switzerland, tannic acid may also be derived from Chinese or Korean galls growing on R. semialata.[166,167] Likewise, the few reports in which reference was made to the type of tannic acid indicated that no unequivocal, well-characterized products were used in clinical and experimental studies carried out from the 1920s to the 1940s. Thus, the use of aleppo,[25,26] quebracho,[84] and catechu[87] tannins was mentioned. These tannins are derived from different plant species and, as is known today, vary considerably in composition; the latter two do not even contain tannic acids in any strict sense as their major constituents (i.e., galloyl-glucose esters) but rather condensed tannins.[168] Just as there was a poor definition of the plant species from which tannic acids were derived, original methods used for isolation were also inadequate and merely consisted of simple solvent extraction procedures. For instance, the extraction of tannic acid from fermented plant galls with water-saturated ether is described in the British Pharmacopoeia.[10] In particular, the purity, expressed as the percentage of tannic acid, of the products obtained in this way was relatively low. Thus, in two studies performed around 1930, the total tannic acid content in several products, as estimated by the hide powder method, was found to range from 55 to 90 percent depending on the extraction solvent and plant material used.[169,170] More recently, it was shown by high-pressure liquid chromatography and other analytical methods that in a tannic acid sample from 1940 the content of galloyl-glucose esters comprised only 35 percent of the total, in addition to high levels of other constituents, such as condensed tannins, flavonoids, and gallic acid.[171] Furthermore, the complexity of tannic acid products or tannin extracts was not appreciated in this period, and it was not until the early fifties, with the introduction of adequate separation techniques, that it could be demonstrated that tannin extracts in general consisted of a large number of different substances.[172,173] It is reasonable to suspect this poor quality of the older tannic acid preparations to have contributed to at least part of the detrimental effects observed in burn patients and toxicity studies. In particular, the presence of contaminants, such as gallic acid, which is a metabolite formed during the breakdown of tannic acid, might have been disadvantageous in this respect. Proof for this assumption was recently acquired in some experiments in which it was shown that gallic acid, even when present in low concentrations, completely blocked the protein-binding capacity of tannic acid preparations.[174] Therefore, it is conceivable that gallic acid, but probably also other impurities, may have hampered the fixation of endogenous burn toxins in the skin, thereby constituting a potential hazard to the liver. The toxic effects observed in several animal studies may be explained in a similar way. Attenuation of the protein-binding capacity may have resulted in a higher availability of unbound tannic acid, which consequently may have given rise to an increase in bodily uptake and elevation of plasma concentrations.

Conclusion

In summary, tannic acid can be considered as one of the more important therapeutics used in the topical treatment of burn patients throughout the 20th century. Its use, however, changed dramatically over time, and many positive reactions regarding the effectiveness were issued shortly after its introduction by Davidson in 1925. However, the tannic acid method became obsolete after the appearance of several reports on hepatotoxicity in the early forties. Only in present times, with advances in the fields of burn research, does a better understanding of the pathophysiology of the burn syndrome, the involvement of the liver therein, and tannic acid research occur. As a result, with the availability of highly purified tannic acids, the usefulness of tannic acid as an adjuvant therapy has again gained interest. This rise and fall in popularity of tannic acid is also reflected in review articles that have been published over the years on this subject. Lee and Rhoads in 194489 stated that tannic acid was applied successfully and, in fact, had produced a decrease in mortality rate despite the occurrence of liver necrosis. In subsequent reviews, the latter aspect was emphasized.[175-177] Conversely, in 1995 Hupkens, et al.,[178] once more made the necessary differentiations in the reports on hepatotoxicity of tannic acid and reevaluated its use for better cosmetic results.

In this respect, a parallel may be drawn between tannic acid and silver, another therapeutic regimen for the local treatment of burns. After a period in which the use of silver was reviled, it has again obtained an important place in the contemporary treatment of burn wounds.[179,180] Similarly, as it appears to be now, highly purified tannic acids might gain interest as a tool to improve wound healing and to reduce scar tissue formation. However, prior to the reintroduction of tannic acid in burn treatment, a thorough benefit-risk analysis should be carried out. This will, in the near future, require controlled prospective studies comparing tannic acid with current standard therapeutic regimens, such as the local application of silver sulfadiazine, with rigorous toxicological assessment in which any detrimental effects of tannic acid on the liver are to be excluded.

In anticipation of such tests, it was attempted in this review to tentatively answer the question of whether or not tannic acid actually is toxic to the liver. From the collected data, it can be concluded that the evidence yet is inconclusive. Thus, many clinical and experimental studies in the past were indicative for a potential hepatotoxic effect of tannic acid. However, tannic acid preparations of ill definition and poor quality were used, often in extremely high concentrations. This could have negatively affected the outcome of these studies. Moreover, liver damage and impairment of liver function also occurred in patients who did not receive tannic acid treatment at all, and these phenomena are now considered part of the burn syndrome. On basis of these considerations, the suggestion by some that tannic acid has been a contributing factor to the death among burn patients seems to be untenable, also in light of the lowered mortality rate found in most clinical studies. It is our opinion that the local application of tannic acid to burn wounds causes no serious hepatic damage, at least not any more than the thermal injury does in itself. A prerequisite is that it is used under strictly controlled conditions, that a highly purified tannic acid product is applied in moderate concentrations (at maximum 2.5- to 5-percent tannic acid), and an adequate pharmaceutical formulation is used, which minimizes decomposition and creates a favorable environment for wound healing.

Acknowledgment

The library staff of Utrecht University is acknowledged for all their efforts to retrieve relevant articles. This study is financially supported by the foundation Achmea Slachtoffer en Samenleving, Zeist, The Netherlands.

References

  1. Hsu WS. Traditional Chinese treatment of burns. In: Yang CC, Hsu WS, Shih TS (eds). Treatment of Burns. Berlin, Germany: Springer, Verlag, 1982:140-50.

  2. Central Council for Research in Indian Medicine and Homoeopathy. Handbook of Domestic Medicine and Common Ayurvedic Remedies. New Delhi, India: Ministry of Health and Family Welfare, Government of India, 1978:41-2.

  3. Moncrief JA. The development of topical therapy. J Trauma 1971;11(11):906-10.

  4. Monafo WW, Tandon SN, Ayvazian VH, et al. Cerium nitrate: A new topical antiseptic for extensive burns. Surgery 1976;80(4):465-73.

  5. Davidson EC. Tannic acid in the treatment of burns. Surg Gynecol Obstet 1925;41:202-21.

  6. Haslam E. Practical Polyphenolics: From Structure to Molecular Recognition and Physiological Action. Cambridge, UK: Cambridge University Press, 1998:10-83.

  7. Mussche R. Isolering, struktuurbepaling en industriële toepassingen van hydrolyseerbare plantaardige looistoffen. Farm Tijdschr België 1989;66(1):2-6.

  8. Gnamm H. Die Gerbmittel; allgemeine Beschreibung der pflanzlichen Gerbmittel. In: Bergmann M, Gnamm H, Vogel W (eds). Die Gerbung mit Pflanzengerbstoffe; Gerbmittel und Gerbverfahren. Wien, Austria: Verlag von Julius Springer, 1931:1-100.

  9. Haslam E. Chemistry of Vegetable Tannins. London, UK: Academic Press, 1966:14-65.

  10. British Pharmacopoeia. Acidum tannicum [Acid. tann.], tannic acid. London, UK: Constable & Co Ltd., 1932:32.

  11. Deutsches Arzneibuch. Acidum tannicum - Gerbsäure. Berlin, Germany: R. v. Decker's Verlag, 1926:32-3.

  12. Pharmacopée Française, 6th edition. Tannin officinale, acidum tannicum. Rennes, France: Imprimeries Oberthur, 1937:1017-9.

  13. Pharmacopoeia of the United States of America, 10th Decennial Revision. Acidum tannicum, tannic acid. Philadelphia, PA: JB Lippincott Company, 1926:28-9.

  14. Anonymous. Studies on the toxic effects of certain burn escharotic herbs. Chinese Med J 1978;4(5):388-93.

  15. Yang CC, Xiao YR, Li YY. Management of the burn wound. In: Yang CC, Hsu WS, Shih TS (eds). Treatment of Burns. Berlin, Germany: Springer Verlag, 1982:41-105.

  16. Shi TS. Use of combined traditional Chinese and western medicine in the management of burns. Panminerva Med 1983;25(3):197-202.

  17. Pfeiffer H. Experimentelle Beiträge zur Ätiologie des primären Verbrennungstodes. Virchows Arch Pathol Anat 1905;180(3):367-435.

  18. Robertson B, Boyd GL. Toxemia of severe superficial burns. J Lab Clin Med 1923;9:1-29.

  19. Gordon RM. Treatment of burns by tannic acid. Lancet 1928(Feb 18):336-7.

  20. Beck CS, Powers JH. Burns treated by tannic acid. Ann Surg 1926;84:19-36.

  21. Fraser J. The treatment of burns in children. BMJ 1927(June 18):1089-92.

  22. Griffith GC. The treatment of burns in the Presbyterian Hospital of Philadelphia. Int Clinics 1928;4:129-31.

  23. Montgomery AH. The tannic acid treatment of burns in children. Surg Gynecol Obstet 1929;48:277-80.

  24. Glover DM. Six years of tannic acid treatment of burns. Surg Gynecol Obstet 1932;54:798-805.

  25. Mitchiner PH. Treatment of burns and scalds with special reference to the use of tannic acid. BMJ 1933;(Mar 18):447-52.

  26. Mitchiner PH. Treatment of burns and scalds with special reference to the use of tannic acid. Lancet 1933;(Feb 4):233-9.

  27. Wilson WC. Extensive burns and scalds. Edinburgh Med J 1935;42:177-92.

  28. Wilson WC, Macgregor AR, Stewart CP. The clinical course and pathology of burns and scalds under modern methods of treatment. Br J Surg 1938;25:826-65.

  29. Fantus B, Dyniewicz HA. Compound solution of tannic acid. J Am Med Assoc 1937;109(3):200-3.

  30. Heggie JF, Heggie RM. Antiseptic analgesic tannic acid jelly for burns. Lancet 1940;(Sept 28):391.

  31. McClure RD, Lam CR. Problems in the treatment of burns; liver necrosis as a lethal factor. Southern Surg 1940;9(4):223-34.

  32. Buis LJ, Hartman FW. Histopathology of the liver following superficial burns. Am J Clin Pathol 1941;11:275-87.

  33. Wells DB. The aseptic tannic acid treatment of diffuse superficial burns. J Am Med Assoc 1933;101:1136-8.

  34. Wells DB, Humphrey HD, Coll JJ. The relation of tannic acid to the liver necrosis occurring in burns. New Engl J Med 1942;226(16):629-36.

  35. Hunt JH, Scott PG. The treatment of burns in out-patients with reinforced tannic acid dressings. Lancet 1932;(Oct 8):774-6.

  36. Bettman AG. Tannic acid and silver nitrate in burns. Surg Gynecol Obstet 1936;62:458-63.

  37. Bettman AG. The rationale of the tannic acid: Silver nitrate treatment of burns. J Am Med Assoc 1937;108(18):1490-4.

  38. Clark AM, Cruickshank R. Observations on the treatment of burns. Lancet 1935;(Jan 26):201-4.

  39. Hartman FW, Schelling V. Effect of acids on certain carbocyclic antiseptics. Proc Soc Exp Bio Med 1935;33:460-7.

  40. Bancroft FW, Rogers CS. The treatment of cutaneous burns. Ann Surg 1926;84(1):1-18.

  41. Bancroft FW, Rogers CS. Late treatment of burns. Arch Surg 1928;16(5):979-99.

  42. Wilson WC. Treatment of burns and scalds by tannic acid. BMJ 1928;(July 21):91-4.

  43. Beekman F. Tannic acid treatment of burns, end-results in one hundred and fourteen cases compared with three hundred and twenty treated by other methods. Arch Surg 1929;18:803-6.

  44. Davidson EC, Penberthy GC. The treatment of burns in children with tannic acid. Proc Internat Postgrad Med Ass 1929;5:265-8.

  45. Herzfeld G. The treatment of burns and scalds by tannic acid. Practitioner 1929;122:106-11.

  46. Mason JB. An evaluation of the tannic acid treatment of burns. Ann Surg 1933;97(5):641-7.

  47. Penberthy GC. Tannic acid treatment of burns. J Michigan Med Soc 1935;34(1):1-4.

  48. Glover DM, Sydow AF. Fifteen years of the tannic acid method of burn treatment. Am J Surg 1941;51:601-19.

  49. Beekman F. In: Discussion following Glover DM, Sydow AF. Fifteen years of the tannic acid method of burn treatment. Am J Surg 1941;51:601-19.

  50. Erb IH, Morgan EM, Farmer AW. The pathology of burns. Ann Surg 1943;117:234-55.

  51. Saltonstall H, Walker J, Rhoads JE, Lee WE. The influence of local treatment of burns on liver function. Ann Surg 1945;121(3):291-300.

  52. McClure RD, Allen CI. Davidson tannic acid treatment of burns, ten year results. Am J Surg 1935;28:370-88.

  53. Leriche R, Jung A. Du traitement des brulures par l'acide tannique. Lyon Chir 1933;30(2):177-9.

  54. Dueño FP. Nuevas ideas en el tratamiento de las quemaduras graves. Arch Med Cir Espec 1930;32(23):593-7.

  55. Floresco A. Le traitement des brulures par l'acide tannique. Gaz Hop Civ Milit 1927;100(78):1281-5.

  56. Van der Spek J. Over de behandeling van brandwonden met versch bereide waterige looizuuroplossingen. Nederlands Tijdschr Geneesk 1931;75:873-7.

  57. Wollesen JM. Gerbsäurebehandlung von Verbrennungen. Chirurg 1936;8(18):732-40.

  58. Von Löhr W, Zacher K. Zur Klinik und Pathologie von Verbrennungen 2. und 3. Grades. Zentralbl Chir 1939;66(1):5-24.

  59. Schreiner K. Die Therapie der Verbrennungen. Wiener Klin Wochenschr 1930;43(28):871-6.

  60. Klug W. Über Behandlung ausgedehnter Verbrennungen. Zeitschr ärzt Fortbildung 1931;28(9):278-81.

  61. Seifert E. Die Tanninbehandlung der frischen Hautverbrennungen und ihre fehlerhafte Anwendungsweise. Zentralbl Chir 1933;60:1051-5.

  62. Wienecke H. Zur Behandlung der Verbrennungen. Med Welt 1933;7:1643-4.

  63. Siber. Die Behandlung grosser Verbrennungen mit und ohne Tannin. Verhandlungen Dtsch Ges Unfallheilk 1934;(Oct 12):110-2.

  64. Liebig AM. Sitzungsberichte aus chirurgischen Gesellschaften. Zentralbl Chir 1937;45:2600-1.

  65. Flörcken H. Die Behandlung der Kriegsverbrennungen. Chirurg 1940;12(4):89-92.

  66. Baltin W. Tanninbehandlung der Verbrennungen aller Grade. Monatsschr Unfallheilk 1942;49:65-80.

  67. Langer M. Ueber die Resultate der Tanninbehandlung bei Verbrennungen im Kindesalter. Wien Klin Wochenschr 1933;46(22):689-90.

  68. Saegesser M. Die Behandlung der Verbrennungen. Chirurg 1940;12(23):708-11.

  69. Fasal P. Versorgung und Behandlung von Brandwunden. Chirurg 1938;10(13):454-62.

  70. Gymnich W. Die Gerbsäure, ein altes Mittel zur modernen Behandlung von Verbrennungen bei plötzlichen Unglücksfällen. Med Welt 1932;6(46):1646.

  71. Saegesser M. Die Tanninsäurebehandlung der Verbrennungen. Schweiz Med Wochenschr 1932;1:117-8.

  72. Hilgenfeldt O. Die Behandlung und die pathogenetischen Grundlagen der Verbrennungen. Erg Chir 1936;29:102-210.

  73. Underhill FP, Carrington GL, Kapsinow R, Pack GT. Blood concentration changes in extensive superficial burns, and their significance for system treatment. Arch Int Med 1923;32:31-49.

  74. Blalock A. Experimental shock (VII) The importance of the local loss of fluid in the production of the low blood pressure after burns. Arch Surg 1931;22:610-6.

  75. Underhill FP, Kapsinow R. The alleged toxin of burned skin. J Lab Clin Med 1931;16:823-30.

  76. McClure GS. Evaporation of water from superficial burns. Arch Surg 1936;32(5):747-55.

  77. Ham AW. Experimental study of the tannic acid treatment of burns with particular reference to its effect on local fluid loss and healing. Ann Surg 1944;120(5):698-706.

  78. McClure RD. The treatment of the patient with severe burns. J Am Med Assoc 1939;113(20):1808-12.

  79. Taylor F. The misuse of tannic acid. J Am Med Assoc 1936;106(14):1144-6.

  80. Cannon B, Cope O. Rate of epithelial regeneration, a clinical method of measurement, and the effect of various agents recommended in the treatment of burns. Ann Surg 1943;117(1):85-92.

  81. McIndoe AH. In: Hunter JB, Willcox W, chairs. Discussion at the joint meeting of the sections of surgery and of therapeutics and pharmacology of the Royal Society of Medicine. Lancet 1940;(Nov 16):621-2.

  82. Wakeley CPG. In: Hunter JB, Willcox W, chairs. Discussion at the joint meeting of the sections of surgery and of therapeutics and pharmacology of the Royal Society of Medicine. Lancet 1940;(Nov 16):621-2.

  83. Mowlem R. The treatment of burns. Proc Royal Soc Med 1941;34:221-4.

  84. Hirshfeld JW, Pilling MA, Maun ME. A comparison of the effects of tanning agents and of Vaseline gauze on fresh wounds of man. Surg Gynec Obstet 1943;76:556-61.

  85. Clowes GHA, Lund CC, Levenson SM. The surface treatment of burns, a comparison of results of tannic acid, silver nitrate, triple dye, and Vaseline or boric ointment as surface treatment in 150 cases. Ann Surg 1943;118(5):761-79.

  86. Seeger SJ. The hydrogen-ion concentration value of tannic acid solutions used in the treatment of burns. Surg Gynec Obstet 1932;55:455-63.

  87. Ullmann K. Bemerkungen über die Bedeutung der Gerbsäurebehandlung für die tägliche Praxis und die Pathologie der schweren Verbrennungszustände. Wiener Klin Wochenschr 1933;46(47):1437-9.

  88. Anagnostidis N. Histologische experimentelle Untersuchungen über die Wirkung einzelner örtlich angewandter Arzneimittel bei Verbrennungen dritten Grades. Dtsch Zeitschr Chir 1939;252:248-56.

  89. Lee WE, Rhoads JE. The present status of the tannic acid method in the treatment of burns. J Am Med Assoc 1944;125(9):610-2.

  90. Aldrich RH. The role of infection in burns, the theory and treatment with special reference to gentian violet. New Engl J Med 1933;208(6):299-309.

  91. Mitchiner PH. Thoughts on four years of war surgery -- 1939 to 1943. BMJ 1944;(Jul 8):37-40.

  92. Atkins HJB. The management of burns. BMJ 1942;(Jun 13):729-31.

  93. Porritt AE. Military surgery in the 'Middle East'. Br J Surg 1944;31:208-21.

  94. Belt TH. Liver necrosis following burns, simulating the lesions of yellow fever. J Pathol Bacteriol 1939;48(3):493-8.

  95. Duffin JD. Liver necrosis following burns. Can Med Ass J 1942;47:138-9.

  96. Wolff WA, Elkinton JR, Rhoads JE. Liver damage and dextrose tolerance in severe burns. Ann Surg 1940;112:158-60.

  97. Abbott WE, Holden WD. Prothrombin test as a diagnostic and prognostic aid. Arch Surg 1942;45:261-71.

  98. Jackson AV. Liver necrosis in burns treated with tannic acid. Med J Australia (Sydney) 1944;2:352-4.

  99. McClure RD, Lam CR, Romence H. Tannic acid and the treatment of burns: An obsequy. Ann Surg 1944;120(3):387-405.

  100. Rae SL, Wilkinson AW. Liver function after burns in childhood, changes in laevulose tolerance. Lancet 1944;(Mar 11):332-9.

  101. Fuchs HK, Lutzeyer W. Behandlung von Verbrennungen mit metallischem Aluminium. Ärztl Wochenschr 1949;4(11/12):181-3.

  102. Stör O. Die Verbrennungskrankheit und ihre Behandlung. Stuttgart, Germany: Ferdinand Enke Verlag, 1952:37-49.

  103. Gillman J, Gillman T. Structure of the liver in fatal burns. S Afr J Med Sci 1948;13:169-81.

  104. Sevitt S. Burns, Pathology and Therapeutic Applications. London, UK: Butterworth & Co. Ltd., 1957:298-308.

  105. Ollinger P. Ist die Tanninbehandlung bei Verbrennungen schädlich? Chirurg 1947;17/18(14):629-35.

  106. Clark EJ, Rossiter RJ. Liver function in rabbits after injection of tannic acid. Lancet 1943;(Aug 21):222-3.

  107. Robinson HJ, Graessle OE. Toxicity of tannic acid. J Pharmacol Exp Ther 1943;77:63-9.

  108. Baker RD, Handler P. Animal experiments with tannic acid, suggested by the tannic acid treatment of burns. Ann Surg 1943;118:417-26.

  109. Cameron GR, Milton RF, Allen JW. Toxicity of tannic acid, an experimental investigation. Lancet 1943;(Aug 14):179-86.

  110. Forbes JC, Evans EI. Tannic acid and liver necrosis. Surg Gynecol Obstet 1943;76:612-3.

  111. Hartman FW, Romence HL. Liver necrosis in burns. Ann Surg 1943;118:402-16.

  112. Barnes JM, Rossiter RJ. Toxicity of tannic acid. Lancet 1943;(Aug 21):218-22.

  113. Lust F, Pfaundler M. Krankheiten des Kinderaltes, Ihre Erkennung und Behandlung in der Praxis. Berlin, Germany: Urban und Shwarzenberg, 1946:16-8.

  114. Ahnefeld FW. Ist die Ablehnung der Tannintherapie bei Verbrennungen berechtigt? Monatsschr Unfallheilk 1954;57:207-15.

  115. Weber E. Die Tanninbehandlung bei der Verbrennungskrankheit. Langenbecks Arch Klin Chir 1955;282:122-4.

  116. Grob M, Stockmann M, Bettex M. Lehrbuch der Kinderchirurgie. Stuttgart, Germany: Georg Thieme Verlag,1957:629-33.

  117. Göring G, Langer G, Koch W, Schröder H. Erfahrungen mit der Verschorfungs- und Koagulationsbehandlung bei Verbrennungen im Kinderalter. Brunsweicher Beitrage Klin Chir 1968;216:545-52.

  118. Hettich R. Die verzögerte primäre Exzision von Verbrennungsdefekten nach Gerbungsbehandlung. Helv Chir Acta 1982;49:575-82.

  119. Hettich R, Koslowski L. Frühbehandlung der Brandwunden. Langenbecks Arch Chir 1984;364:205-11.

  120. Hoekstra MJ, Rogmans MP. Experimental burns in pigs for the evaluation of topical wound therapy. In: Harding KG, Leaper DL, Turner TD (eds). Proceedings of the 1st European Conference on Advances in Wound Management. London, UK: Macmillan Magazines Ltd., 1992:11-3.

  121. Hoekstra MJ, Hupkens P, Dutrieux RP, et al. A comparative burn wound model in the New Yorkshire pig for the histopathological evaluation of local therapeutic regimens: Silver sulfadiazine cream as a standard. Br J Plast Surg 1993;46:585-9.

  122. Hoekstra MJ, Dutrieux RP, Rogmans MP. Tannin ointment alternated with silver sulfadiazine 1% cream versus tannin ointment alternated with silver sulfadiazine 1% liquid. Pre-clinical investigation report. Beverwijk, The Netherlands: Burns Research Institute, 1992.

  123. Heijmen FH, Du Pont JS, Middelkoop E, et al. Cross-linking of dermal sheep collagen with tannic acid. Biomaterials 1997;18:749-54.

  124. Kreis RW, Vloemans AFPM. Tannin ointment. Clinical pilot trial report. Beverwijk: Burns Research Institute, 1992.

  125. Hupkens P, Hoekstra MJ, Vloemans AFPM, Kreis RW. Tannin ointment, follow-up results, Clinical pilot trial report. Beverwijk, The Netherlands: Burns Research Institute, 1993.

  126. Bardeen CR. A review of the pathology of superficial burns, with a contribution to our knowledge of the pathological changes in the organs in cases of rapidly fatal burns. Johns Hopkins Hosp Rep 1898;7:137-79.

  127. Vogt W. Über histologische Befunde beim Verbrennungstode. Virchow's Arch Pathol Anat 1929;273:140-62.

  128. Weiskotten HG. Histopathology of superficial burns. J Am Med Assoc 1919;72(4):259-61.

  129. Brenner F. Geringgradige Verbrennung als Ursache schwerer Organveränderungen. Centralbl Allg Pathol Path Anat 1936;65(4):97-101.

  130. Zinck KH. Pathologische Anatomie der Verbrennung, zugleich ein Beitrag zur Frage der Blutgewebsschranke und zur Morphologie der Eiweisszerfallsvergiftungen. Veröffentl Konstitutions Wehrpathol 1940;46:1-232.

  131. Baker RD. The internal lesions in burns with special reference to the liver and to splenic nodules. Am J Pathol 1945;21:717-39.

  132. Elkinton JR, Wolff WA, Lee WE. Plasma transfusion in the treatment of the fluid shift in severe burns. Ann Surg 1940;112(1):150-7.

  133. James GW, Purnell OJ, Evans EI. The anemia of thermal injury. II. Studies of liver function. J Clin Invest 1951;30:191-9.

  134. Blüthgen H. Beitrag zur Pathologie der Verbrennung. Frankfurt ZeitschrPathol 1943;58:85-118.

  135. Gilmore JP, Fozzard HA. Liver function following thermal injury. Am J Physiol 1960;198(3):491-5.

  136. Schölmerich J, Richter IE, Mastari H, et al. Zur therapeutischen Beeinflussbarkeit der Toxinresorption bei Hautverbrennungen; synthetischer Hautersatz oder Tanningerbung. Anaesthetist 1981;30:185-90.

  137. Reitman S, Frankel S. A colorimetric method for the determination of serum glutamic oxalacetic acid and glutamic pyruvic transaminases. Am J Clin Pathol 1957;28:56-63.

  138. Bocanegra M, Hinostroza F; Kefalides NA. Serum transaminase changes in severe burns. Ann Surg 1963;157(3):438-45.

  139. Reichard H, Liljedahl SO, Birke G. Serum activity of ornithinecarbamoyl transferase and transaminases in severe burns. Acta Chir Scand 1963;126:45-52.

  140. Chlumsk J, Vrabec R, Hyncík V, et al. Clinical manifestation of the impairment of the liver in the course of the burn disease. Acta Chir Plast 1973;15(4):238-46.

  141. Czaja AJ, Rizzo TA, Smith WR, Pruitt BA. Acute liver disease after cutaneous thermal injury. J Trauma 1975;15(10):887-94.

  142. Hiramatsu M, Izawa Y, Hagihara M, et al. Serum lipid peroxide levels of patients suffering from thermal injury. Burns 1984;11:111-6.

  143. Chiarelli A. Abnormal transaminase levels in burned patients. Plast Reconstr Surg 1985;75(1):134-5.

  144. Chiarelli A, Casadei A, Pornaro E, et al. Alanine and aspartate aminotransferase serum levels in burned patients: A long-term study. J Trauma 1987a;27(7):790-4.

  145. Chiarelli A, Siliprandi L, Casadei A, et al. Aminotransferase changes in burned patients. Intensive Care Med 1987b;13:199-202.

  146. Latha B, Ramakrishnan M, Jayaraman V, Babu M. Serum enzymatic changes modulated using trypsin: Chymotrypsin preparation during burn wounds in humans. Burns 1997;23(7/8):560-4.

  147. Arturson G. Serum glutamic oxalacetic transaminase activity in experimental burns. Acta Chir Scand 1961;120:303-8.

  148. Arturson G, Wallenius G. The hepatocellular origin of circulating enzymes in experimental burns. Acta Chir Scand 1963;126:34-44.

  149. Spector AA, Pauli WA. Early changes in serum enzymes in the rat following burn trauma. J Appl Physiol 1963;18(4):818-20.

  150. Ashur H, Ben-Hur N, Kuperman O, Eshchar Y. Liver dysfunction and immunological disturbances in the thermal burn injury. Burns 1979;6(3):160-4.

  151. Nishigaki I, Hagihara M, Hiramatsu, et al. Effect of thermal injury on lipid peroxide levels of rat. Biochem Med 1980;24:185-9.

  152. Carter EA, Kirkham SE, Udall JN, et al. Thermal injury and gastrointestinal function II: Evidence for the production of hepatic dysfunction in the rat following acute burn injury. J Burn Care Rehabil 1986;7(6):475-8.

  153. Nishimura T, DeSerres S, et al. Gene expression and cytokine and enzyme activation in the liver after a burn injury. J Burn Care Rehabil 2000;21:135-41.

  154. Arturson G. Pathophysiological aspects of the burn syndrome. Acta Chir 1961;Suppl 274:1-135.

  155. Teplitz C. Pathology of burns. In: Artz CP, Moncrief JA (eds). The Treatment of Burns, Second Edition. Philadelphia, PA: WB Saunders Co., 1969:22-88.

  156. Talaat SM, El-din Beheri G, Zaki MS, El-Bolkainy N. Prevention of early histopathological changes in the liver in extensive burns. Br J Plast Surg 1973;26:132-9.

  157. Angela G, Marino G, Teich-Alasia S, et al. Histopathology of the liver in 187 patients with severe burns: A needle biopsy study. Bull Clin Rev Burn Inj 1984;1:44.

  158. Schoenenberger GA, Bauer U, Cueni LB, et al. Physical, chemical and biological properties of a specific toxic lipid-protein complex formed in thermally altered mouse skin. Biochim Biophys Acta 1972;263:164-77.

  159. Schoenenberger GA, Cueni LB, Bauer U, et al. Isolation and characterization of a toxic lipid-protein complex formed in mouse skin by controlled thermal energy: Comparison to an inactive precursor derived from thermally unexposed or native skin. Biochim Biophys Acta 1972;263:149-63.

  160. Schoenenberger GA. Burn toxins isolated from mouse and human skin. Monogr Allergy 1975;9:72-139.

  161. Wüst B. Isolierung, physikalisc-chemische Charakterisierung, Immunologie und biologische Eigenschaften eines spezifischen cutanen Verbrennungstoxins und dessen Vorstufe beim Menschen [dissertation]. Basel, Switzerland: Universität Basel, GTP-Verlag, 1977.

  162. Schoenenberger GA, Allgöwer M, Kremer B, Städler K. Neue Gesichtspunkte zur Verbrennungskrankheit. Chirurg 1976;47:582-8.

  163. Kremer B, Frenzel H, Schoelmerich J, et al. Vergleichende transmissions- und rasterelektronenmikroskopische Untersuchungen über Leberveränderungen bei Mäusen nach subletaler Hautverbrennung und intraperitonealer Injektion eines spezifischen cutanen Verbrennungstoxins. Langenbecks Arch Chir Suppl Chir Forum 1977;30:145-50.

  164. Kremer B, Allgöwer M, Scheidegger AM, et al. Toxin-specific ultrastructural alterations of the mouse liver after burn injuries and the possibility of a specific antitoxic therapy. Scand J Plast Reconstr Surg 1979;13:217-22.

  165. Schölmerich J, Kremer B, Richter IE, et al. Effect of cutaneous human or mouse burn toxin on the metabolic function of isolated liver cells. Scand J Plast Reconstr Surg 1979;13:223-30.

  166. Anselmino O, Gilg E (eds). Kommentar zum Deutschen Arzneibuch 6. Ausgabe 1926. Berlin, Germany: Verlag von Julius Springer, 1928:160-6.

  167. Käsermann H (ed). Kommentar zur Pharmacopoea Helvetica, fünfte Edition. Zürich, Switzerland: Selbstverlag des Schweizerisches Apotheker-Vereins, 1949:132-3.

  168. Santappa M, Sundara Rao VS. Vegetable tannins, a review. J Sci Industrial Res 1982;41:705-18.

  169. Chemnitius F. Zur Technik der Tanninfabrikation. J Prakt Chem 1927;117:83-96.

  170. Vogel W. Die Verarbeitung der pflanzlichen Gerbmittel auf Extrakte. In: Bergmann M, Gnamm H, Vogel W (eds). Die Gerbung mit Pflanzengerbstoffe; Gerbmittel und Gerbverfahren. Wien, Austria: Verlag von Julius Springer, 1931:290-364.

  171. De Keukeleire D, Van Peteghem C, Everaert E. Updating of ADI for tannic acid, based on results from recent research and improvement of the quality. Scientific report. Gent, Belgium: University of Gent, 1993.

  172. Kirby KS, Knowles E, White T. Tannins, part II: The complex nature of vegetable tannin extracts. J Soc Leather Trades Chem 1951;35:338-45.

  173. White T, Kirby KS, Knowles E. The complexity of tannin extract composition. J Soc Leather Trades Chem 1952;36:148-55.

  174. Halkes SBA, du Pont JS, Hoekstra MJ, et al. Gallic acid reduces the protein-precipitating capacity of tannic-acid preparations. In: Proceedings of the International Congress and 48th Annual Meeting of the Society for Medicinal Plant Research (GA): Natural products research in the new millennium. Zürich, Switzerland: ETH, 2000:SL06.

  175. Rosenquist H. The primary treatment of extensive burns. Acta Chir Scand 1947;95(Suppl 124):1-128.

  176. Harkins HN. The treatment of burns and freezing. In: Lewis D, Walters W, Blalock A, et al. (eds). Lewis' Practice of Surgery, Volume 1. WF Prior Company Inc., 1955:1-177.

  177. Cope O. The end of the tannic acid era. Harvard Med Alumn Bull 1992;65:17-9.

  178. Hupkens P, Boxma H, Dokter J. Tannic acid as a topical agent in burns: Historical considerations and implications for new developments. Burns 1995;21(1):57-61.

  179. Klasen HJ. Historical review of the use of silver in the treatment of burns. I. Early uses. Burns 2000;26:117-130.

  180. Klasen HJ. A historical review of the use of silver in the treatment of burns. II. Renewed interest for silver. Burns

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