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

Wounds. 2001;13(4) 

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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.[113,114,115,116,117] 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[138,139,140,141,142,143,144,145,146] and in experimentally burned animals.[147,148,149,150,151,152,153] 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.[117,141,147,150,153,154,155,156,157]

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.[158,159,160,161] 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.

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