Presentations of tetramethylammonium hydroxide dermal exposure and the valuable potential of diphoterine solution in decontamination: a retrospective observational study.

BACKGROUND: Tetramethylammonium hydroxide (TMAH) is a quaternary ammonium compound that is both a base corrosive and a cholinergic agonist, and it is widely used in the photoelectric and semiconductor industries. It causes corrosive skin injuries and systemic cholinergic toxicity with death primarily resulting from respiratory failure without efficacious early decontamination. METHODS: A retrospective observational study was performed of all cases of TMAH exposure reported to the Taiwan Poison Control Center between July 2010 and October 2017. Retrieved medical records were independently reviewed by two trained clinical toxicologists. RESULTS: Despite immediate (< 5 min) skin decontamination with copious amounts of tap water, one patient exposed to 25% TMAH involving ≥5% of total body surface area (TBSA) developed significant systemic toxicity. Patients exposed to 25% TMAH involving ≤1% TBSA developed first-degree chemical skin injuries but no systemic toxicity. Among patients exposed to lower concentrations (≤2.38%) of TMAH, the majority only experienced first-degree chemical skin injuries without systemic signs. Patients exposed to 0.5% TMAH involving nearly their entire TBSA developed no chemical skin injuries or systemic toxicity. All patients who had only first-degree chemical skin injuries did not develop systemic toxicity after exposure to either 2.38% or 25% TMAH. CONCLUSIONS: TMAH acts as an alkaline corrosive and cholinergic agonist. Systemic signs attributable to TMA+ can rapidly lead to respiratory failure and death after dermal exposure. We have demonstrated that an amphoteric solution may be efficacious for skin decontamination on-site immediately to prevent or ameliorate such toxicity. This practice especially carries a valuable potential in managing victims (patients) who have been exposed to those chemicals with immediate life-threatening toxicity (e.g. TMAH), suggesting that its early utilization deserves further study.

Corrosive substances ingestion: a review.

Corrosive chemical substance ingestions are a major problem, especially in developing countries, but also in developed countries such as the United States, France, and Belgium. Ingestions may be deliberate as suicide attempts (mostly in adolescents and adults) or accidental (mostly in children). The results can be devastating in terms of individual suffering and disability, but also in terms of resource utilization and costs. In developing countries, outcomes may be worse because of limited medical/surgical resources. Common sequelae include gastrointestinal (GI) tract (esophagus, stomach, pylorus, and duodenum) stricture formation, GI tract perforation, and hemorrhage. Systemic effects may also occur, such as disseminated intravascular coagulation (DIC), multi-organ system failure, and sepsis. Various interventions in the acute phase to reduce the severity of injury have been attempted, but there are no large controlled clinical trials to demonstrate efficacy. Dilation therapy in various forms is commonly used for the treatment of strictures and a variety of surgical procedures including esophagectomy and delayed replacement may be required in severe corrosive injury cases.

Acute chemical skin injuries in the United States: a review.

The objective was to perform a thorough review of published and other available data to elucidate the extent of chemical skin injuries in the US. Chemical skin injuries differ significantly from skin lesions produced by other injury mechanisms, so this review was restricted to the former. Retrieval of relevant published data was performed in PubMed and Google. Other data were retrieved from the American College of Surgeons National Trauma Databank, American Burn Association National Burn Repository, US Department of Labor Bureau of Labor Statistics, websites of all 50 US States Departments of Health, and the National Poison Data System of the American Association of Poison Control Centers. Two areas of significance in disfiguring skin burn injuries and particularly of chemical skin injuries, psychosocial issues and the associated financial burden, have been briefly reviewed. Because of the paucity of published data, international as well as US data have been included. A brief description of an active flushing fluid as an alternative to potable water, Diphoterine® solution, has also been included. Chemical skin injuries generally comprise approximately 2-5% of all skin burns, but sometimes higher percentages have been reported. Data analysis shows that while there are various sources regarding the epidemiology of chemical skin injuries, the total annual number cannot be determined because there is no centralized US national reporting mechanism. Literature and clinical experience demonstrate the importance of chemical skin injuries in USA. Dermal exposures to chemicals can result in mortality and morbidity. Chemical skin injuries can be avoided or ameliorated and preventive advanced measures should be taken to reduce or ameliorate them.

Seventy per cent hydrofluoric acid burns: delayed decontamination with hexafluorine® and treatment with calcium gluconate.

This is a case report of decontamination and treatment of a 70% hydrofluoric acid (HF) dermal splash injury. A worker was splashed with 70% HF, sustaining approximately 10% TBSA first- to third-degree chemical skin burns of the face, trunk, and left thigh and leg. Initial decontamination involved water rinsing, removal of contaminated clothing, more water rinsing, topical application of magnesium oxide, and administration of intravenous narcotics for management of severe pain. After a delay of approximately 3 hours, active skin washing with Hexafluorine®, 5 L, was performed, followed by intravenous, intradermal perilesional, and topical inunction administration of calcium gluconate. Pain relief and a cooling sensation were quite prompt after Hexafluorine® decontamination. Surgical debridement and skin grafting of the more severe burns were required. No significant systemic toxicity developed, although this has occurred in previously reported similar concentrated HF dermal splash exposure cases, some of which resulted in fatality. While burns did develop, the patient was released from the intensive care service after 2 days and, after skin grafting, had a good outcome at 90-day follow-up. Even after a long delay, decontamination with Hexafluorine® appeared to be beneficial in this case.

Part 2. Comparison of emergency washing solutions in 70% hydrofluoric acid-burned human skin in an established ex vivo explants model.

BACKGROUND: Hydrofluoric acid (HF) is a small and partially dissociated acid (pK(a) 3.2), able to deeply penetrate into human skin in addition to the corrosiveness of the hydrogen ion (H(+)) and the toxicity of the fluoride ion (F(-)). However, there has been a lack of experimental studies to objectively characterize the results of human HF skin exposure decontamination. METHODOLOGY/PRINCIPAL FINDINGS: A previously established experimental method using a human skin explants ex vivo model (Part 1. Experimental 70% hydrofluoric acid (HF) burns: Histological observations in an established human skin explants ex vivo model) described the lesions that appeared following 70% HF penetration. Within 5 min, 70% HF penetrates to the dermis. Using the same experimental conditions, a comparison study of two different washing protocols was performed: water + topical calcium gluconate (CaG) versus Hexafluorine(®). In these conditions, washing for 15 min with running tap water followed by topical CaG ointment only delayed burn onset, while severe tissue damage appeared later. In contrast, after washing with Hexafluorine(®) over 10 min, no histological lesions developed. These results are in accordance with the results of accidental human industrial case reports. CONCLUSION/SIGNIFICANCE: Amphoteric and hypertonic Hexafluorine(®) can deactivate H(+) and chelate F(-) ions. Based on these results, it should be considered as a promising first-aid decontamination solution to prevent or minimize significant local and systemic consequences of concentrated HF skin exposures.

Experimental 70% hydrofluoric acid burns: histological observations in an established human skin explants ex vivo model.

BACKGROUND: Hydrofluoric acid (HF) is particularly dangerous due to the potential for systemic effects and induction of severe skin necrosis through two mechanisms: corrosiveness and local tissue toxicity. In addition, because it is only partially dissociated (pK(a) 3.2), it is capable of penetrating deeply into tissues. There is a lack of experimental studies that objectively characterize the behavior of HF diffusion into human skin, specifically the kinetics of tissue penetration resulting in severe cellular lesions. METHODOLOGY/PRINCIPAL FINDINGS: We describe the cutaneous effects of HF using an established ex vivo human skin model. The diffusion of 70% HF starts within the first minute of contact at the epidermal surface and after 2 min reaches the basal layer. In the subsequent minute, the epidermis is destroyed and lesions appear in the papillary dermis after 4 min. Soon after, damage appears in the upper reticular dermis. Thus, 70% HF needs only 5 min of contact to completely penetrate human skin explants. This experiment is reproducible and corroborates previous studies and clinical effects reported in accidental HF exposures. CONCLUSION/SIGNIFICANCE: This study shows that the management of HF chemical skin exposure is a question of minutes, especially for initial decontamination. These experimental observations could be useful for objectively comparing skin decontamination methods. Further studies should help to confirm these preliminary results.

Empiric management of cyanide toxicity associated with smoke inhalation.

Enclosed-space smoke inhalation is the fifth most common cause of all unintentional injury deaths in the United States. Increasingly, cyanide has been recognized as a significant toxicant in many cases of smoke inhalation. However, it cannot be emergently verified. Failure to recognize the possibility of cyanide toxicity may result in inadequate treatment. Findings suggestive cyanide toxicity include: (1) a history of an enclosed-space fire scene in which smoke inhalation was likely; (2) the presence of oropharyngeal soot or carbonaceous expectorations; (3) any alteration of the level of consciousness, and particularly, otherwise inexplicable hypotension (systolic blood pressure ≤90 mmHg in adults). Prehospital studies have demonstrated the feasibility and safety of empiric treatment with hydroxocobalamin for patients with suspected smoke inhalation cyanide toxicity. Although United States Food and Drug Administration (FDA)-approved since 2006, the lack of efficacy data has stymied the routine use of this potentially lifesaving antidote. Based on a literature review and on-site observation of the Paris Fire Brigade, emergency management protocols to guide empiric and early hydroxocobalamin administration in smoke inhalation victims with high-risk presentations are proposed.

Decontamination of tetramethylammonium hydroxide (TMAH) splashes: promising results with Diphoterine in vitro.

Tetramethylammonium hydroxide (TMAH), used in microelectronic industries and research and development, has both corrosive properties and systemic toxicity. Two fatal TMAH occupational exposure cases have been published. Studies comparing initial TMAH decontamination with Diphoterine versus tap water were performed: an in vitro pH titration study and an MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) in vitro cytotoxicity cell viability assay. For pH normalization, 17 times more tap water than Diphoterine was required. In the cytotoxicity test, two-thirds of the cells remained viable after Diphoterine washing, compared with only one-third after tap water washing (p < .001). Diphoterine washing is a promising TMAH decontamination method.

Chemical assault and skin/eye burns: two representative cases, report from the Acid Survivors Foundation, and literature review.

Chemical assault is a significant problem throughout the world, resulting in disfigurement, sometime blindness or vision impairment, and constituting a major economic burden on otherwise overwhelmed health services in developing countries. Two representative cases are presented here. One involved domestic spouse abuse with an acid and the second involved a teen-aged female assaulted with an acid, perhaps for retribution over a local judicial matter. Such atrocities have a world-wide scope, which is reviewed here. Preventive measures are the most appropriate response. However, when such chemical assaults do occur, active measures to mitigate or negate their effects deserve consideration.

Safety of dermal diphoterine application: an active decontamination solution for chemical splash injuries.

Diphoterine (Laboratoire Prevor, Valmondois, France) is an active, amphoteric, polyvalent, chelating, slightly hypertonic decontamination solution for chemical splashes to the skin and eyes. It chemically binds a large number of chemical substances present on the skin surface without causing a significant release of heat (exothermic reactions). Because of its amphoteric properties, it can bind chemically opposite substances such as acids and bases or oxidizers and reducing agents. No adverse effects have been observed in an ongoing postmarketing surveillance program during many years of use in European industrial facilities. Diphoterine has more recently been used in hospitals for delayed management of chemical burns to the skin and eyes. There is interest in having protocols for both immediate and delayed diphoterine use for skin decontamination. Whereas studies of diphoterine efficacy, clinical and in vitro or ex vivo, have been published or are in the process of being prepared for publication, no review has yet been published focusing solely on the safety of this decontamination solution. Therefore, all available studies on the safety of diphoterine are described here, including recent studies demonstrating no harmful effects on the skin. Diphoterine can be used, even on damaged skin, without toxic, irritant, allergenic, or sensitizing effects.

Which cyanide antidote?

Cyanide has several antidotes, with differing mechanisms of action and diverse toxicological, clinical, and risk-benefit profiles. The international medical community lacks consensus about the antidote or antidotes with the best risk-benefit ratio. Critical assessment of cyanide antidotes is needed to aid in therapeutic and administrative decisions that will improve care for victims of cyanide poisoning (particularly poisoning from enclosed-space fire-smoke inhalation), and enhance readiness for cyanide toxic terrorism and other mass-casualty incidents. This paper reviews preclinical and clinical data on available cyanide antidotes and considers the profiles of these antidotes relative to properties of a hypothetical ideal cyanide antidote. Each of the antidotes shows evidence of efficacy in animal studies and clinical experience. The data available to date do not suggest obvious differences in efficacy among antidotes, with the exception of a slower onset of action of sodium thiosulfate (administered alone) than of the other antidotes. The potential for serious toxicity limits or prevents the use of the Cyanide Antidote Kit, dicobalt edetate, and 4-dimethylaminophenol in prehospital empiric treatment of suspected cyanide poisoning. Hydroxocobalamin differs from these antidotes in that it has not been associated with clinically significant toxicity in antidotal doses. Hydroxocobalamin is an antidote that seems to have many of the characteristics of the ideal cyanide antidote: rapid onset of action, neutralizes cyanide without interfering with cellular oxygen use, tolerability and safety profiles conducive to prehospital use, safe for use with smoke-inhalation victims, not harmful when administered to non-poisoned patients, easy to administer.

Diphoterine chemical splash decontamination solution: skin sensitization study in the guinea pig.

Diphoterine is an active eye/skin chemical splash decontamination solution. It was evaluated for sensitization potential in the guinea pig with primary induction (day 1, intradermal injection), sensitization (day 9, topical application), and challenge (day 22, topical application). Allergenicity degree at 24 and 48 hours was based on the percentage of animals showing a reaction. Under these conditions, no irritation was noted at 24 and 48 hours in negative controls and in animals treated with Diphoterine during the challenge phase. Diphoterine showed no allergenicity at 24 and 48 hours. In this study, Diphoterine lacked sensitizing capacity in the guinea pig.

Sodium thiosulfate or hydroxocobalamin for the empiric treatment of cyanide poisoning?

Cyanide poisoning must be seriously considered in victims of smoke inhalation from enclosed space fires; it is also a credible terrorism threat agent. The treatment of cyanide poisoning is empiric because laboratory confirmation can take hours or days. Empiric treatment requires a safe and effective antidote that can be rapidly administered by either out-of-hospital or emergency department personnel. Among several cyanide antidotes available, sodium thiosulfate and hydroxocobalamin have been proposed for use in these circumstances. The evidence available to assess either sodium thiosulfate or hydroxocobalamin is incomplete. According to recent safety and efficacy studies in animals and human safety and uncontrolled efficacy studies, hydroxocobalamin seems to be an appropriate antidote for empiric treatment of smoke inhalation and other suspected cyanide poisoning victims in the out-of-hospital setting. Sodium thiosulfate can also be administered in the out-of-hospital setting. The efficacy of sodium thiosulfate is based on individual case studies, and there are contradictory conclusions about efficacy in animal models. The onset of antidotal action of sodium thiosulfate may be too slow for it to be the only cyanide antidote for emergency use. Hydroxocobalamin is being developed for potential introduction in the United States and may represent a new option for emergency personnel in cases of suspected or confirmed cyanide poisoning in the out-of-hospital setting.

Diphoterine for emergent decontamination of skin/eye chemical splashes: 24 cases.

Chemical skin/eye splashes can cause burns. Standard references recommend decontamination with water. Diphoterine, a polyvalent, hypertonic, amphoteric, chelating solution is an alternative. Occupational medical records of 24 workers in a German metallurgy firm from 1994 to 1998 were reviewed. There were 11 acid eye splashes, 8 acid skin splashes, 4 base eye splashes, and 1 base skin splash. Following Diphoterine decontamination, no burns developed and there were no requirements for burn treatment or sequelae. Three workers had 1 lost workday each. Diphoterine decontamination successfully prevented skin/eye burns in this group of metallurgy workers.

Pediatric cyanide poisoning: causes, manifestations, management, and unmet needs.

Confirmed cases of childhood exposure to cyanide are rare despite multiple potential sources including inhalation of fire smoke, ingestion of toxic household and workplace substances, and ingestion of cyanogenic foods. Because of its infrequent occurrence, medical professionals may have difficulty recognizing cyanide poisoning, confirming its presence, and treating it in pediatric patients. The sources and manifestations of acute cyanide poisoning seem to be qualitatively similar between children and adults, but children may be more vulnerable than adults to poisoning from some sources. The only currently available antidote in the United States (the cyanide antidote kit) has been used successfully in children but has particular risks associated with its use in pediatric patients. Because hemoglobin kinetics vary with age, methemoglobinemia associated with nitrite-based antidotes may be excessive at standard adult dosing in children. A cyanide antidote with a better risk/benefit ratio than the current agent available in the United States is desirable. The vitamin B12 precursor hydroxocobalamin, which has been used in Europe, may prove to be an attractive alternative to the cyanide antidote kit for pediatric patients. In this article we review the available data on the sources, manifestations, and treatment of acute cyanide poisoning in children and discuss unmet needs in the management of pediatric cyanide poisoning.

Water decontamination of chemical skin/eye splashes: a critical review.

Skin/eye chemical splashes are a significant workplace problem. Initial water decontamination is usually recommended, but there are few well-conducted experimental animal and human studies of efficacy. An extensive review of the literature and other available information sources was performed to define the scope of the problem and critically review the evidence for water decontamination efficacy. Although water decontamination can decrease the severity of chemical skin/eye burns, it cannot completely prevent them. An ideal replacement decontamination solution would be sterile, nontoxic, chelating, polyvalent, amphoteric, and slightly hypertonic to retard skin or corneal penetration of the chemical.

Prevention of CS "tear gas" eye and skin effects and active decontamination with Diphoterine: preliminary studies in 5 French Gendarmes.

Ortho-chlorobenzylidene malononitrile (CS) "tear gas" is a lacrimating riot control agent causing eye irritation, excessive lacrimation, and blepharospasm. Diphoterine has been efficacious for decontamination of a wide variety of eye and skin chemical splashes and was tested in CS exposure. Five French Gendarmes either entered a standard training CS exposure chamber, developed eye or skin signs and symptoms, and were post-exposure decontaminated with Diphoterine or used Diphoterine as pre-CS exposure prophylaxis in the eyes and on the face before entering the chamber. Gendarmes who entered the CS chamber without prior application of Diphoterine developed expected effects of excessive lacrimation, eye irritation, and blepharospasm. After post-exposure Diphoterine decontamination, in four Gendarmes these effects rapidly resolved and they were fully operational. When Diphoterine was applied to the eyes and face before entering the CS chamber, the expected effects did not occur and the single Gendarme remained fully operational on exiting the chamber. These results suggest that Diphoterine can prevent or rapidly ameliorate the ocular and dermal effects of CS and allow law enforcement personnel to remain fully operational or rapidly regain operational status after decontamination.

An improved method for emergent decontamination of ocular and dermal hydrofluoric acid splashes.

Accidental hydrofluoric acid (HF) splashes often occur in industrial settings. HF easily penetrates into tissues by initial acid action allowing fluoride ions to penetrate deeply, chelating calcium and magnesium. Resultant hypocalcemia and hypomagnesemia can be fatal. This report describes the utilization of Hexafluorine--a hypertonic, amphoteric, chelating decontamination solution--in workplaces where water decontamination followed by calcium gluconate inunction failed to prevent HF burns and systemic toxicity. Between 1998 and 1999, 16 cases of ocular and dermal HF splashes with either 70% HF or 6% HF/15% nitric acid (HNO3) were decontaminated with Hexafluorine at the worksite. HF burns did not develop and medical treatment other than initial decontamination was not reQuired in 12/16 (75%). In 7/16 (44%) cases, lost work time corresponded to duration of hospital observation (mean < 1 d).