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ArticlePDF AvailableLiterature Review Antidotes and Treatments for Chemical Warfare/Terrorism Agents: An Evidence-Based Review September 2010 · Clinical Pharmacology & Therapeutics 88(3):318-27 DOI: 10.1038/clpt.2010.152 Source · PubMed Authors: George Rodgers at University of Louisville George Rodgers 31.76 · University of Louisville Tania Condurache at University of Louisville Tania Condurache 20.96 · University of Louisville Download full-text PDFRead full-text You're downloading a full-text provided by the authors of this publication. A preview of this full-text is provided by Springer Nature. Download citation Copy link Citations (27) References (52) Abstract This article reviews the evidence supporting the efficacy of antidotes used or recommended for the potential chemical warfare agents of most concern. Chemical warfare agents considered include cyanide, vesicants, pulmonary irritants such as chlorine and phosgene, and nerve agents. The strength of evidence for most antidotes is weak, highlighting the need for additional research in this area. ResearchGate Logo Discover the world's research •17+ million members •135+ million publications •700k+ research projects Join for free Public Full-text 1 Content uploaded by Tania Condurache Author content Content may be subject to copyright. 318 VOLUME 88 NUMBER 3 | SEPTEMBER 2010 | www.nature.com/cpt state art nature publishing group e usual denition of a chemical warfare agent is a chemical agent intended for use in military operations that is designed to seriously injure, kill, or incapacitate opposing forces. Many agents originally designed for classic warfare are now also con- sidered potential weapons in terrorist operations. e concept of chemical warfare has existed for several thousand years. Excellent reviews have been published.1,2 e Chinese reportedly used toxic smoke, including arsenic compounds, as early as in 1000 bc. Over the centuries, many others have employed toxic smoke or vapors in limited ways and with inconsistent results. Various toxins have also been used in attempts to poison water or food sources, with the intent of killing or incapacitating the enemy and oen the supporting civilian population as well. e eighteenth and nine- teenth centuries saw the emergence of chemistry as a branch of science, and during this period chlorine, hydrogen cyanide, phosgene, and, subsequently, the mustard agent chloropicrin and many other compounds were discovered. Several proposals were made to use chemical weapons during the American Civil War, but none were actually used.3 Tab l e 1 summarizes the more mod- ern uses of chemical warfare agents. Since World War I (WWI), a number of international agreements, beginning with the Geneva Protocol in 1925, have attempted to limit the development and use of chemical weapons, with limited success.4 is review focuses on four groups of chemical warfare agents: chemical asphyxiants (cyanide and its various precursors), vesi- cants (sulfur mustard and Lewisite), pulmonary toxins (chlorine and phosgene), and nerve agents (organophosphates (OPs)). Although other chemical agents have been used or proposed, such as ricin, botulinum toxin, and picric acid, these are gener- ally not considered to have signicant potential as warfare or terrorism agents and are not considered here. Biological agents are also not discussed in this review. OVERVIEW OF EVIDENCE FOR EFFICACY OF ANTIDOTES AGAINST CHEMICAL WARFARE AGENTS As is common in many aspects of toxicology, there is a dearth of good data on the ecacy of antidotes and treatment options for use against chemical warfare agents. 5 e gold standard for evidence-based medicine is the prospective randomized control- led trial (RCT) comparing the eectiveness of a new intervention with those of a standard tre atment, a placebo, or no treatment, for a given condition. Both ethics and practicality prohibit the use of prospective randomized trials in humans treated for exposure to chemical warfare agents, although studies have been carried out in relation to some of these chemical agents by military groups in human subjects.6 Fortunately, the opportunities in recent years to conduct such trials on patients poisoned as part of some large- scale terrorist or military action have been rare. As a result, in trying to assess the ecacy of standard or proposed antidotes or treatments, we are le with less-than-perfect data in humans, usually case reports or small case series, or, in some cases, none at all. Because all the chemicals of concern are potentially lethal, one must be cautious in drawing conclusions from individual cases. Also of concern is the fact that much of the existing data in humans relate to scenarios with much missing data, including the timing and quantity of the exposure. is makes the analysis of such data problematic. For instance, the proposed antidotes may appear ineective if not given within an appropriate time frame. If the timing of the exposure is not known, it is dicult to assess such outcome data. For many antidotes or proposed treatments, there are data from animal experiments that we can use to assist in assessments. A major area of current research interest is pro- phylactic treatments, particularly for use by military personnel. is article does not consider possible pre-exposure protective agents or treatments. 1Department of Pediatrics, University of Louisville School of Medicine, Louisville, Kentucky, USA. Correspondence: GC Rodgers Jr (gcrodgers@pol.net) Received 11 May 2010; accepted 7 June 2010; advance online publication 4 August 2010. doi:10.1038/clpt.2010.152 Antidotes and Treatments for Chemical Warfare/ Terrorism Agents: An Evidence-Based Review GC Rodgers Jr1 and CT Condurache1 This article reviews the evidence supporting the efficacy of antidotes used or recommended for the potential chemical warfare agents of most concern. Chemical warfare agents considered include cyanide, vesicants, pulmonary irritants such as chlorine and phosgene, and nerve agents. The strength of evidence for most antidotes is weak, highlighting the need for additional research in this area. CLINICAL PHARMACOLOGY & THERAPEUTICS | VOLUME 88 NUMBER 3 | SEPTEMBER 2010 319 state artstate art CYANIDE POISONING From a toxicology point of view, cyanide is a potent noncom- petitive inhibitor of cytochrome c oxidase and a number of other enzymes. Inactivation of cytochrome oxidase leads to tissue hypoxia, tissue dysfunction, and ultimately death. Cyanide is rapidly absorbed from the lung or gastrointestinal tract, and there is a rapid onset of symptoms involving the central nervous system (CNS) and cardiovascular systems, as well as profound metabolic acidosis. Death can occur within a few minutes. Cyanide is metabolized primarily by the enzyme rhodanese in the presence of a sulfur source, forming the relatively nontoxic metabolite thiocyanate. Cyanide can originate from several sources. It is found in industry in the form of a variety of salts. Cyanide also forms compounds with halogens, such as cyanogen chloride (a gas) and cyanogen bromide (a liquid). Coupled with organic moieties, it forms a variety of nitriles, such as acetonitrile, a common organic solvent and chemical intermediate. e metabolism of some nitriles in humans produces cyanide in vivo. Cyanide is a com- mon component of smoke from burning nitrogen- containing fuels, such as many plastics. In fact, the most common current cause of cyanide poisoning is smoke inhalation. Cyanide in its various forms is considered a likely agent for terrorist use.7 It is relatively easy to obtain and handle, and it can be delivered in a variety of forms through dierent routes. Hydrogen cyanide released into a closed space, such as a building through the HVAC (heating, ventilating, and air- conditioning) system, could result in large-scale casualties. Cyanide has been infrequently used in warfare. The gaseous form, hydrogen cyanide, was tried by the French military during WWI with little eect, because it is lighter than air and rapidly dissipates. Hydrocyanic acid, in combination with cyanogen chloride or bromide added to improve stability (Zyklon B), was used in the German death camps during WWII. HCN was also reportedly used by the Japanese in China during WWII and by the Iraqi military during the Iran–Iraq Wars. Several antidotes are commercially available worldwide to treat cyanide poisoning. ese antidotes have relied on either increasing the rate of endogenous metabolism (thiosulfate as a sulfur source for rhodanese), chelating cyanide (hydroxycobala- min or dicobalt EDTA), or generating methemoglobin, which competitively binds cyanide, liberating cytochrome oxidase (nitrites or 4-dimethylaminophenol (4-DMAP)). Several other antidotes have been proposed in the literature but without any data pertaining to humans. 8–14 Hyperbaric oxygen has also been proposed as a treatment in conjunction with another antidote; a few case reports have appeared, reporting conicting results.15 Excellent reviews of cyanide toxicity and antidotes have been published.16–18 e rst commercially available treatment for cyanide poison- ing was amyl nitrite, rst described as an antidote in 1888 and marketed in combination with sodium nitrite and sodium thio- sulfate. e nitrites presumably produce methemoglobin, which binds cyanide, which is then released and metabolized by rhoda- nese with the help of thiosulfate. is combination was initially marketed as the Lilly Cyanide Antidote Kit (CAK) by Eli Lilly. e amyl nitrite, administered by inhalation, is to be used as the initial treatment, followed by intravenous sodium nitrite and sodium thiosulfate. ere are no reported clinical studies of the ecacy of the CAK, although there are several case reports and small case series describing the apparent eectiveness of sodium thiosulfate with or without amyl nitrite or sodium nitrite in cases with measured and potentially lethal cyanide blood levels.19–25 Animal studies also support the ecacy of sodium thiosulfate given with sodium nitrite. 26,27 Sodium thiosulfate given alone in animal studies has had inconsistent results. 28–30 It has been speculated that this may be because of the slow access of the thiosulfate, which remains primarily in the extracellular spaces, to the rhodanese, which is intracellular.28,30 There has also been no study on the safety of the CAK, although concerns have been raised about the potential for complications from the use of nitrite. It is thought that a level of at least 15% methemoglobin is necessary for the eectiveness of either amyl nitrite or sodium nitrite in cyanide poisoning. 31 Excessive doses of sodium nitrite may produce methemoglobin levels capable of signicantly impeding oxygen transport. is is of particular concern in re/smoke inhalation victims, in whom other risk factors, particularly carbon monoxide exposure, may signicantly increase the risk of hypoxia. 32 e risk of hypoxia under these circumstances will depend on the rate of decline of carboxyhemoglobin relative to the rate of increase of methemo- globin, both of which are dicult to predict. Sodium thiosulfate as a stand-alone antidote has been studied and was found to be relatively nontoxic.33 Although the available data for the ecacy of the CAK are not robust, the ndings are generally consist- ent and strongly suggest that this antidote is eective if used promptly and properly. Table 1 Modern history of the use of chemical warfare agents Conflict/event Agent(s) Used by Second Anglo-Boer War (1899–1902) Picric acid Britain World War I (1914–1918) Dianisidine chlorosulfate Chlorine Diphosgene/phosgene Sulfur mustard Hydrogen cyanide Cyanogen chloride Germany Germany/Britain/France Germany Germany/Britain France France Italy–Ethiopia War (1935–1936) Sulfur mustard Italy World War II (1935–1945) Mustard gas Lewisite Hydrogen cyanide Japan Japan Japan Iran–Iraq Wars (1980s) Lewisite Hydrogen cyanide Sulfur mustard Nerve agents Iraq Iraq Iraq Iraq Yemen Civil War (1967) Nerve agents Sulfur mustard Egypt Egypt Afghanistan War (1980s) Nerve agents Russia Terrorist attacks in Japan (1994–1995) Sarin Aum Shinrikyo 320 VOLUME 88 NUMBER 3 | SEPTEMBER 2010 | www.nature.com/cpt state artstate art In Germany, 4-DMAP is available commercially as an antidote for cyanide poisoning. Like nitrites, 4-DMAP is a methemo- globin generator. 4-DMAP is usually administered intramuscu- larly, either as a single agent or in combination with thiosulfate or dicobalt edetate. No human studies with this agent have been reported, although there are some case reports and series. 16,34,35 ere are limited data from animal studies for 4-DMAP; one of the studies reported 100% survival in dogs given a lethal cya- nide dose intravenously, followed by the antidote. 36 4-DMAP has been reported to have signicant toxicity, including unpre- dictable levels of methemoglobin formation.17 Although the limited data in humans suggest that 4-DMAP can be an eec- tive antidote, its toxicity potential may make it a less desirable alternative. Dicobalt edetate (Kelocyanor) has been available as a cyanide antidote for several years in Great Britain and France. It is pre- sumed to act by complexing cyanide to form cobalticyanide, which is then excreted in the urine. It is administered intrave- nously with glucose to prevent hypoglycemia caused by cobalt toxicity. ere have been no studies with dicobalt edetate in humans. Seven case reports provide the only published data in humans.37–42 Of the seven patients, four survived. Dicobalt edetate has been associated with signicant toxicities, including cardiac toxicity, seizures, hypoglycemia, and anaphylaxis. 17,31 Given that the commercial product contains uncomplexed cobalt, care needs to be taken to not administer the product to patients who may not have been exposed to cyanide poisoning because serious cobalt toxicity may occur. For more than 30 years, hydroxycobalamin has been known, from animal studies, to be an eective antidote for cyanide poisoning.27,43 Hydroxycobalamin has a higher anity for cyanide than do tissue cytochromes, thereby competitively binding and inactivating both free and cytochrome-bound cyanide. e cyanocobalamin formed is readily excreted by the kidney. e product became commercially available in 1996 in France and in 2007 in the United States. Because this is a relatively recent antidote, there are more robust data for hydroxycobalamin in humans. e data include those from two uncontrolled studies, both in patients with smoke inhalation and presumed cyanide exposure and in some case reports and small series.44–49 Borron et al. reported on 69 patients with smoke inhalation and presumed cyanide exposure who were treated in an uncon- trolled, prospective, open-label study in Paris.48 e patients received 5–15 g of hydroxycobalamin, either before reaching the hospital or in the emergency room. Of 69 patients, 50 (72%) survived, 41 of them with no reported sequelae. Of the patients treated, 37 were comatose at presentation, and 14 had an initial cardiopulmonary arrest. In a retrospective uncontrolled study, also from Paris, Fortin et al. reported on 101 patients with smoke inhalation with presumed cyanide exposure, treated in the prehospital setting with 5 g hydroxycobalamin. 45,50 Of the 101 patients, 30 survived, 42 died, and the survival status of the remainder was unknown. irty-eight patients were found in cardiac arrest. Only 2 of this group survived. Of the 12 patients who were hemodynamically unstable at the scene, 9 showed a return of adequate blood pressure aer administration of hydroxy cobalamin. Among the 18 noncomatose patients with some initial neurological impairment, 9 showed improvement in their Glasgow coma scale aer the administration of hydroxy- cobalamin, 8 had no change, and 1 became worse. Minor adverse eects were observed in 6 patients. Both these studies share some aws. Neither study meas- ured blood cyanide levels, making it impossible to determine the severity of cyanide toxicity or even the presence of cyanide. Neither study included a control group, and both studies were in patients with smoke inhalation, in whom the presence of many other potentially toxic chemicals, including carbon monoxide, may have signicantly aected the outcomes. ese aws aside, both studies provide some suggestion that hydroxycobalamin may be an eective antidote in patients who have not reached the stage of cardiovascular collapse. Both studies suggest that the safety prole for hydroxycobalamin is probably superior to those of the other antidotes discussed. To investigate the poten- tial adverse eects of hydroxycobalamin, Uhl et al. conducted a randomized, double-blind, placebo-controlled, ascending-dose study in 136 healthy volunteers. (e remaining references for this article may be found in the Supplementary References online.) No signicant toxicity was observed. As pointed out by several authors, hydroxycobalamin has an advantage over the CAK and 4-DMAP in that it does not further compromise oxygen transport. is makes hydroxycobalamin an ideal agent for prehospital use, an attribute of particular value in the event of a terrorist event. In summary, the limited data available in humans on all of the currently available antidotes for cyanide indicate that they all have ecacy. Data from animal studies support this conclu- sion. ere are no comparative studies in humans. Toxicity data, and concerns about alteration of oxygen transport, suggest that hydroxycobalamin should be the preferred antidote. Additional studies are needed to compare ecacy in humans and to explore the potential value of combining hydroxycobalamin with thiosulfate. VESICANTS Vesicants, as a class, cause damage to the skin and mucous membranes resulting in blistering lesions. Although many vesicant agents have been described as potential weapons, only two, sulfur mustard (mustard gas, HD, yperite, yellow cross, dichloroethylsulde) and Lewisite (2-chlorovinyldichloroarsine) are discussed in any detail in this article. Of these two, sulfur mustard, which was rst synthesized in 1822, has been used more extensively, and its use has been documented in at least 10 conicts beginning in 1917. Sulfur mustard is an alkylat- ing agent with both cytotoxic and mutagenic properties, and it is a known carcinogen. When used militarily, sulfur mustard produces extensive damage to the skin, eyes, and respiratory tract. e toxicology of sulfur mustard has been reviewed. Extensive exposure can cause systemic eects to other organs and to the bone marrow. Although the pathology of injuries is well known, the mechanisms involved are not clearly dened, despite extensive and ongoing research. CLINICAL PHARMACOLOGY & THERAPEUTICS | VOLUME 88 NUMBER 3 | SEPTEMBER 2010 321 state artstate art ere are currently no recognized antidotes for sulfur mustard. However, on the basis of animal studies and analogy from their use in chemotherapy to protect against the toxic side eects of alkylating agents, thiosulfate and N-acetyl--cysteine have been proposed as having possible antidotal eects. Amifostine, an aminothiol, has also been shown to have protective eects against sulfur mustard in rats and mice. Limited animal data suggest that both thiosulfate and N-acetyl--cysteine may have some value in treating sulfur mustard exposures, but there are no corroborative human data, and their use is not currently recommended. Treatment strategies for vesicant exposure are currently directed at minimizing the risks of either acute or chronic seque- lae of exposure. e current recommendations are based on anecdotal reports from treatment of exposed populations as well as from animal studies. Much research in the last decade, in vari- ous in v ivo and in vitro animal models, has been focused on the investigation of protective agents for dermal injury. Historical recommendations have focused on immediate decontamination of the skin. Various authors have recommended simple soap and water, oil or gasoline, diluted household bleach (0.5% sodium hypochlorite), permanganate solutions, iodine preparations, and various adsorbents such as Fuller’s earth, talc, activated char- coal, and our for initial decontamination. An animal study comparing the ecacy of skin decontamination with water and with 0.5% sodium hypochlorite (diluted household bleach) in preventing skin injury from sulfur mustard found no dierence between the two treatments. A number of absorbent or barrier preparations have also been developed and reportedly tested by military groups for decontamination. Treatment of skin burns from sulfur mustard has generally paralleled treatment of thermal burns. A number of studies in animal skin models have looked at the ecacy of topical iodine preparations in preventing or minimizing dermal burns from sulfur mustard. Although it was originally thought that iodine chemically inactivates sulfur mus- tard, it is now clear that this is not so. Although the animal data suggest that iodine preparations would be useful in the early treatment of sulfur mustard burns, there are no data in humans. Another agent traditionally used has been silver sulfadiazine. A comparison study of topical iodine and silver sulfadiazine in a pig skin model found iodine to be superior as an antidote to sulfur mustard, although with limited eect. Early surgical debridement and dermabrasion have also been recommended, on the basis of data from pig skin models. Sollmann reported experimental evaluation, in human student volunteers, of a wide variety of potential initial treatments for sulfur mustard dermal exposure. Many details of these experiments are not reported; however, the conclusions of the author were that three general methods have some value in preventing injury from dermal sulfur mustard exposure: rapid wash with soap and water, use of oils (such as olive or castor oil), and use of solid adsorbents (such as charcoal, talcum, and zinc oxide). In summary, there are very limited useful data on which to base a rm recommen- dation about initial treatment options for dermal exposure and injury caused by sulfur mustard. Sodium hypochlorite solutions appear to chemically inactivate sulfur mustard during initial decontamination, and iodine preparations appear to have some value in reducing damage from exposure, but the quality of the data is poor regarding both interventions. Acute treatment of eye exposures to sulfur mustard has been the subject of considerable concern, but little research. Acute eye injury is the most incapacitating eect of most military sulfur mustard exposures. Sulfur mustard has also been noted to cause many long-term ophthalmologic problems in individuals gassed in military operations or occupationally exposed to the agent. It is generally agreed that sulfur mustard is very rapidly taken up by eye tissues, allowing only a very brief period during which decontamination is of any value in removing the material and preventing injury. A wide variety of ushing solutions have been recommended in the literature on the basis of anecdotal reports, including water, normal saline, 1.5% sodium bicarbonate solu- tion, saturated sodium sulfate or magnesium sulfate solutions (hypertonic solutions), boric acid solutions, 0.5% dichloramine-T solution in a solvent, and dilute solutions of sodium hypochlorite or potassium permanganate. ere are no studies in either animals or humans systematically evaluating the benets of any of these treatments or compar- ing them with one another. Recommendations for treatment of the aected eye aer decontamination are varied and include steroids, antibiotic ointments, topical analgesics, and even no treatment at all. Studies in a rabbit model have shown the poten- tial benets of anti-inammatory drugs such as dexamethasone and diclofenac. ese studies showed some biochemical and pathological evidence of eectiveness, but neither drug treat- ment decreased corneal erosions. Anti-inammatory drugs have shown good eects in other forms of irritant eye injury. In summary, there are no human data on which to base recom- mendations for the decontamination of eyes exposed to sulfur mustard. General toxicologic experience would indicate that prompt ushing is likely to have some value and is unlikely to cause additional harm. Animal data with sulfur mustard indi- cate that the window of opportunity to remove the unabsorbed compound is very short, perhaps ≤5–10 min. In the absence of other information, and considering practical possibilities, it is reasonable to recommend a simple water or saline ush. e quality of the available data is very poor. The third major exposure route for vesicants, including sulfur mustard, is respiratory. Sulfur mustard causes signicant pulmonary pathology if inhaled. ere is also a signicant risk of long-term pulmonary complications aer acute exposure. ere is no specic treatment for the respiratory symptoms of sulfur mustard inhalation. Many authors have recommended steroids and antibiotics in addition to general respiratory support. ere are no studies in either animals or humans to demonstrate the benefits of these therapies after sulfur mustard inhalation, although data from other types of inhalation injury suggest that they might be useful. Even more limited information is available for Lewisite because it has seen only limited military use. Lewisite is an organic arsenical compound, rst developed as a potential military agent in 1918 by Lee Lewis, with both vesicant toxicity 322 VOLUME 88 NUMBER 3 | SEPTEMBER 2010 | www.nature.com/cpt state artstate art and signicant systemic toxicity. Its only documented military use was by Iraq during its wars with Iran. During the early years of WWII, British researchers successfully developed an antidote to Lewisite, British anti-Lewisite (BAL). BAL (dimercaprol or 2,3-dimercaptopropanol) contains two sulydryl groups that form a complex with and inactive arsenic. BAL has subse- quently been successfully used to form complexes with other heavy metals, most notably lead. It was extensively tested during WWII, including in humans. ese data, reported only in mili- tary documents, have been well reviewed, e.g., by Peters. ere are abundant published data related to humans documenting the eectiveness of BAL at chelating lead and mercury; however, there are sparse published data regarding its eect on arsenic. In one study, 48 patients with arsenic-induced encephalopathy were treated successfully with BAL. Peters describes testing done during WWII using a BAL ointment, resulted in favorable outcomes with respect to control of skin and eye damage aer exposure to arsenic. However, no details of these experiments have been published. Stocken and ompson reported experiments in rats with BAL being applied topically 1 h aer Lewisite treatment. Although they do not comment on the appearance of the skin, analysis of the skin 48 h later showed that BAL treatment signicantly reduced the residual bound arsenic in the skin. Inns et al. compared the ecacy of BAL with that of two newer chelators—meso- 2,3-dimercaptosuccinic acid (DMSA) and 2,3-dimercapto-1- propanesulfonic acid (DMPS), both water-soluble analogs of BAL—regarding their ability to prevent systemic toxicity in a rabbit model. eir study employed both intravenous and percu- taneous routes of administration of Lewisite. Although all three chelating agents showed comparable protective eects on survival at equivalent doses, the authors were of the opinion that DMSA and DMPS were superior antidotes because of their lower toxici- ties relative to BAL. e rabbit data also showed that, at higher doses of DMPS and DMSA (doses that are not possible for BAL, given its toxicity), survival was signicantly higher. Aposhian et al. studied the protective eects of BAL, DMSA, and DMPS on the toxicity caused by sodium arsenite in mice; they also concluded that both DMSA and DMPS were superior to BAL, with DMSA being the most eective antidote. Nelson et al. showed, in a guinea pig model, that hypothermia protects against Lewisite-induced skin injury. In that model, protection was further enhanced by the cutaneous application of DMSA. In summary, there are limited data from human and animal studies that BAL is an eective chelating agent for arsenic compounds. It is reasonable to conclude that BAL will be benecial in prevent- ing or minimizing systemic toxicity from Lewisite. Other than Peters’s secondhand reports, there are no published data on the eect of BAL or any chelator on the dermal and ocular toxicity of Lewisite. ere is a reasonable volume of data from animal studies indicating that the less toxic water-soluble analogs of BAL, namely, DMSA and DMPS, are likely to be better antidotes for Lewisite. ere are no data reporting specic skin and eye decontamination methods for Lewisite; however, it is likely that any recommendations made for sulfur mustard will be equally applicable to dermal and eye exposure from Lewisite. PULMONARY IRRITANTS Many chemicals with pulmonary irritant properties have been proposed as potential military/terrorist weapons, but only two are discussed in this article: chlorine and phosgene. Both chlorine and phosgene were used during WWI, sometimes in combina- tion. Both are gases that cause irritation in the lung. Chlorine, with relatively high water solubility, is readily scrubbed in the upper airway, whereas phosgene, with relatively low water solu- bility, penetrates deeper into the lung. Both agents release hydro- chloric acid on reaction with water, and both produce capillary leak with pulmonary edema. ese symptoms appear rapidly aer chlorine exposure, whereas aer phosgene exposure symptoms are oen delayed for many hours. Chlorine is also a signicant irritant to the skin and the eye. Phosgene, but not chlorine, is capable of reacting with nucleophilic groups (amino, hydroxyl, and sulydryl) in tissues, leading to irreversible tissue injury and decreased levels of antioxidants. is mechanism is thought to be responsible for much of the damage caused by phosgene. Chlorine is considered a likely agent for use in terrorist acts because of its ready availability; it is used widely in industry, and large quantities of it are regularly stored and shipped. In addition to military use, a large number of accidental releases of chlorine have occurred during transportation and workplace accidents. ere are no antidotes for exposure to chlorine and phosgene. Chlorine exposures of the skin and eye are easily treated with a water ush to remove the irritant hydrochloric acid. Some controversy exists about optimal treatment for inhalation injury with either of these agents. Basic supportive therapy with humidied oxygen and positive pressure ventilation are the mainstays of treatment. Numerous reports in both animals and humans have documented the apparent value of both oxy- gen and positive pressure, but there have been no controlled human trials. If bronchospasm develops, particularly in indi- viduals with preexisting hyperactive airways, bronchodilators are recommended. ere are no data specically assessing the eectiveness of bronchodilators for chlorine- or phosgene- induced bronchospasm. Several case reports and case series have investigated the ecacy of nebulized sodium bicarbonate (3.5–4%) as an antidote in patients who have inhaled chlorine. is treatment appears to be safe and eective at relieving the discomfort associated with exposure to chlorine. However, none of the reports had a control group, and none assessed the eects on short-term or long-term pulmonary outcome. A controlled study of chlorine inhalation in a sheep model, using nebulized 4% sodium bicarbonate as an antidote, showed improvement in respiratory function as measured by arterial blood gases but no improvement in lung pathology or survival in the treatment group. Corticosteroids have also been recom- mended on the basis of analogy with other inammatory lung diseases. ere are no human studies evaluate the ecacy of corticosteroids as a treatment for chlorine or phosgene inha- lation injury. Several studies in animals have investigated the eects of steroids in chlorine inhalation models. Demnati et al. treated chlorine-exposed rats with dexamethasone 1 h aer expo- sure. Recovery was more rapid in the treatment group as com- pared with the control group. In a pig model, Gunnarsson et al. CLINICAL PHARMACOLOGY & THERAPEUTICS | VOLUME 88 NUMBER 3 | SEPTEMBER 2010 323 state artstate art showed that there was a marked improvement in chlorine-related pulmonary symptoms in animals treated with beclomethasone as compared with controls. Studies in animals to investigate antidotes to phosgene exposure have also demonstrated a reduction in both pulmo- nary edema and mortality rate with steroid administration, both pre-exposure and postexposure. On the other hand, Smith et al. failed to nd any decrease in mortality or pulmonary edema in a porcine model employing treatments with either inhaled budes- onide or intravenous methylprednisolone. On the basis of the presumed mechanism of action of phosgene, several other treat- ments have been tried in animal models. Intratracheal N-acetyl- -cysteine, given aer exposure in a perfused lung rabbit model, showed reduction in lung pathology. In a collection of both in situ and in v ivo experiments, Sciuto and Hurt have also shown ecacy against phosgene-induced lung injury with the use of ibuprofen, aminophylline, and isoproterenol. Kennedy et al. have reported similar results. A large number of other substances have reportedly been tried for reducing phosgene-induced lung injury in animals and humans, but most have proven ineective. In summary, there are no published trials in humans to evalu- ate potential treatments for either chlorine or phosgene inhala- tion injury. Anecdotal reports and data from animal studies, as well as analogy to other inhalation injuries, strongly suggest that there would be a benet from supportive treatment with humidied oxygen and positive pressure. Although there are conicting data from animal studies with respect to the use of steroids, most of the studies have reported positive outcomes with this line of treatment. Data from animal studies suggest that anti-inammatory and antioxidant drugs, such as ibuprofen and N-acetyl--cysteine, may have a role in treating phosgene inha- lation injury. Data in humans are needed to adequately assess these treatments, and none can be routinely recommended on the basis of presently available data. NERVE AGENTS Nerve agents (NAs) are potent OPs with high potential for caus- ing toxicity in humans aer dermal or inhalation exposure. ey were rst discovered in Germany during the 1930s, as an outgrowth of research on OP insecticides. Many of these agents have been described; only four are discussed in this article: tabun (GA), sarin (GB), soman (GD), and VX. Although some of these agents were developed and manufactured by Germany before and during WWII, they were not used in that war. Reports indi- cate that they were probably used by Iraq against both the Kurds and Iran in the 1980s. Sarin was also used in at least two ter- rorist incidents in Japan during the 1990s. As with OP insec- ticides, these agents bind to, and are irreversible inhibitors of, cholinesterase enzymes. A recent analysis suggests that inhibition of acetylcholinesterase (AChE) accounts for >90% of the toxicity exhibited by these agents. Inhibition of AChE leads to accumu- lation of acetylcholine at the synapses. e bond between NA and enzyme is initially amenable to reversal, but it “ages” over time, becoming irreversible. e toxicology of these agents has been extensively studied in both animals and humans. e major dierence in their toxicology relates to the time it takes to “age” the bond between agent and enzyme. Soman, in particular, ages within minutes, whereas the others age over hours (sarin, tabun) or days (VX). ere is a very large body of literature related to toxic exposures of humans to OP insecticides. It is estimated that these widely used products poison several million people annu- ally worldwide. Data on insecticidal OP poisoning in humans are a reasonable surrogate for the lack of data related to NA. e major exposure routes for NA are inhalation and dermal exposure. All these agents are well absorbed by both routes, with rapid onset of symptoms, including respiratory failure and seizures. e traditional treatment includes, aer decontamination, an anti- cholinergic agent to block acetylcholine receptor sites, an oxime to interact with and break the NA–enzyme bond (reactivation), and an anticonvulsant to prevent or treat seizures. Because of the major risk posed by these agents as terrorist weapons, much research has been, and continues to be, done on improved treatment agents and strategies. Because all NAs are water soluble, the usual recommendation for decontamination aer a dermal exposure is removal of clothing and copious washing with soap and water or with water alone. Various military groups also use a variety of adsorbent materials. ese materials are usually composed of activated charcoal and resins. Sodium or calcium hypochlorite solutions have also been recommended, if available. ere are no published human studies assessing or comparing various methods of decontamination aer exposure to an NA. Although other anticholinergics have been tried, atropine is universally recommended and used. One small RCT in patients with OP poisoning compared atropine with glycopyrrolate, an anticholinergic with fewer CNS side eects than atropine. No signicant dierences were found between the two treatments; however, the power was low. Atropine has the advantages of being readily available, stable in solution over a wide tempera- ture range, and readily absorbed aer intramuscular injection. e military outts in many countries supply atropine in auto- injectors (with or without added oxime and benzodiazepine) to troops who are at risk of facing chemical agents. Although atro- pine is usually administered intramuscularly or intravenously, a comparison study in humans has shown equivalent therapeutic and pharmacokinetic response when atropine is administered by inhalation. Atropine competes with acetylcholine for postsynap- tic muscarinic receptors. It does not bind to nicotinic receptors but does cross the blood–brain barrier. It therefore prevents or treats respiratory and cardiac symptoms, and also some of the CNS symptoms, associated with cholinergic excess. Atropine does not reverse peripheral muscle weakness. ere is no upper limit to the atropine dose in OP poisoning, with most authors recommending the resolution of respiratory symptoms as the end point. Excessive atropine can cause signicant cardiac and CNS side eects. Dosing recommendations for atropine have been reviewed. ere are no RCTs involving the use of atro- pine to treat OP poisoning, and such a study may no longer be ethically possible, because the ecacy of atropine is already universally accepted. ere are many reports of atropine use in either NA or OP pesticide poisoning, with apparently favorable response with regard to cardiac, respiratory, and CNS symptoms. Dawson reviewed the animal data on the use of atropine, alone 324 VOLUME 88 NUMBER 3 | SEPTEMBER 2010 | www.nature.com/cpt state artstate art or in combination with an oxime, in the treatment of poisoning with tabun, sarin, soman or VX. As pointed out by numerous authors, it is dicult to interpret data from animal studies in this area because of clear species dierences. Most authorities are of the opinion that guinea pigs, rabbits, and primates are the best animal models for extrapolation to humans. In most studies in animals to investigate the eect of atropine alone, some degree of protective eect is shown. ese eects are gen- erally enhanced if atropine is given with an oxime. In contrast, oxime alone seems to have little protective eect. Human data, obtained from Iran and elsewhere, also suggest that atropine alone is sucient treatment for exposure to any of the NAs. In summary, although there are no published RCTs with the use of atropine in NA poisoning, there are sucient data from reported human experience, combined with data from animal studies, to reasonably conclude that it is an eective antidote for all kinds of OP poisoning, including NA poisoning. Another antidote that is routinely used to treat NA poison- ing is an oxime. Oximes, as reactivators of AChE, were rst described by Wilson and Ginsburg in 1955. Since then, many additional oximes have been synthesized and tested in animals. Four oximes are available for use in humans: pralidoxime (2-PAM and P2S, available in the form of various salts), obidox- ime (Toxogonin or LuH-6), trimedoxime (TMB-4), and HI-6 (asoxime). Pralidoxime (used in the United States and the United Kingdom) is a quaternary pyridinium salt. Obidoxime (used in much of Europe), trimedoxime, and HI-6 are bis-pyridinium salts. Being salts, none of these agents has signicant penetra- tion of the blood–brain barrier, with brain levels of these agents estimated to be 4–10% of plasma levels aer administration. ere is considerable controversy over the ecacy of oximes in OP poisoning. It is clear, from in vit ro and animal models, that ecacy is dependent on the particular oxime, the dose of the oxime (and perhaps the schedule of administration), the par- ticular OP, the animal species, and probably pharmaco genetic dierences that aect the metabolisms of both oxime and OP. is complexity leads to oen contradictory and confusing results. e consensus of data indicates that all the available oximes are capable, in the right circumstances, of reactivating AChE to some degree. e question remains whether these eects, particularly with NA, are clinically signicant. All the oximes available also have signicant potential adverse side eects. is is particularly true of obidoxime, which is hepatotoxic in humans, an eect that frequently surfaces during clinical use and that has led to deaths of patients. ere is a signicant amount of human data regarding oxime usage, although most of these data are from case reports and case series related to insecticidal OP. A number of recent reviews have assessed oxime use and ecacy in OP poisoning. Several published human studies were designed to assess oxime ecacy, all involving patients who had been poisoned with agricultural OP. ese studies compared either the ecacies of atropine alone and atropine in combi- nation with 2-PAM, or those of two dierent dosing regimens of 2-PAM coadministered with atropine. One study also had groups comparing the combination of pralidoxime and atropine with the combination of obidoxime and atropine. Peter et al. reviewed seven of the eight studies that investigated the ecacy of 2-PAM in combination with atropine as compared with that of atropine alone. Of the eight studies that investigated the ecacy of 2-PAM vs. therapy without oxime, three were blinded RCTs. e largest and most recent of these studies, by Eddleston et al. in 235 patients with OP poisoning, prospectively randomized the subjects to receive either atropine alone ( control) or atro- pine in combination with 2-PAM ( treatment). e study was double-blinded and used World Health Organization (WHO)- recommended doses of 2-PAM. e outcome measures were fatality rate, need for intubation, and enzyme reactivation as measured in terms of serial red blood cell AChE levels. e mor- tality rate was nonsignicantly higher in the treatment group (24.8 vs. 15.8%). e need for intubation was also similar in the two groups (21.5% in the treatment group vs. 21.1% in the control group). Serial AChE levels showed clear evidence of signicant enzyme reactivation in the treatment group. e rst of two studies by Cherian et al . involved 110 patients and showed signicantly higher rates of death and need for intubation in the 2-PAM group as compared with the group on atropine alone. e second study by Cherian et al., involving only 21 patients, showed no signicant dierences in mortality (1 patient in each group died), rates of ventilation, or days of intensive care unit stay. Although the 2-PAM dose used in the second Cherian study was larger than the one used in the rst study, it still fell short of the WHO-recommended dose. e other nonrandomized studies of atropine, alone or in combi- nation with 2-PAM, also failed to nd any signicant clinical advantage in the use of 2-PAM. Balali-Mood et al . used a three- armed study design that allowed for a comparison of 2-PAM and obidoxime, each coadministered with atropine. Although the numbers were small (22 patients with obidoxime and 8 with 2-PAM), the study suggested that 2-PAM was preferable to obidoxime because of a lower mortality rate. Respiratory complications were found to be signicantly more likely in the oxime-treated groups. Two patients in the study died from presumed obidoxime hepatotoxicity. Four studies have looked at high-dose vs. low-dose 2-PAM coadministered with atropine. In three of the four studies, high-dose 2-PAM yielded better outcomes, including lower death rates and less need for respiratory support. In the fourth study, the high-dose group showed a higher death rate and an increased rate of development of intermediate syndrome. In addition to the 2-PAM studies discussed here, some case series have been reported for obidoxime and HI-6. It should be noted that none of the above data are in patients poisoned with NA. ere have been several reports of individu- als exposed to sarin or VX in various terrorist and homicidal events in Japan. Unfortunately, because few details of the treat- ment are available and most of the patients were mildly exposed, these reports shed little light on the question of the ecacy of oxime treatment to counteract NA poisoning. Sidell reported on the treatment of ve patients with accidental occupational expo- sure to sarin and soman. Two of the patients, one exposed to sarin and the other to soman, received treatment with atropine and 2-PAM, and both survived. e other three patients had CLINICAL PHARMACOLOGY & THERAPEUTICS | VOLUME 88 NUMBER 3 | SEPTEMBER 2010 325 state artstate art mild exposures. In summary, recent data, particularly from three RCTs, have raised concerns about the clinical ecacy of oxime therapy in OP poisoning. Data from both animal and human studies clearly show that oximes can reactivate cholinesterase enzymes, but signicant clinical eects appear to be absent. It is unclear why there is a disconnect between biochemical evidence of eect and clinical evidence of eect. Clearly, this is an area that urgently requires additional research. In the meantime, it seems prudent to consider the use of oximes to be a therapeutic option but not a requirement for OP or NA poisoning. It is also possible that the development of new, perhaps more eective, oxime derivatives will resolve this issue. e third antidote usually used in OP poisoning is an anti- convulsant, given that cholinesterase inhibitors frequently induce multicentric seizures. Data from animal studies suggest that seizure activity is initially mediated by cholinergic mecha- nisms. If this is le uncontrolled during the initial stages, other neurotransmitter systems begin to participate in the generalized seizure activity, and eventually prolonged seizure activity becomes cholinergic independent. This proposed model explains the early eect of anticholinergics, such as atropine, in controlling OP-induced seizure activity. If seizures are not controlled very shortly aer onset, they become increasingly refractory to atro- pine therapy. During the latter stages of therapy, benzodiazepines have been shown to be the treatment of choice, with many other anticonvulsants showing little or no eect. McDonough et al. have evaluated the relative ecacy of six benzodiazepines against soman-induced seizures in a guinea pig model. Midazolam was the most potent and rapidly acting drug of the group, which also included diazepam, lorazepam, and clonazepam. Midazolam has been shown to have rapid and equivalent activity through the intramuscular and intranasal routes in the guinea pig model of soman-induced seizures, whereas the sublingual route gave sig- nicantly slower results in this model. Midazolam has also been shown to act rapidly through the intraosseous route in a pig model of paraoxon-induced seizures. Control of seizures is essential to Table 2 Evidence for effectiveness of antidotes/treatments for chemical warfare agents Agent Antidote/treatment Strength of evidencea Data source Reference(s)Human Animal Cyanide Nitrite + sodium thiosulfate C-IIa X X 19–27 Sodium thiosulfate alone C-IIb X 28–30 4-DMAP C-IIb X X 16,17,34–36 Dicobalt EDTA C-IIb X 37–42 Hyperbaric oxygen C-IIb X 15 Hydroxycobalamin B-IIa X X 27,43–50 Sulfur mustard Thiosulfate C-IIb X NAC C-IIb X Sodium hypochlorite C-IIb X Iodine C-IIb X Silver sulfadiazine C-IIb X Solid adsorbents C-IIb X X Lewisite BAL B-IIa X X DMSA B-IIa X X DMPS B-IIa X X Chlorine Sodium bicarbonate B-I X X Steroids B-I X Phosgene Steroids B-IIa X Anti-inflammatory agents B-IIb X NAC B-IIb X Organophosphate Atropine A-I X X Nerve agents Oximes A-IIb X X Benzodiazepines A-I X Bicarbonate B-IIb X X Hemoperfusion/hemodialysis B-IIa X Fresh-frozen plasma/bioscavengers B-IIa X X BAL, British anti-Lewisite; 4-DMAP, 4-dimethylaminophenol; DMPS, 2,3-dimercapto-1-propanesulfonic acid; DMSA, meso-2,3-dimercaptosuccinic acid; NAC, N-acetyl-l-cysteine. aMethodologies and policies from the American College of Cardiology Foundation (ACCF)/American Heart Association (AHA) Task Force on Practice Guidelines. Methodology manual for ACCF/AHA guidelines writing committees. Dallas, TX: ACCF and AHA, January 2010. Letters A–C designate the levels of available evidence, with A being extensive and C being very limited. Numbers I–III designate the strength of recommendation, with I being a strong recommendation to use and III being a recommendation not to use. 326 VOLUME 88 NUMBER 3 | SEPTEMBER 2010 | www.nature.com/cpt state artstate art protecting against brain injury in NA poisoning. In summary, there are no RCTs of anticonvulsant therapy in humans with NA or OP poisoning. ere are adequate data from animal studies to conclude that all benzodiazepines are likely to be eective in controlling NA-induced seizures and that midazolam may be the preferred drug of this class. ere also appear to be adequate data from animal studies to support the value of anticholinergic agents, such as atropine, in the control of NA-induced seizures; however, this has no direct relevance because an anticholinergic agent is universally used in NA/OP poisoning for other reasons. Several other agents and procedures have been used, either clinically or experimentally, in patients with OP poisoning. Only one human trial has evaluated the eectiveness of sodium bicarbonate in treating patients with OP poisoning. In an RCT, 26 patients with moderate to severe OP poisoning received sodium bicarbonate (5–6 mEq/kg/day administered intrave- nously) in addition to atropine and 2-PAM. Twenty-seven con- trol patients received atropine and 2-PAM without bicarbonate. Several outcome measures were assessed, but only atropine utilization and length of hospital stay were statistically dier- ent between the groups, both favoring the bicarbonate-treated group. Data from animal and human studies related to bicarbo- nate treatment in OP poisoning have been reviewed. Hemodialytic techniques have also been advocated for treat- ing OP poisoning. An early uncontrolled retrospective study that reported on the use of hemoperfusion in 10 patients con- cluded that the technique was of no value in improving out- comes. Two recent studies have shown conicting results with hemoperfusion. Altintop et al. reported on 25 patients with severe OP poisoning who received hemoperfusion and 27 mildly poisoned patients who did not receive hemoperfusion. All the patients received atropine, 2-PAM, and other traditional supportive measures. ere were seven deaths in the hemo- perfused group and none in the mildly poisoned group. AChE levels were measured in some patients and showed an increase with hemoperfusion. It is dicult to reach any conclusions from this uncontrolled study, although the authors concluded that hemoperfusion may be useful in severe OP poisoning. In another nonrandomized study, Peng et al. reported on a group of 108 patients with severe dichlorvos poisoning, 67 of whom received hemoperfusion. Hemoperfusion was associated with signicantly decreased mortality (7.5 vs. 34.1%), decreased need for ventilation (13.4 vs. 36.6%), shortened intensive care unit stays (4.0 vs. 6.0 days), and shortened length of coma (9 vs. 16 h). ree case reports have described favorable outcomes in patients treated with a combination of hemodialysis and hemoperfusion for poisoning with VX, parathion, and dimethoate. Several addi- tional case reports have reported variable results with charcoal hemoperfusion. One case report describes the use of fresh frozen plasma (FFP) and plasmapheresis in an attempt at bioscavenging in a patient with OP poisoning and sepsis. e authors of the case study speculated that the butyrylcholinesterase in FFP may be the bioscavenger, although other data suggest that this may not be so. In a prospec- tive, partially randomized study of 33 patients with OP poisoning admitted to an intensive care unit, 12 patients received FFP; 10 of these received the treatment from day 2, and the other 2 patients received it only aer the onset of intermediate syndrome, a delayed neuromuscular decit that occurs aer signicant OP poisoning. All the patients also received standard therapy with atropine and 2-PAM, except one patient in each group who received atropine alone. FFP was found to increase butyrylcholinesterase levels. Intermediate syndrome occurred in 28.6% of the control patients but in 0% of the patients who initially received FFP. ere were ve deaths on the whole, three in the control group and two in the treatment group; the latter two patients had received FFP treat- ment only aer they developed intermediate syndrome. Considerable research into the development of other bioscav- engers is under way. e candidate that is in the most advanced stage of development and has completed phase I trials is a recom- binant form of butyrylcholinesterase produced in transgenic goats. A study of human butyrylcholinesterase in pigs poisoned with sarin showed excellent results consistent with eective scavenging by the drug. Other enzymes that either hydrolyze or bind NA are under study. Lipid emulsions, combined with extra- corporeal removal, have also been suggested but not tested. A single, small, human prospective RCT has also investigated the eect of magnesium in 45 patients with OP poisoning. All the patients received atropine and either 2-PAM or obidoxime. In addition, every fourth patient received a 4 g. intravenous infu- sion of magnesium sulfate over the rst 24 h. e death rate (14.7 vs. 0%) and length of hospitalization (5.0 vs. 2.9 days) were both signicantly lower in the magnesium-treated group. A pre- vious report of the use of magnesium sulfate in four patients did not document any signicant clinical response. SUMMARY There is currently a great deal of concern about chemical weapons because of their perceived potential use by terrorist groups. Unlike nuclear or biological agents, many chemical agents are relatively easy to either make or acquire from com- mercial sources. Tab l e 2 summarizes the evidence available in the published literature regarding the eectiveness of antidotes and treatments for exposure to chemical warfare agents. e strength of evidence is categorized using the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines system. is review highlights the facts that not much is known about potential antidotes for these various agents and that much more research is needed. e current use of antidotes is based on very poor evidence relying primarily on animal models, data from poorly controlled studies in humans, and analogy to similar conditions. Recent concise and critical reviews of specic antidotes represent a step for- ward in this area, as do attempts to improve the development of evidence-based medicine in toxicology in general. 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Prehospital administration of hydroxocobalamin for smoke inhalation-associated cyanide poisoning: 8 years of experience in the Paris Fire Brigade. Clin. Toxicol. (Phila). 44 (suppl. 1), 37–44 (2006). Citations (27) References (52) ... In face of the agents that cause respiratory failure, there are procedures, such as direct laryngoscopy and the insertion of supraglottic devices, for establishing a patent airway and, consequently, a reduced risk of death (13)(14) . ... ... Another limitation concerns the instruments on which the ventilatory support techniques were applied. As explained in Figure 2 Therefore, it should be considered that nine of the ten studies in this systematic review were carried out in a skills laboratory, that is, in a closed environment, with ideal brightness, controlled temperature and mannequins, which may not reflect reality (10,14,35) . In addition to the above, scholars in the field comment on the difficulty of developing research studies of this nature with human beings, in relation to the use of chemical warfare agents (14) . ... ... As explained in Figure 2 Therefore, it should be considered that nine of the ten studies in this systematic review were carried out in a skills laboratory, that is, in a closed environment, with ideal brightness, controlled temperature and mannequins, which may not reflect reality (10,14,35) . In addition to the above, scholars in the field comment on the difficulty of developing research studies of this nature with human beings, in relation to the use of chemical warfare agents (14) . ... Systematic review and meta-analysis comparing ventilatory support in chemical, biological and radiological emergencies Article Full-text available Aug 2020 Israel BorgesIsrael Borges · Magali CarvalhoMagali Carvalho · Marcel de Souza Quintana · Alexandre Barbosa de OliveiraAlexandre Barbosa de Oliveira View Show abstract ... Muskelkramper begraenses ved indgift af benzodiazepiner, der bør administreres til alle bevidstløse og alle med krampeanfald. Antidoterne obidoxin og pralidoxim kan anvendes til reaktivering af acetylkolinesterase, inden denne haemmes irreversibelt; herved aftager både de nikotinerge og muskarinerge effekter af nervegas [12,14]. ... ... Behandlingen af forgiftninger med sennepsgas og phosgenoxim er alene symptomatisk [14,16]. Isaer lungeødem og respiratoriske gener skal behandles akut, men forebyggelse af kroniske komplikationer er også vaesentlig. ... ... Débridement af større blaerer som ved regulaere brandsår tilrådes, og antibiotikabehandling vil vaere relevant, mens f.eks. petroleumsgele vil kunne forhindre øjenlågssynekkier [14,16]. ... Chemical Warfare Agents Article Dec 2019 · Ugeskr Laeger Søren Bruno ElmgreenSøren Bruno Elmgreen View Show abstract ... An important point to pose is that chemical agents continue to be a concern used by terroristic organizations, and local-regional wars. These agents have seriously caused short and long-term damages, kill, or incapacitate ordinary and military persons in urban and war fields (5). The first reports of the use of chemical warfare agents have been found in ancient Greek and Roman writings. ... ... The modern uses of the agents have been reported during World War I (WWI). The Geneva Protocol in 1925 was the first major international effort to limit development, and subsequently use these agents during World War II(WW II), as well as their frequent use up to now (5,6). Among the mass destruction weapons, chemical warfare is one of the most brutal created by mankind. ... ... It has strongly alkylating, nucleophilic, lipophilic, cytotoxic, mutagenic and carcinogenic properties. It is known as the "king of the battle gases (5,13). ■ Mechanism of action A few theories explained the mechanism of action of sulfur mustard. ... Therapeutic options to treat mustard gas poisoning - Review Article Full-text available Jul 2019 Mehrdad Rafati-Rahimzadeh · Mehravar RafatiMehravar Rafati · Sohrab KazemiSohrab Kazemi · Ali Akbar MoghadamniaAli Akbar Moghadamnia View Show abstract ... This definition may also be extended to include the infliction of harm that involves animals and plants/ crops (a.k.a., econo-bioterrorism). [271][272][273][274][275] Bioterrorism is often considered jointly with chemical terrorism, which is the release of nerve agents (organophosphorus compounds -e.g., sarin gas); vesicants which damage skin and mucous membranes (mustard gas and Lewisite); agents affecting the airway and lungs (i.e., choking agents, phosgene gas); and/or cyanide agents affecting cellular respiration (e.g., hydrogen cyanide and cyanogen chloride). [276][277][278] Today's risk of bioterrorism is high because of a normative erosion of the social anathema regarding the use of biological and chemical weapons. [279] In addition, the rise of affordable small-scale science and technology capacity linked with the emergence of asymmetrical warfare (i.e., the interplay between smaller international actors versus International Journal of Academic Medicine | Volume 6 | Issue 3 | July-September 2020 traditional monolithic nation states) is a serious threat to populations and resources. ... What’s new in Academic International Medicine? International health security agenda – Expanded and re‐defined Article Full-text available Sep 2020 Nicole K. LeNicole K. Le · Manish GargManish Garg · Ricardo IzurietaRicardo Izurieta · Stanislaw P. StawickiStanislaw P. Stawicki View Show abstract ... This definition may also be extended to include the infliction of harm that involves animals and plants/ crops (a.k.a., econo-bioterrorism) [96][97][98][99][100]. Bioterrorism is often considered jointly with chemical terrorism, which is the release of nerve agents (organophosphorus compounds-e.g., sarin gas); vesicants, which damage skin and mucous membranes (i.e., mustard gas and Lewisite); agents affecting the airway and lungs (i.e., choking agents, phosgene gas); and/or cyanide agents affecting cellular respiration (e.g., hydrogen cyanide and cyanic chloride) [101][102][103]. ... International Health Security: A Summative Assessment by ACAIM Consensus Group Chapter Full-text available Jul 2020 Nicole K. LeNicole K. Le · Manish GargManish Garg · Ricardo IzurietaRicardo Izurieta · Stanislaw P. StawickiStanislaw P. Stawicki View Show abstract ... However, authors of an extensive review of antidotes for a variety of chemical agents concluded that the strength of evidence supporting the use of these antidotes is generally weak and that more research is needed. 24 Other investigators have studied injury related to chemical exposures. Custer et al 25 used an in vitro test lung to simulate pediatric lung injury; the goal was to assess the efficacy of transport and/or emergency ventilators in the setting of masscasualty respiratory failure. ... Chemical-Biological Terrorism and Its Impact on Children Article Jan 2020 · Pediatrics Sarita Chung · Carl R. Baum · Ann-Christine Nyquist View Show abstract ... Undressed victims are sorted to separate injured or symptomatic victims from others. The administration of specific antidotes (e.g., atropine, hydroxocobalamin) should not delay the symptomatic treatment of distress [15]. In cases of radiological and biological risk, except toxins, antidotes may exist but their use may be deferred until advised by an expert. ... The chemical, biological, radiological and nuclear (CBRN) chain of survival: a new pragmatic and didactic tool used by Paris Fire Brigade Article Full-text available Dec 2019 · Crit Care Franck Calamai · Clément DerkenneClément Derkenne · D. JostD. Jost · Bertrand PrunetBertrand Prunet View Current problems of the health protection of Ukrainian Armed Forces servicemen from military toxic agents Article Nov 2019 L.A. Ustinova · V.I. Saglo · V.A. Barkevich · O.B. Kaplyuk View Multidisciplinary Role of Mesoporous Silica Nanoparticles in Brain Regeneration and Cancers: From Crossing the Blood-Brain Barrier to Treatment Article Full-text available Aug 2019 · PART PART SYST CHAR Shruti MendirattaShruti Mendiratta · Menna Hussein · Heba NasserHeba Nasser · Ahmed Atef Ahmed Ali View Show abstract Chemical and Biological Terrorism Incidents and Intensive Care Chapter Jan 2016 R. Steven Tharratt · Timothy E AlbertsonTimothy E Albertson View Show more Alan H Hall Ing Kang Ho Alan H Hall Frédéric Baud Winai Wananukul Recommended publications Discover more Article Chemical warfare agents January 2010 · EXS Kamil KucaKamil Kuca · Miroslav PohankaMiroslav Pohanka Chemical warfare agents are compounds of different chemical structures. Simple molecules such as chlorine as well as complex structures such as ricin belong to this group. Nerve agents, vesicants, incapacitating agents, blood agents, lung-damaging agents, riot-control agents and several toxins are among chemical warfare agents. Although the use of these compounds is strictly prohibited, the ... [Show full abstract] Read more Chapter Brief overview of mechanisms of cyanide antagonism and cyanide antidotes in current clinical use: Ex... March 2016 Alan H HallAlan H Hall Cyanide is unusual among chemical toxicants in that it has not one, but several specific antidotes. There are various mechanisms by which medications may have an impact on cyanide poisoning. These include: agents which induce methemoglobinemia (nitrites, 4-DMAP [4-Dimethylaminophenol]); those which can enhance endogenous biodetoxification pathways, mainly by increasing the conversion of cyanide ... [Show full abstract] Read more Article Full-text available Formulary Forum: Role of Hydroxocobalamin in Acute Cyanide Poisoning June 2008 · Annals of Pharmacotherapy Greene Shepherd · Larissa I VelezLarissa I Velez To review the recently approved cyanide antidote, hydroxocobalamin, and describe its role in therapy. Relevant publications were identified through a systematic search of PubMed using the MeSH terms and key words hydroxocobalamin and cyanide. This search was then limited to human studies published since 2000. Systematic searches were conducted through January 2008. References from identified ... [Show full abstract] View full-text Article Hydroxocobalamin for severe acute cyanide poisoning by ingestion or inhalationB July 2007 · The American journal of emergency medicine C Bismuth · Stephen BorronStephen Borron · Frederic BaudFrederic Baud · Bruno MegarbaneBruno Megarbane This chart review was undertaken to assess efficacy and safety of hydroxocobalamin for acute cyanide poisoning. Hospital records of the Fernand Widal and Lariboisière Hospitals were reviewed for intensive care unit admissions with cyanide poisoning for which hydroxocobalamin was used as first-line treatment from 1988 to 2003. Smoke inhalation cases were excluded. Hydroxocobalamin (5-20 g) was ... [Show full abstract] Read more Article Hydroxocobalamin for Poisoning Caused by Ingestion of Potassium Cyanide: A Case Study July 2008 · Journal of Emergency Medicine Jean-Luc FortinJean-Luc Fortin · Stanislas Waroux · J.P. Giocanti · [...] · Jean-Jacques Kowalski Hydroxocobalamin, a precursor of vitamin B12, has a history of use in the prehospital setting in France for cyanide poisoning, particularly that associated with smoke inhalation. Because cyanide poisoning by ingestion is less common than smoke inhalation-associated cyanide poisoning, less information is available on prehospital use of hydroxocobalamin to treat cyanide poisoning by ingestion. This ... [Show full abstract] Read more Last Updated: 29 Jul 2020 RG Logo ResearchGate Logo or Discover by subject area Recruit researchers Join for free Login App Store Company About us News Careers Support Help Center Business solutions Advertising Recruiting © 2008-2020 ResearchGate GmbH. All rights reserved. Terms · Privacy · Copyright · Imprint
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