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Acute hydrofluoric acid exposure
Review
Acute Hydrofluoric Acid Exposure E. MARTIN CARAVATI, Hydrofluoric acid (HF) is unique among corrosives in the acute toxicity that results from dermal, ocular, inhalation, and oral exposures. The rapidity of onset and severity of injury make it a particularly dangerous chemical. HF is used widely in the industrial, research, and domestic settings. Therefore, it is mandatory that emergency physicians be familiar with the pathophysiology, evaluation, treatment, and potential complications that may result from accidental or intentional exposure to this compound. HISTORY AND EPIDEMIOLOGY An English glassworker first prepared crude HF in about 1720. In the late 1800s and early 1900s HF was used for cleaning sand from castings and for etching glass. It was first commercially produced in 1931. Shortly afterwards, it was used as a catalyst in alkylating processes for making high-octane fuel.’ Since that time, production of HF has increased steadily, reaching 161,260 tons in 1967 and 375,000 tons in 1974.’ In 1976 the National Institute of Occupational Safety and Health (NIOSH) listed 57 occupations with an estimated 22,000 workers who had potential exposure to HF on a daily basis. The semiconductor industry was not included in the 1976 NIOSH list but represents an expanding modern workforce that uses HF extensively in etching glass from the surface of silicon wafers.3 In addition, HF is the primary ingredient of many rust-removing agents that are available to the general public.
From the Division of Emergency Medicine, School of Medicine, and the Intermountain Control Center, Salt Lake City, Utah. Manuscript 1987.
received
Address reprint ment, University UT 84132.
gluconate,
poisoning.
0 1988 W.B. Saunders 0735-6757188
1987; revision
requests to Dr. Caravati: Hospital, 50 North Medical
Key Words: Calcium calcium,
13 March
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$0.00 + .25
hydrofluoric
University Regional
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MD
During 1985 and 1986, a total of 2367 human exposures were reported voluntarily to the American Association of Poison Control Centers Data Collection System.4*5 Of these exposures, 80% were adults, 98% were accidental, and 73% required treatment at a health care facility. Four fatalities occurred, three from ingestion and one secondary to dermal exposure. CHEMICAL PROPERTIES Hydrogen fluoride is a colorless liquid or gas. It is manufactured by allowing sulfuric acid to react with high-grade fluorospar (97% calcium fluoride) in heated kilns. It is produced as a gas, purified, and then condensed into a liquid known as hydrofluoric acid.’ The aqueous solutions will fume above concentrations of 40 to 48%. Concentrated solutions are strong protonic acids, whereas dilute solutions are weak acids. It is 1000 times less dissociated than hydrochloric acid (HF dissociation constant, Kd = 3.53 x 10m4). PATHOPHYSIOLOGY, CLINICAL MANIFESTATIONS, AND THERAPY Ingestion Poisoning from the ingestion of fluoride salts is well documented in the literature.(j The toxicity from the ingestion of HF is notable, however, because of its potency and rapidity of onset, which may result in death. In 1930 Webster’ reported that ingestion of 1 tablespoonful (15 mL) of a 9% HF solution caused death. In 1939 Gettler and Ellerbrook* estimated the smallest lethal total soft-tissue burden of fluorine as 104 mg for 63 kg (140 lbs) of body weight. This value was derived from postmortem analysis of humans who died within 24 hours after fluoride ingestion. In 1964 Greendyke and Hedge’ suggested that the lethal oral dose of HF may be as low as 1.5 g or 20 mg/kg. The discrepancy between the small amounts of fluoride found at postmortem examination and the larger quantity estimated for lethal ingestion lies in the rapidity with which fluoride is removed from the blood by renal excretion and bone deposition. lo Since 1962, eight fatal cases of HF ingestion have 143
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been reported.“-” In two cases, death ensued in less than 1 hour after ingestion.‘2,13 Hemorrhagic gastritis, hypocalcemia, pulmonary edema, and metabolic acidosis were noted. Serum fluoride levels were as high as 5.6 mg/dL (normal, 0.01) 1 hour after ingestion of 90 to 120 mL (3 to 4 oz) of rust remover, denoting rapid absorption of fluoride from the gastrointestinal tract. Initially, gastrointestinal symptoms of nausea, vomiting, abdominal pain, and diarrhea may be present before signs of systemic toxicity are evident (Table I). Therapy
As a first-aid measure in the home, milk should be administered immediately to dilute the acid and perhaps bind some of the fluoride ion. Because of HF’s propensity to cause significant systemic fluoride toxicity, gastric emptying after ingestion of a significant amount would seem desirable. If spontaneous vomiting has not occurred and the time between ingestion and treatment is brief (~90 minutes), then gastric lavage should be considered. The addition of 10% calcium gluconate to the lavage fluid may have an advantage over plain tapwater or saline because of the availability of free calcium to bind the fluoride. The risk of perforating the stomach secondary to the procedure is small compared to the high morbidity and mortality associated with absorption of fluoride and systemic poisoning. There are no data or guidelines for the amount of lavage fluid required for decontamination of the stomach in this setting. However, it should require substantially less volume than that required for removal of tablets or pill fragments. The induction of emesis with syrup of ipecac is not advised. HF is extremely causTABLE 1.
Signs of Acute Systemic
Fluoride
Toxicity
General Malaise Weakness Pallor Cardiopulmonary Tachycardia Hypotension Prolonged QT interval on ECG Ventricular fibrillation Pulmonary edema Neurologicineuromuscular Respiratory depression and paralysis CNS depression Carpopedal spasm Tetany Seizures Metabolic Hypocalcemia Hyperkalemia Hypomagnesemia ABBREVIATIONS: ECG, electrocardiogram;
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tic, and rapid clinical deterioration may ensue secondary to systemic toxicity. The use of neutralizing agents is controversial. After decontamination, the patient should be monitored for signs of airway compromise, gastric perforation, gastric hemorrhage, and systemic toxicity.
Inhalation The vapor pressure of hydrogen fluoride gas over a 70% solution of HF at 26.7”C (80°F) is 1.50 mm Hg, which is similar to that of acetone, carbon tetrachloride. and chloroform. I4 Air containing as little as 5 ppm (5 mg/L) causes irritation of the eyes and nose.‘> It has been suggested that HF contamination of clothes at the chest level could produce atmospheric concentrations of lo4 to lo5 ppm in “the breathing zone.“14 Serious injury from inhalation of HF fumes is rare. It usually involves explosions that produce high concentrations of fumes or exposure of the skin and clothing of the upper body to high concentrations (>50%) of HF. Mayer and Guelich14 reported three cases of inhalation and skin exposure to 70% HF, in which all of the victims developed pulmonary edema and died within 2 hours of exposure. Several cases of inhalation exposure in humans have been reported that resulted in rapid hemorrhagic pulmonary edema, atelectasis, frank tracheobronchial hemorrhage, and death 30 to 150 minutes after exposure.‘6”7 In addition, delayed pulmonary effects have also been described. Kleinfeld’* reported a case in which a man exposed to HF vapors for 5 minutes developed pulmonary edema 3 hours after exposure, had a rapidly fatal course, and died 10 hours after exposure of hemorrhagic pulmonary edema. Pulmonary injury manifesting several days after exposure has been reported by Braun et al. I9 A 49year-old man who suffered 8% total body surface area burns to his face, neck, and legs was initially without respiratory complaints and had a normal chest radiograph on admission. He was treated prophylactically with furosemide, theophylline, methylprednisone, and antibiotics. A few days later, he developed a “massive purulent tracheobronchitis” with Proteus mirabilis and Staphylococcus artreus in his sputum. Bronchoscopy revealed a “band-shaped fibrinous coat” and mucus in the bronchial tree. Two weeks later he developed diffuse hemorrhages in the nasopharynx and right mainstem bronchus. Bronchoscopy was required to remove blood clots that were obstructing the right lung and causing collapse. The patient eventually died 4 weeks after the accident secondary to repeated tracheobronchial bleeding and respiratory insufficiency. These same findings of upper respiratory tract irrita-
CARAVATI W HYDROFLUORIC ACID EXPOSURES
tion, bronchopneumonia, and pulmonary edema and hemorrhages have been shown to occur in rabbits and guinea pigs that were exposed to high concentrations of HF gas.20 Respiratory symptoms may persist for months to years following inhalation injury, as is shown in another case reported by Braun et a1.19 A 38-year-old man inhaled HF fumes and sustained irritation to the pharynx and larynx with persistent cough and hoarseness 1 year later. Examination at that time revealed fibrinous, granulating deposits on thickened vocal cords. Therapy The management of inhalation exposure and injury consists of removing the victim from the source and into fresh air, accompanied by decontamination of clothes and skin. If respiratory symptoms are present, humidified oxygen should be administered and the patient transported to a health care facility where monitoring for laryngeal edema, pneumonitis, pulmonary edema, pulmonary hemorrhage, and systemic toxicity can be undertaken. Trevino et a1.2’ have suggested administering a 2.5 to 3.0% calcium gluconate solution via a nebulizer, although there is no experimental evidence to support its use.
Ocular Exposure Exposure of the eye to HF solution or vapors produces more extensive damage than that of other acids in similar concentrations. Hydrochloric acid produces damage only to the superficial structures of the eye. Its penetration is limited by a precipitated protein barrier. The fluoride ion’s ability to penetrate deep into tissue makes HF acid more destructive to ocular tissues.22 Signs and symptoms of eye exposure include the rapid onset of pain, tearing, conjunctival injection, and cornea1 opacification. Complications include decreased visual acuity, globe perforation, uveitis, glaucoma, conjunctival scarring, lid deformities, and keratitis sicca.23 Hatai and associates24 have reported what they believe to be a case of delayed ocular toxicity. A 3year-old girl sprayed a “wire-wheel cleaner” containing unknown concentrations of phosphoric and hydrofluoric acid into her eyes. Immediate pain and redness were observed, but these resolved after irrigation with water. Results of her eye examination were normal the next day. Four days later, she awoke with red, swollen, painful eyes with purulent drainage. Ophthalmic examination revealed slight cornea1 opacities bilaterally with some thrombosis of the conjunctival vessels. Her vision returned to normal in 30 days after treatment with topical steroids and antibiotics. The extent of damage produced by HF depends on the concentration. In rabbits, McCulley et al.22 found
that exposure to 0.5% HF produced mild initial conjunctival ischemia that resolved in 10 days. Eight percent HF produced severe initial ischemia that was still detectable 65 days after exposure. Twenty percent HF produced immediate cornea1 opacification and necrosis. Therapy All chemical burns of the eye are considered ophthalmic emergencies. Immediate and copious irrigation of the exposed eye(s) is the mainstay of treatment and is more important than transport to a hospital.‘5v23 Irrigation should be continued for at least 30 minutes after exposure, including during transport to a health care facility where an ophthalmic examination can be performed promptly. Local ophthalmic anesthetic drops will increase patient comfort and compliance with prolonged irrigation. The pH of the eye fluid should be checked periodically with litmus paper, and irrigation continued until it is normal. Assessment of visual acuity should be delayed until eye irrigation is completed. Subsequent therapy is aimed at binding dissociated fluoride ion and preventing complications. Attempts to extrapolate dermal therapy to the eye are attractive but fraught with hazard. McCulley and colleagues22 evaluated the toxicity and therapeutic efftcacy of numerous agents on rabbit eyes. Topical ointments of 25% and 50% magnesium oxide (MgO) or magnesium sulfate (MgSO,) and the irrigants water, isotonic saline (NaCI), magnesium chloride (MgCl,), lanthanum chloride (LaCl,), 0.2% benzethonium chloride (Hyamine, Rohm & Haas), 0.03% and 0.05% benz-alkonium chloride (Zephiran, Winthrop), and an isotonic divalent ion mixture were evaluated. The solutions were administered as 1 L over 30 minutes. The irrigants were also administered as 1 mL subconjunctival injections. Ten percent calcium gluconate injections were also evaluated. Single irrigations with 1 L of water, isotonic saline, or MgCl, were the only treatments that were found to be nontoxic and of therapeutic benefit. Benefits included reduced cornea1 epithelial loss and decreased cornea1 inflammation. Repeated irrigations over time were of no additional value and only led to an increased frequency of cornea1 ulceration. The topical ointments of MgO and MgSO,, irrigation with 0.2% Hyamine and 0.05% benzalkonium chloride and subconjunctival infiltration with 10% calcium gluconate all produced marked injury in normal rabbit eyes. Irrigation with CaCl, increased the frequency of cornea1 ulceration in burned eyes. Additive damage to burned eyes was seen with subconjunctival infiltrations of MgCl, and CaCl,. Multiple subconjunctival infiltrations increased the incidence of ulceration eightfold. Hatai and associates 24 have raised the question of 145
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whether irrigation with lactated Ringer’s solution or milk would be more beneficial than normal saline, because of the availability of the calcium ion in these solutions to bind free fluoride ions. Trevino and colleagues” have recommended the use of 1% calcium gluconate drops every 2 to 3 hours for 2 to 3 days after thorough irrigation with saline, although no controlled study is available to attest to the efficacy of this approach. Any significant ocular exposure should be referred to an ophthalmologist for definitive care.
Dermal Exposure The most common anatomic site for exposure to HF is the distal upper extremities. This is a result of the large number of personnel in industry and research who handle concentrated solutions of HF on a daily basis. In addition, relatively dilute solutions of HF (0.6 to 12%) are available to the public in the form of rustremoving and aluminum-cleaning products. Hydrofluoric acid is a highly permeat solute with a permeability coefficient similar to that of water (P = 1.4 x lop4 cm/s), and the transport of fluoride ion through biologic membranes occurs primarily by nonionic diffusion of molecular hydrogen fluoride .26 HF rapidly penetrates the skin and enters the systemic circulation. The application of 0.5 mL of 50% HF to 1.7% total body surface area of albino rats for only 5 minutes caused a dramatic rise in serum fluoride levels, hypocalcemia, hyponatremia, and hyperkalemia within 30 minutes of exposure.27 Fluoride has been found to be toxic to skin cells in vitro at 2 x lop3 mol/L.28 Macroscopically, the acute toxicity of dilute solutions of HF was assessed by Derelanko et a1.‘9 on albino rabbit skin. They found that 2% HF was corrosive when applied for 1 hour and resulted in increased serum concentrations of fluoride. No lesions were associated with 2% solutions applied for a duration of 1 minute, but lesions appeared after exposures of 5 and 15 minutes. Solutions with concentrations as low as 0.01% produced visible lesions in 5 minutes. One of the earliest clinical descriptions of HF burns was provided by Jones in 1939,30 who noted the intense pain and white areas of coagulation and blistering on the skin. Since then, certain distinct characteristics of the burns have been noted (Table 2). These are 1) intense pain that may be delayed in onset for hours and when untreated persists for days; 2) formation of tough, coagulated skin at the burn site; 3) proTABLE 2.
Distinct
Characteristics
Intense pain Coagulated skin at burn site Progressive tissue destruction Predilection for subungual area
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gressive tissue destruction in the absence of treatment; and 4) notable predilection for subungual tissue in digital exposures.31 It has been hypothesized that the severe pain is due to the immobilization of calcium, which results in shifting potassium concentrations and nerve stimulation.3’ Initial presentation may vary from mild skin erythema to severe third-degree burns.3’ Untreated, the lesions progress to indurated, whitish, and blistered vesicles and bullae that contain caseous necrotic tissue.34 Severe burns can progress to ulceration, full-thickness tissue loss, and even loss of digits.35 Scarring and permanent disability may result. The absence of stratum corneum in the subungual area allows rapid penetration into the nail bed and matrix. If allowed to progress, it may destroy bone of the distal phalanx.3h The National Institutes of Health has classified HF burns only according to the concentration of the acid to which the victim is exposed. No reference is made to the duration of exposure. Solutions of up to 20% may not produce erythema and pain until 24 hours after exposure; burns from 20-25% solutions usually manifest themselves 1 to 8 hours; and solutions greater than 50% produce immediate pain and rapid tissue destruction.37 Therupy
The treatment of HF burns of the skin consists of two phases. The first is decontamination of the skin by immediate and copious irrigation with the nearest available nontoxic liquid, usually water. The speed with which irrigation is undertaken is of utmost importance because HF rapidly penetrates the skin. Limiting the duration of exposure decreases the severity of toxicity. The danger of exposure to dilute HF is that it is often not detected by the victim until hours later, when penetration and tissue destruction have already taken place. Irrigation, preferably under a shower or faucet, should be continued for at least 15 to 30 minutes. After irrigation is complete, appropriate wound care, such as cleansing and debridement, is undertaken. Most brief exposures to dilute concentrations of HF will do well with this initial burn care and close follow-up, obviating the need for invasive therapy. Severe pain, however, denotes a more serious burn. Exposure of the subungual tissue to HF may require removal of the nail to facilitate decontamination and local calcium treatment.‘4’31.33’38 This procedure may be avoidable if intra-arterial calcium perfusion is to be done.39 The second phase of treatment is aimed at detoxifying the fluoride ion, usually by promoting formation of an insoluble calcium salt. Some physicians, however, have advocated immediate surgical excision of the burn. In 1969 Scharnweber4’ suggested that topical therapy and local infiltration with calcium gluconate
CARAVATI
was only palliative treatment and that the skin usually required a prolonged healing period. He proposed immediate surgical excision of small, severe burns for cases in which the location on the body lended itself to such an approach. The wound is then closed primarily or by skin grafting. He supported his proposal with data from experimental HF burns to rabbit’s abdomens. Those treated with calcium infiltration required 21 days of healing time, whereas those that underwent excision required only 8 days (time of suture removal). Kohnlein et a1.4’ in 1973 made similar recommendations based on rat experiments. The problems with this approach are 1) it is limited to burns of small surface area; 2) it may be difficult to delineate the extent of tissue involvement at initial presentation; and 3) cosmetic results may be unacceptable. Craig31 recommended surgical excision following failure of conservative treatment with local calcium injections. Therefore, conservative local therapy has been the mainstay of treatment to date (Table 3). Initial excision of the burn is not advised unless it is to debride necrotic tissue. Topical Therapy. One approach to topical therapy involves quaternary ammonium compounds. Some authors have recommended soaking the affected area in a solution of iced Hyamine or benzalkonium for 1 to 6 hours.38.42,43 It is postulated that the quaternary ammonium nitrogen exchanges ionized chloride for fluoride to produce a nonionized fluoride complex.42 All of this experience is anecdotal, however, and Carney et al.*’ illustrated ’ in vitro that Hyamine had no significant effect on lowering the concentration of fluoride ion. In addition, 0.2% Hyamine soaks for 1.5 hours on rats did not arrest progression of burns compared with controls.44 Magnesium-based soaks, gels, and pastes have been TABLE 3. Comparison of Calcium Hydrofluoric Acid Burns
Local Gel Skin impermeable to Ca2+ Limited efficacy
Therapies
Infiltration
Simple, noninvasive Painless application Fingernail may require removal Widely used May be done at home
Tissue receives Ca* + Relatively efficacious Invasive, nonvascular Painful injections Fingernail may require removal Widely used May be done on outpatient
Least expensive
Acceptable
cost
for Local
Arterial Perfusion Tissue receives Ca* + Relatively efficacious Invasive, vascular Painless perfusion Avoids fingernail removal Limited experience Requires hospitalization, infusion pump, angiogram Most expensive
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recommended as topical treatment on the basis of anecdotal clinical experience.‘4*30*45 In rat studies, magnesium soaks and ointments were no more effective than control treatments.44*46 Magnesium chloride has been shown to be less effective in lowering fluoride ion concentration in vitro than calcium chloride.28 Liberal and frequent application of 2.5% calcium gluconate gel to HF burns has been recommended21,43 and is probably the topical therapy of choice. Experimentally, it has been shown to be more effective than water or magnesium ointment in limiting burn severity in rats when applied to burns caused by 70% HF for 60-seconds’ duration. 46 In burns caused by 48% HF for lo-minutes’ duration, calcium gluconate gel was no better than control treatments4’ The main limitation of topical therapy is the impermeability of the skin to the calcium. Percutaneous penetration of calcium ion into subcutaneous tissue may be enhanced by formulating the gel with dimethyl sulfoxide (DMS0).47 A calcium gel is not stocked in most hospital pharmacies. A 2.5% calcium gluconate gel may be formulated by mixing 3.5 g of calcium gluconate powder USP to 150 mL (5 oz) of a water-soluble lubricant. A dressing soaked with a calcium salt solution and applied to the burn is a suitable alternative. The gel or dressing may be secured with an occlusive barrier (e.g., Latex glove or plastic wrap) if prolonged topical therapy is desired. Infiltration Therapy. In 1939 Jones3’ recommended infiltrating HF burns with calcium gluconate, and many physicians have followed suit since then.‘4*‘7,31-33*36*44 The technique of injecting 10% calcium gluconate through a 30-gauge needle at a maximum dose of 0.5 mL/cm* of skin is widely accepted.33 Many authors have attested to the near-immediate relief of pain after injection and state that the elimination of pain may be used as a guide to therapy. Recurrence of pain indicates the need for additional injections.33*44 Extreme pain and patient uncooperativity may necessitate block anesthesia before infiltration, thus negating patient symptoms as a guide to further therapy. Injection of 10% calcium gluconate into normal rat skin is toxic.48 Carney et a1.28did not find calcium salts toxic to guinea pig skin cells in vitro, however. It has been advised to dilute the calcium salt to a 5% solution with isotonic saline to reduce irritation of tissues and decrease scarring.*l This dilution may be particularly important when infiltrating the face. Calcium gluconate decreases fluoride concentration in vitro,28 and infiltration of HF-induced burns in rats has shortened healing time.44*49 Multiple injections at 24-hour intervals were no more effective than a single treatment.49 Dibbell et a1.33 do not recommend infiltration for exposures to less than 20% HF unless the burns appear to be deep or extremely painful. Harris and associates48 raised more controversy in 147
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1981 when they found that 10% magnesium sulfate and magnesium acetate injections were more effective than control and 10% calcium gluconate in rats. The failure of 10% calcium gluconate may have been due to its inherent toxicity in that study. No controlled human studies have been performed to date. The overwhelming clinical experience to date has been with calcium gluconate, and it is the agent of choice. The infiltration of calcium chloride may cause tissue necrosis, and its use is not recommended. Despite the acceptance of local infiltration with calcium gluconate, several disadvantages have been noted with this technique, especially when treating the digits: 1) the injections may be very painful, requiring block anesthesia; 2) vascular compromise may result from infiltration of too much fluid and may promote tissue necrosis; 3) local hyperosmolarity and inherent toxicity of calcium to skin cells may promote more tissue damage; 4) limited amounts of calcium can be delivered to the tissue-O.5 mL of 10% calcium gluconate contains 4.2 mg of elemental calcium which can neutralize only 0.025 mL of 20% HF2’; and 5) removal of the nail is often required when subungual tissue is involved. In view of these potential problems, a new method of delivering calcium to the affected tissue via arterial perfusion is currently being investigated. Intra-arterial Infusion of Calcium. In 1982 Kohnlein and Achinger5’ reported on the treatment of 13 patients with distal upper extremity burns, predominantly involving the digits, with intra-arterial infusions of calcium gluconate. Twelve of 13 exposures were to 20% HF. Healing times averaged 2 to 4 weeks. Three patients required skin grafting. No adverse reactions were noted. Since then, Pegg et al.,” Velvart,j2 and Vance et a1.39have reported on an additional 33 patients treated in this manner. The technique varied slightly between investigators, but generally it consisted of the following: 1) the arterial supply to the injured area was identified via arteriogram; 2) an intra-arterial catheter was placed in the appropriate vascular supply in close proximity to the lesion (e.g., radial, ulnar, or brachial artery); 3) a dilute solution of calcium salts was infused over 4 hours; 4) the solutions used were a) lo-mL solution of 10% calcium gluconate or calcium chloride mixed in 40 to 50 mL of 5% dextrose and repeated if pain returned within 4 hours,39 or b) 10 mL of 20% calcium gluconate in 40 mL of normal saline for radial or ulnar artery infusion, and 20 mL of 20% calcium gluconate in 80 mL of normal saline for brachial artery infusion and repeated at 12-hour intervals if needed.41,52 The sooner the therapy was begun, the better the response obtained. Velvart noted that if more than 6 hours had passed since injury, tissue necrosis was not prevented by this method, but pain relief occurred up to 24 hours after exposure. All of 148
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Vance’s patients had perfusions begun 6 hours or more after exposure, and marked pain relief was noted along with the return of normal skin color to blanched areas. 39 The efficacy of this method from these cases is difficult to determine because adequate controls were absent in all reports. In general, however, pain relief was achieved and most patients required more than one treatment to maintain relief. Subsequently, Vance and associates53 reported treating three patients with an intra-arterial magnesium sulfate solution. All patients developed tissue necrosis, which led the authors to conclude that the magnesium perfusion was of no benefit. This calcium chloride perfusion technique is attractive because it avoids the disadvantages and complications of local infiltration therapy. It also allows delivery of higher doses of calcium in a more uniform manner to the tissues. It requires, however, an invasive vascular procedure that may have complications, such as arterial spasm or thrombosis. It requires more time, resources, and expense, such as monitoring of serum calcium, an infusion pump, and probable hospital admission for repeated infusions. This technique has not been proved to be superior to local infiltration, and it should be reserved for use on severe distal extremity burns and by those who are comfortable with the technique and have considerable experience in the evaluation and treatment of these burns. Systemic
Toxicity
Systemic fluoride toxicity has occurred from derma1,54-56 inhalation,” and oral”*‘3 exposures to HF. Twenty-one deaths have been reported in the literature. 9.11-14.1~19.54-56 Burke and associates5’ reported the case of a 30year-old man who was exposed to up to 50 mL of 100% HF, which resulted in a 2.5% total body surface area burn of the face, neck, and arm. The patient was washed under a shower, had magnesium oxide dressings applied, and had the burned skin infiltrated with 240 mL of 10% calcium gluconate. He experienced nausea and vomiting and became stuporous, responding for 24 hours only to painful stimuli. Blood levels 6 hours after exposure were less than 0.3 mg/dL (normal, O.Ol), but the urinary fluoride level was 87.0 mgi L. Seventy-five percent of the total urinary fluoride was excreted in the first 24 hours, and then excretion continued at 20 mg/L for 2 days. The patient survived. Tepperman” reported another case of a 2.5% total body surface area burn from 70% HF that produced blood levels of 0.3 mg/dL and resulted in a fatality. This patient’s serum calcium level was 2.2 mg/dL; magnesium, 0.6 mg/dL; and arterial pH. 7.21. Recurrent episodes of ventricular fibrillation occurred, and
CARAVATI n HYDROFLUORIC ACID EXPOSURES
he died 9.5 hours after exposure. Mayer and Gross54 also reported systemic acidosis, hypocalcemia, and hypomagnesemia in a patient with a serum fluoride level of 0.4 mg/dL. Other potential metabolic abnormalities that may occur include hyperkalemia, hyponatremia, and hyperphosphatemia.58 In addition, Mayer54 described microscopic changes in the myocardium that are similar to “catecholamine myocarditis” or myofibrillar degeneration. Histologic myocardial damage was also described by Greendyke and Hedge’ and by McIvor56 after 7 to 10% total body surface area bums. Machle et al.” exposed rabbits to inhalation of HF and noted heart muscle necrosis, congestion, and edema in 20% of the animals. Inhalation of HF not only can cause local adverse effects but also leads to rapid absorption of fluoride into the blood stream and may cause significant systemic toxicity. In workers exposed to an atmosphere containing 3 mg of F/m3, there was almost an immediate rise in urinary fluoride levels.i6 Morris and Smith59 exposed the upper respiratory tract of rats to varying concentrations of HF gas (36, 96, and 176 mg of F/m3) and found that plasma fluoride concentrations correlated very highly (Y = 0.98) with airborne levels. This absorption should not be surprising because fluoride ion is known to equilibrate rapidly across biologic membranes. Acute pulmonary edema has been seen with systemic HF poisoning without apparent inhalation exposure and should be anticipated.13 Therapy
All patients having significant exposures should have intravenous access established and be monitored for cardiac arrhythmias. Observation should be continued for 24 to 48 hours. Hypocalcemia should be anticipated in significant exposures, whether by skin, ingestion, or inhalation, and corrected with 10% intravenous calcium gluconate. I7 Trevino et al.*l recommend adding 20 mL of 10% calcium gluconate prophylactically to the first liter of crystalloid solution, in order to raise the available amount of calcium in the blood. Serial serum calcium measurements should be obtained for the duration of the intoxication. Correcting systemic acidosis with sodium bicarbonate to near normal seems logical and should be guided by arterial blood gas measurements. Mild alkalosis may be beneficial in acute fluoride toxicity according to Reynolds and associates.60 They found that rats pretreated with sodium bicarbonate to yield alkalosis lived twice as long and had better blood pressure, heart rate, and urine output at any given serum fluoride concentration than those rats who were acidotic. They also found that the renal clearance of fluoride was higher in the alkalotic rat.
Cardiac arrhythmias may occur secondary to electrolyte imbalance, acidosis, or hypoxia, and the underlying cause should be identified and corrected. Fluoride-induced hyperkalemia may play a significant role in producing arrhythmias. Dialysis may be required to remove the excess serum potassium and fluoride.61 Hypotension should be managed with volume expansion and vasopressors, if needed. SUMMARY Significant local and systemic toxicity may occur from hydrofluoric acid by all routes of exposure. Prompt decontamination by removal from the source and copious irrigation of eyes and skin are essential to reduce morbidity and mortality. Ingestion of small amounts of HF can lead to rapid systemic poisoning and death. Calcium gluconate therapy has become the preferred method of detoxifying the fluoride ion, aithough its efficacy is based mainly on anecdotal reports and poorly controlled clinical studies. Therefore, more basic research is needed to elucidate the pathophysiology of local toxicity and the best therapeutic modalities to limit injury. All significant exposures should be evaluated by health care personnel familiar with the potential toxicity of this compound. The author thanks Wanda S. Updike, MD, for her assistance in reviewing the manuscript; and Darla Taylor for her secretarial support.
REFERENCES 1. Zenz C, Kindwall EP, et al: Selected potentially hazardous substances commonly encountered. In Zenz C (ed): Developments in Occupational Medicine. Chicago, Year Book, 1980, pp 358-360 2. NIOSH Criteria for a Recommended Standard: Occupational Exposure to Hydrogen Fluoride. HEW publication no. (NIOSH) 78-143. Washington, DC, NIOSH, March 1976 3. LaDou J: Health issues in the microelectronics industry. State Art Rev Occ Med 1986;1:1-11 4. Litovitz TL, Veltri JC: 1986 annual report of the American Association of Poison Control Centers National Data Collection System. Am J Emerg Med 1987;5:405-445 5. Litovitz TL, Normann S, Veltri JC: 1985 annual report of the American Association of Poison Control Centers Data Collection System. Am J Emerg Med 1986;4:427-458 6. Lidbeck WL, Hill 18, Beeman JA: Acute sodium fluoride poisoning. JAMA 1943;121:826 7. Webster RW: Legal Medicine and Toxicology. Philadelphia, Saunders 1930, p 389 8. Gettler AO, Ellerbrook L: Toxicology of fluorides. Am J Med Sci 1939;197:625-638 9. Greendyke RM, Hodge HC: Accidental death due to hydrofluoric acid. J Forensic Sci 1984;9:383-390 10. Hodge HC: Metabolism of fluorides. JAMA 1981;177:313316 11. Curry AS: Twenty-one uncommon cases of poisoning. Br Med J 1962;1:687-689 149
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12. Menchel SM, Dunn WA: Hydrofluoric acid poisoning. Am J Forensic Med Pathol 1984;5:245-248 13. Manoguerra AS, Neuman TS: Fatal poisoning from acute hydrofluoric acid ingestion. Am J Emerg Med 1986;4:362363 14. Mayer L, Guelich J: Hydrogen fluoride inhalation and burns. Arch Environ Health 1963;7:445-447 15. Grant WM: Toxicology of the Eye, ed 3. Springfield, IL, Charles C Thomas, 1986, pp 490-492 16. Watson AA, Oliver JS, Thorpe JW: Accidental death due to inhalation of hydrofluoric acid. Med Sci Law 1973;13:277279 17. Dieffenbacher PF, Thompson JH: Burns from exposure to anhydrous hydrofluoric acid. J Occup Med 1962;4:325326 18. Kleinfeld M: Acute pulmonary edema of chemical origin. Arch Environ Health 1965;10:942-946 19. Braun J, Stob H, Zober A: Intoxication following the inhalation of hydrogen fluoride. Arch Toxicol 1984;56:50-54 20. Machle W, Thamann F, et al: The effects of the inhalation of hydrogen fluoride. J Ind Hyg 1934;16:129-145 21. Trevino MA, Herrmann GH, Sprout WL: Treatment of severe hydrofluoric acid exposures. J Occup Med 1983;25:861863 22. McCulley JP, Whiting DW, et al: Hydrofluoric acid burns of the eye. J Occup Med 1983;25:447-450 23. Vaughan D, Asbury T: General Ophthalmology, ed 11. Los Altos, CA, Lange, 1986, p 340 24. Hatai JK, Weber JN, Diozaki K: Hydrofluoric acid burn of the eye: report of possible delayed toxicity. J Toxicol Cut Ocular Toxicol 1986;5:17%184 25. Trevino MA, Herrmann GH, Sprout WL: Further evaluation of hydrofluoric acid burns of the eye. J Occup Med 1984;26:483 26. Gutknecht J, Walter A: Hydrofluoric and nitric acid transport through lipid bilayer membranes. Biochem Biophys Acta 1981;644:153-156 27. Kono K, Yoshida Y, et al: An experimental study on the biochemical consequences of hydrofluoric acid burns. Bull Osaka Med Sch 1982;28:124-133 28. Carney SA, Hall M, et al: Rationale of the treatment of hydrofluoric acid burns. Br J Ind Med 1974;31:317-321 29. Derelanko MJ, Gad SC, et al: Acute dermal toxicity of dilute hydrofluoric acid. J Toxicol Cut Ocular Toxicol 1985;4:73-85 30. Jones AT: The treatment of hydrofluoric acid burns. J Ind Hyg Toxicol 1939;21:205-212 31. Craig RDP: Hydrofluoric acid burns of the hands. Br J Plast Surg 1964;17:53-59 32. Klauder JV, Shelanski L, Gabriel K: Industrial uses of compounds of fluorine and oxalic acid. Arch Ind Health 1955;12:412-419 33. Dibbel DG, lverson RE, et al: Hydrofluoric acid burns of the hand. J Bone Joint Surg 1970;52A:931-936 34. Shewmake SW, Anderson BG: Hydrofluoric acid burns: a report of a case and review of the literature. Arch Dermatol 1979;115:593-596 35. Dale RH: Treatment of hydrofluoric acid burns. Br Med J 1951 ;1:728-732 36. Blunt CP: Treatment of hydrofluoric acid skin burns with injection with calcium gluconate. Ind Med Surg 1964;33:869-871 37. Division of Industrial Hygiene, National Institutes of Health: hydrofluoric acid burns. Ind Med 1943;12:634
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38. Wetherhold JM, Shepherd FP: Treatment of hydrofluoric acid burns. J Occup Med 1964;6:193-195 39. Vance MV, Curry SC, et al: Digital hydrofluoric acid burns: treatment with intra-arterial calcium infusion. Ann Emerg Med 1986;15:890-896 40. Scharnweber HC: Treatment of hydrofluoric acid burns of the. skin by immediate surgical excision. Ind Med 1969;38:31-32 41. Kohnlein HE, Merkle P, Springorum HW: Hydrogen fluoride burns: experiments and treatment. Surg Forum 1973;24:50 42. Reinhardt CF, Hume WG, et al: Hydrofluoric acid burn treatment. J Am Ind Hyg 1966;27:166-171 43. MacKinnon MA: Treatment of hydrofluoric acid burns. J Occup Med 1986;28:804 44. lverson RE, Laub DR, Madison MS: Hydrofluoric acid burns. Plast Reconstr Surg 1971;48:107-112 45. Jordan JK, Dean BS, Krenzelok EP: Hydrofluoric acid exposures: is home therapy possible [abstract]? Vet Hum Toxicol 1986;28:486 46. Bracken WM, Cuppage F, et al: Comparative effectiveness of topical treatments for hydrofluoric acid burns. J Occup Med 1985;27:733-739. 47. Zachary LS, Reus W, et al: Treatment of experimental hydrofluoric acid burns. J Burn Care 1986;7:35-39 48. Harris JC, Rumack BH, Bregman DJ: Comparative efficacy of injectable calcium and magnesium salts in the therapy of hydrofluoric acid burns. Clin Toxicol 1981;18:10271032 49. Paley A, Seifter J: Treatment of experimental hydrofluoric acid corrosion. Proc Sot Exp Biol Med 1941;46:19&192 50. Kohnlein HE, Achinger R: A new method of treatment of the hydrofluoric acid burns of the extremities, Chir Plast 1982;6:297-305 51. Pegg SP, Siu S, Gillett G: Intra-arterial infusions in the treatment of hydrofluoric acid burns. Burns 1985;11:440-443 52. Velvart J: Arterial perfusion for hydrofluoric acid burns. Hum Toxicol 1983;2:233-238 53. Vance M, Curry S, et al: An update on the treatment of digital hydrofluoric acid burns with intra-arterial infusion techniques [abstract]. Vet Hum Toxicol 1986;28:486 54. Mayer TG, Gross PL: Fatal systemic fluorosis due to hydrofluoric acid burns. Ann Emerg Med 1985;14:149-153 55. Tepperman PB: Fatality due to acute systemic fluoride poisoning following a hydrofluoric acid skin burn. J Occup Med 1980;22:691-692 56. Mclvor ME: Delayed fatal hyperkalemia in a patient with acute fluoride intoxication. Ann Emerg Med 1987;16:1165-1167 57. Burke WJ, Hoegg UR, Phillips RE: Systemic fluoride poisoning resulting from a fluoride skin burn. J Occup Med 1973;15:39-41 58. Kono K, Yoshida Y, Harada A, et al: An experimental study on the biochemical consequences of hydrofluoric acid burns. Bull Osaka Med Sch 1982;28:124-133 59. Morris JB, Smith FA: Regional deposition and absorption of inhaled hydrogen fluoride. Toxicol Appl Pharmacol 1982;62:81-89 60. Reynolds KE, Whitford GM, Pashley DH: Acute fluoride toxicity: the influence of acid-base status. Toxicol Appl Pharmacol 1978;45:415-427 61. Mclvor ME, Cummings CE, Mower MM, et al: Sudden cardiac death from acute fluoride intoxication: the role of potassium. Ann Emerg Med 1987;16:777-781
Acute Hydrofluoric Acid Exposure E. MARTIN CARAVATI, Hydrofluoric acid (HF) is unique among corrosives in the acute toxicity that results from dermal, ocular, inhalation, and oral exposures. The rapidity of onset and severity of injury make it a particularly dangerous chemical. HF is used widely in the industrial, research, and domestic settings. Therefore, it is mandatory that emergency physicians be familiar with the pathophysiology, evaluation, treatment, and potential complications that may result from accidental or intentional exposure to this compound. HISTORY AND EPIDEMIOLOGY An English glassworker first prepared crude HF in about 1720. In the late 1800s and early 1900s HF was used for cleaning sand from castings and for etching glass. It was first commercially produced in 1931. Shortly afterwards, it was used as a catalyst in alkylating processes for making high-octane fuel.’ Since that time, production of HF has increased steadily, reaching 161,260 tons in 1967 and 375,000 tons in 1974.’ In 1976 the National Institute of Occupational Safety and Health (NIOSH) listed 57 occupations with an estimated 22,000 workers who had potential exposure to HF on a daily basis. The semiconductor industry was not included in the 1976 NIOSH list but represents an expanding modern workforce that uses HF extensively in etching glass from the surface of silicon wafers.3 In addition, HF is the primary ingredient of many rust-removing agents that are available to the general public.
From the Division of Emergency Medicine, School of Medicine, and the Intermountain Control Center, Salt Lake City, Utah. Manuscript 1987.
received
Address reprint ment, University UT 84132.
gluconate,
poisoning.
0 1988 W.B. Saunders 0735-6757188
1987; revision
requests to Dr. Caravati: Hospital, 50 North Medical
Key Words: Calcium calcium,
13 March
Company
$0.00 + .25
hydrofluoric
University Regional
of Utah Poison
accepted
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Emergency DepartDrive, Salt Lake City,
acid, intra-arterial
MD
During 1985 and 1986, a total of 2367 human exposures were reported voluntarily to the American Association of Poison Control Centers Data Collection System.4*5 Of these exposures, 80% were adults, 98% were accidental, and 73% required treatment at a health care facility. Four fatalities occurred, three from ingestion and one secondary to dermal exposure. CHEMICAL PROPERTIES Hydrogen fluoride is a colorless liquid or gas. It is manufactured by allowing sulfuric acid to react with high-grade fluorospar (97% calcium fluoride) in heated kilns. It is produced as a gas, purified, and then condensed into a liquid known as hydrofluoric acid.’ The aqueous solutions will fume above concentrations of 40 to 48%. Concentrated solutions are strong protonic acids, whereas dilute solutions are weak acids. It is 1000 times less dissociated than hydrochloric acid (HF dissociation constant, Kd = 3.53 x 10m4). PATHOPHYSIOLOGY, CLINICAL MANIFESTATIONS, AND THERAPY Ingestion Poisoning from the ingestion of fluoride salts is well documented in the literature.(j The toxicity from the ingestion of HF is notable, however, because of its potency and rapidity of onset, which may result in death. In 1930 Webster’ reported that ingestion of 1 tablespoonful (15 mL) of a 9% HF solution caused death. In 1939 Gettler and Ellerbrook* estimated the smallest lethal total soft-tissue burden of fluorine as 104 mg for 63 kg (140 lbs) of body weight. This value was derived from postmortem analysis of humans who died within 24 hours after fluoride ingestion. In 1964 Greendyke and Hedge’ suggested that the lethal oral dose of HF may be as low as 1.5 g or 20 mg/kg. The discrepancy between the small amounts of fluoride found at postmortem examination and the larger quantity estimated for lethal ingestion lies in the rapidity with which fluoride is removed from the blood by renal excretion and bone deposition. lo Since 1962, eight fatal cases of HF ingestion have 143
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been reported.“-” In two cases, death ensued in less than 1 hour after ingestion.‘2,13 Hemorrhagic gastritis, hypocalcemia, pulmonary edema, and metabolic acidosis were noted. Serum fluoride levels were as high as 5.6 mg/dL (normal, 0.01) 1 hour after ingestion of 90 to 120 mL (3 to 4 oz) of rust remover, denoting rapid absorption of fluoride from the gastrointestinal tract. Initially, gastrointestinal symptoms of nausea, vomiting, abdominal pain, and diarrhea may be present before signs of systemic toxicity are evident (Table I). Therapy
As a first-aid measure in the home, milk should be administered immediately to dilute the acid and perhaps bind some of the fluoride ion. Because of HF’s propensity to cause significant systemic fluoride toxicity, gastric emptying after ingestion of a significant amount would seem desirable. If spontaneous vomiting has not occurred and the time between ingestion and treatment is brief (~90 minutes), then gastric lavage should be considered. The addition of 10% calcium gluconate to the lavage fluid may have an advantage over plain tapwater or saline because of the availability of free calcium to bind the fluoride. The risk of perforating the stomach secondary to the procedure is small compared to the high morbidity and mortality associated with absorption of fluoride and systemic poisoning. There are no data or guidelines for the amount of lavage fluid required for decontamination of the stomach in this setting. However, it should require substantially less volume than that required for removal of tablets or pill fragments. The induction of emesis with syrup of ipecac is not advised. HF is extremely causTABLE 1.
Signs of Acute Systemic
Fluoride
Toxicity
General Malaise Weakness Pallor Cardiopulmonary Tachycardia Hypotension Prolonged QT interval on ECG Ventricular fibrillation Pulmonary edema Neurologicineuromuscular Respiratory depression and paralysis CNS depression Carpopedal spasm Tetany Seizures Metabolic Hypocalcemia Hyperkalemia Hypomagnesemia ABBREVIATIONS: ECG, electrocardiogram;
system. 144
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tic, and rapid clinical deterioration may ensue secondary to systemic toxicity. The use of neutralizing agents is controversial. After decontamination, the patient should be monitored for signs of airway compromise, gastric perforation, gastric hemorrhage, and systemic toxicity.
Inhalation The vapor pressure of hydrogen fluoride gas over a 70% solution of HF at 26.7”C (80°F) is 1.50 mm Hg, which is similar to that of acetone, carbon tetrachloride. and chloroform. I4 Air containing as little as 5 ppm (5 mg/L) causes irritation of the eyes and nose.‘> It has been suggested that HF contamination of clothes at the chest level could produce atmospheric concentrations of lo4 to lo5 ppm in “the breathing zone.“14 Serious injury from inhalation of HF fumes is rare. It usually involves explosions that produce high concentrations of fumes or exposure of the skin and clothing of the upper body to high concentrations (>50%) of HF. Mayer and Guelich14 reported three cases of inhalation and skin exposure to 70% HF, in which all of the victims developed pulmonary edema and died within 2 hours of exposure. Several cases of inhalation exposure in humans have been reported that resulted in rapid hemorrhagic pulmonary edema, atelectasis, frank tracheobronchial hemorrhage, and death 30 to 150 minutes after exposure.‘6”7 In addition, delayed pulmonary effects have also been described. Kleinfeld’* reported a case in which a man exposed to HF vapors for 5 minutes developed pulmonary edema 3 hours after exposure, had a rapidly fatal course, and died 10 hours after exposure of hemorrhagic pulmonary edema. Pulmonary injury manifesting several days after exposure has been reported by Braun et al. I9 A 49year-old man who suffered 8% total body surface area burns to his face, neck, and legs was initially without respiratory complaints and had a normal chest radiograph on admission. He was treated prophylactically with furosemide, theophylline, methylprednisone, and antibiotics. A few days later, he developed a “massive purulent tracheobronchitis” with Proteus mirabilis and Staphylococcus artreus in his sputum. Bronchoscopy revealed a “band-shaped fibrinous coat” and mucus in the bronchial tree. Two weeks later he developed diffuse hemorrhages in the nasopharynx and right mainstem bronchus. Bronchoscopy was required to remove blood clots that were obstructing the right lung and causing collapse. The patient eventually died 4 weeks after the accident secondary to repeated tracheobronchial bleeding and respiratory insufficiency. These same findings of upper respiratory tract irrita-
CARAVATI W HYDROFLUORIC ACID EXPOSURES
tion, bronchopneumonia, and pulmonary edema and hemorrhages have been shown to occur in rabbits and guinea pigs that were exposed to high concentrations of HF gas.20 Respiratory symptoms may persist for months to years following inhalation injury, as is shown in another case reported by Braun et a1.19 A 38-year-old man inhaled HF fumes and sustained irritation to the pharynx and larynx with persistent cough and hoarseness 1 year later. Examination at that time revealed fibrinous, granulating deposits on thickened vocal cords. Therapy The management of inhalation exposure and injury consists of removing the victim from the source and into fresh air, accompanied by decontamination of clothes and skin. If respiratory symptoms are present, humidified oxygen should be administered and the patient transported to a health care facility where monitoring for laryngeal edema, pneumonitis, pulmonary edema, pulmonary hemorrhage, and systemic toxicity can be undertaken. Trevino et a1.2’ have suggested administering a 2.5 to 3.0% calcium gluconate solution via a nebulizer, although there is no experimental evidence to support its use.
Ocular Exposure Exposure of the eye to HF solution or vapors produces more extensive damage than that of other acids in similar concentrations. Hydrochloric acid produces damage only to the superficial structures of the eye. Its penetration is limited by a precipitated protein barrier. The fluoride ion’s ability to penetrate deep into tissue makes HF acid more destructive to ocular tissues.22 Signs and symptoms of eye exposure include the rapid onset of pain, tearing, conjunctival injection, and cornea1 opacification. Complications include decreased visual acuity, globe perforation, uveitis, glaucoma, conjunctival scarring, lid deformities, and keratitis sicca.23 Hatai and associates24 have reported what they believe to be a case of delayed ocular toxicity. A 3year-old girl sprayed a “wire-wheel cleaner” containing unknown concentrations of phosphoric and hydrofluoric acid into her eyes. Immediate pain and redness were observed, but these resolved after irrigation with water. Results of her eye examination were normal the next day. Four days later, she awoke with red, swollen, painful eyes with purulent drainage. Ophthalmic examination revealed slight cornea1 opacities bilaterally with some thrombosis of the conjunctival vessels. Her vision returned to normal in 30 days after treatment with topical steroids and antibiotics. The extent of damage produced by HF depends on the concentration. In rabbits, McCulley et al.22 found
that exposure to 0.5% HF produced mild initial conjunctival ischemia that resolved in 10 days. Eight percent HF produced severe initial ischemia that was still detectable 65 days after exposure. Twenty percent HF produced immediate cornea1 opacification and necrosis. Therapy All chemical burns of the eye are considered ophthalmic emergencies. Immediate and copious irrigation of the exposed eye(s) is the mainstay of treatment and is more important than transport to a hospital.‘5v23 Irrigation should be continued for at least 30 minutes after exposure, including during transport to a health care facility where an ophthalmic examination can be performed promptly. Local ophthalmic anesthetic drops will increase patient comfort and compliance with prolonged irrigation. The pH of the eye fluid should be checked periodically with litmus paper, and irrigation continued until it is normal. Assessment of visual acuity should be delayed until eye irrigation is completed. Subsequent therapy is aimed at binding dissociated fluoride ion and preventing complications. Attempts to extrapolate dermal therapy to the eye are attractive but fraught with hazard. McCulley and colleagues22 evaluated the toxicity and therapeutic efftcacy of numerous agents on rabbit eyes. Topical ointments of 25% and 50% magnesium oxide (MgO) or magnesium sulfate (MgSO,) and the irrigants water, isotonic saline (NaCI), magnesium chloride (MgCl,), lanthanum chloride (LaCl,), 0.2% benzethonium chloride (Hyamine, Rohm & Haas), 0.03% and 0.05% benz-alkonium chloride (Zephiran, Winthrop), and an isotonic divalent ion mixture were evaluated. The solutions were administered as 1 L over 30 minutes. The irrigants were also administered as 1 mL subconjunctival injections. Ten percent calcium gluconate injections were also evaluated. Single irrigations with 1 L of water, isotonic saline, or MgCl, were the only treatments that were found to be nontoxic and of therapeutic benefit. Benefits included reduced cornea1 epithelial loss and decreased cornea1 inflammation. Repeated irrigations over time were of no additional value and only led to an increased frequency of cornea1 ulceration. The topical ointments of MgO and MgSO,, irrigation with 0.2% Hyamine and 0.05% benzalkonium chloride and subconjunctival infiltration with 10% calcium gluconate all produced marked injury in normal rabbit eyes. Irrigation with CaCl, increased the frequency of cornea1 ulceration in burned eyes. Additive damage to burned eyes was seen with subconjunctival infiltrations of MgCl, and CaCl,. Multiple subconjunctival infiltrations increased the incidence of ulceration eightfold. Hatai and associates 24 have raised the question of 145
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whether irrigation with lactated Ringer’s solution or milk would be more beneficial than normal saline, because of the availability of the calcium ion in these solutions to bind free fluoride ions. Trevino and colleagues” have recommended the use of 1% calcium gluconate drops every 2 to 3 hours for 2 to 3 days after thorough irrigation with saline, although no controlled study is available to attest to the efficacy of this approach. Any significant ocular exposure should be referred to an ophthalmologist for definitive care.
Dermal Exposure The most common anatomic site for exposure to HF is the distal upper extremities. This is a result of the large number of personnel in industry and research who handle concentrated solutions of HF on a daily basis. In addition, relatively dilute solutions of HF (0.6 to 12%) are available to the public in the form of rustremoving and aluminum-cleaning products. Hydrofluoric acid is a highly permeat solute with a permeability coefficient similar to that of water (P = 1.4 x lop4 cm/s), and the transport of fluoride ion through biologic membranes occurs primarily by nonionic diffusion of molecular hydrogen fluoride .26 HF rapidly penetrates the skin and enters the systemic circulation. The application of 0.5 mL of 50% HF to 1.7% total body surface area of albino rats for only 5 minutes caused a dramatic rise in serum fluoride levels, hypocalcemia, hyponatremia, and hyperkalemia within 30 minutes of exposure.27 Fluoride has been found to be toxic to skin cells in vitro at 2 x lop3 mol/L.28 Macroscopically, the acute toxicity of dilute solutions of HF was assessed by Derelanko et a1.‘9 on albino rabbit skin. They found that 2% HF was corrosive when applied for 1 hour and resulted in increased serum concentrations of fluoride. No lesions were associated with 2% solutions applied for a duration of 1 minute, but lesions appeared after exposures of 5 and 15 minutes. Solutions with concentrations as low as 0.01% produced visible lesions in 5 minutes. One of the earliest clinical descriptions of HF burns was provided by Jones in 1939,30 who noted the intense pain and white areas of coagulation and blistering on the skin. Since then, certain distinct characteristics of the burns have been noted (Table 2). These are 1) intense pain that may be delayed in onset for hours and when untreated persists for days; 2) formation of tough, coagulated skin at the burn site; 3) proTABLE 2.
Distinct
Characteristics
Intense pain Coagulated skin at burn site Progressive tissue destruction Predilection for subungual area
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gressive tissue destruction in the absence of treatment; and 4) notable predilection for subungual tissue in digital exposures.31 It has been hypothesized that the severe pain is due to the immobilization of calcium, which results in shifting potassium concentrations and nerve stimulation.3’ Initial presentation may vary from mild skin erythema to severe third-degree burns.3’ Untreated, the lesions progress to indurated, whitish, and blistered vesicles and bullae that contain caseous necrotic tissue.34 Severe burns can progress to ulceration, full-thickness tissue loss, and even loss of digits.35 Scarring and permanent disability may result. The absence of stratum corneum in the subungual area allows rapid penetration into the nail bed and matrix. If allowed to progress, it may destroy bone of the distal phalanx.3h The National Institutes of Health has classified HF burns only according to the concentration of the acid to which the victim is exposed. No reference is made to the duration of exposure. Solutions of up to 20% may not produce erythema and pain until 24 hours after exposure; burns from 20-25% solutions usually manifest themselves 1 to 8 hours; and solutions greater than 50% produce immediate pain and rapid tissue destruction.37 Therupy
The treatment of HF burns of the skin consists of two phases. The first is decontamination of the skin by immediate and copious irrigation with the nearest available nontoxic liquid, usually water. The speed with which irrigation is undertaken is of utmost importance because HF rapidly penetrates the skin. Limiting the duration of exposure decreases the severity of toxicity. The danger of exposure to dilute HF is that it is often not detected by the victim until hours later, when penetration and tissue destruction have already taken place. Irrigation, preferably under a shower or faucet, should be continued for at least 15 to 30 minutes. After irrigation is complete, appropriate wound care, such as cleansing and debridement, is undertaken. Most brief exposures to dilute concentrations of HF will do well with this initial burn care and close follow-up, obviating the need for invasive therapy. Severe pain, however, denotes a more serious burn. Exposure of the subungual tissue to HF may require removal of the nail to facilitate decontamination and local calcium treatment.‘4’31.33’38 This procedure may be avoidable if intra-arterial calcium perfusion is to be done.39 The second phase of treatment is aimed at detoxifying the fluoride ion, usually by promoting formation of an insoluble calcium salt. Some physicians, however, have advocated immediate surgical excision of the burn. In 1969 Scharnweber4’ suggested that topical therapy and local infiltration with calcium gluconate
CARAVATI
was only palliative treatment and that the skin usually required a prolonged healing period. He proposed immediate surgical excision of small, severe burns for cases in which the location on the body lended itself to such an approach. The wound is then closed primarily or by skin grafting. He supported his proposal with data from experimental HF burns to rabbit’s abdomens. Those treated with calcium infiltration required 21 days of healing time, whereas those that underwent excision required only 8 days (time of suture removal). Kohnlein et a1.4’ in 1973 made similar recommendations based on rat experiments. The problems with this approach are 1) it is limited to burns of small surface area; 2) it may be difficult to delineate the extent of tissue involvement at initial presentation; and 3) cosmetic results may be unacceptable. Craig31 recommended surgical excision following failure of conservative treatment with local calcium injections. Therefore, conservative local therapy has been the mainstay of treatment to date (Table 3). Initial excision of the burn is not advised unless it is to debride necrotic tissue. Topical Therapy. One approach to topical therapy involves quaternary ammonium compounds. Some authors have recommended soaking the affected area in a solution of iced Hyamine or benzalkonium for 1 to 6 hours.38.42,43 It is postulated that the quaternary ammonium nitrogen exchanges ionized chloride for fluoride to produce a nonionized fluoride complex.42 All of this experience is anecdotal, however, and Carney et al.*’ illustrated ’ in vitro that Hyamine had no significant effect on lowering the concentration of fluoride ion. In addition, 0.2% Hyamine soaks for 1.5 hours on rats did not arrest progression of burns compared with controls.44 Magnesium-based soaks, gels, and pastes have been TABLE 3. Comparison of Calcium Hydrofluoric Acid Burns
Local Gel Skin impermeable to Ca2+ Limited efficacy
Therapies
Infiltration
Simple, noninvasive Painless application Fingernail may require removal Widely used May be done at home
Tissue receives Ca* + Relatively efficacious Invasive, nonvascular Painful injections Fingernail may require removal Widely used May be done on outpatient
Least expensive
Acceptable
cost
for Local
Arterial Perfusion Tissue receives Ca* + Relatively efficacious Invasive, vascular Painless perfusion Avoids fingernail removal Limited experience Requires hospitalization, infusion pump, angiogram Most expensive
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recommended as topical treatment on the basis of anecdotal clinical experience.‘4*30*45 In rat studies, magnesium soaks and ointments were no more effective than control treatments.44*46 Magnesium chloride has been shown to be less effective in lowering fluoride ion concentration in vitro than calcium chloride.28 Liberal and frequent application of 2.5% calcium gluconate gel to HF burns has been recommended21,43 and is probably the topical therapy of choice. Experimentally, it has been shown to be more effective than water or magnesium ointment in limiting burn severity in rats when applied to burns caused by 70% HF for 60-seconds’ duration. 46 In burns caused by 48% HF for lo-minutes’ duration, calcium gluconate gel was no better than control treatments4’ The main limitation of topical therapy is the impermeability of the skin to the calcium. Percutaneous penetration of calcium ion into subcutaneous tissue may be enhanced by formulating the gel with dimethyl sulfoxide (DMS0).47 A calcium gel is not stocked in most hospital pharmacies. A 2.5% calcium gluconate gel may be formulated by mixing 3.5 g of calcium gluconate powder USP to 150 mL (5 oz) of a water-soluble lubricant. A dressing soaked with a calcium salt solution and applied to the burn is a suitable alternative. The gel or dressing may be secured with an occlusive barrier (e.g., Latex glove or plastic wrap) if prolonged topical therapy is desired. Infiltration Therapy. In 1939 Jones3’ recommended infiltrating HF burns with calcium gluconate, and many physicians have followed suit since then.‘4*‘7,31-33*36*44 The technique of injecting 10% calcium gluconate through a 30-gauge needle at a maximum dose of 0.5 mL/cm* of skin is widely accepted.33 Many authors have attested to the near-immediate relief of pain after injection and state that the elimination of pain may be used as a guide to therapy. Recurrence of pain indicates the need for additional injections.33*44 Extreme pain and patient uncooperativity may necessitate block anesthesia before infiltration, thus negating patient symptoms as a guide to further therapy. Injection of 10% calcium gluconate into normal rat skin is toxic.48 Carney et a1.28did not find calcium salts toxic to guinea pig skin cells in vitro, however. It has been advised to dilute the calcium salt to a 5% solution with isotonic saline to reduce irritation of tissues and decrease scarring.*l This dilution may be particularly important when infiltrating the face. Calcium gluconate decreases fluoride concentration in vitro,28 and infiltration of HF-induced burns in rats has shortened healing time.44*49 Multiple injections at 24-hour intervals were no more effective than a single treatment.49 Dibbell et a1.33 do not recommend infiltration for exposures to less than 20% HF unless the burns appear to be deep or extremely painful. Harris and associates48 raised more controversy in 147
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1981 when they found that 10% magnesium sulfate and magnesium acetate injections were more effective than control and 10% calcium gluconate in rats. The failure of 10% calcium gluconate may have been due to its inherent toxicity in that study. No controlled human studies have been performed to date. The overwhelming clinical experience to date has been with calcium gluconate, and it is the agent of choice. The infiltration of calcium chloride may cause tissue necrosis, and its use is not recommended. Despite the acceptance of local infiltration with calcium gluconate, several disadvantages have been noted with this technique, especially when treating the digits: 1) the injections may be very painful, requiring block anesthesia; 2) vascular compromise may result from infiltration of too much fluid and may promote tissue necrosis; 3) local hyperosmolarity and inherent toxicity of calcium to skin cells may promote more tissue damage; 4) limited amounts of calcium can be delivered to the tissue-O.5 mL of 10% calcium gluconate contains 4.2 mg of elemental calcium which can neutralize only 0.025 mL of 20% HF2’; and 5) removal of the nail is often required when subungual tissue is involved. In view of these potential problems, a new method of delivering calcium to the affected tissue via arterial perfusion is currently being investigated. Intra-arterial Infusion of Calcium. In 1982 Kohnlein and Achinger5’ reported on the treatment of 13 patients with distal upper extremity burns, predominantly involving the digits, with intra-arterial infusions of calcium gluconate. Twelve of 13 exposures were to 20% HF. Healing times averaged 2 to 4 weeks. Three patients required skin grafting. No adverse reactions were noted. Since then, Pegg et al.,” Velvart,j2 and Vance et a1.39have reported on an additional 33 patients treated in this manner. The technique varied slightly between investigators, but generally it consisted of the following: 1) the arterial supply to the injured area was identified via arteriogram; 2) an intra-arterial catheter was placed in the appropriate vascular supply in close proximity to the lesion (e.g., radial, ulnar, or brachial artery); 3) a dilute solution of calcium salts was infused over 4 hours; 4) the solutions used were a) lo-mL solution of 10% calcium gluconate or calcium chloride mixed in 40 to 50 mL of 5% dextrose and repeated if pain returned within 4 hours,39 or b) 10 mL of 20% calcium gluconate in 40 mL of normal saline for radial or ulnar artery infusion, and 20 mL of 20% calcium gluconate in 80 mL of normal saline for brachial artery infusion and repeated at 12-hour intervals if needed.41,52 The sooner the therapy was begun, the better the response obtained. Velvart noted that if more than 6 hours had passed since injury, tissue necrosis was not prevented by this method, but pain relief occurred up to 24 hours after exposure. All of 148
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Vance’s patients had perfusions begun 6 hours or more after exposure, and marked pain relief was noted along with the return of normal skin color to blanched areas. 39 The efficacy of this method from these cases is difficult to determine because adequate controls were absent in all reports. In general, however, pain relief was achieved and most patients required more than one treatment to maintain relief. Subsequently, Vance and associates53 reported treating three patients with an intra-arterial magnesium sulfate solution. All patients developed tissue necrosis, which led the authors to conclude that the magnesium perfusion was of no benefit. This calcium chloride perfusion technique is attractive because it avoids the disadvantages and complications of local infiltration therapy. It also allows delivery of higher doses of calcium in a more uniform manner to the tissues. It requires, however, an invasive vascular procedure that may have complications, such as arterial spasm or thrombosis. It requires more time, resources, and expense, such as monitoring of serum calcium, an infusion pump, and probable hospital admission for repeated infusions. This technique has not been proved to be superior to local infiltration, and it should be reserved for use on severe distal extremity burns and by those who are comfortable with the technique and have considerable experience in the evaluation and treatment of these burns. Systemic
Toxicity
Systemic fluoride toxicity has occurred from derma1,54-56 inhalation,” and oral”*‘3 exposures to HF. Twenty-one deaths have been reported in the literature. 9.11-14.1~19.54-56 Burke and associates5’ reported the case of a 30year-old man who was exposed to up to 50 mL of 100% HF, which resulted in a 2.5% total body surface area burn of the face, neck, and arm. The patient was washed under a shower, had magnesium oxide dressings applied, and had the burned skin infiltrated with 240 mL of 10% calcium gluconate. He experienced nausea and vomiting and became stuporous, responding for 24 hours only to painful stimuli. Blood levels 6 hours after exposure were less than 0.3 mg/dL (normal, O.Ol), but the urinary fluoride level was 87.0 mgi L. Seventy-five percent of the total urinary fluoride was excreted in the first 24 hours, and then excretion continued at 20 mg/L for 2 days. The patient survived. Tepperman” reported another case of a 2.5% total body surface area burn from 70% HF that produced blood levels of 0.3 mg/dL and resulted in a fatality. This patient’s serum calcium level was 2.2 mg/dL; magnesium, 0.6 mg/dL; and arterial pH. 7.21. Recurrent episodes of ventricular fibrillation occurred, and
CARAVATI n HYDROFLUORIC ACID EXPOSURES
he died 9.5 hours after exposure. Mayer and Gross54 also reported systemic acidosis, hypocalcemia, and hypomagnesemia in a patient with a serum fluoride level of 0.4 mg/dL. Other potential metabolic abnormalities that may occur include hyperkalemia, hyponatremia, and hyperphosphatemia.58 In addition, Mayer54 described microscopic changes in the myocardium that are similar to “catecholamine myocarditis” or myofibrillar degeneration. Histologic myocardial damage was also described by Greendyke and Hedge’ and by McIvor56 after 7 to 10% total body surface area bums. Machle et al.” exposed rabbits to inhalation of HF and noted heart muscle necrosis, congestion, and edema in 20% of the animals. Inhalation of HF not only can cause local adverse effects but also leads to rapid absorption of fluoride into the blood stream and may cause significant systemic toxicity. In workers exposed to an atmosphere containing 3 mg of F/m3, there was almost an immediate rise in urinary fluoride levels.i6 Morris and Smith59 exposed the upper respiratory tract of rats to varying concentrations of HF gas (36, 96, and 176 mg of F/m3) and found that plasma fluoride concentrations correlated very highly (Y = 0.98) with airborne levels. This absorption should not be surprising because fluoride ion is known to equilibrate rapidly across biologic membranes. Acute pulmonary edema has been seen with systemic HF poisoning without apparent inhalation exposure and should be anticipated.13 Therapy
All patients having significant exposures should have intravenous access established and be monitored for cardiac arrhythmias. Observation should be continued for 24 to 48 hours. Hypocalcemia should be anticipated in significant exposures, whether by skin, ingestion, or inhalation, and corrected with 10% intravenous calcium gluconate. I7 Trevino et al.*l recommend adding 20 mL of 10% calcium gluconate prophylactically to the first liter of crystalloid solution, in order to raise the available amount of calcium in the blood. Serial serum calcium measurements should be obtained for the duration of the intoxication. Correcting systemic acidosis with sodium bicarbonate to near normal seems logical and should be guided by arterial blood gas measurements. Mild alkalosis may be beneficial in acute fluoride toxicity according to Reynolds and associates.60 They found that rats pretreated with sodium bicarbonate to yield alkalosis lived twice as long and had better blood pressure, heart rate, and urine output at any given serum fluoride concentration than those rats who were acidotic. They also found that the renal clearance of fluoride was higher in the alkalotic rat.
Cardiac arrhythmias may occur secondary to electrolyte imbalance, acidosis, or hypoxia, and the underlying cause should be identified and corrected. Fluoride-induced hyperkalemia may play a significant role in producing arrhythmias. Dialysis may be required to remove the excess serum potassium and fluoride.61 Hypotension should be managed with volume expansion and vasopressors, if needed. SUMMARY Significant local and systemic toxicity may occur from hydrofluoric acid by all routes of exposure. Prompt decontamination by removal from the source and copious irrigation of eyes and skin are essential to reduce morbidity and mortality. Ingestion of small amounts of HF can lead to rapid systemic poisoning and death. Calcium gluconate therapy has become the preferred method of detoxifying the fluoride ion, aithough its efficacy is based mainly on anecdotal reports and poorly controlled clinical studies. Therefore, more basic research is needed to elucidate the pathophysiology of local toxicity and the best therapeutic modalities to limit injury. All significant exposures should be evaluated by health care personnel familiar with the potential toxicity of this compound. The author thanks Wanda S. Updike, MD, for her assistance in reviewing the manuscript; and Darla Taylor for her secretarial support.
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