J: HOUSEHOLD PRODUCTS

HISTORY AND EPIDEMIOLOGY

Joseph Lister, often considered the father of modern surgery, revolutionized surgical treatment and dramatically reduced surgical mortality by introducing the concept of antisepsis to the surgical theatre.⁵⁰ It was Lister’s ­understanding that microorganisms contributed to infection and sepsis from even the most trivial wounds that led to his search for chemicals that would ­prevent such infection. Lister demonstrated that phenol, a chemical that was used to treat foul-smelling sewage, could be used to clean dirty wounds of patients with compound fractures and dramatically increase survival rates. Soon thereafter, the use of phenol was expanded to surgical instrument cleaning and as a surgical hand scrub wash, ushering in the ­modern surgical era.

Antiseptics, disinfectants, and sterilants are a diverse group of germicides used to prevent the transmission of microorganisms to patients (Table 101–1). Although these terms are sometimes used interchangeably and some of these xenobiotics are used for both antisepsis and disinfection, the distinguishing characteristics between the groups are important to emphasize. An antiseptic is a chemical that is applied to living tissue to kill or inhibit microorganisms. Iodophors, chlorhexidine, and the alcohols (ethanol and isopropanol) are commonly used antiseptics. A disinfectant is a chemical that is applied to inanimate objects to kill microorganisms. Bleach (sodium hypochlorite), phenolic compounds, formaldehyde, hydrogen peroxide liquid, ortho-phthalaldehyde, and quaternary ammonium compounds are examples of currently used disinfectants. Neither antiseptics nor disinfectants have complete sporicidal activity. A sterilant is a chemical that is applied to inanimate objects to kill all microorganisms as well as spores. Ethylene oxide, glutaraldehyde, hydrogen peroxide gas, and peracetic acid are examples of sterilants. Many of the xenobiotics used to kill microorganisms also demonstrate considerable human toxicity.^18,69,180

The choice of disinfectant or sterilant depends on the degree of risk for infection involved in use of medical and surgical instruments and patient care items. Surgical instruments and cardiac and urinary catheters that enter the vascular system or other sterile tissues (so-called critical items) must be cleaned with a sterilant while instruments that contact mucous membranes or nonintact skin such as gastrointestinal (GI) endoscopes and laryngoscope blades (semicritical items) are cleaned with a high-level disinfectant such as ortho-phthalaldehyde or 7.5% hydrogen peroxide. Noncritical items such as bedpans, blood pressure cuffs, crutches, and computers are those that come in contact with intact skin but not mucous membranes and are cleaned with intermediate-level and low-level disinfectants such as bleach or phenol. Whether a chemical is classified as a sterilant or disinfectant depends on how it is used. Device sterilization with glutaraldehyde 3% requires a 10-hour cleaning cycle whereas high-level disinfection using the same chemical requires a 25-minute cleaning cycle.

The use of these xenobiotics evolved during the 20th century as their toxicity and the principles of microbiology became better understood. Two of the more toxic antiseptics—iodine and phenol—were gradually replaced by the less toxic iodophors and substituted phenols. The use of mercuric ­chloride was superseded by the organic mercurials such as merbromin and thimerosal, which also proved toxic. In recent years, newer xenobiotics, such as quaternary ammonium compounds, ethylene oxide, glutaraldehyde, and a peracetic acid–hydrogen peroxide mixture, are more extensively used.

ANTISEPTICS

Chlorhexidine

This cationic biguanide has had extensive use as an antiseptic since the early 1950s. It is found in a variety of skin cleansers, usually as a 4% emulsion, and is also found in some mouthwash.

Clinical Effects

Few cases of deliberate ingestion of chlorhexidine are reported. Symptoms are usually mild, and GI irritation is the most likely effect after ingestion.²⁵ Chlorhexidine has poor enteral absorption. In one case, ingestion of 150 mL of a 20% chlorhexidine gluconate solution resulted in oral cavity edema and significant irritant injury of the esophagus.¹³⁰ In the same case, liver enzyme concentrations rose to 30 times normal on the fifth day after ingestion. Liver biopsy showed lobular necrosis and fatty degeneration. In another case, the ingestion of 30 mL of a 4% solution by an 89-year-old woman did not result in any GI injury.⁵² An 80-year-old woman with dementia ingested 200 mL of a 5% chlorhexidine solution and subsequently aspirated.⁷⁹ She rapidly developed hypotension, respiratory distress, coma, and died 12 hours following ingestion.

Intravenous administration of chlorhexidine is associated with acute respiratory distress syndrome (ARDS)⁹⁰ and hemolysis.²⁸ Inhalation of vaporized chlorhexidine causes methemoglobinemia, likely as a consequence of the conversion of chlorhexidine to p-chloraniline.²¹¹ Methemoglobinemia due to this degradation product was also reported after the ingestion of a 0.5% chlorhexidine in 70% ethanol solution.¹⁰⁷ This patient was successfully treated with methylene blue. In one patient, the rectal administration of 4% chlorhexidine resulted in acute colitis with ulcerations.⁶⁸

Topical absorption of chlorhexidine is negligible. Contact dermatitis is reported in up to 8% of patients who received repetitive topical applications of chlorhexidine.⁶⁹ More ominously, anaphylactic reactions, including shock, are associated with dermal application.^7,148 Some of these cases of chlorhexidine-­related anaphylaxis occurred during surgery, appearing 15 to 45 minutes after application of the antiseptic.¹³ Eye exposure results in ­corneal damage.²⁰⁵

Management

Treatment guidelines for chlorhexidine exposure are similar to those for other potential caustics (Chap. 103). Patients with significant symptoms should undergo endoscopy, but the need for such extensive evaluation is uncommon.

Hydrogen Peroxide

Hydrogen peroxide, an oxidizer with weak antiseptic properties, has a long history of use as an antiseptic and a disinfectant.²¹⁵ This oxidizer is generally available in 2 strengths: dilute, with a concentration of 3% to 9% by weight (usually 3%), sold for home use; and concentrated, with a concentration greater than 10%, used primarily for industrial purposes. Commercial-­strength hydrogen peroxide is commonly found in solutions varying from 27.5% to 70%. Home uses for dilute hydrogen peroxide include cerumen removal, mouth gargle, vaginal douche, enema, and hair bleaching. Dilute hydrogen peroxide is also used as a veterinary emetic. Commercial uses of the more concentrated solutions include bleaching and cleansing textiles and wool, and producing foam rubber and rocket fuel. A 35% hydrogen peroxide solution is also available to the general public in health food stores and is sold as “hyperoxygenation therapy” and as an additive to oxygenate health food drinks.⁸⁶ This potentially dangerous therapy is suggested as a treatment for a variety of conditions, including AIDS and cancer.

Toxicity from hydrogen peroxide occurs after ingestion, inhalation, injection, wound irrigation, rectal administration, dermal exposure, and ophthalmic exposure.²¹⁵ Hydrogen peroxide has 2 main mechanisms of toxicity: local tissue injury and gas formation. The extent of local tissue injury and amount of gas formation are determined by the concentration of the hydrogen peroxide. Dilute hydrogen peroxide is an irritant, and concentrated hydrogen peroxide is a caustic. Gas formation results when hydrogen peroxide interacts with tissue catalase, liberating molecular oxygen, and water. At standard temperature and pressure, 1 mL of 3% hydrogen peroxide liberates 10 mL of oxygen, whereas 1 mL of the more concentrated 35% hydrogen peroxide liberates more than 100 mL of oxygen. Gas formation results in life-threatening embolization. The ingestion of “2 sips” of 33% hydrogen peroxide resulted in cerebral gas embolization and hemiplegia.¹⁷³ Gas embolization is a result of dissection of gas under pressure into the tissues or of liberation of gas in the tissue or blood following absorption. The use of hydrogen peroxide in partially closed spaces, such as operative wounds, or its use under pressure during wound irrigation increases the likelihood of embolization.

Clinical Effects

Airway compromise manifested by stridor, drooling, apnea, and radiographic evidence of subepiglottic narrowing occurs.⁴⁴ The combination of local tissue injury and gas formation from the ingestion of concentrated hydrogen peroxide causes abdominal bloating, abdominal pain, vomiting, and ­hematemesis.^55,123 Endoscopy shows esophageal edema and erythema and significant gastric mucosal erosions.^162,182

Symptoms consistent with sudden oxygen embolization include rapid deterioration in mental status, cyanosis, respiratory failure, seizures, ischemic ECG changes, and acute paraplegia.^57,119 A 2-year-old boy died after ingesting 120 to 180 mL of 35% hydrogen peroxide.³⁰ Antemortem chest radiography showed gas in the right ventricle, mediastinum, and portal venous system. Portal vein gas is also a prominent feature in other cases.^55,85,155 Arterialization of oxygen gas embolization results in cerebral infarction.¹⁸⁹ Encephalopathy with cortical visual impairment²³ and bilateral hemispheric infarctions detected by MRI imaging occurred after ingestion of concentrated hydrogen peroxide.⁸⁹ In a case of acute paraplegia after the ingestion of 50% hydrogen peroxide, MRI revealed discrete segmental embolic infarctions of the cervical and thoracic spinal cord as well as both cerebral hemispheres and left cerebellar hemisphere.¹¹⁹

Death from intravenous injection of 35% hydrogen peroxide is also reported.¹¹² The application of a concentrated hydrogen peroxide solution to the scalp and hair as part of a hair highlighting procedure resulted in a severe scalp injury, including necrosis of the galea aponeurotica.¹⁸³

Clinical sequelae from the ingestion of dilute hydrogen peroxide are usually much more benign.^44,76 Nausea and vomiting are the most common symptoms.⁴⁴ A whitish discoloration is noted in the oral cavity. Gastrointestinal injury is usually limited to superficial mucosal irritation, but multiple gastric and duodenal ulcers, accompanied by hematemesis, and diffuse hemorrhagic gastritis are reported.^76,136 Portal venous gas embolization occurs as a result of the ingestion of 3% hydrogen peroxide.^31,136,166

The use of 3% hydrogen peroxide for wound irrigation results in significant complications. Extensive subcutaneous emphysema occurred after a dog bite to a human’s face was irrigated under pressure with 60 mL of 3% hydrogen peroxide.¹⁹² Systemic oxygen embolism, causing hypotension, cardiac ischemia, and coma, resulted from the intraoperative irrigation of an infected herniorrhaphy wound.¹² Gas embolism, resulting in intestinal gangrene, was reported to occur following colonic lavage with 1% hydrogen peroxide during surgical treatment of meconium ileus.¹⁸⁷ Multiple cases of acute colitis are reported as a complication of administering 3% hydrogen peroxide enemas.¹³² The use of 3% hydrogen peroxide as a mouth rinse is associated with the development of oral ulcerations.¹⁷⁰ Ophthalmic exposures result in conjunctival injection, burning pain, and blurry vision.^44,131 Optic neuropathy including transient blindness (ability to visualize shadows only) and subsequent optic atrophy from possible inhalational of hydrogen peroxide is described.⁴⁵ Cough, wheezing, and shortness of breath is associated with occupational exposure to peracetic acid–hydrogen peroxide mixtures used to clean endoscopic equipment.³⁶

Diagnosis

A careful examination should be performed to detect any evidence of gas formation. A chest radiograph is recommended to assess for gas in the cardiac chambers, mediastinum, or pleural space. Likewise, an abdominal radiograph is also recommended to assess for gas in the GI tract or portal system and define the extent of bowel distension. Magnetic resonance imaging and CT imaging are reasonable to detect brain and spinal cord lesions secondary to gas embolism and should be obtained if patient experiences neurologic effects.^5,89,119 For those with clinical presentations consistent with esophageal, gastric or intestinal injury, endoscopic evaluation is recommended.¹⁶²

Management

The treatment of patients with hydrogen peroxide ingestions depends, to a large degree, on whether the patient has ingested a diluted or concentrated solution. Those with ingestions of concentrated solutions require expeditious evaluation. There is not enough evidence to support the dilution with milk or water. Nasogastric or orogastric aspiration of hydrogen peroxide is reasonable to consider if the patient presents immediately after ingestion. Induced emesis and activated charcoal are contraindicated. Gastric suctioning for patients with abdominal distension from gas formation is recommended. Place patients with clinical or radiographic evidence of gas in the heart in the Trendelenburg position to prevent gas from blocking the right ventricular outflow tract. Careful aspiration of intracardiac air through a central venous line is recommended in patients in extremis.³⁰ Hyperbaric therapy is recommended in cases of life-threatening gas embolization after hydrogen peroxide ingestion.^{55,85,119,138,155,211} We recommend home observation for asymptomatic patients who unintentionally ingest small amounts of 3% hydrogen peroxide.

Iodine and Iodophors

Iodine is one of the oldest topical antiseptics.¹⁸⁴ Iodine usually refers to molecular iodine, also known as I₂, free iodine, and elemental iodine, which is the active ingredient of iodine-based antiseptics. The use of ethanol as the solvent, such as in tincture of iodine, allows substantially more concentrated forms of I₂ to be available. Iodine (I₂) and tincture of iodine ingestions are much less common than in the past as a result of the change in antiseptic use from iodine to iodophor antiseptics.⁴⁶

Iodophors have molecular iodine compounded to a high-­molecular-weight carrier or to a solubilizing xenobiotic. Povidone-iodine, a commonly used iodophor, consists of iodine linked to polyvinylpyrrolidone (povidone). ­Iodophors, which limit the release of molecular iodine and are generally less toxic, are the current standard iodine-based antiseptic preparations. ­Iodophor preparations are formulated as solutions, ointments, foams, surgical scrubs, wound-packing gauze, and vaginal preparations. The most common preparation is a 10% povidone-iodine solution that contains 1% “available” iodine (referring to all oxidizing iodine species), but only 0.001% free iodine (­referring only to molecular iodine).^18,69

Iodine is used to disinfect medical equipment and drinking water. Iodine is effective against bacteria, viruses, protozoa, and fungi, and is used both prophylactically and therapeutically.⁴² Iodine is cytotoxic and also an oxidant. It is thought to work by binding amino and heterocyclic nitrogen groups, oxidizing sulfhydryl groups, and saturating double bonds. Iodine also iodinates tyrosine groups.⁶⁹ It appears to induce apoptosis through ­oxidative stress.⁹⁵

Significant systemic absorption of iodine from topical iodine or iodophor preparations is rare.¹⁵⁷ Markedly elevated iodine concentrations occur in patients who receive topical iodophor treatments to areas of dermal breakdown, such as burn injuries.¹⁰⁹ Significant absorption occurs when iodophors are applied to the vagina, perianal fistulas, umbilical cords, and the skin of low-birth-weight neonates.²¹² The mucosal application of ­povidone-iodine during a hysteroscopy procedure resulted in acute kidney injury (AKI) that transiently required hemodialysis.¹⁴ A fatality following intraoperative irrigation of a hip wound with povidone-iodine was also reported.³⁷ In this latter case, the postmortem serum iodine concentration was 7,000 mcg/dL (normal: 5–8 mcg/dL).

Clinical Effects

Problems associated with the use of iodine include unpleasant odor, skin irritation, allergic reactions, and clothes staining. Ingestion of iodine causes abdominal pain, vomiting, diarrhea, GI bleeding, delirium, hypovolemia, anuria, and circulatory collapse. Severe caustic injury of the GI tract occurs. The ingestion of approximately 45 mL of a 10% iodine solution resulted in death from multisystem failure 67 hours after ingestion.⁴⁸ In another case, the ingestion of 200 mL of tincture of iodine containing 60 mg/mL iodine and 40 mg/mL potassium iodide in 70% v/v ethanol resulted in AKI and severe hemolysis.¹²⁶

Reports of adverse consequences from iodophor ingestions are rare. In one case report, a 9-week-old infant died within 3 hours of receiving povidone-iodine by mouth.¹⁰⁶ In this unusual case, the child was administered 15 mL of povidone-iodine mixed with 135 mL of polyethylene glycol by nasogastric tube over a 3-hour period for the treatment of infantile colic. ­Postmortem examination showed an ulcerated and necrotic intestinal tract. A blood iodine concentration of 14,600 mcg/dL was recorded. Significant ­toxicity from intentional ingestions of iodophors in adults is not documented.

Acid–base disturbances are among the most significant abnormalities associated with iodine and iodophors. Metabolic acidosis occurred in several burn patients after receiving multiple applications of povidone-iodine ointment.^109,158 These patients had elevated serum iodine concentrations and normal lactate concentrations. The exact etiology of the acidosis remains unclear. Postulated mechanisms for the acidosis include the povidone-iodine itself (pH 2.43), bicarbonate consumption from the conversions of I₂ to NaI, and decreased renal elimination of H⁺ as a consequence of iodine ­toxicity.¹⁵⁸ Metabolic acidosis associated with an elevated lactate concentration after iodine ingestion likely reflects tissue destruction.⁴²

Electrolyte abnormalities also occur following the absorption of iodine. A patient with decubitus ulcers who received prolonged wound care with povidone-iodine–soaked gauze developed hypernatremia, hyperchloremia, metabolic acidosis, and AKI.³⁷ The hyperchloremia was thought to be caused by a spurious elevation of measured chloride ions as a consequence of the interference of iodine with the chloride assay. This interference occurs on the Technicon STAT/ION autoanalyzer, but does not occur when the silver halide precipitation assay is used.⁴² Spurious hyperchloremia from iodine (or iodide) results in the calculation of a low or negative anion gap (Chaps. 7 and 12).^24,54 The spurious effect of iodide on chloride and anion gap occurs even with very low serum iodide concentrations (<1 mEq/L) and the degree of anion gap deviation does not reliably predict the amount of iodide present.¹⁰⁵

Other problems associated with topical absorption of iodine-­containing preparations are hypothyroidism (particularly in neonates),^24,193 ­hyperthyroidism,^169,174 elevated liver enzyme concentrations, neutropenia, anaphylaxis,¹ and hypoxemia.⁴² Because of the lack of consistency between iodine concentrations and clinical manifestations, and because many of these patients had significant secondary medical problems that contributed to their symptoms, the exact relationship between iodine absorption and the development of a specific clinical syndrome remains speculative. However, a clinical controlled trial that compared preterm infants exposed to either topical iodinated antiseptics or to chlorhexidine-containing antiseptics showed that the infants exposed to topical iodine-containing antiseptics were more likely to have higher TSH concentrations and elevated urine iodine concentrations than were those in the chlorhexidine group.¹¹⁶

Contact dermatitis can result from repetitive applications of iodophors.¹²⁷ A dermal burn results from the trapping of an iodophor solution under the body of a patient in a pooled dependent position or under a ­tourniquet.^118,142 Aspiration pneumonitis is rarely described following the intraoperative application of povidone-iodine prior to craniofacial surgeries.²⁷ These patients generally recover with supportive care.

Management

The patient who ingests iodine requires expeditious evaluation, stabilization, and decontamination. If signs of perforation are absent, it is ­reasonable to proceed with careful nasogastric or orogastric aspiration and lavage to limit the caustic effect of the iodine. In symptomatic patients, irrigation with a starch solution is recommended to convert iodine to the much less toxic iodide and, in the process, turn the gastric effluent dark blue-purple. This change in color is a useful guide in determining when lavage can be terminated. If starch is not available, milk or 100 mL of a solution of 1% to 3% sodium thiosulfate is a reasonable alternative to convert any remaining iodine to iodide. We recommend early endoscopy in patients with significant symptoms to help assess the extent of the GI injury. ­Hemodialysis and continuous venovenous hemodiafiltration were used successfully to enhance elimination of iodine in a patient with CKD with iodine ­toxicity who developed renal deterioration after undergoing continuous ­mediastinal irrigation with povidone-iodine.⁹⁹ The benefit of hemodialysis or continuous venovenous hemodiafiltration is unknown in patients with normal kidney function and therefore not routinely recommended at this time.

Most patients with iodophor ingestion require only supportive management. The use of starch or sodium thiosulfate is reasonable in symptomatic patients.

Potassium Permanganate

Potassium permanganate (KMnO₄) is a violet water-soluble xenobiotic that is usually sold as crystals or tablets or as a 0.01% dilute solution.⁹⁶ Historically, it was used as an abortifacient, urethral irrigant, lavage fluid for alkaloid poisoning, and snakebite remedy. Currently, potassium permanganate is most often used in baths and wet bandages as a dermal antiseptic, particularly for patients with eczema.

Potassium permanganate is a strong oxidizer, and poisoning results in local and systemic toxicity.¹⁹⁵ Upon contact with mucous membranes, potassium permanganate reacts with water to form manganese dioxide, potassium hydroxide, and molecular oxygen. Local tissue injury is the result of contact with the nascent oxygen, as well as the caustic effect of potassium hydroxide. A brown-black staining of the tissues occurs from the manganese dioxide. Systemic toxicity occurs from free radicals generated by absorbed permanganate ions.²²¹

Clinical Effects

Dermal contact leads to cutaneous staining. Following ingestion, initial symptoms include nausea and vomiting. Laryngeal edema and ulceration of the mouth, esophagus, and, to a lesser extent, the stomach, result from the caustic effects. Airway obstruction and fatal GI perforation and hemorrhage are reported.^43,133,150 Esophageal strictures and pyloric stenosis are potential late complications.¹⁰³

Although potassium permanganate is not well absorbed from the GI tract, systemic absorption occurs, resulting in life-threatening toxicity. ­Systemic effects include hepatotoxicity, AKI, methemoglobinemia, hemolysis, hemorrhagic pancreatitis, airway obstruction, ARDS, disseminated intravascular coagulation, and cardiovascular collapse.^{114,125,133,150} Elevation in blood and serum manganese concentrations also occurs, confirming systemic absorption.

Chronic ingestion of potassium permanganate results in classic manganese poisoning (manganism) characterized by behavioral changes, hallucinations, and delayed onset of parkinsonian-like symptoms. A 66-year-old man who ingested 10 g of potassium permanganate instead of potassium iodate over a 4-week period (because of medication mislabeling) developed impaired concentration and autonomic and visual symptoms. He also developed abdominal pain, gastric ulceration, and alopecia. Serum manganese concentration was elevated. Nine months later, the patient had extrapyramidal signs consistent with parkinsonism (Chap. 94).⁸³

Management

Because the consequential effects of potassium permanganate ingestion are a result of the liberation of strong alkalis, immediate assessment for evidence of airway compromise should be performed in such a patient. Dilution with milk or water is reasonable. Patients with symptoms consistent with caustic injury should undergo early upper–GI tract endoscopy.⁹⁶ Corticosteroids are recommended if laryngeal edema is present. When systemic toxicity is suspected, of liver enzymes, blood urea nitrogen, creatinine, lipase, serum manganese, and methemoglobin concentrations all will help in the evaluation. We recommend methylene blue for clinically significant methemoglobinemia (Antidotes in Depth: A43). Dermal irrigation with dilute oxalic acid removes cutaneous staining.¹⁹⁵ The administration of N-acetylcysteine (Antidotes in Depth: A3) to increase reduced glutathione production, thereby limiting free radical–mediated oxidative injury in cases of systemic potassium ­permanganate poisoning, is suggested, but there is inadequate evidence to support routine use at this time.²²¹

OTHER ANTISEPTICS

Alcohols

Ethanol and isopropanol (Chaps. 76 and 106) are commonly used as skin antiseptics. When sold as rubbing alcohol, the standard concentration for these solutions is usually 70%. In recent years, alcohol-based hand ­sanitizers containing 60% to 95% ethyl or isopropyl alcohol have become ubiquitous throughout patient care units, jails, and some public buildings as a primary infection control measure. Their antiseptic action is a result of their ability to coagulate proteins. Isopropanol is slightly more germicidal than ethanol.⁶⁹ The alcohols have limited efficacy against viruses or spores. Isopropanol tends to be more irritating than ethanol and causes more ­pronounced central nervous system depression.²¹³ Unfortunately, readily available alcohol-based sanitizers are a tempting source for patients admitted with alcohol abuse disorders.^51,217 In one report, a patient was admitted to the hospital with chest pain. While in the hospital the patient became hypotensive and delirious. He was later found in the bathroom drinking an alcohol-based hand wash that contained 63% isopropanol.⁵¹ The ­clinical effects and treatment for alcohol poisoning are discussed in Chaps. 76 and 106.

Chlorine and Chlorophors

Chlorine, one of the first antiseptics, is still used in the treatment of the ­community water supply and in swimming pools. Chlorine is a potent pulmonary irritant that can cause severe bronchospasm and ARDS. Chapter 121 ­contains a further discussion of chlorine.

Sodium hypochlorite (NaClO), found in household bleaches and in Dakin solution, remains a commonly used disinfectant. First used in the late 1700s to bleach clothes, its usefulness arises from its oxidizing capability, measured as “available chlorine,” and its ability to release hypochlorous acid (HClO) slowly. It is used to clean blood spills and to sterilize certain medical instruments. A 0.5% hypochlorite solution is sometimes recommended for dermal and soft-tissue wound decontamination after exposure to biologic and chemical warfare agents (Chaps. 126 and 127).⁸⁶ Toxicity from hypochlorite is mainly a result of its irritant effects. The ingestion of large amounts of household liquid bleach (5% sodium hypochlorite) on rare occasions can result in esophageal burns with subsequent stricture formation.⁵⁶ In a cat model of bleach ingestion, a high incidence of mucosal injury and stricture formation was noted.²¹⁶ However, the vast majority of household bleach ingestions in humans do not cause significant GI injuries.¹⁵⁹ Accordingly, we recommend not performing routine endoscopic evaluation when assessing asymptomatic patients with household liquid bleach ingestions. Endoscopy is reasonable in symptomatic patients. Endoscopy is recommended in symptomatic patients who ingest a more concentrated “industrial strength” bleach preparation such as 35% sodium hypochlorite, because of the increased likelihood of local tissue injury (Chap. 103).

Mercurials

Both inorganic mercurials, such as mercuric bichloride (HgCl₂), and organic mercurials, such as merbromin (C₂₀H₈Br₂HgNa₂O₆) (mercurochrome) and thimerosal (C₉H₉HgNaO₂S) (merthiolate), which both contain 49% mercury, were previously used as topical antiseptics. The usefulness of mercurials is significantly limited because of their relatively weak bacteriostatic properties and the many concerns associated with mercury toxicity (Chap. 95). Repeated application of topical mercurial causes significant absorption and systemic toxicity.^139,176 The use of high-dose hepatitis B immunoglobulin (HBIG) causes mercury toxicity because of the use of thimerosal as a preservative in the HBIG preparation.¹²¹ In one case, a 44-year-old man received 250 mL of HBIG (containing about 30 mg of thimerosal) over 9 days following liver transplantation.¹²¹ He developed speech difficulties, tremor, and ­chorea. His whole blood mercury concentration was 104 mcg/L (normal <10 mcg/L).

DISINFECTANTS

Formaldehyde

Formaldehyde is a water-soluble, highly reactive gas at room temperature. Formalin consists of an aqueous solution of formaldehyde, usually containing approximately 37% formaldehyde and 12% to 15% methanol. Formaldehyde is irritating to the upper airways, and its odor is readily detectable at low concentrations. Lethality in adults follows ingestion of as little as 30 to 60 mL of formalin.⁴⁹

Formerly used as a disinfectant and fumigant, its role as a disinfectant is now largely confined to the maintenance of hemodialysis machines. Nonetheless, formaldehyde has many other applications. Formaldehyde is widely used in construction including wood processing and the manufacturing of furniture, textiles, and carpeting.¹⁰¹ Health care workers are probably most familiar with the use of formaldehyde as a tissue fixative and embalming agent. Medical students are routinely exposed to formalin in the anatomy laboratory.¹⁶⁷

Exposure to formaldehyde, a potent tissue fixative results in both local and systemic symptoms, causing coagulation necrosis, protein precipitation, and tissue fixation. Ingestions of formalin results in significant gastric injury, including hemorrhage, diffuse necrosis, perforation, and stricture.^3,11 The most extensive damage appears in the stomach, with only occasional involvement of the small intestine and colon.²²⁰ Chemical fixation of the stomach occurs. Esophageal involvement is not very prominent and, if present, is usually limited to its distal segment.

The most striking and rapid systemic manifestation of formaldehyde poisoning is anion gap metabolic acidosis, resulting both from tissue injury and from the conversion of formaldehyde to formic acid. Although the methanol component of the formalin solution is readily absorbed and produces methanol concentrations reportedly as high as 40 mg/dL,^22,49 the rapid metabolism of formaldehyde to formic acid is responsible for much of the metabolic acidosis (Chap. 106).

Clinical Effects

Patients presenting after formalin ingestions complain of the rapid onset of severe abdominal pain, vomiting, and diarrhea. Altered mental status and coma usually follow rapidly. Physical examination demonstrates epigastric tenderness, hematemesis, cyanosis, hypotension, and tachypnea. Profound hypotension is due to decreased myocardial contractility, as well as hypovolemic shock.^78,203 Early endoscopic findings include ulceration, necrosis, perforation, and hemorrhage of the stomach, with infrequent esophageal involvement. Chemical pneumonitis occurs after significant inhalational exposure.¹⁶¹ Intravascular hemolysis is described in hemodialysis patients whose dialysis equipment contained residual formaldehyde after undergoing routine cleaning.^152,165

Occupational and environmental exposure to formaldehyde receives considerable attention. In particular, there is concern over the potential off-gassing of formaldehyde from the widely used urea formaldehyde building insulation and particle board.¹⁴⁹ Headache, nausea, skin rash, sore throat, nasal congestion, and eye irritation are associated with the use of these ­polymers.³⁹ Formaldehyde, at concentrations as low as 1 ppm, causes significant irritation to mucous membranes of the upper respiratory tract and conjunctivae.^82,120 Formaldehyde is also a potential sensitizer for immune-mediated reversible bronchospasm.⁷⁵ The exact immunologic mechanism is not yet elucidated, although it is likely that formaldehyde acts as a hapten. In addition, formaldehyde is a dermal sensitizer.¹⁹⁴

Concerns about the health effects from the off-gassing of formaldehyde in trailers used by the Federal Emergency Management Agency (FEMA) after Hurricane Katrina illustrates the potential public health issues related to low-level formaldehyde exposure.¹²⁴ A Centers for Disease Control and Prevention (CDC) investigation revealed that air formaldehyde concentrations in closed, unventilated trailers are, in fact, high enough to cause acute symptoms in some people.⁴ Long-term effects after these exposures remain undefined.

Formaldehyde exposure is associated with an increased incidence of nasopharyngeal carcinoma.^2,71,156,177 Although its role in the pathogenesis of cancer in humans is the subject of much debate,^33,128 formaldehyde is classified as a Group 1, known, carcinogen by the International Agency for Research on Cancer (IARC).

Management

Dilution with water is reasonable for the immediate management of a patient who has ingested formalin. Gastric aspiration with a small-bore nasogastric or orogastric tube is also reasonable to limit systemic absorption. Activated charcoal should not be used. Significant acidemia is treated with sodium bicarbonate and folinic acid (Chap. 106). Immediate hemodialysis removes the accumulating formic acid as well as the parent molecules formaldehyde and methanol and is reasonable in refractory acidemia (Antidotes in Depth: A33 and A34).^6,49 Early endoscopy is recommended for all patients with significant GI manifestations to assess the degree of burn injury. Surgical intervention is required for those with suspected severe burns, tissue necrosis and/or perforation.²²⁰ Emergent gastrectomy, as well as late surgical intervention to relieve formaldehyde-induced gastric outlet obstruction, is rarely required.^72,104

Phenol

Phenol is one of the oldest antiseptics. It is rarely used as an antiseptic today, because of its toxicity, and is replaced by the many phenolic derivatives. Currently, phenol is used as a disinfectant and chemical intermediary. The concentration of phenol in consumer products can vary significantly, from 0.1% to 4.7% in various lotions, ointments, gels, gargles, lozenges, and throat sprays and up to 89% in nail cauterizer solution.⁶⁹ Although many cases of phenol poisoning were reported in the past, acute oral overdoses of phenol-containing solutions are uncommon today.⁶²

Phenol acts as a caustic causing cell wall disruption, protein denaturation, and coagulation necrosis. It also acts as a central nervous system (CNS) stimulant. Intentional ingestion of concentrated phenol, ingestion of phenol-containing water, occupational exposure to aerosolized phenol, dermal contact, and parenteral administration result in symptomatic phenol poisoning. Phenol demonstrates excellent skin penetrance and causes severe dermal burns, resulting in potentially fatal systemic toxicity within minutes to hours.^16,113 Deaths from parenteral administration of phenol are reported. The lethal oral dose is as little as 1 g.⁸⁴

Clinical Effects

Clinical manifestations can be divided into local and systemic symptoms. Systemic symptoms from GI or dermal absorption of phenol are usually more dangerous than the local effects. Manifestations of systemic toxicity include CNS and cardiac manifestations. Central nervous system effects include central stimulation, seizures, lethargy, and coma.⁶⁵ In a study of patients who had ingested Creolin (26% phenol), CNS toxicity predominated.¹⁹⁶ Of the 52 patients who were evaluated at the hospital, 9 developed lethargy and 2 developed coma. Seizures were not reported. Cardiac signs and symptoms from phenol include tachycardia, bradycardia, and hypotension.⁶⁵ Parenteral absorption of 10 mL concentrated 89% phenol resulted in hypoxemia, ARDS, pulmonary nodular opacities, and AKI requiring intubation and ­hemodialysis.⁶⁴ This last case was associated with a phenol concentration of 87 mg/dL (normal <2 mg/dL).

Other systemic effects include hypothermia, metabolic acidosis, methemoglobinemia, and rabbit syndrome.^84,97 Rabbit syndrome is most commonly observed as a distinctive extrapyramidal effect from antipsychotics and is characterized by fine rapid repetitive movements of the perioral musculature resembling a rabbit’s chewing movements. Increased acetylcholine release and a relative dopaminergic hypofunction explain the development of rabbit syndrome after phenol exposure.⁹⁷

Local toxicity to the GI tract from the ingestion of phenol results in nausea, painful oral lesions, vomiting, severe abdominal pain, bloody diarrhea, and dark urine.^8,94 Serious GI burns are uncommon, and strictures are rare. White patches in the oral cavity occur. In the Creolin study cited above, only 1 of 17 patients who underwent endoscopy had a significant esophageal burn.¹⁹⁶ Dermal exposures to phenol usually result in a light-brown staining of the skin. Excessive dermal absorption of phenol during chemical peeling procedures is associated with dysrhythmias and many of the other toxic manifestations.^208,214

Markedly elevated blood and urine concentrations of phenol are detected after ingestion, or dermal absorption, of phenol and phenol-containing compounds.^16,84

Management

When phenol is mixed with water, a bilayer with unique properties is created that makes it difficult to remove from tissues. A variety of treatments are suggested for dermal and gastric decontamination of phenol. A study using a rat model showed that cutaneous decontamination with a low-molecular-weight polyethylene glycol solution decreased mortality, systemic effects, and dermal burns.²¹ Although this study suggested that polyethylene ­glycol (PEG) was superior to water as a decontamination, a subsequent study using a swine model could not demonstrate a difference between these 2 ­therapies.¹⁶⁴ In another swine model, PEG 400 and 70% isopropanol were both superior to water washes and equally effective in decreasing dermal burn.¹³⁵ Given the lack of definitive efficacy data, either low-molecular-weight PEG, for example, PEG 300 or 400 (not to be confused with high-molecular-weight PEG that is used for whole-bowel irrigation), or high-flow water are reasonable for dermal irrigation and careful gastric decontamination. Endoscopic evaluation, for symptomatic patients to determine the extent of GI injury is recommended.

Substituted Phenols and Other Related Compounds

Hexachlorophene, a trichlorinated bis-phenol, is considered generally less tissue-toxic than phenol. During the 1970s, an association was observed between repetitive whole-body washing of premature infants with 3% hexachlorophene and the development of vacuolar encephalopathy and cerebral edema.¹²⁹ There are also multiple reports of significant neurologic toxicity and death in children who became toxic after ingesting hexachlorophene.⁷⁷ In addition, fatalities also occurred after patients absorbed substantial amounts of hexachlorophene during the treatment of burns.²⁹ The use of hexachlorophene has declined significantly. Currently used substituted phenols include a sodium solution of octylphenoxyethoxyethyl ether sulfonate, chloroxylenol and cresol.

Clinical Effects

A sodium solution of octylphenoxyethoxyethyl ether sulfonate and lanolin is a safe antiseptic. Irritative effects such as nausea, vomiting, and diarrhea are the main adverse effects following ingestion.

In a study of poisoning admissions to Hong Kong hospitals, the ingestion of a household disinfectant that contained 4.8% chloroxylenol, 9% pine oil, and 12% isopropanol accounted for 10% of admissions.²⁶ Aspiration (perhaps, in part, because of the pine oil) occurred in 8% of these patients, resulting in upper airway obstruction, pneumonia, and ARDS. More common symptoms included nausea, vomiting, sore mouth, sore throat, drowsiness, abdominal pain, and fever. Dermal contact with Dettol results in full-thickness chemical burns.⁴⁰

Cresol, a mixture of 3 isomers of methylphenol, has better antiseptic activity than phenol and is a commonly used disinfectant. Exposure to concentrated cresol results in significant local tissue injury, hemolysis, AKI, hepatic injury, and CNS and respiratory depression.^40,70,98,219 Phenol concentrations, as well as cresol concentrations, serve as markers of exposure.²¹⁹

Management

Treatment is supportive care emphasizing decontamination.

Quaternary Ammonium Compounds

Quaternary ammonium compounds, positively charged compounds where 4 organic groups are linked to a nitrogen atom (NR₄⁺), are cationic surfactants (surface-active agent) that are used as disinfectants, detergents, and sanitizers. Chemically, the quaternary ammonium compounds are synthetic derivatives of ammonium chloride, and structurally similar to other quaternary ammonium derivatives, such as carbamate cholinesterase inhibitors and neuromuscular blockers. Other cationic surfactants include the pyridinium compounds and the quinolinium compounds. Benzalkonium chloride was one of the most commonly employed quaternary ammonium compounds in the past. Many newer quaternary ammonium compounds have supplanted its use. However, nebulized solutions used for the treatment of asthma, including albuterol and ipratropium bromide, contain small amounts of benzalkonium chloride.

Clinical

Quaternary ammonium compounds are usually less toxic than phenol or formaldehyde. Most of the infrequent complications that are described result from ingestions of benzalkonium chloride. Complications of these ingestions include burns to the mouth and esophagus, CNS depression, elevated liver enzyme concentrations, metabolic acidosis, and hypotension.^80,147,210 Paralysis is also occasionally described as a complication of these ingestions and is presumably a result of cholinesterase inhibition at the neuromuscular junction.⁶² Chronic inhalational exposure is associated with occupational asthma.¹⁷ Topical use of the quaternary ammonium compounds causes contact dermatitis.¹⁹⁰ Ingestion of a 2.25% ammonium chloride solution, marketed as a bacteriostatic for algae and odor humidifier treatment, results in serious GI and pulmonary injury.⁶⁷

Ingestions of other cationic surfactants, such as the pyridinium-derived cetrimonium bromide are associated with corrosive burns to the mouth, lips, and tongue.¹³⁷ Peritoneal irrigation with cetrimonium bromide produces metabolic abnormalities, hypotension, and methemoglobinemia.^9,134 Intravenous administration of cetrimonium bromide leads to hemolysis, muscle paralysis, and cardiac arrest.⁵⁸

Management

Treatment recommendations following the ingestion of the quaternary ammonium compounds and other cationic surfactants are similar to those for other potentially caustic ingestions. Emergency department evaluation is recommended for all patients who ingest more than a taste of a dilute (<1%) solution. Therapy is mainly supportive care. Endoscopy is indicated if signs and symptoms suggest the possibility of a burn.

STERILANTS

Ethylene Oxide

Ethylene oxide (C₂H₄O) is a gas that is commonly used to sterilize heat-­sensitive material in health care facilities. Unlike antiseptics and disinfectants, which generally do not exhibit full sporicidal activity, sterilants, such as ethylene oxide, inactivate all organisms. Ethylene oxide is also used in the synthesis of many chemicals, including ethylene glycol, surfactants, rocket propellants, and petroleum demulsifiers, and is used as a fumigant. Ethylene oxide has a cyclic ester structure that acts as an alkylating agent, reacting with most cellular components, including DNA and RNA.

Medical attention regarding ethylene oxide toxicity has centered on its mutagenic and possible carcinogenic effects.¹⁰⁸ Approximately 270,000 workers (including 96,000 hospital workers) in the United States are at risk for occupational exposure to ethylene oxide.¹⁹⁹ Retrospective studies suggest a possible excess incidence of leukemia and gastric cancer in ethylene oxide exposed workers.^81,199 The 2008 IARC updated monographs concluded that there was limited evidence for carcinogenicity in humans, with an association with lymphatic, hematopoietic, and breast cancers. However, sufficient evidence for the carcinogenicity of ethylene oxide was found in experimental animals. Evidence suggests direct-acting alkylating effects leading to ­genotoxicity. Ethylene oxide was subsequently placed in IARC group I—­carcinogenic to humans.⁸⁷ An increased incidence of spontaneous ­abortions is associated with occupational exposure to ethylene oxide.⁷⁴

Clinical Effects

The acute toxicity of ethylene oxide is mainly the result of its irritant effects, including conjunctival, upper respiratory tract, GI, and dermal irritation. Dermal burns from acute exposure to ethylene oxide are reported. Acute exposure to a broken ethylene oxide ampule (17 g) by a 43-year-old recovery room nurse resulted in nausea, lightheadedness, malaise, syncope, and recurrent seizures.¹⁸¹ There were no long-term complications. In another case of acute exposure, coma was followed by an irreversible parkinsonism.¹⁰

Chronic exposure to high concentrations of ethylene oxide causes mild cognitive impairment and motor and sensory neuropathies.^20,63,146 Hazard studies of occupational exposure have demonstrated no increased incidence of cancer in exposed populations over the expected occurrence rate.^32,198,204

Management

Treatment for patients with ethylene oxide exposure is supportive.

Glutaraldehyde

Glutaraldehyde is a liquid solution used in the cold sterilization of nonautoclavable endoscopic, surgical, and dental equipment. It is also employed as a tissue fixative, embalming fluid, preservative, and tanning agent, in radiographic solutions, and in the treatment of warts.⁶⁰ Glutaraldehyde (C₅H₈O₂) is a dialdehyde with 2 active carbonyl groups that is less volatile than formaldehyde. It kills all microorganisms, including viruses and spores. The sterilant ability of glutaraldehyde results from the alkylation of sulfhydryl, hydroxyl, carboxyl, and amino groups, within microbes interfering with RNA, DNA, and protein synthesis.¹⁷⁹ It is prepared as a 2% alkaline solution in 70% isopropanol. Health care workers are exposed to glutaraldehyde vapors when equipment is processed in poorly ventilated areas, or in open immersion baths or after spills. Under these circumstances, the evaporation of glutaraldehyde results in the increase in ambient air concentrations that exceeds recommended limits. Approximately 35,000 workers are occupationally exposed to glutaraldehyde annually.¹⁶⁰ To prevent exposure, OSHA recommends the use of personal protective equipment with elbow-length gloves of butyl rubber or nitrile, gowns and eye protection. Local exhaust ventilation at the point of release should include either a local exhaust hood or ductless hood. Enclosed processing is also recommended when available. Respirators should be available in the event that ventilation fails for any reason.¹⁵³ Patients are exposed when diagnostic instruments are inadequately rinsed following cold sterilization with glutaraldehyde.

Clinical

Clinical signs and symptoms are comparable to those of formaldehyde exposure, although human toxicity data are limited. Animal studies show that the inhalational and dermal toxicity of glutaraldehyde are similar to those of formaldehyde at equivalent doses.²⁰²

Glutaraldehyde is a mucosal irritant. Coryza, epistaxis, headache, asthma, chest tightness, palpitations, tachycardia, and nausea are all associated with glutaraldehyde vapor exposure.^{15,34,143,154} Occupational asthma, contact dermatitis, and ocular inflammation also occur.^38,151,186 Colitis is reported following the use of endoscopes contaminated with residual glutaraldehyde solution.¹⁸⁸ Patients with glutaraldehyde-induced colitis typically present with fever, chills, severe abdominal pain, bloody diarrhea, and an elevated white blood cell count within 48 hours after colonoscopy or sigmoidoscopy.

The IARC has not ranked the carcinogenic potential of glutaraldehyde.

Management

Treatment recommendations are similar to those for patients with formaldehyde exposure. Prompt removal from the exposure is essential. Copious irrigation with water is recommended for dermal decontamination. Severe inhalational exposures require hospital admission for observation, supportive care, and treatment of bronchospasm.

In recent years, some hospitals have started using ortho-phthalaldehyde (OPA) or a mixture of hydrogen peroxide and peracetic acid as alternatives to glutaraldehyde for high-level disinfection.¹⁷² These alternative disinfectants do not appear to have the pulmonary or dermal sensitizing properties associated with glutaraldehyde, although they do cause some irritation to skin and mucous membranes.¹⁷² A single case of occupational asthma related to OPA exposure was reported in 2014, proven with a specific inhalation ­challenge, and represents the only reported case in the literature.¹⁷⁵ Oropharyngeal and laryngeal burns are also reported in a patient exposed to residual OPA during transesophageal echocardiography.¹⁸⁵

OTHER PRODUCTS

Boric Acid

Boric acid is an odorless, transparent crystal, although it is most commonly available as a finely ground white powder. It is also available as a 2.5% to 5% aqueous solution. Boric acid (H₃BO₃), prepared from borax (sodium borate; Na₂B₄O₇⋅10 H₂O), was first used as an antiseptic by Lister in the late 19th century. Although used extensively over the years for antisepsis and irrigation, boric acid is only weakly bacteriostatic. As a result of its germicidal limitations and its inherent toxicity, boric acid is nearly obsolete in modern antiseptic therapy. Nonetheless, it continues to be used as an antimicrobial to treat such conditions as vulvovaginal candidiasis.^88,100,163 Boric acid is also employed in the treatment of cockroach infestation and as a soap, contact lens solution, toothpaste, and food preservative.⁶⁶ Recently, do-it-yourself recipes for children’s slime, a squishy colorful play material, include boric acid as a major ingredient.⁴⁷

Boric acid is readily absorbed through the GI tract, wounds, abraded skin, and serous cavities. Absorption does not occur through intact skin. Boric acid is predominantly eliminated unchanged by the kidney. Small amounts are also excreted into sweat, saliva, and feces.⁵⁹ Boric acid is concentrated in the brain and liver.

The exact mechanism of action of toxicity remains unclear. Although it is an inorganic acid, it is not a caustic. Local effects are limited to tissue irritation.

Over the years, boric acid developed a reputation as an exceptionally potent toxin. This reputation derived in great part from a series of reports involving neonatal exposures to boric acid resulting in high morbidity and mortality. Life-threatening toxicity resulted from the repetitive topical application of boric acid for the treatment of diaper rash or the use of infant formulas unintentionally contaminated with boric acid.^59,218 Fatality rates greater than 50% were reported in some series.²¹⁸ Although infants appear to be the most sensitive to the toxic effects of boric acid, many cases of significant toxicity are also reported in adults. These cases date predominantly from the first half of the 20th century when boric acid was widely used as an irrigant. Routes of exposure to boric acid, resulting in fatalities, include wound irrigation, pleural irrigation, rectal washing, bladder irrigation, and vaginal packing.²⁰⁹

Clinical Effects

Boric acid poisoning usually involves multiple exposures over a period of days. Gastrointestinal, dermal, CNS, and renal manifestations predominate. The initial effects—nausea, vomiting, diarrhea, and occasionally crampy abdominal pain—are frequently confused with an acute gastroenteritis. At times, the emesis and diarrhea are greenish blue.²¹⁸ Following the onset of GI signs and symptoms, the majority of patients develop a characteristic intense generalized erythroderma.²¹⁸ This rash, described as producing a “boiled lobster” appearance, appears indistinguishable from toxic epidermal necrolysis or staphylococcal scalded skin syndrome in the neonate.^122,178 The rash is especially noticeable on the palms, soles, and buttocks.⁵⁹ Typically, extensive desquamation takes place within 1 to 2 days. On occasion, prominent mucous membrane involvement of the oral cavity and conjunctivae is also ­apparent.²¹⁸ At the time of development of the erythroderma, patients, particularly young infants, develop prominent signs of CNS irritability, resembling meningeal irritation. Seizures, delirium, and coma occur.⁵⁹ Acute kidney injury is common, both as a result of the renal elimination of this compound and prerenal azotemia from GI losses.⁵⁹ Other complications of boric acid poisoning include hepatic injury, hyperthermia, and cardiovascular collapse. A marked decrease in the incidence of significant boric acid poisoning is attributed to the abandonment of boric acid as an irrigant and particularly its removal from the nursery setting.

Two retrospective studies on boric acid ingestions suggest that a single acute ingestion of boric acid is generally quite benign.^115,117 In these studies, 79% to 88% of patients remained asymptomatic. Symptoms, when present, primarily consist of nausea and vomiting. None of the 1,184 patients in these 2 studies manifested the generalized erythroderma so commonly described in previous reports. Central nervous system manifestations of acute overdose were infrequent and limited to occasional lethargy and headache. Kidney injury did not occur following single acute ingestions.

Fatalities from massive acute ingestion of boric acid are reported in both unintentional ingestions in children and intentional ingestions in adults.^66,171 Fatality resulted from a single ingestion of 2 cups (280 g) of boric acid crystals dissolved in water by a 45-year-old man. Signs and symptoms on presentation (2 days after ingestion) included nausea, vomiting, green diarrhea, lethargy, hypotension, AKI, and a prominent “boiled lobster” rash on his trunk and extremities. In another case, the ingestion of 30 g of boric acid by a 77-year-old man resulted in similar symptoms and death 63 hours postingestion, despite hemodialysis.⁹¹

Long-term chronic exposure to boric acid results in alopecia in adults and seizures in children.¹⁴⁵ A 32-year-old woman who over a 7-month period ingested commercial mouthwash products containing boric acid developed progressive hair loss.²⁰¹ The chronic application of a commercial preparation of borax and honey mixture to pacifiers resulted in the development of recurrent seizures in 9 infants, which resolved after the mixture was withheld.^61,145

Management

Treatment of boric acid toxicity is supportive care. Activated charcoal is not recommended because of its relatively poor adsorptive capacity for boric acid.⁴¹ Because boric acid has a low molecular weight and relatively small volume of distribution, in cases of massive oral overdose or AKI, hemodialysis, or perhaps exchange transfusion in infants, is reasonable in shortening the half-life of boric acid.^{35,117,141,206} Although forced diuresis is suggested by others to enhance renal elimination, this is highly unlikely to be successful and is not recommended.²⁰⁷

Chlorates

Sodium chlorate is a strong oxidizer. At one time, the chlorate salts sodium chlorate and potassium chlorate were used as medicinals to treat inflammatory and ulcerative lesions of the oral cavity and could be found in ­various mouthwash, toothpaste, and gargle preparations.¹⁹⁷ Although their use as local antiseptics is obsolete, chlorates are used as herbicides and in the manufacture of matches, explosives, and dyestuffs.⁹² Historically, cases have included dispensing errors that confused sodium chlorate with sodium sulfate or sodium chloride.⁹² Sodium chlorate in the form of white crystals was mistaken for table sugar in one case.⁷³ A case of significant toxicity from the inhalation of atomized chlorates is also reported.⁹² More recent cases of chlorate poisoning continue to result from the ingestion of sodium chlorate–­containing weed killers^168,197 and industrial chemicals.¹¹¹

Sodium chlorate is rapidly absorbed from the GI tract and eliminated predominantly unchanged from the kidneys.⁹³ Its systemic effects are chiefly hematologic and renal. The major mechanism of toxicity of chlorate is its ability to oxidize hemoglobin and increase red blood cell membrane rigidity.¹⁹¹ Consequently, significant methemoglobinemia and hemolysis result. Methemoglobinemia occurs prior to or after the development of ­hemolysis.^144,200 The hemolysis and the resultant hemoglobinuria secondarily causes disseminated intravascular coagulation and potential renal toxicity. Chlorates are also directly toxic to the proximal renal tubule.¹¹⁰ The worsening kidney function is especially problematic because of its adverse effect on chlorate elimination. Chlorates also act locally as a GI irritant and cause mild CNS depression after absorption (Chap. 124).⁶²

Clinical

Clinical signs and symptoms of chlorate poisoning usually begin 1 to 4 hours after ingestion.¹⁰² The earliest manifestations are nausea, vomiting, diarrhea, and crampy abdominal pain. Subsequently, the patient exhibits cyanosis from the methemoglobinemia and black-brown urine from the hemoglobinuria. Obtundation and anuria ensue. Laboratory studies demonstrate methemoglobinemia, anemia, Heinz bodies, ghost cells, fragmented spherocytes, metabolic acidosis, thrombocytopenia, and abnormal coagulation.⁵³ ­Hyperkalemia is particularly problematic if the patient ingests potassium chlorate preparations.¹⁴⁰ In a case of chlorate poisoning from the ingestion of 120 potassium chlorate–containing matchsticks, an MRI revealed symmetric abnormal signal intensity within the deep gray matter and medial ­temporal lobes.¹⁴⁰ This finding can be explained by the increased vulnerability to oxygen deprivation of the basal ganglia. Follow-up MRI 2 months later was normal.

Management

In symptomatic patients with chlorate ingestions, it is reasonable to pursue GI decontamination.⁷³ The utility of methylene blue in the treatment of symptomatic chlorate-induced methemoglobinemia has been questioned as a consequence of the inactivation by chlorates of glucose-6-phosphate dehydrogenase, an enzyme that is required for methylene blue to effectively reduce methemoglobin.^191,200 Nevertheless, more recent experience suggests that early use of methylene blue prior to the onset of hemolysis is beneficial due to the necessity of the intact erythrocyte for methylene blue to be efficacious and thus a reasonable treatment.^19,111 Exchange transfusion and hemodialysis are reasonable in the treatment of patients with severe chlorate poisoning.^144,200 Because the chlorate ion is easily dialyzable, hemodialysis will be effective in removal of chlorate as well as in treating concomitant AKI.^92,102,110

SUMMARY

• Many of the more toxic xenobiotics, such as iodine, phenol, and chlorates, are no longer commonly used as cleansers but are still available in some health care and occupational settings.

• Formaldehyde exposures, though also uncommon, cause significant respiratory toxicity and is potentially carcinogenic.

• Frequently employed antiseptics, are chlorhexidine, octylphenoxyethoxyethyl ether sulfonate, and many of the currently used quaternary ammonium compounds. Iodine, phenol, and quaternary ammonium compounds are caustic when ingested.

• Ingestions of the iodophors do not usually cause significant toxicity, but absorption through other routes produces significant adverse effects.

• Ingestion of concentrated hydrogen peroxide results in life-threatening injuries. Boric acid causes a dermatitis.

REFERENCES

INTRODUCTION

Many different products have been used as moth repellents. In the United States, paradichlorobenzene has largely replaced both camphor and naphthalene as the most common active component of moth repellent and moth flakes because of its lower toxicity. However, life-threatening ­camphor and naphthalene toxicity still occurs, especially in immigrant communities, from exposures to imported camphor or naphthalene-containing ­products.^3,48,65,80 Therefore, toxicity of camphor, naphthalene, and paradichlorobenzene all remain possible following exposure to moth repellents.

CAMPHOR

History and Epidemiology

Camphor (2-bormanone, 2-camphonone), a cyclic ketone of the terpene group, is an essential oil originally distilled from the bark of the camphor tree, Cinnamomum camphora. Today, camphor is synthesized from the hydrocarbon pinene, a derivative of turpentine oil. Camphor has been used for centuries as an aphrodisiac, fumigant, contraceptive, abortifacient, suppressor of lactation, analeptic, cardiac stimulant and antiseptic.^{1,56,72,96,108} Camphor is a commonly used ingredient found in many nonprescription remedies for cold symptoms, cold sores, and in muscle liniments.^2,75,77,93 Camphor is also rarely abused as a stimulant (Chap. 42).⁷⁰

Camphorated oil and camphorated spirits contain varying concentrations of camphor. Historically, most camphorated oil was prepared as a 20% weight (of solute) per weight (of solvent) (w/w) solution of camphor with cottonseed oil, and most camphorated spirits contained 10% w/w camphor with isopropyl alcohol. Toxicity and death following ingestion of camphorated oil, which was confused with castor oil and cod liver oil, prompted the FDA to ban the nonprescription sale of camphorated oil in the United States in 1980.^76,123,126 The FDA ban of camphorated oil was followed in 1983 by a restriction on camphor concentration to less than 11% in nonprescription camphor-containing products.¹²⁶ However, camphorated oil is still used as a herbal remedy and muscle liniment, and products containing greater than 11% camphor can be purchased in local stores of various ethnic communities in the United States and in other countries.^48,65,118

Common camphor-containing products include ointments used for herpes simplex on the lips (usually <1% camphor), muscle liniments, rubefacients (usually 4%–7% camphor), and camphor spirits (usually 10% camphor). Paregoric, camphorated tincture of opium, contains a combination of anhydrous morphine (0.4 mg/mL), ethanol (46%), benzoic acid (4 mg/mL), and a small amount of camphor.⁶⁹ For industrial uses, strengths up to 100% camphor are sold legally in the United States. Occupational exposures to camphor occur during the manufacture of plastic, celluloid, lacquer, varnish, explosives, embalming fluids, numerous pharmaceuticals and cosmetics.⁶⁹

Although products containing lower concentrations of camphor are implicitly safer, life-threatening toxicity and death still result from misuse or intentional overdose. Most reported cases of acute camphor poisoning are unintentional ingestions of camphor-containing products mistaken for other medications or therapeutic misadventures from nonprescription products, including home remedies.^{3,50,65,99,119} According to data obtained by the American Association of Poison Control Centers (AAPCC), there are approximately 13,000 exposures to camphor-containing products each year, with a majority of the exposure, approximately 80%, occurring in children under the age of 5 years (Chap. 130).

Prior to the FDA ban of camphorated oil and restriction on camphor ­content in nonprescription products, there was a high incidence of systemic manifestations such as vertigo, confusion, delirium, seizures and coma reported in children younger than 5 years.¹³¹ In a group of 530 patients with camphor exposures, 15% presented with systemic effects and 4% had seizures.^41,93 Unfortunately, limited data are available with regard to the true incidence of symptoms associated with camphor toxicity since the FDA ruling in 1983. According to AAPCC data, 8 reported deaths (1 child and 7 adults) were attributable to camphor over the past 25 years. Although a majority of the patients with unintentional exposures remain asymptomatic and do not present to a health care facility, significant morbidity from unintentional camphor exposures continue to occur in children.^3,48,65,118 The public health implication of camphor exposure in children is of great concern because of the simultaneous lack of therapeutic value of their products and their potential life-threatening toxicity.

Pharmacology

Camphor is a colorless glassy solid. Its pharmacologic activity is not well studied, and its mechanism of action remains unclear. Therapeutic use of camphor as an expectorant is limited, and its anti-infective property is being explored. Camphor, a major component in the essential oil of many plant species, demonstrates bacteriostatic and fungistatic activities against select microorganisms (eg, Enterococcus hirae, Staphylococcus aureus, and Candida albicans) in several in vitro studies.^{64,105,120,132} Imine derivatives of camphor under investigation have antiviral effects against influenza virus (A and H1N1 subtypes) through inhibition of viral hemagglutinin.^113-115 No therapeutic benefit of camphor is proven in any well-controlled clinical trials although camphor provides limited local analgesic and antipruritic effects, much safer alternatives are available for these indications.

Pharmacokinetics and Toxicokinetics

There are limited pharmacokinetic and toxicokinetic data for camphor. Ingestion is the most common route of exposure that results in significant camphor toxicity.^3,65,70,80 However, toxicity also occurs following inhalation, intranasal instillation, intraperitoneal administration, dermal, and from transplacental transfer, resulting in fetal death.^48,65,97,110 Camphor is a highly lipophilic compound that is rapidly absorbed from the gastrointestinal tract and is detected in the blood within 15 to 20 minutes following ingestion.^93,101 Because of the lack of experimental data, the bioavailability from each route of exposure is unknown. A peak blood camphor concentration was achieved in 90 minutes when rats were administered an oral dose of 1 g/kg.³⁵ A significant amount of camphor is absorbed through normal skin. Dermal absorption of camphor is slow, but can produce systemic toxicity up to 72 hours following exposure.^48,65 The volume of distribution is estimated at 2 to 4 L/kg with protein binding of approximately 61%.^69,70

Camphor is predominantly metabolized in the liver and eliminated by the kidneys. Up to 59% of the camphor is eliminated in urine as glucuronides, but unchanged camphor (<1%) and other oxidative metabolites are also found in the urine.^70,103,108 Five inactive metabolites are produced by hydroxylation of a methylene group (the predominant pathway) and reduction of the oxo group.¹⁰³ Inactive metabolites, 3-hydroxycamphor, 5-hydroxycamphor (major metabolite), 8-hydroxycamphor, 9-hydroxycamphor, and borneol, are either conjugated with glucuronic acid or further oxidized and eliminated by the kidneys.^70,103 The exact site of camphor metabolism is unknown, but CYP 2A6 and NADPH-P450 reductase are known to be involved.^49,84 A volunteer study in which 200 mg of camphor with Tween 80 as a solvent (10 mL) or without the solvent was ingested demonstrated, in humans, plasma elimination half-lives of 93 minutes and 167 minutes, respectively following oral administration.⁶⁹ A comparable elimination half-life of 144 minutes was found in an animal model.³⁵ Small amounts of camphor are eliminated by exhalation, as noted by characteristic breath odor but no studies have assessed the significance of this route of elimination.^70,75

The reported toxic dose of camphor is highly variable.^50,112 A potential lethal dose of 50 to 500 mg/kg of camphor is often cited for humans.^41,80,93 Yet, as little as 1 g of camphor resulted in death in a 19-month-old infant, whereas up to 42 g of camphor was ingested by an adult who recovered.^2,112 There are insufficient data to suggest a clear toxic dose range of camphor. However, there is evidence to suggest that camphor causes life-threatening toxicity at low doses (estimated exposure of 700–1,500 mg) based on a series of case reports in both adults and children.^{75,93,112,118}

Workplace standards determined by the Occupational Safety and Health Administration (OSHA) has set the permissible exposure limit (PEL) at 2 mg/m³.¹²⁵ The American Conference of Governmental Industrial ­Hygienists (ACGIH) threshold limit value (TLV) is 12 mg/m³ (2 ppm), whereas the short-term exposure limit (STEL) is 19 mg/m³ (3 ppm). The National ­Institute for Occupational Safety and Health (NIOSH) Immediately Dangerous To Life or Health Concentration (IDLH) is 200 mg/m³.¹²⁴

Pathophysiology

The mechanism of toxicity of camphor is unknown. Camphor is an irritant. Pathologic changes following ingestion include cerebral edema, neuronal degeneration, fatty changes in the liver, centrilobular congestion of the liver, and hemorrhagic lesions in the skin, gastrointestinal tract, and kidneys.^62,112,139

Clinical Manifestations

Exposure to camphor can often be detected by its characteristic aromatic odor (Chap. 25). Ingestion of camphor typically produces oropharyngeal ­irritation, nausea, vomiting, and abdominal pain. Generalized tonic–clonic seizures usually occur within 1 to 2 hours of ingestion.^13,17 The onset of systemic toxicity, particularly CNS toxicity, occurs as early as 5 minutes after ingestion.^30,33,75,112 Most seizures are brief and self-limited, although some patients experience multiple seizures, including status epilepticus.^43,48,68,111 Delayed seizures are reported occurring up to 9 hours following ingestion and up to 72 hours following dermal exposure.^49,105 Central nervous system (CNS) depression is common, but camphor rarely compromises respiratory function.^29,68 Other neurologic manifestations include headache, lightheadedness, transient visual changes, confusion, myoclonus, and hyperreflexia.^65,102 ­Psychiatric manifestations include agitation, anxiety, and hallucinations.^51,65,68 Dermal effects include flushing and petechiae.^29,55 Camphor does not typically cause life-threatening ­cardiovascular effects, although a case of myocarditis is reported.¹⁹ Deaths are reported secondary to status epilepticus.^16,29,77,110 Transient elevation of hepatic aminotransferases concentrations were observed in acute ingestion of ­camphor.^62,101,110 Chronic administration of camphor to a child caused altered mental status and elevated hepatic aminotransferase concentrations suggestive of Reye syndrome.⁶² When hepatotoxicity occurs, however, camphor does not typically produce morphologic changes in the liver characteristic of Reye syndrome. Albuminuria was also reported.¹¹²

Camphor crosses the placenta. Both fetal demise and delivery of healthy neonates are reported in mothers following intentional and unintentional ingestion.^19,101,139 Specific dose-related toxicity cannot be determined from these case reports.

Inhalational and dermal exposures to camphor typically result in mucous membrane and dermal irritation, respectively.⁴⁷

Diagnostic Testing

No specific diagnostic test is available or indicated when managing patients with camphor toxicity. Camphor and its metabolites can be identified in blood and urine,^70,103 but these tests are not clinically useful.^53,70,103

Management

Gastric decontamination is not well studied in patients with acute camphor ingestion. Camphor is rapidly absorbed from the gastrointestinal tract because of its high lipophilicity and vomiting is common. The benefit of gastrointestinal decontamination rapidly diminishes with time following acute ingestion. Gastric lavage was commonly performed in patients with acute camphor ingestions, but it is no longer routinely performed or recommended.^41,93 The utility of activated charcoal in acute camphor ingestion is unknown. One animal study showed the administration of activated charcoal (2 g/kg; 2:1 activated charcoal to toxin ratio) immediately following camphor ingestion did not alter the gastrointestinal absorption of camphor.³⁵ There are no human data in support of the use of activated charcoal in camphor ingestions. It remains reasonable to administer activated charcoal following a large recent ingestion if no contraindications exist.

Patients who should be evaluated in a health care facility after an acute ingestion include those who have signs or symptoms consistent with camphor toxicity, those who ingest more than 30 mg/kg of camphor, suicidal patients, and any patient with a significant occupational exposure.⁷⁷

There is no antidote for camphor. Most patients survive with supportive care. Although the management of camphor-induced seizures is not well studied, the first-line therapy recommended for camphor-induced seizures are a benzodiazepines. Repeat doses of benzodiazepines are often needed to control seizures. If benzodiazepines fail to control seizures, other sedative-hypnotics, including propofol or pentobarbital, should be administered. Case reports suggest that most patients who develop life-threatening camphor toxicity develop symptoms within a few hours postexposure. Based on this, an observation period of at least 4 hours is reasonable following a potentially toxic ingestion. In case reports, hemodialysis with a lipid dialysate and either hemoperfusion using an ­Amberlite resin or charcoal hemoperfusion successfully removed camphor.^42,68,69,78 However, isolated lipid hemodialysis or lipid dialysis in combination with hemoperfusion is neither routinely recommended nor widely available.

NAPHTHALENE

History and Epidemiology

Naphthalene, an aromatic bicyclic hydrocarbon, is commonly found in products such as moth repellents, toilet-bowl and diaper-pail deodorizers, and soil fumigants.¹¹⁶ It is the single most abundant component of coal tar, approximately 11% by weight, and is used in the manufacture of numerous commercial and industrial products.^25,116 Both crude oil and refined products such as gasoline and diesel fuels contain naphthalene.

Historically, naphthalene toxicity resulted from its use as an antihelminthic and an antiseptic.¹¹¹ In more recent years, unintentional and intentional ingestions of mothballs containing naphthalene became the major etiology of naphthalene toxicity.^{73,108,117,138} A single naphthalene mothball can contain between 0.5 and 5 g of naphthalene depending on its size.⁴ ­Toilet-bowl and diaper-pail deodorizers containing naphthalene also cause toxicity.^29,148 Chronic exposure to naphthalene occurs in occupational setting with variable amounts of exposure depending on the industry. The most common use of naphthalene is in the production of phthalic anhydride, a compound used in chemical feedstock.⁴⁶ Other industrial uses of naphthalene include carbamate insecticides, dye intermediates, synthetic resins, bathroom (­urinal) air fresheners, fuel additives, plasticizers, and the manufacture of other ­chemicals.^46,116 Naphthalene is also generated as a by-product of combustion and is present in ambient air at low concentrations.⁴⁶

Most unintentional exposures to naphthalene-containing moth repellents occur in children and do not cause life-threatening toxicity. According to data from the AAPCC, there are 1,200 to 1,900 naphthalene exposures annually. During the past 25 years, one death occurred from suicide whereas reports of “major toxicity” occurred rarely (Chap. 130). Mothball vapors are also intentionally inhaled as a form of “recreational” inhalant abuse.^71,138

Pharmacology, Pharmacokinetics, and Toxicokinetics

Naphthalene is a white, flakey crystalline solid with a noxious odor. ­Synonyms include white tar and tar camphor. Naphthalene toxicity is reported following ingestion, dermal application, and inhalation.^34,106,129 The absorption of naphthalene is not well studied. Naphthalene metabolism is complex and varies considerably among species and different anatomical regions.²¹ For instance, an in vitro study using human liver microsomes showed that ­multiple CYP450 enzymes are involved in naphthalene metabolism: 1A1, 1A2, 1B1, 2A6, 2B6, 2C19, 2D6, 2E1, and 3A4.²⁷ Metabolic pathways involve several intermediates and generate multiple reactive metabolites: 1,2-­naphthalene oxide, 1,4-­naphthoquinone, 1,2-naphthoquinone, and 1,2-dihydroxy-3,4-­epoxy-1,2,3,4-tetrahydronaphthalene^4,21,22 (Fig. 102–1).

Naphthalene is initially metabolized to an unstable epoxide ­intermediate, naphthalene 1,2-oxide, in both human and animals.^4,22,116 1,2-Naphthalene oxide reacts with cellular components such as DNA and protein to form covalent adducts or can be spontaneously converted to 1-naphthol and 2-naphthol, which undergo glucuronidation or sulfation to form conjugates that are subsequently eliminated in urine.^4,21,22 Glutathione-S-transferase and glutathione play an important role in detoxification of 1,2-naphthalene oxide by converting the reactive epoxide to nonreactive mercapturic acid metabolites.^21,22,76 The depletion of glutathione prior to naphthalene exposure increases acute injury in lung Clara cells, one of the target organs of naphthalene toxicity in mice.^94,95

Reactive hepatic metabolites, 1-naphthol (α-naphthol), 1,2-naphthoquinone, and 1.4-naphthoquinone, are cytotoxins that deplete intracellular glutathione stores and generate reactive oxygen species.^4,116,147 They are responsible for the oxidative stress leading to naphthalene-induced hemolysis and methemoglobinemia.

The toxic amount of naphthalene reported is highly variable. As little as one naphthalene mothball resulted in hemolysis in an infant.^40,148 Workplace standards include the OSHA PEL, which is 50 mg/m³ (10 ppm), ACGIH TLV, which is 52 mg/m³ (10 ppm), and the ACGIH STEL, which is 79 mg/m³ (15 ppm); NIOSH IDLH is 250 ppm (US Department of Labor OSHA).¹²⁵

Pathophysiology

Naphthalene-induced (via oxidative metabolites: 1-naphthol, 1,2-naphthoquinone, and 1,4-naphthoquinone) hemolysis and methemoglobinemia result when physiologic compensatory mechanisms to oxidative stress are overwhelmed. It is important to understand how oxidant stress affects erythrocytes and the normal mechanisms that erythrocytes use to prevent and reverse the effects of oxidant stress.

Oxidant stressors cause methemoglobinemia and/or hemolysis. When oxidant stress causes an iron atom from any of the 4 globin chains of hemoglobin to be oxidized from the ferrous state (Fe²⁺) to the ferric state (Fe³⁺), methemoglobin is formed (Chap. 124). When oxidant stress causes hemoglobin denaturation, the heme groups and the globin chains dissociate and precipitate in the erythrocyte, forming Heinz bodies. An erythrocyte with denatured hemoglobin is more susceptible to hemolysis (Chap. 20).

Hemolysis and methemoglobinemia can occur independently or simultaneously in patients with either normal or deficient glucose-6-phosphate dehydrogenase (G6PD) activity.^58,129,148 Patients with G6PD deficiency are at much greater risk of hemolysis rather than methemoglobinemia because of their decreased glutathione stores.^79,129,147 Glucose-6-phosphate dehydrogenase affects all races, but is most prevalent in patients of African, Mediterranean, and Asian descent. The gene that codes for G6PD is X-linked; consequently, men are affected more often than women.

Infants are also at increased risk of methemoglobinemia because fetal hemoglobin is more susceptible to the formation of methemoglobin. Moreover, cytochrome-b₅ reductase (a nicotinamide adenine dinucleotide {NADH}-dependent enzyme) activity in infants is approximately 50% lower than adults, impairing the reduction of methemoglobin to hemoglobin.^45,54,63

Injuries to other organs, that is, eyes, lungs, and liver, occurred in animals after exposure to naphthalene.^{39,89,98,116,130} However, there is a significant interspecies variation in the degree of toxicity. Human data on organ toxicity beyond hematologic effects of naphthalene are limited. A few case reports link the development of cataracts to occupational exposure; however, the causal relationship remains questionable.⁸⁹ Oxidative destruction of lens proteins is theorized to result in cataract formation.¹¹⁶ Animal studies show that oxidative stress from naphthalene results in pulmonary epithelial necrosis and hepatic injury by lipid peroxidation.^39,98,116 However, there is no report of hepatotoxicity or pulmonary toxicity in humans following naphthalene exposure.

Clinical Manifestations

Clinically significant toxicity from naphthalene exposure occurs rarely. However, if present, both acute and chronic exposures to naphthalene result in similar toxicity.^29,86,147 Ingestion and inhalational exposures to naphthalene commonly cause headache, nausea, vomiting, diarrhea, abdominal pain, fever, and altered mental status.^29,74,91 Dermal exposure results in dermatitis.⁴⁴

Hemolysis and methemoglobinemia, caused by naphthalene metabolite 1-naphthol, occurs infrequently as a result of naphthalene exposure. They become clinically evident as early as 24 to 48 hours postexposure, but more typically on the third day postexposure because of the time necessary for the hepatic metabolism of naphthalene.^34,73 Anemia secondary to hemolysis often does not reach its nadir until 3 to 5 days postexposure.^9,121

Signs and symptoms of hemolysis and methemoglobinemia include tachycardia, tachypnea, shortness of breath, cyanosis, jaundice, dark urine, generalized weakness, decreased exercise tolerance, and altered mental status (Chap. 124). Acute kidney injury is reported as a complication of naphthalene-induced hemolysis and hemoglobinuria. Naphthalene and its metabolites cross the placenta.¹¹ Naphthalene pica during pregnancy causes both maternal and fetal toxicity. Hemolytic anemia in children born to mothers who had naphthalene toxicity at the time of delivery is believed to be related to the maternal naphthalene exposure.¹⁴⁷ Data on the development cataracts following naphthalene exposure in human are inconclusive.⁸²

Based on animal data on carcinogenicity, naphthalene is classified by the International Agency for Research on Cancer (IARC) as a Group 2B carcinogen (possibly carcinogenic to humans) and by the EPA as a Group C possible human carcinogen.^46,60 The data supporting human carcinogenicity of naphthalene are limited. There are several case reports that associate exposure with laryngeal cancer in East Germany and colorectal cancer in Nigeria, but causal relationship cannot be determined.^7,46

Diagnostic Testing

No specific diagnostic testing is indicated, although both naphthalene and its metabolites are identifiable in blood and urine. Identification of 1-­naphthol and 2-naphthol in the urine confirms exposure to naphthalene. Qualitative or quantitative testing for naphthalene or its metabolites is not clinically indicated when managing a patient with an acute overdose.⁹²

The presentation of naphthalene-induced hemolysis is similar to that of hemolysis from other causes. Hyperbilirubinemia from hemolysis is characterized by an elevation of the unconjugated (indirect) bilirubin and a relatively normal conjugated (direct) fraction. Serum haptoglobin is usually low because the haptoglobin–hemoglobin complex is cleared by the kidneys. Both the direct and indirect Coombs tests are negative in naphthalene-induced hemolytic anemia. Lactate dehydrogenase is elevated due to its release from hemolyzed red blood cells. Hemoglobinuria is suggested by a urine dipstick that reacts strongly positive for hemoglobin with a paucity or absence of red blood cells on microscopic examination of the urine sediment. Hemoglobinemia is differentiated from myoglobinuria, which has a comparable urine sediment, by measuring the serum creatine phosphokinase and myoglobin which will be elevated in patients with rhabdomyolysis and myoglobinuria but not in those with hemolysis and hemoglobinuria.

Examination of a peripheral blood smear is useful in identifying hemolysis before a patient develops clinical or laboratory evidence of anemia. Hemolysis is present when red blood cell (RBC) abnormalities are present including schistocytes, anisocytosis, microspherocytosis, reticulocytosis, nucleated RBCs, Blister cells, and Heinz body (Chap. 20). Peripheral smear abnormalities and anemia often occurs within the first 24 hours following ­ingestion.^{29,107,147,148} Testing for G6PD activity is not recommended during an acute episode of hemolysis. Reticulocytes have higher G6PD activity than do older RBCs. If G6PD activity is measured during an episode of hemolysis when many of the older RBCs have already been destroyed, false elevation or normal G6PD activity is observed. It is best to delay testing for G6PD activity for a few months following an episode of hemolysis. Family members of patients with life-threatening G6PD deficiency should also be tested.

Naphthalene-induced methemoglobinemia is similar in presentation to methemoglobinemia from other xenobiotics. The percentage of methemoglobin is rapidly determined using a cooximeter (Chap. 124).

Management

Most patients with an unintentional exposure to no more than one naphthalene-containing mothball do not require medical evaluation. Patients who should be evaluated in a health care facility following an acute ingestion include those who recently ingested more than one naphthalene-containing mothball equivalent, those with signs or symptoms of toxicity, especially hemolysis and/or methemoglobinemia, those with known or suspected G6PD deficiency, all intentional ingestions, and those patients with substantial inhalational exposures, particularly those occurring in an occupational setting.

Gastrointestinal decontamination is not well studied in patients who have ingested naphthalene. Most patients with unintentional exposures do not require gastrointestinal decontamination. Administration of activated charcoal, 1 g/kg, although not of proven efficacy, is reasonable because it is considered safe. Repeat doses of activated charcoal 0.5 g/kg and/or whole-bowel irrigation with polyethylene glycol electrolyte lavage solution would only reasonable for patients with large ingestions of naphthalene who are expected to have significant ongoing gastrointestinal absorption.

Diagnostic testing within the first 24 to 48 hours postexposure will detect the onset of methemoglobinemia and/or hemolysis before a patient becomes symptomatic. Most low-risk patients who are asymptomatic within the first 24 to 48 hours postexposure and who have no laboratory evidence of hemolysis or methemoglobinemia should be managed as outpatients if reevaluation within 24 to 48 hours can be arranged. Patients who are discharged should be instructed to return if they become symptomatic. Admission recommended for high-risk patients, those with laboratory evidence of hemolysis and/or methemoglobinemia, and those who cannot be reliably managed as outpatients.

Patients with life-threatening hemolysis and anemia should be transfused with packed red blood cells. However, most healthy patients will be able to compensate for the hemolysis and will not require a transfusion. For patients with symptomatic methemoglobinemia methylene blue 1 to 2 mg/kg (0.1–0.2 mL/kg of a 1% solution) is recommended intravenously. Repeat doses may be necessary (Antidotes in Depth: A43).

PARADICHLOROBENZENE

History and Epidemiology

Paradichlorobenzene (1,4-dichlorobenzene) is widely used as a deodorizer, disinfectant, repellent, fumigant, insecticide, fungicide, and industrial solvent. Today, paradichlorobenzene is the most common component of moth repellents and deodorants for restrooms in the United States. Low-level exposure to paradichlorobenzene in the United States is extremely common as a result of environmental contamination from release of paradichlorobenzene to air by industrial facilities.⁹⁰ The primary route of human exposure is inhalation in either an occupational setting or from indoor air where paradichlorobenzene is used as a deodorizer or moth repellent.⁹⁰ Paradichlorobenzene is also found in both water and numerous food items, including pork and fresh vegetables, from environmental contamination.^90,102,133 Consequently, approximately 96% to 98.3% of the US population, including children as young as 2 years old, have detectable 2,5-dichlorophenol, a metabolite of paradichlorobenzene, in the urine.^57,58,144 Analysis of urine samples from the participants of National Health and Nutrition Examination Survey (NHANES) showed that urinary 2,5-dichlorobenzene concentrations decreased between the 2003–2004 and 2009–2010 survey periods. However, highest urinary concentrations were noted among 6- to 11-year-old children and adults older than 60 years.¹⁴⁴ The health effects of the low-level paradichlorobenzene exposure from environmental contamination are unclear. Recent population-based (NHANES) studies suggest a dose-dependent increase in the prevalence of diabetes, thyroid dysfunction, metabolic syndrome, obesity, earlier age of menarche, and food allergies.^{22,23,61,123,134-137} These findings do not establish a clear causal relationship, but further research is warranted to investigate the relationship between environmental paradichlorobenzene exposure and its potential adverse health effects.

Approximately 150 paradichlorobenzene exposures are reported annually. The majority of the cases are unintentional exposures to paradichlorobenzene-containing moth repellents, predominantly occurring in children (<5 years old), which do not cause toxicity. According to the AAPCC data, no deaths or major toxicity were reported between 1995 and 2015, and only 15 cases of paradichlorobenzene exposures experienced moderate toxicity during the same period (Chap. 130).

Pharmacology, Pharmacokinetics, Toxicokinetics, and Pathophysiology

Paradichlorobenzene is a colorless solid with a noxious odor. It is available as pure white crystals, as a solid in combination with other chemicals, or as a liquid dissolved in volatile solvents or oil.¹⁰ Paradichlorobenzene is well absorbed via ingestion, inhalation, and dermal exposure. ­Inhalation toxicokinetics show that there is rapid distribution and ­accumulation in tissues, specifically in adipose tissue.^14,27,55,146 This contributes to sustained serum paradichlorobenzene concentrations and clinical toxicity after cessation of chronic exposure, a phenomenon known as “coasting.”^56,36 ­Starvation increases paradichlorobenzene release owing to utilization of adipose tissues.^13,52 Paradichlorobenzene undergoes hepatic metabolism by ­several CYP450 enzymes including 1A1, 1A2, 2B1, 2E1 (primary iso­enzyme), and 3A1 and 3A4 to its primary metabolite, 2,5-dichlorophenol.^20,36,52,56 With several other minor metabolites (2,5-dichlorohydroquinone, 2,5-dichlorophenylmethyl sulfide, 2,5-dichlorophenylmethyl sulfone), 2,5-dichlorophenol is eliminated primarily via urinary excretion as either sulfated or glucuronidated conjugates.^14,36,52,146

The mechanism of the toxicologic effect of paradichlorobenzene has not been studied to date. Although rare, paradichlorobenzene toxicity is reported following ingestion and inhalation.^59,81

Workplace standards include the OSHA PEL, which is 450 mg/m³ (75 ppm) time-weighted average (TWA), ACGIH TLV, which is 60 mg/m³ (10 ppm) TWA, and the ACGIH STEL, which is 675 mg/m³ (110 ppm); NIOSH IDLH is 150 ppm.¹²⁶

Clinical Manifestations

Paradichlorobenzene is considered to have less toxicity than camphor and naphthalene. However, cases of clinical toxicity from paradichlorobenzene are reported ranging from hemolytic anemia to toxic leukoencephalopathy following acute and/or chronic exposure.^{13,27,37,38,56} Although paradichlorobenzene is absorbed following inhalation, ingestion and cutaneous exposures, ingestion, and inhalation are the routes of exposure that lead to toxicity.^37,38,56,83 Acute unintentional exposure to paradichlorobenzene typically causes limited transient clinical effects such as nausea and vomiting, headache, and mucous membrane irritation.^32,59 However, significant neuropsychiatric dysfunction, specifically cerebellar dysfunction, motor weakness, behavioral changes, and cognitive decline, is reported following chronic intentional and occupational exposure.^37,38,56 In most cases, neurologic and cognitive deficits associated with paradichlorobenzene developed after several months of exposure and seldom had complete resolution after cessation of paradichlorobenzene exposure.^13,36,56,83 Other clinical signs and symptoms from chronic exposure include pulmonary granulomatosis, hepatotoxicity, acute kidney injury, an ichthyosislike dermatosis, aplastic anemia, and dyspnea.^37,38,85,140

Hemolytic and aplastic anemias are reported, as well as methemoglobinemia, following acute paradichlorobenzene ingestion.^53,109

Paradichlorobenzene is classified by IARC as a Group 2B, possibly carcinogenic to humans, based on evidence of carcinogenicity from experimental animal studies. In mice and rats, chronic exposure was associated with the development of both hepatocellular carcinomas and adenomas in male and female mice, and renal tubular cell adenocarcinoma and mononuclear cell leukemia developed in male mice.^{5,6,16,87,88,143} Evidence for carcinogenicity in humans from paradichlorobenzene exposure is limited. One case series reported 5 cases of leukemia that were associated with paradichlorobenzene exposure.^88,142 No additional epidemiologic data on human carcinogenesis from paradichlorobenzene exposure is available.

Diagnostic Testing

Both paradichlorobenzene and its primary metabolite, 2,5-­dichlorophenol, can be identified in blood and urine following exposure.^14,59 ­However, ­detectable serum or urine concentrations of paradichlorobenzene or 2,5-dichlorobenzene are difficult to interpret as they are universally ­present in healthy adults and children as a common environmental contaminant.^56,57,146 In one study, a sample of 1,000 adults in the United States had detectable concentrations of 2,5-dichlorophenol and paradichlorobenzene in their urine and blood, 98% and 96%, respectively, without evidence of clinical toxicity. The mean 2,5-dichlorophenol and paradichlorobenzene concentrations in urine and blood were 200 and 2.1 mcg/L, respectively. A similar frequency of detectable 2,5-dichlorophenol concentrations in urine was also detected in healthy children.⁵⁷ Quantifying the amount of paradichlorobenzene in the urine of workers is useful for monitoring occupational exposures.⁴⁰ Overall, qualitative or quantitative testing for paradichlorobenzene or its metabolites is not generally indicated when managing a patient with an acute overdose. Structural CNS abnormalities, including toxic leukoencephalopathy, are occasionally noted on imaging studies such as MRI.¹³ Hyperintense signals are seen in specific anatomic locations including periventricular white matter, corpus callosum, deep cerebellar nuclei, the parieto-occipital region and internal capsule.^13,27,56

Management

Most unintentional exposures to paradichlorobenzene do not cause severe or life-threatening toxicity. It is reasonable to manage asymptomatic patients with unintentional exposures as outpatients. Patients who should be evaluated in a health care facility include those with clinical signs or symptoms, suicidal patients, and patients who have had a large exposure.

Gastrointestinal decontamination has not been studied in patients who ingest paradichlorobenzene. Most patients with unintentional exposures do not require gastrointestinal decontamination. However, administration of activated charcoal, 1 g/kg, is reasonable for patients with large, intentional ingestions. If present, gastrointestinal effects such as nausea and vomiting should be managed with supportive care, including fluid resuscitation and antiemetics. Laboratory testing is generally not helpful in the acute setting unless there is clinical evidence for hemolysis or methemoglobinemia. Transfusion of packed RBCs is recommended for symptomatic anemia resulting from acute hemolysis. Methylene blue is recommended for symptomatic methemoglobinemia.

It is reasonable for asymptomatic patients to follow up as outpatients for reevaluation in 24 to 48 hours postexposure as delayed development of hemolysis or methemoglobinemia is possible, but rare. Careful discharge instructions should be provided to patients should they become symptomatic.

Management of paradichlorobenzene-induced neurotoxicity such as encephalopathy, cerebellar dysfunction, psychomotor retardation and cognitive decline from chronic exposure is mainly supportive. Improvement of neuropsychiatric symptoms is variable; complete recovery is possible, although infrequent, after cessation of exposure, but residual neurotoxic effects are frequently present.^36,56,83

MOTH REPELLENT RECOGNITION

Health care providers occasionally must determine whether a mothball is made of naphthalene, paradichlorobenzene, or camphor because management and prognosis for each is different. When the container is unavailable, as is often the case, mothballs are difficult to distinguish based on appearance, odor, texture, or size. Most mothballs are white, crystalline, and have a noxious odor.¹⁴¹ Camphor moth repellents are more oily than both naphthalene and paradichlorobenzene mothballs. If controls are available, moth repellents are frequently differentiated based on their odor and texture.⁸ Although most new paradichlorobenzene moth repellents are slightly larger than most new naphthalene moth repellents, all moth repellents shrink over time when exposed to air, making size an unreliable differentiating characteristic. Identifying a moth repellent as paradichlorobenzene often permits outpatient management, saving both hospital resources and unnecessary concern. The tests described in Table 102–1 and shown in Fig. 102–2 might allow rapid identification of the component of an unknown moth repellent. When performing these tests, it is most helpful to have camphor, naphthalene, and paradichlorobenzene controls available for comparison.

SUMMARY

• Paradichlorobenzene has largely replaced both camphor and naphthalene as a moth repellent in the United States, but exposures to all 3 compounds occur, especially in immigrant communities.

• It is reasonable to administer activated charcoal in patients with large ingestions if no contraindications are present, such as CNS depression, active vomiting, or seizures.

• Seizures commonly occur after camphor ingestion, and deaths due to status epilepticus are reported. Camphor-induced seizures are responsive to benzodiazepines, propofol, and barbiturates.

• Hemolytic anemia and methemoglobinemia occur after naphthalene and, less frequently, following paradichlorobenzene ingestions. ­Appropriate supportive care, packed red blood cell transfusions, and methylene blue administration are recommended for symptomatic patients.

• Simple radiography and buoyance tests are helpful in identifying the unknown moth repellent.

Acknowledgment

Edward K. Kuffner, MD, contributed to this chapter in previous editions.

REFERENCES

HISTORY AND EPIDEMIOLOGY

A caustic is a xenobiotic that causes both functional and histologic damage on contact with tissue surfaces. As early as 1927, legislation in the United States governing the packaging of alkali- and acid-containing products mandated that warning labels be placed on these products. In response to the recognition that caustic exposures were more frequent in children, the Federal Hazardous Substances Act and Poison Prevention Packaging Act were passed in 1970. These acts mandated that all caustics with a concentration greater than 10% be sold in child-resistant containers. By 1973, the household concentration triggering mandatory child-resistant packaging was lowered to 2%. In addition, the subsequent development of poison prevention education dramatically decreased the incidence of unintentional caustic injuries in children in the United States. The positive impact of both regulatory legislation and public health intervention is evident when observing the decreasing number of significant exposures in the United States compared to the number of exposures in developing nations that lack these policies.

In the United States, even though legislation limiting the concentration of caustics has existed since the early 20th century, exposures to both acids and alkalis continue to be significant. Data collected from the 5 most recent years of the American Association of Poison Control Centers Annual Reports of the National Poison Data System revealed 37,272 acid exposures and 18,801 alkali exposures. Of these, 4,405 (12%) of acid and 3,153 (17%) of alkali exposures resulted in moderate to major outcomes and a total of 26 deaths occurred (Chap. 130).

Caustic exposures follow a bimodal age distribution pattern with peak occurrences in the pediatric population age 1 to 5 years and again in adulthood. In children, exposures usually consist of household products and occur most often in an unsupervised setting. In adults, exposures to household or industrial products result from occupational exposure, suicide attempts, and assaults. Although less frequent, intentional exposures by adults are invariably more significant. One study noted that although children comprised 39% of admissions for caustic ingestions, adults comprised 81% of patients requiring treatment.³⁸

Exposure to caustics occurs via the dermal, ocular, respiratory, and ­gastrointestinal route. Caustics cause diverse histologic and functional damage on contact with tissues depending on the tissue and caustic involved. Table 103–1 lists common caustics and the products that contain them. Many are available for home use, in both solid and liquid forms, with variations in viscosity, concentration, and pH.

The severity of a caustic injury is often not immediately evident in patients who present shortly after exposure. Predicting which patients will require rapid interventions to prevent morbidity and mortality requires the determination and evaluation of multiple clinical and laboratory parameters. This chapter reviews the pathophysiology and approach to patients with potentially serious exposures.

PATHOPHYSIOLOGY

Although there are many ways to categorize caustics, they are most typically classified as acids or alkalis. An acid is a proton donator and causes significant injury, generally at a pH below 3. An alkali is a proton ­acceptor and causes significant injury, generally when the pH is above 11. Chapter 10 contains a more detailed discussion of the chemistry of acids and bases. The extent of injury is modulated by duration of contact; ability of the ­caustic to penetrate tissues; volume, pH, and concentration; the presence or absence of food in the stomach; and a property known as titratable acid/alkaline reserve (TAR). Titratable acid/alkaline reserve quantifies the amount of neutralization needed to bring the pH of a caustic to that of physiologic tissues. Neutralization of caustics takes place at the expense of the tissues, resulting in the release of thermal energy, producing burns. Generally, as the TAR of a caustic increases, so does the ability to produce tissue ­damage.^5,42 Some caustics, such as zinc chloride and phenol, have a high TAR and are capable of producing severe burns even though their pH is near physiologic. Beyond tissue damage, some caustics have the potential to cause systemic toxicity.

Alkalis

Following exposure to an alkaline xenobiotic, dissociated hydroxide (OH^–) ions penetrate tissue surfaces, producing a histologic pattern of liquefactive necrosis (Figs. 103–1 and 103–2). This process includes protein dissolution, collagen destruction, fat saponification, cell membrane emulsification, transmural thrombosis, and cell death.⁵ Animal studies of alkali exposure to the eye⁴¹ demonstrate rapid formation of corneal epithelial defects with eventual deep penetration that may lead to perforation. Similarly, animal studies of the esophagus demonstrate that erythema and edema of the mucosa occur within seconds followed by an inflammatory reaction extending to the submucosa and muscular layers. The alkali, such as sodium hydroxide (“lye”), continues to penetrate until the OH^– concentration is sufficiently neutralized by the tissues.^5,55

Although federal regulations have lowered the maximal available household concentration of many caustics, 2 industrial-strength products seem to be readily available and therefore warrant special mention: ammonium hydroxide and sodium hypochlorite. Ammonia (ammonium hydroxide) products are weak bases—partially dissociated in water—that cause significant esophageal burns, depending on the concentration and volume ingested.³⁸ Household ammonium hydroxide ranges in concentration from 3% to 10%. Strictures are reported in patients who ingested 28% ­solutions.⁷¹ Sodium hypochlorite is the major component in most industrial and household bleaches. Severe injuries typically only occur in patients with large-volume ingestions of concentrated products and most other patients do well with supportive care.^15,38 A series of 393 patients with household bleach ingestions demonstrated no stricture formation.⁵ Likewise, a canine model found that although vomiting was commonly associated with bleach ingestion, no esophageal lesions were noted, and perforation occurred only ­following prolonged contact.⁵⁴

Ingestion of button batteries were once considered a unique caustic exposure. Composed of metal salts and a variety of alkaline xenobiotics, such as sodium and potassium hydroxide, leakage of battery contents was a legitimate concern. In recent years, however, new techniques used in the production of button batteries that effectively prevent leakage have shifted the concern following their ingestion from that of a caustic to a foreign body exposure with the significant potential for electrical injury.

Household detergents, such as laundry powders, laundry detergent pods (LDPs),⁸³ and dishwasher detergents, contain silicates, carbonates, and phosphates and have the potential to induce caustic burns and strictures, even when ingested unintentionally.¹⁶ Although airway compromise rarely occurs after ingestion of traditional detergents,^16,23,59 the majority of exposures to traditional products result in only minor toxicity and usually do not require ­hospitalization. Compared to children with traditional non-LDP exposures, LDP exposures are associated with a higher incidence of adverse health effects, including mental status depression and respiratory ­compromise.^10,26,49 At this time it is unclear if the adverse health effects observed with LDP versus non-LDP exposures are due to unique contents or differences in pH, concentration, tensile strength, or the delivery vehicle.

Cationic detergents include quinolinium compounds, pyridinium compounds, and quaternary ammonium salts. These are frequently found in products developed for industrial use, as well as household fabric softeners. A concentration greater than 7.5% can cause severe burns.⁵⁸

Acids

In contrast to alkaline exposures, following exposure to an acid, hydrogen (H⁺) ions desiccate epithelial cells, producing an eschar and resulting in a histologic pattern of coagulation necrosis. This process leads to edema, erythema, mucosal sloughing, ulceration, and necrosis of tissues. Dissociated anions of the acid (Cl^–, SO₄^2–, PO₄^3–) also act as reducing agents, further injuring tissue. Ophthalmic exposure to acid results in coagulative necrosis that tends to prevent further penetration into deeper layers of the eye.

In most series, following an acid ingestion, both the gastric and esophageal mucosa are equally affected.^21,103 On occasion, the esophagus is spared damage while severe injury is noted in the stomach^29,38 (Fig. 103–3). This result tends to be a rarer finding than concomitant injury to both stomach and esophagus and is probably related to the rapid transit time of liquid acids through the upper gastrointestinal tract. Skip lesions from acid ingestions are reported and presumed to be a function of viscosity and contact time.³⁸ Additionally, acid-induced pylorospasm is reported to lead to gastric outlet obstruction, antral pooling, and perforation.^21,102 A cat model of the effects of sulfuric acid on the esophagus revealed a coagulative necrosis of the mucosa with whitish discoloration of the tissues and underlying smooth muscle spasm.⁵ Other animal models demonstrate chronic generalized esophageal motility dysfunction and shortening.^86,88

Chapters 95, 101, and 104 contain a more detailed discussion of mercury, phenol, and hydrofluoric acid, respectively, each a unique caustic.

Classification and Progression of Caustic Injury

Esophageal burns, secondary to both alkali and acid exposures, are classified based on endoscopic visualization that employs a grading system similar to that used with dermal burns (Table 103–2).^19,28,33,102 Human case reports, postmortem studies, histologic inspection of surgical specimens, and experimental animal models reveal a consistent pattern of injury and repair following caustic injury.⁸⁰ As wound healing of gastrointestinal tract tissue occurs, neovascularization and fibroblast proliferation take place, laying down new collagen and replacing the damaged tissue with granulation tissue. A similar pattern of repair occurs following caustic injuries of the eye.

Burns of the esophagus typically persist for up to 8 weeks as remodeling takes place and is often followed by esophageal shortening. If the initial injury penetrates deeply, there is progressive narrowing of the esophageal lumen. The dense scar formation presents clinically as a stricture. Strictures can evolve over a period of weeks to months, leading to dysphagia and significant nutritional deficits.

CLINICAL MANIFESTATIONS

The gastrointestinal tract, respiratory tract, eyes, and skin of the patient are potential sites of caustic injury. Caustics produce severe pain on contact with any of these tissues. By far, the majority of long-term morbidity and mortality from caustic exposure results from ingestion.

In general, despite variation in the mechanism of injury, patients who have ingested either alkalis or acids present and are managed in a similar manner. Depending on the type, amount, and formulation (solid vs liquid) as well as the percentage of tissue exposed, ingestion has the potential to produce severe pain of the lips, mouth, throat, chest, or abdomen. Oropharyngeal edema and burns lead to drooling and rapid airway compromise. Symptoms and findings of esophageal involvement include dysphagia and odynophagia, whereas epigastric pain and hematemesis are typical of gastric involvement.

Respiratory tract damage occurs through direct inhalation or aspiration of vomitus, leading to the clinical manifestations of hoarseness, stridor, and respiratory distress. Injury results in epiglottitis, laryngeal edema and ulceration, pneumonitis, and impaired gas exchange. Tachypnea or hyperpnea results from either direct injury or as a compensatory response to a metabolic acidosis, which often is associated with elevated lactate concentrations from necrotic tissue or hemodynamic compromise.

Visual changes, eye pain, redness, burns, or ulceration of the eyes suggest ophthalmic exposure. Skin contact with caustics can result in pain, burns, and/or ulceration.

Predictors of Injury

The severity of injury following a caustic ingestion varies from mild with complete recovery to severe with associated morbidity and mortality. Many attempts have been made to define a method for clinical identification of patients with severe esophageal injuries based on signs and symptoms at presentation in an effort to avoid unnecessary procedures and admission for patients with less severe injury, while identifying patients at risk for severe complications. Various studies, mostly involving alkaline xenobiotics, examine the predictive value of stridor, oropharyngeal burns, drooling, vomiting, and abdominal pain.

One prospective study of 79 children evaluated for vomiting, drooling, and stridor found that a combination of 2 or more of these signs was predictive of significant esophageal injury as visualized on endoscopy.¹⁹ Another study found that drooling, buccal mucosal burns, and an elevated white blood cell count elevation were significant independent predictors of severe ­gastrointestinal tract injury following acid ingestions.³⁷ Two additional retrospective studies found that all children with clinically significant injury had symptoms on presentation, but that no single symptom or combination of symptoms could identify all patients with esophageal injury.^15,35 A ­prospective study of alkali ingestions in both adults and children found that stridor was 100% specific for significant esophageal injury, but this was based on only 3 patients with this finding.³³ However, other authors have found signs or symptoms at presentation to lack prognostic utility in caustic ingestions. A retrospective study of 378 children admitted for a caustic injury found that signs or symptoms could not be used to predict significant esophageal injury.²⁸ A prospective evaluation of 41 patients after caustic ingestion found that signs and symptoms were unreliable in predicting the extent and severity of injury.¹⁰³

Variation in findings between studies may be due to the population studied (pediatric vs adult), differences in the type of caustic ingested (acid vs alkali), and/or the circumstances associated with the ingestion (intentional vs unintentional). Additionally, studies evaluating the presence or absence of oropharyngeal burns as a predictor of distal esophagogastric injury repeatedly found this finding to be poorly predictive.^{1,19,28,33,76,90} In one study, esophageal injury was present 51.5% of the time in the absence of oropharyngeal lesions, and 22.2% of these were second- and third-degree burns.⁷⁶