FORMALIN

Classification | Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

Specific Substances

1) Aqueous formaldehyde
2) Formic aldehyde solution
3) Formalin 100%
4) Formalin 40%
5) Formol
6) Ph Eur. 5.5 (formaldehyde solution (35%) with methyl alcohol)
7) USP 29 (Formaldehyde Solution) (contains 36.5 or 37% formaldehyde with methyl alcohol)

1.2.1) MOLECULAR FORMULA
1) C-H2-O
2) HCHO

Available Forms Sources

1) Formalin is an aqueous solutions containing from 37% to 56% formaldehyde, by weight, with varying amounts of methanol as a stabilizer (usually 10% to 15%) to prevent polymerization(Bingham et al, 2001; NFPA, 2002).
2) Formalin is incompatible with the following: strong oxidizers, alkalis, acids, phenols, urea, oxides, isocyanates, caustics, and anhydrides (Pohanish, 2002).
3) Of note, the names formalin and formol have been used to describe formaldehyde solution(s), but in some countries they may be trademarks (Sweetman, 2007).

1) BACKGROUND

a) Formaldehyde is a gas at room temperature. It is a water-soluble, colorless, pungent, irritating and highly reactive gas (Baselt, 2004; Bingham et al, 2001; Pandey et al, 2000). Pure formaldehyde is not sold commercially due to its tendency to polymerize. It is most commonly available as formalin, a liquid that is created by mixing formaldehyde (usually 37 g of formaldehyde gas to 100 mL solution) and water. Because this solution will polymerize, 10% to 15% of methyl alcohol (methanol; stabilized) is added (HSDB, 2006; Bingham et al, 2001). Other aqueous solutions of formaldehyde are referred to as unstabilized (methanol-free) and the solutions may contain n-butanol, ethanol, or urea (HSDB, 2006).

1) The designations "Formalin 40" or "Formalin 100" signify solutions containing 40 g of formaldehyde per 100 mL solution (Budavari, 1996). Other listed names: Formaldehyde solution; Formaldehyde, solutions (Formalin)(Corrosive).

c) This document is primarily focused on formalin, an aqueous solution containing both formaldehyde and methanol; exposures are generally intentional or accidental ingestions. For occupational exposure, which is usually due to inhalation of the gas or direct contact with the liquid please refer to the FORMALDEHYDE management.

2) INDUSTRIAL/HOUSEHOLD

a) Formalin is used as a disinfectant agent in hospitals and households (Strubelt et al, 1990; Koppel et al, 1990).

3) MEDICAL/VETERINARY

a) Formalin is used as a bactericidal disinfectant which is effective against fungi and many viruses. It has been used in the disinfection of blankets and bedding in hospitals, and in the disinfection of dialysis equipment (Sweetman, 2007).
b) Formalin is used in medicine in the following areas: as a preservative (10% v/v in saline) of surgical specimens by pathology departments, for the treatment of uncontrolled intravesical hemorrhage, and radiation-induced hemorrhagic proctitis and cystitis, and to prevent hydatid cyst dissemination (Sweetman, 2007; Pandey et al, 2000).
c) Formalin, when applied to intact skin, hardens the epidermis, and can produce hardening and whitening of the skin along with a local anesthetic effect. 3% v/v solutions have been used in the treatment of warts on the hands and feet (Sweetman, 2007).

4) INTENTIONAL MISUSE

a) Formalin has been used to ensure the uniform distribution of phencyclidine (PCP) in adulterated marijuana cigarettes. Smoking the substance while still wet is believed to increase the length of time the drug can be smoked. This method has been referred to as "illy", "wet", "fry", "dip", "dank", "sherm" or "hydro" and described as marijuana soaked in "embalming fluid" (formalin) used to enhance the euphoric effects of marijuana and PCP (D'Onofrio et al, 2006; Nelson et al, 1999).

Overview

Life Support

Clinical Effects

0.2.1)

A) NOTE: This document is primarily focused on formalin, an aqueous solution containing both formaldehyde and methanol. For occupational exposure, which is usually due to inhalation of the gas or direct contact with the liquid please refer to the FORMALDEHYDE management.
B) SOURCES: Formalin is a liquid that is created by mixing formaldehyde and water (usually 37 g of formaldehyde gas to 100 mL solution). Because this solution will polymerize, 10% to 15% of methanol (stabilized) is added. Formalin is used as a bactericidal disinfectant for dialysis equipment and blankets and bedding in hospitals and as a preservative (10% v/v in saline) of surgical specimens by pathology departments. It is also used to treat uncontrolled intravesical hemorrhage and radiation-induced hemorrhagic proctitis and cystitis, and to prevent hydatid cyst dissemination. Formalin 3% v/v solution has been used in the treatment of warts on the hands and feet. INTENTIONAL MISUSE: Formalin has been used to ensure the uniform distribution of phencyclidine (PCP) in adulterated marijuana cigarettes. Smoking the substance while still wet is believed to increase the length of time the drug can be smoked. This method has been referred to as "illy," "wet," "fry," "dip," "dank," "sherm," or "hydro" and has been described as marijuana soaked in "embalming fluid" (formalin) to enhance the euphoric effects of marijuana and PCP.
C) TOXICOLOGY: Formaldehyde is metabolized to formic acid by aldehyde dehydrogenase with eventual conversion to carbon dioxide and water via a folate-dependent pathway. Methanol causes intoxication similar to ethanol and is metabolized to formaldehyde and formic acid via alcohol dehydrogenase and aldehyde dehydrogenase, respectively. Formic acid causes a metabolic acidosis and causes blindness through direct retinal toxicity.
D) EPIDEMIOLOGY: Uncommon poisoning which can result in significant morbidity and death.
E) WITH POISONING/EXPOSURE

1) TOXICITY: Formalin is a strong irritant. Expected clinical effects following oral exposure initially include gastrointestinal tract damage (eg, ulcers, perforation). Central nervous system effects can include unconsciousness, seizures, and coma. Metabolic acidosis may occur due to high serum concentrations of formic acid and lactic acid. Cardiovascular effects may include severe tachycardia. Circulatory collapse is also possible due to decreased cardiac output because of severe metabolic acidosis. Other effects can include liver and renal injury which can lead to jaundice, albuminuria, hematuria and anuria. Gastric stricture is a late complication of formalin ingestion. Hemolysis has been reported in patients exposed to formalin parenterally from hemodialysis equipment. Ingestion of formalin is relatively rare due to its pungent odor and strong irritant effects. However, ingestion of large amounts of formalin may lead to systemic methanol poisoning. Refer to the METHANOL management for further information. Chronic exposures may increase the risk of cancer and occupational asthma.

0.2.3)

A) Shock may develop with severe exposures. Tachypnea may develop in patients with metabolic acidosis. Hypothermia may be seen.

Laboratory Monitoring

Treatment Overview

0.4.2)

A) MANAGEMENT OF MILD TO MODERATE TOXICITY

1) Removal from inhalational exposure is the primary treatment. Supportive care with oxygen or bronchodilators can be administered. Patients with oral ingestions should be observed for evidence of upper airway, esophageal, or gastric burns and for evidence of metabolic acidosis. Those findings suggest a more severe poisoning.

B) MANAGEMENT OF SEVERE TOXICITY

1) Patients with evidence of caustic injury should be treated in the same manner as any other caustic exposure. Patients with evidence of upper airway edema should be intubated early. Patients with deliberate or large ingestions and those with symptoms suggestive of esophageal or gastric burns (eg, stridor, vomiting, drooling, odynophagia) will need endoscopy to examine the extent of the burns after the patient has been stabilized, ideally within 12 hours of exposure. Perforation is possible, so patients with clinical signs of perforation or deep gastric burns on endoscopy will need surgical exploration.
2) Patients with severe or worsening metabolic acidosis should have immediate hemodialysis and also receive intravenous sodium bicarbonate. Sodium bicarbonate can be bolused at 1 to 2 mEq/kg and repeated as needed with close monitoring of arterial blood gases. Intravenous folic acid (50 mg IV every 4 hours) should also be administered as it may help eliminate the formic acid. Hypotension and cardiovascular collapse should be treated with standard ACLS protocols. Intravenous fluid support and vasopressors should be administered as needed. Formalin contains methanol (usually 10% to 15%). Institute fomepizole or ethanol therapy (methanol greater than 25 mg/dL or acidosis) as necessary. Refer to METHANOL management for more information on treatment of methanol toxicity.
3) Treatment for severe inhalational exposures is primarily supportive. Supplemental oxygen should be administered as needed. Mechanical ventilation may be needed. Administer bronchodilators for bronchospasm.

C) DECONTAMINATION

1) PREHOSPITAL: Remove from exposure and remove contaminated clothing. Contaminated skin and eyes should be irrigated with water. Activated charcoal should be avoided.
2) HOSPITAL: If a patient presents quickly after a large oral ingestion, consider placing a nasogastric tube for gastric aspiration of the liquid. Activated charcoal should not be used since the patient may need endoscopy.

D) AIRWAY MANAGEMENT

1) Patients who are comatose, have altered mental status, or have direct pulmonary or upper airway injury may need mechanical respiratory support and orotracheal intubation.

E) ANTIDOTE

1) None.

F) ENHANCED ELIMINATION

1) Hemodialysis will efficiently remove formaldehyde, formic acid, and methanol, and should be used in cases of severe or worsening acidosis. Folate can also be administered to augment elimination of formic acid at a dose of 50 mg IV every 4 hours (CHILDREN: 1 mg/kg).

G) PATIENT DISPOSITION

1) HOME CRITERIA: Any patient ingesting formalin should be sent to a healthcare facility. Patients with significant eye irritation, or more than mild pulmonary or skin irritation should also be sent to a healthcare facility for evaluation. Patients with mild eye, skin, or respiratory irritation can be managed at home with decontamination.
2) OBSERVATION CRITERIA: After oral ingestions, patients should be observed for 6 hours for evidence of esophageal or gastric injury. Patients asymptomatic after that time can be discharged.
3) ADMISSION CRITERIA: Patients with evidence of esophageal or gastric injury, pulmonary injury, or severe metabolic acidosis should be admitted to a monitored setting.
4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing severe poisonings and for recommendations on determining the need for hemodialysis. Consult a gastroenterologist for endoscopy in patients with deliberate or large ingestions, and those with symptoms (eg, stridor, vomiting, drooling, odynophagia).

H) PITFALLS

1) Independent treatment for methanol may be needed for formalin ingestions. Lack of oromucosal burns does not rule out esophageal or gastric burns.

I) PHARMACOKINETICS/TOXICOKINETICS

1) Formaldehyde is rapidly absorbed in the oral and inhalational routes and rapidly metabolized (half life, 1.5 minutes) to formic acid. Dermal absorption is minimal. Methanol is rapidly absorbed after ingestion and can be absorbed with inhalation of high concentrations. The apparent half-life of methanol is approximately 8 to 28 hours. The volume of distribution is approximately 0.6 L/kg. It is not protein bound.

J) DIFFERENTIAL DIAGNOSIS

1) The differential diagnosis includes conditions that present as respiratory irritants from an inhalation exposure such as ammonia or chlorine. The differential diagnosis from an oral exposure is primarily other ingestions causing caustic injuries such as acid or alkalis.

0.4.3)

A) INHALATION: Move patient to fresh air. Monitor for respiratory distress. If cough or difficulty breathing develops, evaluate for respiratory tract irritation, bronchitis, or pneumonitis. Administer oxygen and assist ventilation as required. Treat bronchospasm with an inhaled beta2-adrenergic agonist. Consider systemic corticosteroids in patients with significant bronchospasm.

0.4.4)

A) PREHOSPITAL CARE: Irrigation with sterile water or saline, a commercial eye irrigation kit, or tap water should be started prior to admission.
B) CAUSTIC EYE DECONTAMINATION: Immediately irrigate each affected eye with copious amounts of water or sterile 0.9% saline for about 30 minutes. Irrigating volumes up to 20 L or more have been used to neutralize the pH. After this initial period of irrigation, the corneal pH may be checked with litmus paper and a brief external eye exam performed. Continue direct copious irrigation with sterile 0.9% saline until the conjunctival fornices are free of particulate matter and returned to pH neutrality (pH 7.4). Once irrigation is complete, a full eye exam should be performed with careful attention to the possibility of perforation.

0.4.5)

A) OVERVIEW

1) DECONTAMINATION: Remove contaminated clothing and jewelry and place them in plastic bags. Wash exposed areas with soap and water for 10 to 15 minutes with gentle sponging to avoid skin breakdown. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Range Of Toxicity

Clinical Effects

Summary Of Exposure

Vital Signs

3.3.1)

A) Shock may develop with severe exposures. Tachypnea may develop in patients with metabolic acidosis. Hypothermia may be seen.

3.3.2)

A) TACHYPNEA secondary to metabolic acidosis following ingestion is common (Allen et al, 1970; Kline, 1925) .

3.3.3)

A) HYPOTHERMIA may be seen (HSDB , 1999; EPA, 1985).

3.3.4)

A) HYPOTENSION and cardiovascular collapse may occur following large exposure (Kline, 1925).

Cardiovascular

3.5.2)

A) TACHYCARDIA

1) WITH THERAPEUTIC USE

a) Tachycardia and profound hypotension have been reported in several cases of formalin exposure following the use of formalin solutions or packs soaked with pure formalin to assist in the removal of hepatic hydatid cysts (Strubelt et al, 1990).

2) WITH POISONING/EXPOSURE

a) Severe tachycardia has been reported following the ingestion of formalin (Pandey et al, 2000; Koppel et al, 1990).
b) CASE REPORT: A 28-year-old man intentionally ingested 150 mL of 40% formalin solution, and he developed tachycardia (150 beats/min) and hypotension (90/50 mmHg) after admission (Yanagawa et al, 2007).

B) SHOCK

1) WITH THERAPEUTIC USE

a) Therapeutic administration of formalin solution or packs soaked with formalin have produced severe hypotension (Strubelt et al, 1990).

2) WITH POISONING/EXPOSURE

a) Profound hypotension and circulatory collapse have occurred following the ingestion of formalin (Yanagawa et al, 2007; Pandey et al, 2000; Koppel et al, 1990). Hypotension may develop within a few hours of ingestion (Yanagawa et al, 2007).
b) In a review of 25 hospitalizations due to formalin ingestion that have occurred since 1950, 7 out of the 8 deaths reported were due to circulatory collapse and 1 was related to respiratory insufficiency (Yanagawa et al, 2007).
c) PATHOLOGY: Circulatory collapse is thought to develop following the absorption of formalin and the production of formic acid, which leads to severe metabolic acidosis and acute renal failure (Pain et al, 1988). It remains unclear whether shock is due to severe local irritation or systemic toxicity (Koppel et al, 1990).

C) PULMONARY THROMBOEMBOLISM

1) WITH THERAPEUTIC USE

a) Pulmonary embolism and fatal cardiovascular derangements have been reported after intravesical instillation of formalin. Effects included sinus tachycardia, hypotension, increased central venous pressure, hypoxia, and acidosis (Oshima et al, 1990; Lourie et al, 1977).
b) CASE REPORT: Pulmonary embolism occurred after intravesical instillation of formalin during a radical cystectomy in a 59-year-old man with bladder cancer. Severe hypotension (40/30 to 60/40 mmHg) occurred within 3 minutes of starting the instillation and was unresponsive to vasopressors and volume replacement (IV fluids and whole blood). However, the patient's blood pressure spontaneously improved about 35 minutes later and the operation was completed without incident. Heparin therapy was started and ventilatory support was continued; the patient was successfully weaned within 6 hours and made an uneventful recovery. Pulmonary embolism was confirmed by angiography. The authors suggested that formalin may have caused intravascular thrombi, which could result in pulmonary embolism (Oshima et al, 1990).

3.5.3)

A) ANIMAL STUDIES

1) A small controlled study of artificially ventilated rats showed significant decreases in blood pressure, heart rate, peripheral resistance, and cardiac output following infusion of formalin 0.01 mL (formaldehyde at 0.12 mmol/kg/min). It was determined that the cardiotoxic effects of formalin were due to formaldehyde; methanol did not appear to effect cardiovascular changes in this setting. Administration of cysteine was only able to delay death and attenuate the cardiovascular-depressive effects. Its clinical utility appeared limited (Strubelt et al, 1990).

Respiratory

3.6.2)

A) HYPERVENTILATION

1) WITH POISONING/EXPOSURE

a) Tachypnea secondary to metabolic acidosis following ingestion is common (Allen et al, 1970; Kline, 1925).

B) PLEURAL EFFUSION

1) WITH POISONING/EXPOSURE

a) Pleural effusions have been observed in patients following the ingestion of formalin (Yanagawa et al, 2007; Koppel et al, 1990).
b) CASE REPORT: Extensive pleural effusions requiring bilateral chest tube drainage developed in a 28-year-old man after ingesting 150 mL of 40% formalin. Symptoms developed approximately 48 hours after exposure. The patient had a prolonged hospital course that included the development of adult respiratory distress syndrome, bilateral pneumonia, and sepsis. Mechanical ventilation was stopped on day 43, with discharge to home on day 73 (Yanagawa et al, 2007).

C) ADULT RESPIRATORY DISTRESS SYNDROME

1) WITH POISONING/EXPOSURE

a) Respiratory insufficiency progressing to adult respiratory distress syndrome (ARDS) has been reported following intentional ingestion of formalin (Yanagawa et al, 2007; Koppel et al, 1990). Deaths have been reported, despite aggressive care. One patient developed persistent pneumonia with fever and recurrent pneumothoraces following ingestion. Intensive care efforts included high-frequency jet ventilation of both lungs, but respiratory function continued to deteriorate and ARDS developed. Eight weeks after exposure the patient died of cardiac failure (Koppel et al, 1990).
b) CASE REPORT: ARDS developed within 24 hours in a 28-year-old man after he ingested 150 mL of formalin. Following a prolonged hospital course that included bacterial pneumonia, sepsis, and enteritis induced by methicillin-resistant Staphylococcus aureus, the patient was weaned from mechanical ventilation on hospital day 43 and discharged to home on day 73 (Yanagawa et al, 2007).

Neurologic

3.7.2)

A) SEIZURE

1) WITH POISONING/EXPOSURE

a) Seizures may occur following formalin ingestion (Pandey et al, 2000; Burkhart et al, 1990). Seizure has also been reported following long-term occupational exposure to formalin vapors (Kilburn, 1994).

1) CASE REPORT: A 58-year-old man ingested 120 mL of a formalin solution and developed severe metabolic acidosis and grand mal seizures approximately 5.5 hours postingestion; seizures were unresponsive to diazepam or phenytoin. The patient died of a cardiac arrest approximately 12 hours after exposure, despite resuscitation efforts (Burkhart et al, 1990).

B) CENTRAL NERVOUS SYSTEM DEFICIT

1) WITH POISONING/EXPOSURE

a) Dizziness, lethargy, ataxia, and coma may occur following ingestion (Allen et al, 1970; Kline, 1925) .

Gastrointestinal

3.8.2)

A) VOMITING

1) WITH POISONING/EXPOSURE

a) Formalin is a strong irritant; immediate vomiting may occur following ingestion (Yanagawa et al, 2007).

B) GASTRITIS

1) WITH POISONING/EXPOSURE

a) Ingestion of formaldehyde and methanol was associated with a burning sensation in the chest followed by immediate abdominal pain, cramps, vomiting, and diarrhea (Sidhu & Sidhu, 1999).
b) Corrosive gastritis has been reported (Hawley & Harsch, 1999; Roy et al, 1962; Vinson & Harrington, 1929).
c) Hemorrhagic gastritis and hematemesis may occur following ingestion of concentrated solutions (Bartone et al, 1968; Kline, 1925) .

C) GASTROINTESTINAL HEMORRHAGE

1) WITH POISONING/EXPOSURE

a) Gastrointestinal hemorrhage has been reported following the ingestion of formalin. Mild hemorrhage and gastric ulcers are common following ingestion of formalin because formalin fixes the tissue, resulting in hemostasis (Yanagawa et al, 2007; Koppel et al, 1990).

D) PERFORATION OF STOMACH

1) WITH POISONING/EXPOSURE

a) Gastric erosion and perforation have been observed following ingestion (Yanagawa et al, 2007). Penetrating mucosal necrosis has also been reported following ingestion (Koppel et al, 1990).
b) Perforation of the stomach has been reported as a delayed complication of formaldehyde ingestion that resulted in severe gastric burns and necrosis (Allen et al, 1970).

E) PYLORIC STENOSIS

1) WITH POISONING/EXPOSURE

a) Gastric outlet obstruction secondary to prepyloric scarring has been reported as a delayed complication of formaldehyde ingestion (Hawley & Harsch, 1999).

F) INJURY OF GASTROINTESTINAL TRACT

1) WITH POISONING/EXPOSURE

a) Oral exposure can result in necrosis and ulceration of the lining of the stomach and intestines (Pandey et al, 2000; Morgan, 1989).
b) CASE REPORT: A 28-year-old man intentionally ingested 150 mL of a 40% formalin solution and developed immediate vomiting with erosion of the oropharyngeal mucosa. On hospital day 4, an upper gastrointestinal endoscopy showed esophageal erosion and diffuse gastric ulcers. Severe abdominal pain developed on day 6, and an emergency laparotomy was performed due to the development of ascites with hemorrhage; a thickened gastric wall and multiple hemorrhages were noted with no evidence of perforation. The patient was discharged on hospital day 73 following a protracted hospital course which included sepsis and pneumonia. A follow-up gastroscopy on day 132 showed regenerated mucosa with scattered linear scars (Yanagawa et al, 2007).
c) CASE SERIES: In a review of hospitalized cases of formalin ingestion, gastrointestinal complications included gastritis, hemorrhage, cicatricial gastric stenosis, perforation, and hard and leathery changes of the gastric wall. Of the 25 cases reported, 8 patients died, with 7 deaths related to circulatory collapse (Yanagawa et al, 2007).
d) CASE REPORT: In another fatality, the stomach appeared hard, white, and leathery, while the esophagus and small intestine had no notable signs of injury at the time of autopsy (Burkhart et al, 1990).
e) Dysphagia may occur several weeks after exposure and is usually related to esophageal stricture. Fibrosis may develop and may continue for up to 3 months after exposure. On average, strictures appear 2 to 4 weeks after formaldehyde ingestion (Pandey et al, 2000).

G) COLITIS

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Unintentional instillation of 10% formalin into the colon resulted in acute colitis. The patient recovered without stricture formation (Munoz-Navas & Garcia-Villareal, 1992).

Hepatic

3.9.2)

A) LIVER DAMAGE

1) WITH POISONING/EXPOSURE

a) Hepatotoxicity has been reported following ingestion of formalin (Pandey et al, 2000).

B) HYPERBILIRUBINEMIA

1) WITH POISONING/EXPOSURE

a) Hyperbilirubinemia is a relatively late finding that has been reported following a suicidal ingestion of formalin. Autopsy findings in one patient showed hepatosplenomegaly with icterus and moderate congestion of the liver parenchyma (Koppel et al, 1990).

C) FIBROSIS OF BILE DUCT

1) WITH THERAPEUTIC USE

a) Biliary sclerosis developed following the instillation of formalin solution in 4 patients with hepatic hydatid cysts. Jaundice developed in 3, with 1 patient developing obstructive jaundice 3 years after exposure. Two patients developed biliary fistulas. One patient remained jaundice with sclerosing cholangitis, which lead to progressive biliary cirrhosis; the patient died 1 year after exposure (Pain et al, 1988).

Genitourinary

3.10.2)

A) ACUTE RENAL FAILURE SYNDROME

1) WITH POISONING/EXPOSURE

a) Acute oliguric renal failure has occurred following intentional formalin ingestion requiring dialysis and hemofiltration (Pandey et al, 2000; Koppel et al, 1990). Although renal function deteriorated quickly following exposure, the authors were unable to conclude whether it renal failure was the result of direct nephrotoxicity or secondary to severe shock (Koppel et al, 1990).

Acid-Base

3.11.2)

A) ACIDOSIS

1) WITH POISONING/EXPOSURE

a) ANION GAP METABOLIC ACIDOSIS rapidly ensues following formalin ingestion, due to metabolism of formaldehyde and methanol to formic acid. Methanol present in formalin solutions contributes to the metabolic acidosis from formic acid (Yanagawa et al, 2007; Pandey et al, 2000; Burkhart et al, 1990; Koppel et al, 1990; Strubelt et al, 1990; Pain et al, 1988; Eells et al, 1981).

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Monitor vital signs, mental status, comprehensive metabolic panel, CBC, and arterial or venous blood gas in symptomatic patients.
B) Obtain a baseline ECG; continuous cardiac monitoring is indicated in patients following a significant exposure.
C) Monitor renal function and hepatic enzyme following a significant exposure.
D) Monitor blood METHANOL concentration after a significant formalin ingestion.
E) Formic acid concentrations can be measured by specialist laboratories, but are not generally useful to guide therapy due to delays in obtaining results.
F) Endoscopy should be performed to evaluate gastrointestinal injuries after formalin ingestion.

4.1.2)

A) ACID/BASE

1) Monitor acid-base status in symptomatic patients.

B) BLOOD/SERUM CHEMISTRY

1) Monitor CBC following a significant ingestion; gastrointestinal hemorrhage may occur.
2) Liver enzyme concentrations, renal function, and serum electrolytes should be monitored.

C) METHANOL

1) Monitor blood METHANOL concentration after a significant formalin exposure.

4.1.4)

A) OTHER

1) CARDIAC MONITORING

a) Obtain a baseline ECG as necessary; continuous cardiac monitoring is indicated in patients following a significant exposure.

2) ENDOSCOPY

a) Upper gastrointestinal endoscopy should be performed to evaluate for burns after formalin ingestion.

3) FORMALDEHYDE CONCENTRATIONS

a) In general, studies indicated that high plasma concentrations of formaldehyde are transient in humans, a trace baseline concentration frequently or almost always exists (an average of 2.61 mcg formaldehyde per gram of venous blood was reported in humans). In another study, exposure to 1.9 ppm of formaldehyde for a period of 40 minutes did not produce a significantly elevated blood concentration. The variability in blood formaldehyde concentration in human volunteers suggests that the use of blood samples for measuring formaldehyde exposure is not useful (Pandey et al, 2000).

Treatment

Life Support

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) Patients with evidence of esophageal or gastric injury, pulmonary injury, or severe metabolic acidosis should be admitted to a monitored setting.

6.3.1.2) HOME CRITERIA/ORAL

A) Any patient ingesting formalin should be sent to a healthcare facility. Patients with significant eye irritation, or more than mild pulmonary or skin irritation should also be sent to a healthcare facility for evaluation. Patients with mild eye, skin, or respiratory irritation can be managed at home with decontamination.

6.3.1.3) CONSULT CRITERIA/ORAL

A) Consult a poison center or medical toxicologist for assistance in managing severe poisonings and for recommendations on determining the need for hemodialysis. Consult a gastroenterologist for endoscopy in patients with deliberate or large ingestions, and those with symptoms (eg, stridor, vomiting, drooling, odynophagia).

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) After oral ingestions, patients should be observed for 6 hours for evidence of esophageal or gastric injury. Patients asymptomatic after that time can be discharged.

Monitoring

Oral Exposure

6.5.1)

A) PREHOSPITAL: Remove from exposure and remove contaminated clothing. Contaminated skin and eyes should be irrigated with water. Activated charcoal should be avoided.

6.5.2)

A) SUMMARY: If a patient presents quickly after a large oral ingestion, consider placing a nasogastric tube for gastric aspiration of the liquid. Activated charcoal should not be used since the patient may need endoscopy.
B) NASOGASTRIC SUCTION

1) INDICATIONS: Consider insertion of a small, flexible nasogastric tube to aspirate gastric contents after large, recent ingestion of caustics. The risk of worsening mucosal injury (including perforation) must be weighed against the potential benefit.
2) PRECAUTIONS:

a) SEIZURE CONTROL: Is mandatory prior to gastric emptying.
b) AIRWAY PROTECTION: Alert patients - place in Trendelenburg and left lateral decubitus position, with suction available. Obtunded or unconscious patients - cuffed endotracheal intubation. COMPLICATIONS:

1) Complications of gastric aspiration may include: aspiration pneumonia, hypoxia, hypercapnia, mechanical injury to the throat, esophagus, or stomach (Vale, 1997). Combative patients may be at greater risk for complications.

C) ACTIVATED CHARCOAL

1) Activated charcoal should not be administered following caustic ingestions. Activated charcoal will not reduce caustic injury, and it will obscure endoscopy findings.

6.5.3)

A) MONITORING OF PATIENT

1) Monitor vital signs, mental status, comprehensive metabolic panel, CBC, and arterial or venous blood gas in symptomatic patients.
2) Obtain a baseline ECG; continuous cardiac monitoring is indicated in patients following a significant exposure.
3) Monitor renal function and hepatic enzyme following a significant exposure.
4) Monitor blood METHANOL concentration after a significant formalin ingestion.
5) Formic acid concentrations can be obtained but will probably not be obtainable in a clinically useful time frame.
6) Endoscopy should be performed to evaluate gastrointestinal injuries after formalin ingestion.

B) HYPOTENSIVE EPISODE

1) SUMMARY

a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.

2) DOPAMINE

a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).

3) NOREPINEPHRINE

a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
b) DOSE

1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).

C) ACIDOSIS

1) METABOLIC ACIDOSIS: Treat severe metabolic acidosis (pH less than 7.1) with sodium bicarbonate, 1 to 2 mEq/kg is a reasonable starting dose(Kraut & Madias, 2010). Monitor serum electrolytes and arterial or venous blood gases to guide further therapy.
2) Monitor methanol concentrations. Fomepizole and emergent dialysis is recommended for patients with significant metabolic acidosis or elevated methanol concentrations.

D) ENDOSCOPIC PROCEDURE

1) RECOMMENDATION: Consider upper gastrointestinal endoscopy or laryngoscopy to evaluate for esophageal, gastric, or laryngeal/tracheal injury, respectively if any of the following conditions exist:

a) History of deliberate ingestion. Gastrointestinal (dysphagia, abdominal pain, vomiting, oral mucosal injury) or laryngeal (cough, stridor) symptoms are present. Formalin (37% formaldehyde and 10% to 15% methanol) can produce gastric and esophageal lesions.

2) There is little information regarding the use of corticosteroids or surgery in the setting of formalin ingestion. The following information is derived from experience with other corrosives.

a) SUMMARY: Obtain consultation concerning endoscopy as soon as possible and perform endoscopy within the first 24 hours when indicated.
b) INDICATIONS: Most studies associating the presence or absence of gastrointestinal burns with signs and symptoms after caustic ingestion have involved primarily alkaline ingestions. Because acid ingestion may cause severe gastric injury with fewer associated initial signs and symptoms, endoscopic evaluation is recommended in any patient with a definite history of ingestion of a strong acid, even if asymptomatic.
c) RISKS: Numerous large case series attest to the relative safety and utility of early endoscopy in the management of caustic ingestion.

1) REFERENCES: Gaudreault et al, 1983; Symbas et al, 1983; Crain et al, 1984; (Schild, 1985; Moazam et al, 1987; Sugawa & Lucas, 1989; Previtera et al, 1990; Zargar et al, 1991; Vergauwen et al, 1991; Gorman et al, 1992; Nuutinen et al, 1994)

d) The risk of perforation during endoscopy is minimized by (Zargar et al, 1991):

1) Advancing across the cricopharynx under direct vision
2) Gently advancing with minimal air insufflation
3) Never retroverting or retroflexing the endoscope
4) Using a pediatric flexible endoscope
5) Using extreme caution in advancing beyond burn lesion areas
6) Most authors recommend endoscopy within the first 24 hours of injury, not advancing the endoscope beyond areas of severe esophageal burns, and avoiding endoscopy during the subacute phase of healing when tissue slough increases the risk of perforation (5 to 15 days after ingestion) (Zargar et al, 1991).

e) GRADING

1) Several scales for grading caustic injury exist. The likelihood of complications such as strictures, obstruction, bleeding and perforation is related to the severity of the initial burn (Zargar et al, 1991):
2) Grade 0 - Normal examination
3) Grade 1 - Edema and hyperemia of the mucosa; strictures unlikely.
4) Grade 2A - Friability, hemorrhages, erosions, blisters, whitish membranes, exudates and superficial ulcerations; strictures unlikely.
5) Grade 2B - Grade 2A plus deep discreet or circumferential ulceration; strictures may develop.
6) Grade 3A - Multiple ulcerations and small scattered areas of necrosis; strictures are common, complications such as perforation, fistula formation, or gastrointestinal bleeding may occur.
7) Grade 3B - Extensive necrosis through visceral wall; strictures are common, complications such as perforation, fistula formation, or gastrointestinal bleeding are more likely than with 3A.

f) FOLLOW UP - If burns are found, follow 10 to 20 days later with barium swallow or esophagram.

E) CORTICOSTEROID

1) CORROSIVE INGESTION/SUMMARY: The use of corticosteroids for the treatment of caustic ingestion is controversial. Most animal studies have involved alkali-induced injury (Haller & Bachman, 1964; Saedi et al, 1973). Most human studies have been retrospective and generally involve more alkali than acid-induced injury and small numbers of patients with documented second or third degree mucosal injury.
2) FIRST DEGREE BURNS: These burns generally heal well and rarely result in stricture formation (Zargar et al, 1989; Howell et al, 1992). Corticosteroids are generally not beneficial in these patients (Howell et al, 1992).
3) SECOND DEGREE BURNS: Some authors recommend corticosteroid treatment to prevent stricture formation in patients with a second degree, deep-partial thickness burn (Howell et al, 1992). However, no well controlled human study has documented efficacy. Corticosteroids are generally not beneficial in patients with a second degree, superficial-partial thickness burn (Caravati, 2004; Howell et al, 1992).
4) THIRD DEGREE BURNS: Some authors have recommended steroids in this group as well (Howell et al, 1992). A high percentage of patients with third degree burns go on to develop strictures with or without corticosteroid therapy and the risk of infection and perforation may be increased by corticosteroid use. Most authors feel that the risk outweighs any potential benefit and routine use is not recommended (Boukthir et al, 2004; Oakes et al, 1982; Pelclova & Navratil, 2005).
5) CONTRAINDICATIONS: Include active gastrointestinal bleeding and evidence of gastric or esophageal perforation. Corticosteroids are thought to be ineffective if initiated more than 48 hours after a burn (Howell, 1987).
6) DOSE: Administer daily oral doses of 0.1 milligram/kilogram of dexamethasone or 1 to 2 milligrams/kilogram of prednisone. Continue therapy for a total of 3 weeks and then taper (Haller et al, 1971; Marshall, 1979). An alternative regimen in children is intravenous prednisolone 2 milligrams/kilogram/day followed by 2.5 milligrams/kilogram/day of oral prednisone for a total of 3 weeks then tapered (Anderson et al, 1990).
7) ANTIBIOTICS: Animal studies suggest that the addition of antibiotics can prevent the infectious complications associated with corticosteroid use in the setting of caustic burns. Antibiotics are recommended if corticosteroids are used or if perforation or infection is suspected. Agents that cover anaerobes and oral flora such as penicillin, ampicillin, or clindamycin are appropriate (Rosenberg et al, 1953).
8) STUDIES

a) ANIMAL

1) Some animal studies have suggested that corticosteroid therapy may reduce the incidence of stricture formation after severe alkaline corrosive injury (Haller & Bachman, 1964; Saedi et al, 1973a).
2) Animals treated with steroids and antibiotics appear to do better than animals treated with steroids alone (Haller & Bachman, 1964).
3) Other studies have shown no evidence of reduced stricture formation in steroid treated animals (Reyes et al, 1974). An increased rate of esophageal perforation related to steroid treatment has been found in animal studies (Knox et al, 1967).

b) HUMAN

1) Most human studies have been retrospective and/or uncontrolled and generally involve small numbers of patients with documented second or third degree mucosal injury. No study has proven a reduced incidence of stricture formation from steroid use in human caustic ingestions (Haller et al, 1971; Hawkins et al, 1980; Yarington & Heatly, 1963; Adam & Brick, 1982).
2) META ANALYSIS

a) Howell et al (1992), analyzed reports concerning 361 patients with corrosive esophageal injury published in the English language literature since 1956 (10 retrospective and 3 prospective studies). No patients with first degree burns developed strictures. Of 228 patients with second or third degree burns treated with corticosteroids and antibiotics, 54 (24%) developed strictures. Of 25 patients with similar burn severity treated without steroids or antibiotics, 13 (52%) developed strictures (Howell et al, 1992).
b) Another meta-analysis of 10 studies found that in patients with second degree esophageal burns from caustics, the overall rate of stricture formation was 14.8% in patients who received corticosteroids compared with 36% in patients who did not receive corticosteroids (LoVecchio et al, 1996).
c) Another study combined results of 10 papers evaluating therapy for corrosive esophageal injury in humans published between January 1991 and June 2004. There were a total of 572 patients, all patients received corticosteroids in 6 studies, in 2 studies no patients received steroids, and in 2 studies, treatment with and without corticosteroids was compared. Of 109 patients with grade 2 esophageal burns who were treated with corticosteroids, 15 (13.8%) developed strictures, compared with 2 of 32 (6.3%) patients with second degree burns who did not receive steroids (Pelclova & Navratil, 2005).

3) Smaller studies have questioned the value of steroids (Ferguson et al, 1989; Anderson et al, 1990), thus they should be used with caution.
4) Ferguson et al (1989) retrospectively compared 10 patients who did not receive antibiotics or steroids with 31 patients who received both antibiotics and steroids in a study of caustic ingestion and found no difference in the incidence of esophageal stricture between the two groups (Ferguson et al, 1989).
5) A randomized, controlled, prospective clinical trial involving 60 children with lye or acid induced esophageal injury did not find an effect of corticosteroids on the incidence of stricture formation (Anderson et al, 1990).

a) These 60 children were among 131 patients who were managed and followed-up for ingestion of caustic material from 1971 through 1988; 88% of them were between 1 and 3 years old (Anderson et al, 1990).
b) All patients underwent rigid esophagoscopy after being randomized to receive either no steroids or a course consisting initially of intravenous prednisolone (2 milligrams/kilogram per day) followed by 2.5 milligrams/kilogram/day of oral prednisone for a total of 3 weeks prior to tapering and discontinuation (Anderson et al, 1990).
c) Six (19%), 15 (48%), and 10 (32%) of those in the treatment group had first, second and third degree esophageal burns, respectively. In contrast, 13 (45%), 5 (17%), and 11 (38%) of the control group had the same levels of injury (Anderson et al, 1990).
d) Ten (32%) of those receiving steroids and 11 (38%) of the control group developed strictures. Four (13%) of those receiving steroids and 7 (24%) of the control group required esophageal replacement. All but 1 of the 21 children who developed strictures had severe circumferential burns on initial esophagoscopy (Anderson et al, 1990).
e) Because of the small numbers of patients in this study, it lacked the power to reliably detect meaningful differences in outcome between the treatment groups (Anderson et al, 1990).

6) ADVERSE EFFECTS

a) The use of corticosteroids in the treatment of caustic ingestion in humans has been associated with gastric perforation (Cleveland et al, 1963) and fatal pulmonary embolism (Aceto et al, 1970).

F) SURGICAL PROCEDURE

1) In severe cases of gastrointestinal necrosis or perforation, emergent surgical consultation should be obtained. The need for gastric resection or laparotomy in the stable patient is controversial (Chodak & Passaro, 1978; Dilawari et al, 1984).
2) LAPAROTOMY/LAPAROSCOPY - Early laparotomy or laparoscopy should be considered in patients with endoscopic evidence of severe esophageal or gastric burns after acid ingestion to evaluate for the presence of transmural gastric or esophageal necrosis (Estrera et al, 1986; Meredith et al, 1988; Wu & Lai, 1993). Emergent laparotomy should be strongly considered in any patient with hypotension, altered mental status, or acidemia (Hovarth et al, 1991).

a) STUDY - In a retrospective study of patients with extensive transmural gastroesophageal necrosis after caustic ingestion, all 4 patients treated in the conventional manner (endoscopy, steroids, antibiotics, and repeated evaluation for the occurrence of esophagogastric necrosis and perforation) died, while all 3 patients treated with early laparotomy and immediate esophagogastric resection survived (Estrera et al, 1986).
b) Wu & Lai (1993) reported the results of emergency surgical resection of the alimentary tract in 28 patients who had extensive corrosive injuries due to the ingestion of acids or other caustics. Operative mortality was most frequently associated with sepsis. Non-fatal bleeding, infections, biliary or bronchial fistulas were other noted complications. Morbidity and mortality were related to the severity of the damage and the extent of surgery required.

1) Immediate postoperative management included antibiotics, extensive respiratory care, tracheobronchial toilet, maintenance of fluid, electrolyte and acid-base balance, and jejunostomy feeding or total parenteral nutrition.

G) METHYL ALCOHOL CAUSING TOXIC EFFECT

1) Administer fomepizole or ethanol and perform dialysis in patients with significant methanol poisoning secondary to formalin ingestion. See METHANOL document for further details.

H) SEIZURE

1) SUMMARY

a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).

2) DIAZEPAM

a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .

3) NO INTRAVENOUS ACCESS

a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).

4) LORAZEPAM

a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).

5) PHENOBARBITAL

a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).

6) OTHER AGENTS

a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):

1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).

Eye Exposure

6.8.1)

A) Begin irrigation immediately with copious amounts of water or sterile 0.9% saline, which ever is more rapidly available. Lactated Ringer's solution may also be effective. Once irrigation has begun, instill a drop of local anesthetic (eg, 0.5% proparacaine) for comfort; switching from water to slightly warmed sterile saline may also improve patient comfort (Singh et al, 2013; Spector & Fernandez, 2008; Ernst et al, 1998; Grant & Schuman, 1993a). In one study, isotonic saline, lactated Ringer's solution, normal saline with bicarbonate, and balanced saline plus (BSS Plus) were compared and no difference in normalization of pH were found; however, BSS Plus was better tolerated and more comfortable (Fish & Davidson, 2010).

1) Continue irrigation for at least an hour or until the superior and inferior cul-de-sacs have returned to neutrality (check pH every 30 minutes), pH of 7.0 to 8.0, and remain so for 30 minutes after irrigation is discontinued (Spector & Fernandez, 2008; Brodovsky et al, 2000). After severe alkaline burns, the pH of the conjunctival sac may only return to a pH of 8 or 8.5 even after extensive irrigation (Grant & Schuman, 1993a). Irrigating volumes up to 20 L or more have been used to neutralize the pH (Singh et al, 2013; Fish & Davidson, 2010). Immediate and prolonged irrigation is associated with improved visual acuity, shorter hospital stay and fewer surgical interventions (Kuckelkorn et al, 1995; Saari et al, 1984).
2) Search the conjunctival sac for solid particles and remove them while continuing irrigation (Grant & Schuman, 1993a).
3) For significant alkaline or concentrated acid burns with evidence of eye injury irrigation should be continued for at least 2 to 3 hours, potentially as long as 24 to 48 hours if pH not normalized, in an attempt to normalize the pH of the anterior chamber (Smilkstein & Fraunfelder, 2002). Emergent ophthalmologic consultation is needed in these cases (Spector & Fernandez, 2008).

6.8.2)

A) BURN

1) After splash exposure to significant concentrations (25%) severe eye injury may develop in a delayed fashion (12 hours or more) despite a benign initial presentation (Grant & Schuman, 1993). Patients with exposure to significant concentrations of formaldehyde should be evaluated by an ophthalmologist. The following treatment information is derived from experience with other corrosives.
2) ASSESSMENT CAUSTIC EYE BURNS: It may take 48 to 72 hours after the burn to assess correctly the degree of ocular damage (Brodovsky et al, 2000a).
3) The 1965 Roper-Hall classification uses the size of the corneal epithelial defect, the degree of corneal opacification and extent of limbal ischemia to evaluate the extent of the chemical ocular injury (Brodovsky et al, 2000a; Singh et al, 2013):

a) GRADE 1 (prognosis good): Corneal epithelial damage; no limbal ischemia.
b) GRADE 2 (prognosis good): Cornea hazy; iris details visible, ischemia less than one-third of limbus.
c) GRADE 3 (prognosis guarded): Total loss of corneal epithelium; stromal haze obscures iris details; ischemia of one-third to one-half of limbus.
d) GRADE 4 (prognosis poor): Cornea opaque; iris and pupil obscured, ischemia affects more than one-half of limbus.

4) A newer classification (Dua) is based on clock hour limbal involvement as well as a percentage of bulbar conjunctival involvement (Singh et al, 2013):

a) GRADE 1 (prognosis very good): 0 clock hour of limbal involvement and 0% conjunctival involvement.
b) GRADE 2 (prognosis good): Less than 3 clock hour of limbal involvement and less than 30% conjunctival involvement.
c) GRADE 3 (prognosis good): Greater than 3 and up to 6 clock hour of limbal involvement and greater than 30% to 50% conjunctival involvement.
d) GRADE 4 (prognosis good to guarded): Greater than 6 and up to 9 clock hour of limbal involvement and greater than 50% to 75% conjunctival involvement.
e) GRADE 5 (prognosis guarded to poor): Greater than 9 and less than 12 clock hour of limbal involvement and greater than 75% and less than 100% conjunctival involvement.
f) GRADE 6 (very poor): Total limbus (12 clock hour) involved and 100% conjunctival involvement.

5) SUMMARY

a) If ocular damage is minor, artificial tears/lubricants, topical cycloplegics, and antibiotics may be all that are needed.

6) ARTIFICIAL TEARS

a) To promote re-epithelization, preservative-free artificial tears/lubricants (eg, hyaluronic acid hourly) may be used (Fish & Davidson, 2010; Tuft & Shortt, 2009).

7) TOPICAL CYCLOPLEGIC

a) Use to guard against development of posterior synechiae and ciliary spasm (Brodovsky et al, 2000b; Grant & Schuman, 1993a). Cyclopentolate 0.5% or 1% eye drops may be administered 4 times daily to control pain (Tuft & Shortt, 2009; Spector & Fernandez, 2008).

8) TOPICAL ANTIBIOTICS

9) PAIN CONTROL

a) If pain control is required, oral or parenteral NSAIDs or narcotics are preferred to topical ocular anesthetics, which may cause local corneal epithelial damage if used repeatedly (Spector & Fernandez, 2008; Grant & Schuman, 1993a). However, topical 0.5% proparacaine has been recommended (Spector & Fernandez, 2008).

10) SUMMARY

a) If the damage is minor, the above may be all that is needed. For grade 3 or 4 injuries, one or more of the following may be used, only with ophthalmologic consultation: acetazolamide, topical timolol, topical steroids, citrate, ascorbate, EDTA, cysteine, NAC, penicillamine, tetracycline, or soft contact lenses.

11) ARTIFICIAL TEARS

a) To promote re-epithelization, preservative-free artificial tears/lubricants (eg, hyaluronic acid hourly) may be used (Fish & Davidson, 2010; Tuft & Shortt, 2009).

12) PAIN CONTROL

13) CARBONIC ANHYDRASE INHIBITOR

a) Acetazolamide (250 mg orally 4 times daily) may be given to control increased intraocular pressure (Singh et al, 2013; Tuft & Shortt, 2009; Spector & Fernandez, 2008).

14) TOPICAL STEROIDS

a) DOSE: Dexamethasone 0.1% ointment 4 times daily to reduce inflammation. If persistent epithelial defect is present, discontinue dexamethasone by day 14 to reduce the risk of stromal melt (Tuft & Shortt, 2009). Other sources suggest that corticosteroids should be stopped if the epithelium has not covered surface defects by 5 to 7 days (Grant & Schuman, 1993b).
b) Topical prednisolone 0.5% has also been used. A further increase in corneoscleral melt may occur if topical steroids are used alone. In one study, topical prednisolone 0.5% was used in combination with topical ascorbate 10%; no increase in corneoscleral melt was observed when topical steroids were used until re-epithelization (Singh et al, 2013; Fish & Davidson, 2010).
c) In one retrospective study, fluorometholone 1% drops were administered every 2 hours initially, then decreased to four times daily when there was evidence of progressive corneal reepithelialization and lessened inflammation, and discontinued when corneal reepithelialization was complete (Brodovsky et al, 2000).

1) STUDY: The combination of intensive topical corticosteroids, topical citrate and ascorbate, and oral citrate and ascorbate was associated with improved best corrected visual acuity and a trend towards more rapid corneal reepithelialization in Grade 3 alkali burns in one retrospective study (Brodovsky et al, 2000).

15) ASCORBATE

a) Oral or topical ascorbate may be used to promote epithelial healing and reduce the risk of stromal necrosis (Fish & Davidson, 2010).
b) DOSE: Ascorbate 10% 4 times daily topically or 1 g orally (2 g/day) (Singh et al, 2013; Tuft & Shortt, 2009).
c) Ascorbate is needed for the formation of collagen and the concentration of ascorbate in the anterior chamber is decreased when the ciliary body is damaged by alkali burns (Tuft & Shortt, 2009; Grant & Schuman, 1993b). In one retrospective study, ascorbate drops (10%) were administered every 2 hours, then decreased to 4 times a day when there was evidence of progressive corneal reepithelialization and lessened inflammation, and discontinued when corneal reepithelialization was complete. These patients also received 500 mg of oral ascorbate 4 times daily, until discharge from the hospital (Brodovsky et al, 2000).

16) CITRATE

a) Topical citrate may be used to promote epithelial healing and reduce the risk of stromal necrosis (Fish & Davidson, 2010).
b) DOSE: Potassium citrate 10% 4 times daily topically (Tuft & Shortt, 2009).
c) Citrate chelates calcium, and thereby interferes with the harmful effects of neutrophil accumulation, such as release of proteolytic enzymes and superoxide free radicals, phagocytosis and ulceration (Grant & Schuman, 1993b). In one retrospective study, 10% citrate drops were administered every 2 hours, then decreased to 4 times a day when there was evidence of progressive corneal reepithelialization and lessened inflammation, and discontinued when corneal reepithelialization was complete. These patients also received a urinary alkalinizer containing 720 mg of citric acid anhydrous and 630 mg of sodium citrate anhydrous 3 times daily, until discharge from the hospital (Brodovsky et al, 2000).

17) COLLAGENASE INHIBITORS

a) Inhibitors of collagenase can inhibit collagenolytic activity, prevent stromal ulceration, and promote wound healing. Several effective agents, such as cysteine, n-acetylcysteine, sodium ethylenediamine tetra acetic acid (EDTA), calcium EDTA, penicillamine, and citrate, have been recommended (Singh et al, 2013; Tuft & Shortt, 2009; Perry et al, 1993; Seedor et al, 1987).
b) TETRACYCLINE: Has been found to have an anticollagenolytic effect. Systemic tetracycline 50 mg/kg/day reduced the incidence of alkali-induced corneal ulcerations in rabbits (Seedor et al, 1987).
c) DOXYCYCLINE: Decreased epithelial defects and collagenase activity in a rabbit model of alkali burns to the eye (Perry et al, 1993). DOSE: 100 mg twice daily (Tuft & Shortt, 2009).

18) ANTIBIOTICS

a) An antibiotic ophthalmic ointment or drops should be used for as long as epithelial defects persist (Brodovsky et al, 2000b; Grant & Schuman, 1993a). Topical erythromycin or tetracycline ointment may be used (Spector & Fernandez, 2008). In patients with severe burns, a topical fluoroquinolone antibiotic drop 4 times daily may also be used (Tuft & Shortt, 2009). A topical fourth generation fluoroquinolone has been recommended as an antimicrobial prophylaxis in patients with large epithelial defect (Fish & Davidson, 2010).

19) TOPICAL CYCLOPLEGIC

a) Cyclopentolate 0.5% or 1% eye drops may be administered 4 times daily to control pain (Tuft & Shortt, 2009; Spector & Fernandez, 2008).

20) SOFT CONTACT LENSES

a) A bandage contact lens (eg, silicone hydrogel) may make the patient more comfortable and protect the surface (Fish & Davidson, 2010; Tuft & Shortt, 2009). Hydrophilic high oxygen permeability lenses are preferred (Singh et al, 2013). Soft lenses with intermediate water content and inherent rigidity may facilitate reepithelialization. The use of 0.5 normal sodium chloride drops hourly and artificial tears or lubricant eyedrops instilled 4 times a day may help maintain adequate hydration and lens mobility.

21) SURGICAL THERAPY CAUSTIC EYE INJURY

a) Early insertion of methylmethacrylate ring or suturing saran wrap over palpebral and cul-de-sac conjunctiva may prevent fibrinosis adhesions and reduce fibrotic contracture of conjunctiva, but the advantage of such treatments is not clear.
b) Limbal stem cell transplantation has been used successfully in both the acute stage of injury and the chronically scarred healing phase in patients with persistent epithelial defects after chemical burns (Azuara-Blanco et al, 1999; Morgan & Murray, 1996; Ronk et al, 1994).
c) In some patients, amniotic membrane transplantation (AMT) has been successful in improving corneal healing and visual acuity in patients with persistent epithelial defects after chemical burns. It can restore the conjunctival surface and decrease limbal stromal inflammation (Fish & Davidson, 2010; Sridhar et al, 2000; Su & Lin, 2000; Meller et al, 2000; Azuara-Blanco et al, 1999).
d) Control glaucoma. Remove any cataracts formed (Fish & Davidson, 2010; Tuft & Shortt, 2009).
e) In patients with severe injury, tenonplasty can be performed to promote epithelialization and prevent melting (Tuft & Shortt, 2009).
f) A keratoprosthesis placement has also been indicated in severe cases (Fish & Davidson, 2010). Penetrating keratoplasty is usually delayed as long as possible as results appear to be better with a greater lag time between injury and keratoplasty (Grant & Schuman, 1993a).

B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Dermal Exposure

6.9.1)

A) DERMAL DECONTAMINATION

1) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Enhanced Elimination

1) Dialysis may be effective in removing methanol, formate, and formic acid which are all dialyzable substances, and should be considered in those patients with significant metabolic acidosis, elevated serum methanol concentrations, or in patients with acute renal failure (Pandey et al, 2000; Koppel et al, 1990).

Abstracts

Case Reports

1) CASE REPORT: After ingesting an unknown amount of formalin with suicidal intent, a 55-year-old woman and a 34-year-old man were admitted to the hospital with extensive gastrointestinal corrosive damage, circulatory shock, metabolic acidosis (in part due to high plasma concentrations of formic acid of 6.09 mmol/L (280 mcg/mL)), respiratory insufficiency, and impairment of renal function which rapidly progressed to acute renal failure.

a) Both patients underwent dialysis and hemofiltration treatment. A gastrectomy was performed in the male patient. The further clinical course in both patients was characterized by sepsis and protracted pulmonary complications. Both patients died after developing adult respiratory distress syndrome and global cardiac insufficiency; the female patient died 3 weeks after exposure and the male patient, at 8 weeks (Koppel et al, 1990).

2) CASE REPORT: A 26-year-old woman ingested 45 mL of a 37% (v/v) formaldehyde solution. Ninety-six hours after ingestion endoscopy revealed the esophageal mucosa to be edematous and ulcerated with patches of black slough along the entire length (Kochhar et al, 1986).

a) The stomach was hyperemic with superficial ulcerations of the distal body and antrum. Four weeks later the esophagus was completely healed, but cicatrization of the distal body and antrum of the stomach had developed.

Range Of Toxicity

Summary

Minimum Lethal Exposure

1) Ingestion of as little as 30 mL of 37% formalin has been reported to cause death in an adult (Olson, 1999; OSHA, 2002a).
2) Ingestion of 36 mg/kg of formaldehyde was lethal in humans. Ingestion of 30 to 60 mL of formalin may be lethal in an adult (HSDB - Hazardous Substances Data Bank, 2007) and up to 90 mL in one study (Pandey et al, 2000).

1) A 41-year-old woman died approximately 21 hours after ingesting 120 mL of formalin (37% formaldehyde solution containing 12.5% methanol) despite aggressive care (Eells et al, 1981).

Maximum Tolerated Exposure

1) A 28-year-old man intentionally ingested 150 mL of 40% formalin and had a prolonged hospital course which included: metabolic acidosis, adult respiratory distress syndrome, bilateral pleural effusions, corrosive gastric ulcers and hemorrhage without perforation, pneumonia, sepsis and toxic epidermal necrolysis. Mechanical ventilation was stopped on hospital day 43 with discharge to home on day 73. Follow-up gastroscopy approximately 4.5 months after exposure showed regeneration of the stomach mucosa and scattered linear scars (Yanagawa et al, 2007).
2) An adult female drank approximately 120 mL of 10% formaldehyde solution and developed severe abdominal pain and shock. She was treated successfully with only home care, but she required surgery for persistent episodes of epigastric distress, and nausea and vomiting; findings included diffuse ulceration, fibrosis and contracture of the stomach and almost complete obstruction. Gastrectomy was performed and the patient made a complete recovery (Baselt, 2000).

Serum Plasma Blood Concentrations

7.5.2)

A) TOXIC CONCENTRATION LEVELS

1) GENERAL

a) In general, studies indicated that high plasma concentrations of formaldehyde are transient in humans. A trace baseline concentration frequently or almost always exists (an average of 2.61 mcg formaldehyde per gram of venous blood was reported in humans). In another study, exposure to 1.9 ppm of formaldehyde for a period of 40 minutes did not produce a significantly elevated blood concentration. The variability in blood formaldehyde concentration in human volunteers suggests that the use of blood samples for measuring formaldehyde exposure is not useful (Pandey et al, 2000).

2) INGESTION

a) Ingestion of 120 mL of formalin in an adult female (37% formaldehyde, 12.5% methanol) resulted in an initial formaldehyde concentration of 4.8 mg/L, which dropped quickly to 1 to 2 mg/L over the next 15 hours; blood formic acid concentrations ranged between 250 to 500 mg/L. Death occurred 21 hours after ingestion (Eells et al, 1981; Baselt, 2004).
b) At 5.5 hours after ingestion of 120 mL of formalin, a 58-year-old man had a peak serum formaldehyde and formic acid concentrations of 10.5 and 1360 mg/L, respectively. It was also noted his methanol concentrations continued to rise until the time of his death (approximately 12 hours after ingestion). The authors suggested that the continued rise in methanol concentration was due to formaldehyde causing delayed absorption by "fixing" the stomach, which was noted to be hard and leathery at the time of autopsy (Burkhart et al, 1990).
c) A woman was found dead after ingesting an unknown amount of a formalin solution containing 35% formaldehyde and 11% methanol. At autopsy, a methanol blood concentration was 0.04% (400 mg/L) with only trace amounts of formaldehyde found; gastric contents contained a total of 900 mg methanol and 4500 mg of formaldehyde (Baselt, 2004).

Pharmacology Toxicology

Toxicologic Mechanism

1) Formaldehyde exposure can occur in various ways and in minimal concentrations it is non-toxic to humans. The pH of formalin is neutral; however the corrosive effects when ingested are similar to that caused by acid (necrosis) and alkali (severe inflammation) ingestions. Formaldehyde ingestions can lead to significant gastrointestinal injury, as well as systemic effects including liver and renal damage, acidosis and central nervous system depression. Severity is dependent on the dose (ie, concentration, exposure frequency and duration) (Pandey et al, 2000).

a) Once ingested formaldehyde quickly converts for formic acid which can rapidly necrose cells in the liver, kidneys, heart, and brain. Local gastrointestinal injury is due to the necrotic effects of formaldehyde on mucous membranes with the degree of injury being dependent on the duration of exposure. Methanol poisoning is also a factor in formalin exposure. The presence of methanol in the gastrointestinal tract can lead to pyloric spasm increasing the risk of extensive lesions. Methanol also leads to the accumulation of formic acid and lactic acids causing metabolic acidosis (Pandey et al, 2000).

Physicochemical

Physical Characteristics

Ph

Molecular Weight

Other

1) 0.8 ppm (CHRIS, 2001)
2) 0.83 ppm (reported range 0.05 to 1.0 ppm) (ACGIH, 1991)
3) OHM/TADS (2001) reports the following odor thresholds (OHM/TADS, 2001):

1) Lower: 0.8 ppm
2) Medium: 49.9 ppm
3) Upper: 102 ppm

4) Clayton & Clayton (1993) reports that most persons are able to detect formaldehyde at concentrations below 1 ppm; mild sensory irritation at 2 to 5 ppm; unpleasant at 5 to 10 ppm; and, intolerable at concentrations in excess of 25 ppm (Clayton & Clayton, 1993).
5) 20 ppm is quickly irritating to the eyes (Lewis, 2000).

1) 50 ppm (lower taste threshold) (OHM/TADS, 2001)

Animal Toxicology

References

General Bibliography

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FORMALIN

Classification | Detailed evidence-based information

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Specific Substances

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Life Support

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Summary Of Exposure

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Maximum Tolerated Exposure

Serum Plasma Blood Concentrations

Toxicologic Mechanism

Physical Characteristics

Ph

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Other

General Bibliography