Substances Included Synonyms

Therapeutic Toxic Class

A)

Specific Substances

1) Azacyclohexane
2) Cyclopentimine
3) Cypentil
4) Hexahydropyridine
5) Hexazone
6) Pentamethyleneimine
7) Pentamethylenimine
8) Piperidine
9) Pyridine, hexahydro-
10) NIOSH/RTECS TM 3500000
11) CAS 110-89-4

1.2.1) MOLECULAR FORMULA
1) C5-H11-N

Available Forms Sources

A)

1) Piperidine comes in both 95% and 98% pure. It is a clear, colorless liquid, and has a fish-like, or amine-like pungent odor (AAR, 1998; HSDB, 2000; Clayton & Clayton, 1994a; Lewis, 1996a).

B)

1) Piperidine is naturally occurring in fish and other food items, including black pepper, baked ham, coffee, and milk. Piperidine is also manufactured through the electrolytic reduction of pyridine and corresponding derivatives (Ashford, 1994a; HSDB, 2000; Clayton & Clayton, 1994a).

C)

1) Piperidine has commercial uses as a solvent, chemical intermediate, curing agent, catalyst and complexing agent. It is also used in agricultural and pharmaceuticals (analgesics, germicides, anesthetics) and as a wetting agent (Clayton & Clayton, 1994a; HSDB, 2000; Lewis, 1996a).

Overview

Life Support

A)

Clinical Effects

0.2.1)

A) USES: Piperidine is an alkaline corrosive agent used as a solvent, chemical intermediate, curing agent, catalyst and complexing agent. It is also used in agricultural and pharmaceuticals (analgesics, germicides, anesthetics) and as a wetting agent.
B) TOXICOLOGY: As an alkaline corrosive, piperidine may cause liquefaction necrosis. It can saponify the fats in the cell membrane, destroying the cell and allowing deep penetration into mucosal tissue. In gastrointestinal tissue an initial inflammatory phase may be followed by tissue necrosis (sometimes resulting in perforation), then granulation and finally stricture formation.
C) EPIDEMIOLOGY: Exposure is unusual; piperidine is generally available for industrial use only.
D) WITH POISONING/EXPOSURE

1) Limited data regarding specific human toxicity following piperidine exposure is available. The following effects could be expected to occur, based on exposure data of other alkaline corrosives.
2) MILD TO MODERATE ORAL TOXICITY: Patients with mild ingestions may only develop irritation or grade I (superficial hyperemia and edema) burns of the oropharynx, esophagus or stomach; acute or chronic complications are unlikely. Patients with moderate toxicity may develop grade II burns (superficial blisters, erosions and ulcerations) are at risk for subsequent stricture formation, particularly esophageal. Some patients (particularly young children) may develop upper airway edema.

a) Alkaline corrosive ingestion may produce burns to the oropharynx, upper airway, esophagus and occasionally stomach. Spontaneous vomiting may occur. The absence of visible oral burns does NOT reliably exclude the presence of esophageal burns. The presence of stridor, vomiting, drooling, and abdominal pain are associated with serious esophageal injury in most cases.
b) PREDICTIVE: The grade of mucosal injury at endoscopy is the strongest predictive factor for the occurrence of systemic and GI complications and mortality.

3) SEVERE ORAL TOXICITY: May develop deep burns and necrosis of the gastrointestinal mucosa. Complications often include perforation (esophageal, gastric, rarely duodenal), fistula formation (tracheoesophageal, aortoesophageal), and gastrointestinal bleeding. Hypotension, tachycardia, tachypnea and, rarely, fever may develop. Stricture formation (esophageal, less often oral or gastric) is likely to develop long term. Esophageal carcinoma is another long term complication. Upper airway edema is common and often life threatening. Severe toxicity is generally limited to deliberate ingestions in adults in the US, because alkaline products available in the home are generally of low concentration.
4) INHALATION EXPOSURE: Mild exposure may cause cough and bronchospasm. Severe inhalation may cause upper airway edema and burns, stridor, and rarely acute lung injury.
5) OCULAR EXPOSURE: Ocular exposure can produce severe conjunctival irritation and chemosis, corneal epithelial defects, limbal ischemia, permanent visual loss and in severe cases perforation.
6) DERMAL EXPOSURE: Mild exposure causes irritation and partial thickness burns. Prolonged exposure or high concentration products can cause full thickness burns.

0.2.3)

A) Tachypnea, tachycardia, and elevated blood pressure occurred in animal studies.

0.2.4)

A) WITH POISONING/EXPOSURE

1) Piperidine spilled into the eyes may cause moderate to severe damage. Permanent corneal damage and paralysis of the eye muscles have been seen in experimental animals.

0.2.5)

A) WITH POISONING/EXPOSURE

1) When injected into experimental animals, piperidine has a pronounced pressor effect.

0.2.6)

A) WITH POISONING/EXPOSURE

1) Respiratory distress and asthmatic breathing have been reported.

0.2.7)

A) WITH POISONING/EXPOSURE

1) Various types of CNS toxicity have been reported, such as ataxia, lethargy, dizziness, insomnia, anxiety, tremors, and seizures.

0.2.8)

A) WITH POISONING/EXPOSURE

1) Nausea, vomiting, abdominal pain, anorexia, and diarrhea have been reported.

0.2.9)

A) WITH POISONING/EXPOSURE

1) Jaundice has been observed.

0.2.10)

A) WITH POISONING/EXPOSURE

1) Bladder paralysis may occur.

0.2.14)

A) WITH POISONING/EXPOSURE

1) Skin irritation and burns have been reported in both humans and experimental animals.

0.2.15)

A) WITH POISONING/EXPOSURE

1) Muscular weakness and paralysis have been reported.

0.2.20)

A) At the time of this review, no studies were found on the possible reproductive effects of piperidine in humans.
B) Piperidine was fetotoxic in rats, but was not found to be teratogenic in cows and rats. A change in litter size and decreased embryo size and weight were seen in rat studies.
C) At the time of this review, no data were available to assess the potential effects of exposure to this agent during lactation.

0.2.21)

A) At the time of this review, no studies on the potential carcinogenicity of piperidine in humans were found.

Laboratory Monitoring

A)

B)

C)

D)

E)

Treatment Overview

0.4.2)

A) There is no information available about treatment of piperidine-induced corrosive injury; the following data is derived from experience with other corrosive agents.
B) MANAGEMENT OF MILD TO MODERATE ORAL TOXICITY

1) Perform early (within 12 hours) endoscopy in patients with stridor, drooling, vomiting, significant oral burns, difficulty swallowing or abdominal pain, and in all patients with deliberate ingestion. If burns are absent or grade I severity, patient may be discharged when able to tolerate liquids and soft foods by mouth. If mild grade II burns, admit for intravenous fluids, slowly advance diet as tolerated. Perform barium swallow or repeat endoscopy several weeks after ingestion (sooner if difficulty swallowing) to evaluate for stricture formation.

C) SEVERE ORAL TOXICITY

1) Resuscitate with 0.9% saline; blood products may be necessary. Early airway management in patients with upper airway edema or respiratory distress. Early (within 12 hours) gastrointestinal endoscopy to evaluate for burns. Early bronchoscopy in patients with respiratory distress or upper airway edema. Early surgical consultation for patients with severe grade II or grade III burns, large deliberate ingestions, or signs, symptoms or laboratory findings concerning for tissue necrosis or perforation.

D) DILUTION

1) Dilute with 4 to 8 ounces of water may be useful if it can be performed shortly after ingestion in patients who are able to swallow, with no vomiting or respiratory distress; then the patient should be NPO until assessed for the need for endoscopy. Neutralization, activated charcoal, and gastric lavage are all contraindicated.

E) AIRWAY MANAGEMENT

1) Aggressive airway management in patients with deliberate ingestions or any indication of upper airway injury.

F) ANTIDOTE

1) None

G) ENDOSCOPY

1) Should be performed as soon as possible (preferably within 12 hours, not more than 24 hours) in any patient with deliberate ingestion, adults with any signs or symptoms attributable to inadvertent ingestion, and in children with stridor, vomiting, or drooling after inadvertent ingestion. Endoscopy should also be considered in children with dysphagia or refusal to swallow, significant oral burns, or abdominal pain after unintentional ingestion. Children and adults who are asymptomatic after inadvertent ingestion do not require endoscopy. The grade of mucosal injury at endoscopy is the strongest predictive factor for the occurrence of systemic and GI complications and mortality. The absence of visible oral burns does NOT reliably exclude the presence of esophageal burns.

H) CORTICOSTEROIDS

1) The use of corticosteroids to prevent stricture formation is controversial. Corticosteroids should not be used in patients with grade I or grade III injury, as there is no evidence that it is effective. Evidence for grade II burns is conflicting, and the risk of perforation and infection is increased with steroid use.

I) STRICTURE

1) A barium swallow or repeat endoscopy should be performed several weeks after ingestion in any patient with grade II or III burns or with difficulty swallowing to evaluate for stricture formation. Recurrent dilation may be required. Some authors advocate early stent placement in these patients to prevent stricture formation.

J) SURGICAL MANAGEMENT

1) Immediate surgical consultation should be obtained on any patient with grade III or severe grade II burns on endoscopy, significant abdominal pain, metabolic acidosis, hypotension, coagulopathy, or a history of large ingestion. Early laparotomy can identify tissue necrosis and impending or unrecognized perforation, early resection and repair in these patients is associated with improved outcome.

K) PATIENT DISPOSITION

1) OBSERVATION CRITERIA: Patients with alkaline corrosive ingestion should be sent to a health care facility for evaluation. Patients who remain asymptomatic over 4 to 6 hours of observation, and those with endoscopic evaluation that demonstrates no burns or only minor grade I burns and who can tolerate oral intake can be discharged home.
2) ADMISSION CRITERIA: Symptomatic patients, and those with endoscopically demonstrated grade II or higher burns should be admitted. Patients with respiratory distress, grade III burns, acidosis, hemodynamic instability, gastrointestinal bleeding, or large ingestions should be admitted to an intensive care setting.

L) PITFALLS

1) The absence of oral burns does NOT reliably exclude the possibility of significant esophageal burns.
2) Patients may have severe tissue necrosis and impending perforation requiring early surgical intervention without having severe hypotension, rigid abdomen, or radiographic evidence of intraperitoneal air.
3) Patients with any evidence of upper airway involvement require early airway management before airway edema progresses.
4) The extent of eye injury (degree of corneal opacification and perilimbal whitening) may not be apparent for 48 to 72 hours after the burn. All patients with corrosive eye injury should be evaluated by an ophthalmologist.

M) DIFFERENTIAL DIAGNOSIS

1) Acid ingestion, gastrointestinal hemorrhage, or perforated viscus.

0.4.3)

A) DECONTAMINATION

1) Administer oxygen as necessary. Monitor for respiratory distress.

B) AIRWAY MANAGEMENT

1) Manage airway aggressively in patients with significant respiratory distress, stridor or any evidence of upper airway edema. Monitor for hypoxia or respiratory distress.

C) BRONCHOSPASM

1) Treat with oxygen, inhaled beta agonists and consider systemic corticosteroids.

0.4.4)

A) DECONTAMINATION

1) Exposed eyes should be irrigated with copious amounts of 0.9% saline for at least 30 minutes, until pH is neutral and the cul de sacs are free of particulate material.
2) An eye examination should always be performed, including slit lamp examination. Ophthalmologic consultation should be obtained. Antibiotics and mydriatics may be indicated.

0.4.5)

A) OVERVIEW

1) DECONTAMINATION

a) Remove contaminated clothes and any particulate matter adherent to skin. Irrigate exposed skin with copious amounts of water for at least 15 minutes or longer, depending on concentration, amount and duration of exposure to the chemical. A physician may need to examine the area if irritation or pain persist.

Range Of Toxicity

A)

B)

C)

Clinical Effects

Summary Of Exposure

A)

B)

C)

D)

1) Limited data regarding specific human toxicity following piperidine exposure is available. The following effects could be expected to occur, based on exposure data of other alkaline corrosives.
2) MILD TO MODERATE ORAL TOXICITY: Patients with mild ingestions may only develop irritation or grade I (superficial hyperemia and edema) burns of the oropharynx, esophagus or stomach; acute or chronic complications are unlikely. Patients with moderate toxicity may develop grade II burns (superficial blisters, erosions and ulcerations) are at risk for subsequent stricture formation, particularly esophageal. Some patients (particularly young children) may develop upper airway edema.

a) Alkaline corrosive ingestion may produce burns to the oropharynx, upper airway, esophagus and occasionally stomach. Spontaneous vomiting may occur. The absence of visible oral burns does NOT reliably exclude the presence of esophageal burns. The presence of stridor, vomiting, drooling, and abdominal pain are associated with serious esophageal injury in most cases.
b) PREDICTIVE: The grade of mucosal injury at endoscopy is the strongest predictive factor for the occurrence of systemic and GI complications and mortality.

3) SEVERE ORAL TOXICITY: May develop deep burns and necrosis of the gastrointestinal mucosa. Complications often include perforation (esophageal, gastric, rarely duodenal), fistula formation (tracheoesophageal, aortoesophageal), and gastrointestinal bleeding. Hypotension, tachycardia, tachypnea and, rarely, fever may develop. Stricture formation (esophageal, less often oral or gastric) is likely to develop long term. Esophageal carcinoma is another long term complication. Upper airway edema is common and often life threatening. Severe toxicity is generally limited to deliberate ingestions in adults in the US, because alkaline products available in the home are generally of low concentration.
4) INHALATION EXPOSURE: Mild exposure may cause cough and bronchospasm. Severe inhalation may cause upper airway edema and burns, stridor, and rarely acute lung injury.
5) OCULAR EXPOSURE: Ocular exposure can produce severe conjunctival irritation and chemosis, corneal epithelial defects, limbal ischemia, permanent visual loss and in severe cases perforation.
6) DERMAL EXPOSURE: Mild exposure causes irritation and partial thickness burns. Prolonged exposure or high concentration products can cause full thickness burns.

Vital Signs

3.3.1)

A) Tachypnea, tachycardia, and elevated blood pressure occurred in animal studies.

3.3.2)

A) WITH POISONING/EXPOSURE

1) Intravenous injection into dogs and cats stimulated respirations (Clayton & Clayton, 1994).

3.3.4)

A) WITH POISONING/EXPOSURE

1) Intravenous injection into dogs and cats caused a significant and sustained elevation of blood pressure (Clayton & Clayton, 1994).

3.3.5)

A) WITH POISONING/EXPOSURE

1) Intravenous injection into dogs and cats caused an increase in heart rate (Clayton & Clayton, 1994).

Heent

3.4.1)

A) WITH POISONING/EXPOSURE

1) Piperidine spilled into the eyes may cause moderate to severe damage. Permanent corneal damage and paralysis of the eye muscles have been seen in experimental animals.

3.4.2)

A) WITH POISONING/EXPOSURE

1) Headache has occurred after exposure (Plunkett, 1976).

3.4.3)

A) WITH POISONING/EXPOSURE

1) Conjunctivitis may be seen following exposure (Plunkett, 1976).
2) Paralysis of ocular musculature may be seen (Plunkett, 1976).
3) Severe eye injury with permanent corneal damage has been seen after piperidine instillation into rabbit eyes (Clayton & Clayton, 1994).
4) Solutions adjusted to pH 11 tested on rabbit corneas showed only slight graying of the cornea. Adjusted to pH 10, this agent caused no significant damage (Grant & Schuman, 1993).
5) Severe eye irritation was noted in the rabbit using the Standard Draize test (RTECS , 2000).

3.4.6)

A) WITH POISONING/EXPOSURE

1) Paralysis of the vocal cords may occur after exposure (Plunkett, 1976).
2) Sore throat may occur (EPA, 1985).

Cardiovascular

3.5.1)

A) WITH POISONING/EXPOSURE

1) When injected into experimental animals, piperidine has a pronounced pressor effect.

3.5.3)

A) ANIMAL STUDIES

1) HYPERTENSION

a) Piperidine has a pronounced pressor effect. Increases in blood pressure were seen in dogs and cats injected with 5 to 10 mg/kg. This dose also increases pulse and respiratory rate (Clayton & Clayton, 1994).

2) TACHYCARDIA

a) Intravenous injection into dogs and cats caused an increase in heart rate (Clayton & Clayton, 1994).

Respiratory

3.6.1)

A) WITH POISONING/EXPOSURE

1) Respiratory distress and asthmatic breathing have been reported.

3.6.2)

A) BRONCHOSPASM

1) WITH POISONING/EXPOSURE

a) Asthmatic breathing and respiratory tract irritation may be seen after exposure (Plunkett, 1976).

3.6.3)

A) ANIMAL STUDIES

1) DYSPNEA

a) Poisoned animals showed respiratory distress (Clayton & Clayton, 1994). This effect has not been reported in exposed humans.

Neurologic

3.7.1)

A) WITH POISONING/EXPOSURE

1) Various types of CNS toxicity have been reported, such as ataxia, lethargy, dizziness, insomnia, anxiety, tremors, and seizures.

3.7.2)

A) DIZZINESS

1) WITH POISONING/EXPOSURE

a) Dizziness has been reported (Plunkett, 1976).

B) ANXIETY

1) WITH POISONING/EXPOSURE

a) Anxiety associated with insomnia may be seen (Plunkett, 1976).

C) ATAXIA

1) WITH POISONING/EXPOSURE

a) Ataxia may occur (Plunkett, 1976).

D) SEIZURE

1) WITH POISONING/EXPOSURE

a) Seizures as well as tremors and incoordination have been reported (Plunkett, 1976; Clayton & Clayton, 1994).

E) CENTRAL NERVOUS SYSTEM DEFICIT

1) WITH POISONING/EXPOSURE

a) Lethargy, weakness, and CNS depression may be seen (O'Donoghue, 1985).

3.7.3)

A) ANIMAL STUDIES

1) PARALYSIS

a) Muscular paralysis has been reported with acute exposure in experimental animals (Clayton & Clayton, 1994).

Gastrointestinal

3.8.1)

A) WITH POISONING/EXPOSURE

1) Nausea, vomiting, abdominal pain, anorexia, and diarrhea have been reported.

3.8.2)

A) LOSS OF APPETITE

1) WITH POISONING/EXPOSURE

a) Anorexia may be seen (Plunkett, 1976).

B) VOMITING

1) WITH POISONING/EXPOSURE

a) Salivation, nausea, vomiting, and diarrhea, as well as abdominal pain may occur after exposure (Plunkett, 1976; Clayton & Clayton, 1994; HSDB , 2000).

Hepatic

3.9.1)

A) WITH POISONING/EXPOSURE

1) Jaundice has been observed.

3.9.2)

A) JAUNDICE

1) WITH POISONING/EXPOSURE

a) Jaundice may be seen following exposure (Plunkett, 1976).

Genitourinary

3.10.1)

A) WITH POISONING/EXPOSURE

1) Bladder paralysis may occur.

3.10.2)

A) RETENTION OF URINE

1) WITH POISONING/EXPOSURE

a) Paralysis of the urinary bladder has been reported (Plunkett, 1976).

Dermatologic

3.14.1)

A) WITH POISONING/EXPOSURE

1) Skin irritation and burns have been reported in both humans and experimental animals.

3.14.2)

A) ECZEMA

1) WITH POISONING/EXPOSURE

a) Eczema with skin pruritus and erythema may be seen (Plunkett, 1976).

B) CHEMICAL BURN

1) WITH POISONING/EXPOSURE

a) Skin exposure to the liquid for under 3 minutes caused severe burns in humans (Linch, 1965; HSDB , 2000).

3.14.3)

A) ANIMAL STUDIES

1) IRRITATION

a) GUINEA PIGS - Moderately severe skin damage has been seen in guinea pigs tested with piperidine (Clayton & Clayton, 1994).
b) RABBITS - Piperidine was found to be a severe skin irritant in rabbits using the Standard Draize test and an irritant in the Open Draize test (RTECS , 2000).

Musculoskeletal

3.15.1)

A) WITH POISONING/EXPOSURE

1) Muscular weakness and paralysis have been reported.

3.15.2)

A) PARALYSIS

1) WITH POISONING/EXPOSURE

a) Muscular weakness and paralysis have been reported (EPA, 1985; Clayton & Clayton, 1994).

Reproductive

3.20.1)

A) At the time of this review, no studies were found on the possible reproductive effects of piperidine in humans.
B) Piperidine was fetotoxic in rats, but was not found to be teratogenic in cows and rats. A change in litter size and decreased embryo size and weight were seen in rat studies.
C) At the time of this review, no data were available to assess the potential effects of exposure to this agent during lactation.

3.20.2)

A) CONGENITAL ANOMALY

1) It has been suggested that some piperidine alkaloids might be teratogenic based on structural similarities to other known teratogens (Keeler & Panter, 1989; Keeler & Balls, 1978).
2) Piperidine-containing plants, such as POISON HEMLOCK, TREE TOBACCO, and LUNARA LUPINE, have caused skeletal abnormalities and reduced fetal movement in goats (Panter et al, 1990a) 1990b).

B) LACK OF EFFECT

1) No teratogenic effects were seen in studies, but rats given 4.3 and 28.7 ppm had decreased embryo size and weight. No such changes were seen at 0.9 ppm (Timofievskaya, 1975). A change in litter size was found in rat studies (RTECS , 2000).
2) Piperidine has been tested in the rat and cow, and has not been found to be teratogenic (Timofievskaya, 1975; Keeler & Balls, 1978).

3.20.3)

A) LACK OF INFORMATION

1) A change in litter size was found in rat studies (RTECS , 2000). Rats given 4.3 and 28.7 parts per million had decreased embryo size and weight. No such changes were seen at 0.9 parts per million (Timofievskaya, 1975).

3.20.4)

A) LACK OF INFORMATION

1) At the time of this review, no data were available to assess the potential effects of exposure to this agent during lactation.

Carcinogenicity

3.21.1)

A) IARC Carcinogenicity Ratings for CAS110-89-4 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):

1) Not Listed

3.21.2)

A) At the time of this review, no studies on the potential carcinogenicity of piperidine in humans were found.

3.21.4)

A) LACK OF EFFECT

1) Administration of 75 weeks of sodium nitrite (0.05%) and piperidine was not tumorigenic in rats (Garcia & Lijinsky, 1973).

Genotoxicity

A)

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Obtain a complete blood count in symptomatic patients following piperidine ingestion.
B) In patients with signs and symptoms suggesting severe burns, perforation, or bleeding (or adults with deliberate, high volume or high concentration ingestions), obtain renal function tests, serum electrolytes, INR, PTT, type and crossmatch for blood, and monitor urine output. Serum lactate and base deficit may also be useful in these patients.
C) Monitor pulse oximetry or arterial blood gases in patients with signs and symptoms suggestive of upper airway edema or burns.
D) Obtain an upright chest x-ray in patients with signs and symptoms suggesting severe burns, perforation, or bleeding (or adults with deliberate, high volume or high concentration ingestions) to evaluate for pneumomediastinum or free air under the diaphragm. The absence of these findings does NOT rule out the possibility of necrosis or perforation of the esophagus or stomach. Obtain a chest radiograph in patients with pulmonary signs or symptoms.
E) Several weeks after ingestion, barium contrast radiographs of the upper GI tract are useful in patients who sustained grade II or III burns, to evaluate for strictures.

4.1.2)

A) HEMATOLOGIC

1) Obtain a complete blood count in patients with symptomatic piperidine ingestion.

B) COAGULATION STUDIES

1) In patients with signs and symptoms suggesting severe burns, perforation, or bleeding, obtain renal function tests, PT or INR, PTT, and type and crossmatch for blood.

4.1.3)

A) OTHER

1) Monitor urine output in patients with significant gastrointestinal burns, perforation, or bleeding.

4.1.4)

A) OTHER

1) MONITORING

a) Monitor pulse oximetry or arterial blood gases in patients with signs and symptoms suggestive of upper airway burns.

Radiographic Studies

A)

1) Obtain an upright chest x-ray in patients with significant signs and symptoms to evaluate for pneumomediastinum or free air under the diaphragm.
2) The absence of these findings does NOT rule out the possibility of necrosis or perforation of the esophagus or stomach (Davis et al, 1972; Allen et al, 1970).
3) Obtain a chest x-ray in patients with significant pulmonary signs or symptoms.
4) A water-soluble contrast material should be used initially to exclude esophageal perforation in patients with GI burns associated with alkaline ingestions, as water soluble contrast causes less injury than barium if it extravasates into tissue (Kirsh & Ritter, 1976; Chen et al, 1988).
5) Barium esophagogram performed once perforation has been excluded may be useful to evaluate extent of injury or presence of strictures (Leape et al, 1971; Lowe et al, 1979; Chen et al, 1988).

Methods

A)

1) Identification and measurement of piperidine in body fluids can be accomplished with high performance liquid chromatography (HPLC) and chemiluminescence or gas-liquid chromatography (Clayton & Clayton, 1994).

B)

1) A method developed by von Eules using sodium B-naphthoquinone-4-sulfonate to develop a red color will determine piperidine levels down to 5 mcg/mL (Clayton & Clayton, 1982).

Treatment

Life Support

A)

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) Symptomatic patients, and those with endoscopically demonstrated grade II or higher burns should be admitted. Patients with respiratory distress, grade III burns, acidosis, hemodynamic instability, gastrointestinal bleeding, or large ingestions should be admitted to an intensive care setting.

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) Patients with alkaline corrosive ingestion should be sent to a health care facility for evaluation. Patients who remain asymptomatic over 4 to 6 hours of observation, and those with endoscopic evaluation that demonstrates no burns or only minor grade I burns and who can tolerate oral intake can be discharged home.

Monitoring

A)

B)

C)

D)

E)

Oral Exposure

6.5.1)

A) DILUTION

1) DILUTION: If no respiratory compromise is present, administer milk or water as soon as possible after ingestion. Dilution may only be helpful if performed in the first seconds to minutes after ingestion. The ideal amount is unknown; no more than 8 ounces (240 mL) in adults and 4 ounces (120 mL) in children is recommended to minimize the risk of vomiting (Caravati, 2004).

B) ACTIVATED CHARCOAL

1) Activated charcoal may induce vomiting and obscure endoscopy findings. Routine use is NOT recommended.

6.5.2)

A) DILUTION

1) DILUTION: If no respiratory compromise is present, administer milk or water as soon as possible after ingestion. Dilution may only be helpful if performed in the first seconds to minutes after ingestion. The ideal amount is unknown; no more than 8 ounces (240 mL) in adults and 4 ounces (120 mL) in children is recommended to minimize the risk of vomiting (Caravati, 2004).

B) GASTRIC DECONTAMINATION

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 may induce vomiting and obscure endoscopy findings. It is not routinely recommended.

6.5.3)

A) OBSERVATION REGIMES

1) Carefully observe patients with ingestion exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.

B) 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, 2010; 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).

C) ACUTE LUNG INJURY

1) ONSET: Onset of acute lung injury after toxic exposure may be delayed up to 24 to 72 hours after exposure in some cases.
2) NON-PHARMACOLOGIC TREATMENT: The treatment of acute lung injury is primarily supportive (Cataletto, 2012). Maintain adequate ventilation and oxygenation with frequent monitoring of arterial blood gases and/or pulse oximetry. If a high FIO2 is required to maintain adequate oxygenation, mechanical ventilation and positive-end-expiratory pressure (PEEP) may be required; ventilation with small tidal volumes (6 mL/kg) is preferred if ARDS develops (Haas, 2011; Stolbach & Hoffman, 2011).

a) To minimize barotrauma and other complications, use the lowest amount of PEEP possible while maintaining adequate oxygenation. Use of smaller tidal volumes (6 mL/kg) and lower plateau pressures (30 cm water or less) has been associated with decreased mortality and more rapid weaning from mechanical ventilation in patients with ARDS (Brower et al, 2000). More treatment information may be obtained from ARDS Clinical Network website, NIH NHLBI ARDS Clinical Network Mechanical Ventilation Protocol Summary, http://www.ardsnet.org/node/77791 (NHLBI ARDS Network, 2008)

3) FLUIDS: Crystalloid solutions must be administered judiciously. Pulmonary artery monitoring may help. In general the pulmonary artery wedge pressure should be kept relatively low while still maintaining adequate cardiac output, blood pressure and urine output (Stolbach & Hoffman, 2011).
4) ANTIBIOTICS: Indicated only when there is evidence of infection (Artigas et al, 1998).
5) EXPERIMENTAL THERAPY: Partial liquid ventilation has shown promise in preliminary studies (Kollef & Schuster, 1995).
6) CALFACTANT: In a multicenter, randomized, blinded trial, endotracheal instillation of 2 doses of 80 mL/m(2) calfactant (35 mg/mL of phospholipid suspension in saline) in infants, children, and adolescents with acute lung injury resulted in acute improvement in oxygenation and lower mortality; however, no significant decrease in the course of respiratory failure measured by duration of ventilator therapy, intensive care unit, or hospital stay was noted. Adverse effects (transient hypoxia and hypotension) were more frequent in calfactant patients, but these effects were mild and did not require withdrawal from the study (Wilson et al, 2005).
7) However, in a multicenter, randomized, controlled, and masked trial, endotracheal instillation of up to 3 doses of calfactant (30 mg) in adults only with acute lung injury/ARDS due to direct lung injury was not associated with improved oxygenation and longer term benefits compared to the placebo group. It was also associated with significant increases in hypoxia and hypotension (Willson et al, 2015).

D) BURN OF GASTROINTESTINAL TRACT

1) There is limited information specific to the therapy of piperidine induced gastrointestinal burns. The following information is derived from experience with other caustics.
2) ENDOSCOPY

a) SUMMARY: Obtain consultation concerning endoscopy as soon as possible, and perform endoscopy within the first 24 hours when indicated.
b) INDICATIONS: Endoscopy should be performed in adults with a history of deliberate ingestion, adults with any signs or symptoms attributable to inadvertent ingestion, and in children with stridor, vomiting, or drooling after unintentional ingestion (Crain et al, 1984). Endoscopy should also be performed in children with dysphagia or refusal to swallow, significant oral burns, or abdominal pain after unintentional ingestion (Gaudreault et al, 1983; Nuutinen et al, 1994). Children and adults who are asymptomatic after accidental ingestion do not require endoscopy (Gupta et al, 2001; Lamireau et al, 2001; Gorman et al, 1992).
c) RISKS: Numerous large case series attest to the relative safety and utility of early endoscopy in the management of caustic ingestion.

1) REFERENCES: (Dogan et al, 2006; Symbas et al, 1983; Crain et al, 1984a; Gaudreault et al, 1983a; 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)

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.
g) SCINTIGRAPHY - Scans utilizing radioisotope labelled sucralfate (technetium 99m) were performed in 22 patients with caustic ingestion and compared with endoscopy for the detection of esophageal burns. Two patients had minimal residual isotope activity on scanning but normal endoscopy and two patients had normal activity on scan but very mild erythema on endoscopy. Overall the radiolabeled sucralfate scan had a sensitivity of 100%, specificity of 81%, positive predictive value of 84% and negative predictive value of 100% for detecting clinically significant burns in this population (Millar et al, 2001). This may represent an alternative to endoscopy, particularly in young children, as no sedation is required for this procedure. Further study is required.
h) MINIPROBE ULTRASONOGRAPHY - was performed in 11 patients with corrosive ingestion . Findings were categorized as grade 0 (distinct muscular layers without thickening, grade I (distinct muscular layers with thickening), grade II (obscured muscular layers with indistinct margins) and grade III (muscular layers that could not be differentiated). Findings were further categorized as to whether the worst appearing image involved part of the circumference (type a) or the whole circumference (type b). Strictures did not develop in patients with grade 0 (5 patients) or grade I (4 patients) lesions. Transient stricture formation developed in the only patient with grade IIa lesions, and stricture requiring repeated dilatation developed in the only patient with grade IIIb lesions (Kamijo et al, 2004).

3) CORTICOSTEROIDS

a) 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.
b) 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).
c) 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).
d) 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).
e) 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).
f) 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).
g) 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).
h) STUDIES

1) ANIMAL

a) 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).
b) Animals treated with steroids and antibiotics appear to do better than animals treated with steroids alone (Haller & Bachman, 1964).
c) 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).

2) HUMAN

a) 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).
b) META ANALYSIS

1) 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).
2) 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).
3) 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).

c) Smaller studies have questioned the value of steroids (Ferguson et al, 1989; Anderson et al, 1990), thus they should be used with caution.
d) 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).
e) 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).

1) 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).
2) 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).
3) 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).
4) 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).
5) 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).

f) ADVERSE EFFECTS

1) 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).

4) SURGICAL THERAPY

a) SUMMARY: Initially if severe esophageal burns are found a string may be placed in the stomach to facilitate later dilation. Insertion of a specialized nasogastric tube after confirmation of a circumferential burn may prevent strictures. Dilation is indicated after 2 to 4 weeks if strictures are confirmed. If dilation is unsuccessful colonic intraposition or gastric tube placement may be needed. Early laparotomy should be considered in patients with evidence of severe esophageal or gastric burns on endoscopy.
b) STRING - If a second degree or circumferential burn of the esophagus is found a string may be placed in the stomach to avoid false channel and to provide a guide for later dilation procedures (Gandhi et al, 1989).
c) STENT - The insertion of a specialized nasogastric tube or stent immediately after endoscopically proven deep circumferential burns is preferred by some surgeons to prevent stricture formation (Mills et al, 1978; (Wijburg et al, 1985; Coln & Chang, 1986).

1) STUDY - In a study of 11 children with deep circumferential esophageal burns after caustic ingestion, insertion of a silicone rubber nasogastric tube for 5 to 6 weeks without steroids or antibiotics was associated with stricture formation in only one case (Wijburg et al, 1989).

d) DILATION - Dilation should be performed at 1 to 4 week intervals when stricture is present(Gundogdu et al, 1992). Repeated dilation may be required over many months to years in some patients. Successful dilation of gastric antral strictures has also been reported (Hogan & Polter, 1986; Treem et al, 1987).
e) COLONIC REPLACEMENT - Intraposition of colon may be necessary if dilation fails to provide an adequate sized esophagus (Chiene et al, 1974; Little et al, 1988; Huy & Celerier, 1988).
f) LAPAROTOMY/LAPAROSCOPY - Several authors advocate laparotomy or laparoscopy in patients with endoscopic evidence of severe esophageal or gastric burns to evaluate for the presence of transmural gastric or esophageal necrosis (Cattan et al, 2000; Estrera et al, 1986; Meredith et al, 1988; Wu & Lai, 1993).

1) STUDY - In a retrospective study of patients with extensive transmural esophageal necrosis after caustic ingestion, all 4 patients treated in the conventional manner (esophagoscopy, 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).

Inhalation Exposure

6.7.1)

A) Move patient from the toxic environment to fresh air. Monitor for respiratory distress. If cough or difficulty in breathing develops, evaluate for hypoxia, respiratory tract irritation, bronchitis, or pneumonitis.
B) OBSERVATION: Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
C) INITIAL TREATMENT: Administer 100% humidified supplemental oxygen, perform endotracheal intubation and provide assisted ventilation as required. Administer inhaled beta-2 adrenergic agonists, if bronchospasm develops. Consider systemic corticosteroids in patients with significant bronchospasm (National Heart,Lung,and Blood Institute, 2007). Exposed skin and eyes should be flushed with copious amounts of water.

6.7.2)

A) OBSERVATION REGIMES

1) Carefully observe patients with ingestion exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.

B) 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, 2010; 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).

C) ACUTE LUNG INJURY

1) ONSET: Onset of acute lung injury after toxic exposure may be delayed up to 24 to 72 hours after exposure in some cases.
2) NON-PHARMACOLOGIC TREATMENT: The treatment of acute lung injury is primarily supportive (Cataletto, 2012). Maintain adequate ventilation and oxygenation with frequent monitoring of arterial blood gases and/or pulse oximetry. If a high FIO2 is required to maintain adequate oxygenation, mechanical ventilation and positive-end-expiratory pressure (PEEP) may be required; ventilation with small tidal volumes (6 mL/kg) is preferred if ARDS develops (Haas, 2011; Stolbach & Hoffman, 2011).

a) To minimize barotrauma and other complications, use the lowest amount of PEEP possible while maintaining adequate oxygenation. Use of smaller tidal volumes (6 mL/kg) and lower plateau pressures (30 cm water or less) has been associated with decreased mortality and more rapid weaning from mechanical ventilation in patients with ARDS (Brower et al, 2000). More treatment information may be obtained from ARDS Clinical Network website, NIH NHLBI ARDS Clinical Network Mechanical Ventilation Protocol Summary, http://www.ardsnet.org/node/77791 (NHLBI ARDS Network, 2008)

3) FLUIDS: Crystalloid solutions must be administered judiciously. Pulmonary artery monitoring may help. In general the pulmonary artery wedge pressure should be kept relatively low while still maintaining adequate cardiac output, blood pressure and urine output (Stolbach & Hoffman, 2011).
4) ANTIBIOTICS: Indicated only when there is evidence of infection (Artigas et al, 1998).
5) EXPERIMENTAL THERAPY: Partial liquid ventilation has shown promise in preliminary studies (Kollef & Schuster, 1995).
6) CALFACTANT: In a multicenter, randomized, blinded trial, endotracheal instillation of 2 doses of 80 mL/m(2) calfactant (35 mg/mL of phospholipid suspension in saline) in infants, children, and adolescents with acute lung injury resulted in acute improvement in oxygenation and lower mortality; however, no significant decrease in the course of respiratory failure measured by duration of ventilator therapy, intensive care unit, or hospital stay was noted. Adverse effects (transient hypoxia and hypotension) were more frequent in calfactant patients, but these effects were mild and did not require withdrawal from the study (Wilson et al, 2005).
7) However, in a multicenter, randomized, controlled, and masked trial, endotracheal instillation of up to 3 doses of calfactant (30 mg) in adults only with acute lung injury/ARDS due to direct lung injury was not associated with improved oxygenation and longer term benefits compared to the placebo group. It was also associated with significant increases in hypoxia and hypotension (Willson et al, 2015).

D) BRONCHOSPASM

1) BRONCHOSPASM SUMMARY

a) Administer beta2 adrenergic agonists. Consider use of inhaled ipratropium and systemic corticosteroids. Monitor peak expiratory flow rate, monitor for hypoxia and respiratory failure, and administer oxygen as necessary.

2) ALBUTEROL/ADULT DOSE

a) 2.5 to 5 milligrams diluted with 4 milliliters of 0.9% saline by nebulizer every 20 minutes for three doses. If incomplete response, administer 2.5 to 10 milligrams every 1 to 4 hours as needed OR administer 10 to 15 milligrams every hour by continuous nebulizer as needed. Consider adding ipratropium to the nebulized albuterol; DOSE: 0.5 milligram by nebulizer every 30 minutes for three doses then every 2 to 4 hours as needed, NOT administered as a single agent (National Heart,Lung,and Blood Institute, 2007).

3) ALBUTEROL/PEDIATRIC DOSE

a) 0.15 milligram/kilogram (minimum 2.5 milligrams) diluted with 4 milliliters of 0.9% saline by nebulizer every 20 minutes for three doses. If incomplete response administer 0.15 to 0.3 milligram/kilogram (maximum 10 milligrams) every 1 to 4 hours as needed OR administer 0.5 mg/kg/hr by continuous nebulizer as needed. Consider adding ipratropium to the nebulized albuterol; DOSE: 0.25 to 0.5 milligram by nebulizer every 20 minutes for three doses then every 2 to 4 hours as needed, NOT administered as a single agent (National Heart,Lung,and Blood Institute, 2007).

4) ALBUTEROL/CAUTIONS

a) The incidence of adverse effects of beta2-agonists may be increased in older patients, particularly those with pre-existing ischemic heart disease (National Asthma Education and Prevention Program, 2007). Monitor for tachycardia, tremors.

5) CORTICOSTEROIDS

a) Consider systemic corticosteroids in patients with significant bronchospasm. PREDNISONE: ADULT: 40 to 80 milligrams/day in 1 or 2 divided doses. CHILD: 1 to 2 milligrams/kilogram/day (maximum 60 mg) in 1 or 2 divided doses (National Heart,Lung,and Blood Institute, 2007).

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

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) CONSULTATION

1) Because of the potential for severe eye injury following direct ocular contact, prolonged initial flushing and early ophthalmologic evaluation are advisable.

B) INJURY OF GLOBE OF EYE

1) EVALUATION

a) 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).
b) 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):

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

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

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

2) MINOR INJURY

a) SUMMARY

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

b) ARTIFICIAL TEARS

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

c) TOPICAL CYCLOPLEGIC

1) 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).

d) TOPICAL ANTIBIOTICS

1) 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).

e) PAIN CONTROL

1) 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).

3) SEVERE INJURY

a) SUMMARY

1) 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.

b) ARTIFICIAL TEARS

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

c) PAIN CONTROL

1) 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).

d) CARBONIC ANHYDRASE INHIBITOR

1) 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).

e) TOPICAL STEROIDS

1) 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).
2) 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).
3) 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).

a) 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).

f) ASCORBATE

1) Oral or topical ascorbate may be used to promote epithelial healing and reduce the risk of stromal necrosis (Fish & Davidson, 2010).
2) DOSE: Ascorbate 10% 4 times daily topically or 1 g orally (2 g/day) (Singh et al, 2013; Tuft & Shortt, 2009).
3) 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).

a) 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).

g) CITRATE

1) Topical citrate may be used to promote epithelial healing and reduce the risk of stromal necrosis (Fish & Davidson, 2010).
2) DOSE: Potassium citrate 10% 4 times daily topically (Tuft & Shortt, 2009).
3) 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).

a) 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).

h) COLLAGENASE INHIBITORS

1) 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).
2) 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).
3) 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).

i) ANTIBIOTICS

1) 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).

j) TOPICAL CYCLOPLEGIC

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

k) SOFT CONTACT LENSES

1) 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.

4) SURGICAL THERAPY

a) SURGICAL THERAPY CAUSTIC EYE INJURY

1) 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.
2) 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).
3) 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).
4) Control glaucoma. Remove any cataracts formed (Fish & Davidson, 2010; Tuft & Shortt, 2009).
5) In patients with severe injury, tenonplasty can be performed to promote epithelialization and prevent melting (Tuft & Shortt, 2009).
6) 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).

C) SUPPORT

1) Treatment should include recommendations listed in the INHALATION EXPOSURE section when appropriate.

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

Dermal Exposure

6.9.1)

A) 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

A)

1) No studies have addressed the utilization of extracorporeal elimination techniques in poisoning with this agent.

Abstracts

Case Reports

A)

1) SPECIFIC AGENT

a) An atmospheric level of 2 to 5 ppm developed when piperidine was being removed from drums. Although toxic symptoms did not develop, the odor could only be tolerated for a short time (Nawakowski, 1980).

Range Of Toxicity

Summary

A)

B)

C)

Minimum Lethal Exposure

A)

1) The minimum lethal human dose to this agent has not been delineated.

Maximum Tolerated Exposure

A)

1) IRRITATION THRESHOLD - A level of 26 ppm (90 mg/m(3)) was the threshold for irritation in human volunteers (Bararova & Migukina, 1975).
2) 30 to 60 mg/kg may cause symptoms (EPA, 1985).

B)

1) CHRONIC TOXICITY

a) Animals given 2.87 ppm had altered brain electrical activity, cardiovascular toxicity, and disordered spermatogenesis. Decreased body weight gain and toxicity to liver and kidneys were seen (Bararova, 1973).
b) At 0.57 ppm there was decreased arterial pressure, increased skin capillary permeability and neuromuscular irritability. The 0.57 ppm level is thought to be near the "threshold" of chronic toxicity (Bararova, 1973).

Workplace Standards

A)

1) Not Listed

B)

1) Not Listed

C)

1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
5) MAK (DFG, 2002): Not Listed
6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

D)

1) Not Listed

Toxicity Information

7.7.1)

A) References: HSDB, 2000 RTECS, 2000

1) LD50- (INTRAPERITONEAL)MOUSE:

a) 50 mg/kg

2) LD50- (ORAL)MOUSE:

a) 30 mg/kg

3) LD50- (ORAL)RAT:

a) 400 mg/kg

4) TCLo- (INHALATION)RAT:

a) 10 mg/m(3) for 4H/17W-I

Pharmacology Toxicology

Toxicologic Mechanism

A)

B)

C)

Physicochemical

Physical Characteristics

A)

Ph

A)

Molecular Weight

A)

Other

A)

1) <2ppm (Clayton & Clayton, 1994) Snyder, 1990)

Animal Toxicology

References

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PIPERIDINE

Classification | Detailed evidence-based information

Therapeutic Toxic Class

Specific Substances

Available Forms Sources

Life Support

Clinical Effects

Laboratory Monitoring

Treatment Overview

Range Of Toxicity

Summary Of Exposure

Vital Signs

Heent

Cardiovascular

Respiratory

Neurologic

Gastrointestinal

Hepatic

Genitourinary

Dermatologic

Musculoskeletal

Reproductive

Carcinogenicity

Genotoxicity

Monitoring Parameters Levels

Radiographic Studies

Methods

Life Support

Patient Disposition

Monitoring

Oral Exposure

Inhalation Exposure

Eye Exposure

Dermal Exposure

Enhanced Elimination

Case Reports

Summary

Minimum Lethal Exposure

Maximum Tolerated Exposure

Workplace Standards

Toxicity Information

Toxicologic Mechanism

Physical Characteristics

Ph

Molecular Weight

Other

General Bibliography