COPPER SULFATE

Classification | Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

Specific Substances

1) Blue copper
2) Blue copperas
3) Blue stone
4) Blue vitriol
5) Copper basic sulfate
6) Copper monosulfate
7) Cupric sulfate
8) Roman vitriol
9) Sulfuric acid, copper (2+) salt
10) TNCS 53
11) Triangle
12) CAS 7758-98-7 (anhydrous)
13) CAS 7758-99-8 (pentahydrate)
14) COPPER SULPHATE
15) DRIED CUPRIC SULFATE
16) SALT (1:1)
17) SULFURIC ACID, COPPER(2+)

1.2.1) MOLECULAR FORMULA
1) O4-S.Cu
2) O4-S.Cu.5H2-O
3) CuSO4
4) CuSO4.5H2O

Available Forms Sources

1) Copper sulfate is a naturally-occurring inorganic salt, and is available as dust, wettable powders, and fluid concentrates (TOXNET, 1986). It is blue or white rhombic crystals, crystalline granules, or hygroscopic powder (Lewis, 1996).

1) This copper compound has the greatest number of uses. It is used in agriculture, animal husbandry, steel-making, treatment of natural asphalts, and in the petroleum industry (Clayton & Clayton, 1994). It is used in leather manufacturing (Bhowmik et al, 2001). Copper sulfate has sometimes been used as an emetic (Clayton & Clayton, 1994), however, it is NOT RECOMMENDED FOR THIS PURPOSE.
2) Copper sulfate is used as an inorganic fungicide, algaecide, herbicide, and molluscide (TOXNET, 1986).
3) One of the constituents of Clinitest(R) tablets is copper sulfate, 20 mg per tablet (Prod Info Clinitest(R) tablets, 1996).
4) Copper sulfate may be found in childrens' chemistry sets and crystal gardens (Walsh et al, 1977; Gulliver, 1991). It is found in chemistry laboratories in colleges (Bhowmik et al, 2001).
5) Although uncommon in the US, copper sulfate has been a common agent used for suicide in India and Bangladesh (Bhowmik et al, 2001; Walsh et al, 1977).

Overview

Life Support

Clinical Effects

0.2.1)

A) USES: Copper sulfate, a soluble copper salt, is used in agriculture, animal husbandry, steel-making, treatment of natural asphalts, in leather-making, and in the petroleum industry. It has also been used as an inorganic fungicide, algaecide, herbicide, and molluscide.
B) TOXICOLOGY: Copper sulfate produces hemolysis by increasing oxidation of hemoglobin sulfhydryl groups, leading to increased red blood cell permeability. Copper inhibits the sulfhydryl group enzymes, such as G6PD and glutathione reductase, which protect the cell from free oxygen radicals.
C) EPIDEMIOLOGY: In the US, copper sulfate toxicity is rare. In India and Bangladesh, copper sulfate has been a common agent used for suicide.
D) WITH POISONING/EXPOSURE

1) SUMMARY: Copper sulfate may be toxic by inhalation, ingestion, injection and topical exposure.
2) INGESTION: Acute ingestion can cause irritation, severe nausea and vomiting, salivation, abdominal pain, epigastric burning, hemolysis, gastrointestinal bleeding with hemorrhagic gastritis, hematemesis, and melena, anemia, hypotension, tachycardia, jaundice, seizures, coma, shock, and death. Hepatic and renal failure may develop several days after acute ingestion. Methemoglobinemia may rarely occur. Stools, vomitus, saliva, and mucous membranes are often stained green or blue.
3) INHALATION EXPOSURE: Burning copper sulfate may result in irritating and poisonous gases which may irritate the respiratory tract and lungs and can cause metal fume fever, a benign and self-limited condition manifesting with cough, chest tightness, chills, and muscle aches.
4) INJECTION: Intravenous and subcutaneous injection of copper sulfate can result in acute renal failure, gastrointestinal bleeding, coagulopathy, metabolic acidosis, hemolysis, hepatic injury, and death. Initial symptoms of vomiting, abdominal pain, hematemesis, and diarrhea can began within 15 minutes of the injections.
5) TOPICAL EXPOSURE: Copper sulfate is a strong irritant to skin and mucous membranes, including nose, throat, and eyes.

0.2.3)

A) WITH POISONING/EXPOSURE

1) Increased temperature may be noted in some cases.
2) Hypotension may occur following ingestions.
3) Tachycardia was reported in a child following an acute ingestion.

0.2.21)

A) At the time of this review, no studies were found on the possible carcinogenic activity of copper sulfate in humans.

Laboratory Monitoring

Treatment Overview

0.4.2)

A) MANAGEMENT OF MILD TO MODERATE TOXICITY

1) Treatment is symptomatic and supportive. Vomiting may be protracted; administer IV fluids and antiemetics as necessary.

B) MANAGEMENT OF SEVERE TOXICITY

1) Treatment is symptomatic and supportive. Treat severe hypotension with IV 0.9% NaCl at 10 to 20 mL/kg. Add dopamine or norepinephrine if unresponsive to fluids. Endoscopy should be performed within the first 24 hours post-ingestion, and should be avoided from 2 days to 2 weeks post-ingestion since wound tensile strength is lowest and the risk of perforation is highest during this time. Endoscopy is indicated for all adults with deliberate ingestion, and for children with stridor, vomiting, or drooling. Consider endoscopy in children with dysphagia, refusal to swallow, significant oral burns, or abdominal pain. If second or third degree burns are found, follow 10 to 20 days later with barium swallow or esophagram. The role of corticosteroids is controversial, but generally not indicated. Antibiotics are indicated for definite infection or patients with gastroesophageal perforation. Consider early laparotomy in patients with severe esophageal and/or gastric burns.

C) DECONTAMINATION

1) PREHOSPITAL: Vomiting may occur within minutes of ingestion and may be prolonged. Copper sulfate is a caustic agent, capable of extensive mucosal damage, including perforation of the gastrointestinal tract. Prehospital decontamination with activated charcoal is not recommended because it may cause further complications and obscure endoscopy findings.
2) HOSPITAL: Gastric lavage and activated charcoal are not recommended because they may cause further complications and obscure endoscopy findings. Some clinicians may choose to insert a small, flexible nasogastric tube through the mouth, if the patient is alert and cooperative, in an attempt to remove the corrosive substance following a recent ingestion.

D) AIRWAY MANAGEMENT

1) Patients may be at risk for aspiration due to intense vomiting. Airway protection may be needed. Ensure adequate ventilation and perform endotracheal intubation early in patients with pulmonary toxicity.

E) ANTIDOTE

1) SUMMARY: There is little clinical experience in the use of chelators in the setting of acute copper intoxication. Data on efficacy is derived from patients with chronic copper intoxication (ie, Wilson disease, Indian childhood cirrhosis) and animal studies. Penicillamine, dimercaprol (BAL), succimer, and edetate calcium disodium (CaNa2EDTA) have been used, although specific dosing with CaNa2EDTA, in the presence of acute copper poisoning, has not been established. D-penicillamine is considered the drug of choice for Wilson disease, a condition of chronic copper overload. Chelation therapy is generally recommended in symptomatic patients. If the patient is asymptomatic, confirmation from the laboratory should be obtained before instituting chelation therapy.
2) PENICILLAMINE: ADULT: 1 to 1.5 g/day orally in 4 divided doses. CHILD: 15 to 30 mg/kg/day in 3 to 4 divided doses. Avoid if penicillin allergic. Monitor for proteinuria, hematuria, rash, leukopenia, and thrombocytopenia.
3) DIMERCAPROL (BAL): May be appropriate in patients unable to take penicillamine due to vomiting or gastrointestinal injury, or in patients with renal failure. ADULT: 2.5 to 5 mg/kg IM every 4 hours for 2 days, then 2.5 mg/kg every 12 hours on day 3, and 1 to 2 times daily thereafter for 1 to 2 weeks, depending on clinical response.
4) SUCCIMER: May be used in patients with mild to moderate copper poisoning, in lieu of d-penicillamine. ADULT: 10 mg/kg 3 times daily for 5 days, followed by 10 mg/kg 2 times daily for 14 days. CHILD: 350 mg/m(2) 3 times daily for 5 days, followed by 350 mg/m(2) 2 times daily for 14 days.

F) METHEMOGLOBINEMIA

1) Initiate oxygen therapy. Treat with methylene blue if patient is symptomatic (usually at methemoglobin concentrations greater than 20% to 30% or at lower concentrations in patients with anemia, underlying pulmonary or cardiovascular disease). METHYLENE BLUE: INITIAL DOSE/ADULT OR CHILD: 1 mg/kg IV over 5 to 30 minutes; a repeat dose of up to 1 mg/kg may be given 1 hour after the first dose if methemoglobin levels remain greater than 30% or if signs and symptoms persist. NOTE: Methylene blue is available as follows: 50 mg/10 mL (5 mg/mL or 0.5% solution) single-dose ampules and 10 mg/1 mL (1% solution) vials. Additional doses may sometimes be required. Improvement is usually noted shortly after administration if diagnosis is correct. Consider other diagnoses or treatment options if no improvement has been observed after several doses. If intravenous access cannot be established, methylene blue may also be given by intraosseous infusion. Methylene blue should not be given by subcutaneous or intrathecal injection. NEONATES: DOSE: 0.3 to 1 mg/kg.

G) RHABDOMYOLYSIS

1) Administer sufficient 0.9% saline to maintain urine output of 2 to 3 mL/kg/hr. Monitor input and output, serum electrolytes, CK, and renal function. Diuretics may be necessary to maintain urine output. Urinary alkalinization is NOT routinely recommended.

H) ENHANCED ELIMINATION

1) Hemodialysis has no role, except in cases of renal failure secondary to copper toxicity. Exchange transfusion may have a small, theoretical benefit, but there is little literature to support recommending this treatment.

I) PATIENT DISPOSITION

1) HOME CRITERIA: Patients who are asymptomatic may be managed at home.
2) OBSERVATION CRITERIA: Patients with a significant exposure should be monitored during the first 6 hours after exposure.
3) ADMISSION CRITERIA: Patients that are severely symptomatic should be admitted to an intensive care setting for frequent monitoring.
4) CONSULT CRITERIA: Due to the unusual nature of this exposure, consult a toxicologist or poison center once a history or suspected history of exposure has been determined.

J) PITFALLS

1) Failing to identify perforation, not recognizing high grade esophageal injuries and not placing an NG tube early in the course of management. Not recognizing hemolysis and/or methemoglobinemia.

K) PHARMACOKINETICS

1) Approximately 30% of ingested copper sulfate is absorbed from the gastrointestinal tract. In therapeutic states, copper is 7% bound to albumin and 93% bound to ceruloplasmin. In healthy individuals, the estimated volume of distribution is 1.95 L/kg. Greater than 99% of ingested copper sulfate is excreted in the feces.

L) TOXICOKINETICS

1) When absorbed in toxic doses, copper is concentrated in the liver, but elevated copper concentrations have been described in other organs (eg, kidney, lung).

M) PREDISPOSING CONDITIONS

1) Wilson disease, a genetic condition of chronic copper overload, can predispose patients to more serious effects due to their inherent inability to eliminate copper.

N) DIFFERENTIAL DIAGNOSIS

1) Patients can be easily confused with other causes of GI irritation (eg, acids, alkalies, alkylating agents, colchicine), or shock.

0.4.3)

A) Inhalation exposures should be monitored for respiratory distress, bronchospasm, or severe pulmonary irritation. Treat bronchospasm with inhaled beta2 agonists. Administer oxygen as needed.

0.4.4)

A) Irrigate exposed eyes with copious amounts of room temperature water for at least 15 minutes. A slit-lamp examination and ophthalmologic consult may be needed for copper or copper alloy foreign bodies lodged in the eye.

0.4.5)

A) OVERVIEW

1) Remove contaminated clothing and wash exposed area thoroughly with soap and water. A physician may need to examine the area if irritation or pain persists.

0.4.6)

A) Parenteral injections, including intravenous and subcutaneous, have been reported in suicidal poisonings. Signs and symptoms are similar to those resulting from ingestions. Refer to the Oral Exposures treatment section.

Range Of Toxicity

Clinical Effects

Summary Of Exposure

Vital Signs

3.3.1)

A) WITH POISONING/EXPOSURE

1) Increased temperature may be noted in some cases.
2) Hypotension may occur following ingestions.
3) Tachycardia was reported in a child following an acute ingestion.

3.3.3)

A) WITH POISONING/EXPOSURE

1) Increased temperature may be noted in acute intoxications (Franchitto et al, 2008; Blundell et al, 2003; Akintonwa et al, 1989).

3.3.4)

A) WITH POISONING/EXPOSURE

1) Hypotension may develop with severe poisoning (Oldenquist & Salem, 1999; Agarwal et al, 1993; Schwartz & Schmidt, 1986; Chuttani, 1965).

3.3.5)

A) WITH POISONING/EXPOSURE

1) Tachycardia may develop secondary to hypovolemia or hemolysis (Franchitto et al, 2008; Blundell et al, 2003; Cole & Lirenman, 1978).

Heent

3.4.3)

A) WITH POISONING/EXPOSURE

1) IRRITATION: Eye exposure to copper sulfate crystals or solution has resulted in temporary inflammation, conjunctivitis, and corneal discoloration. Particles left in the conjunctiva have caused necrosis, corneal opacities, and symblepharon (Grant, 1993). Corneal ulceration, tissue destruction, and clouding have been reported (Clayton & Clayton, 1994).

3.4.6)

A) WITH POISONING/EXPOSURE

1) METALLIC TASTE: Acute systemic intoxication may produce a metallic taste in the mouth (Burnett, 1989; Stein et al, 1976).
2) IRRITATION: Concentrated copper sulfate solutions may cause extensive mucosal irritation and damage to the pharyngeal and esophageal lining (Isolauri et al, 1986).
3) STAINING: Oral mucosa may be stained blue following an ingestion (Takeda et al, 2000).

Cardiovascular

3.5.2)

A) HYPOTENSIVE EPISODE

1) WITH POISONING/EXPOSURE

a) Hypotension has been reported following acute ingestion (Schwartz & Schmidt, 1986; Chugh et al, 1977; Stein et al, 1976; Papadoyanakis et al, 1969) and intravenous and subcutaneous injection (Oldenquist & Salem, 1999).
b) Hypotension secondary to gastrointestinal bleeding developed in 5 of 19 patients (26%) requiring hemodialysis after acute copper sulfate poisoning (Agarwal et al, 1993).
c) CASE REPORT: Refractory shock secondary to copper sulfate ingestion has been reported in a 62-year-old man. Erosive esophagitis and gastritis with ulcers were found, but no intra-abdominal bleeding was detected. A dopamine infusion eventually maintained blood pressure at 110/60 mmHg (Schwartz & Schmidt, 1986).
d) CASE REPORT: Hypovolemic shock with systolic blood pressure remaining at about 50 mmHg and refractory to treatment has been reported in a suicidal copper sulfate ingestion (Nakatani et al, 1994).
e) INCIDENCE: In a retrospective review of medical records over a 10-year period involving 35 patients with copper sulfate poisoning, hypotension was reported in 20% of patients. The amount of copper sulfate ingested was unknown; however, the estimated mean serum copper concentration at presentation was 104.5 +/- 56.7 mcg/dL (Naha et al, 2012).

B) SINUS TACHYCARDIA

1) WITH POISONING/EXPOSURE

a) Tachycardia may develop, usually secondary to hypovolemia or hemolysis (Eisnor et al, 2015; Franchitto et al, 2008; Blundell et al, 2003; Cole & Lirenman, 1978).
b) CASE REPORT: Multiple ventricular extrasystoles, tachycardia, and occasional unifocal bigeminy were reported in a 2-year-old boy who ingested 30 mL of a supersaturated copper sulfate solution (Cole & Lirenman, 1978).
c) CASE REPORT: Sinus tachycardia was reported following ingestion of 2 tablespoons of copper sulfate by a 26-year-old woman (Holleran, 1981).
d) CASE REPORT: A 2-year-old boy became tachycardic (140 beats/min) within 5 hours of ingesting 50 mL of copper sulfate solution (Blundell et al, 2003).
e) INCIDENCE: In a retrospective review of medical records over a 10-year period involving 35 patients with copper sulfate poisoning, tachycardia was reported in 37% of patients. The amount of copper sulfate ingested was unknown; however, the estimated mean serum copper concentration at presentation was 104.5 +/- 56.7 mcg/dL (Naha et al, 2012).

C) CARDIAC ARREST

1) WITH POISONING/EXPOSURE

a) CASE REPORT: An 11-year-old girl developed cardiac arrest 2 hours after ingesting a copper sulfate solution (Gulliver, 1991).

Respiratory

3.6.2)

A) FIBROSIS OF LUNG

1) WITH POISONING/EXPOSURE

a) Workers spraying grapevines with a copper sulfate solution developed granulomatous interstitial pulmonary fibrosis (TOXNET, 1986).
b) CASE REPORT: Chest x-ray showed early interstitial edema in a 62-year-old man following suicidal copper sulfate ingestion (Schwartz & Schmidt, 1986).

B) PULMONARY ASPIRATION

1) WITH POISONING/EXPOSURE

a) CASE REPORT: One patient with acute copper sulfate ingestion developed aspiration pneumonia following emesis and CNS depression (Lamont & Duflou, 1988).

C) IRRITATION SYMPTOM

1) WITH POISONING/EXPOSURE

a) Burning copper sulfate may result in irritating and poisonous gases which may irritate the respiratory tract and lungs and can cause metal fume fever (TOXNET, 1986).

D) TRACHEOBRONCHITIS

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 19-year-old woman developed abdominal pain and vomiting that was blue in color after ingesting more than 10 g of copper sulfate solution. She was also hypersalivating and tachycardic. Endoscopy demonstrated grade 2 esophagitis, gastritis, duodenitis, and ulcerations, and a bronchoscopy indicated bronchial blue-green staining and tracheobronchitis. Her serum copper level was greater than 500 mcg/dL. On hospital day 1, she developed hemolysis, methemoglobinemia, and acute renal failure. Therapy included penicillamine 1.5 grams, hemodialysis, exchange transfusions, methylene blue, folate, and zinc. Chelation with calcium disodium edetate, dimercaprol, and trientine were unavailable. Following 2 courses of hemodialysis, copper was undetectable in the dialysate; however, her neurological status deteriorated and her renal function did not improve. The family withdrew care after 14 days, and the patient died (Eisnor et al, 2015).

3.6.3)

A) ANIMAL STUDIES

1) IRRITATION

a) RATS: Experiments with rats have demonstrated that copper sulfate instilled intratracheally can cause an acute pulmonary inflammatory response (Hirano et al, 1990).

2) HYPERTENSION PULMONARY

a) SHEEP: Intravenous copper sulfate resulted in pulmonary hypertension in sheep, with a significant reversible increase in pulmonary vascular resistance (PVR) and a slight transient increase in systemic vascular resistance (SVR) (Ahmed et al, 1981).

Neurologic

3.7.2)

A) CENTRAL NERVOUS SYSTEM DEFICIT

1) WITH POISONING/EXPOSURE

a) Lethargy and coma have been reported (Takeda et al, 2000; Agarwal et al, 1993; Schwartz & Schmidt, 1986; Chuttani, 1965).
b) Hepatic coma may occur in severe cases of copper sulfate-induced liver failure (Agarwal et al, 1993).
c) Coma may develop due to uremia from renal damage (Clayton & Clayton, 1994; Mehta et al, 1985).
d) CASE REPORT: A 2-year-old boy became comatose with a Glasgow Coma Scale of 8 within an hour after ingesting 50 mL of copper sulfate solution but was alert and smiling approximately 3 hours postingestion (Blundell et al, 2003).

B) TREMOR

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Flapping tremor was reported in a patient with no other neurologic symptoms following an acute ingestion (Akintonwa et al, 1989).

C) PSYCHOTIC DISORDER

1) WITH POISONING/EXPOSURE

a) Toxic psychosis has been reported in patients several days after ingestion of "spiritual water" containing copper sulfate (Akintonwa et al, 1989).

D) MUSCLE WEAKNESS

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Motor weakness of the right lower extremity was reported following intentional intravenous and subcutaneous copper sulfate injection (50 mg) by an adult (Oldenquist & Salem, 1999).

Gastrointestinal

3.8.2)

A) GASTROENTERITIS

1) WITH POISONING/EXPOSURE

a) Initial symptoms following ingestion may include a metallic taste, excessive salivation, vomiting, a burning sensation in the epigastrium, and bloody diarrhea (Franchitto et al, 2008; Behera et al, 2007; Jantsch et al, 1985; Woolard, 1978; Agarwal et al, 1975). Stools, vomitus, saliva, and mucous membranes are often stained green or blue. Spontaneous vomiting is very common following ingestion (Takeda et al, 2000).

1) Following parenteral copper sulfate administration, there generally are no symptoms of nausea, vomiting, diarrhea, or hematemesis (Bhowmik et al, 2001).

b) INCIDENCE: In a retrospective review of medical records over a 10-year period involving 35 patients with copper sulfate poisoning, diarrhea, burning epigastric pain, and bloody stools were reported in 46%, 43%, and 31% of patients, respectively. The amount of copper sulfate ingested was unknown; however, the estimated mean serum copper concentration at presentation was 104.5 +/- 56.7 mcg/dL (Naha et al, 2012).
c) CASE SERIES: Nausea, vomiting, and diarrhea have been reported in several persons exposed to copper sulfate in contaminated tea (Nicholas, 1968).
d) CASE REPORT: Nausea, vomiting, hematemesis, and diarrhea were reported within 15 minutes of parenteral injection of copper sulfate by an adult (Oldenquist & Salem, 1999).
e) CASE REPORT: Gastritis associated with hematemesis was reported in a 20-year-old woman who intentionally ingested an unknown amount of copper sulfate crystals (Malik & Mansur, 2011).
f) CASE REPORT: A 19-year-old woman developed abdominal pain and vomiting that was blue in color after ingesting more than 10 g of copper sulfate solution. She was also hypersalivating and tachycardic. Endoscopy demonstrated grade 2 esophagitis, gastritis, duodenitis, and ulcerations, and a bronchoscopy indicated bronchial blue-green staining and tracheobronchitis. Her serum copper level was greater than 500 mcg/dL. On hospital day 1, she developed hemolysis, methemoglobinemia, and acute renal failure. Therapy included penicillamine 1.5 grams, hemodialysis, exchange transfusions, methylene blue, folate, and zinc. Chelation with calcium disodium edetate, dimercaprol, and trientine were unavailable. Following 2 courses of hemodialysis, copper was undetectable in the dialysate; however, her neurological status deteriorated and her renal function did not improve. The family withdrew care after 14 days, and the patient died (Eisnor et al, 2015).

B) VOMITING

1) WITH POISONING/EXPOSURE

a) Copper sulfate induces rapid onset of repeated vomiting (98% of patients within 15 minutes of ingestion), with 2 to 10 episodes of vomiting following a single oral dose. The vomitus is characteristically greenish-blue (Higny et al, 2014; Blundell et al, 2003; Faure et al, 2003; Takeda et al, 2000; James et al, 1999; Gulliver, 1991). The emetic effect appears to be secondary to the irritant effects of copper. Vomiting and hematemesis have been reported to occur within 15 minutes of intravenous and subcutaneous injection (Oldenquist & Salem, 1999).
b) Acute ingestion of as little as 250 mg of copper sulfate generally results in prompt gastrointestinal irritation and associated emesis (Stein et al, 1976). As little as 15 mg may produce gastrointestinal symptoms (Nadig, 1994).
c) INCIDENCE: In a retrospective review of medical records over a 10-year period involving 35 patients with copper sulfate poisoning, vomiting and hematemesis were reported in 86% and 11% of patients, respectively. The amount of copper sulfate ingested was unknown; however, the estimated mean serum copper concentration at presentation was 104.5 +/- 56.7 mcg/dL (Naha et al, 2012).

C) GASTROINTESTINAL HEMORRHAGE

1) WITH POISONING/EXPOSURE

a) Gastric and small intestinal mucosae had erosions, areas of hemorrhage, and greenish staining in 1 case (Chuttani, 1965).
b) CASE REPORT: Necrosis of the intestinal mucosa and perforation was reported at autopsy in a 36-year-old man following a suicidal ingestion (Papadoyanakis et al, 1969).
c) CASE REPORT: Following a suicidal ingestion of copper sulfate, methanol, and ethylene glycol, esophagoscopy revealed corrosion and necrosis of the esophagus and stomach with edematous and hemorrhagic lesions. A fundal perforation was noted (Isolauri et al, 1986).
d) INCIDENCE: In 19 patients requiring hemodialysis after copper sulfate ingestion, 7 (37%) developed gastrointestinal bleeding; in 5 (26%) this was severe enough to cause significant hypotension (Agarwal et al, 1993).
e) CASE REPORT/CHILD: Following the ingestion of a small amount of copper sulfate crystals, a 25-month-old child developed a gastric mucosal hemorrhagic burn but no evidence of systemic copper toxicity. Over the next 48 hours, the boy continued to have blue-stained nasogastric drainage. A full recovery was reported with conservative management (James et al, 1999).
f) CASE REPORT: A 29-year-old man presented with vomiting, diarrhea, and fever approximately 1 day after intentionally ingesting homemade rodent poison containing an unknown amount of copper sulfate. Physical exam indicated epigastric tenderness without guarding. A gastroduodenal endoscopy demonstrated ulcer perforation of the pyloric antrum with gastrointestinal hemorrhage. The patient gradually recovered and was transferred to the psychiatric department for further evaluation (Franchitto et al, 2008).
g) INCIDENCE: In a retrospective review of medical records over a 10-year period involving 35 patients with copper sulfate poisoning, gastrointestinal bleeding was reported as a complication in 41% of survivors (n=27) and in 38% of nonsurvivors (n=8). The amount of copper sulfate ingested was unknown; however, the estimated mean serum copper concentration at presentation was 104.5 +/- 56.7 mcg/dL (Naha et al, 2012).

D) PANCREATITIS

1) WITH POISONING/EXPOSURE

a) INCIDENCE: In a retrospective review of medical records over a 10-year period involving 35 patients with copper sulfate poisoning, pancreatitis was reported as a complication in 11% of survivors (n=27) and in 38% of nonsurvivors (n=8). The amount of copper sulfate ingested was unknown; however, the estimated mean serum copper concentration at presentation was 104.5 +/- 56.7 mcg/dL (Naha et al, 2012).

Hepatic

3.9.2)

A) LIVER ENZYMES ABNORMAL

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Jaundice and elevated liver enzyme concentrations (SGOT 79 units/L and SGPT 270 units/L) were reported in a 20-year-old woman who intentionally ingested an unknown amount of copper sulfate crystals (Malik & Mansur, 2011).
b) In a retrospective review of medical records over a 10-year period involving 35 patients with copper sulfate poisoning, acute liver injury was reported in 10 out of 27 (37%) survivors compared to 6 out of 8 (75%) non-survivors. The mean AST concentration of survivors (n=27) was 223.85 +/- 247.31 units/L as compared with 489.57 +/- 374.02 units/L in nonsurvivors (n=8; p=0.031). The mean ALT concentration of survivors was 66.31 +/- 92.18 units/L as compared with 192.86 +/-168.75 units/L in nonsurvivors (p=0.012) (Naha et al, 2012).

B) HEPATIC NECROSIS

1) WITH POISONING/EXPOSURE

a) Jaundice appears on the second or third day following ingestion and may be accompanied by hepatomegaly and liver tenderness; biopsies may reveal centrilobular necrosis and biliary stasis (Nadig, 1994; Akintonwa et al, 1989; Kurisaki et al, 1988; Ashraf, 1970; Papadoyanakis et al, 1969). Liver enzyme levels are generally elevated (Ashraf, 1970; Singh & Singh, 1968) .
b) CASE REPORT: Three days after ingestion of 250 grams of copper sulfate, a patient's serum bilirubin increased to 6.5 mg/dL and hepatic enzymes increased more than 100 fold over normal levels. Creatine phosphokinase increased to 5620 international units. Within 1 week following chelation therapy, liver abnormalities spontaneously subsided (Jantsch et al, 1985).
c) CASE REPORT: A 22-year-old man developed severe abdominal pain, vomiting, diarrhea, metabolic acidosis, and hemolysis after intentional intravenous self-injection of 1 gram of copper sulfate in water and subsequently died 3 days postinjection. Autopsy revealed submassive hepatic necrosis and acute renal tubular necrosis (Behera et al, 2007).

C) HEPATIC FAILURE

1) WITH POISONING/EXPOSURE

a) Death may occur due to hepatic failure (Akintonwa et al, 1989; Agarwal et al, 1975) .
b) CASE SERIES: In 19 patients requiring hemodialysis following copper sulfate ingestion, 11 (58%) developed jaundice and 1 (5%) died of hepatic encephalopathy (Agarwal et al, 1993).
c) CASE REPORT: Jaundice, increased serum liver enzymes (AST 300 units/L; LDH 13,800 units/L), and increased total bilirubin (14.6 mg/dL) were reported after parenteral copper sulfate injection by a 47-year-old man (Oldenquist & Salem, 1999).

Genitourinary

3.10.2)

A) ACUTE RENAL FAILURE SYNDROME

1) WITH POISONING/EXPOSURE

a) INCIDENCE: Acute renal failure developed in 20% to 40% of patients with acute copper intoxication and may have been due to intravascular hemolysis with deposition of erythrocyte breakdown products in the renal tubules (Dash, 1989). Acute tubular necrosis may occur (Takeda et al, 2000).
b) ONSET: Anuria or oliguria may appear 24 to 48 hours after ingestion, accompanied by an aminoaciduria and proteinuria (Franchitto et al, 2008; Oldenquist & Salem, 1999; Akintonwa et al, 1989; Chugh et al, 1977; Chugh et al, 1977a) .
c) CASE REPORT: A 21-year-old man was admitted to the emergency department with acute renal failure and intravascular hemolysis following an intravenous injection of copper sulfate dissolved in tap water as a suicide attempt. After 6 weeks, hemodialysis, which was administered 3 to 4 times per week, was discontinued. However, serum creatinine remained static at 5 mg%. A percutaneous renal biopsy done at 8 weeks revealed chronic tubulointerstitial nephritis (Bhowmik et al, 2001).
d) CASE REPORT: Acute renal failure (BUN 200 mg/dL; serum creatinine 16 mg/dL) was reported in a 20-year-old woman who intentionally ingested an unknown amount of copper sulfate crystals. With supportive care, including 4 hemodialysis sessions and 2 exchange transfusions, she gradually recovered with a serum creatinine concentration of 0.9 mg/dL reported 6 weeks postingestion (Malik & Mansur, 2011).
e) INCIDENCE: In a retrospective review of medical records over a 10-year period involving 35 patients with copper sulfate poisoning, acute renal failure was reported as a complication in 48% of survivors (n=27) and in 63% of nonsurvivors (n=8). The amount of copper sulfate ingested was unknown; however, the estimated mean serum copper concentration at presentation was 104.5 +/- 56.7 mcg/dL (Naha et al, 2012).
f) CASE REPORT: A 19-year-old woman developed abdominal pain and vomiting that was blue in color after ingesting more than 10 g of copper sulfate solution. She was also hypersalivating and tachycardic. Endoscopy demonstrated grade 2 esophagitis, gastritis, duodenitis, and ulcerations, and a bronchoscopy indicated bronchial blue-green staining and tracheobronchitis. Her serum copper level was greater than 500 mcg/dL. On hospital day 1, she developed hemolysis, methemoglobinemia, and acute renal failure. Therapy included penicillamine 1.5 grams, hemodialysis, exchange transfusions, methylene blue, folate, and zinc. Chelation with calcium disodium edetate, dimercaprol, and trientine were unavailable. Following 2 courses of hemodialysis, copper was undetectable in the dialysate; however, her neurological status deteriorated and her renal function did not improve. The family withdrew care after 14 days, and the patient died (Eisnor et al, 2015).

B) ACUTE TUBULAR NECROSIS

1) WITH POISONING/EXPOSURE

a) Biopsies showing swelling or necrosis of the tubular cells, glomerular congestion, and occasional hemoglobin casts have been reported. Necrosis appeared to be due to direct toxicity to renal tubular cells, as many of these patients did not have severe hemolysis or hypotension (Dash, 1989; Kurisaki et al, 1988).
b) CASE REPORT: A 22-year-old man developed severe abdominal pain, vomiting, diarrhea, metabolic acidosis, and hemolysis after intentional intravenous self-injection of 1 gram of copper sulfate in water and subsequently died 3 days postinjection. Autopsy revealed submassive hepatic necrosis and acute renal tubular necrosis (Behera et al, 2007).

C) BLOOD IN URINE

1) WITH POISONING/EXPOSURE

a) Hemoglobinuria, hematuria, and albuminuria have been reported (Malik & Mansur, 2011; Franchitto et al, 2008; Oldenquist & Salem, 1999; Mehta et al, 1985; Walsh et al, 1977) .
b) CASE REPORT: Oxyhemoglobinuria in a 22-year-old man following ingestion of 175 grams of copper sulfate has been reported (Mittal, 1972).
c) INCIDENCE: In a retrospective review of medical records over a 10-year period involving 35 patients with copper sulfate poisoning, hematuria was reported in 26% of patients. The amount of copper sulfate ingested was unknown; however, the estimated mean serum copper concentration at presentation was 104.5 +/- 56.7 mcg/dL (Naha et al, 2012).

Acid-Base

3.11.2)

A) ACIDOSIS

1) WITH POISONING/EXPOSURE

a) Metabolic acidosis has been described in patients with hemodialysis-induced copper toxicity (Eastwood et al, 1983; Klein et al, 1972). This effect was due to the copper cation but could probably occur with copper sulfate as well.
b) CASE REPORT: Metabolic acidosis developed in a 21-year-old man with acute renal failure following a self-injection of copper sulfate solution. Hemodialysis was started after worsening sensorium and acidosis. The patient improved, with a sequelae of chronic interstitial nephritis (Bhowmik et al, 2001).
c) CASE REPORT: A 22-year-old man developed metabolic acidosis following intentional intravenous injection of 1 gram of copper sulfate in water (Behera et al, 2007).

Hematologic

3.13.2)

A) HEMOLYSIS

1) WITH POISONING/EXPOSURE

a) Red blood cell hemolysis has been reported following acute ingestion (Eisnor et al, 2015; Valsami et al, 2012; Malik & Mansur, 2011; Faure et al, 2003; Takeda et al, 2000; Walsh et al, 1977; Chugh et al, 1977; Singh & Singh, 1968) and parenterally (Behera et al, 2007; Bhowmik et al, 2001; Oldenquist & Salem, 1999). Death has resulted from severe intravascular hemolysis in several cases (Papadoyanakis et al, 1969; Singh & Singh, 1968) .
b) INCIDENCE: In a group of 19 patients requiring hemodialysis following copper sulfate ingestion, 9 (47%) developed evidence of intravascular hemolysis (Agarwal et al, 1993).
c) Acute hemolytic anemia with negative direct and indirect Coombs tests has been reported in copper poisoning from copper tubing in dialysate equipment (Manzler & Schreiner, 1970).
d) CASE REPORT/CHILD: Hemolysis was reported in a 2-year-old boy 24 hours following ingestion of 50 mL of copper sulfate solution. The child was pale and jaundiced with a hemoglobin concentration of 95 g/L and a serum bilirubin level of 137 mcmol/L. Hematologic tests showed marked acanthocytosis and Heinz bodies in greater than 90% of red blood cells. Over the next 3 days, the patient became increasingly pale and jaundiced, secondary to the hemolysis, with the serum bilirubin level peaking at 191 mcmol/L. The hemoglobin level rapidly decreased to 44 g/L. Following a transfusion with red blood cells, the child gradually recovered with a serum bilirubin level of 21 mcmol/L and a hemoglobin level of 84 g/L at hospital discharge (approximately 6 days postingestion) (Blundell et al, 2003).
e) CASE REPORT/ADULT: Intravascular hemolysis was reported in a 29-year-old man approximately 3 days (hospital admission day 2) after intentionally ingesting homemade rodent poison containing an unknown amount of copper sulfate. At time of hospital admission, his hemoglobin level and hematocrit were 16.9 g/dL and 49.9%, respectively. By day 3, his hemoglobin level and hematocrit had decreased to 6.6 g/dL and 18.9%, respectively. The patient gradually recovered following chelation therapy and red cell transfusions (Franchitto et al, 2008).
f) INCIDENCE: In a retrospective review of medical records over a 10-year period involving 35 patients with copper sulfate poisoning, hemolysis was reported as a complication in 74% of survivors (n=27) and in 50% of nonsurvivors (n=8). The amount of copper sulfate ingested was unknown; however, the estimated mean serum copper concentration at presentation was 104.5 +/- 56.7 mcg/dL (Naha et al, 2012).

B) METHEMOGLOBINEMIA

1) WITH POISONING/EXPOSURE

a) Methemoglobinemia has rarely been reported (Eisnor et al, 2015; Valsami et al, 2012; Eastwood et al, 1983; Chugh & Sakhuja, 1979; Chugh et al, 1975; Matter et al, 1969) .

1) CASE REPORT: A 6-week-old infant developed methemoglobinemia due to a high copper and nitrate content in well water (CDC, 1993). The methemoglobinemia may be secondary to red blood cell hemolysis and occurs intravascularly (Ansay, 1984).

b) INCIDENCE: In 19 patients requiring hemodialysis following copper sulfate ingestion, 8 (42%) developed methemoglobinuria (Agarwal et al, 1993).
c) CASE REPORT: A 47-year-old man developed methemoglobinemia (6.3% of total hemoglobin) following intentional injection of 50 mg copper sulfate solution (Oldenquist & Salem, 1999).

C) SULFHEMOGLOBINEMIA

1) WITH POISONING/EXPOSURE

a) Sulfhemoglobinemia has been rarely reported (Salvati et al, 1969).

Dermatologic

3.14.2)

A) SKIN IRRITATION

1) WITH POISONING/EXPOSURE

a) Skin contact may result in severe irritant contact dermatitis and may produce systemic toxicity, especially if applied to injured skin as occurred when copper sulfate was previously used in burn treatment (Nadig, 1994).

B) DISCOLORATION OF SKIN

1) WITH POISONING/EXPOSURE

a) A 2-year-old boy developed blue staining of the lips after ingesting 50 mL of copper sulfate solution. The oral mucosa remained normal (Blundell et al, 2003).

C) SKIN NECROSIS

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 22-year-old man died after intentionally injecting himself intravenously with 1 gram of copper sulfate in water. Examination of the body at autopsy revealed an area of central dark necrosis at the injection site. Dissection at the injection site showed greyish-black discoloration of the subcutaneous tissues (Behera et al, 2007).

Musculoskeletal

3.15.2)

A) RHABDOMYOLYSIS

1) WITH POISONING/EXPOSURE

a) Rhabdomyolysis has been reported with serum CPK levels greater than 5000 international units (Jantsch et al, 1985).
b) CASE REPORT: A serum CPK of 2528 units/L and a positive urine myoglobin were reported in an adult following intravenous and subcutaneous injection of copper sulfate (50 mg) (Oldenquist & Salem, 1999).
c) CASE REPORT: Rhabdomyolysis, with a peak serum CPK level of 3804 international units on the sixth day and urine and serum myoglobin of 1015 mcg/day and greater than 300 nanogram/mL, respectively, on the second day, were reported following an ingestion of about 8 grams of copper sulfate in an 18-year-old man. Hemolysis and acute renal failure were also diagnosed. The patient recovered following vigorous chelation therapy, hemoperfusion, and hemodiafiltration (Takeda et al, 2000).
d) CASE REPORT: Rhabdomyolysis, methemoglobinemia, mild renal and liver dysfunction, and intravascular hemolysis were reported in a 25-year-old man who intentionally ingested an unknown amount of copper sulfate solution. With supportive treatment and administration of dimercaprol, the patient recovered (Valsami et al, 2012).

Immunologic

3.19.3)

A) ANIMAL STUDIES

1) IMMUNE SYSTEM DISORDER

a) MICE: Impairment of both cellular and humoral immune responses, dose and duration related, occurred in mice administered copper sulfate in the drinking water (Pocino et al, 1991).

Reproductive

3.20.2)

A) ANIMAL STUDIES

1) Copper sulfate was teratogenic in mice (Lecyk, 1980; O'Shea & Kaufman, 1979), chickens (King, 1977), and hamsters (Ferm & Hanlon, 1974). It was not teratogenic in sheep, but did cause abortions (James et al, 1966).

3.20.3)

A) METHEMOGLOBINEMIA

1) Copper sulfate specifically can induce methemoglobinemia (Todd, 1962; Todd & Thompson, 1965). Methemoglobinemia is generally unfavorable to the fetus because fetal hemoglobin is more easily oxidized to methemoglobin than the adult form, is converted back to hemoglobin more slowly, and the reduction in oxygen-carrying capacity is more critical to the unborn than to adults.
2) With copper sulfate, however, the methemoglobinemia may be secondary to red blood cell hemolysis and occurs intravascularly (Ansay, 1984).

Carcinogenicity

3.21.1)

A) IARC Carcinogenicity Ratings for CAS7758-98-7 (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 were found on the possible carcinogenic activity of copper sulfate in humans.

3.21.3)

A) LACK OF INFORMATION

1) At the time of this review, no studies were found on the possible carcinogenic activity of copper sulfate in humans.

3.21.4)

A) NEOPLASM

1) Chickens administered 10 mg/kg parenterally developed endocrine tumors (NIOSH, 1986).

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Monitor vital signs.
B) Obtain serial liver function tests, renal function tests, electrolytes, and CBC.
C) Monitor methemoglobin levels in cyanotic patients.
D) Whole blood copper concentrations can be measured. Given various laboratory processing times, the serum copper may not be immediately available to guide the care of acutely poisoned patients. Nevertheless, a baseline serum copper concentration may be useful to document and guide subsequent clinical management.

4.1.2)

A) BLOOD/SERUM CHEMISTRY

1) Obtain serial liver function tests, renal function tests, electrolytes, and CBC.
2) Whole blood copper levels should be obtained in acutely ill patients. Baseline liver function and renal function tests should be obtained and monitored daily until symptoms abate.

a) Serum copper concentrations normally range from 10.5 to 23 micromoles/liter (Bentur et al, 1988).
b) Serum copper levels increase with age in men. Mean levels by age 80 were 1.3 mcg/mL, compared with 1.05 mcg/mL in 20-year-old men (Madaric et al, 1994).

B) HEMATOLOGIC

1) Monitor methemoglobin levels and indices of hemolysis in cyanotic patients.

4.1.3)

A) URINARY LEVELS

1) Normal daily excretion of copper in the urine is less than 0.6 micromole/day (Bentur et al, 1988).

4.1.4)

A) OTHER

1) MONITORING

a) Monitor vital signs.

Methods

1) Copper determinations can be done by atomic absorption spectrophotometry (Bentur et al, 1988; Kurisaki et al, 1988; Gulliver, 1991; Walsh et al, 1977).

Treatment

Life Support

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) Patients that are severely symptomatic should be admitted to an intensive care setting for frequent monitoring.

6.3.1.2) HOME CRITERIA/ORAL

A) Patients who are asymptomatic may be managed at home.

6.3.1.3) CONSULT CRITERIA/ORAL

A) Due to the unusual nature of this exposure, consult a toxicologist or poison center once a history or suspected history of exposure has been determined.

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) Patients with a significant exposure should be monitored during the first 6 hours after exposure.

Monitoring

Oral Exposure

6.5.1)

A) Copper sulfate is a caustic agent, capable of extensive mucosal damage, including perforation of the gastrointestinal tract. Prehospital decontamination with activated charcoal is not recommended because it may cause further complications and obscure endoscopy findings.

6.5.2)

A) NASOGASTRIC SUCTION

1) Copper sulfate is a caustic agent, capable of extensive mucosal damage, including perforation of the gastrointestinal tract. Some clinicians may choose to insert a small, flexible nasogastric tube through the mouth, if the patient is alert and cooperative, in an attempt to remove the corrosive substance following a recent ingestion.

a) The decision should be based on the amount of the ingestion, the concentration of the copper sulfate, and the risk and potential benefit to the patient.

2) In the typical pediatric ingestion involving small volumes of corrosive materials, nasogastric suction is unlikely to be of benefit. In suicidal ingestions involving large quantities of material and an increased likelihood of severe mucosal burns, the risk of causing perforation may outweigh the potential benefit of removing caustic material.

B) ACTIVATED CHARCOAL

1) There are no in vivo studies demonstrating adsorption of copper sulfate to activated charcoal. Activated charcoal may obscure endoscopy findings after ingestion of corrosive copper sulfate and is NOT recommended.

6.5.3)

A) SUPPORT

1) MANAGEMENT OF MILD TO MODERATE TOXICITY

a) Treatment is symptomatic and supportive. Vomiting may be protracted; administer IV fluids and antiemetics as necessary.

2) MANAGEMENT OF SEVERE TOXICITY

a) Treatment is symptomatic and supportive. Treat severe hypotension with IV 0.9% NaCl at 10 to 20 mL/kg. Add dopamine or norepinephrine if unresponsive to fluids. Endoscopy should be performed within the first 24 hours postingestion, and should be avoided from 2 days to 2 weeks postingestion since wound tensile strength is lowest and the risk of perforation is highest during this time. Endoscopy is indicated for all adults with deliberate ingestion, and for children with stridor, vomiting, or drooling. Consider endoscopy in children with dysphagia, refusal to swallow, significant oral burns, or abdominal pain. If second or third degree burns are found, follow 10 to 20 days later with barium swallow or esophagram. The role of corticosteroids is controversial, but generally not indicated. Antibiotics are indicated for definite infection or patients with gastroesophageal perforation. Consider early laparotomy in patients with severe esophageal and/or gastric burns.

B) MONITORING OF PATIENT

1) Monitor vital signs.
2) Obtain serial liver function tests, renal function tests, electrolytes, and CBC.
3) Monitor methemoglobin levels in cyanotic patients.
4) Whole blood copper concentrations can be measured. Given various laboratory processing times, the serum copper may not be immediately available to guide the care of acutely poisoned patients. Nevertheless, a baseline serum copper concentration may be useful to document and guide subsequent clinical management.

C) ENDOSCOPIC PROCEDURE

1) Perform early endoscopy (within 12 hours) on patients who have ingested copper sulfate, who have abdominal pain, stridor, drooling, persistent vomiting or pain with swallowing, or patients with large deliberate ingestions, to evaluate for caustic injury.
2) The following recommendations are extrapolated from experience with ingestion of acids and/or alkaline corrosives.
3) SUMMARY: Obtain consultation concerning endoscopy as soon as possible, and perform endoscopy within the first 24 hours when indicated.
4) 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).
5) RISKS: Numerous large case series attest to the relative safety and utility of early endoscopy in the management of caustic ingestion.

a) 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)

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

a) Advancing across the cricopharynx under direct vision
b) Gently advancing with minimal air insufflation
c) Never retroverting or retroflexing the endoscope
d) Using a pediatric flexible endoscope
e) Using extreme caution in advancing beyond burn lesion areas
f) 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).

7) GRADING

a) 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):
b) Grade 0 - Normal examination
c) Grade 1 - Edema and hyperemia of the mucosa; strictures unlikely.
d) Grade 2A - Friability, hemorrhages, erosions, blisters, whitish membranes, exudates and superficial ulcerations; strictures unlikely.
e) Grade 2B - Grade 2A plus deep discreet or circumferential ulceration; strictures may develop.
f) Grade 3A - Multiple ulcerations and small scattered areas of necrosis; strictures are common, complications such as perforation, fistula formation or gastrointestinal bleeding may occur.
g) 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.

8) FOLLOW UP - If burns are found, follow 10 to 20 days later with barium swallow or esophagram.
9) 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.
10) 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).

D) 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).

E) CHELATION THERAPY

F) PENICILLAMINE

1) Penicillamine increases urinary copper excretion in experimental animal models (Owen et al, 1975), complexes copper in vitro (Borchard & Schneider, 1974), and slows or reverses the progression of hepatic disease in patients with chronic copper intoxication (Wilson's disease and Indian childhood cirrhosis) (Bhusnurmath et al, 1991; Schilsky et al, 1991).
2) D-penicillamine has been used to treat acute copper intoxication, but data regarding efficacy are lacking (Faure et al, 2003; Hantson et al, 1996; Jantsch et al, 1985; Holtzman & Haslam, 1968).

a) Takeda et al (2000) reported chelation with a combination of dimercaprol (1800 mg/day) and penicillamine (900 mg/day) in an 18-year-old man who ingested about 8 grams of copper sulfate. In addition, 4 sessions of hemoperfusion and 5 sessions of hemodiafiltration were performed for copper-induced rhabdomyolysis, acute renal failure and hemolysis. On the 15th day, the patient was discharged, but continued penicillamine for 4 more weeks until hemolytic anemia resolved. It was not clear if chelation enhanced copper clearance in this patient (Takeda et al, 2000).
b) CASE REPORT/FATALITY: A 19-year-old woman developed abdominal pain and vomiting that was blue in color after ingesting more than 10 g of copper sulfate solution. She was also hypersalivating and tachycardic. Endoscopy demonstrated grade 2 esophagitis, gastritis, duodenitis, and ulcerations, and a bronchoscopy indicated bronchial blue-green staining and tracheobronchitis. Her serum copper level was greater than 500 mcg/dL. On hospital day 1, she developed hemolysis, methemoglobinemia, and acute renal failure. Therapy included penicillamine 1.5 grams, hemodialysis, exchange transfusions, methylene blue, folate, and zinc. Chelation with calcium disodium edetate, dimercaprol, and trientine were unavailable. Following 2 courses of hemodialysis, copper was undetectable in the dialysate; however, her neurological status deteriorated and her renal function did not improve. The family withdrew care after 14 days, and the patient died (Eisnor et al, 2015).
c) USUAL ADULT DOSE

1) 1 to 1.5 g/day given orally in 4 divided doses (Nelson, 2011).

d) USUAL PEDIATRIC DOSE

1) 15 to 30 mg/kg/day in 3 to 4 divided doses. Initially, a small dose may be given to minimize side effects and then increased gradually (eg, 25% of the desired dose in week 1, 50% in week 2, and the full dose by week 3) (Caravati, 2004; Prod Info DEPEN(R) titratable oral tablets, 2009).

3) PRECAUTIONS

a) Patients allergic to penicillin products may have cross-sensitivity to penicillamine (Prod Info DEPEN(R) titratable oral tablets, 2009).
b) Monitor for proteinuria and hematuria; heavy metals may also cause renal toxicity (Prod Info DEPEN(R) titratable oral tablets, 2009).
c) Monitor CBC with differential, platelet count, and hepatic enzymes (Prod Info DEPEN(R) titratable oral tablets, 2009).

4) ADVERSE EFFECTS

a) COMMON SIDE EFFECTS/CHRONIC DOSING: Fever, anorexia, nausea, vomiting, diarrhea, abdominal pain, proteinuria, and myalgia(Prod Info DEPEN(R) titratable oral tablets, 2009).

1) SERIOUS ADVERSE EFFECTS: Nephrotic syndrome, hypersensitivity reactions, leukopenia, thrombocytopenia, aplastic anemia, agranulocytosis, cholestatic hepatitis, and various autoimmune responses (Prod Info DEPEN(R) titratable oral tablets, 2009; Feehally et al, 1987; Kay, 1986).

5) PREGNANCY

a) Penicillamine is considered FDA pregnancy category D(Prod Info CUPRIMINE(R) oral capsules, 2004); it should be avoided if possible in pregnant patients.
b) Use of penicillamine throughout pregnancy has been associated with connective tissue abnormalities, hydrocephalus, cerebral palsy, cardiac and great vessel anomalies, webbing of fingers and toes, and arthrogryposis multipex (Linares et al, 1979; Solomon et al, 1977; Anon, 1981; Beck et al, 1981; Rosa, 1986). However, the teratogenic effect when used in low doses or for short periods of time, as in metal chelation, has yet to be determined.

G) DIMERCAPROL

1) BAL increases urinary copper excretion in patients with Wilson's disease (Schilsky et al, 1991) and complexes copper in vitro (Borchard & Schneider, 1974). It has been used in patients with acute copper sulfate intoxication but data regarding efficacy are lacking (Hantson et al, 1996; Jantsch et al, 1985; Walsh et al, 1977; Fairbanks, 1967).
2) Dimercaprol may be appropriate in patients unable to take penicillamine due to vomiting or gastrointestinal injury, or in patients with renal failure (Nelson, 2011).
3) DOSE: ADULT: 2.5 to 5 mg/kg IM every 4 hours for 2 days, then 2.5 mg/kg every 12 hours on day 3, and 1 to 2 times daily thereafter for 1 to 2 weeks, depending on clinical response (Jones & Flanagan, 2004).
4) ADVERSE EFFECTS: Adverse effects may include nausea, vomiting, abdominal pain, tachycardia, headache, sweating, lacrimation, myalgias, a feeling of constriction of the throat, chest, and hands, and a burning sensation of the lips, mouth, throat, and eyes (Jones & Flanagan, 2004).

H) SUCCIMER

1) Succimer may be used in patients with mild to moderate copper poisoning, in lieu of d-penicillamine (Nelson, 2011).
2) DOSE: ADULT: 10 mg/kg 3 times daily for 5 days, followed by 10 mg/kg 2 times daily for 14 days. CHILD: 350 mg/m(2) 3 times daily for 5 days, followed by 350 mg/m(2) 2 times daily for 14 days (Howland, 2011).

I) EDETATE CALCIUM DISODIUM

1) Calcium disodium EDTA has been used to treat patients with acute copper sulfate intoxication but data regarding efficacy are lacking (Walsh et al, 1977).
2) CASE REPORT: A 29-year-old man intentionally ingested homemade rodent poison containing an unknown amount of copper sulfate and subsequently developed vomiting, diarrhea, fever, GI hemorrhage, and intravascular hemolysis. Following hospital admission (approximately 1 day post-ingestion) calcium disodium EDTA was initiated at a dose of 1 gram every 12 hours in 250 mL of 5% dextrose administered intravenously over a 1-hour period and continued for a total of 3 days. After regression of GI signs and symptoms, chelation therapy was switched to oral dimercaprol, administered at a dose of 3 mg/kg four times daily for a total of 5 days. Following chelation therapy, the patient gradually recovered and was transferred to the psychiatric department for further evaluation (Franchitto et al, 2008).

J) UNITHIOL

1) Administration of sodium 2,3-dimercaptopropanesulfonate (DMPS) to mice shortly after copper sulfate intoxication prevented the development of renal tubular degeneration and renal necrosis as well as hepatic lesions which are normally seen in mice following copper poisoning (Mitchell et al, 1982).
2) In vitro, DMPS administration has worsened copper-induced hemolysis, and therefore, is NOT recommended as chelation therapy in copper-poisoned patients (Nelson, 2011).

K) METHEMOGLOBINEMIA

1) SUMMARY

a) Determine the methemoglobin concentration and evaluate the patient for clinical effects of methemoglobinemia (ie, dyspnea, headache, fatigue, CNS depression, tachycardia, metabolic acidosis). Treat patients with symptomatic methemoglobinemia with methylene blue (this usually occurs at methemoglobin concentrations above 20% to 30%, but may occur at lower methemoglobin concentrations in patients with anemia, or underlying pulmonary or cardiovascular disorders). Administer oxygen while preparing for methylene blue therapy.

2) METHYLENE BLUE

a) INITIAL DOSE/ADULT OR CHILD: 1 mg/kg IV over 5 to 30 minutes; a repeat dose of up to 1 mg/kg may be given 1 hour after the first dose if methemoglobin levels remain greater than 30% or if signs and symptoms persist. NOTE: Methylene blue is available as follows: 50 mg/10 mL (5 mg/mL or 0.5% solution) single-dose ampules (Prod Info PROVAYBLUE(TM) intravenous injection, 2016) and 10 mg/1 mL (1% solution) vials (Prod Info methylene blue 1% intravenous injection, 2011). REPEAT DOSES: Additional doses may be required, especially for substances with prolonged absorption, slow elimination, or those that form metabolites that produce methemoglobin. NOTE: Large doses of methylene blue may cause methemoglobinemia or hemolysis (Howland, 2006). Improvement is usually noted shortly after administration if diagnosis is correct. Consider other diagnoses or treatment options if no improvement has been observed after several doses. If intravenous access cannot be established, methylene blue may also be given by intraosseous infusion. Methylene blue should not be given by subcutaneous or intrathecal injection (Prod Info methylene blue 1% intravenous injection, 2011; Herman et al, 1999). NEONATES: DOSE: 0.3 to 1 mg/kg (Hjelt et al, 1995).
b) CONTRAINDICATIONS: G-6-PD deficiency (methylene blue may cause hemolysis), known hypersensitivity to methylene blue, methemoglobin reductase deficiency (Shepherd & Keyes, 2004)
c) FAILURE: Failure of methylene blue therapy suggests: inadequate dose of methylene blue, inadequate decontamination, NADPH dependent methemoglobin reductase deficiency, hemoglobin M disease, sulfhemoglobinemia, or G-6-PD deficiency. Methylene blue is reduced by methemoglobin reductase and nicotinamide adenosine dinucleotide phosphate (NADPH) to leukomethylene blue. This in turn reduces methemoglobin. Red blood cells of patients with G-6-PD deficiency do not produce enough NADPH to convert methylene blue to leukomethylene blue (do Nascimento et al, 2008).
d) DRUG INTERACTION: Concomitant use of methylene blue with serotonergic drugs, including serotonin reuptake inhibitors (SRIs), selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), norepinephrine-dopamine reuptake inhibitors (NDRIs), triptans, and ergot alkaloids may increase the risk of potentially fatal serotonin syndrome (U.S. Food and Drug Administration, 2011; Stanford et al, 2010; Prod Info methylene blue 1% IV injection, 2011).

3) TOLUIDINE BLUE OR TOLONIUM CHLORIDE (GERMANY)

a) DOSE: 2 to 4 mg/kg intravenously over 5 minutes. Dose may be repeated in 30 minutes (Nemec, 2011; Lindenmann et al, 2006; Kiese et al, 1972).
b) SIDE EFFECTS: Hypotension with rapid intravenous administration. Vomiting, diarrhea, excessive sweating, hypotension, dysrhythmias, hemolysis, agranulocytosis and acute renal insufficiency after overdose (Dunipace et al, 1992; Hix & Wilson, 1987; Winek et al, 1969; Teunis et al, 1970; Marquez & Todd, 1959).
c) CONTRAINDICATIONS: G-6-PD deficiency; may cause hemolysis.

L) RHABDOMYOLYSIS

1) SUMMARY: Early aggressive fluid replacement is the mainstay of therapy and may help prevent renal insufficiency. Diuretics such as mannitol or furosemide may be added if necessary to maintain urine output but only after volume status has been restored as hypovolemia will increase renal tubular damage. Urinary alkalinization is NOT routinely recommended.
2) Initial treatment should be directed towards controlling acute metabolic disturbances such as hyperkalemia, hyperthermia, and hypovolemia. Control seizures, agitation, and muscle contractions (Erdman & Dart, 2004).
3) FLUID REPLACEMENT: Early and aggressive fluid replacement is the mainstay of therapy to prevent renal failure. Vigorous fluid replacement with 0.9% saline (10 to 15 mL/kg/hour) is necessary even if there is no evidence of dehydration. Several liters of fluid may be needed within the first 24 hours (Walter & Catenacci, 2008; Camp, 2009; Huerta-Alardin et al, 2005; Criddle, 2003; Polderman, 2004). Hypovolemia, increased insensible losses, and third spacing of fluid commonly increase fluid requirements. Strive to maintain a urine output of at least 1 to 2 mL/kg/hour (or greater than 150 to 300 mL/hour) (Walter & Catenacci, 2008; Camp, 2009; Erdman & Dart, 2004; Criddle, 2003). To maintain a urine output this high, 500 to 1000 mL of fluid per hour may be required (Criddle, 2003). Monitor fluid input and urine output, plus insensible losses. Monitor for evidence of fluid overload and compartment syndrome; monitor serum electrolytes, CK, and renal function tests.
4) DIURETICS: Diuretics (eg, mannitol or furosemide) may be needed to ensure adequate urine output and to prevent acute renal failure when used in combination with aggressive fluid therapy. Loop diuretics increase tubular flow and decrease deposition of myoglobin. These agents should be used only after volume status has been restored, as hypovolemia will increase renal tubular damage. If the patient is maintaining adequate urine output, loop diuretics are not necessary (Vanholder et al, 2000).
5) URINARY ALKALINIZATION: Alkalinization of the urine is not routinely recommended, as it has never been documented to reduce nephrotoxicity, and may cause complications such as hypocalcemia and hypokalemia (Walter & Catenacci, 2008; Huerta-Alardin et al, 2005; Brown et al, 2004; Polderman, 2004). Retrospective studies have failed to demonstrate any clinical benefit from the use of urinary alkalinization (Brown et al, 2004; Polderman, 2004; Homsi et al, 1997).

M) EXPERIMENTAL THERAPY

1) AMMONIUM THIOMOLYBDATE has been successfully administered to sheep for the prevention and treatment of chronic copper sulfate poisoning (Gooneratne et al, 1981). Use of ammonium thiomolybdate for copper toxicity in humans has not been reported, and it is not readily available.

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) SUPPORT

1) Copper fumes may cause metal fume fever or respiratory signs such as wheezing or rales on auscultation. Be prepared to administer respiratory support to symptomatic patients. Copper may be absorbed by this route. Chelation therapy may be indicated.

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

Eye Exposure

6.8.1)

A) Exposed eyes should be irrigated with copious amounts of water for at least 30 minutes. An examination should always be performed. Ophthalmologic consultation should be considered.

6.8.2)

A) IRRIGATION

1) Eye contact may result in severe irritation, especially with higher concentrations that remain in the eye for any length of time. Necrosis may occur if a particle of copper sulfate is left in the eye (Grant, 1993).

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).

6.9.2)

A) IRRITATION SYMPTOM

1) Treat dermal irritation or burns with standard topical therapy. Patients developing dermal hypersensitivity reactions may require treatment with systemic or topical corticosteroids or antihistamines.
2) Skin exposure may result in severe irritation.

B) MONITORING OF PATIENT

1) Monitor serum and urine copper concentrations in patients with significant dermal exposure. Absorption secondary to dermal exposure is expected only when the skin is already injured, as in third degree burns or dermal ulcerations (Bentur et al, 1988). Chelation therapy should be considered if copper concentrations are excessive.
2) GREEN HAIR: Use of shampoos containing D-penicillamine (250 milligrams in 5 milliliters of water and 5 milliliters of shampoo) (Person, 1985) or calcium EDTA (Goldschmidt, 1979) have been effective in removing green color due to copper exposure from hair.

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

Enhanced Elimination

1) Methods to enhance elimination have not been shown to be useful in removing copper sulfate after overdose. Hemodialysis may be necessary to treat renal failure after copper sulfate overdose. Exchange transfusion has been used to treat hemolysis.

1) Hemodialysis to remove copper was ineffective in a 41-year-old patient who ingested copper sulfate (Agarwal et al, 1975), but may be indicated in patients with renal failure secondary to copper poisoning. Agarwal et al (1993) used hemodialysis in 19 patients with copper sulfate-induced renal failure; 12 of 19 patients survived.
2) CASE REPORT: A 20-year-old woman developed acute renal failure, intravascular hemolysis, jaundice, and cyanosis after intentionally ingesting an unknown amount of copper sulfate crystals. Following 4 hemodialysis sessions with 2 sessions of exchange transfusion, using 3 units of blood with each session, the patient gradually recovered without sequelae (Malik & Mansur, 2011).
3) CASE REPORT/FATALITY: A 19-year-old woman developed abdominal pain and vomiting that was blue in color after ingesting more than 10 g of copper sulfate solution. She was also hypersalivating and tachycardic. Endoscopy demonstrated grade 2 esophagitis, gastritis, duodenitis, and ulcerations, and a bronchoscopy indicated bronchial blue-green staining and tracheobronchitis. Her serum copper level was greater than 500 mcg/dL. On hospital day 1, she developed hemolysis, methemoglobinemia, and acute renal failure. Therapy included penicillamine 1.5 grams, hemodialysis, exchange transfusions, methylene blue, folate, and zinc. Chelation with calcium disodium edetate, dimercaprol, and trientine were unavailable. Following 2 courses of hemodialysis, copper was undetectable in the dialysate; however, her neurological status deteriorated and her renal function did not improve. The family withdrew care after 14 days, and the patient died (Eisnor et al, 2015).

1) Continuous peritoneal dialysis with salt-poor albumin over 60 hours resulted in removal of 9.1 milligrams of copper in a child who had ingested approximately 10 to 60 grams of copper sulfate. Concentration of copper in the albumin-containing dialysate was 38 micrograms/deciliter, compared with copper concentrations of 3.88 to 4.02 when dialysate without albumin was used. Exchange transfusion was also done during this time and may have contributed to removal of copper (Cole & Lirenman, 1978; Cole & Lirenman, 1978).

1) CASE REPORT: Four sessions of hemoperfusion and 5 sessions of hemodiafiltration were performed on a patient with myoglobinemia, mild rhabdomyolysis and hemolysis to prevent worsening acute renal failure following ingestion of approximately 8 grams of copper sulfate. No measurements of copper concentrations were reported; the patient survived (Takeda et al, 2000).

1) CASE REPORT: A 20-year-old woman developed acute renal failure, intravascular hemolysis, jaundice, and cyanosis after intentionally ingesting an unknown amount of copper sulfate crystals. Following 4 hemodialysis sessions with 2 sessions of exchange transfusion, using 3 units of blood with each session, the patient gradually recovered without sequelae (Malik & Mansur, 2011).

Abstracts

Case Reports

1) A 42-year-old man ingested 250 grams of copper sulfate. Within 10 minutes, severe epigastric pain, vomiting, and a metallic taste occurred (Jantsch et al, 1985). Examination 90 minutes postingestion revealed vomiting, sinus tachycardia, and microscopic hematuria. Vomiting subsided within 10 hours.

a) Dimercaprol was initially administered, followed by activated charcoal, cathartic, and D-penicillamine. Within 3 days the serum bilirubin rose to 6.5 mg/dL with increased serum levels of hepatic enzymes and CPK. No hemolysis or oliguria were noted.
b) The serum copper level was 1423 mcg/dL. Liver function tests normalized within a week (Jantsch et al, 1985).

1) An 18-month-old boy was admitted to a hospital following ingestion of 3 grams of cupric sulfate. Spontaneous bluish vomiting and lethargy were noted. The initial serum copper level was 1650 mcg/dL (Walsh et al, 1977).

a) Progressive obtundation occurred during the next few hours. At 24 hours, he was alert, with a serum copper level of 230 mcg/dL. On the second day, acute hemolytic anemia developed, with hemoglobinuria, decreased G-6-PD activity, hematuria, glycosuria, cylindruria, and proteinuria.
b) The urine returned to normal and hemoglobin stabilized after 5 days. Dimercaprol, EDTA, and penicillamine were administered.

2) A 2-year-old boy ingested approximately 10 grams of copper sulfate (30 mL of a supersaturated solution) and vomited immediately (Cole & Lirenman, 1978). Within 16 hours after ingestion, he was lethargic, febrile, and anuric, with tachycardia (150 beats/min) and EKG abnormalities (multiple ventricular extrasystoles, unifocal bigeminy). Intravascular hemolysis ensued over the next 18 hours.

a) The serum copper level was 14 mcg/dL at 40 hours after ingestion. Peritoneal dialysis and exchange transfusion were performed, removing a total of about 11 mg of copper. The child recovered and was discharged from hospital on day 28 (Cole & Lirenman, 1978).

Range Of Toxicity

Summary

Minimum Lethal Exposure

1) Acute poisonings from ingestion of copper sulfate, some of them fatal, were reported from New Delhi. Dosage estimates ranged from 1 to 12 grams of copper sulfate (Clayton & Clayton, 1994).

1) Administration of 2 grams of cupric sulfate resulted in death in a 44-year-old woman (Stein et al, 1976).
2) In a series of 14 pediatric chemistry set poisonings, 7 cases including one fatality resulted from ingestion of copper sulfate solution. Mucklow (1997) estimated an incidence of 0.3 cases of chemistry set poisoning per 100,000 children (Mucklow, 1997).
3) A copper sulfate oral emesis solution (2.5 grams in 1750 milliliters of water) was given to a 25-year-old woman who had ingested about 20 tablets of diazepam (2.5 milligrams/tablet). She died 3 days later with death attributed to copper-induced acute hemolysis and acute renal failure (Liu et al, 2001).
4) A 22-year-old man developed severe abdominal pain, vomiting, diarrhea, metabolic acidosis, and intravascular hemolysis after intentionally intravenously injecting 1 gram of copper sulfate, mixed with water, into the right cubital fossa. He died approximately 3 days post-injection due to multi-organ failure (Behera et al, 2007).
5) A 19-year-old woman developed abdominal pain and vomiting that was blue in color after ingesting more than 10 g of copper sulfate solution. She was also hypersalivating and tachycardic. Endoscopy demonstrated grade 2 esophagitis, gastritis, duodenitis, and ulcerations, and a bronchoscopy indicated bronchial blue-green staining and tracheobronchitis. Her serum copper level was greater than 500 mcg/dL. On hospital day 1, she developed hemolysis, methemoglobinemia, and acute renal failure. Therapy included penicillamine 1.5 grams, hemodialysis, exchange transfusions, methylene blue, folate, and zinc. Chelation with calcium disodium edetate, dimercaprol, and trientine were unavailable. Following 2 courses of hemodialysis, copper was undetectable in the dialysate; however, her neurological status deteriorated and her renal function did not improve. The family withdrew care after 14 days, and the patient died (Eisnor et al, 2015).

Maximum Tolerated Exposure

1) The lowest published toxic dose for humans by the oral route is 120 mcg/kg with nausea and vomiting reported (RTECS , 2002).
2) Doses as low as 250 mg of copper sulfate may result in toxic blood levels if spontaneous emesis does not occur or gastric evacuation is not undertaken (Stein et al, 1976). Even with forceful emesis, doses in excess of 1 gram copper sulfate may produce toxicity (Chugh et al, 1977).
3) DRINKING WATER: EPA limit for copper sulfate is 1 ppm in drinking water (TOXNET, 1986).

1) PEDIATRIC

a) Ingestion of 3 grams copper sulfate resulted in hemolytic anemia and renal tubular damage in an 18-month-old boy (Walsh et al, 1977).
b) Ingestion of 30 mL of a super-saturated solution of copper sulfate (approximately 10 grams) resulted in serious toxicity (vomiting, anuria, lethargy, ECG abnormalities, intravascular hemolysis) with survival in a 2-year-old boy (Cole & Lirenman, 1978).

2) ADULT

a) Ingestion of 250 grams of copper sulfate was survived by a 42-year-old man (Jantsch et al, 1985).
b) A previously healthy 18-year-old man ingested approximately 8 grams of copper sulfate solution and reported to the hospital one hour later. He developed rhabdomyolysis, acute renal failure and hemolysis. Following aggressive chelation therapy, hemoperfusion and hemodiafiltration, the patient recovered (Takeda et al, 2000).
c) A 65-year-old man presented to the emergency department with nausea, blue-green vomiting, abdominal pain, and diarrhea, after ingesting approximately 25 mL of a liquid thought to be sparkling water but was later determined to be a diluted copper sulfate solution (100 g copper sulfate in 250 mL of water). Total estimated copper sulfate dose was approximately 10 g. Physical examination showed mucositis and pharyngitis, but there was no evidence of bleeding (no hematemesis and digital rectal exam was negative). An endoscopy indicated pharyngeal edema and diffuse gastroduodenitis without lesions. His plasma copper concentration at admission was 144 mcg/dL (N=70 to 170 mcg/dL). Following 4 days of chelation therapy, his plasma copper concentration decreased to 64 mcg/dL. There were no complications and the patient was discharged from the ICU the next day (Higny et al, 2014).

Serum Plasma Blood Concentrations

7.5.1)

A) THERAPEUTIC CONCENTRATION LEVELS

1) ADULT

a) Average serum copper level in a healthy male is 17.31 micromole/liter (1.1 milligram/liter) (Bentur et al, 1988).
b) Mean normal serum blood levels of copper are reported as 109 micrograms percent (range 89 to 137 micrograms percent) in men, and 120 micrograms percent (range 87 to 153 micrograms percent) in women (Walsh et al, 1977).
c) In whole blood, average copper level in an adult is 1.6 to 2.7 milligrams/liter (Chuttani, 1965).

7.5.2)

A) TOXIC CONCENTRATION LEVELS

1) ACUTE

a) Severe intoxication or lethality has been associated with serum copper levels greater than 500 micrograms per deciliter (Agarwal et al, 1975).

2) CASE REPORTS

a) PEDIATRIC

1) An 11-year-old girl died 2 hours after accidentally ingesting copper sulfate solution (29 micrograms/milliliter) from a crystal growing set (Gulliver, 1991). Blood and serum copper levels were 16 and 25 micrograms/milliliter, respectively, approximately one hour after ingestion. Blood copper level was 66 micrograms/milliliter postmortem.

b) ADULT

1) In a 42-year-old male, serum copper level of 1423 micrograms/deciliter (normal < 100) was reported one day after ingestion of 250 grams of crystalline copper sulfate (Jantsch et al, 1985).
2) Serum copper level of 195 micrograms/deciliter was reported 3 days after a 22-year-old male intravenously injected a small amount of copper sulfate in tap water into his left antecubital vein. One month later, after hemodialysis therapy for acute renal failure, his serum copper level was 50 micrograms/deciliter. Sequelae of chronic interstitial nephritis developed (Bhowmik et al, 2001).

Workplace Standards

1) Not Listed

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

1) Not Listed

Toxicity Information

7.7.1)

A) References: Lewis, 1996 RTECS, 2002

1) LD50- (INTRAPERITONEAL)MOUSE:

a) 18 mg/kg

2) LD50- (ORAL)MOUSE:

a) 369 mg/kg

3) LD50- (ORAL)RAT:

a) 300 mg/kg

4) LD50- (SUBCUTANEOUS)RAT:

a) 43 mg/kg

Pharmacology Toxicology

Pharmacologic Mechanism

Toxicologic Mechanism

Physicochemical

Physical Characteristics

Molecular Weight

Other

1) The EPA limit is 1 ppm of copper sulfate in drinking water in order to prevent a metallic taste and provide adequate protection from toxicity (TOXNET, 1986).

Animal Toxicology

References

General Bibliography

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FeedBack

COPPER SULFATE

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

Acid-Base

Hematologic

Dermatologic

Musculoskeletal

Immunologic

Reproductive

Carcinogenicity

Monitoring Parameters Levels

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

Serum Plasma Blood Concentrations

Workplace Standards

Toxicity Information

Pharmacologic Mechanism

Toxicologic Mechanism

Physical Characteristics

Molecular Weight

Other

General Bibliography