Supportive care is the cornerstone to the effective management of patients with acute copper poisoning, emphasizing antiemetic therapy, fluid and electrolyte correction, and normalization of vital signs prior to the consideration of chelation therapy. Gastrointestinal decontamination is of limited concern because the onset of emesis generally occurs within minutes of ingestion and is often protracted. In patients who present shortly after the ingestion of a liquid copper solution and who have not yet vomited, aspiration with a nasogastric tube may remove copper ions in solution or suspended in gastric materials. In one case, even after extensive vomiting, nasogastric aspiration still removed a blue solution, but removing this remaining volume is unlikely to provide significant clinical benefit.17 Although oral activated charcoal is unlikely to be harmful, it is of unproved benefit, and it may hinder the ability to perform gastrointestinal endoscopy to evaluate the corrosive effects of a copper salt on the mucosal surface.17 For this reason, even though activated charcoal may adsorb the remaining copper in the proximal gastrointestinal tract, it is relatively contraindicated in most situations. Advanced therapy for patients with kidney failure may include hemodialysis, and for patients with life-threatening hepatic failure, liver transplantation may be needed.
Chelation therapy should be initiated when hepatic, hematologic complications, or other concerning or severe manifestations of poisoning are present. Studies on the efficacy of chelation therapy following acute copper salt poisoning are limited. Even when administered early and appropriately, organ damage and death still occur. Application of the data from the existing literature is complex because of the lack of controlled studies of human copper poisoning. Although animal models and uncontrolled human data exist, the results are frequently contradictory. Three chelators are clinically available, and most data regarding dosing and efficacy data are derived either from chelator use in the treatment of patients with Wilson disease or from their effects on copper elimination during chelation of patients manifesting toxicity from other metals.
Most patients with copper poisoning are initially treated with intramuscular British anti-Lewisite (BAL).113 Although BAL may be less effective, its use is appropriate in patients in whom vomiting or gastrointestinal injury prevents oral d-penicillamine administration. Furthermore, because the BAL–copper complex primarily undergoes biliary elimination, whereas d-penicillamine undergoes renal elimination, BAL proves useful in patients with kidney failure. When tolerated, d-penicillamine therapy should be started simultaneously or shortly after the initiation of therapy with BAL (Antidotes in Depth: A25).
Calcium disodium ethylenediaminetetraacetate (CaNa2EDTA) reduces the oxidative damage induced by copper ions in experimental models.123 However, it does not greatly enhance the elimination of copper when used for the chelation of other metals.114 In addition, short-term use of CaNa2EDTA inactivates dopamine β-hydroxylase in humans, presumably by chelating the copper moiety from its active site.32 However, because the in vivo activity of this enzyme is restored following the addition of exogenous copper, the potential for inhibition of the formation of neuronal norepinephrine during the treatment of acute poisoning is unknown. Successful clinical use of CaNa2EDTA is reported.38,86,113 Interestingly, CuCaEDTA is used as a copper supplement in animals, and overdose of this formulation results in copper poisoning suggesting that its chelating ability is limited.39 (See Antidotes in Depth: A27).
d-Penicillamine (Cuprimine), a structurally distinct metabolite of penicillin, is an orally bioavailable monothiol chelator. It is used in the treatment of lead, mercury, and copper toxicity, as well as in the management of rheumatoid arthritis and scleroderma. It has also more recently been investigated for its antiangiogenesis effects in cancer therapy, which occur by chelation of copper that serves as a cofactor for growth factors, such as fibroblast growth factor.115 d-Penicillamine is effective in preventing copper-induced hemolysis in patients with Wilson disease. Its protective mechanism is primarily mediated through chelation of unbound copper ions, rendering them unable to participate in redox reactions.62 The d-penicillamine–copper complex undergoes rapid renal clearance in patients with competent kidneys. The use of d-penicillamine is not formally studied in patients with acute copper salt poisoning, but case studies and animal models suggest that copper elimination is enhanced.18,41,51 In patients with Wilson disease, it dramatically increases the urinary elimination.117 The recommended adult dose is 1 to 1.5 g/d given orally in four divided doses, and although formal pediatric dosing recommendations are not available, some recommend the adult dose and others suggest 20 mg/kg/d orally every 12 hours.49 d-Penicillamine is also indicated for the treatment of chronic exogenous copper poisoning, such as Indian childhood cirrhosis. Initiation early in the course of disease and discontinuation of the exposure to copper are associated with hepatic recovery and dramatically improved survival rates.12
Although d-penicillamine appears to be effective, it is associated with several significant complications. In nearly 50% of patients treated with d-penicillamine for Wilson disease, there is worsening of the neurologic findings.20 Subacute toxicities of d-penicillamine include aplastic anemia, agranulocytosis, kidney and lung toxicity, and loss of trace metals.54 Long-term use of d-penicillamine is also associated with the development of cutaneous lesions and immunologic dysfunction. However, in the brief treatment necessary for acutely poisoned patients, the major risk is the potential for hypersensitivity reactions that occur in 25% of patients who are allergic to penicillin. This hypersensitivity reaction is likely related to contamination of the pharmaceutical preparation with penicillin, rather than immunologic cross-reactivity.50,59 The use of d-penicillamine during pregnancy is associated with congenital abnormalities, although all of the data are derived from women with Wilson disease who were receiving long-term therapy.91
Succimer is sometimes described as an ineffective copper chelator, although it is able to triple the baseline copper elimination in a murine model. Given its ease of use, relative safety, and benefit in experimental models,1 succimer may be used in lieu of d-penicillamine in patients with mild or moderate poisoning. Under these circumstances, the use of standard lead poisoning dosing regimens is warranted (Chap. 96 and Antidotes in Depth: A26).
DMPS, an experimental chelator that is gaining popularity for the treatment of arsenic poisoning, prevents acute tubular necrosis in copper-poisoned mice.78 DMPS also proved to be the most effective of a panel of chelators in a murine model of copper sulfate poisoning,58 and it substantially increased urinary copper elimination in nonpoisoned, healthy individuals.116 However, DMPS, unlike d-penicillamine, forms intramolecular disulfide bridges, which liberates an electron. Although this accounts for its potency as a reducing agent, it also probably explains its propensity to worsen copper-induced hemolysis in vitro.2 Because an adequate analysis of risk versus benefit is unavailable, DMPS should not be used to chelate copper-poisoned patients at this time.
Trientine (triethylenetetramine), an orally bioavailable chelator, is the second-line therapy for patients with Wilson disease, but its use in patients with acute copper poisoning is unreported. It has recently been studied for its role as a copper chelator in patients with Alzheimer disease.31 Zinc therapy to induce metallothionine synthesis, which is also of proven efficacy in Wilson disease, has an unknown role in the treatment of acute copper poisoning. The need for several weeks of zinc therapy prior to realizing full efficacy makes its therapeutic use in acutely poisoned patients questionable. Although large oral doses of zinc salts may limit the absorption of copper ion, the concomitant gastrointestinal irritant effects of zinc ion make this therapy impractical.
Tetrathiomolybdate, an FDA-recognized chelator with orphan drug status although not marketed, may be available through compounding pharmacies, typically as ammonium tetrathiomolybdate. In uncontrolled studies, tetrathiomolybdate is suggested to benefit copper-poisoned animals,88 but its use in acute copper poisoning in humans is unstudied. Tetrathiomolybdate depleted the copper stores in a patient with cancer who purchased the compound over the Internet as an “alternative” antiangiogenesis therapy.67
Clioquinol, a xenobiotic used 50 years ago as an antiparasitic, was discontinued due to epidemic optic neuropathy that may have been associated with its ability to chelate copper ions.102 Clioquinol is currently under investigation as a therapy for Alzheimer disease,10 but it has not been studied for patients with acute or chronic copper poisoning.
Limited data exist regarding the elimination of copper ions by various extracorporeal means. Hemodialysis membranes undoubtedly allow copper ions to cross, based on the epidemics in which hemodialysis using copper-rich water inadvertently resulted in copper poisoning.35 Although copper should be similarly cleared by hemodialysis, its relatively large volume of distribution limits the potential clinical usefulness of this technique. Furthermore, copper ions are highly protein bound, and the dialyzable concentration is typically less than 1 pmol/L, suggesting that hemodialysis would have little clinical usefulness. This fact is supported by case reports in which serum, tissue, or dialysate concentrations of copper are assessed.4,86 Furthermore, given the propensity of hemodialysis to lyse erythrocytes, which may release stored copper and worsen toxicity, hemodialysis is not recommended except as indicated for kidney failure.
Molecular adsorbents recirculating system (MARS) and single-pass albumin dialysis (SPAD), modified forms of hemodialysis in which albumin is included in the dialysate, are reported to rapidly and substantially lower the serum copper concentrations in patients with fulminant Wilson disease, allowing a bridge to hepatic transplantation.24,30 A single patient with Wilson disease was treated with albumin dialysis using a 44 g/L albumin-containing dialysate and a slow dialysate flow rate (1–2 L/h) in a manner similar to routine continuous venovenous hemodiafiltration; this reportedly removed 105 mg of copper and normalized the serum copper concentration.63 The risk associated with hemolysis likely remains, and caution should be used when extrapolating therapy from Wilson disease to exogenous copper poisoning.
Exchange transfusion is of undefined, but probably limited, benefit in acute copper sulfate poisoning.73,124 Plasma exchange enhanced the elimination of copper in patients with fulminant Wilson disease.61,63 Copper removal ranged from 3 to 12 mg per treatment, but it is unclear if either of these removal techniques would be beneficial following an ingestion of gram quantities of copper sulfate. The same warning as above about inadvertent red cell lysis applies.
Peritoneal dialysis is not useful in patients with fulminant Wilson disease.65 Peritoneal dialysis removed less than 700 μg in a copper sulfate–poisoned child whose copper concentration was 207 μg/dL.46 However, in the same patient, the addition of albumin to the dialysate removed 9 mg of copper at a time when the child’s serum copper concentration had already fallen substantially.
Management of the hepatic toxicity requires little more than standard supportive care. The potential benefit of N-acetylcysteine has not been studied, although it is useful in many forms of fulminant hepatic failure and is warranted in most hepatotoxic patients. Liver transplantation should be considered, but specific criteria for transfer to a specialized liver unit or for transplant, other than those that are applicable for Wilson disease or other more common etiologies of fulminant hepatic failure, are undefined.
There are no controlled data on the treatment of acute copper poisoning in pregnancy. The available data on pregnant women with Wilson disease document that d-penicillamine is teratogenic and that zinc may be the preferred therapy.