What is the evidence supporting the use of intravenous copper for copper deficiency?
Background
Copper is an essential trace element involved in key enzymatic pathways and required for biochemical, structural, and functional processes involved in growth and development.1-3 Absorption of copper occurs in the stomach and proximal duodenum.3 Patients at risk for copper deficiency include those with malabsorptive conditions, individuals undergoing increased loss or demand of copper, those undergoing bariatric surgery, and individuals with a rare genetic disorder known as Menkes disease, among other conditions.1,3,4 Bariatric surgery is thought to lead to copper deficiency since a large portion of the stomach and duodenum are bypassed from surgery.5 Excessive zinc supplementation can also lead to an increased loss of copper because copper and zinc compete for binding to metallothionein protein. Metallothionein has a higher binding affinity toward copper compared to zinc; additionally, zinc regulates the amount of metallothionein synthesized. An excess of zinc increases synthesis of metallothionein, leading to an increase in copper bound to metallothionein. The bound copper will be excreted, leading to deficiency. Patients with major burns have an increased metabolic demand during the wound healing process due to an extensive loss of trace elements.1,6 Consequently, major burns can result in copper deficiency. The mechanism of copper deficiency in Menkes disease occurs due to a deficient adenosine triphosphate 7A transporter in cell membranes leading to low serum copper levels, but accumulation of copper in the tissues.1,4
It is important to treat copper deficiency because of its association with hematologic, neurologic, and cutaneous manifestations.1 Treatment for copper deficiency should be initiated promptly, as hematologic effects are usually reversible within 4 to 12 weeks, but neurologic effects may only stabilize and not fully resolve after treatment.3-5 Long-term use of oral copper is the typical treatment, although parenteral administration may be indicated in some cases. The purpose of this article is to provide evidence on when it may be appropriate to use intravenous cupric chloride (IV copper) for the treatment of copper deficiency and describe the recommended dose, dilution, and administration parameters.
Copper Deficiency
The recommended dietary allowance (RDA) of copper is 900 μg/day in adults, 890 μg/day in children ages 14 to 18 years, 700 μg/day in children ages 9 to 13 years, 440 μg/day in children ages 4 to 8 years, and 340 μg/day in children ages 1 to 3 years.7 The recommended adequate intake of copper in infants is 200 to 220 μg/day.
Ceruloplasmin levels are usually measured when copper deficiency is suspected since it is an acute phase protein responsible for transporting most of the copper in serum.1,7 Normal serum levels of copper and ceruloplasmin are not well-defined, but according to the World Health Organization, normal serum copper ranges from 0.8 to 1.2 µg/mL (80 to 120 μg/dL) in adults. In general, most sources report copper deficiency as serum copper <0.8 µg/mL and ceruloplasmin <20 mg/dL. The hematologic effects of copper deficiency most commonly present as an anemia or leukopenia.1 Neurologic manifestations of copper deficiency can present as a myeloneuropathy gait disorder, dysfunction in the posterior column of the spinal cord, spasticity, or sensory ataxia.2,3
Guidelines
Cupric chloride solution for injection has a labeled indication for use as a supplement to IV solutions given for peripheral nutrition (PN) to maintain copper serum levels and prevent symptoms of copper deficiency.8 As an off-label indication, there is limited evidence on appropriate dosing, administration, or dilution of parenteral copper for the treatment of copper deficiency. A multi-society guideline published in 2019 by the American Association of Clinical Endocrinologists (AACE), American Society for Metabolic and Bariatric Surgery (ASMBS), Obesity Medicine Association (OMA), and American Society of Anesthesiologists (ASA) on micronutrient supplementation for patients undergoing bariatric procedures provides dosing recommendations for IV copper in copper deficiency.9 The ASMBS 2016 guidelines for surgical weight loss patients present identical recommendations as the multi-society guideline.10 For the treatment of mild to moderate copper deficiency, oral copper should be used for repletion.9,10 If a patient has severe copper deficiency, IV copper at doses of 2 to 4 mg/day may be required for normalization of serum copper levels and resolution of clinical symptoms. Both guidelines also recommend monitoring of serum copper levels every 3 months after normalization of copper levels. Table 1 summarizes these dosing recommendations.
| Table 1. Dosing of IV copper.8-10 | ||
|---|---|---|
| Source | Recommended dosing | Other information |
| Cupric chloride. Package insert. Hospira, Inc; 20218 | Adults on PN: 0.5 to 1.5 mg copper/day (1.25 to 3.75 mL/day) Pediatrics on PN: 20 μg copper/kg/day (0.05 mL/kg/day) Infants weighing <1500 g may require higher doses due to requirements for growth | Supplied as 4 mg/10 mL vial (copper 0.4 mg/mL) |
| AACE/TOS/ASMBS/OMA/ASA 20199 | Severe copper deficiency: 2 to 4 mg/day IV copper for 6 days or until normalization of copper serum levels and resolution of signs/symptoms | Recommendation Grade D (primarily based on expert opinion) |
| ASMBS 201610 | Severe copper deficiency: 2 to 4 mg/day IV copper for 6 days or until normalization of copper serum levels and resolution of signs/symptoms | Recommendation Grade C, BEL 3 (weak evidence) |
| Abbreviations: AACE=American Association of Clinical Endocrinologists; ASA=American Society of Anesthesiologists; ASMBS=American Society for Metabolic and Bariatric Surgery; BEL=best evidence level; IV=intravenous; OMA=Obesity Medicine Association; PN=peripheral nutrition; TOS=The Obesity Society. |
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Neither guideline comments on appropriate methods of dilution nor administration of IV copper for treating copper deficiency. According to the package insert, IV cupric chloride should be diluted in at least 100 mL of fluid due to the acidic pH of the solution; however, the compatible fluids are not specified.8 Table 2 summarizes the dilution, administration, and duration of treatment described in 2 case reports and 1 small randomized-controlled trial (RCT).6,11,12
| Table 2. Dilution, administration, and duration of IV copper therapy.6,8,11,12 | |||
|---|---|---|---|
| Source | Dilution | Administration/duration | Other information |
| Cupric chloride. Package insert. Hospira, Inc; 20218 | Requires dilution in at least 100 mL fluid | Intended for use as an additive to IV solutions in PN. Direct IV injection without dilution is contraindicated due to its acidic pH | Supplied as 4 mg/10 mL vial (copper 0.4 mg/mL) Compatible fluids are not specified |
| Yarandi 201411 Case report | IV copper (copper sulfate) diluted in 100 mL of NS | IV infusion over 4 hours daily for 5 days, followed by oral copper every 6 hours | Patient presented with optic neuropathy, myeloneuropathy, and anemia with severe copper deficiency and a history of bariatric surgery and use of zinc-containing denture cream Copper and ceruloplasmin serum levels normalized by day 13 |
| Btaiche 201112 Case report | IV copper (cupric chloride) diluted in 100 mL of NS | IV infusion over 2 hours daily for 7 days, followed by oral copper 2 to 3 times daily with IV copper infused once weekly for approximately 5 months IV copper was administered in PN when patient was readmitted months later | Patient presented with myeloneuropathy, optic neuropathy, and pancytopenia with severe copper deficiency and a history of bariatric surgery Copper serum level increased to 0.6 μg/mL after 9 days Weekly IV copper with oral copper administration corrected serum copper concentrations. Hematologic parameters improved first, but neurologic symptoms relapsed after initial improvement. PN was initiated after relapse and neurologic symptoms significantly improved. |
| Berger 20076 Prospective, randomized, PC trial | 59 μmol (3.75 mg) copper (copper gluconate) diluted in 250 mL of NS | IV infusion over 12 hours daily for 14 to 21 days | Patients in the treatment group had better wound healing and lower number of infectious complications compared to the placebo group. |
| Abbreviations: IV=intravenous; NS=normal saline; PC=placebo-controlled; PN=peripheral nutrition. |
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Additional Literature
A literature search was conducted to identify trials evaluating use of IV copper. Table 3 summarizes the 2 relevant trials identified, published in 2007 and 2011.6,13 In the small RCT by Berger et al, IV copper was administered as replacement therapy in 21 patients with major burns.6 The patients were given 250 mL of normal saline (NS) containing 3.75 mg copper administered IV daily over 12 hours for 14 to 21 days depending on body surface area burn percentage. Administration of 2 other trace elements were included in the RCT, which may be a limitation since the study was not focused solely on IV copper administration. In the cohort study by Prodan et al, 3 patients with severe copper deficiency were treated with IV copper at doses of 2 to 8 mg elemental copper daily.13 The study did not mention methods used for dilution of IV copper. Additionally, since the results were presented collectively for the 15 patients regardless of route of administration, it was unclear if any of the 3 patients who received IV copper had improvement in neurologic function. Some strengths of the study were the long duration of follow-up, and assessment of neurologic function as a clinical outcome. A limitation of both trials were the small sample sizes.6,13 No additional literature was identified evaluating the use of IV copper in copper deficiency.
| Table 3. Trials evaluating IV copper.6,13 | ||||
|---|---|---|---|---|
| Design/duration | Subjects | Interventions | Results | Conclusion |
| Berger 20076 Prospective, randomized, PC trial in Switzerland Duration: 14 days if burns covered 20% to 60% BSA (n=16); 21 days if burns covered >60% BSA (n=5) | Patients (N=21) aged 16 to 65 years with major burns >20% of BSA were stratified by total burned BSA percentage, presence/absence of inhalation injury, and age (younger or older than 50 years) | Treatment with large doses of TE supplement including copper, to replace acute exudative losses, starting within 12 hours of burn injury Randomly assigned to 250 mL of NS containing 59 μmol (3.75 mg) copper, 4.8 μmol selenium, and 574 μmol zinc administered IV daily over 12 hours (n=11) vs. placebo (n=10) Copper supplement was supplied as copper gluconate powder and mixed with TE solution | In patients assigned to the TE group compared to placebo, plasma copper concentration was significantly higher after day 5 (p=0.013). Clinical outcomes assessed in patients assigned to the TE group showed better wound healing (p=0.02) and lower number of infectious complications occurring during the first 30 days of admission (p=0.015), compared to placebo. There were no significant differences in length of mechanical ventilation, ICU stay, or hospital stay between groups. Safety assessment for copper toxicity showed no difference in LFTs between groups. | In patients with major burns, TE supplementation administered IV containing copper is safe and associated with improvement in clinical outcomes of wound healing and reduction in number of infectious complications. |
| Prodan 201113 Cohort study Duration: 12 months | US veterans (N=15) aged 44 to 90 years with copper deficiency presenting with neurologic (myeloneuropathy n=9; CNS demyelination n=2; myelopathy n=2; neuropathy n=2) and hematologic (anemia n=14; leukopenia n=7) symptoms. Mean serum levels of copper, ceruloplasmin, and zinc at baseline were the following: copper=30.6 μg/dL (range, 0 to 66 μg/dL), ceruloplasmin=13.2 mg/dL (range, 2 to 21.8 mg/dL), zinc=108.8 μg/dL (range, 64 to 195 μg/dL). The mean BI of ADL score at the time of diagnosis was 74 points, with possible scores ranging 0 to 100. | Treatment with IV copper followed by oral copper (n=3), or oral copper only (n=12) Doses of IV copper ranged from 2 to 8 mg/day elemental copper Serum copper levels were monitored every 3 months | Hematologic parameters normalized for all patients within 3 months after IV or oral copper treatment. Serum copper levels normalized in all patients within 12 months. There was gradual improvement in neurologic function as improved gait, vibratory, and joint position sense in the lower extremities (n=10) within 6 to 10 months. The mean BI score (measuring items of self-care, transfers, and mobility) after 12 months was 83 points (mean increase of 9 points; p=0.007); a higher BI score is associated with greater ability for functional independence. There was an inverse linear correlation between change in BI score and duration of copper deficiency prior to treatment (R= -0.68; p=0.005) | In patients with copper deficiency, early administration of copper within 6 to 12 months from onset of symptoms can show an improvement in ADL and neurologic function when treated for a duration of 12 months. |
| Abbreviations: ADL=activities of daily living; BI=Barthel Index; BSA=body surface area; CNS=central nervous system; ICU=intensive care unit; IV=intravenous; LFT=liver function test; NS=normal saline; PC=placebo-controlled; R=relationship; TE=trace element; US=United States. |
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Conclusion
Treatment for copper deficiency depends on the severity of the deficiency.9,10 Patients with a mild to moderate copper deficiency typically receive oral copper. Patients with severe copper deficiency presenting with hematologic and neurologic symptoms may require treatment with IV copper. There is limited evidence on appropriate dose, dilution, and administration of IV copper outside of use in PN. In general, IV copper should be diluted in at least 100 mL of compatible fluid.8 Case reports and case series have demonstrated safe dilution and administration in NS, with infusion time lasting 2 to 4 hours and up to 12 hours in combination with other trace elements.6,11,12 Duration of IV therapy has been documented from 5 to 7 days and up to 21 days, but in general, should continue until severe symptoms resolve and the patient can be transitioned to oral therapy.
References
- Altarelli M, Ben-Hamouda N, Schneider A, Berger MM. Copper deficiency: causes, manifestations, and treatment. Nutr Clin Pract. 2019;34(4):504-513. doi:10.1002/ncp.10328
- Kumar N. Copper deficiency myeloneuropathy. In: Amnioff MJ, Wilterdink JL, eds. UpToDate. Wolters Kluwer; 2021. Accessed August 22, 2022. https://www.uptodate.com/contents/copper-deficiency-myeloneuropathy?search=copper%20deficiency&source=search_result&selectedTitle=1~80&usage_type=default&display_rank=1
- Gwathmey KG, Grogan J. Nutritional neuropathies. Muscle Nerve. 2020;62(1):13-29. doi:10.1002/mus.26783
- Copper deficiency. In: Ehrlich A, ed. DynaMed. EBSCO Industries, Inc; 2022. Accessed August 22, 2022. https://www.dynamed.com/condition/copper-deficiency-23
- Rees Parrish C, O’Donnell K. Copper deficiency: like a bad penny. Pract Gastroenterol. 2020;44(7):24-32. Accessed August 31, 2022. https://practicalgastro.com/2020/08/13/copper-deficiency-like-a-bad-penny/
- Berger MM, Baines M, Raffoul W, et al. Trace element supplementation after major burns modulates antioxidant status and clinical course by way of increased tissue trace element concentrations. Am J Clin Nutri. 2007;85(5):1293-1300. doi: 10.1093/ajcn/85.5.1293
- Institute of Medicine (US) Panel on Micronutrients. Copper. Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. Washington (DC): National Academies Press (US); 2001:chap 7.
- Cupric chloride. Package insert. Hospira, Inc; 2021. Accessed August 22, 2022. https://labeling.pfizer.com/ShowLabeling.aspx?id=4396
- Mechanick JI, Apovian C, Brethauer S, et al. Clinical practice guidelines for the perioperative nutrition, metabolic, and nonsurgical support of patients undergoing bariatric procedures – 2019 update: Cosponsored by American Association of Clinical Endocrinologists/American College of Endocrinology, The Obesity Society, American Society for Metabolic and Bariatric Surgery, Obesity Medicine Association, and American Society of Anesthesiologists. Obesity (Silver Spring). 2020;28(4):O1-O58. doi:10.1002/oby.22719
- Parrott J, Frank L, Rabena R, et al. American Society for Metabolic and Bariatric Surgery integrated health nutritional guidelines for the surgical weight loss patient 2016 update: micronutrients. Surg Obes Relat Dis. 2017;13(5):727-741. doi:10.1016/j.soard.2016.12.018
- Yarandi SS, Griffith DP, Sharma R, Mohan A, Zhao VM, Ziegler TR. Optic neuropathy, myelopathy, anemia, and neutropenia caused by acquired copper deficiency after gastric bypass surgery. J Clin Gastroenterol. 2014;48(10):862-865. doi:10.1097/MCG.0000000000000092
- Btaiche IF, Yeh AY, Wu IJ, Khalidi N. Neurologic dysfunction and pancytopenia secondary to acquired copper deficiency following duodenal switch: case report and review of the literature. Nutr Clin Pract. 2011;26(5):583-592. doi:10.1177/0884533611416127
- Prodan CI, Rabadi M, Vincent AS, Cowan LD. Copper supplementation improves functional activities of daily living in adults with copper deficiency. J Clin Neuromuscul Dis. 2011;12(3):122-128. doi:10.1097/CND.0b013e3181dc34c0
Prepared by:
Amanda McCrone, PharmD Candidate Class of 2023
University of Illinois at Chicago College of Pharmacy
Reviewed by:
Rachel Brunner, PharmD
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy
November 2022
The information presented is current as of September 19, 2022. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.