549255

research-article2014

PENXXX10.1177/0148607114549255Journal of Parenteral and Enteral NutritionPalm and Dotson

Case Report

Copper and Zinc Deficiency in a Patient Receiving Long-Term Parenteral Nutrition During a Shortage of Parenteral Trace Element Products

Journal of Parenteral and Enteral Nutrition Volume XX Number X Month 201X 1­–4 © 2014 American Society for Parenteral and Enteral Nutrition DOI: 10.1177/0148607114549255 jpen.sagepub.com hosted at online.sagepub.com

Eric Palm, PharmD1; and Bryan Dotson, PharmD, BCPS2,3

Abstract Drug shortages in the United States, including parenteral nutrition (PN) components, have been common in recent years and can adversely affect patient care. Here we report a case of copper and zinc deficiency in a patient receiving PN during a shortage of parenteral trace element products. The management of the patient’s deficiencies, including the use of an imported parenteral multi–trace element product, is described. (JPEN J Parenter Enteral Nutr. XXXX;xx:xx-xx)

Keywords parenteral nutrition; minerals/trace elements; nutrition

In recent years, drug shortages in the United States have been common, including individual parenteral nutrition (PN) components.1 This has included the electrolytes and micronutrients (vitamins and trace elements). Copper and zinc are essential trace elements involved in the function of many enzymes, and both are routinely included in PN prescriptions.2 Although deficiency of these trace elements occurs rarely in adults, risk factors include intestinal malabsorption syndromes and longterm use of PN without trace elements.2 Clinical manifestations of copper deficiency include anemia, neutropenia, gait difficulty, and lower extremity numbness.2 Zinc deficiency can present with impaired wound healing, immune compromise, diarrhea, and alopecia.2 There are few published cases in the literature of nutrient deficiencies occurring as a result of PN product shortages.3,4 Here we describe a case of copper and zinc deficiency in a patient receiving PN during a shortage of parenteral trace element products in the United States and the management of the patient’s deficits.

Case Report The patient is a 57-year-old woman with a history of hypertension and obesity. In 2007, she underwent gastric bypass and over subsequent years required multiple other surgeries (eg, gastric bypass revision, ventral hernia surgery). Following these procedures, the patient developed multiple enterocutaneous fistulas. Due to the fistula location, enteral nutrition was not feasible, and the patient received home PN over several years. In June 2013, the home infusion company that supplied PN was affected by a national shortage of parenteral trace element products. At this time, the fixed-dose parenteral multi– trace element products and most individual intravenous (IV)

trace elements were not available. There were short periods of time where the patient’s home infusion company was able to obtain parenteral zinc and selenium, but for the majority of the next 6 months, the patient received PN without trace elements. Although there were absorption concerns, the patient was instructed to take an oral multivitamin with trace elements once daily since there were no other options. In January 2014, the patient presented to our institution for elective repair of a recurrent ventral hernia and excision of an enterocutaneous fistula. Surgery was performed on the day of hospital admission. Upon presentation to the hospital, there were no abnormalities noted on neurological examination. Initial laboratory values were within normal limits, except for a hemoglobin of 9.6 g/dL (reference range, 11.5–15.1 g/dL) and a hematocrit of 30% (reference range, 34.4%–44.2%). The patient had normocytic anemia with a mean corpuscular volume of 87.7 fL (reference range, 82–97 fL). Initial medications in the hospital aside from PN included subcutaneous heparin for prophylaxis of venous thromboembolism, pantoprazole, insulin lispro, and as-needed hydromorphone. The initial hospital PN prescription contained standard doses of macronutrients, electrolytes, and injectable multivitamins. The patient also received From the 1Detroit Medical Center–Sinai-Grace Hospital, Detroit, Michigan; 2Department of Pharmacy, Harper University Hospital, Detroit, Michigan; and 3Wayne State University, Detroit, Michigan. Financial disclosure: None declared. Received for publication April 30, 2014; accepted for publication August 7, 2014. Corresponding Author: Bryan Dotson, PharmD, BCPS, Harper University Hospital, 3990 John R., Detroit, MI 48201, USA. Email: [email protected]

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5 mg of zinc and 60 mcg of selenium daily in PN. Other trace elements were unavailable due to drug shortages. On hospital day 16, serum trace element levels were checked. These are send-out tests at our institution with a turnaround time of approximately 1 week. At this time, the patient was clinically stable but was receiving IV antibiotics for an intra-abdominal infection. Serum copper was low at 24 mcg/ dL (3.78 µmol/L) (reference range, 80–155 mcg/dL [12.6–24.4 µmol/L]), and serum zinc was low at 48 mcg/dL (7.34 µmol/L) (reference range, 60–120 mcg/dL [9.18–18.36 µmol/L]). Other serum trace element concentrations were within normal limits: selenium was 26 mcg/L (0.33 µmol/L) (reference range, 23– 190 mcg/L [0.29–2.4 µmol/L]), manganese was 1.7 mcg/L (30.94 µmol/L) (reference range, 0–2 mcg/L [0–36.4 µmol/L]), and chromium was 2.3 mcg/L (42.09 nmol/L) (reference range, ≤5 mcg/L [≤91.5 nmol/L]). Impaired wound healing was present, which is a clinical manifestation of zinc deficiency.2 The patient’s wounds were inflamed with purulent discharge and did not fully heal over time. Multiple abdominal washouts, dressing changes, and negative-pressure wound therapy (V.A.C.; Kinetic Concepts, San Antonio, TX, USA ) were also required. The patient also presented with anemia, which is one of the clinical manifestations of copper deficiency. To further work up the patient’s anemia, iron studies, vitamin B12, and folate concentrations were checked. Serum iron was 33 mcg/ dL (reference range, 50–170 mcg/dL), total iron binding capacity was 161 mcg/dL (reference range, 250–450 mcg/dL), iron saturation was 21% (reference range, 20%–50%), and serum ferritin was 455 ng/mL (reference range, 10–291 ng/mL). Serum vitamin B12 was 824 pg/mL (reference range, 211–911 pg/mL) and serum folate was 10.2 ng/mL (reference range, 5.4–24 ng/mL). When the patient’s nutrient deficiencies were diagnosed, parenteral multi–trace element products and parenteral copper were not available due to drug shortages. Enteral supplementation was also not possible because of altered gastrointestinal (GI) anatomy and enterocutaneous fistulas. A diatrizoate megluminesodium (Gastrografin, Bracco Diagnostics, Monroe Township, NJ, USA) study was performed and showed leakage of contrast into the peritoneal cavity. It was decided to initiate a special adult multi–trace element product that has recently received Food and Drug Administration (FDA) regulatory discretion for importation and distribution (Addamel-N; Fresenius Kabi, LLC, Lake Zurich, IL; lot 12GF802) (Table 1).5,6 Starting on hospital day 23, the patient received 10 mL of Addamel-N daily in PN, which contains the recommended daily requirements of trace elements, including 1.3 mg of copper and 6.5 mg of zinc.5,6 Each PN bag infused over 24 hours and contained 100 g of amino acids, 300 g of dextrose, 40 g of lipid, 40 mEq of NaCl, 40 mEq of Na acetate, 20 mmol of NaPO4, 30 mEq of KCl, 10 mEq of K acetate, 10 mmol of KPO4, 20 mEq of magnesium sulfate, 10 mL of injectable multivitamins, and 10 mL of Addamel-N. Since the patient had documented zinc deficiency, an additional 6 mg of zinc was added to the PN solution each day as zinc chloride.

Table 1.  Trace Element Content of Adult Multi–Trace Element Products.2,5,6

Trace Elements Copper, mg Chromium, mcg Manganese, mcg Selenium, mcg Zinc, mg Iron, mg Molybdenum, mcg Iodine, mg Fluorine, mg

Recommended Daily Requirements 0.3–0.5 10–15 60–100 20–60 2.5–5

Multitrace-5 Concentrate Addamel-N (1 mL) (10 mL) 1 10 500 60 5 0 0 0 0

1.3 10 270 32 6.5 1.1 19 0.13 0.95

PN bags were visually inspected, and there was no evidence of incompatibilities or an unstable admixture. The patient’s hospital stay was complicated by intraabdominal abscesses, high-output enterocutaneous fistulas, and atrial fibrillation, and multiple subsequent surgeries were performed (eg, small bowel resection, partial hemicolectomy, and multiple abdominal washouts). The patient received PN for her entire 93-day hospitalization. Liver function tests, including aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, total bilirubin, and direct bilirubin, were monitored weekly, and the values continued to stay within normal limits. The patient eventually made a sufficient recovery and was discharged to a subacute rehabilitation facility on hospital day 93. Trace element levels were last checked approximately 2 weeks before discharge, which was 54 days after Addamel-N was started. Serum copper was slightly below normal at 76 mcg/dL (11.96 µmol/L), and serum zinc was within the normal range at 104 mcg/dL (15.91 µmol/L).

Discussion PN product shortages in the United States have been common in recent years.1 Causes of drug shortages include quality problems such as contamination and impurities, lack of raw materials, discontinuation of production because of limited profitability, and demands that exceed available supplies.1 These shortages can have a major impact on patient care. In one recent national survey, 70% of respondents reported that PN-related product shortages interfered with the ability to meet micronutrient needs, and 16% of respondents reported that PN-related product shortages directly affect patient outcome.7 Since trace element deficiencies may go undetected when at-risk patients are not closely monitored, clinicians should observe patients for signs and symptoms of nutrient deficiencies during shortages of parenteral trace element products. Serum trace element levels should also be obtained

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as necessary. Special attention should be given to patients receiving long-term PN, especially those who receive PN without trace elements. PN drug shortages can create challenges for clinicians, and the management of these shortages can be time and labor consuming. The American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) has developed recommendations to assist clinicians in managing patients during shortages of parenteral trace element products.8 When parenteral multi–trace element products are not available, clinicians should consider the use of enteral trace element products, individual IV trace elements, or imported products authorized for use by the FDA.8 There are few published cases in the literature of nutrient deficiencies occurring in adults as a result of PN product shortages.3,4 Recent reports have described a PN-dependent patient who developed either copper or zinc deficiency during a shortage of parenteral trace element products.3,4 These patients were managed with a combination of enteral trace element products and U.S. parenteral multi–trace element products.3,4 To our knowledge, our case report is the first to describe the successful use of an imported product to manage nutrient deficiencies during a shortage of parenteral trace element products. Our case report is also novel because the patient had a deficiency of more than one trace element. Addamel-N is a European fixed-dose parenteral multi– trace element product used as a supplement in IV nutrition to meet the daily requirements of trace elements in adults.5,6 The FDA recently authorized the importation of Addamel-N into the United States during the prolonged national shortage of U.S. parenteral trace element products.6 Table 1 compares the trace element content of a standard daily dose of Addamel-N and Multitrace-5 Concentrate (American Regent Laboratories, Inc, Shirley, NY, USA), a widely used parenteral multi–trace element product in the United States. One difference between these products is that the U.S. product does not contain iron, molybdenum, iodine, and fluorine.6 There are also minor differences in the dose of individual trace elements and the salts of the active ingredients present in these products.6 Although it is unclear if any of these differences are clinically important, there are some points to consider with the use of Addamel-N. First, barcodes found on an ampule of Addamel-N are not appropriately recognized by U.S. scanning systems and should not be used.6 Second, although Addamel-N has been shown to be compatible with European PN formulations containing lipids, we are not aware of similar tests conducted with U.S. products.6 One recent survey of U.S. clinicians regarding IV trace element product shortages found that 28% of respondents add Addamel-N to PN formulations containing lipids, and none reported any evidence of incompatibilities or an unstable admixture.9 However, if possible, we recommend adding Addamel-N to IV fluids or dextrose–amino acid PN formulations and hang lipids separately as a piggyback. Finally, Addamel-N is significantly more expensive than U.S. enteral and parenteral trace element

products. For these reasons, we recommend the use of imported Addamel-N only when it is the only viable option, as was the case with our patient. Several limitations of our case report should be mentioned. First, copper and zinc deficiency was diagnosed based on low serum concentrations. Although serum copper levels were monitored, ceruloplasmin concentrations were not checked. The patient did have clinical signs of zinc and copper deficiency, such as impaired wound healing and anemia. However, we could not establish a cause-effect relationship between these symptoms and nutrient deficiencies. A low serum iron was also present, which could have caused the anemia. Second, it is unclear whether serum zinc levels were low in our patient because she received PN lacking zinc for several months or if other factors were also responsible, such as the loss of large volumes of GI fluid from an enterocutaneous fistula.2 We also could not rule out the possibility that confounding factors (eg, infection, inflammation, and metabolic stress) falsely lowered serum zinc concentrations.2 Third, serum trace element levels were not checked in our patient prior to hospitalization. It is therefore unknown what the patient’s serum copper and zinc concentrations were before parenteral trace elements were omitted from PN. Fourth, studies have found that PN solutions can be contaminated with trace elements found in other components.10 It is unclear if trace element contaminants were present in bags of PN that were administered to our patient. Finally, the patient was unsure of the brand of oral multivitamins with trace elements she was taking prior to hospitalization. It is unclear if this product contained a full spectrum of trace elements at a recommended dose. The disintegration, dissolution, and bioavailability of this product are also unknown.

Conclusion PN product shortages in the United States have been common in recent years, and this case report is an example of how drug shortages can adversely affect patient care. Clinicians should monitor patients closely for nutrient deficiencies during shortages of parenteral trace element products and use alternative methods for administering supplements when necessary. The A.S.P.E.N. recommendations for managing PN trace element product shortages is a useful resource, and the effectiveness of these recommendations for managing patients during drug shortages should be further investigated.8 We report the first case of successful use of Addamel-N, an imported fixed-dose parenteral multi–trace element product, to manage nutrient deficiencies in a patient receiving PN during a shortage of parenteral trace element products in the United States.

References 1. Hassig TB, McKinzie BP, Fortier CR, Taber D. Clinical management strategies and implications for parenteral nutrition drug shortages in adult patients. Pharmacotherapy. 2014;34(1):72-84.

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2. Vanek VW, Borum P, Buchman A, et al. A.S.P.E.N. position paper: recommendations for changes in commercially available parenteral multivitamin and multi-trace element products. Nutr Clin Pract. 2012;27(4):440-491. 3. Pramyothin P, Kim DW, Young LS, Wichansawakun S, Apovian CM. Anemia and leukopenia in a long-term parenteral nutrition patient during a shortage of parenteral trace element products in the United States. JPEN J Parenter Enteral Nutr. 2013;37(3):425-429. 4. Franck AJ. Zinc deficiency in a parenteral nutrition–dependent patient during a parenteral trace element product shortage. JPEN J Parenter Enteral Nutr. 2014;38(5):637-639. 5. Addamel N [package insert]. Lake Zurich, IL: Fresenius Kabi USA. n.d. 6. Dear healthcare professional letter. Adult multi-trace element availability. Fresenius Kabi USA, 2013. http://www.fda.gov/downloads/Drugs/ DrugSafety/DrugShortages/UCM355392.pdf. Accessed April 25, 2014.

7. Boullata JI, Guenter P, Mirtallo JM. A parenteral nutrition use survey with gap analysis. JPEN J Parenter Enteral Nutr. 2013;37(2):212-222. 8. American Society for Parenteral and Enteral Nutrition. Parenteral nutrition trace element product shortage considerations. http://www.nutritioncare. org/Professional_Resources/Drug_Shortages/Parenteral_Nutrition_Trace_ Element_Product_Shortage_Considerations/. Accessed April 25, 2014. 9. American Society for Parenteral and Enteral Nutrition. A.S.P.E.N. intravenous trace element shortage survey report (June 2014). http://www. nutritioncare.org/News/Product_Shortages/Trace_Element_Shortage_ Survey_Data_Released/. Accessed August 2, 2014. 10. Pluhator-Murton MM, Fedorak RN, Audette RJ, Marriage BJ, Yatscoff RW, Gramlich LM. Trace element contamination of total parenteral nutrition. 1. Contribution of component solutions. JPEN J Parenter Enteral Nutr. 1999;23(4):222-227.

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Copper and Zinc Deficiency in a Patient Receiving Long-Term Parenteral Nutrition During a Shortage of Parenteral Trace Element Products.

Drug shortages in the United States, including parenteral nutrition (PN) components, have been common in recent years and can adversely affect patient...
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