Anemia and Leukopenia in a Long‐Term Parenteral Nutrition Patient During a Shortage of Parenteral Trace Element Products in the United States

Recently, drug shortages in the United States have affected multiple components of the parenteral nutrition (PN) solution. A 62‐year‐old patient with systemic sclerosis who was dependent on home PN due to intestinal dysmotility developed anemia and leukopenia approximately 4 months after parenteral copper was withheld from her PN solution due to drug shortages. The patient was not able to tolerate a sufficient amount of oral multivitamins with trace elements due to severe dysphagia. Her serum copper and ceruloplasmin concentrations were undetectable, confirming the diagnosis of severe copper deficiency. The hematological abnormalities promptly resolved with copper supplementation. This report emphasizes the importance of close monitoring for nutrient deficiencies during drug shortages and supplementing with oral or enteral nutrition when feasible, particularly in high‐risk patients such as those with intestinal malabsorption or short bowel syndrome who are dependent on long‐term PN.     

Copper Levels in Cholestatic Infants on Parenteral Nutrition

Background: Copper levels are primarily regulated by biliary excretion. In cholestatic patients, there is a concern that the standard dose of copper in parenteral nutrition (PN) will result in excessive copper levels. This study looked retrospectively at cholestatic infants receiving PN with measured copper levels to ascertain if this is an actual clinical concern. Methods: All infants from the previous 10 years receiving PN who had a copper level checked and were cholestatic were reviewed. Children with metabolic or liver structural anomalies were excluded from the review. Of the 28 patients found, 26 had gastrointestinal disorders, and 82% of these infants were on the standard PN copper dose (20 µg/kg/d). Results: Only one elevated copper level was found in a child with congenital heart disease, but 13 low levels were found. A smaller number of follow‐up copper levels demonstrated that despite cholestasis, some patients require copper supplementation above standard recommendations. Conclusion: Cholestasis does not appear to impair copper excretion enough to result in elevated levels. In fact, infants with gastrointestinal disorders may require higher than standard dosing. Monitoring copper levels appears to be necessary to appropriately regulate copper dosing for cholestatic infants receiving PN.     

Micronutrient supplementation in parenteral nutrition in Spanish hospitals

Several years ago, it was recommended not to add vitamins or oligoelements to parenteral nutrition (PN) solutions and to administer them immediately after the addition of the micronutrients to avoid their decay. Nowadays, it has been observed that with multilayer bags, ternary mixtures and sunlight protection vitamins degradation is minimal. Daily intake of micronutrients is necessary in the critically ill, malnourished or long-term PN patients. Aiming at knowing the schedules of use of micronutrients in PN in Spanish hospitals and the way PN bags are prepared regarding the factors conditioning their stability, we undertook a telephone survey to the pharmacists in charge of PN at the different hospitals. We compared the data obtained with those from other surveys performed in 2001 and 2003. Pharmacists from 97 hospitals answered the questionnaire (answer rate 88%). The hospital sizes ranged 104-1728 beds. As compared to the data form preceding years, we observed a better adequacy to the current recommendations, although there are still 30% of the hospitals that administer micronutrients on an every other day basis independent of the clinical situation of the patients. In most of the hospitals, multilayer bags are used and/or sunlight protection and ternary mixtures. According to these results showing the different criteria for administering vitamins and oligoelements in PN solutions, it seems necessary to elaborate consensus documents that adapt to the reality of the diverse practices besides promoting the performance of well-designed clinical studies establishing the requirements under special clinical situations.     

The prevalence of coagulation abnormalities in hospitalized patients receiving lipid-based parenteral nutrition

BACKGROUND: Vitamin K is not a component of the multivitamin preparation added to parenteral nutrition (PN) solutions, and hospitalized patients receiving parenteral nutrition support are at risk of developing vitamin K deficiency. METHODS: In this study, 84 consecutive patients receiving PN were followed up prospectively to determine the incidence of a raised international normalized ratio (INR). All patients received lipid in their PN, which contains approximately 30 microg of vitamin K/100 mL. RESULTS: Patients were followed up for the course of PN or up to 4 weeks if they needed longer total parenteral nutrition. A raised INR compared with baseline developed in 3.6% of patients. All elevations were mild, and no patients developed clinical bleeding. CONCLUSIONS: It may be unnecessary to routinely supplement patients with vitamin K if they are receiving a lipid emulsion containing significant amounts of vitamin K. For patients receiving warfarin therapy, it will be important for nutrition support services to be aware of the vitamin K content of the lipid emulsion they are using as patients receiving a multivitamin preparation containing vitamin K and lipid emulsion may receive increased amounts of vitamin K, which could lead to warfarin resistance.     

Determinants of insulin availability in parenteral nutrition solutions

BACKGROUND: Management of hyperglycemia in patients receiving parenteral nutrition (PN) often includes the addition of regular insulin to the PN solution. A literature review has shown insulin availability in such solutions to range from 10% to 95%. This discrepancy in availability may be due to differences in the composition of the PN solution, the final concentration of insulin, or the assay method used to determine insulin concentrations. The purpose of this study was to evaluate insulin recovery from a standard PN solution used at our medical center. METHODS: Solutions were manually prepared in our pharmacy according to standard practice. Multivitamins and trace elements were added to 1 of 2 L of solution each day. Each of 3 simulated patients received 2 L of solution per day for 3 consecutive days. Samples from each bottle were drawn at baseline, 1 hour after the start of infusion, and 1 hour before the end of infusion and were subsequently analyzed for immunoreactive insulin levels by radioimmunoassay. RESULTS: Recovery of insulin from solutions containing multivitamins and trace elements was much greater (95%) than from those without (5%). CONCLUSIONS: The presence of multivitamins and trace elements is a major determinant of insulin availability in PN solutions. Additional research is necessary to determine the mechanism mediating this effect and to assess its clinical significance.     

Dosing and monitoring of trace elements in long-term home parenteral nutrition patients

Background: Trace elements (TEs) dosing and monitoring in home parenteral nutrition (PN) patients vary with their underlying conditions. Methods: This retrospective observational study evaluated parenteral TE dosing, serum TE concentrations and monitoring, and dose‐concentration relationships between TE doses and serum TE concentrations in 26 adult and adolescent home PN patients. Results: There was a total of 40,493 PN days. Average parenteral zinc doses of 9.1 mg/d and 7.6 mg/d resulted in the majority of serum zinc concentrations (90%) within normal range in patients with and without short bowel syndrome (SBS), respectively. Selenium at about 70 mcg/d resulted in about 60% of serum selenium concentrations within normal range, with 38% of values below normal in patients with and without SBS alike. Copper at 1 mg/d resulted in 22.5% of serum copper concentrations above the normal range. The majority of serum manganese (94.6%) and chromium (96%) concentrations were elevated. Serum TE concentrations were infrequently monitored. Significant relationships existed between doses and serum concentrations for zinc (P < .0001), manganese (P = .012), and chromium (P < .0001) but not for selenium or copper. Conclusions: TE doses in home PN should be individualized and adjusted based on regular monitoring of TE status. In long‐term home PN patients, higher zinc and selenium doses may be necessary to maintain their normal serum concentrations. Lower copper doses and restrictions of manganese and chromium supplementation may be needed to avoid their accumulation. Relationships between TE doses and serum TE concentrations vary for each TE and underlying clinical conditions.     

Iron Deficiency in Long‐Term Parenteral Nutrition Therapy

Background: Iron is not routinely added to parenteral nutrition (PN) formulations in the United States because of the risk of anaphylaxis and concerns about incompatibilities. Studies have shown that iron dextran in non‐lipid‐containing PN solutions is safe. Data are limited on iron status, prevalence of iron deficiency anemia (IDA), and efficacy of intravenous iron infusion in long‐term home PN (HPN). We aimed to determine the incidence of IDA and to examine the effectiveness of parenteral iron replacement in patients receiving HPN. Methods: Medical records of patients receiving HPN at the Mayo Clinic from 1977 to 2010 were reviewed. Diagnoses, time to IDA development, and hemoglobin, ferritin, and mean corpuscular volume (MCV) values were extracted. Response of iron indices to intravenous iron replacement was investigated. Results: Of 185 patients (122 women), 60 (32.4%) were iron deficient. Five patients were iron deficient, and 18 had unknown iron status before HPN. Of 93 patients who had sufficient iron storage, 37 had IDA development after a mean of 27.2 months (range, 2–149 months) of therapy. Iron was replaced by adding maintenance iron dextran to PN or by therapeutic iron infusion. Patients with both replacement methods had significant improvement in iron status. With intravenous iron replacement, mean ferritin increased from 10.9 to 107.6 mcg/L (P < .0001); mean hemoglobin increased from 11.0 to 12.5 g/dL (P = .0001); and mean MCV increased from 84.5 to 89.0 fL (P = .007). Conclusions: Patients receiving HPN are susceptible to IDA. Iron supplementation should be addressed for patients who rely on PN.     

Excessive Aluminum Accumulation in the Bones of Patients on Long‐Term Parenteral Nutrition

Background: Aluminum (Al) contamination of parenteral nutrition (PN) solutions remains a concern for long‐term PN patients. Al accumulates particularly in bone. Excessive exposure to Al may result in increased Al body burden and impaired bone formation and mineralization, leading to bone disease. Although the U.S. Food and Drug Administration (FDA) has limited Al contamination in large‐volume parenteral solutions, small‐volume parenterals may still contribute considerable amounts of Al to PN solutions. The goal of this study is to determine whether or not long‐term adult PN patients remain at risk for increased bone Al accumulation. Methods: We measured Al accumulation in autopsy bones from 7 patients who had received PN for 2–21 years and compared bone Al levels with those in living control patients undergoing hip or knee replacement. Electrothermal atomic absorption spectrometry was used for bone Al measurements. Results: When compared with bone Al content in controls, markedly elevated Al levels (P < .0001) were found in the bones of all but 1 patient, who received PN for only 2 years before death. Even greater Al accumulation was found for PN patients who developed late renal impairment (P = .0159). Conclusions: We conclude that long‐term adult PN patients continue to be at risk for Al toxicity.     

Aluminum exposure from pediatric parenteral nutrition: meeting the new FDA regulation

BACKGROUND: Aluminum toxicity can cause serious central nervous system and bone toxicities. Aluminum is a contaminant of parenteral nutrition (PN) solution components. Premature neonates requiring high doses of calcium and phosphate to mineralize their bones, children with impaired renal function, and children on PN therapy for prolonged duration are at the highest risk. Effective in July 2004, the U.S. Food and Drug Administration (FDA) mandated labeling requirements for aluminum content in all PN solution components. To assess the aluminum exposure in neonatal and pediatric populations, this study aims to determine patients' daily aluminum load (mug/kg/d) delivered from PN solutions. METHODS: The study included all inpatients who received PN during calendar year 2006 (13,384 PN patient days). The calculated parameters of mug/kg/d and mug/L of parentally administered aluminum were stratified according to patient age and weight. Aluminum content by product and manufacturer were tabulated. RESULTS: Forty-nine percent of the PN patient days were in patients weighing < 3 kg. These patients also received the largest amounts of aluminum (range, 30-60 mug/kg/d). Meeting the FDA regulation was possible only in patients weighing > 50 kg. CONCLUSIONS: Currently available parenteral products used to make PN solutions contain amounts of aluminum that make it impossible to meet the new FDA rule of <5 mug/kg/d of aluminum exposure. Manufacturers must identify, develop, and adopt new methods to reduce the aluminum contamination in their products. Health care professionals should calculate aluminum loads in patients and make informed decisions when choosing PN products.     

Choline deficiency is associated with increased risk for venous catheter thrombosis

BACKGROUND: Patients with intestinal failure who require long-term parenteral nutrition (PN) develop catheter thrombosis as a complication. This patient group may also develop choline deficiency because of a defect in the hepatic transsulfuration pathway in the setting of malabsorption. This study was undertaken to determine whether choline deficiency is a risk factor for development of catheter thrombosis. METHODS: Plasma free and phospholipid-bound choline concentrations were measured in a group of 41 patients that required long-term PN. Episodes of catheter thrombosis from onset of PN to the time of blood testing were recorded. RESULTS: Sixteen (39%) patients developed catheter thrombosis, and 5 of these had recurrent catheter thrombosis. Plasma free choline was 7.7 +/- 2.7 nmol/mL in patients with no history of catheter thrombosis and 6.2 +/- 1.7 nmol/mL in patients with previous catheter thrombosis (p = .076 by Wilcoxon rank-sum test). The partial correlation between plasma free choline concentration and the frequency of clots after controlling for catheter duration was r = -0.33 (p = .038). The relative risk for catheter thrombosis in subjects with a plasma free choline concentration <8 nmol/mL was 10.0, 95% confidence interval (1.134-88.167). Plasma phospholipid-bound choline concentration was 2191.7 +/- 679.0 nmol/mL in patients with previous catheter thrombosis and 2103.3 +/- 531.2 nmol/mL in patients without history of catheter thrombosis (p = NS). CONCLUSION: Choline deficiency is a significant risk factor for development of catheter thrombosis in patients with intestinal failure who require PN.     

Precipitation of trace elements in parenteral nutrition mixtures

Trace elements are an essential additive to parenteral nutrition (PN) mixtures. Previous studies have indicated that certain trace elements, in particular copper and iron, may interact with complete PN mixtures leading to precipitate formation. The causes of these incompatibilities have not been fully elucidated. The purpose of this study was to determine factors responsible for common trace element incompatibilities, using X-ray energy dispersive spectroscopy to examine the elemental content of precipitates isolated from stored PN mixtures with added trace elements. Results indicated that copper sulphide precipitated most rapidly in PN mixtures containing Vamin 9 and in mixtures stored in multilayered bags. Copper sulphide precipitation was delayed in PN mixtures containing Vamin 14 and was not observed in PN mixtures stored in EVA bags. Iron phosphate precipitates were observed in Synthamin-containing PN mixtures after storage, but this was prevented in mixtures containing vitamins stored in multilayered bags.     

Copper deficiency during total parenteral nutrition: clinical analysis of three cases

Three adult cases in which copper deficiency developed during long-term total parenteral nutrition (TPN) without copper supplementation have been described, together with a brief review of the literature. All three patients were suffering from malabsorption when TPN was instituted, and overt symptoms of copper deficiency developed an average of 5.8 months after the start of TPN. Clinically, leukopenia with neutropenia and low plasma levels of copper and ceruloplasmin were seen in all cases. The dosage of copper administration in these cases was 0.3 to 7.2 mg of copper/day, or 5.3 to 133 micrograms of copper/kg/day, with total doses of 7 to 176 mg of copper.     

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 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.     

Differences in the serum amino acid pattern of injured and infected children promoted by two parenteral nutrition solutions

The effects of two parenteral nutrition (PN) amino acid solutions (FreAmine II and F080) on the serum amino acid levels of 51 children, 27 affected by multiple trauma and 24 by bacterial sepsis, and aged from 1 month to 12 years, were studied. Serum amino acids were determined on day 1 immediately before administrating PN, and on day 5 during PN. Trauma patients on F080 exhibited higher levels of alanine, aspartate, asparagine, leucine, isoleucine, valine, total branched-chain amino acids (BCAA) and total essential amino acids than those on FreAmine II; in contrast septic children showed similar levels of serum amino acids on both PN solutions. BCAA were lower in septics than in trauma patients, probably as a consequence of an increased utilization of these amino acids in sepsis because of the higher organ protein synthesis typical of this situation. The phenylalanine/tyrosine ratio was found elevated both in septic and trauma children, but it decreased after PN in the latter when using an enriched BCAA solution. Utilization of this solution, partly corrects the metabolic disturbances induced by stress, but the metabolical responses induced either by sepsis or trauma are partially different which may have important implications for patient care.     

Parenteral nutrition-associated liver disease in adult and pediatric patients.

There are essentially 3 types of hepatobiliary disorders associated with parenteral nutrition (PN) therapy: steatosis, cholestasis, and gallbladder sludge/stones. Reported prevalence rates of PN-associated liver disease (PNALD) vary greatly, and there are distinct differences between adult and pediatric patients. Various etiologic factors have been evaluated for significance in contributing to PNALD, including enteral feeding history, septic events, bacterial overgrowth, length of intestinal resection, and prematurity/low birth weight. Etiologic factors specifically related to the PN formulation or nutrient intake have also been evaluated, including excessive calorie intake, dextrose-to-lipid ratio, amino acid dose, taurine deficiency, IV fat emulsion (IVFE) dose, carnitine deficiency, choline deficiency, and continuous vs cyclic infusion. Minor increases in serum aminotransferase concentrations are relatively common in patients receiving PN therapy and generally require no intervention. The primary indicator of cholestasis is a serum conjugated bilirubin >2 mg/dL. When a patient receiving PN develops liver complications, it is necessary to rule out all treatable causes and minimize other risk factors. All potential hepatotoxic medications and herbal supplements should be eliminated. Modifications to the PN regimen that may be helpful include reduction of calories, reduction of IVFE dose to <1 g/kg/d, supplementation of taurine in the infant, and use of cyclic infusion. Initiation of even small amounts of enteral nutrition and use of ursodiol may be beneficial in stimulating bile flow. In the long-term PN patient with severe and progressive liver disease, intestinal or liver transplantation may be the only remaining treatment option.     

Home parenteral nutrition support in adults: experience of a medical center in Asia

BACKGROUND: Parenteral nutrition (PN) support is mandatory in patients with gut failure. Short bowel syndrome is a term used for symptoms and pathophysiological disorders brought about by the removal or malfunction of a large portion of the small bowel. Inflammatory bowel disease, vascular disease, and malignancy are the most common causes of short bowel syndrome in adults. There are many complications associated with chronic use of PN. Cholestasis, nutrient deficiency, small bowel bacterial overgrowth, and catheter-related infections were noted in these patients. Due to the various etiologies, we tried to find the optimal method to manage these patients. METHODS: We reviewed all patients over 16 years old, from 1989 to 2002, who required home PN support for at least 30 days. Charts were reviewed to obtain information regarding demographics, nutrition management, outcome, and complications related to PN. Survival was estimated by using the Kaplan-Meier method. The association of survival with primary disease, length of small bowel, age, and gender was assessed by proportional hazard regression analysis. RESULTS: There were 31 patients who needed home PN support during this period, 14 male and 17 female. The average age was 55 (median age, 53; range, 28-88); the average period of PN administration was 19 months (median, 7; range, 1-115 months). The most common indications for home PN were alimentary tract obstruction and short bowel syndrome. Most deaths were related to their original diseases and catheter-related sepsis. Malignant diseases were a major indication for home PN (HPN). However, 20% of these patients with incurable diseases lived longer than 1 year. The disease patterns were different from those in western societies. Most patients had malignancies and vascular insults in our series. There was much less inflammatory bowel disease in our patients than in western countries; catheter-related infections were frequent and caused 25% of mortality. CONCLUSIONS: HPN is very important to patients with intestinal failure or who are waiting for recovery from temporal intestine insufficiency. Even in malignant diseases, a significant number of patients survived for >1 year with treatment of HPN. Most complications related to their underlying diseases and associated infections. Improving patient education and treatment might improve the prognosis of these patients and expand the application of this technique to help more patients with small intestine failure.     

Systemic inflammatory mediators and bone homeostasis in intestinal failure

BACKGROUND: A proinflammatory state has been described in patients with intestinal failure. The prevalence of metabolic bone disease in this group is considerable. It is not known whether this proinflammatory state is related to bone parameters, though bone disease is recognized as a proinflammatory process in postmenopausal women. The purpose of this study was to examine whether inflammation was related to bone disease. METHODS: Eight patients with parenteral nutrition (PN)-dependent intestinal failure but no recent infections or immunosuppressive medications had serum assayed for interleukin-6 (IL-6), tumor necrosis factor (TNF)-alpha, and its receptors (TNFR-I and TNFR-II), C-reactive protein, and whole blood for lymphocyte proliferation. Routine clinical laboratory measures of vitamin D, parathyroid hormone, serum calcium, and phosphorus within 3 months of the inflammatory measures were compared by Pearson's correlation to the inflammatory measures. RESULTS: Mean values for calcium, phosphorus, and albumin were normal, but 25-hydroxy vitamin D was reduced and parathyroid hormone and alkaline phosphatase elevated. Serum total calcium was negatively related to TNFR-II, TNF-alpha and positively to T-helper cells. Longer PN dependence was associated with inflammation and negatively with T-helper cells. CONCLUSIONS: These preliminary findings are hypothesis generating only but support an association of low calcium and longer duration of PN with inflammation in patients with intestinal failure. Whether the inflammation results from vitamin D deficiency or the vitamin D deficiency develops secondary to excessive use of activated vitamin D to modulate inflammation from some other cause, such as a component of PN or repeated infectious challenge, requires further study.