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The Role of an Intravenous Fat Emulsion Composed of Fish Oil in a Parenteral Nutrition-Dependent Patient With Hypertriglyceridemia

Kathleen Gura, PharmD^*
Robbert Strijbosch, MD^*
Sarah Arnold, PharmD^*
Christopher McPherson, PharmD
Mark Puder, MD, PhD^*

^* Children's Hospital Boston, Boston, Massachusetts; and the University of North Carolina, Chapel Hill, North Carolina

Correspondence: Correspondence: Kathleen Gura, PharmD, Children's Hospital Boston, 300 Longwood Avenue, Boston, MA 02115. Electronic mail may be sent to kathleen.gura{at}childrens.harvard.edu.

Hypertriglyceridemia is a common complication in patients receiving parenteral nutrition (PN). Management typically involves withholding the IV fat emulsion (IVFE) until serum triglyceride levels normalize. In some instances, this practice may predispose patients to the development of essential fatty acid deficiency (EFAD) unless alternative therapies such as oral or topical oils are used. This is especially true in patients unable to tolerate enteral intake. We describe the management of hypertriglyceridemia in a 12-year-old boy dependent on PN who developed EFAD due to prolonged use of fat-free PN. His course was further complicated by PN-associated liver disease. Treatment involved the use of an IVFE derived from fish oils. Within 3 weeks, there was clinical improvement in EFAD and hypertriglyceridemia. The patient's triene:tetraene ratio decreased from 0.207 to 0.044 (normal: 0.013–0.05). Similarly, his serum triglyceride levels decreased from 628 mg/dL to 183 mg/dL (normal: <200 mg/dL). After 2 months of treatment, he was successfully transitioned to enteral feedings; hepatic function normalized, as did the essential fatty acid profile and serum triglycerides levels. This suggests that using fish-oil-based IVFE may be an effective alternative to conventional IVFE in PN-dependent patients whose clinical course is complicated by hypertriglyceridemia.

Parenteral nutrition (PN) provides the necessary nutrition requirements for patients who are unable to absorb sufficient nutrients due to intestinal abnormalities or in which there is a contraindication to using the gastrointestinal (GI) tract. Typically, PN is administered in conjunction with IV fat emulsion (IVFE) to provide an alternative to carbohydrates as a source of nonprotein calories and to prevent essential fatty acid deficiency (EFAD). In some instances, patients are unable to tolerate IVFE due to allergy to one of its components or due to an inability to clear the fats efficiently. Hypertriglyceridemia occurs in up to 33% of patients receiving PN.¹ In most cases, the treatment for PN-induced hypertriglyceridemia is to reduce the dose or discontinue the IVFE infusion for 4–6 hours to allow for clearance. In some instances, the IVFE may be held for several days and only resumed to provide sufficient fat calories to prevent EFAD. PN therapy typically includes the avoidance of excessive carbohydrates; thus, optimum calories may not be administered if additional calories cannot be provided as fat. Further, the discontinuation of lipids for a prolonged period of time in response to hypertriglyceridemia can predispose patients to biochemical and clinical evidence of EFAD.

Orally administered fish oil supplements are often used to reduce serum triglyceride levels. More recently, case reports using parenteral fish oils have emerged for the treatment of PN-associated liver disease. We report a PN-dependent patient with hypertriglyceridemia and his management using a lipid formulation of fish oils and its potential new role as an alternative to soy-based IVFEs.

	Case Report

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The patient was a 12-year-old boy with cerebral palsy, neurofibromatosis, seizure disorder, and severe gastroesophageal reflux. On admission, his medications included clonazepam, baclofen, and metoclopramide. For >9 years, his seizures were successfully controlled with valproic acid. When he was an infant, a Nissen fundoplication was performed for his reflux. This was later revised at age 11. A year after his revision, he developed a gangrenous small bowel obstruction that required a small bowel resection. This was complicated by an enterocutaneous fistula located at the proximal jejunum. His postoperative course was further complicated by pseudomonas urosepsis, resulting in hemodynamic instability. He also developed diabetes insipidus, fluid and electrolyte imbalances, cholestasis, and abdominal ascites.

Nutrition History
The patient's admission weight was 22 kg (<3rd percentile, 54% standard). His estimated basal energy expenditure (BEE) using World Heath Organization (WHO) criteria was 1140 kcal/d (1036 kcal x 1.1 stress activity factor). His recommended dietary intake was estimated to be 55 kcal/kg/d, with 1 g/kg/d as protein. Initially, the admitting team used a goal intake of 1200 kcal/d. This was considerably lower than his preadmission intake. Before his hospitalization, his diet consisted of Nutren 1.5 (Nestlé Nutrition, Glendale, CA), 6 cans/d. This provided 2160 kcal/d and 3.9 g protein/kg. Per the transfer notes from the referring facility, this high-calorie, high-protein diet was necessary to allow for growth, given his high degree of seizure activity and frequency of muscle spasms.

At the time the intestinal obstruction developed, he underwent a laparotomy; a central venous catheter was placed for the provision of PN. On postoperative day 8, he returned to the operating room for surgical repair of an anastomotic breakdown and the placement of a jejunostomy feeding tube. He was unable to tolerate adequate enteral nutrition due to the development of a jejunal fistula, and PN was continued.

Initially, his PN consisted of 144 g/d of dextrose, 21.6 g/d of amino acids (Aminosyn; Hospira, Lake Forest, IL) that infused at 60 mL/h x 24 hours, along with 22 g/d IVFE (Intralipid; Baxter Health-care/Fresenius Kabi, Deerfield, IL). The PN formula provided 801 kcal, 1 g/kg/d protein, and 1 g/kg/d fat. Approximately 61% of his total calories were provided as carbohydrates (6.5 g/kg/d) with a glucose infusion rate (GIR) of 4.5 mg/kg/min. Several days later, his PN regimen reached a goal rate that provided 216 g of dextrose and 28.8 g of amino acids at 1440 mL/d, with 1 g/kg/d provided as fat and 1.3 g/kg/d protein. This delivered a total of 1069 kcal/d, with 68% of total calories provided as carbohydrate, 11% as protein, and 21% as fat. His carbohydrate intake was determined to be 9.8 g/kg/d, with a glucose infusion rate of 6.8 mg/kg/min, higher than the usual 5 mg/kg/min used in adults but not unusual for a child of this age. The distribution of nonprotein calories to g nitrogen was 207:1, which was considered acceptable by team members given the patient's age and clinical condition. This regimen was well tolerated for several weeks, and there was no evidence of hyperglycemia or hypertriglyceridemia.

Indirect calorimetry (IC) was conducted 1 week after the second operation, using the Vmax V29 metabolic monitor (SensorMedics, Yorba Linda, CA). The results showed that the patient was moderately hypermetabolic. His resting energy expenditure (REE) was determined to be 1517 kcal/d (140% of predicted REE level of 1080 kcal/d 67 using the Schofield norms) and his respiratory quotient (RQ) was 0.69, suggesting that he was not being overfed and perhaps even underfed (500 kcal less than measured). Further, the RQ of 0.69 was indicative that he was actually breaking down his fat stores.

View larger version (17K): [in this window] [in a new window]   Figure 1. Serum triglyceride levels in a 12-year-old boy receiving parenteral nutrition improved after initiation of IV fish oil emulsion therapy. Before the discontinuation of conventional soy-containing lipid emulsions, the patient's serum triglyceride levels peaked at 628 mg/dL. Initial management involved holding further administration of fat emulsion until the triglyceride levels were <200 mg/dL. Although serum triglyceride levels did improve, this practice resulted in the patient developing biochemical evidence of essential fatty acid deficiency (EFAD) 6 weeks after the development of hypertriglyceridemia. When Omegaven (Fresenius Kabi, Bad Homburg, Germany) was started, serum triglyceride levels were still slightly elevated; however, the patient now also had evidence of EFAD. Within 10 days of receiving this alternative lipid source, serum triglyceride levels markedly improved, as did his essential fatty acid profile.

In addition to biochemical evidence of EFAD, the patient had elevated serum transaminases, including an aspartate amino transferase (AST) of 581 units/L (normal, 2–40 units/L) and alanine amino transferase (ALT) of 291 units/L (normal, 3–30 units/L; Table 1). He then became jaundiced, with his serum total bilirubin level peaking at 9.4 mg/dL (normal, 0.3–1.2 mg/dL) and direct serum bilirubin reaching 6.3 mg/dL (normal, 0–0.4 mg/dL). Due to concerns of overfeeding and his worsening clinical state, a second IC measurement was obtained and showed that he had become moderately hypocatabolic, with an REE of 877 kcal/d (75% of predicted REE level of 1162 kcal/d), with an RQ of 0.95. At that time, he was receiving 100% of his calories parenterally, ranging from 899 to 1069 kcal/d, depending on fat intake. He was still unable to tolerate any enteral feedings. According to the IC findings, the dextrose content in the PN was reduced to 144 g/d. Despite having evidence of hyperglycemia, no insulin was added to his regimen.

On day 87 of hospitalization (day 42 of PN), in response to his worsening hepatic function and continued hypertriglyceridemia, coupled with biochemical evidence of EFAD, an alternative IVFE (Omegaven; Fresenius Kabi AG, Bad Homburg, Germany), was added to his PN regimen. The rationale for the use of this product was based on our previous experience using a fish-oil-based IVFE in an adolescent boy with EFAD secondary to soy allergy and our recently published findings that -3 rich lipid emulsions may prevent or treat PN-associated liver disease.^2,3 Unlike the more commonly used IVFEs, such as Intralipid (Kabi Pharmacia, Clayton, NC) and Liposyn, both of which contain soybean oils, this product contains only fish oils (Table 3). Because it is not commercially available in the United States, compassionate approval for its use was obtained from both the FDA and the Children's Hospital Boston Investigational Review Board and informed consent from the child's parent. Intralipid was discontinued and he received 200 mL (20 g, 0.7–1 g/kg/d) Omegaven daily for 71 days in addition to his PN. The fish-oil–based fat emulsion was administered via y-site administration into his PN line and infused over 12 hours. He continued to receive 144 g/d dextrose, 28.8 g/d of amino acids in his PN, providing an average of 830 kcal/d. Within 2 weeks of starting the fish-oil–based IVFE, his biochemical evidence of EFAD improved and eventually normalized by 5 weeks, with a T:T ratio of 0.035 and a decreased Mead acid of 30 µmol/L. His hypertriglyceridemia and hyperglycemia also normalized by day 18 of therapy. Likewise, his hepatic function improved and his jaundice resolved, despite the fact that he continued to receive all of his nutrition parenterally. Before starting parenteral fish oil, he had several serious wound infections and fistulas that would not close. Although he did not experience any further wound infections after starting parenteral fish oil, he did have 2 bloodstream infections in the first month of therapy, both of which quickly resolved. The first, due to Enterobacter cloacae, occurred in conjunction with a urinary tract infection and resolved upon removal of the central venous catheter; the second bloodstream infection, due to Staphylococcus species, was successfully managed with appropriate antibiotic therapy. After 29 days of parenteral fish oil therapy, the patient's biochemical evidence of cholestasis resolved, despite remaining NPO before closure of the fistula at the jejunostomy feeding tube site. On postoperative day 53, the patient returned to the operating room for resection of the enterocutaneous fistula and a jejunojejunostomy. A liver biopsy showed diffuse hepatocellular damage, with ballooning giant cell transformation, pseudoacinar transformation, and cholestasis and mild portal chronic inflammatory infiltrate and mild portal fibrosis. Once bowel sounds returned, he was slowly transitioned back to his home nasogastric tube feeding regimen of 240 mL of Nutren (Nestle Nutrition, Glendale, CA) 1.5 6 times daily. He was discharged to home 3 weeks after his last operation and has remained stable.

	Discussion

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Iatrogenic Hypertriglyceridemia
In the pediatric patient, hypertriglyceridemia is defined as a serum triglyceride level >200 mg/dL. It develops from a confluence of risk factors, including infection or inflammation, hypothyroidism, renal and liver failure, insulin resistance, diet, or drugs.^4,5 Nutrition factors associated with hypertriglyceridemia include excessive macronutrients (either as carbohydrates or fat), poor glycemic control, and carnitine deficiency.¹ If left untreated, patients with severe hypertriglyceridemia (ie, serum triglyceride levels >1000 mg/dL) may develop complications such as pancreatitis, lipid pneumonitis, and neurologic changes.⁶

Medications including corticosteroids, estrogens, retinoids, cyclosporine, antihypertensives, interferon -2-b, L-asparaginase, antiretroviral agents, meropenem, rapamycin, and antiepileptic drugs are known to cause hypertriglyceridemia.^4,7 Common mechanisms of drug-induced hypertriglyceridemia include decreased clearance of triglycerides, increased triglyceride and very-low-density lipoprotein (VLDL) production, or a combination of both.^4,8 Soybean-oil–based IVFE can also predispose patients to hypertriglyceridemia. In addition to oil, IVFEs provide about 20% of their calories as glycerin (glycerol) and egg emulsifier. These products are formulated as an emulsion in which the long-chain FAs are suspended in a superficial layer of phospholipids. Depending upon concentration of IVFE (10%, 20%, or 30%) and the volume of IVFE administered, the amount of phospholipids will vary dramatically. For this reason, the use of 10% IVFE is discouraged in children because of the high phosphospholipid content per g of fat.⁹ Further, high lipid infusion rates, >0.15 g/kg/h, may exceed the rate of metabolism and can lead to accumulation and further increase in serum triglycerides.¹⁰ This accumulation of lipids in the hepatic Kupffer cells and hepatocytes may further impair liver function.¹¹ Although massive hypertriglyceridemia associated with fatty liver and abdominal pain is uncommon, it is a clinically important and underrecognized complication. Pancreatitis, lipemia retinalis, lipid pneumonitis, neurologic changes, consumption coagulopathy, and xanthoma have all been associated with hypertriglyceridemia.¹²

Treatment Options
Treatment of pediatric hypertriglyceridemia in the PN-dependent patient should begin at the source of the disorder. Traditional nonpharmacologic recommendations such as lifestyle modification clearly would be minimally practical or beneficial in this patient. Nutrition factors associated with hypertriglyceridemia are mentioned above and should be addressed with initial therapy. Guidelines for the administration of specialized nutrition support in pediatrics offer recommendations for the management of hypertriglyceridemia in patients requiring IVFE, including use of 20% IVFE and avoidance of overfeeding.¹³ If a serum triglyceride level exceeds 200 mg/mL, the lipid emulsion may be held. Because of its ability to induce lipoprotein lipase, heparin is often added to PN at a dose of 1 unit/mL of PN to enhance the lipid clearance.¹⁴ Insulin can also promote clearing of triglycerides as it promotes both fat storage and its mobilization.¹⁵ The hormone prompts glycogenesis, the formation of glyceride and glycerol, and FA synthesis from glucose, and inhibits the release of FAs by forming -glycerophosphate, resulting in triglyceride formation.¹⁶ Carnitine, a derivative of the amino acid lysine, has also been added to PN for this purpose.¹⁷ Carnitine is essential for the transport of free FAs from the cytosol to the mitochondrial matrix, where FAs are oxidized.¹⁸ In addition to lowering serum triglycerides, carnitine also lowers total cholesterol levels while increasing concentrations of high-density lipoproteins (HDL).¹⁹

In this case, our patient was already receiving carnitine supplementation because of its theoretical role as a hepatoprotective agent in patients treated with valproic acid, a medication with known hepatotoxic properties.²⁰ Valproic acid can also deplete carnitine stores.²¹ By accepting and shuttling unmetabolized acyl groups from the mitochondria, carnitine is able to eliminate acyl drugs or acyl metabolites of a drug and thus effect the detoxification of the agent.^22,23

Although unlikely, valproic acid use was considered a plausible cause of this patient's increased transaminases. Hepatotoxic effects associated with valproic acid use typically occur during the first 6 months of therapy, although they can occur at any time. In a retrospective review of reported cases, children under the age of 2 years seem to be at greatest risk for developing fatal hepatotoxicity.²⁴ In this case, the patient was 12 years old at the onset of his transaminase elevations and had been treated with valproic acid for over 9 years. Further, clinical improvement in hepatic function occurred despite continuing to receive the medication, suggesting that PN use may have been the cause for his hepatic dysfunction.

Failure of these interventions may require the use of pharmacologic agents (ie, statins or gemfibrozil) or plasma pheresis. Experience with pharmacologic therapies in pediatric patients is limited and should be used with caution. In most cases, successful therapy arises from proper management of the underlying cause of hypertriglyceridemia. In this case, initial management involved holding the IVFE until the serum triglyceride level decreased to an acceptable level, minimizing overfeeding, and continuing carnitine supplements.

EFAD
Essential fatty acids (EFAs) cannot be synthesized in human tissues and must be obtained from the diet.²⁵ EFAs are needed for processes including maintaining the integrity of the skin and the structure of cell membranes, and the synthesis of prostaglandins and leukotrienes.²⁴ EFAs include linoleic (LA, an -6) and -linolenic (ALA, an -3) acids. -3 FAs are found most abundantly in green plants, ocean microalgae, and soybeans. -6 FAs are found in nuts, seeds, and vegetable and seed oils. The body can derive other FAs, such as arachidonic acid (AA, another -6) from LA and eicosapentaenoic (EPA, another -3) and docosahexaenoic acid (DHA, also an -3) from ALA, but fish oil is a more efficient source as it does not rely on the conversion of ALA to DHA and EPA or LA to AA. In fact, fish oils contain mainly EPA and DHA, whereas vegetable oils predominantly contain LA or ALA. EPA and DHA may decrease hypertension, reduce elevated cholesterol and triglycerides, prevent atherosclerosis, and improve skin disorders.^26–29 Requirements of EFAs are 1%–2% of dietary calories for children and 4%–5% for infants. The suggested ratio of -6 to -3 FAs is variable, without consensus.³⁰ Previous recommendations suggest a balance of 10:1, but emerging data indicate that a ratio as low as 2:1 would be beneficial in ill patients.^31,32 Soybean and olive-oil-based emulsions contain a ratio of approximately 7:1 and 9:1, respectively.³³

Deficiency can develop when intake of EFAs is inadequate (<1%–2% of total calories).^34,35 This condition occurs with malabsorption syndromes, increased physical requirements, chronic malnutrition, or the use of PN with inadequate fat intake.³⁴ Patients with EFAD may show adverse effects, including skin lesions, reproductive failure, growth retardation, reduced learning, impaired vision, and polydipsia, as well as susceptibility to infections.^34,35 The decline in -3 and -6 FA concentrations that is characteristic of EFAD is accompanied by a corresponding increase in the percentage of -9 FAs (Mead acid), which the body produces as a result of the elongation and desaturation of oleic acid that is produced by de novo lipogenesis. As Mead acid typically accumulates in conditions of EFAD, the ratio of this compound to AA (ie, the T:T ratio) is used as a diagnostic marker for EFAD. Until recently, plasma values of T:T above 0.2 were considered abnormal, whereas levels >0.4 were considered diagnostic for EFAD.³⁶ Siguel et al³⁷ have since developed more sensitive age-based range criteria that suggest T:T ratios >0.05 and Mead acid to AA ratios >0.2 are more reflective of EFAD. It must also be noted that the T:T ratio does not reflect -3 FA status. Physical signs and symptoms of EFAD can vary, depending on the specific FA that is deficient. Biochemical abnormalities appear in 1–2 weeks in children, whereas physical signs and symptoms may not appear for 4–6 weeks.³⁵

EFAD may be treated with a variety of modalities that may be administered topically, orally, or IV. In the absence of IVFE, donor plasma has even been administered to patients with EFAD.³⁸ Topical products, including safflower and corn oils (both of which do not provide adequate linolenic acid), have been used with slow and unpredictable results and may take 2–3 weeks to take effect.^39,40 In the absence of enteral feedings, the most reliable therapy for EFAD consists of IVFE. The products used in the United States are rich in -6 FAs derived from soybean oil with or without safflower oils. An alternative lipid emulsion, available in Europe and Asia and not FDA approved, is Omegaven, which consists of 100% fish oil and is rich in -3 FAs with very little -6 FAs. This lipid emulsion, when dosed at approximately 1 g/kg/d, provides sufficient EFAs to prevent EFAD, although this dose is considerably higher than the 0.2 g/kg/d recommended by its manufacturer.⁴¹ Unlike other IVFEs, Omegaven is not intended to be used as monotherapy but rather as a supplement added to conventional lipid emulsions as an additional source of -3 FAs.

-3 FAs
-3 FAs have been used for the treatment of inflammatory bowel disease (IBD), autoimmune disorders, peripheral vascular disease, adult respiratory distress syndrome, cardiovascular disease, and psychosis.^42–47 These agents are proposed to provide benefit by attenuating the immune or inflammatory response. Additionally, unsaturated FAs are necessary for normal growth and development. Several studies suggest that -3 FAs may increase cell-mediated immune responses through the action of prostaglandins.^43–48 The inhibitory effects of FAs on immune function seem to be mediated by changes in surface adhesion on leukocytes and lymphocytes. -3 FAs also have hypolipidemic activity, primarily reducing triglyceride concentrations by reducing VLDL.⁴⁹ The mechanism of action is not entirely understood; however, possible mechanisms include the inhibition of acyl coenzyme A: 1,2-diacylglycerol acyltransferase and increased peroxisomal β-oxidation in the liver.⁵⁰ Furthermore, these esters may diminish the synthesis of triglycerides in the liver because EPA and DHA are poor substrates for the enzymes responsible for triglyceride synthesis and because they inhibit esterification of other FAs. Recently, the FDA approved the use of a purified oral fish oil capsule (Omacor; Reliant Pharmaceuticals, Liberty Corner, NJ) for the management of hypertriglyceridemia and mixed lipoprotein disorders.⁵¹ There is currently no parenteral product approved for use in the United States.

The FDA regards -3 FAs as "generally recognized as safe" in dosages of <3 g/d.⁵² There are several theoretical adverse effects associated with -3 FAs, including increased LDL-cholesterol levels and deterioration of glycemic control in patients with type 2 diabetes mellitus.⁵³ Critical analysis of these previously published studies, however, has since concluded that glycemic control is not adversely impacted and -3 FAs may actually be beneficial in the diabetic patient.^54–56 Excessive bleeding has been thought to be a risk associated with -3 use, but to date, there has been no clinical evidence of this complication. In this case report, our patient's hyperglycemia resolved despite not receiving any insulin, and he had no evidence of bleeding.

Studies in surgical patients and septic patients have displayed the utility of increased intake of -3 FAs in patients with inflammation or infection.⁵⁷ Several randomized, controlled trials showed an increased immune cytokine production and suppressed monocyte generation of proinflammatory cytokines and decreased C-reactive protein levels.^57–60 This is similar to our experience. Before starting therapy with Omegaven, the patient's serum C-reactive protein level was as high as 8.78 mg/dL (<0.5 mg/dL). Soon after starting Omegaven, it began to drop and eventually returned to normal within 1 month. This is similar to reports by Weiss and colleagues, who showed a down-regulation of the inflammatory response and decreased postoperative immunosuppression with parenteral fish oil therapy.⁶¹ In our case, the patient did have a transient increase in his C-reactive protein levels after starting to receive fish oil IVFE, but this occurred after he returned to the operating room for resection of the enterocutaneous fistula. Unlike the patient's course prior to infusion of fish oil, however, his C-reactive protein increase was not accompanied by a corresponding increased in serum bilirubin levels. Likewise, there is some evidence that IV fish oil may reduce complication rates. One study showed a significant decrease in reoperation rates in patients with abdominal sepsis.⁶² Other clinical studies have shown a tendency toward numerous benefits in surgical patients, including infection, thrombosis, length of hospital stay, and mortality.⁶³

	Summary

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A novel approach of using of fish-oil-based IVFE for the treatment of hypertriglyceridemia in a PN-dependent patient is described. In addition to correcting EFAD, it also helped improve serum triglyceride levels and provided an important source of nonprotein calories in a patient who could not tolerate other forms of conventional fat emulsions.

Further, by switching to an alternative lipid source, it may have contributed to the improvement of the patient's PN-associated liver disease, as evidenced by normalization of serum bilirubin levels and resolution of jaundice. This suggests that better alternatives to currently available parenteral fat emulsions are needed. A randomized clinical trial evaluating these alternatives to conventional practice is warranted.

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Nutrition in Clinical Practice, Vol. 22, No. 6, 664-672 (2007)
DOI: 10.1177/0115426507022006664


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