Imad F Btaiche
Clinical Associate Professor of Pharmacy/Clinical Pharmacist
Department of Pharmacy Services
University of Michigan Hospitals and Health Centres
Ann Arbor, MI
Parenteral nutrition (PN)-associated cholestasis (PNAC) is common in PN-dependent patients. Predisposing factors to PNAC include bowel rest, over–feeding and short-bowel syndrome.(1,2) Serum conjugated bilirubin concentrations ≥2mg/dl and jaundice are characteristics of PNAC.(3) Because bowel rest alters intestinal integrity and immunity, initiation of enteral or oral feeding and decreasing PN are crucial to prevent PNAC.(2) Also, cyclic PN infusion is recommended to avoid the continuous nutrient load on the liver and help prevent PNAC.(4) Administration of ursodiol improves bile flow and reduces the signs and symptoms of cholestasis. However, ursodiol effects may be limited due to decreased absorption in patients with ileal resection.(5) Sincalide, a synthetic analogue of the C-terminal octapeptide fragment of cholecystokinin, has been used investigationally to induce gallbladder contraction. Studies have failed to demonstrate the benefits of sincalide in preventing PNAC.(6)
Cholelithiasis (gallstone formation) is due to decreased gallbladder contractility during fasting. The absence of intestinal stimulation during PN therapy causes decreased secretion of cholecystokinin, a hormone secreted in the duodenum in response to meals that causes gallbladder contraction. When gallbladder contractility is reduced, bile flow is decreased and gallstones are formed.(7) Oral or enteral feeding is the best approach to prevent cholelithiasis. Studies have failed to show a substantial benefit of sincalide in the prevention of cholelithiasis.(8)
Hepatic steatosis (fatty liver) in PN patients is mainly caused by excessive carbohydrate and/or lipid overfeeding. Avoiding dextrose and/or lipid overfeeding and providing a balanced PN would prevent hepatic steatosis. A balanced PN regimen should provide 50–60% of total calories from dextrose, 20–30% of calories from lipids and the remaining 10–20% calories from amino acids.(9)
Metabolic bone disease
Metabolic bone disease (MBD), including osteomalacia and osteoporosis, may occur with PN, especially in PN-dependent patients. MBD is the result of deficiencies of calcium, phosphorus and vitamin D,(10) as well as aluminium toxicity.(11) Calcium and phosphorus deficiencies result from their limited intake due to solution compatibility limitation. Aluminium contaminants are mainly found in parenteral multivitamins, trace elements, and calcium and phosphate salts. Aluminium accumulation occurs in patients with renal insufficiency and causes impairment of calcium bone fixation. The Food and Drug Administration (FDA) issued rules specifying limits on aluminium concentrations in parenterals used to make PN. The FDA also set a safe upper limit for parenteral aluminium intake at 5µg/kg/day.(12) Maximising calcium and phosphorus intake is essential to prevent MBD. Pharmacy should use products with the lowest aluminium content to prepare PN solutions.
Hydrous dextrose is the major energy source in PN. Hyperglycaemia in PN patients is caused by dextrose overfeeding and is exacerbated by patient-specific underlying conditions. Hyperglycaemia is associated with increased risk of infections, and glycaemic control improves patient outcome.(13) In critically ill surgical patients, continuous insulin infusion to target serum glucose concentrations between 80 and 110mg/dl resulted in a significant reduction in morbidity and mortality.(14)
With uncontrolled hyperglycaemia, the dextrose infusion rate should be kept at ≤2mg/kg/min. Once glycaemic control is achieved, the dextrose infusion rate can be advanced to the caloric goal, but not exceeding 4mg/kg/min. When insulin is required, continuous insulin infusion provides a flexible, safe and effective method for glucose control.(15)
Hypertriglyceridaemia associated with PN is primarily caused by dextrose and/or lipid overfeeding. Severe hypertriglyceridaemia (serum triglyceride concentrations >1,000mg/dl) may cause acute pancreatitis. When hypertriglyceridaemia occurs, reducing the dextrose and/or lipid dose is required. Also, extending lipid infusion time with an infusion rate ≥0.12g/kg/h improves lipid clearance.(16) Lipid infusion should be held when serum triglyceride concentrations are >400mg/dl. Providing 300ml of the 20% lipid emulsion twice weekly would prevent essential fatty acid deficiency in adults.(15) The 20% and 30% lipid emulsions are better cleared than the 10% emulsion due to their lower phospholipid content. They are a better alternative to use in patients with hypertri‑glyceridaemia.(17,18) Despite the promise of medium- chain triglycerides (MCTs) for improved clearance over long-chain triglycerides (LCTs), the use of parenteral MCT/LCT formulations has yielded mixed results.(19)
Refeeding syndrome describes the fluid and electrolyte imbalances and vitamin deficiencies that occur in severely malnourished individuals during rapid nutritional repletion. Electrolyte abnormalities include hypophosphataemia, hypokalaemia and hypomagnesaemia. These abnormalities, if severe, may be associated with organ dysfunction. In cachectic patients, PN should be started and advanced slowly. Aggressive supplementation of phosphorus, potassium and magnesium is necessary. Multivitamin intake with additional supplementation of thiamine 100mg/day and folic acid 1mg/day is indicated.(20)
Trace mineral abnormalities
Manganese accumulation may occur in PN patients, especially when biliary manganese elimination is impaired in patients with cholestasis. Manganese toxicity typically presents as neurotoxicity. Regular monitoring of serum manganese concentrations is recommended, especially in cholestatic patients receiving PN. Withholding manganese in PN reverses the neurological symptoms.(21)
Copper deficiency has been reported following the omission of copper from PN. The most critical manifestation of copper deficiency is pancytopenia, which may lead to death.(22) When copper is restricted in PN, serum copper concentrations should be routinely measured every two to three months to avoid copper deficiency. Early copper supplementation can reverse the clinical symptoms of copper deficiency.(23)
Zinc deficiency due to excessive intestinal zinc losses may occur in patients with diarrhoea and high-output fistulas. Empiric intravenous zinc supplementation at 15mg/day can be used in these patients to prevent zinc deficiency. Regular monitoring of zinc levels is indicated.(24)
Selenium deficiency may occur with malabsorption syndromes (eg, high enterocutaneous fistula fluid losses, diarrhoea, short-bowel syndrome). Selenium supplementation is guided by serum selenium concentrations. Regular monitoring of plasma selenium concentrations is necessary.(24)
Iron deficiency may occur in patients with mal‑absorption syndromes and in pregnant women with hyperemesis gravidarum. Parenteral iron is used in patients who cannot absorb or tolerate oral iron. Iron dextran can be added to lipid-free PN after an iron tolerance test is performed. Regular monitoring of iron status is indicated.(25)
PN can be associated with serious complications (see Box). Oral or enteral nutrition is the preferred feeding method. PN should be used only when the oral or enteral route cannot be used.
- Colomb V, Goulet O, Rambaud C, et al. Transplant Proc 1992;24:1054-5.
- Cavicchi M, Beau P, Crenn P, et al. Ann Intern Med 2000;132:525-32.
- Vileisis RA, Inwood RJ, Hunt CE. JPEN J Parenter Enteral Nutr 1981;5:67-9.
- Hwang TL, Lue MC, Chen LL. Hepatogastroenterology 2000;47:1347-50.
- Hofmann AF. Scand J Gastroenterol 1994;29 Suppl 204:1-15.
- Teitelbaum DH, Tracy TF Jr, Aouthmany MM, et al. Pediatrics 2005;115:1332-40.
- Allen B, Bernhoft R, Blanckaert N, et al. Am J Surg 1981;141:51-6.
- Tsai S, Strouse PJ, Drongowski RA, et al. J Pediatr Surg 2005;40:263-7.
- Btaiche IF, Khalidi N. Am J Health-Syst Pharm 2004;61:2050-9.
- Prestridge LL, Schanler RJ, Shulman R, et al. J Pediatr 1993;122:761-8.
- Ott SM, Maloney NA, Klein GL, et al. Ann Intern Med 1983;98:910-4.
- Department of Health and Human Services, Food and Drug Administration. Aluminum in large and small volume parenterals used in total parenteral nutrition. Federal Regist 2000; (Docket No. 90N-0056): 2000;65:4103-11.
- Butler SO, Btaiche IF, Alaniz C. Pharmacotherapy 2005; 25:963-76.
- Van Den Berghe G, Wouters PJ, Weekers F, et al. N Engl J Med 2001;345:1359-67.
- Btaiche IF, Khalidi N. Am J Health-Syst Pharm 2004;61:1938-49.
- Iriyama K, Tsuchibashi T, Urata H, et al. Br J Surg 1996;83:946-8.
- Rigaud D, Serog P, Legrand A, et al. JPEN J Parenter Enteral Nutr 1984;8:529-34.
- Kalfarentzos F, Kokkinis K, Leukaditi K, et al. Clin Nutr 1998;17:31-4.
- Ulrich H, Pastores SM, Katz DP, et al. Nutrition 1996;12:231-8.
- Kraft MD, Btaiche IF, Sacks GS. Nutr Clin Pract 2005;20:625-33.
- Alves G, Thiebot J, Tracqui A, et al. JPEN J Parenter Enteral Nutr 1997;21:41-5.
- Spiegel GE. JPEN Parenter Enteral Nutr 1999;23:169-72.
- Hurwitz M. Nutr Clin Pract 2004;19:305-8.
- Btaiche IF. Chronic complications associated with parenteral nutrition. In: Schumock GT, Dunsworth TS, Brundage DM, et al, editors. Pharmacotherapy Self-Assessment Program (PSAP-V), 5th ed. Kansas City (MO): American College of Clinical Pharmacy; 2005. p. 163-80.
- Kumpf VJ. Nutr Clin Pract 2003;18:318-26.
American Society for Parenteral and Enteral Nutrition (ASPEN)
European Society for Parenteral and Enteral Nutrition (ESPEN)
American Society for Clinical Nutrition (ASCN)