January 2008 Issue

Enhancing the Safety of Parenteral Nutrition
By Theresa A. Fessler, MS, RD, CNSD
Today’s Dietitian
Vol. 10 No. 1 P. 42

Parenteral nutrition (PN), while a lifesaving therapy, also carries risks with potential for serious harm—even death. Practitioners should be aware of several aspects of PN use that affect patient safety. Careful attention to catheter care and PN formula content and administration, as well as appropriate monitoring, can maximize this therapy’s safety.

Catheter Infections
One of the most frequent and serious complications for patients on PN is a catheter-related bloodstream infection (CRBSI). The central venous catheter (CVC) insertion site and catheter hub are the primary areas where microorganisms can enter, adhere, and multiply inside the CVC lumen. Sometimes, CVCs can be colonized by microorganisms from a distant site of infection in the body, and very rarely from the PN solution itself.1,2

The first sign of CRBSI is usually fever and/or chills. CRBSI prevention involves using aseptic technique and proper skin antisepsis at the catheter site and carefully cleaning the catheter hubs. The Centers for Disease Control and Prevention (CDC) has specific recommendations for decreasing infection risk (see sidebar), and research on several other interventions to reduce infection risk is underway.2,3 Patients should be monitored regularly for the presence of fever or chills and elevation in white blood cell counts.

Another type of catheter infection can be localized to the catheter insertion/exit site or, in the case of implanted or tunneled catheters, in the subcutaneous cuff or tunnel. Monitoring for local site infection includes periodic checks of the catheter insertion area for purulence or redness.1

Refeeding Syndrome
Dangerous metabolic complications can occur when initiating PN in severely malnourished patients but can be prevented with proper PN initiation and advancement.

Patients at risk include those with little or no feeding for more than seven days, recent severe weight loss, alcoholism, anorexia, and chronic disease. The most severe response to refeeding syndrome is death due to cardiac and/or pulmonary failure. Serum phosphorus, potassium, and magnesium can dangerously decline as these minerals shift intracellularly in response to glucose intake and insulin release. Phosphorus is further used in glucose metabolism and energy production. Thiamine can also be quickly depleted, and it is a critical cofactor in carbohydrate metabolism. Fluid overload and pulmonary edema can occur because of reduced cardiac size and function in cachectic patients.4

To minimize the risks of refeeding syndrome, PN should be started cautiously at very low calorie levels and gradually increased after three to five days. In my facility, we initiate feedings at 15 to 20 kilocalories per kilogram for extremely malnourished patients.5 Serum electrolyte levels should be monitored daily. Potassium, magnesium, and phosphorus should be supplemented, if needed, prior to and during feeding. Multivitamin use is important, with additional thiamin if severe deficiency is suspected or neurologic abnormalities occur. Care should be taken to avoid excessive fluid and sodium administration, which is more likely to happen if both PN and maintenance fluids are infusing.4,5

Particulate Contamination
In 1994, two young women died of massive pulmonary emboli after receiving PN that was later found to contain calcium and phosphorus crystals.6 The FDA subsequently published a safety alert with specific pharmacy mixing instructions and recommending the use of in-line filters.7 In later years, similar case reports surfaced, one in which pulmonary artery occlusion and alveolar granulomas subsided after discontinuation of PN.8,9

Intravenous (IV) fluids contain microscopic particulate matter due to contamination during manufacture, storage, and mixing. Microscopic particles of talc, plastic, and glass have been found in PN fluids.10 Particles of 5 microns or larger can obstruct capillary blood flow in various organs, causing inflammatory and neoplastic reactions.10,11 Formation of precipitate depends on calcium and phosphorus content, pH, and order of mixing. Precipitation can occur over time and as the solution warms, and therefore cannot be seen at the time of mixing. Filters can reduce but not eliminate these risks, as precipitate may form distal to the filter.12,13

To decrease risks of infusing particulate matter, care should be taken in formula prescription and pharmacy compounding, avoiding excessive calcium and phosphorus. Calcium gluconate is preferred, as it is less reactive than calcium chloride. In cases of hypophosphatemia, phosphorus replacement doses separate from PN are safer. For lipid-containing solutions, 1.2 micron filters are recommended and 0.22 micron filters for solutions that do not contain lipid. Lipid particles are too large for 0.22 micron filters, which, if used, could cause emulsions to destabilize.11

Many IV medications are not compatible with PN solutions. Coinfusion of medications through the same tubing should be avoided. If coinfusion is determined to be necessary due to limited IV access, pharmacists should be consulted to verify compatibility based on current literature or manufacturer instructions.11 In September 2007, the FDA reported that IV calcium-containing fluids, including PN, should not be infused at the same time or within 48 hours of Rocephin (ceftriaxone), even if a separate line and site are used, because of precipitation risk.14

Trace Elements
Iron: Administration of IV iron dextran has the risk for anaphylactic reactions. This risk is low but can be severe, so a test dose is normally done prior to infusion of therapeutic doses, and it is not to be routinely added to PN. Iron is not to be used in lipid-containing solutions because trivalent cations (Fe 3+) can destabilize lipid emulsions. Iron dextran has, in some cases, been added to lipid-free PN, but iron overload is a risk, so periodic reevaluation is necessary. IV iron may also worsen infection risk. Oral iron is safer, but for patients without enough gastrointestinal (GI) absorptive capacity, IV iron dextran, sodium ferric gluconate, or iron sucrose can be administered in a clinic setting. Serum ferritin should be monitored every three months.15,16

Manganese: Standard PN trace element mixtures contain more manganese than is currently recommended. This is because the formulations were developed more than 25 years ago when the requirement was thought to be higher. PN also contains a small amount of contaminant manganese. During long-term PN, blood and tissue manganese levels can elevate to toxic levels in patients with normal liver function and cholestatic liver failure. Manganese is primarily excreted in bile. Symptoms of manganese toxicity include headache, tremor, and Parkinson’s-like gait dysfunction. Increased signal intensity on MRI has been found in patients with manganese toxicity, which can resolve in five months after reduction or elimination of manganese exposure.

Whole blood or erythrocyte manganese levels should be checked every three to four months and more often for patients with cholestasis or if toxicity symptoms are present. Manganese should be omitted from PN for those with elevated blood manganese levels, symptoms of toxicity, or cholestatic liver failure.15

Copper: Copper, like manganese, is primarily excreted in bile and has the potential to become elevated in patients with cholestasis. Copper toxicity is known to cause liver damage. For patients with cholestasis, eliminate or decrease the amount of copper in PN. Since deficiency can still occur, monitor serum copper levels and watch for signs of deficiency, such as anemia.15

Insulin in PN: Regular human insulin can be added to PN, but hypoglycemia is a risk. However, physiologic stress, such as from infection or trauma, and use of corticosteroids can worsen hyperglycemia and increase insulin needs. Insulin dose may need to be adjusted daily or added at a basal level and supplemented with sliding scale insulin. Glucose should be monitored every six hours until levels are stabilized. In the intensive care setting, glucose control is better achieved with more frequent monitoring and a separate insulin drip.11 Patients who will require insulin in home PN should be given clear instructions and equipment to check glucose during the PN cycle and at times when PN is not infusing until levels are stable.

Aluminum contamination: All components of PN solutions contain aluminum as a contaminant, both from the raw materials and due to leaching from glass containers during sterilization and storage. The highest contributors of aluminum in PN formulas are amino acid solutions (because of the volume used), calcium gluconate, phosphate salts, and trace element components. Potassium phosphate contains much more aluminum than sodium phosphate does.

Aluminum has been implicated in PN-related metabolic bone disease, neurologic dysfunction, and microcytic anemia. Aluminum is mainly excreted in urine. Neonates are at higher risk for aluminum toxicity because of immature renal function and relatively higher needs for calcium and phosphorus. Aluminum binds to transferrin and can interfere with hemoglobin synthesis. The affinity of transferrin for aluminum is decreased if iron is already bound to it.17

In 2004, the FDA mandated a warning statement and labeling rules for parenteral solutions. The warning states that aluminum intake greater than 4 to 5 micrograms per kilogram per day for patients with impaired kidney function or premature neonates can cause accumulation of aluminum associated with central nervous system and bone toxicity. Aluminum content expected at the time of product expiration must be listed on labels for small-volume (less than 100 milliliters) solutions. Aluminum content is limited to 25 micrograms per liter for large-volume (more than 100 milliliters) parenteral solutions.17

If calculating aluminum exposure based on product labels, it is difficult or even impossible to keep aluminum below 5 micrograms per kilogram while providing adequate nutrition, especially for patients with low body mass index and neonates.18,19 Since aluminum content can increase over time, use of fresher solutions can help decrease aluminum exposure. Measured aluminum content in PN solutions far from their expiration date has been found to be significantly lower than that calculated from labels.18

Periodically review and compare products for aluminum content, as it can change with different batches from the same company and among different manufacturers. Sodium phosphate should be used instead of potassium phosphate whenever possible. Choose brands of calcium gluconate with less labeled aluminum content, as some have found it to vary considerably. Use separate or extra trace element components judiciously, as most contain high concentrations of aluminum. If extra zinc is required, use zinc chloride, as it is much lower in aluminum than zinc sulfate.

Liver Dysfunction
PN-associated liver disease (PNALD) is a major problem with long-term PN use. End-stage liver disease has been reported in 15% to 40% of adults on long-term PN, and the prevalence is greater for neonates.20

The causes of PNALD are not yet fully understood, and they are likely multifactorial. Bacterial and fungal infections can cause cholestasis. Excessive dextrose or lipid calories can cause steatosis. It is postulated that phytosterols in IV fat emulsions may impair biliary flow and a lack of certain nutrients can lead to liver dysfunction.21

Several steps can be taken to help prevent PNALD. First, PN should be used only when necessary—when the GI tract is nonfunctional. Cycling PN over eight to 12 hours instead of continuous infusion, avoidance of overfeeding of dextrose and lipid, care to prevent CRBSI, and prompt treatment of small bowel bacterial overgrowth are all ways to help prevent liver damage.

Neonatal formulas contain additional taurine, as premature infants are at risk for deficiency. Taurine is needed for adequate bile flow, and its supplementation has been associated with a reduction in PN-associated cholestasis in infants.21 Omega-3 fatty acid emulsions are currently under experimental use as they show promising results in reversal of PNALD in infants (see this issue’s “Food for Thought” article).22

To prevent biliary stasis in adults, various drugs can be used, and in some cases cholecystectomy is performed. The safest recommendation is for patients to take oral food on a regular basis, such as is possible for most patients with short bowel syndrome. Food intake stimulates gallbladder contraction and bile flow.20,21

Blood levels of carnitine and choline, nutrients not found in standard PN, can decline after several weeks of PN. Carnitine can be added to PN or taken orally. Carnitine supplementation has been shown to prevent steatosis in neonates, but there is no evidence to date that it helps prevent PNALD in adults. Resolution of hepatic steatosis and normalization of liver enzyme levels have been reported after choline supplementation in PN, but more research is needed to find its role in helping prevent PNALD.21 Choline is not currently available for routine IV use, but oral choline or lecithin (phosphatidyl choline) is an option for some patients.

Monitor liver enzymes and bilirubin weekly in hospitalized patients and monthly for those on long-term PN. If abnormalities are found, physicians should evaluate to rule out other causes of liver disease. Intestinal or combined liver-intestinal transplantation is increasingly utilized for children and adults, with improving outcomes. Early referral for transplantation should be considered for patients with permanent intestinal failure, especially if PNALD is diagnosed.23

Metabolic Bone Disease
Since the 1980s, long-term PN use has been associated with osteomalacia, osteopenia, and osteoporosis, yet the problem is still poorly understood. Metabolic bone disease can result in vertebral and stress fractures, loss of height, and bone pain. Likely etiologies include aluminum exposure, micronutrient deficiencies, excessive urinary calcium loss, and metabolic acidosis. Underlying GI disorders such as inflammatory bowel disease and use of corticosteroid and other medications are partly responsible for bone disease in PN patients. Nutrient deficiencies that can affect bone include calcium, phosphorus, magnesium, vitamin D, vitamin K, and fluoride.24

Several strategies can help promote bone health. The most obvious is the provision of adequate calcium and phosphorus, recommended at 15 milliequivalents of calcium and 15 millimoles of phosphorus per day for adults on long-term PN. Periodic measurements of 24-hour urine for calcium and magnesium can be done to help ensure proper balance. Excessive amino acid intake should be avoided, as excessive protein intake can increase calcium excretion. It has also been postulated that the reduction in pH from excessive amino acids may increase calcium carbonate loss from bones.24 Adjustment of the PN content acetate may be necessary in cases of metabolic acidosis, which can occur in renal disease or with loss of bicarbonate from excessive diarrhea, ostomy, or fistula drainage. Minimizing aluminum content of PN is important, especially for neonates. Patients should be advised to exercise regularly.

Dual-energy x-ray absorptiometry, a method to assess bone mineral density, is recommended every two to five years for stable patients and more often for those with bone disease. Since parathyroid hormone (PTH) and vitamin D are closely involved in bone metabolism, 25-hydroxy-vitamin D and PTH levels should be periodically monitored. Endocrinologists should be consulted if metabolic bone disease is suspected. Medications such as IV bisphosphonates may be prescribed.24

RDs can positively impact the safety of PN in many ways—first by using PN only when medically indicated, and further by careful monitoring and providing advice and recommendations to patients and physicians regarding infection risk and appropriate content and administration of PN.

— Theresa A. Fessler, MS, RD, CNSD, is a nutrition support specialist at the University of Virginia Health System in Charlottesville and a freelance writer.

Selected General Guidelines for Preventing Parenteral Nutrition (PN) Catheter-related Bloodstream Infections

• For multilumen catheters, designate one port to be dedicated only to PN solution.

• Replace administration sets for lipid-containing PN every 24 hours and for non–lipid-containing dextrose and amino acid formulas, every 72 hours.

• Clean injection ports with 70% alcohol or an iodophor before accessing.

• During dressing changes, disinfect clean skin with 2% chlorhexidine (preferred) or tincture of iodine, an iodophor, or 70% alcohol.

• Replace catheter site dressings:

- when they become damp, loosened, or soiled; and

- for short-term central venous catheter (CVC): every two days for gauze and every seven days for transparent dressings.

• Replace dressing for tunneled or implanted CVC sites once per week until site is healed.

— Source: Centers for Disease Control and Prevention. Guidelines for the prevention of intravascular catheter-related infections. MMWR Morb Mortal Wkly Rpt. 2002;51(RR-10):1-26.

For More Information

Refeeding Syndrome available here.

Trace Elements in PN available here.

Hepatobiliary Disorders Associated With Long-term Parenteral Nutrition Use21

• Hepatic steatosis: accumulation of fat in liver cells. Signs include elevation of serum aminotransferase levels and lesser elevation in alkaline phosphatase and bilirubin.

• Cholestasis: impairment in bile secretion or biliary obstruction. Signs include elevation in direct bilirubin and alkaline phosphatase, with or without jaundice. Aminotransferase levels may also be elevated.

• Cholecystitis: inflammation of the gallbladder due to biliary sludge or gallstones because of lack of enteral stimulation.

Possible Etiologies of Parenteral Nutrition-associated Liver Disease21

• Use of continuous, rather than cyclic, PN;

• Overfeeding of parenteral dextrose and or intravenous fat emulsion (IVFE);

• IVFE emulsions used at greater than 1 gram per kilogram body weight for adults;

• Phytosterol and high omega-6 fatty acid content of IVFE;

• Lack of enteral/gastrointestinal stimulation (oral intake or tube feeding);

• Recurrent septic events;

• Recurrent or untreated small bowel bacterial overgrowth;

• Deficiency of carnitine;

• Deficiency of choline; or

• Deficiency of taurine (neonates).

1. Gupta S, Steiger E, Sands M. Vascular access for the patient receiving parenteral nutrition. In: Buchman A (ed). Clinical Nutrition in Gastrointestinal Disease. Thorofare, N.J.: Slack; 2006.

2. O’Grady N, Alexander M, Dellinger EP, et al. Guidelines for the prevention of intravascular catheter-related infections. MMWR Morbi Mortal Wkly Rpt. 2002;51(RR10):1-29.

3. Raad I, Hanna H, Maki D. Intravascular catheter-related infections: advances in diagnosis, prevention, and management. Lancet Infect Dis. 2007;7:645-657.

4. Kraft MD, Btaiche IF, Sacks GS. Review of the refeeding syndrome. Nutr Clin Pract. 2005; 20:625-633.

5. McCray S, Walker S, Parrish CR. Much ado about refeeding. Pract Gastroenterol. 2005; 29:26-44.

6. Hill SE, Heldman LS, Goo EDh, et al. Fatal micovascular pulmonary emboli from precipitation of a total nutrient admixture solution. J Parenter Enteral Nutr. 1996;20(6):81-87.

7. Food and Drug Administration. Safety alert: Hazards of precipitation associated with parenteral nutrition. Am J Hosp Pharm. 1994;51:1427-1428.

8. Reedy JS, Kuhlman JE, Voytovich M. Microvascular pulmonary emboli secondary to precipitated crystals in a patient receiving total parenteral nutrition. Chest. 1999;115(3):892-895

9. McNearney T, Bajaj C, Boyars M, et al. Total parenteral nutrition associated crystalline precipitates resulting in pulmonary artery occlusions and alveolar granulomas. Digest Dis Sci. 2003;48(7):1352-1354.

10. Ball, PA. Intravenous in-line filters: Filtering the evidence. Curr Opin Clin Nutr Metab Care. 2003;6(3):319-325.

11. Mirtallo J, Canada T, Johnson D, et al. Safe practices for parenteral nutrition. J Parenter Enteral Nutr. 2004;28:S39–S70.

12. Knowles JB, Cusson G, Smith M, et al. Pulmonary deposition of calcium phosphate crystals as a complication of home total parenteral nutrition. J Parenter Enteral Nutr. 1989;13(2):209-213

13. Robinson LA, Wright BT. Central venous catheter occlusion caused by body-heat-mediated calcium phosphate precipitation. Am J Hosp Pharm. 1982;39(1):120-121.

14. U.S. Food and Drug Administration. Safety alert for drugs, biologics, medical devices and dietary supplements. Available here. Accessed November 16, 2007.

15. Fessler T. Trace element monitoring and therapy for adult patients receiving long-term total parenteral nutrition. Pract Gastroenterol. 2005;29(3):44-65.

16. Kumpf VJ. Update on parenteral iron therapy. Nutr Clin Pract. 2003;18(4):318-326.

17. Gura KM, Puder M. Recent developments in aluminum contamination of products used in parenteral nutrition. Curr Opin Clin Nutr Metab Care. 2006;9(3):239-246.

18. Speerhas RA, Seidner DL. Measured versus estimated aluminum content of parenteral nutrient solutions. Am J Health-Syst Pharm. 2007;64(7):740-746.

19. Cardelli TN, Fortin MG, Creech MB. Can aluminum content in home parenteral nutrition solutions be safely reduced to meet FDA guidelines for all patient populations? Nutr Clin Pract. 2007;22:105-106.

20. Buchman AL. Complications of long-term parenteral nutrition. In: Buchman A (ed). Clinical Nutrition in Gastrointestinal Disease. Thorofare, N.J.: Slack; 2006.

21. Kumpf VJ. Parenteral nutrition-associated liver disease in adult and pediatric patients. Nutr Clin Pract. 2006;21(3):279-290.

22. Gura KM, Duggan CP, Collier SB, et al. Reversal of parenteral nutrition-associated liver disease in two infants with short bowel syndrome using parenteral fish oil: implications for future management. Pediatrics. 2006;118(1):197-201.

23. Matarese LE, Costa G, Bond G, et al. Therapeutic efficacy of intestinal and multivisceral transplantation: survival and nutrition outcome. Nutr Clin Pract. 2007;22(5):474-481.

24. Ferrone M, Geraci M. A review of the relationship between parenteral nutrition and metabolic bone disease. Nutr Clin Pract. 2007;22(3):329-339.