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Precipitates can develop in parenteral nutrition admixtures because of a number of factors such as the concentration, pH, and phosphate content of the amino acid solutions, the calcium and phosphorus additives, the order of mixing, or the mixing process. The consequences can be serious. In one cohort study of hospitalized patients who received peripheral parenteral nutrition, a subgroup developed unexplained chest pain, dyspnea, cardiopulmonary arrest, or new interstitial infiltrates on chest radiograph. A change in the amino acid source of a parenteral nutrition mixture was associated with respiratory adverse events that ranged from interstitial infiltrates to sudden death. The events apparently resulted from infusion of calcium phosphate precipitate in an opaque admixture, and the deposition of the crystals in the pulmonary microvasculature (147).

The United States Food and Drug Administration issued a safety alert in 1994 regarding the potentially life-threatening formation of precipitates in parenteral nutrition admixtures (148). They had received reports of two deaths and at least two cases of respiratory distress during intravenous infusion of a three-in-one parenteral nutrition mixture (amino acids, carbohydrates, lipids). The mixture contained 10% FreAmine III (amino acids + magnesium acetate + phosphoric acid + potassium chloride + sodium acetate + sodium chloride), dextrose, calcium gluconate, potassium phosphate, other minerals, and a lipid emulsion. The solution may have contained a precipitate of calcium phosphate. Autopsies revealed diffuse microvascular pulmonary emboli containing calcium phosphate.

The FDA has recommended the following steps to decrease the hazard of injury through precipitation (149):

1. The amounts of phosphorus and calcium added to the admixture are critical. The solubility of the added calcium should be calculated from the volume at the time that the calcium is added. It should not be based on the final volume. The line should be flushed between the addition of any potentially incompatible components.

2. A lipid emulsion in a three-in-one admixture obscures the presence of a precipitate. Therefore, if a lipid emulsion is needed, either use a two-in-one admixture with the lipid infused separately, or add the calcium before the lipid emulsion according to the recommendations in 1 above. If the amount of calcium or phosphate which must be added is likely to cause a precipitate, some or all of the calcium should be administered separately. Such separate infusions must be properly diluted and slowly infused to avoid serious adverse events related to the calcium.

3. During the mixing process, parenteral nutrition admixtures should be periodically agitated to check for precipitates. This check should be conducted both before and during the infusion. Patients and caregivers should be trained to inspect for signs of precipitation. They should also be trained to stop the infusion and seek medical assistance if precipitates are noted.

4. A filter should be used when infusing either central or peripheral parenteral nutrition admixtures. Data are not available to determine which size filter is most effective in trapping precipitates.

5. Parenteral nutrition mixtures should be administered within the following time frames: if stored at room temperature, the infusion should be started within 24 hours after mixing; if stored at refrigerated temperatures, the infusion should be started within 24 hours of rewarming. Because warming parenteral nutrition mixtures may contribute to the formation of precipitates, once administration begins, care should be taken to avoid excessive warming of the mixture.

Mirtallo has added to the FDA guidelines, stressing the need to ensure that an appropriate dose of calcium is prescribed, to follow appropriate procedures when mixing parenteral nutrition solutions and to use automatic mixing devices strictly in accordance with the manufacturer's instructions (150). He has stressed the fact that more information is needed to substantiate the usefulness of filters in preventing adverse effects caused by the infusion of particulate matter present in parenteral nutrition admixtures.

It has been pointed out that calcium phosphate precipitates more readily in warm than in cold solutions. Precipitation can occur in solution at room temperature, even if an identical cold solution is clear. A precipitate can also form when a clear solution, stored refrigerated or at room-temperature, is warmed to body temperature. Thus, visual inspection and even in-line filters, if they are distal to the side of precipitation, may not prevent infusion of the precipitate (151).

Drug contamination

Since the introduction of parenteral nutrition in hospital care the potential microbiological risks associated with the manufacture, preparation, and administration of these products have abated but not disappeared (133,152). Fatal infectious complications still occur. The parenteral nutrition mixture is a good growth medium for microorganisms, more conducive to microbial growth than glucose or amino acid solutions. Storage of mixtures allows time for microbial multiplication, often to counts of millions per ml. Commonly isolated organisms from parenteral nutrition solutions are coagulase-negative staphylococci, S. aureus, Candida species, Serratia species, and Enterobacter species. Infection with Malassezia furfur is a rare but serious complication strongly associated with parenteral nutrition in young children, now documented in some 50 reports (153). Candida infection is a particular problem in patients receiving parenteral nutrition. Even organisms such as S. epidermidis and Bacillus species, relatively non-pathogenic in normal circumstances, can multiply in the infusion to such large numbers as to have disastrous effects. Many of these commensal organisms tend to be insensitive to antibiotics. In an open-system aseptic process of preparation the estimated risk of contamination, according to the World Health Organization, is one in 3000. Microbiological and environmental quality control assurance needs to be continuous.

The average rate of episodes of catheter-related bacteremia in patients receiving parenteral nutrition is 35%. Higher rates are reported for long-term patients. Patients with a nosocomial infection have an 11-fold higher risk of acquiring an additional nosocomial infection compared with those with no infection. Prompt removal of the catheter and targeted antimicrobial treatment remains the standard approach for febrile episodes in these circumstances. However, many catheter-related infections caused by coagulase-negative staphylococci can successfully be treated with the catheter still in place (154).

Drug administration route

Local extravasation of parenteral nutrition fluid can occur. Two patients developed an intense inflammatory reaction that was successfully controlled with repeated local administration of the hyaluronidase analogue chon-droitin sulfatase (155). Although the exact mechanism of tissue toxicity by extravasated parenteral nutrition is not understood, it seems likely to be related to osmolarity, pH, and ions. The area affected may become blistered, with darkening of the skin, or ischemic, depending on whether the skin thickness is partially or fully damaged. In children, extravasation can have devastating consequences, such as deep necrosis, amputation, severe sequelae in the affected limb, or other complications, such as subdural collection of fat emulsion, liporrhachis, and acute abdomen after intra-abdominal extravasation. Children are at special risk, because very young infants and children are unable to communicate the pain that results from the pressure of extravasated fluid. Other individuals in this situation are comatose patients, those under general anesthesia, and patients who are being resuscitated. Other risk factors that predispose to extravasation are related to venepuncture technique, state of the patient, and medication delivery. Special care should be taken when high-osmolarity (1000-1700 mosmol/l) peripheral parenteral nutrition is administered, as fluids of this osmolarity are likely to cause severe tissue damage if extravasated. Fluids should not generally exceed 600-900 mosmol/l in order to minimize the risk of this complication. The position of the catheter needs to be regularly checked. Fat emulsions are harmless to the tissues if extravasated.

After a preterm infant developed parenteral nutrition ascites after infusion through a low umbilical vein catheter, a follow-up study of eight patients, all of whom developed hypotension and ascites, showed that each had an umbilical vein catheter overlying the liver on plain X-ray (156). The catheters had been in place for a mean of 8.9 days before extravasation. Ultrasound in four patients showed hepatic parenchymal damage around the umbilical vein catheter tip. Parenteral nutrition given through abnormally placed umbilical vein catheters is not without risk, and correct placing of the catheter is paramount.

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