This series of articles is intended to help pharmacists provide in-service courses to other health professionals in the hospital and institutional setting. These articles will appear from time to time. This article reviews parenteral nurition therapy. The in-service materials are prepared by M. Saljoughian, Pharm.D., Ph.D., from the department of pharmacy of Alta Bates Summit Medical Center, Berkeley, CA.
Total Parenteral Nutrition (TPN) is an essential form of patient care and supportive therapy in a wide variety of disease states, and its value in promoting recovery is undisputed. Parenteral nutrition admixtures represent one of the most complex pharmaceutical formulations prepared by the pharmacist on a daily basis. Its IV delivery to the central circulation requires continuous monitoring with regard to sterility, compatibility and the stability of the final admixture. Total Pareneteral Nutrition fluids are complex mixtures of amino acids, dextrose, electrolytes, vitamins, trace elements and sterile water. Due to the high concentration of the ingredients, serious and sometimes fatal harm can occur to patients if there are errors in compounding and interpreting labels for this type of intravenous therapy.1 A special report for practitioners for parenteral nutrition formulations was recently published and includes information concerning proper labeling of solutions, estimating nutritional needs, and guidelines for compounding and quality assurance.2 Nutrition support pharmacists have an important role in monitoring TPN orders and supervising their preparation.
When patients are not able to consume adequate amounts of fluid and calories to maintain normal nutritional status, clinicians recommend TPN on short- or long-term bases. Patients with malabsorption disorders, under radiation therapy, small bowel resection, burn, sepsis, severe trauma, gastrointestinal obstruction, severe vomiting (e.g., hyperemesis gravidarum) and diarrhea (e.g., opportunistic types seen in patients with AIDS) are examples of clinical situations in which this mode of intravenous therapy may be required. Normally the content of PN formula dictates the route of its infusion via central, peripheral or femoral vein. Central infusion has a number of advantages, such as including no osmolality restriction, and allows for longer-term access and higher concentrations of solutions, but it is more invasive and has risks for arterial injuries. Peripheral parenteral nutrition (PPN) is used when central venous alimentation is not possible or is not necessary (brief transition periods of 5 to 7 days).3 It also avoids risks of central catheter.
The response and tolerance by the patient to infusion of glucose, amino acid and fat is very important. In these situations, the release of fat from endogenous stores is accelerated and there is an increased need for glucose. The amount of urea production significantly increases as a result of net body protein breakdown During periods of illness and injury, the lean body mass depletion is accelerated; therefore, initiation of parenteral nutrition is an important consideration. In these situations a number of methods are used to determine energy requirements: The Harris-Benedict Equation is used to determine the basal energy expenditure (BEE), use of indirect calorimetry for ventilated patients and when it is hard to determine the patient's weight. In normal conditions caloric needs are satisfied through glucose, lipid, and protein are as follows: Glucose (3.4 Kcal/g); Lipid (9 Kcal/g); Protein (4 Kcal/g).3
DAILY ELECTROLYTES ADDITIONS TO PN FORMULATION
||PRN to balance acid-base|
||PRN to balance acid-base|
|*Recommended Dietary Allowance |
The TPN Order
When ordering and preparing TPN, the physical appearance, weight and laboratory data are of principal pharmaceutical importance in assessing the patient nutritional status. The total body weight of an individual includes a measure of body cell mass, skeletal mass and body fat. The patient's weight can be measured against a variety of standards, and is the basis by which protein and energy requirements are determined. Factors that predispose to malnutrition and weight loss must be identified at this point. Overhydration and underhydration could result in an excess or underfeeding and patients in these states need special attention. Changes in body weight will not necessarily correlate with changes in nutritional status. For example, a patient who has lost weight following severe diarrhea will have less body water but may not necessarily have actual loss in body cell mass. In addition, patients who develop edema may gain weight as a result of fluid accumulation and not any increase in body cell mass.1-3 Water maintenance and replacement fluid needs are determined by the heat the body produces and the load of solutes in body fluids.
Each order is a complex prescription that requires pharmacist review prior to preparation. A typical formula for macronutrient concentrations that does not exceed 1 Kcal/mL is amino acid (10%), dextrose (70%) and fat (20%). In patients with fluid restriction, the final volume will be 1000 mL or less; sometimes more concentrated stock solutions need to be used to make the formula preparation feasible. The dose of parenteral nutrients in the acute care settings should be directed to modest calorie support and metabolic management. Positive nitrogen balance is a long-term goal during nutritional support and should be based on the patient's energy needs. Once an appropriate weight has been determined, the dosing of macronutrient is simple. For adults, protein and calorie requirements are determined based on two main parameters: the degree of metabolic stress and the body's ability to utilize them. For infants, growth is an additional parameter. The daily energy requirements are as follows: Adults (25-30 Kcal/Kg), Preterm Neonates (120-140 Kcal/Kg), Infants 6-12 months (80-100 Kcal/Kg).3
Nutrition support pharmacists review the PN orders on a daily basis and recommend adjustment of the electrolytes and other nutrients based on the lab results. Consultation with clinical nutritionist sometimes is necessary.
Implementation of Parenteral Nutrition Admixtures
When implementing parenteral nutrition regimens in patients, the following steps should be considered:
1. Determine the daily fluid amount required, being sure to add additional fluid amounts lost as diarrhea or other measured losses.
2. Estimate daily nonprotein calorie needs; be sure to limit lipid calories to no more than 30% of total calories.
3. Estimate protein needs, being sure that total protein amounts do not exceed 15% of total caloric intake.
4. Add lipid formulations in the admixture or administer separately. Considerable controversy exists concerning potential stability problems if lipids are included with protein and dextrose mixtures.
5. Add sterile water to dilute concentrated dextrose and amino acid sources to yield final concentrations of up to 5%25% amino acid and dextrose concentrations, respectively.
6. Add electrolytes, vitamins and trace elements (micronutritionals) to the protein and dextrose mixtures depending on the stability of the mixture.
7. In PPN the amount of dextrose should not exceed 10%.
Electrolytes such as sodium, potassium, calcium, magnesium, phosphorus, chloride and acetate are necessary components of parenteral nutrition for the maintenance of numerous cellular functions, including acid-base balance and cellular growth. Electrolytes may be given to maintain normal serum concentrations or to rectify deficits. Clinicians sometimes order IV boluses of these electrolytes to adjust severe deficiencie. The patient's age is one of the main factors in determining daily dosage of electrolytes.
Vitamins and Trace Elements
Vitamins are a vital and necessary component of parenteral nutrition admixtures: Special consideration should be given to thiamine (vitamin B1, the first vitamin to become deficient), vitamin K and folic acid. Ascorbic acid is only added up to 2000 mg/day for its antioxidant effects. Vitamin K should not be administered to patients who receive warfarin concomitantly. Multivitamins formulated for adults should not be given to pediatric patients in PN since their formulations contain preservatives.
Trace elements are very important in patients receiving long-term PN therapy. The development of clinically significant trace mineral deficiencies, such as cardiomyopathy and muscle weakness with selenium deficiency makes selenium and other trace elements such as zinc, molybdenum and iodide an essential mineral supplementation. Deficiencies in zinc have been noted in patients with concomitant ostomy losses and/or severe diarrhea. Signs of zinc deficiency may include dysgeusia (distortion of taste perception), ileus (obstruction of the bowel), hair loss, delayed wound healing and seborrheic dermatitis.4 Patients who present with a diabetes-like syndrome may be experiencing chromium deficiency due to insulin resistance. Copper deficiency may manifest as a hypo-chromic, normocytic anemia with or without neutropenia, osteoporosis, decreased hair and skin pigmentations. Manganese deficiencies include nausea and vomiting, color changes in hair, growth retardation and fat accumulation. Other vitamins and micronutrients such as pyridoxine, niacinamide, vitamin E, biotin and dexpanthernol can be added to TPN as required on individual bases.
L-cysteine hydrochloride is an example of a nutritional additive necessary in pediatric parenteral nutrition due to a lack of enzymes necessary to make this amino acid in this population. It must be admixed at the time of PN preparation to prevent its oxidation to the dimer cystine. L-cysteine is an acidic amino acid and has buffering capacity to prevent pH changes. Other additives, such as L-glutamine, are added to PN admixtures, but L-cysteine is the only nutritional adjunct that has an FDA-approved indication.
Insulin (10-100 U/L), heparin (1000-2000 U/L) and H2-antagonists, such as famotadine (20-40 mg/day), are routinely added into the PN orders by physicians and the dosing and concomitant use in patients are reviewed and adjusted by the pharmacists. As an example, hyperinsulinemia can cause significant shifts in potassium and phosphorus into the intracellular compartments and induce metabolic problems in severely malnourished patients. If a patient needs to receive pantoprazole (Protonix), it should be given in a separate line and not mixed with PN due to incompatibility. Patients who receive pantoprazole separately do not need famotadine in their TPN. Also, the amount of lipid needs to be adjusted if the patient is receiving propofol, a lipid-based emulsion drug.
Many antibiotics are physically and visually compatible with TPN, if they are administered in a Y-site injection at certain concentrations. Examples are ampicillin, cefazolin, erythromycin, gentamycin, imipenem-cilastatin and vancomycin.8
Compounding the PN Order
Once the nutritional prescription has been ordered and reviewed by the pharmacist, the pharmacy technician begins the compounding process under the supervision of a pharmacist. Pharmacist supervision for certification of the procedure ensures the pharmaceutical integrity of the final product. As soon as the admixture has been successfully compounded, a label is affixed to the TPN bag that clearly and concisely displays the complete content. Once the TPN admixture is dispensed from the pharmacy, its proper storage and use should be communicated to the nursing and medical staff. This includes the use of in-line filters, Y-site compatibility data of medications with TPN, as well as the identification of an unstable formulation, and procedures to follow once discovered.
The classic example of PN physiological incompatibility can be seen with calcium and phosphate salts. Calcium and calcium salts in solution easily make insoluble products with anions of carbonates and phosphates.
For most adult patients, calcium (200 mg or 5 mmol) and phosphate (1000 mg or 30 mmol) can be safely given in central PN admixture of 1500 mL or more. Calcium gluconate is a better salt as it is least dissociated into its free form in PN admixtures.
Physicochemical stability of PN admixtures is a pharmaceutical challenge and the pharmacist must ensure that the PN is stable during the period of infusion. Expiration date typically assigned to TPN in the hospital setting is 24 to 48 hours, and in the homecare setting, 7 to 14 days. Storing TPN under refrigeration (4oC8oC) decreases the degradation rates of most components. Certain additives may pose stability concerns that may affect compatibility. As an example, the addition of ascorbic acid more than 2000 mg as an antioxidant may form a highly reactive terminal degradation product, oxalic acid, that will react with calcium to form insoluble calcium oxalate.5 Pharmacists routinely screen TPN orders and question additives that are present in unusually high concentrations.
If appropriately selected and monitored, parenteral nutrition is safe and very effective. However, it may be associated with numerous complications; such as mechanical, infectious, and metabolic.
Mechanical: Mechanical complications include malfunctions with tubing, administration sets and the catheter or infusion pump failure. These complications may include catheter misdirection, arterial puncture, venous thrombosis and air embolism. If these problems cannot be repaired, the catheter may need to be replaced.
Infection: Infectious-related complications may be a major threat to patients receiving centrally infused parenteral nutrition. Infections may develop during preparation due to a lack of aseptic technique. Catheter-related infections have been identified as a major cause of complications in patients receiving parenteral nutrition. Patients with an infection from a catheter may present with the following signs and symptoms: fever, chills, mental status changes, hypotension or glucose intolerance. In situations in which the source of contamination is not evident, the catheter should be evaluated as a potential source, because blood cultures are drawn from the peripheral site and/or the central catheter. Catheter-related infection protocols are controversial because various facilities may have different protocols. Currently, there is no standard protocol.
Metabolic: Although nutritional support is for the metabolic care of the patient, but certain complications have been reported by PN therapy. For example, excessive energy intake is associated with severe and potentially life-threatening complications when used in either severe metabolic stress or in case of extreme malnutrition. As an example, excessive dextrose administration could cause major metabolic stress to the immune system, hepatic function, respiration and even electrolyte balance. Metabolic complications associated with parenteral nutrition may be potentially fatal if left untreated. Studies demonstrate that long-term hyperalimentation may be linked to persistent abnormalities in hepatic enzymes and may cause progression to chronic liver disease. Complications may arise from inappropriate nutrient intake. Therefore, vitamins, trace elements and essential fatty acids should be provided to all patients receiving parenteral nutrition.6
In some patients with preexisting conditions, manipulation of the TPN formula or solution components may be required. The most common considerations are related to hepatic dysfunction, renal dysfunction, pancreatitis, chronic obstructive pulmonary disease (COPD), or pregnancy. Hyperphosphatemia and hypophosphatemia are common concerns in patients with acute renal failure (ARF), because phosphate is an electrolyte that is excreted renally. Like potassium, large amounts of phosphorus may be liberated from tissue breakdown in ARF. Hypermagnesemia is also common in ARF secondary to impaired excretion and endogenous release from tissue breakdown. Although serum magnesium concentrations do not decline as fast as potassium, monitoring is still essential. By infusing branched chain amino acids as the main source of protein, improvements in serum liver function tests and nutritional measures (nitrogen balance) have been noted and, in some instances, mortality declines.7 In patients receiving hemodialysis, studies consistently demonstrate a potential loss of amino acids during treatment. Patients with COPD are generally malnourished and it is believed that a catabolic state predisposes these patients to infections. Hyperemesis gravidarum is a complication of pregnancy in which excessive vomiting can lead to severe maternal nutrition deprivation. TPN has been used in pregnancy complicated by hyperemesis gravidum.9
TPN Admixture as a Drug Delivery Vehicle
When a TPN admixture is considered for use as a drug delivery vehicle, three basic criteria must be considered:
1. The drug must be physicochemically stable over the desired infusion period. If the admixture is not a cycled infusion, but rather a continuous infusion over 24 hours, it should be considered unsuitable as a PN additive and given separately.
2. The drug must be compatible with the nutritional components as well as other drugs present in the PN admixture.
3. The drug dose does not need to be changed every 24 hours.
Monitoring and Patient Assessment
Clinicians continuously assess and optimize the patients' response to PN therapy. Feeding weight and a reliable weight history are required for all consultations and nutrition support. Also, daily specific laboratory analyses must be carefully performed to provide the most useful information for adjusting the TPN formula for the electrolytes, micro- and macronutrients.
Glucose and electrolyte concentrations should be monitored to avoid alterations in these values. Initially, glucose and electrolyte concentrations should be monitored every 4-6 hours to avoid hyperglycemia and serious electrolyte shifts when solutions are infused. Additional laboratory values should include a complete blood cell count with differential, liver transaminase profile, prealbumin and albumin, urinary urea nitrogen (UUN), and a full lipid profile.10
The Role of the Pharmacist
It is important for pharmacists to understand the complexities involved with this type of therapy. The pharmacist should be able to assess each case individually to ensure that an adequate amount of nutrition is administered. In order to have therapeutic success, specific laboratory and physical parameters must be selected and properly monitored. Potential complications can be minimized if special attention is paid to each step of the preparation and administration of total parenteral nutrition solutions. Cooperation between the clinician, pharmacist and dietitian results in the best outcome for those patients who are candidates for the administration of TPN.
TPN CASE STUDY:
A.S. is a 65 year old male who was admitted to the hospital due to losing weight, weakness with upper quadrant pain and dark urine for the last two weeks. He said he had been feeling well, with good appetite. No other complaint such as liver disease, respiratory distress or food intolerance was reported. He is currently taking no medication. He had been a heavy drinker and smoker, but quit these habits ten years ago. He is 5 feet and 6 inches and his weight is 110 pounds (50 Kg). His medical records indicate that his weight was 160 pounds one month ago. Lab values are all within normal limits, except lymphocytes 6% (15-40) and alkaline phosphatase of 2231 IU/L (77-260).
PROGNOSIS: HEPATIC OR PANCREATIC DISEASE.
After admission, the physician asked the pharmacist to design a TPN to deliver a non-protein calorie formula of 2000 Cal/day with 60 gram amino acid with an infusion volume of 2 liters before a possible surgery.
Note: In patients losing weight, nutrient calculations should be based on actual body weight. For obese patients whose body weight is more than 120% of their ideal body weight, calculations are based on ideal body weight (adipose tissue is metabolically inactive).
Step 1: Calculate Basal Energy Expenditure (BEE) for this patient (Method 1)
BEEmen = 66.67+13.75 (Weight)+5 (Height)6.76 (Age)
BEE = 66.67+13.75 (50Kg)+5 (165 Cm)6.76 (65Y)
BEE = 66.67+ 687.5+825439 = 1140 Calories.
Activity factor for ambulatory patients is 1.3.
BEE = 1140 X 1.3 = 1480 Calories
Method 2: Use 30-35 Cal/Kg/day =1500-1750 Calories for this patient.
Step 2: Calculate the patient's daily fluid requirement
1500 mL for the first 20 Kg + 20 mL/Kg of actual weight.
mL/day = 1500 mL + (5020 = 30 X 20 mL) = 2100 mL (approximately 2 Liters).
Step 3: Protein Intake: Patient is moderately stressed and based on his weight he needs 1-1.2 g/Kg/day or 1.2gm X 50 = 60 gm protein that can be given as synthetic amino acid (one gram of AA equals one gram of protein).
Step 4: Non-Protein Calories:
The use of fat in this patient is not recommended and the physician wants a carbohydrate based nutrient formula.
Dextrose: 3.4 Cal/gm
1 gm X 2000 Cal = 3.4 Cal X A
A= 588 gm total dextrose
588 gm X 1000 mL = 2100 X B
B= 280 gm dextrose/L (28%)
60 gm X 1000mL = 2100 X C
C= 28.6 gm (2.8%)
Note: Based on the above requirements the use of a standard base solution of (25% dextrose) and (4.25% AA) would work well.
Hospital Formulary includes: Dextrose 70% in water, Amino Acid (10%) and Sterile Water. Volumes needed to compound one liter TPN base are calculated as follows:
Dextrose: 280 gm X 100 mL = 70 gm X D
D= 400 mL
Amino Acid: 28.6 gm X 100 mL = 10 gm X E
E= 286 mL
Water: 1000 mL 400 mL (Dextrose) 286 mL (AA) = 314 mL
Note: If the patient had to receive fat as non-protein calories, the amount of fat would be 40%-60% of the total 2000 calories. 10% and 20% IV fat emulsion generate 1.1Cal/mL and 2Cal/mL, respectively.
Electrolytes should be calculated based on the individual needs (lab values) and standard guidelines. Suggested electrolyte requirements/1000 Kcal are: Na 40-50 mEq; K 40 mEq; Mg 8-12 mEq; Ca 2-5 mEq and Phosphates 15-25 mM.
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