2 Indications for Parenteral Nutrition
3 Types of Parenteral Nutrition
4 Components of Total Parenteral Nutrition
5 Prescribing TPN
6 Monitoring the Effectiveness of Nutritional Therapy
7 Complications in the Hospitalized Patient Receiving Parenteral Nutrition
Parenteral nutrition becomes necessary when the gastrointestinal tract has insufficient function as to afford sufficient fluid, electrolyte and nutrient absorption. Indications for this therapy include prolonged postoperative ileus, prolonged intestinal obstruction, short bowel syndrome, various malabsorptive disorders, proximal enteric fistulas for which an enteral feeding tube cannot be placed distal to, severe acute pancreatitis and severe mucositis/esophagitis. Parenteral nutrition, although typically delivered through a large central vein, can also be infused peripherally with special techniques. Rarely, intradialytic parenteral nutrition is required. Parenteral nutrition
From: Clinical Gastroenterology: Nutrition and Gastrointestinal Disease Edited by: M.H. DeLegge © Humana Press Inc., Totowa, NJ
includes macronutrients (protein in the form of a balanced, free amino acid solution, carbohydrate in the form of a dextrose monohydrate and fat in the form of a lipid emulsion), fluid, electrolytes (sodium, potassium, magnesium and acetate/chloride to adjust pH), minerals (calcium, phosphorous, iron in some individuals), trace minerals (zinc, copper, selenium) and vitamins (water and fat-soluble). Numerous complications may develop as a result of parenteral nutrition including mechanical issues related to the catheter for solution delivery or its insertion, that include infection, occlusion (venous thrombosis or non-thrombotic occlusion), electrolyte disturbances and hyperglycemia, as well as hepatic, renal, pulmonary, and bone complications. Therapy should be appropriately prescribed and rigorously monitored for efficacy and safety.
Key Words: Parenteral nutrition, Malnutrition
Parenteral nutrition (PN) is necessary when enteral feedings are either contraindicated or cannot be provided in sufficient quantities to meet necessary nutritional requirements to maintain life and overcome malnutrition in certain patients. It the late 1960s the question was asked if total parenteral nutrition (TPN) could be another means of supplying nutrition other than enteral nutrition (EN) or peripheral parenteral nutrition (PPN). The use of enteral nutrition had already been an established means of delivering nutrition since ancient times, where rectal feedings were used to deliver nutrition [1, 2]. PPN was initially developed in 1955 and was used until 1965 until serious side effects of Lipomul™ led to its discontinuation from the United States market in the early 1960s . The absence of a lipid emulsion posed a major problem in the delivery of glucose, because large hypertonic volumes were being infused peripheral veins. Later in the decade, TPN was shown to be an effective method of administering nutrition after Stanley Dudrick and Johnathan Rhoads initially inserted catheters into the superior vena cava of beagle dogs to provide their sole source of nutrition from 72 to 256 days . Later they showed that the administration of TPN could improve the growth and clinical status of malnourished infants . Since that time, TPN has become and is still considered to be lifesaving therapy in certain clinical scenarios. Currently, PN is often recommended if enteral intake (oral or tube feeding) has been or is anticipated to be inadequate for a 5- to 10-day period . However, carefully performed, prospective, randomized controlled trials to support the efficacy of this approach are few in number. Due to the lack of controlled data, the use of PN requires an integration of information from heterogeneous sources, including: pertinent clinical trials, clinical expertise in the illness or injury being treated, reasonable estimates of inadequate enteral intake and clinical expertise in nutritional therapy.
The purpose of TPN is to provide the critically ill and non-critically ill patients with all of the basic nutrient requirements, which include: fluids, proteins, carbohydrates, fats, minerals, trace elements and vitamins. The intent is to help the patient recover from preexisting nutritional deprivation and/or significant multiorgan system failure and to prevent malnutrition from dictating the patient clinical course . Malnutrition can potentially cause a number of deleterious outcomes such as: increased susceptibility to infection, poor wound healing, increased frequency of decubitus ulcers, overgrowth of bacteria in the gastrointestinal tract and abnormal nutrient losses through the stool [8-12]. These alterations result in increased morbidity and mortality among malnourished, hospitalized patients [13-17].
PN is indicated to prevent adverse effects of malnutrition in patients who are unable to consume adequate nutrition via oral or enteral routes. In general, PN is indicated if the small intestine and/or colon is anticipated to be dysfunctional, obstructed or inaccessible for longer than 5 to 10 days [6, 18]. Short bowel syndrome (SBS), radiation enteritis, proximal fistulas that nasoenteric feeding tubes cannot be placed distal to, mucosal disease of the small bowel causing malabsorption, distal high output gastrointestinal fistulas, non-operative mechanical obstructions, persistent postoperative ileus, intestinal pseudoobstruction unresponsive to enteral feedings, intractable vomiting, severe diarrhea (>500ml/day), severe mucositis/esophagitis, severe acute pancreatitis and small bowel or colonic obstructions (including strictures) are examples of disease states that are indications for PN (Table 11.1).
Table 11.1 Indications for Total Parenteral Nutrition
1. Malabsorption a. Short bowel syndrome (SBS) (<150 cm small bowel in the absence of colon in continuity or <100 cm small bowel with colon in continuity)
b. Radiation enteritis c. Other (refractory sprue, microvillus inclusion disease and others)
4. High output gastrointestinal fistulas for which feeding distal to the fistula is impossible or would result in inadequate absorptive surface for adequate absorption
5. Severe mucositis/esophagitis
6. Intractable vomiting
3. types of parenteral nutrition
3.1. TPN (also referred to as central parenteral nutrition or CPN)
TPN can be accomplished via percutaneous infraclavicular subclavian vein catheterization with advancement of the catheter tip to the junction of the superior vena cava and right atrium. Cannulation of a large-bore, high-flow central vein such as the superior vena cava permits infusion of hyperosmolar (usually >1,600m0sm/l) nutrient solutions that cannot be not tolerated by smaller, low-flow peripheral veins. Central catheterization of the subclavian vein is preferred because lower rates of bacterial colonization have been observed when compared to other routes of central catherization . There have been many other approaches that have been successfully performed when the subclavian vein is not accessible such as: internal jugular, basilic, saphenous and femoral vein catheterization. Thoracotomy with direct insertion into the right azygos vein  or right atrial appendage has also been performed when more accessible access is unavailable. A peripheral approach to access the central veins can be accomplished using a peripherally inserted catheter (PICC) to provide TPN. Though this technique is associated with a dramatically lower risk of associated pneumothorax, there is a higher risk of thrombosis compared to percutaneous insertion if the catheter tip is placed proximal to the superior vena cava [21, 22].
3.2. Peripheral Parenteral Nutrition (PPN)
PPN should be provided to patients who require only short-term therapy, which is defined as less than 5 to 10 days. These patients should also be able to meet some, but not all of their nutritional requirements via enteral means. Essential to the development of PPN was the development of a non-toxic fat emulsion and recognition that fat emulsions administered with dextrose represented an optimal provision of energy . The use of the peripheral vein to provide nutritional support avoids many of the potential mechanical and infectious complications of TPN [24,25], but is associated with a high risk of developing thrombophlebitis, due to the hypertonic nature of the solution as well as the osmolality rate (product of osmolality and infusion rate) [26-28]. There are several factors in the pathogenesis of thrombophlebitis in patients receiving PPN: (1) osmolality, pH and lipid content of the PPN solution and the presence of particulate matter; (2) diameter length and composition of the catheter; (3) duration, rate and volume of the infusion; (4) diameter and anatomic position of the vein; (5) insertion technique [29, 30]. Early studies of PPN using crystalline amino acid-and glucose-based solutions found phlebitis rates of almost 100 percent when the osmolarity was increased above 600mosmol/l [31, 32]. A correlation between hyperosmolarity and phlebitis is not apparent when lipid-based solutions are utilized. Kane et al. randomized 36 patients to receive feeds of osmolarity of 1,200 or 1,700 mosmol/l. They found no difference in the incidence of thrombophlebitis . Similarly, Williams et al. demonstrated no significant difference in the incidence of thrombophelibitis between patients receiving lipid-based feeds with an osmolality of 650mosmol/kg and the those receiving an osmolality of 860mosmol/kg (13 and 18 percent, respectively) . There are ways to reduce the risk of the development of thrombophlebitis: (1) administration of 10 mg of hydrocortisone and 1,000 units of heparin per liter of PN solution, (2) avoidance of medications in the PN solution that are known to cause thrombophlebitis (acyclovir, aminoglyco-sides, amphotericin, erythromycin, high-dose penicillin, phenytoin, potassium and vancomycin), (3) dextrose solutions of greater than 10% concentration or 900m0sm should not be used and (4) at least 50% of the total energy should be provided as lipid emulsion. Adherence to these principles can decrease the risk of the development of thrombophlebitis [23, 35].
3.3. Intradialytic Parenteral Nutrition (IDPN)
Malnutrition is an important problem in patients treated with chronic hemodialysis or peritoneal dialysis. It occurs in 40 to 70 percent of patients (depending upon the method used to measure nutritional status), with an increasing length of time on dialysis correlating with an increasing decline in nutritional parameters [36, 37]. Prior to initiating IDPN, the presence of certain pathologic processes such as: under-dialysis [38, 39], drug toxicity, gastroparesis [40,41] and singultus  need to be ruled out. Similar to the aforementioned forms of parenteral nutrition, IDPN is indicated only in patients who cannot tolerate enteral supplementation and who do not have available central venous access.
There are certain limitations to IDPN. It is the most costly and least efficient nutritional supplement. IDPN often costs twice as much as dialysis itself, and only 70 percent of the nutrients are actually delivered to the patient because of loss into the dialysate . Malnutrition may persist, since IDPN is administered only 3 days per week for approximately 4h . It may be associated with a lower than expected delivered dose of dialysis, possibly due to increased urea generation . Nevertheless, IDPN is convenient (because it is delivered during dialysis) and is likely to be beneficial in some patients . However, although a number of studies suggest that IDPN provides substantial benefit, most were case reports, retrospective or poorly designed . In one study, a 9-month treatment period was associated with a 12 percent rise in the plasma albumin concentration and an apparent improvement in survival (64 versus 52 percent in patients not receiving IDPN) . However, the applicability of these findings is uncertain since the study was retrospective, IDPN was compared to no therapy rather than other nutritional interventions and the two groups were not strictly comparable at baseline .
The optimal indications for IDPN have not been established. The use of this modality should be provided to malnourished dialysis patient who cannot tolerate oral supplements, but who can consume at least 50 percent of the prescribed caloric intake. If this degree of oral intake cannot be reached, either a nasoenteral feeding tube with nighttime enteral nutrition or, if oral intake is not tolerated, the institution of TPN should be considered . Total parenteral nutrition is often required in the rare patient with severe malabsorption, severe malnutrition, or severe intolerance of oral supplements. Although generally well tolerated, TPN solutions typically contain added potassium, phosphorus and magnesium. Thus, patients with endstage renal disease receiving TPN are at risk for the development of hyperkalemia, hyperphosphatemia and hypermagnesemia. Elimination of the added electrolytes can prevent these problems, but carries the reverse risk of electrolyte deficiencies with prolonged therapy. The patient should then be carefully monitored, and electrolytes should be added if the plasma levels fall below the normal range. There is a theoretical risk of developing hypoglycemia with abrupt discontinuation of IDPN secondary to the longer half-life of insulin as compared to dextrose. This has been studied, including a randomized trial that showed that progressive versus abrupt discontinuation of TPN did not reveal a significant change in counter-regulatory hormones or increased hypoglycemia [50-52]. Nevertheless, close monitoring of blood glucose values should still occur. The rate should not be greater than 150ml/h to avoid profound hyperglycemia. Blood glucose monitoring should be frequent during the infusion and at 30 and 60 min after the infusion to detect reactive hypoglycemia. The rate is then gradually increased so that the full liter can be infused during a 4-h dialysis session .
The specific formulation prescribed for a patient depends on the patient's estimated nutrient requirements and ability to tolerate specific nutrients without adverse effects. The patient's protein, energy and fluid requirements are the most important considerations in designing an appropriate parenteral formulation. For example, basal energy expenditure (BEE) of a relatively unstressed middle-aged patient with restricted activity, who has no fever or other hypermetabolic condition, should be maintained in an acceptable range of approximately 20-25 kcal (7.2 kJ)/kg/body weight/day. The BEE is the amount of energy required to perform metabolic functions at rest and is influenced by both body size and illness. BEE classically is estimated by the Harris-Benedict equation [53-55]. The use of this measurement in the critically ill has traditionally involved multiplication by a stress factor of 0.5 to 2.5 [54, 56]. However, the use of the stress factor may result in overfeeding and may predispose the patient to liver steatosis, hyperglycemia, electrolyte imbalances, respiratory embarrassment due to increased CO2 production and macrophage dysfunction. There is evidence to suggest that the total energy expenditure is maximal during the 2nd week of critical illness and may reach 50 to 60Kcal/kg per day . However, there are no data supporting the delivery of nutritional support at this caloric level.
One of the primary sources of energy is glucose. Dextrose is usually the predominant energy source in TPN formulations and is the required fuel for erythrocytes, white blood cells, bone marrow and the renal medulla because they lack the enzymatic machinery to oxidize fatty acids, whereas the brain prefers to use glucose as fuel, but can use other sources. Dextrose given parenterally is in the form of a monohydrate providing 3.4kcal/g. It is readily available in various concentrations in liquid form. Using dextrose as a primary means to meet large energy needs within a reasonable fluid volume requires an extremely hypertonic solution (Table 11.2). Providing calories as dextrose stimulates insulin secretion and decreases hepatic glucose output, thereby reducing the need for skeletal muscle protein to provide amino acid precursors for gluconeogenesis. In addition, direct oxidation of dextrose spares the oxidation of amino acids.
Another major source of energy is lipid. Lipid emulsions consist of tiny droplets (<0.5 ^m) with hydrophobic triglycerides as the core and cholesterol derived from egg yolk phospholipids, soybean oil or a combination of soybean and safflower oil triglycerides surrounded by a solubilizing and stabilizing surface layer of the emulsifying phospholipids. Lipid emulsions should not be used in patients who have an allergy to eggs. Glycerol is added during the manufacturing process rendering lipid emulsions isotonic to plasma. Once in the bloodstream, lipid emulsion particles rapidly acquire apolipoproteins from contact with circulating high density lipoprotein particles and are metabolized in a similar fashion to chylomicrons. Once sufficient
4.2. Lipid Emulsion
Osmolalities and energy values of intravenous dextrose solutions
278 523 896 1,250 1,410 1,569 3660
170 320 510 680 850 1,020 2,330
Dextrose conc. (in grams) Osmolality (mOsm/kg H20) kcal/l
Fig. 11.1. Cutaneous rash associated with fatty acid deficiency.
amounts of dextrose have been provided to meet the requirements of glucose-dependent tissues and the brain, lipid calories are effective as glucose calories in conserving body nitrogen and supporting protein metabolism [58, 59]. When used as a caloric source, typically 20% to 30% of total calories are provided; 2% to 4% of the total calories should be given as linoleic acid as a minimum to prevent fatty acid deficiency . Administering a TPN solution devoid of lipid can cause biochemical evidence of essential fatty acid deficiency within 2 weeks  (Figs. 11.1 and 11.2).
Providing a portion of infused calories as lipid reduces plasma insulin concentration, sodium and water retention and hepatic fat accumulation . Lipid emulsions may be used in the setting of pancreatitis, not associated with hypertriglyceridemia as long as the triglyceride concentration is monitored as with any other patient who is receiving intravenous lipids .
Uncommon side effects of lipid infusions include fever, headache, back pain, dyspnea, chills, nausea, chest pain and oily taste. Lipid emulsion can cause pulmonary dysfunction , hepatic phospholipi-dosis , impaired immune system function , pancreatitis , decreased platelet aggregation , fat overload syndrome  and hypersensitivity reactions .
4.3. Use of Medium-Chain Triglycerides to Decrease the Risk of Immunosuppression in Lipid Emulsions
Lipid emulsions (LE) for parenteral use are complex emulsions containing fatty acids, glycerol, phospholipids and tocopherol in variable amounts and concentrations. Fatty acids may have different impacts on phagocytic cells according to their structure. Experimental and clinical studies have consistently shown that LE modifies monocyte/macrophage and polymorphonuclear phagocytosis causing an inhibitory effect on the functional activity of the phagocytic system. Though this is still clinically controversial, current formulations of lipid emulsions may have a harmful impact because TPN with lipids is recommended in hypercatabolic conditions where inflammation and infection are present. Over the past 2 decades, the clinical use of lipid emulsion for the nutritional support of hospitalized patients has relied exclusively on long-chain triglycerides, or LCTs, providing both a safe, calorically dense alternative to dextrose and a source of essential fatty acids needed for biological membranes and maintenance of immune function. LE based on long-chain triglycerides (LCTs) are the main parenteral fat source and may have adverse effects on the immune system, especially when given in high doses over a short period of time. Recent studies have demonstrated that LE containing medium chain triglycerides (MCT) may have some advantages because of their positive effects on polymorphonuclear cells, macrophages and cytokine production, particularly in critically ill or immunocompro-mised patients . In a study where patients underwent abdominal surgery in which TPN was considered to be necessary, Koller et al. randomized patients to a conventional prescription in which lipid was composed of (LCTs) or to an isocaloric mixture of LCTs and MCTs. There was a statistically significant increase in the relatively non-inflammatory leukotriene, LT-B5, in those patients receiving the MCT product . A double-blind study performed by Grau et al. showed that there were fewer intraabdominal abscesses in the group receiving a lipid emulsion containing a MCT mixture as compared to a mixture containing LCTs. Lower mortality was observed in the group receiving MCTs, but this did reach statistical significance . Montero et al. observed that septic patients who received a mixture of MCT and LCT had a significant increase in certain nutritional parameters (retinol-binding protein and nitrogen balance), when compared to those receiving LCT only. There was no difference in mortality or hospital stay .
4.4. Protein (Amino Acids)
The purpose of providing amino acids is to maintain the nitrogen balance and replete lean tissue in cachetic patients. The amount of protein needed to achieve these goals is affected by the amount of nonprotein calories provided and the patient's clinical condition. Insufficient non-protein calories, catabolic illness, protein losing enteropathy, nephropathy, hemodialysis and peritoneal dialysis increased protein requirements. In general, most hospitalized patients need 0.8 to 1.5 g of protein per kilogram (kg) body weight per day.
Formulations of crystalline L-amino acids have been developed for specific clinical problems, with varying claims for superiority in certain clinical situations such as renal and hepatic failure, trauma and growth in infants. The eight amino acids essential for physiologically normal adults are present in all formulas, as are histidine and arginine, which are needed for young children. Glycine, alanine and proline are present in moderately high concentrations in general adult formulations as sources of nonessential amino nitrogen. The ratio by weight of essential to total amino acids in the pediatric and adult solutions varies between 0.41 and 0.54; higher ratios are present in formulas intended for patients with renal or hepatic failure. Some amino acid formulas contain sodium bisulfate as a preservative, and thus patients with hypersensitivity to sulfa should not receive these formulas. Even though the energy cost of amino acids is high, amino acids delivered to patients should be included in the estimate of energy provided by the PN. There is a small contribution from amino acids involved in the daily synthesis and accumulation of stored glucose (as glycogen derived from gluconeogenesis from amino acids is limited).
Crystalline amino acids are available in concentrations of 8.5% to 15%. The amino acid solution is then diluted with an appropriate amount of dextrose to achieve a desired concentration, usually between 3.5% to 5.0%. In patients with non-oliguric renal failure in patients who are dialysis dependent, protein intake should not be restricted due to increased losses via the dialysate. This amounts to 6 to 8 g in hemodialysis, 12 to 16 g during peritoneal dialysis and continuous hemofiltration. In hepatic failure the concentration should be less than 3.5% [18, 75]. In patients who are fluid restricted or undergoing fluid restriction, a concentration of greater than 4.25% should be used.
Solutions containing only essential amino acids have been developed for patients with acute renal failure. It was initially thought that by only providing essential amino acids an overall lower amino acid load would be created that would result in a lesser deterioration of renal function and would help to synthesize non-essential amino acids. Unfortunately, when compared to mixed formulations of essential and non-essential amino acids, there was no improvement in renal function . Amino acids metabolism is more effective when a formulation of mixed essential/non-essential amino acids is used . Nevertheless, there may be benefit from the addition of histidine to the renal formulas. Between 67% to 100% of the total amino acids in these formulas are composed of the eight amino acids and histidine. Histidine is considered to be an essential amino acid in patients with renal failure. In a small study, Druml et al. showed that histidine clearance is elevated when compared to controls in acute renal failure, chronic renal failure and hemodialysis patients . Recently, Yatzidis et al. showed that oral supplementation with histidine along with glycine, aspartic acid, glutamic acid, glutamine and arginine increased urine volumes within a 24-h period and decreased 24-h albuminuria . Further studies need to be performed to show the effectiveness of supplemental histidine combined with parenteral formulations in renal dysfunction.
4.5. The Role of Branched Chain Amino Acids (BCAA)
Modified amino acid solutions have been developed for specific disease states and physiologic conditions. Solutions containing high concentrations of BCAA have been advocated for the use in patients with hepatic encephalopathy. These solutions contain 35% to 40% of branched chain amino acids, whereas standard formulas only contain 20%. The clinical efficacy of parenteral BCAA-enriched TPN solutions in patients with acute hepatic encephalopathy were evaluated in nine prospective randomized controlled trials through 1989. Five of the trials were reviewed using meta-analytical methodology to pool data across studies . Patients who received BCAA-enriched solutions demonstrated a statistically significant improvement in mental recovery from high-grade encephalopathy during short-term (7-14 days) nutritional therapy. There was enough heterogeneity in mortality rates among the studies to preclude a meaningful aggregation of accrued mortality data. Although a pooled analysis of all of the trials suggested a beneficial effect of BCAA-enriched formulas as a primary therapy in patients with acute hepatic encephalopathy, the studies had several shortcomings that limit their use in current clinical practice. For example, the control groups usually received suboptimal, and possibly harmful, nutritional support consisting of high-dextrose solutions without amino acids. Another study only compared BCAA-enriched TPN with a standard amino acid TPN solution. None of the studies reported on the complications associated with nutritional therapy or whether short-term benefits of nutritional therapy led to a long-term reduction in complications. More recent reviews that included additional data concluded there was no affect on mortality from BCAA use and that the current evidence-based literature did not support the routine use of BCAAs [81-83]. Data from a subsequent 1-year double-blind randomized multicenter trial of 174 patients found that treatment with oral BCAA supplementation significantly reduced the length of hospital stay, mortality, anorexia and improved Child-Pugh score, although the compliance was poor . A Cochrane-based review of the use of BCAA in patients with chronic hepatic encephalopathy identified 11 randomized trials that included a total of 556 patients . A significant improvement was seen in BCAA use on the severity of hepatic encephalopathy, but mortality was unaffected. Although this positive outcome was observed, the studies that elucidated this were those of poor methodological quality. The concept that increasing the plasma BCAA:AAA (aromatic amino acids) ratio leads to decreased encephalopathy has been questioned by some investigators as brain uptake of BCAA in some cirrhotics may be similar to that of healthy controls  and may be a better correlate of hepatic function than the degree of encephalopathy in others .
The fluid component must meet individual requirements as determined by evaluation of the clinical and laboratory data. In addition to clinical factors that could cause excessive retention or loss, consideration must be given to insensible fluid losses, fluid intake with medications and infusions designed to keep veins patent. Meticulous recording of fluid intake and output is necessary. Assessment of volume status by hemodynamic monitoring may be necessary in critically ill patients. PN mixtures can be administered to patients with varying fluid needs. Similar to the acute care setting, the extra fluid requirements can be added to the PN mixture in the home setting. In a fluid-restricted patient, both dextrose and amino acid concentrations can be increased and the opposite can be performed in volume overloaded patients. For patients receiving continuous ambulatory peritoneal dialysis (CAPD), the amount of glucose absorption from the dialysate should be estimated and included in the calculation of delivered calories. Fluid that is incorporated in the PN composition should not be used as a replacement fluid for additional losses beyond maintenance needs in this patient population .
Prior to adding electrolytes to PN, electrolyte imbalances should be corrected prior to initiating parenteral nutrition. Parenteral nutrition should not be used as replacement fluid for additional losses of electrolytes beyond maintenance. Parenteral electrolyte content should be adjusted to the patient's serum electrolyte concentration.
Sodium bicarbonate interferes with calcium phosphate compatibility and should not be used in parenteral nutrition solutions. Sodium bicarbonate also should not be injected in the vein that is being used for PN.
The original vitamin concentrations for intravenous formulations were based on the recommendations proposed by the Nutrition Advisory Group of the AMA in 1975 . Ten years later, an FDA/AMA
sponsored workshop proposed several changes for parenteral formulations of vitamins and in 2000 vitamin K was added. Long-term vitamin A should be avoided in renal failure due to the potential of possibility of toxic accumulation as this vitamin cannot be removed during dialysis.
There is acceptable evidence that indicates that iron, copper and selenium are essential human nutrients. Though considered an essential nutrient, iodine deficiency may not occur in patients receiving TPN secondary to the use of betadine® (Iodophor) . Chromium (CrJ supplementation is unnecessary due to its intrinsic concentration in TPN components [90, 91]. Manganese (Mn2) is essential for several non-human species, but clear evidence for Mn2 deficiency in humans is lacking. A single case of molybendum deficiency has been documented in a patient receiving long-term PN . Clinical signs and symptoms of zinc, selenium and copper deficiency are listed in Table 11.3.
(1) Insulin: If a patient's blood sugar concentration is sufficiently elevated as to require a continuous insulin drip, PN should not be initiated until the blood glucose is controlled. The patient's blood glucose should be 150-180mg/dl before PN is started. This will avoid glucosuria
Table 11.3 Risk Factors and Etiologies of Refeeding syndrome
1. Prolonged starvation
2. Anorexia nervosa
3. Prolonged vomiting and diarrhea
4. Nasogastric suction
6. Metastatic cancer
7. Prolonged intravenous hydration
8. Uncontrolled diabetes mellitus
9. Abdominal surgery
11. Depression in the elderly with subsequent fluid and electrolyte loss, impairment of neutrophil chemotaxis and natural killer cell activity . When insulin is necessary, usually one unit of regular insulin per 10 g dextrose (i.e., 10 units with D10, 25 units with D25) will often be sufficient. This should be added directly to the parenteral nutrition after solution compounding just prior to use as insulin adheres to glass and intravenous tubing. The suggested maximum dose of insulin should be 2 units of regular insulin per gram of dextrose (i.e., 50 units/l of D25). If there are episodes of hyperglycemia, a sliding scale of insulin should be ordered to cover the hyperglycemic episodes. The use of the sliding scale dosage of insulin should be incorporated in the TPN formulation. This is accomplished by adding 2/3 of the previous day's sliding scale dosage into the following day's PN. The total insulin dose needs to be divided by the total number of liters of daily PN. If hyperglycemia continues, the dextrose concentration should be reduced and the source of the hyperglycemia should be investigated. Increasing the insulin dosage not only can cause hypoglycemia, but it activates the Na/K/ATPase pump, which shifts potassium intracel-luarly and decreases the serum potassium concentration, which can cause hypokalemia [18, 94]. A recent retrospective analysis determined that increased blood glucose levels in patients receiving PN were associated with an increased risk of cardiac complications, infection, systemic sepsis, acute renal failure and death. These effects were independent of age, sex or prior diabetes status .
(2) Heparin and corticosteroids: It appears that heparin and corticos-teroids have a synergistic effect in reducing thrombophlebitis in those patients receiving PPN. This finding has been demonstrated on patients receiving crystalloid infusions of parenteral nutrition [95-97]. 0ne thousand units of heparin and 5 to 10 mg of hydrocortisone may be added to each liter of PPN to reduce the risk of phlebitis [95-97].
(3) Albumin: The use of albumin in parenteral nutritional support is controversial. Exogenous albumin infusions will not directly improve a patient's nutritional status. There is evidence that it can improve oncotic pressure and can improve edema in the setting of hypoal-buinemia . Albumin provides up to 75% of the normal oncotic pressure in the intravascular space when the serum concentration is <3.0g/dl . There is little increase in the plasma oncotic pressure as the serum albumin increases above 3.0g/dl . It is still unclear if the provision of exogenous albumin leads to improved enteral formula tolerance in hypoalbuminemic patients. 0ne study showed an improvement in enteral feeding tolerance when serum albumin was increased from 3.0g/dl to 3.4g/dl . Another study found that when patients with a serum albumin of <2.5g/dl receiving TPN were given exogenous albumin there was no improvement in morbidity or mortality as compared to placebo . Other studies have found that enteral feeding tolerance was unaffected by serum albumin concentration and 97% of the patients studied with an albumin less than <2.5g/dl tolerated enteral feeding [103-104]. If the use of albumin is being contemplated, a slow infusion should be used rather than a rapid bolus injection as the half-life is prolonged in the former. An increased serum albumin concentration may persist for up to a week . The total albumin deficit should be calculated and used as an endpoint in the use of supplemental albumin using this formula:
Deficit (g) = weight (kg) x 3dl/kg x 3.5-initial serum albumin g/dl
The 3 dl/kg reflects the average percent of exchangeable albumin in the plasma compartment . (4) Acid suppression: H2 antagonists may be added to parenteral nutrition solutions to control excessive gastric secetion in new onset short bowel syndrome, stress ulcer prophylaxis or the treatment of peptic ulcer disease. It is more cost effective to add H2 antagonists to the formulation than to infuse them separately. Proton pump inhibitors are not stable in TPN solutions and therefore should not be added. If necessary, they should be infused separately.
Prior to initiating TPN, a patient's fluid and nutrient requirements need to be assessed. The assessment requires a careful medical examination, including a history, physical examination and laboratory studies to evaluate for specific nutrient deficiencies and to determine nutritional needs of the patient. In particular, a complete biochemical evaluation should be performed before starting nutritional support. Energy requirements can be roughly estimated using the Harris-Benedict equation, although this formula has not been validated in critically ill patients.
Men: BEE = 66 + (13.7 x weight) + (5 x height) - (6.8 x age) Women: BEE = 655.1 + (9.6 x weight) + (1.8 x height) - (4.7 x age)
Weight is expressed in kg.
Height is expressed in cm.
Age is expressed in years.
BEE= basal energy expenditure
It should be noted that the thermodynamic effect of food (typically 15-25% of the energy content of food) used to metabolize that food is added to the BEE to obtain the resting energy expenditure (REE). Careful monitoring is needed to ensure safety and adequate therapy. Vital signs, body weight, fluid intake and fluid output need to be evaluated daily. Serum electrolytes, phosphorus and glucose should be measured every 2 days until stable and then rechecked weekly while the patient is hospitalized. Patients receiving TPN should be monitored daily for refeeding edema , hypophosphatemia  (Table 11.3) and hypokalemia . Glucose concentration should be checked three times per day to achieve euglycemia. The ideal blood glucose concentration should be between 100-160mg/dl in order to reduce the incidence of infectious complications . New onset glucose intolerance in patients receiving TPN may represent an early sign of sepsis . In patients who have abnormal glucose homeostasis, finger-stick evaluations for glucose should be performed regularly. Regular insulin can be added to the nutrient solution to maintain blood glucose concentrations between 100 and 160mg/dl, which may reduce the risk of infection [93, 94]. The direct addition of insulin to the parenteral nutrient solution reduces the risk of hypoglycemia, which can occur when insulin is given subcutaneously and infusion of the TPN solution has been inadvertently or purposely stopped . TPN infusion is typically started at a rate of 25 to 50ml/h. This rate is then increased by 25 ml/h until the predetermined rate is achieved .
If lipid emulsions are being given, serum triglyceride concentration should be evaluated early in the course of TPN to document adequate clearance. Triglyceride concentrations of greater than 400 mg/dl require either reduction of the rate of infusion or complete discontinuation of lipid supplementation, although patients with triglyceride concentrations >1,000mg/dl are at risk for developing acute pancreatitis [110, 111]. Retrospective studies in infants suggested an inverse relationship between the rate of lipid infusion and infectious morbidity . However, in an extensive clinical trial in patients undergoing bone marrow transplantation while receiving TPN there was no evidence that moderate doses of lipid emulsions containing long-chain triglycerides (LCT) were associated with increased incidence of bacterial or fungal infections .
Protein requirements depend upon the degree of catabolic stress to which the patient is exposed. Unstressed, well-nourished individuals require between 0.8 and 1.0 g of protein per kilogram of ideal body weight per day . Postoperative patients generally require between 1.2 and 1.5 g of protein per kilogram of ideal body weight per day . Highly catabolic patients (i.e., patients with burns or sepsis) require at least 2g of protein per kilogram of ideal body weight per day . Renal or hepatic failure patients should receive 0.6g protein/kg/day as a minimum requirement. Six to 9 g of additional protein/kg/day should be given to patients undergoing hemodialysis or chronic venovenous dialysis [114-115]. Twelve to 16 g protein/kg/day should be given to patients undergoing peritoneal dialysis [114-115]. This will result in 1.2 to 1.4g/kg/day of protein delivered. In patients receiving IDPN, a typical infusion is a single liter and includes approximately 7 kcal/kg from dextrose, 1.6g/kg of lipid emulsion and 0.22 g/kg of amino acids.
5.3. Writing TPN Orders
Please refer to Table 11.4 for more information.
6. monitoring the effectiveness of nutritional therapy
The best method of assessing the effectiveness of supplemental nutritional therapy is calculating a nitrogen balance in hospitalized patients. Nitrogen balance, which is the difference between the intake and output of nitrogen, is determined by measuring protein intake over 12 or 24 h and urinary excretion of total urine urea nitrogen over the same time interval. 0ne way to determine nitrogen intake:
N (g) = gproteinperday/6.25
The average protein is 15% nitrogen, hence 6.25 is used as the denominator.
In order to calculate nitrogen output either the total urine nitrogen (TUN) or urine urea nitrogen (UUN) should be calculated, though the TUN is preferable. The UUN represents on average only 80% to 90% of the TUN. In order to calculate a UUN an accurate 24-h urine measurement is needed. In order to calculate nitrogen balance the intake must be subtracted from the output 
Nitrogen balance = Nitrogen intake — Nitrogen output OR
Nitrogen balance = Nitrogen intake — (UUN + 4) OR (TUN + 2)
Table 11.4 Steps in Writing TPN Orders
1. Determine ideal body weight (IBW)
2. Calculate the non-protein caloric requirement. IBW = 70 kg
70 kg x 25 kcal ■ kg - 1 ■ day - 1 = 1, 750 kcal/day
3. Calculate the protein requirement IBW = 70 kg
70 kg x 1.4 g protein ■ kg - 1 ■ day - 1 = 98 g protein/day
4. Determine the optimal concentration of amino acid and carbohydrate solutions while taking volume into account. Consider an example of a 5% amino acid solution (contains 50 g of protein/l) and a 25% dextrose solution (contains 250 g of dextrose/l)
a. Protein requirement
98 g protein/day/50g protein/l = 1.96l/day OR 1,960 ml/day OR 82ml/h b. Non-protein calorie requirement
1, 960 ml/day x (250 g dextrose/1, 000 ml) x 3.4kcal/gdextrose = 1,666 kcal/day
5. Determine the extra calories needed a. 1,750 kcal- 1,666 kcal = 84 kcal b. The extra calories that are needed can be delivered via lipid emulsion. Lipids are available in 10% and 20% concentrations in units of 50 ml; 50 ml of 10% lipid contains 50 kcal. Therefore, the patient can receive 84 ml of the 10% lipid emulsion in the TPN to make up the difference in caloric needs. A minimal amount of lipids needs to be given in order to prevent the development of essential fatty acid deficiency. The minimal accepted amount is 4% of the total provided calories in the form of linoleic acid.
A positive or negative protein balance is used to determine the adequacy of protein and energy intake of the patient . In the initial stages of critical illness, the goal of nutritional therapy is to maintain a nitrogen balance of zero. A negative balance of 0 to 5g would represent moderate stress, and greater than 5g would represent severe stress. Once the anabolic or recovery phase is entered, the goal is to maintain a positive nitrogen balance to allow for repletion of protein stores . Achievement of a positive nitrogen balance not only requires sufficient protein and amino acids, but adequate calories as well .
7. complications in the hospitalized patient receiving parenteral nutrition
There are multiple complications associated with the use of PN. These can be divided into mechanical, vascular, infectious, metabolic and gastrointestinal. The incidence of most complications is reduced with careful management and supervision by an experienced nutritional support team.
Central venous catheter insertion (CVC) can cause damage to local structures. A misguided approach can cause pneumothorax, hemothorax, thoracic duct injury, chylothorax, brachial plexus injury, subclavian and carotid artery puncture. Even when the subclavian vein is successfully cannulated, other mechanical complications can still occur. The catheter may be advanced upward into the internal jugular vein, or the tip of the catheter can be sheared off completely if it is withdrawn back through an introducer needle.
Air embolism can occur during insertion or afterward if the connection between the catheter and intravenous tubing is not well secured. The catheter can become occluded because of thrombosis or precipitation of electrolyte salts. Subclavian vein thrombosis occurs commonly (in approximately 25% to 50% of patients) , but clinically significant manifestations such as upper extremity edema, superior vena cava syndrome or pulmonary embolism are rare during short-term TPN [120, 121]. Fatal microvascular pulmonary emboli caused by nonvisible calcium and phosphorus precipitate identified in the total nutrient admixtures have been reported [122, 123]. The iatrogenic mortality in these patients underscores the importance of maintaining strict pharmacy standards regarding physical-chemical compatibility. Furthermore, in-line filters should be used with all PN solutions despite careful inspection of solutions. These filters can be used to filter out particulate, precipitate or microbial contamination depending on the size of the pores in the filters. The smallest pulmonary capillaries are 5 ^m in diameter, whereas the size limit for visually detecting microprecipitates is 50 to 100^m .
(1) Complications secondary to catheter occlusion (Algorithm 11.1): The following findings may indicate catheter occlusion: (a) the inability
Slower TPN and/or lipid emulsion infusion, resistance to flushing of catheter, leakage or swelling of the exit site
Empirically treat for possible thrombosis with TPA (2mg In 2 ml)
Attempt aspiration in 60 min
Consider minidose warfarin (1-2mg daily)
Contrast study of catheter to verify occlusion
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