ACP medicine, 3rd Edition
Enteral and Parenteral Nutrition
Brant Lutsi MD1
Alan Buchman MD, MSPH, FACP2
1Gastroenterology Fellow, Northwestern University Feinberg School of Medicine
2Medical Director and Associate Professor of Medicine and Surgery, Northwestern University Feinberg School of Medicine
The authors have no commercial relationships with manufacturers of products or providers of services discussed in this chapter.
The body requires nutrients to provide the energy that it needs to maintain metabolic homeostasis and routine organ function. When the amount of protein or total calories available to meet these needs is insufficient, malnutrition results. Mechanisms of malnourishment include alterations in food intake or delivery to absorptive organs, inadequate food absorption or digestion, and an increase in the metabolic needs of the body because of abnormal physiologic states or diseases. In certain circumstances, malnutrition can result in adverse clinical and pathophysiologic consequences.
Alternative routes of nutrient administration have been developed for those patients who are unable to eat or digest sufficient food to prevent malnutrition. Enteral nutrition (EN) is the process of providing food, typically in liquid form, to the gastrointestinal tract for absorption. EN is generally delivered through a nasogastric or orogastric feeding tube or an endoscopically or surgically placed gastric or small bowel feeding tube. Alternatively, when food cannot be administered to the GI tract or the GI tract cannot adequately absorb or digest food, nutrient substrates can be administered through an intravenous line; this process is termed parenteral nutrition (PN). Reliance on PN as the sole source of nutrition is termed total parenteral nutrition (TPN).
Clinical Consequences of Malnutrition
Malnutrition can have negative effects on both healthy persons and those with comorbid disease. Profound malnutrition can become life-threatening when the body mass index (BMI) declines below 15 kg/m2, and death is inevitable when a person's lean tissue weight loss exceeds 40%.1 Less profound degrees of malnutrition and weight loss can have adverse effects as well. Healthy volunteers subjected to weight loss of 15% to 20% showed significant declines in measures of fitness and handgrip strength; such measures remained abnormal up to 20 weeks after dietary normalization.2
Significant malnutrition has organ-specific effects. Patients with weight loss of greater than 25% can develop changes in cardiac size and function, as well as rhythm disturbances such as prolongation of the QT interval and ventricular arrhythmias.3,4 Impairment of GI function, such as delayed gastric emptying, atrophy of the small intestine mucosa, and increased intestinal permeability, can occur.5,6 Severe malnutrition may alter kidney function, with decreases in both glomerular filtration and urine concentrating ability in extreme cases. Hematologic effects can include deficiencies in the numbers of most cell lines, as well as alterations in their innate immune function, thus increasing susceptibility to infection.7,8,9 Protein deficiency in particular may result in poor wound healing and remodeling.10,11,12
Significant malnourishment increases length of hospital stay; in one study, length of hospital stay was increased by an average of 5 days.13Treatment costs may be as much as 50% higher in malnourished patients than in adequately nourished ones.14
Perhaps the most difficult task in preventing malnourishment is ascertaining which patients are at risk for nutrition-related complications, and which of these would benefit from nutritional supplementation. Several methods of determining overall nutritional status have been evaluated, including the use of serum biomarkers such as albumin and transferrin.
In one cohort of 509 patients admitted to a Veterans Affairs hospital, hypoalbuminemic patients were shown to have a significantly higher mortality: 25% of patients with a serum albumin level of less than 3.4 g/dl died, compared with only 2% of patients with a normal serum albumin level.15 Hypoalbuminemia has also been shown to correlate with postoperative surgical morbidity and mortality.16
The serum albumin level can sometimes provide an inaccurate assessment of nutritional status and risk, however. Factors such as volume status and ongoing inflammation can significantly affect values. Decreased serum albumin or prealbumin concentrations may reflect the rise of an acute phase reactant. For these reasons, the use of hypoalbuminemia alone for nutritional assessment is generally not recommended.
Transferrin, a protein synthesized by the liver, has a short half-life and is not stored to any significant extent in the liver; these qualities make transferrin ideal for use as a diagnostic measure of acute alterations in nutritional status. However, serum transferrin levels can be affected by changes in intravascular volume status and conditions such as iron deficiency and infections, which limits the use of transferrin as a tool for nutritional assessment.
Weight and Body Mass
Weight loss greater than 10% has been correlated with worse clinical outcomes.17 However, loss of body mass from catabolism can be obscured by changes in fluid volume, especially in hospitalized patients.
BMI, which is calculated by dividing body weight in kilograms by height in meters squared (kg/m2), is a useful screening tool for categorizing patients as underweight, normal, overweight, or obese, thus helping to identify those who may be at risk for nutrition-related complications. A BMI of less than 15 can be associated with significant mortality. However, BMI is dependent on accurate weight assessments and is influenced by volume status.
Subjective Global Assessment
The subjective global assessment (SGA) is a tool for identifying patients who are malnourished and for predicting their risk of progression to nutrition-related complications.18 The SGA assesses nutritional status on the basis of components in the history and physical examination. After assessment, patients are categorized into SGA class A, B, or C. Of the three classes, patients in SGA class C have the highest degree of malnourishment and are at the highest risk for nutrition-related complications.
The SGA has gained wide acceptance as a screening tool and has been validated in a number of studies as a predictive model for nutrition-related complications.19,20,21 The SGA should be administered to all hospitalized patients upon admission to help identify patients who are likely to benefit from nutritional support.
Benefits of Enteral and Parenteral Nutrition
Since its advent in the 1970s, PN has gained wide acceptance and use, often with only the presumption of benefit. Heterogeneity of primary outcomes, patient populations, and methodologic techniques have limited the broad application of data from single-center studies evaluating the efficacy of PN.
Perhaps the most useful data on PN have come from meta-analysis. A 2001 technical review by the American Gastroenterology Association (AGA) assessed the efficacy of PN by examining data from the most robust source, randomized controlled trials (RCTs).22 The AGA's meta-analysis of 82 RCTs found no statistically significant difference between standard therapy and PN in terms of overall survival, total complication rate, or length of hospitalization; moreover, PN was associated with an increased rate of infectious complications. Most trials in this meta-analysis excluded severely malnourished patients, however. This exclusion eliminated the group that would be expected to garner the most benefit from PN and also prohibits the generalization of the study results to this group.
Similar results were found in a meta-analysis of 26 RCTs that compared TPN with standard therapy (i.e., oral diet plus intravenous dextrose) in critically ill or surgical patients.23 In this meta-analysis, TPN had no effect on overall mortality, but the analysis demonstrated a trend toward lower complication rates in those patients with protein-energy malnutrition who received TPN. Complication rates were found to be lower with TPN formulations that did not contain lipids. However, conclusions based on this analysis are limited by the heterogeneity of the studies used, their age, and their methodologic quality.
In patients without clinical contraindication to the use of the GI tract, EN has traditionally been preferred over PN. This recommendation is based on previous reports of lower overall cost, fewer complications, and improved patient outcomes with the use of EN. However, the results of several recent studies that compared EN and PN with regard to specific patient outcomes and complication rates have called these premises into question. In a meta-analysis of prospective RCTs comparing EN and TPN in which TPN was administered at or above levels required to meet estimated needs, there was no difference in mortality between the two groups.24 EN was associated with a significantly lower risk of infections (even when catheter-related infections were excluded) but a higher rate of nutrition-related complications, although most of these were minor (e.g., diarrhea or abdominal discomfort). A review of nutritional support in the intensive care setting found similar mortality with EN and TPN, but a significantly lower risk of infectious complications was seen with EN.25
Enteral and Parenteral Nutrition in Specific Clinical Settings
For any given clinical scenario, the value of nutritional support is more easily determined by applying the data from research on similar scenarios, rather than trying to generalize research results to all scenarios [see Table 1].
Table 1 Indications for Parenteral Nutrition
Acute pancreatitis is believed to result from the premature activation of trypsinogen into the active proteolytic enzyme trypsin within the acinar cells of the pancreas, which stimulates autodigestion and severe inflammation. This hypothesis has strongly influenced the use of nutritional therapy in patients with acute pancreatitis. Nearly all treatment algorithms exclude the use of early feeding or proximal EN to avoid stimulating pancreatic enzyme production and thereby worsening inflammation and autodigestion. In any event, most episodes of pancreatitis are mild and resolve without the need for nutritional support.26
In patients who fail to improve with bowel rest and intravenous fluids, supplemental nutrition with EN is indicated.26,27,28,29 All common forms of EN induce pancreatic stimulation, but TPN does not; however, TPN is associated with higher rates of complications—in particular, infectious complications—in patients with acute pancreatitis. Even in severe necrotizing pancreatitis, EN is associated with fewer overall complications.29 Neither EN nor TPN has been shown to improve mortality in acute pancreatitis.
To minimize pancreatic stimulation, enteral feeding catheters are placed within the jejunum and advanced at least 80 cm beyond the ligament of Treitz.30 Elemental formulas are used, because they are generally low in fat.31
The clinical importance of preventing pancreatic stimulation remains unknown, however, and it is currently undergoing reexamination. A 2005 study comparing nasogastric feeding with nasojejunal feeding in patients with acute severe pancreatitis found no significant difference in mortality or complication rates.32 Further studies are needed to corroborate these findings. Currently, distal small bowel feeding with the goal of limited pancreatic stimulation remains the recommended therapeutic nutritional strategy in those patients for whom nutritional support is indicated.
Inflammatory Bowel Disease
Malnutrition is common in inflammatory bowel disease (IBD), which comprises Crohn disease and ulcerative colitis. Patients may have deficiencies of different types of micronutrients and macronutrients as a result of decreased oral intake, increased metabolic demand, nutrient loss, or malabsorption from the GI tract. More than 30% of patients with IBD who are admitted to the hospital are significantly malnourished.33 Both EN and PN can be used as primary or adjunctive therapy to prevent malnutrition and its complications in these patients. In addition, both EN and PN have been shown to induce remission in some patient populations with active IBD.
On the basis of cost, complication rates, and pathophysiologic benefit, EN is preferred to PN in patients with IBD unless EN is otherwise contraindicated. Contraindications include bowel obstruction, certain high-output fistulas, ileus, and toxic megacolon. EN may still be used in fistulizing disease if the feeding catheter can be placed distal to the fistula tract.
The current recommendation is to use EN as adjunctive rather than primary therapy in patients with IBD. The use of EN as primary therapy for Crohn disease has been shown to induce remission in up to 60% of patients within 2 months34,35,36; however, a meta-analysis suggested that corticosteroids induce remission at higher rates.37 Elemental or peptide-based enteral formulas appear to be no better than standard formulas for inducing remission. In one study, the use of a diet with altered fat content (i.e., high linoleate and low oleate levels) improved remission rates with EN alone but remained inferior to prednisone therapy.38 EN is clearly associated with fewer complications than are corticosteroids. EN has never been compared with standard diet alone, however, so it remains unclear whether EN affords any greater efficacy. If any additional efficacy does exist, it may be related to the fact that enteral formulas are typically sterile. Sterile formulas may reduce bacterial processes within the gut; such processes have long been postulated to be a trigger of Crohn disease, although this remains unproved.
Total bowel rest has long been a therapeutic strategy in patients with moderate or severe IBD. The use of TPN for nutritional support makes this strategy feasible. However, this approach has been questioned because of its potential adverse side effects. For example, bowel rest may promote the induction of bacterial gut translocation or endotoxin transmigration, which may worsen disease.39,40,41
Patients with Crohn disease are at increased risk for the development of enterocutaneous fistulas (ECF), especially after surgical intervention. Significant malnutrition has been reported in 55% to 90% of patients with ECF.42 Before the availability of EN or TPN, mortality was high in patients with ECF, particularly high-output ECF (> 500 ml/24 hr).
TPN has been shown to improve mortality and fistula closure rates in patients with ECF.43 However, if there is a significant portion of normal small intestine between the ligament of Treitz and a proximal fistula, EN should be used rather than PN. This may be accomplished by the placement of a feeding catheter or tube distal to the fistula. If EN is contraindicated because of the location of the ECF or because of patient intolerance, TPN should be used.
Patients with a low-output ECF should receive approximately 1.0 to 1.5 g/kg of protein daily and enough calories to meet their daily energy requirements. Patients with a high-output ECF should receive 1.5 to 2.5 g/kg of protein daily; because of nutrient loss, such patients often require as much as twice the average number of daily calories to meet their energy needs.
Significant malnutrition is common in patients with advanced liver disease, regardless of the cause of the liver disease.44 Malnutrition can be seen in up to 20% of patients with early cirrhosis and is universal among patients receiving orthotopic liver transplantation (OLT)45,46; it is associated with a worse outcome in patients with alcoholic liver disease and with lower survival after OLT, irrespective of the cause of liver failure.47,48
Aggressive oral or EN supplementation has been shown to improve prognosis, limit hospital admissions, and help prevent nutrition-related complications in patients with alcoholic cirrhosis.49,50,51 Liver disease is associated with alterations in amino acid metabolism that are characterized by low levels of circulating branched-chain amino acids (BCAAs) (i.e., leucine, isoleucine, and valine) and elevated levels of aromatic amino acids (i.e., phenylalanine, tryptophan, and tyrosine).52 BCAAs can be effective in the treatment of hepatic encephalopathy,53,54 correcting nitrogen balance without further exacerbating the complications of cirrhosis. Two large RCTs have shown that long-term treatment with oral BCAAs in patients with cirrhosis decreases the frequency of hepatic failure and its associated complications.55,56 A meta-analysis of the inclusion of BCAAs in TPN showed improved recovery and reduced short-term mortality from hepatic encephalopathy57; however, subsequent reviews of these data have called into question the validity of these conclusions.58,59
Current consensus guidelines recommend the use of preoperative nutritional support for 7 days for all surgical patients who are moderately to severely malnourished.60 When possible, EN should be used rather than PN in the perioperative setting, to reduce the risk of complications and overall cost. In patients undergoing resection of GI malignancies, supplementing a regular oral diet with a formula rich in arginine, omega-3 fatty acids, and nucleic acid for 5 days preoperatively has been shown to reduce major morbidity (by approximately 50%), infectious complications, length of hospital stay, and overall costs.61,62 Systemic reviews have shown that early postoperative enteral feeding reduces the risk of infectious complications and shortens hospital stay without significant risk of complication.63,64
Chemotherapy and radiation therapy for malignant disease can result in complications, such as mucositis, anorexia, and nausea, that can lead to significant nutritional deficiency. Nevertheless, consensus recommendations have advised against the routine empirical use of PN in patients undergoing chemotherapy or radiation therapy; these recommendations are based on studies showing higher rates of infection, tumor unresponsiveness, and mortality with PN.65,66,67
Nutrition therapy may be useful in certain specific oncologic settings, however. A study in which PN was given for 1 week before bone marrow transplantation in a group of well-nourished patients showed improvement in rates of disease-free survival, time to relapse, and overall survival at 1 year, compared with the use of intravenous fluids alone.67 A comparison of EN and PN in patients undergoing bone marrow transplantation demonstrated no difference in disease-related outcomes, but significantly higher rates of catheter-related complications and overall treatment costs were seen in the PN group.68 PN has shown clear benefit in patients with GI obstruction from either primary or metastatic malignancy.69 As in most other situations, EN should be used in preference to PN in patients with malignant disease unless EN is otherwise contraindicated.
Patients with esophageal cancer are at higher risk for malnourishment (78.9%) than patients with other malignancies.70 Nutritional support can improve outcomes after esophagectomy.71 In most cases of esophageal cancer, the GI tract is usually functional distal to the esophageal tumor; thus, patients with esophageal cancer usually do not require PN. EN can be administered through a percutaneous endoscopic gastrostomy (PEG) tube or nasojejunal tube placed at the time of surgery. This allows early enteral feeding postoperatively and preserves gut function.72,73
Access for Nutritional Therapy
EN can be delivered through a feeding tube in the stomach, duodenum, or jejunum. Although gastric feeding is the most physiologic, conditions such as severe gastroesophageal reflux, pancreatitis, gastroparesis, or gastrectomy may preclude its use. Small bowel feeding necessitates continuous, rather than bolus, feedings and limits mucosal absorptive exposure, which can be critical in disease states such as the short gut syndrome.
The type of feeding tube and route of placement is often affected by the patient's underlying condition, anatomy, and expected duration of need for nutritional support. In patients expected to require short-term EN (usually defined as lasting less than 6 weeks), nasogastric (prepyloric) or nasojejunal (postpyloric) tubes are typically preferred. In several studies comparing the use of prepyloric feeding tubes with the use of postpyloric tubes, including studies in critically ill patients, no statistically significant difference in rates of aspiration pneumonia were seen.74,75,76
With nasally placed feeding tubes, the use of small-caliber tubes helps to prevent complications such as rhinitis, sinusitis, and nasopharyngeal irritation. Most feeding tubes are made of silicone rubber or polyurethane. Tubes made of silicone rubber are the softest and most comfortable for patients, but silicone tubes are more likely to clog than polyurethane ones.
For patients who are expected to need long-term EN, enterostomy tubes are typically used. Such tubes can be placed endoscopically (PEG), fluoroscopically, or surgically. PEG tubes are contraindicated in patients with ascites, severe portal hypertension, or esophageal obstruction. In addition, PEG tube placement requires adequate abdominal transillumination to avoid injury to overlying organs such as the colon. The benefits of nutritional supplementation via an enterostomy tube must be weighed against the risk of complications [see Table 2].
Table 2 Complications of Percutaneous Endoscopic Gastrostomy Tube Placement
The choice of parenteral access, like that of enteral access, is often made on the basis of the type, amount, and expected duration of nutritional support the patient needs. Short-term parenteral feeding (i.e., for less than 2 weeks) of patients with minimal to moderate nutritional deficiencies can be administered through a superficial vein in the upper extremity. With peripheral access, lipid-rich formulations are typically used in order to limit solution osmolarity. Dextrose-based solutions have significantly higher osmolarity; at levels greater than 900 mOsm/L, this may result in significant thrombophlebitis of peripheral veins.
Patients who require more prolonged nutritional therapy or who have higher caloric needs should receive parenteral nutrition through a central venous catheter. These single-lumen or multilumen catheters are usually placed in the internal jugular or subclavian vein after percutaneous needle localization using the Seldinger technique. The catheter tip is positioned in the superior vena cava, just proximal to the right atrium. This placement allows for rapid dilution of hyperosmolar solutions to prevent local vessel wall injury. When necessary, central venous catheters may be placed in the lower extremity, with the terminal tip positioned within the inferior vena cava. Single-lumen catheters have been associated with a lower risk of infection, as compared with multilumen catheters77; in addition, use of the subclavian artery as the site of insertion is associated with less risk of infection.78
Central access can also be achieved with a peripherally inserted central catheter (PICC). A PICC line can be placed at the bedside; it is inserted into the basilic or cephalic vein and advanced until the tip sits in the superior vena cava. PICC lines can be reliably used for 6 to 8 weeks; they have been associated with significantly fewer serious complications (e.g., pneumothorax, hemothorax, and vascular injury) than centrally placed catheters.79 The most common complication associated with PICC lines is local phlebitis.80
If a patient requires long-term home PN, a tunneled catheter or subcutaneous port should be used. These catheters are placed in the operating room or in a radiology suite and thus are significantly more costly, but they provide convenient and practical access. Early complications usually occur during placement and include pneumothorax (1% to 4%); vascular perforation; or, less commonly, air embolus and right atrial perforation.81 Later complications include catheter infections, catheter occlusion, or venous thrombosis82 [seeComplications, below].
Basal Energy Expenditure
In healthy persons, basal energy expenditure (BEE), or basal metabolic rate (BMR), which is measured in kilocalories a day, can be predicted with the Harris-Benedict equation [see Table 3]. For patients substantially on bed rest, metabolic requirements consist of the BEE value plus about 30%, which in most patients is about 31 kcal/kg a day. An expert group has suggested that for patients in the intensive care unit, a daily intake in excess of 25 kcal/kg should be avoided because of an increased risk of hyperglycemia and infection.83 Therefore, 25 to 30 kcal/kg/day will meet the needs of most patients, except those with burns.
Table 3 The Harris-Benedict Equation for Calculating Basal Energy Expenditure
Total energy requirements are more difficult to accurately predict in critically ill obese patients than in lean ones. This may be because of increased resting energy expenditure per lean body mass, as well as a variable response to illness-related stress. Energy requirements can be estimated more accurately in obese patients by using an adjusted body weight in the Harris-Benedict equation; the adjusted body weight is the ideal body weight plus 50% of the excess body weight.84 The energy requirements of underweight patients can be more accurately predicted by using actual body weight rather than ideal body weight. Malnutrition reduces the expected BEE by as much as 35%; injury, sepsis, and, especially, burns increase requirements.85,86 In one study of critically ill patients in respiratory failure, the maximal degree of hypermetabolism was about 30%.86
Indirect calorimetry may be the best method for calculating energy needs for patients in whom the Harris-Benedict equation may provide inaccurate estimates (e.g., those with critical illness or significant obesity). Indirect calorimetry is the quantification of the resting energy expenditure (REE). In immobilized critically ill patients, REE is equal to total daily energy expenditure and, therefore, energy requirement. The REE is calculated by use of an equation utilizing the directly measured quantities of exhaled carbon dioxide and oxygen. Multiple equations with slight derivations in formula exist. In patients who are critically ill, such as those with major trauma or who require mechanical ventilation, the REE calculated by indirect calorimetry has been found to be 70% to 140% of the BEE estimated by the Harris-Benedict equation.87,88 The Harris-Benedict equation has also been shown to overestimate the energy requirements in acutely ill surgical patients by as much as 59%.89
A measure used to assess patients receiving nutritional therapy is the respiratory quotient (RQ), which is calculated by dividing the volume of carbon dioxide exhaled by the volume of oxygen inhaled (VCO2/VO2) over a given period. Although an RQ below 0.7 has been considered consistent with underfeeding and a RQ greater than 1.0 reliably indicative of overfeeding, a 2003 study demonstrated that only 28% of overfed patients had a respiratory quotient greater than 1.0.90
Because indirect calorimetry is based on measurements of gas exchange, variability of exchange during measurement may alter its accuracy. Estimates may be inaccurate if there is an undetected gas leak in the ventilator system during measurement.
The body has no storage mechanism for protein; excess protein is catabolized, and the nitrogenous excess is excreted in the urine. Nitrogen balance can be used to estimate total protein balance. Under normal conditions, the body typically needs approximately 0.75 g of protein per kilogram of ideal body weight each day to maintain a net nitrogen balance. Conditions such as increased metabolic stress and increased protein consumption raise daily protein requirements to 1.0 to 1.6 g/kg/day. Intravenously administered amino acids have the same effect on net nitrogen balance as do orally ingested proteins with a similar amino acid composition.91 Enteral formulas typically contain approximately 20% of protein from BCAAs. Specialized formulas contain up to 50% of protein from BCAAs, but the additional efficacy of these formulas compared with standard formulas remains controversial. Enteral formulas containing dipeptides and tripeptides exist and can be used for patients with altered gut function, because the small intestine absorbs these molecules more efficiently than it absorbs single amino acids.
Protein restriction is no longer routinely encouraged for patients with liver disease, even those patients with encephalopathy, because it may exacerbate preexisting malnourishment, which is common in these patients. In patients with renal disease, on the other hand, the use of a restricted-protein diet (as low as 0.58 g/kg/day) may delay the progression of renal failure and the need for dialysis.92 Once on dialysis, however, especially peritoneal dialysis, patients require increased protein (1.2 to 1.4 g/kg/day).
Energy (Carbohydrates and Lipids)
Carbohydrates consisting of monosaccharide and polysaccharides usually account for approximately 70% to 80% of total calories in enteral and parenteral formulas. Dextrose, a monosaccharide isomer of glucose, is the main carbohydrate in parenteral formulas. Carbohydrates are not an absolute requirement in enteral or parenteral formulas, because they can be synthesized in the body through proteolysis or lipolysis. However, glucose is essential to the function of certain organs, cells, and tissues, including the brain, red and white blood cells, and the renal medulla. Although the liver stores excess glucose in the form of glycogen, which can be readily converted back to glucose, glycogen supplies are limited; they are depleted in less than 24 hours in times of severe metabolic stress.93
Carbohydrates are considered the primary source of energy in nutrient therapy because of their positive effects on nitrogen balance; they not only prevent muscle protein loss but also stimulate its production.94,95 After essential amino acid requirements and minimal glucose requirements are met, there is no significant difference in the protein-sparing effects between glucose or lipids in the malnourished patient.96,97,98
Emulsions of intravenous lipids are used in TPN both to provide energy and to prevent essential fatty acid deficiency. Typically, PN formulas contain approximately 10% to 30% of their total energy as lipids. Higher lipid content has not been shown to provide significant clinical advantage.99 At least 2% to 4% of total calories should be in the form of lipids containing linoleic fatty acid to prevent essential fatty acid deficiency.
The typical daily dose of intravenous lipid should be approximately 0.5 to 1 g/kg. Lipid emulsions are more energy dense than those derived from dextrose (9 kcal/g versus 3.4 kcal/g). In patients with significant volume overload, substitution of lipid for dextrose will aid in fluid restriction. Substituting lipid for dextrose in the PN of critically ill patients with hyperglycemia may also help prevent infectious complications.
Most lipid emulsions used for PN are manufactured from soybean or safflower oil. These oils are predominantly made up of long-chain triglycerides (LCTs). LCTs are precursors to prostaglandins, leukotrienes, and thromboxanes and have been shown to have deleterious effects on lung function, specifically in patients with acute lung injury.100,101,102,103 Medium-chain triglycerides (MCTs) are oxidized faster and contain significantly fewer precursors to these substances.104 The use of TPN formulas with mixed LCTs and MCTs in place of LCTs alone has been suggested to prevent pulmonary side effects, but studies on this topic have proved inconclusive.104,105,106 The suggestion that parenteral lipids may have an immunosuppressive effect also remains controversial.107,108 On the other hand, enteral feeding with a formula enriched with eicosapentaneoic acid and γ-linolenic acid, which are found in fish and borage oils, was shown to improve pulmonary inflammatory cell recruitment, decrease length of need for mechanical ventilation, diminish the development of new organ failure, and reduce length of ICU stay for patients with acute respiratory distress syndrome.109,110
Vitamins and Minerals
The body requires trace minerals both as nutrients and electrolytes. Recommended daily amounts of minerals and vitamins for patients on nutrition therapy are listed [see Tables 4 and 5].
Table 4 Daily Electrolyte and Trace Element Requirements for Adults on Nutritional Therapy
Table 5 Recommendations for Vitamins in Adults on Total Parenteral Nutrition
Zinc is excreted through the GI tract; zinc deficiency can develop in patients with conditions that cause an increase in GI tract output, such as IBD, short gut syndrome, or diarrhea. Zinc deficiency can lead to impaired immune function, poor wound healing, dermatitis, and hypogeusia. Zinc is a metalloenzyme of alkaline phosphatase; for that reason, low levels of alkaline phosphatase may suggest zinc deficiency.
Selenium deficiency may develop in patients on long-term TPN. It may result in reversible cardiomyopathy and other complications.111,112
Long-term PN may also result in copper deficiency, with associated hematologic complications such as pancytopenia.113,114 However, the cholestatic liver disease that is also seen with long-term TPN may diminish copper excretion in the biliary system and predispose to copper overload.115 Therefore, copper levels should be monitored closely in patients receiving long-term TPN, and copper content in formula should be reduced or eliminated if levels become significantly elevated. Copper overload is most likely a secondary phenomenon in PN patients with cholestatic liver disease rather than the cause of the liver disease.116
Hypermanganesemia can also be seen in patients on long-term TPN and has been associated with a syndrome resembling Parkinson disease.117,118 Serum levels should be monitored intermittently, and TPN formulas should be adjusted appropriately.
In general, the average daily fluid intake should be approximately 1,500 ml plus 20 ml for every kilogram of ideal body weight greater than 20 kg. Daily fluid requirements may also be estimated as 30 to 40 ml/kg of actual body weight.119 Requirements increase by 10% for every 1° C increase in core body temperature above normal. Additional fluid intake may be needed in states of significant fluid loss, such as diarrhea, fistula drainage, or nasogastric suction. If the patient is unable to drink adequate amounts, fluid is included as a component of TPN. Any additional fluid requirements beyond maintenance should be provided separately from PN infusions. Monitoring should include frequent measurement of blood urea nitrogen (BUN) and serum creatinine levels for early detection of dehydration. In addition, urine output should be closely followed as a measure of volume status; in patients with normal renal function, average daily urine output should be at least 1,000 ml.
Immunonutrition refers to the addition of specific components to EN and PN formulas to enhance immune function and thereby prevent infectious complications. In a review of pooled data from 26 studies evaluating immunonutrition in critically ill patients, the use of formulas containing increased levels of substances such as omega-3 fatty acids, glutamine, and arginine was associated with a statistically significant reduction in the incidence of abdominal abscesses, hospital-acquired pneumonia, and bacteremia.120 Overall mortality was unaffected. Other studies of immunonutrition in critically ill patients have produced conflicting results, however, with some studies showing increases in mortality and others, decreases.120,121,122,123,124 Thus, the use of immunonutrition in critically ill patients remains controversial. Further studies are needed to determine a possible role for immunonutrition in mild to moderately ill patients. A systematic review of preoperative patients treated with immunonutrition found reduced infectious complications and reduced length of hospital stay, highlighting an area of potential benefit.125
Studies of glutamine supplementation in patients with severe burns have reported improved wound healing, decreased length of hospital stay, and lower mortality.126,127 Although glutamine is relatively safe, its parenteral use outside of research protocols has not been approved by the Food and Drug Administration.
Only sparse data support the use of immunonutrition in other conditions. One study has suggested that the inclusion of omega-3 fatty acids in PN may reduce mortality and disease-related complications in a variety of diseases, but further research is needed.128
Monitoring of the Patient Receiving Nutrition Support
Patients with significant malnutrition are at risk for the development of the refeeding syndrome and its complications.129 Thus, such patients should be monitored closely when initiating both PN and EN. Before initiating PN, the clinician should measure serum electrolytes—especially phosphorus, magnesium, and potassium—and correct any abnormalities.
Serum glucose should be measured before initiation and reassessed daily until levels become stable. In patients with diabetes mellitus or those in the ICU, glucose should be monitored several times daily. Insulin therapy should be initiated when the serum glucose level exceeds 120 mg/dl. In patients on long-term PN, once stability has been achieved, serum glucose may be monitored as infrequently as three times yearly. Additionally, oral fluid intake, urine output, weight, and other parameters of total fluid balance should be monitored closely.
After initiation of PN, serum should be obtained from all patients on a daily basis for measurement of calcium, magnesium, phosphorus, creatinine, and BUN. Once stability is achieved, these levels may be checked weekly. Consensus recommendations for monitoring have been made for patients requiring long-term PN.119 Serum electrolytes (i.e., sodium, potassium, chloride, and bicarbonate) should be measured frequently at first and then periodically thereafter. Patients receiving a lipid emulsion as a part of their PN should have serum triglyceride levels monitored until they are stable; thereafter, the serum triglyceride level should be measured when changes are made to the lipid component. Liver function should be monitored periodically to assess for PN-associated liver disease. Bone densitometry should be performed at the outset of treatment when long-term use of PN is expected and periodically thereafter to evaluate for PN-associated metabolic bone disease. Deficiencies in zinc, copper, selenium, fat-soluble vitamins, and iron can occur in patients on long-term PN.130Consensus recommendations for screening for these nutrient deficiencies are lacking, however. Evaluation for deficiency of these nutrients should be performed when clinically indicated, although serum or plasma concentrations may not necessarily correlate with tissue concentrations.
Patients should be taught to inspect the skin around the intravenous catheter site to recognize early infection. Self-monitoring for symptoms during infusion of PN may allow early recognition of infectious complications.
There is no single preferred or standard method for determining the efficacy of EN or PN. Protein levels and caloric intake can be assessed by calculating the nitrogen balance, starting 3 to 4 days after initiation of nutritional therapy. Nitrogen balance is calculated by subtracting nitrogen excretion from nitrogen intake [see Figure 1]. Daily nitrogen intake is calculated by dividing the amount of protein administered daily, measured in grams, by 6.25; this formula is based on the fact that the average protein is 16% nitrogen, and about 95% of the nitrogen in protein is absorbed. For nitrogen excretion, the value used is total urinary nitrogen (TUN), measured in a 24-hour urine collection. When TUN cannot be measured, nitrogen loss may be calculated by taking a 24-hour measurement of urine urea nitrogen and adding to it 4 g as a correction factor to account for the unmeasured nitrogen that is lost in a form other than urea. When a negative nitrogen balance is present, catabolism occurs. When a positive nitrogen balance is present, anabolism occurs. A nitrogen balance that is positive by at least 4 g is typically required for anabolism in the setting of adequate total caloric replacement.
Figure 1. Initiation of nutritional therapy. For long-term total parenteral nutrition (TPN), central venous access can be via a single-lumen tunneled catheter or port. For short-term TPN, sites for a temporary central venous catheter (CVC) are, in descending order of preference, the subclavian, jugular, or femoral vein. (EN—enteral nutrition; PICC—peripherally inserted central catheter; PN—parenteral nutrition; PPN—partial parenteral nutrition; TPN—total parenteral nutrition)
Alternatively, the adequacy of nutritional therapy can be assessed by monitoring the patient's weight or by measuring serum proteins, such as prealbumin. However, the patient's weight can be affected by fluid shifts; in addition, the prealbumin level may be falsely elevated in patients with systemic inflammation, and it may be falsely depleted in patients with protein-losing enteropathies.
Aggressive or rapid refeeding with EN or PN in patients who are severely malnourished may lead to a constellation of metabolic derangements termed the refeeding syndrome [see Table 6]. The hallmark of this syndrome is a severe derangement in serum phosphate levels resulting from the rapid intracellular transport of phosphate. Profound hypophosphatemia, hypokalemia, and hypomagnasemia may lead to complications such as cardiac arrhythmias, neuromuscular dysfunction, seizures, rhabdomyolysis, hemolysis, and respiratory failure.129 In addition, an increased carbohydrate load may precipitate sodium and water retention and subsequent edema. Hyperglycemia is common and can induce insulin secretion, which may further exacerbate hypokalemia.131
Table 6 Metabolic Complications of Parenteral Nutrition
The best way to prevent the refeeding syndrome is through the gradual introduction of nutritional supplementation, especially the carbohydrate component. Carbohydrates can be restricted, but protein and fat restriction is unnecessary. Frequent monitoring of electrolyte levels and rapid intravenous correction of any deficiencies are important preventive measures.
Metabolic Bone Disease
Although older studies showed that long-term TPN was associated with osteomalacia and osteoporosis,132,133,134 more recent studies have found that bone loss is not significantly higher in TPN patients than in healthy cohorts.135,136 This suggests that metabolic bone disease in patients on long-term TPN may be related principally to the underlying disease that necessitated TPN. Nevertheless, patients on long-term TPN should be screened regularly for metabolic bone disease and treated appropriately if it begins to develop.
Long-term use of TPN has been associated with biliary sludge, gallbladder distention, cholelithiasis, and acalculous cholecystitis. Biliary sludge develops in as many as half of patients as early as 4 weeks after starting TPN, and it develops in nearly all patients by 6 weeks.137Bile stasis likely arises from a lack of gallbladder stimulation. Cholecystokinin (CCK), which stimulates gallbladder contraction, can be used to prevent biliary stasis, but the use of parenteral CCK is often limited by side effects, which include nausea, vomiting, and abdominal pain.138 EN, even at low doses, or pulsed intravenous infusions of amino acids can significantly reduce the formation of gallbladder sludge by stimulating gallbladder contraction.139
Serum hepatic aminotransferase levels—and, less often, bilirubin or alkaline phosphatase levels—can become elevated after 4 to 7 weeks of TPN.140 Long-term TPN use has been associated with the development of end-stage liver disease in 15% to 40% of patients.141,142 Steatosis or steatohepatitis are the most common liver abnormalities in adult patients on long-term TPN.143,144 Less commonly, hepatic cholestasis may complicate long-term PN. Patients with severely diminished amounts of small intestine appear to be at the highest risk for the development of hepatic disease with home TPN.145
Choline deficiency is common in patients on TPN and has been associated with elevated transaminase levels and hepatic steatosis.146Moreover, parenteral supplementation of choline has been shown to improve hepatic steatosis and normalize aminotransferase levels.147
Cholestasis has been linked to lipid doses greater than 1 g/kg/day.141 This may be related to the accumulation of lipid components within the hepatocyte and their stimulation of inflammatory cytokines. Elevated levels of manganese have been correlated with the development of hepatic cholestasis,117 but it is not known whether this is a cause or a consequence of cholestatic liver disease in these patients, given that manganese is excreted through the biliary system. In patients with liver disease who are on TPN, manganese levels should be monitored, and nutritional therapy should be adjusted accordingly. Ursodeoxycholic acid is commonly prescribed for the treatment of cholestatic liver disease associated with TPN. Studies in children have shown some beneficial results, but results in adults have been less impressive.148,149
The most common complication in patients receiving PN is catheter-related infection. Episodes of catheter sepsis, the most common infectious complication, occur on average every 2 to 3 patient-years,82,150,151 and it occurs more frequently in inpatients. Less common are infections of the catheter exit site or tunnel. Staphylococcus species cause most of these infections, although gram-negative organisms such as Klebsiella and Escherichia coli are commonly encountered as well. Catheter sepsis, and sometimes exit site infections, can be treated without removal of the catheter, whereas tunnel infections typically require catheter removal because of the poor penetration of antibiotic into the subcutaneous space.152
Catheter sepsis usually presents as fever or dyspnea, often only at the time of PN infusion; if not treated appropriately, more progressive symptoms of systemic infection follow. When catheter sepsis is suspected, the PN infusion should be held for at least 24 hours, and blood cultures, including fungal cultures, should be obtained. Empirical antibiotics covering both coagulase-negative Staphylococcus and gram-negative organisms should be initiated.
Most cases of catheter sepsis can be treated with a 4-week course of intravenous antibiotics alone.153 Indications for catheter removal include fungal or mycobacterial infection,151,154 septic shock, or failure to defervesce after 48 to 72 hours of appropriate antibiotic therapy.
The use of an antibiotic lock (i.e., a catheter infusion of an antibiotic such as vancomycin, 2 ml of 25 µg/ml, mixed with sodium heparin, 10 U/ml) can be effective in patients with recurrent uncomplicated catheter sepsis.155 The addition of an antibiotic lock to intravenous antibiotics for episodes of catheter sepsis has been shown to improve treatment success rates, particularly in coagulase-negative staphylococcal infections.156 The use of an antibiotic lock alone for 7 days has also been suggested as a possible treatment strategy for these infections.157
Exit Site and Tunnel Infections
Exit site infections are identified by the presence of a purulent exudate that can be expressed from the skin at the exit site of a subcutaneously tunneled catheter. This type of infection is generally caused by Staphylococcus species. A tunnel infection can be identified by a cutaneous red streak over the subcutaneous tunnel.
To prevent catheter-related infection, the skin around the exit site should be cleansed with 2% chlorhexidine; this is superior to 10% povidone-iodine.158 Great care must also be given in the cleansing of the catheter hub, especially in patients receiving long-term PN. Perhaps the most important prophylactic measure against catheter-related infections is appropriate teaching of nursing staff and of patients who administer self care.151
Central catheter occlusion is the second most common line complication in patients receiving PN, occurring in up to 25% of all patients receiving long-term catheterization.159,160 Catheter occlusion may be thrombotic or nonthrombotic. Nonthrombotic occlusions are more common and may be secondary to mechanical disruption of the catheter, precipitation of infused medications and parenteral formula substrates, and lipid deposition within the catheter lumen. Hydrochloric acid, sodium hydroxide, or ethanol can be used to relieve nonthrombotic occlusions.161,162,163
Thrombotic occlusions arise from the development of a fibrin sheath around the base of the catheter after disruption of the vein intima.164,165 If not recognized early, thrombotic occlusions may necessitate replacement of the catheter. Catheter thrombosis may be prevented by the use of very low dose warfarin (1 to 2 mg daily)166 or frequent catheter flushes with heparin (100 U/ml with 0.6 to 3 ml, depending on catheter size).167
Nephropathy and a significant decrease in the glomerular filtration rate may develop in patients on long-term TPN.168,169 Creatinine clearance has been shown to decline by approximately 3.5% a year in adult patients on long-term PN.169 Renal dysfunction in these patients may be related to recurrent infections or contamination of the parenteral formula with substances such as chromium or cadmium. Chromium has been associated with decreased renal function in children,170 but these results have not been as clearly demonstrated in adults.171 A prospective study of 40 patients on long-term PN found that renal insufficiency was associated with chronic dehydration in 70% of patients affected.172
Enteral Nutrition Complications
Enteral feeding tubes may become clogged with food or medicine substrate after long-term use. Typically, the tube can be unclogged by flushing with carbonated soda products or pancreatic enzymes activated with sodium bicarbonate in a saline solution.
Nasoenteric tubes can cause erosions or ulcerations of the nasal mucosa. In addition, extended use can lead to infectious complications such as sinusitis and otitis media [see Table 7]. If patients are expected to need nutritional support for longer than 4 to 6 weeks, it is recommended that a nasoenteric tube be replaced with a PEG tube to prevent these complications and enhance patient comfort.
Table 7 Complications of Enteral Nutrition
The most common complication of EN is the development of GI symptoms such as abdominal pain, nausea, or diarrhea. Diarrhea is the most common GI complication and can have a variety of etiologic mechanisms, including concomitant antibiotic use or the inclusion of sorbitol in the enteral formula.173
Ethical Issues in Enteral and Parenteral Nutrition
Nutritional support should be initiated only when there is a clear likelihood that the potential benefit outweighs the risks. Nutritional support should not be used in patients with advanced or terminal disease (e.g., metastatic malignancy) because it is unlikely to provide significant benefit or improve quality of life. Patients with metastatic disease have only an approximately 15% rate of survival with the use of home TPN174; most have no significant improvement in quality of life,175 and their life expectancy is usually only 2 to 3 months.175,176,177Similarly, EN in patients with end-stage dementia is unlikely to improve survival or prevent the development of infection or pressure ulcers.178
Competent patients must be allowed to make their own informed decisions about nutritional support. Patients who are near death rarely choose nutritional support when given the opportunity,179 and patients in the terminal state of illness are often comfortable with very limited amounts of food or water.180 The physician is under no legal obligation to initiate nutritional support when there is no evidence of potential benefit, irrespective of the wishes of the patient's surrogate medical decision makers. Withholding and withdrawing nutritional support are legally equivalent. However, studies have shown that physicians are often reluctant to discontinue nutritional support despite medical futility or even potential harm.181 Decisions to withhold or withdraw nutritional support must be made on a case-by-case basis with consideration of all contributing factors and outcomes.
- Stein Z, Susser M, Saenger G, Famine and human development: the Dutch hunger winter of 1944–45. Oxford University Press, London, 1975
- Allison SP: The uses and limitations of nutritional support: the Arvid Wretlind Lecture given at the 14th ESPEN Congress in Vienna, 1992. Clin Nutr 11:319, 1992
- Gottdiener JS, Gross HA, Henry WL, Effects of self-induced starvation on cardiac size and function in anorexia nervosa. Circulation 58:425, 1978
- Thurston J, Marks P: Electrocardiographic abnormalities in patients with anorexia nervosa. Br Heart J 36:719, 1974
- Hernandez G, Velasco N, Wainstein C, Gut mucosal atrophy after a short enteral fasting period in critically ill patients. J Crit Care 14:73, 1999
- Hunger Disease: Studies by the Jewish Physicians in the Warsaw Ghetto. Winick M, Ed. New York: John Wiley and Sons, New York, 1979
- Scrimshaw NS, SanGiovanni JP: Synergism of nutrition, infection, and immunity: an overview. Am J Clin Nutr 66:464S, 1997
- Nova E, Samartin S, Gomez S, The adaptive response of the immune system to the particular malnutrition of eating disorders. Eur J Clin Nutr 56(suppl 3):S34, 2002
- Chandra RK: Nutrition, immunity and infection: from basic knowledge of dietary manipulation of immune responses to practical application of ameliorating suffering and improving survival. Proc Natl Acad Sci U S A 93:14304, 1996
- Levenson S, Seifter E, Van Winkle W Jr: Nutrition. Fundamentals of Wound Management. Hunt TK, Dunphy JE, Eds. Appleton Century Crofts, New York, 1979, p 286
- Ruberg RL: Role of nutrition in wound healing. Surg Clin North Am 64:705, 1984
- Irvin TT: Effects of malnutrition and hyperalimentation on wound healing. Surg Gynecol Obstet 146:33, 1978
- Robinson G, Goldstein M, Levine GM: Impact of nutritional status on DRG length of stay. JPEN J Parenter Enteral Nutr 11:49, 1987
- Reilly JJ, Hull SF, Albert N Jr: Economic impact of malnutrition: a model system for hospitalized patients. JPEN J Parenter Enteral Nutr 12:371, 1988
- Reinhardt GF, Myscofski JW, Wilkens DB, Incidence and mortality of hypoalbuminemic patients in hospitalized veterans. JPEN J Parenter Enteral Nutr 4:357, 1980
- Gibbs J, Cull W, Henderson W, Preoperative serum albumin level as a predictor of operative mortality and morbidity: results from the National VA Surgical Risk Study. Arch Surg 134:36, 1999
- Dewys WD, Begg C, Lavin PT, Prognostic effect of weight loss prior to chemotherapy in cancer patients. Eastern Cooperative Oncology Group. Am J Med 69:49, 1980
- Detsky AS, McLaughlin JR, Baker JP, What is subjective global assessment of nutritional status? JPEN 11:8, 1987
- Thoresen L, Fjeldstad I, Krogstad K, Nutritional status of patients with advanced cancer: the value of using the subjective global assessment of nutritional status as a screening tool. Palliat Med 16:33, 2002
- Sacks GS, Dearman K, Repogle WH, Use of subjective global assessment to identify nutrition-associated complications and death in geriatric long-term care facility residents. J Am Coll Nutr 19:570, 2000
- Norman K, Schutz T, Kemps M, The Subjective Global Assessment reliably identifies malnutrition-related muscle dysfunction. Clin Nutr 24:143, 2005
- Koretz RL, Lipman TO, Klein S: AGA technical review on parenteral nutrition. Gastroenterology 121:970, 2001
- Heyland DK, MacDonald S, Keefe L, Total parenteral nutrition in the critically ill patient: a meta-analysis. JAMA 280:2013, 1998
- Braunschweig CL, Levy P, Sheean PM, Enteral compared with parenteral nutrition: a meta-analysis. Am J Clin Nutr 74:534, 2001
- Gramlich L, Kichian K, Pinilla J, Rodych NJ, Does enteral nutrition compared to parenteral nutrition result in better outcomes in critically ill adult patients? A systematic review of the literature. Nutrition 20:843, 2004
- Abou-Assi S, Craig K, O'Keefe SJ: Hypocaloric jejunal feeding is better than total parenteral nutrition in acute pancreatitis: results of a randomized comparative study. Am J Gastroenterol 97:2255, 2002
- McClave SA, Greene LM, Snider HL, Comparison of the safety of early enteral vs parenteral nutrition in mild acute pancreatitis. JPEN J Parenter Enteral Nutr 21:14, 1997
- Windsor AC, Kanwar S, Li AG, Compared with parenteral nutrition, enteral feeding attenuates the acute phase response and improves disease severity in acute pancreatitis. Gut 42:431, 1998
- Kalfarentzos F, Kehagias J, Mead N, Enteral nutrition is superior to parenteral nutrition in severe acute pancreatitis: results of a randomized prospective trial. Br J Surg 84:1665, 1997
- O'Keefe SJ, Lee RB, Anderson FP, Physiological effects of enteral and parenteral feeding on pancreaticobiliary secretion in humans. Am J Physiol Gastrointest Liver Physiol 284:G27, 2003
- Kaushik N, Pietraszewski M, Holst JJ, Enteral feeding without pancreatic stimulation. Pancreas 31:353, 2005
- Eatock FC, Chong P, Menezes N, A randomized study of early nasogastric versus nasojejunal feeding in severe acute pancreatitis. Am J Gastroenterol 100:432, 2005
- Pirlich M, Schutz T, Kemps M, Prevalence of malnutrition in hospitalized medical patients: impact of underlying disease. Dig Dis 21:245, 2003
- Rigaud D, Cosnes J, Le Quintrec Y, Controlled trial comparing two types of enteral nutrition in treatment of active Crohn's disease: elemental versus polymeric diet. Gut 32:1492, 1991
- Gonzalez-Huix F, de Leon R, Fernandez-Banares F, Polymeric enteral diets as primary treatment of active Crohn's disease: a prospective steroid controlled trial. Gut 34:778, 1993
- O'Morain C, Segal AW, Levi AJ: Elemental diet as primary treatment of acute Crohn's disease: a controlled trial. Br Med J (Clin Res Ed) 288:1859, 1984
- Zachos M, Tondeur M, Griffiths AM: Enteral nutritional therapy for inducing remission of Crohn's disease. Cochrane Database Syst Rev (3):CD000542, 2001
- Gassull MA, Fernandez-Banares F, Cabre E, Fat composition may be a clue to explain the primary therapeutic effect of enteral nutrition in Crohn's disease: results of a double blind randomised multicentre European trial. Gut 51:164, 2002
- Alverdy JC, Aoys E, Moss GS: Total parenteral nutrition promotes bacterial translocation from the gut. Surgery 104:185, 1988
- Ambrose NS, Johnson M, Burdon DW, Incidence of pathogenic bacteria from mesenteric lymph nodes and ileal serosa during Crohn's disease surgery. Br J Surg 71:623, 1984
- Takagi K, Yamamori H, Toyoda Y, Modulating effects of the feeding route on stress response and endotoxin translocation in severely stressed patients receiving thoracic esophagectomy. Nutrition 16:355, 2000
- Berry SM, Fischer JE: Classification and pathophysiology of enterocutaneous fistulas. Surg Clin North Am 76:1009, 1996
- Lloyd DA, Gabe SM, Windsor AC: Nutrition and management of enterocutaneous fistula. Br J Surg 93:1045, 2006
- McCullough AJ, Bugianesi E: Protein-calorie malnutrition and the etiology of cirrhosis. Am J Gastroenterol 92:734, 1997
- DiCecco SR, Wieners EJ, Wiesner RH, Assessment of nutritional status of patients with end-stage liver disease undergoing liver transplantation. Mayo Clin Proc 64:95, 1989
- Prijatmoko D, Strauss BJ, Lambert JR, Early detection of protein depletion in alcoholic cirrhosis: role of body composition analysis. Gastroenterology 105:1839, 1993
- Mendenhall CL, Moritz TE, Roselle GA, Protein energy malnutrition in severe alcoholic hepatitis: diagnosis and response to treatment. The VA Cooperative Study Group #275. JPEN J Parenter Enteral Nutr 19:258, 1995
- Merli M, Riggio O, Dally L: Does malnutrition affect survival in cirrhosis? PINC (Policentrica Italiana Nutrizione Cirrosi). Hepatology 23:1041, 1996
- Kearns PJ, Young H, Garcia G, Accelerated improvement of alcoholic liver disease with enteral nutrition. Gastroenterology 102:200, 1992
- Hirsch S, Bunout D, de la Maza P, Controlled trial on nutrition supplementation in outpatients with symptomatic alcoholic cirrhosis. JPEN J Parenter Enteral Nutr 17:119, 1993
- Cabre E, Gonzalez-Huix F, Abad-Lacruz A, Effect of total enteral nutrition on the short-term outcome of severely malnourished cirrhotics: a randomized controlled trial. Gastroenterology 98:715, 1990
- Blonde-Cynober F, Aussel C, Cynober L: Abnormalities in branched-chain amino acid metabolism in cirrhosis: influence of hormonal and nutritional factors and directions for future research. Clin Nutr 18:5, 1999
- Plauth M, Egberts EH, Hamster W, Long-term treatment of latent portosystemic encephalopathy with branched-chain amino acids: a double-blind placebo-controlled crossover study. J Hepatol 17:308, 1993
- Marchesini G, Dioguardi FS, Bianchi GP, Long-term oral branched-chain amino acid treatment in chronic hepatic encephalopathy: a randomized double-blind casein-controlled trial. The Italian Multicenter Study Group. J Hepatol 11:92, 1990
- Marchesini G, Bianchi G, Merli M, Nutritional supplementation with branched-chain amino acids in advanced cirrhosis: a double-blind, randomized trial. Gastroenterology 124:1792, 2003
- Muto Y, Sato S, Watanabe A, Effects of oral branched-chain amino acid granules on event-free survival in patients with liver cirrhosis. Clin Gastroenterol Hepatol 3:705, 2005
- Naylor CD, et al: Parenteral nutrition with branched-chain amino acids in hepatic encephalopathy: a meta-analysis. Gastroenterology 97:1033, 1989
- Gluud C: Branched-chain amino acids for hepatic encephalopathy? Hepatology 13:812, 1991
- Erikkson LS, Conn HO: Branched-chain amino acids in hepatic encephalopathy. Gastroenterology 99:604, 1990
- Klein S, Kinney J, Jeejeebhoy K, Nutrition support in clinical practice: review of published data and recommendations for future research directions. National Institutes of Health, American Society for Parenteral and Enteral Nutrition, and American Society for Clinical Nutrition. JPEN J Parenter Enteral Nutr 21:133, 1997
- Gianotti L, Braga M, Nespoli L, A randomized controlled trial of preoperative oral supplementation with a specialized diet in patients with gastrointestinal cancer. Gastroenterology 122:1763, 2002
- Braga M, Gianotti L, Nespoli L, Nutritional approach in malnourished surgical patients: a prospective randomized study. Arch Surg 137:174, 2002
- Marik PE, Zaloga GP: Early enteral nutrition in acutely ill patients: a systematic review. Crit Care Med 29:2264, 2001
- Lewis SJ, Egger M, Sylvester PA, Early enteral feeding versus “nil by mouth” after gastrointestinal surgery: systematic review and meta-analysis of controlled trials. BMJ 323:773, 2001
- Parenteral nutrition in patients receiving cancer chemotherapy. American College of Physicians. Ann Intern Med 110:734, 1989
- McGeer AJ, Detsky AS, O'Rourke K: Parenteral nutrition in cancer patients undergoing chemotherapy: a meta-analysis. Nutrition 6:233, 1990
- Weisdorf SA, Lysne J, Wind D, Positive effect of prophylactic total parenteral nutrition on long-term outcome of bone marrow transplantation. Transplantation 43:833, 1987
- Szeluga DJ, Stuart RK, Brookmeyer R, Nutritional support of bone marrow transplant recipients: a prospective, randomized clinical trial comparing total parenteral nutrition to an enteral feeding program. Cancer Res 47:3309, 1987
- Saito H: [Parenteral and enteral nutrition in surgical patients with intestinal obstruction]. Nippon Rinsho 59(suppl 5):550, 2001
- Larrea J, Vega S, Martinez T, [The nutritional status and immunological situation of cancer patients]. Nutr Hosp 7:178, 1992
- Gabor S, Renner H, Matzi V, Early enteral feeding compared with parenteral nutrition after oesophageal or oesophagogastric resection and reconstruction. Br J Nutr 93:509, 2005
- Sax HC, Souba WW: Enteral and parenteral feedings: guidelines and recommendations. Med Clin North Am 77:863, 1993
- Mercer CD, Mungara A: Enteral feeding in esophageal surgery. Nutrition 12:200, 1996
- Mullan H, Roubenoff RA, Roubenoff R: Risk of pulmonary aspiration among patients receiving enteral nutrition support. JPEN J Parenter Enteral Nutr 16:160, 1992
- Strong RM, Condon SC, Solinger MR, Equal aspiration rates from postpylorus and intragastric-placed small-bore nasoenteric feeding tubes: a randomized, prospective study. JPEN J Parenter Enteral Nutr 16:59, 1992
- Reed RL 2nd, Eachempati SR, Russell MK, Endoscopic placement of jejunal feeding catheters in critically ill patients by a “push” technique. J Trauma 45:388, 1998
- Dezfulian C, Lavelle J, Nallamothu BK, Rates of infection for single-lumen versus multilumen central venous catheters: a meta-analysis. Crit Care Med 31:2385, 2003
- Kemp L, Burge J, Choban P, The effect of catheter type and site on infection rates in total parenteral nutrition patients. JPEN J Parenter Enteral Nutr 18:71, 1994
- Ryder MA: Peripheral access options. Surg Oncol Clin N Am 4:395, 1995
- Loughran SC, Borzatta M: Peripherally inserted central catheters: a report of 2506 catheter days. JPEN J Parenter Enteral Nutr 19:133, 1995
- Feliciano DV, Mattox KL, Graham JM, Major complications of percutaneous subclavian vein catheters. Am J Surg 138:869, 1979
- Richards DM, Deeks JJ, Sheldon TA, Home parenteral nutrition: a systematic review. Health Technol Assess 1:i, 1997
- Kreymann KG, Berger MM, Deutz NE, ESPEN Guidelines on Enteral Nutrition: intensive care. Clin Nutr 25:210, 2006
- Barak N, Wall-Alonso E, Sitrin MD: Evaluation of stress factors and body weight adjustments currently used to estimate energy expenditure in hospitalized patients. JPEN J Parenter Enteral Nutr 26:231, 2002
- Allard JP, Pichard C, Hoshino E, Validation of a new formula for calculating the energy requirements of burn patients. JPEN J Parenter Enteral Nutr 14:115, 1990
- Detsky AS, Baker JP, Mendelson RA, Evaluating the accuracy of nutritional assessment techniques applied to hospitalized patients: methodology and comparisons. JPEN J Parenter Enteral Nutr 8:153, 1984
- Carlsson M, Nordenstrom J, Hedenstierna G: Clinical implications of continuous measurement of energy expenditure in mechanically ventilated patients. Clin Nutr 3:103, 1984
- Weissman C, Kemper M, Askanazi J, Resting metabolic rate of the critically ill patient: measured versus predicted. Anesthesiology 64:673, 1986
- Mann S, Westenskow DR, Houtchens BA: Measured and predicted caloric expenditure in the acutely ill. Crit Care Med 13:173, 1985
- McClave SA, Lowen CC, Kleber MJ, Clinical use of the respiratory quotient obtained from indirect calorimetry. JPEN J Parenter Enteral Nutr 27:21, 2003
- Anderson GH, Patel DG, Jeejeebhoy KN: Design and evaluation by nitrogen balance and blood aminograms of an amino acid mixture for total parenteral nutrition of adults with gastrointestinal disease. J Clin Invest 53:904, 1974
- Klahr S, Levey AS, Beck GJ, The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal disease. Modification of Diet in Renal Disease Study Group. N Engl J Med 330:877, 1994
- Wolfe RR: Carbohydrate metabolism in the critically ill patient: implications for nutritional support. Crit Care Clin 3:11, 1987
- Fukagawa NK, Minaker KL, Rowe JW, Insulin-mediated reduction of whole body protein breakdown: dose-response effects on leucine metabolism in postabsorptive men. J Clin Invest 76:2306, 1985
- Mortimore GE, Poso AR: Intracellular protein catabolism and its control during nutrient deprivation and supply. Annu Rev Nutr 7:539, 1987
- Macfie J, Smith RC, Hill GL: Glucose or fat as a nonprotein energy source? A controlled clinical trial in gastroenterological patients requiring intravenous nutrition. Gastroenterology 80:103, 1981
- Greenberg GR, Marliss EB, Anderson GH, Protein-sparing therapy in postoperative patients: effects of added hypocaloric glucose or lipid. N Engl J Med 294:1411, 1976
- Roulet M, Detsky AS, Marliss EB, A controlled trial of the effect of parenteral nutritional support on patients with respiratory failure and sepsis. Clin Nutr 2:97, 1983
- Delafosse B, Viale JP, Tissot S, Effects of glucose-to-lipid ratio and type of lipid on substrate oxidation rate in patients. Am J Physiol 267:E775, 1994
- Skeie B, Askanazi J, Rothkopf MM, Intravenous fat emulsions and lung function: a review. Crit Care Med 16:183, 1988
- Greene HL, Hazlett D, Demaree R: Relationship between Intralipid-induced hyperlipemia and pulmonary function. Am J Clin Nutr 29:127, 1976
- Sundstrom G, Zauner CW, Arborelius M Jr: Decrease in pulmonary diffusing capacity during lipid infusion in healthy men. J Appl Physiol 34:816, 1973
- Venus B, Smith RA, Patel C, Hemodynamic and gas exchange alterations during Intralipid infusion in patients with adult respiratory distress syndrome. Chest 95:1278, 1989
- Ball MJ, White K: Comparison of medium and long chain triglyceride metabolism in intensive care patients on parenteral nutrition. Intensive Care Med 15:250, 1989
- Faucher M, Bregeon F, Gainnier M, Cardiopulmonary effects of lipid emulsions in patients with ARDS. Chest 124:285, 2003
- Lekka ME, Liokatis S, Nathanail C, The impact of intravenous fat emulsion administration in acute lung injury. Am J Respir Crit Care Med 169:638, 2004
- Battistella FD, Widergren JT, Anderson JT, A prospective, randomized trial of intravenous fat emulsion administration in trauma victims requiring total parenteral nutrition. J Trauma 43:52, 1997
- Lenssen P, Bruemmer BA, Bowden RA, Intravenous lipid dose and incidence of bacteremia and fungemia in patients undergoing bone marrow transplantation. Am J Clin Nutr 67:927, 1998
- Gadek JE, DeMichele SJ, Karlstad MD, Effect of enteral feeding with eicosapentaenoic acid, gamma-linolenic acid, and antioxidants in patients with acute respiratory distress syndrome. Enteral Nutrition in ARDS Study Group. Crit Care Med 27:1409, 1999
- Singer P, Theilla M, Fisher H, Benefit of an enteral diet enriched with eicosapentaenoic acid and gamma-linolenic acid in ventilated patients with acute lung injury. Crit Care Med 34:1033, 2006
- Yusuf SW, Rehman Q, Casscells W: Cardiomyopathy in association with selenium deficiency: a case report. JPEN J Parenter Enteral Nutr 26:63, 2002
- Hatanaka N, Nakaden H, Yamamoto Y, Selenium kinetics and changes in glutathione peroxidase activities in patients receiving long-term parenteral nutrition and effects of supplementation with selenite. Nutrition 16:22, 2000
- Spiegel JE, Willenbucher RF: Rapid development of severe copper deficiency in a patient with Crohn's disease receiving parenteral nutrition. JPEN J Parenter Enteral Nutr 23:169, 1999
- Fuhrman MP, Herrmann V, Masidonski P, Pancytopenia after removal of copper from total parenteral nutrition. JPEN J Parenter Enteral Nutr 24:361, 2000
- Pluhator-Murton MM, Fedorak RN, Audette RJ, Trace element contamination of total parenteral nutrition. 1. Contribution of component solutions. JPEN J Parenter Enteral Nutr 23:222, 1999
- Blaszyk H, Wild PJ, Oliveira A, Hepatic copper in patients receiving long-term total parenteral nutrition. J Clin Gastroenterol 39:318, 2005
- Fell JM, Reynolds AP, Meadows N, Manganese toxicity in children receiving long-term parenteral nutrition. Lancet 347:1218, 1996
- Pal PK, Samii A, Calne DB: Manganese neurotoxicity: a review of clinical features, imaging and pathology. Neurotoxicology 20:227, 1999
- Guidelines for the use of parenteral and enteral nutrition in adult and pediatric patients. ASPEN Board of Directors and the Clinical Guidelines Task Force. JPEN J Parenter Enteral Nutr 26(1 suppl):1SA, 2002
- Montejo JC, Zarazaga A, Lopez-Martinez J, Immunonutrition in the intensive care unit: a systematic review and consensus statement. Clin Nutr 22:221, 2003
- Galban C, Montejo JC, Mesejo A, An immune-enhancing enteral diet reduces mortality rate and episodes of bacteremia in septic intensive care unit patients. Crit Care Med 28:643, 2000
- Bower RH, Cerra FB, Bershadsky B, Early enteral administration of a formula (Impact) supplemented with arginine, nucleotides, and fish oil in intensive care unit patients: results of a multicenter, prospective, randomized, clinical trial. Crit Care Med 23:436, 1995
- Atkinson S, Sieffert E, Bihari D: A prospective, randomized, double-blind, controlled clinical trial of enteral immunonutrition in the critically ill. Guy's Hospital Intensive Care Group. Crit Care Med 26:1164, 1998
- Bertolini G, Iapichino G, Radrizzani D, Early enteral immunonutrition in patients with severe sepsis: results of an interim analysis of a randomized multicentre clinical trial. Intensive Care Med 29:834, 2003
- Heyland DK, Novak F, Drover JW, Should immunonutrition become routine in critically ill patients? A systematic review of the evidence. JAMA 286:944, 2001
- Garrel D, Patenaude J, Nedelec B, Decreased mortality and infectious morbidity in adult burn patients given enteral glutamine supplements: a prospective, controlled, randomized clinical trial. Crit Care Med 31:2444, 2003
- Peng X, Yan H, You Z, Clinical and protein metabolic efficacy of glutamine granules-supplemented enteral nutrition in severely burned patients. Burns 31:342, 2005
- Heller AR, Rossler S, Litz RJ, Omega-3 fatty acids improve the diagnosis-related clinical outcome. Crit Care Med 34:972, 2006
- Solomon SM, Kirby DF: The refeeding syndrome: a review. JPEN J Parenter Enteral Nutr 14:90, 1990
- Forbes GM, Forbes A: Micronutrient status in patients receiving home parenteral nutrition. Nutrition 13:941, 1997
- Crook MA, Hally V, Panteli JV: The importance of the refeeding syndrome. Nutrition 17:632, 2001
- Lipkin EW, Ott SM, Klein GL: Heterogeneity of bone histology in parenteral nutrition patients. Am J Clin Nutr 46:673, 1987
- Foldes J, Rimon B, Muggia-Sullam M, Progressive bone loss during long-term home total parenteral nutrition. JPEN J Parenter Enteral Nutr 14:139, 1990
- Staun M, Tjellesen L, Thale M, Bone mineral content in patients on home parenteral nutrition. Clin Nutr 13:351, 1994
- Haderslev KV, Tjellesen L, Haderslev PH, Assessment of the longitudinal changes in bone mineral density in patients receiving home parenteral nutrition. JPEN J Parenter Enteral Nutr 28:289, 2004
- Cohen-Solal M, Baudoin C, Joly F, Osteoporosis in patients on long-term home parenteral nutrition: a longitudinal study. J Bone Miner Res 18:1989, 2003
- Messing B, Bories C, Kunstlinger F, Does total parenteral nutrition induce gallbladder sludge formation and lithiasis? Gastroenterology 84:1012, 1983
- Silberstein EB, Marcus CS: Unreported side effect of sincalide. Radiology 190:902, 1994
- Nealon WH, Upp JR Jr, Alexander RW, Intravenous amino acids stimulate human gallbladder emptying and hormone release. Am J Physiol 259:G173, 1990
- Grau T, Bonet A, Rubio M, Liver dysfunction associated with artificial nutrition in critically ill patients. Crit Care 11:R10, 2007
- Cavicchi M, Beau P, Crenn P, Prevalence of liver disease and contributing factors in patients receiving home parenteral nutrition for permanent intestinal failure. Ann Intern Med 132:525, 2000
- Chan S, McCowen KC, Bistrian BR, Incidence, prognosis, and etiology of end-stage liver disease in patients receiving home total parenteral nutrition. Surgery 126:28, 1999
- Sax HC, Talamini MA, Brackett K, Hepatic steatosis in total parenteral nutrition: failure of fatty infiltration to correlate with abnormal serum hepatic enzyme levels. Surgery 100:697, 1986
- Baker AL, Rosenberg IH: Hepatic complications of total parenteral nutrition. Am J Med 82:489, 1987
- Luman W, Shaffer JL: Prevalence, outcome and associated factors of deranged liver function tests in patients on home parenteral nutrition. Clin Nutr 21:337, 2002
- Buchman AL, Mouzkarzel A, Jenden DJ, Low plasma free choline is prevalent in patients receiving long term parenteral nutrition and is associated with hepatic aminotransferase abnormalities. Clin Nutr 12:33, 1993
- Buchman AL, Ament ME, Sohel M, Choline deficiency causes reversible hepatic abnormalities in patients receiving parenteral nutrition: proof of a human choline requirement: a placebo-controlled trial. JPEN J Parenter Enteral Nutr 25:260, 2001
- Spagnuolo MI, Iorio R, Vegnente A, Ursodeoxycholic acid for treatment of cholestasis in children on long-term total parenteral nutrition: a pilot study. Gastroenterology 111:716, 1996
- Beau P, Labat-Labourdette J, Ingrand P, Is ursodeoxycholic acid an effective therapy for total parenteral nutrition-related liver disease? J Hepatol 20:240, 1994
- National Nosocomial Infections Surveillance (NNIS) System Report, data summary from January 1992 through June 2004, issued October 2004. National Nosocomial Infections Surveillance System. Am J Infect Control 32:470, 2004
- Buchman AL, Moukarzel A, Goodson B, Catheter-related infections associated with home parenteral nutrition and predictive factors for the need for catheter removal in their treatment. JPEN J Parenter Enteral Nutr 18:297, 1994
- Buchman AL: Complications of long-term home total parenteral nutrition: their identification, prevention and treatment. Dig Dis Sci 46:1, 2001
- Widmer AF: Management of catheter-related bacteremia and fungemia in patients on total parenteral nutrition. Nutrition 13(4 suppl):18S, 1997
- Lecciones JA, Lee JW, Navarro EE, Vascular catheter-associated fungemia in patients with cancer: analysis of 155 episodes. Clin Infect Dis 14:875, 1992
- Messing B, Peitra-Cohen S, Debure A, Antibiotic-lock technique: a new approach to optimal therapy for catheter-related sepsis in home-parenteral nutrition patients. JPEN J Parenter Enteral Nutr 12:185, 1988
- Fortun J, Grill F, Martin-Davila P, Treatment of long-term intravascular catheter-related bacteraemia with antibiotic-lock therapy. J Antimicrob Chemother 58:816, 2006
- Lee JY, Ko KS, Peck KR, In vitro evaluation of the antibiotic lock technique (ALT) for the treatment of catheter-related infections caused by staphylococci. J Antimicrob Chemother 57:1110, 2006
- Maki DG, Ringer M, Alvarado CJ: Prospective randomised trial of povidone-iodine, alcohol, and chlorhexidine for prevention of infection associated with central venous and arterial catheters. Lancet 338:339, 1991
- Beathard GA: Catheter thrombosis. Semin Dial 14:441, 2001
- Stephens LC, Haire WD, Kotulak GD: Are clinical signs accurate indicators of the cause of central venous catheter occlusion? JPEN J Parenter Enteral Nutr 19:75, 1995
- Sando K, Fujii M, Tanaka K, Lock method using sodium hydroxide solution to clear occluded central venous access devices. Clin Nutr 16:185, 1997
- Werlin SL, Lausten T, Jessen S, Treatment of central venous catheter occlusions with ethanol and hydrochloric acid. JPEN J Parenter Enteral Nutr 19:416, 1995
- Pennington CR, Pithie AD: Ethanol lock in the management of catheter occlusion. JPEN J Parenter Enteral Nutr 11:507, 1987
- Hoshal VL Jr, Ause RG, Hoskins PA: Fibrin sleeve formation on indwelling subclavian central venous catheters. Arch Surg 102:253, 1971
- Cassidy FP Jr, Zajko AB, Bron KM, Noninfectious complications of long-term central venous catheters: radiologic evaluation and management. AJR Am J Roentgenol 149:671, 1987
- Bern MM, Lokich JJ, Wallach SR, Very low doses of warfarin can prevent thrombosis in central venous catheters: a randomized prospective trial. Ann Intern Med 112:423, 1990
- Moreno JM, Valero MA, Gomis P, Central venous catheter occlusion in home parenteral nutrition patients. Clin Nutr 17:35, 1998
- Moukarzel AA, Ament ME, Buchman A, Renal function of children receiving long-term parenteral nutrition. J Pediatr 119:864, 1991
- Buchman AL, Moukarzel A, Ament ME, Serious renal impairment is associated with long-term parenteral nutrition. JPEN J Parenter Enteral Nutr 17:438, 1993
- Moukarzel AA, Song MK, Buchman AL, Excessive chromium intake in children receiving total parenteral nutrition. Lancet 339:385, 1992
- Buchman AL, Moukarzel A, Ament ME: The role of chromium and cadmium toxicity in TPN-induced nephropathy. J Clin Nutr Gastroenterol 7:39, 1992
- Lauverjat M, Hadj Aissa A, Vanhems P, Chronic dehydration may impair renal function in patients with chronic intestinal failure on long-term parenteral nutrition. Clin Nutr 25:75, 2006
- Edes TE, Walk BE, Austin JL: Diarrhea in tube-fed patients: feeding formula not necessarily the cause. Am J Med 88:91, 1990
- Malcolm R, Robson JR, Vanderveen TW, Psychosocial aspects of total parenteral nutrition. Psychosomatics 21:115, 1980
- Bozzetti F, Cozzaglio L, Biganzoli E, Quality of life and length of survival in advanced cancer patients on home parenteral nutrition. Clin Nutr 21:281, 2002
- Sharp JW, Roncagli T: HPN in advanced malignancies. JPEN J Parenter Enteral Nutr 16:190, 1992
- King LA, Carson LF, Konstantinides N, Outcome assessment of home parenteral nutrition in patients with gynecologic malignancies: what have we learned in a decade of experience? Gynecol Oncol 51:377, 1993
- Finucane TE, Christmas C, Travis K: Tube feeding in patients with advanced dementia: a review of the evidence. JAMA 282:1365, 1999
- Lo B, McLeod GA, Saika G: Patient attitudes to discussing life-sustaining treatment. Arch Intern Med 146:1613, 1986
- McCann RM, Hall WJ, Groth-Juncker A: Comfort care for terminally ill patients: the appropriate use of nutrition and hydration. JAMA 272:1263, 1994
- Solomon MZ, O'Donnell L, Jennings B, Decisions near the end of life: professional views on life-sustaining treatments. Am J Public Health 83:14, 1993
Editors: Dale, David C.; Federman, Daniel D.