The impact of nutritional support on the outcome and quality of life of the gynecologic oncology patient has been widely recognized. To facilitate the appropriate institution of nutritional support, an understanding of the classification of malnutrition and its diagnosis is essential. Physicians should also be familiar with enteral and parenteral nutrition, their means of delivery, and their associated complications. There should also be appropriate monitoring of the response to therapy. A team approach by physician, nutritionist, and pharmacist is ideal for achieving these goals.
About 40% to 55% of adult hospitalized patients in the United States are malnourished or at risk for malnutrition, and 12% are severely malnourished (1,2,3). Similar percentages of malnutrition have been documented in thousands of hospitalized patients throughout the world (4). A study of 67 consecutively hospitalized gynecologic oncology patients found a 54% prevalence of malnutrition (95% confidence interval, 41% to 66%) (3). In 2004, the same investigators evaluated gynecologic oncology patients in a prospective cohort trial (5). Subjective assessment utilized the Subjective Global Assessment (SGA), while objective assessment utilized the Prognostic Nutrition Index (PNI). They showed an incidence of malnutrition of 61% and 70% respectively.
It is important to screen patients to remain in accordance with the Joint Commission for Accreditation of Health Care Organizations (JCAHO) 1995 and the 2006 National Institute for Clinical Excellence recommendations (6). The time to identify a patient as needing nutritional support is not upon hospital admission, but at the time of diagnosis of cancer (7,8).
Predisposing conditions frequently found in malnourished hospitalized patients include:
It is typical for undernourished patients to have more than one predisposing condition (9).
Undernourished patients also commonly have vitamin and trace element deficiencies, particularly of vitamins A, D, E, B12, and iron. Decreased stores of these vitamins can be detected in early malnutrition. Because vitamins are stored in small amounts, the provision of only dextrose and water intravenously leads to their rapid depletion, abnormal enzyme function, and clinical signs of vitamin deficiency.
Normal Body Metabolism
According to the first law of thermodynamics, the energy derived from ingested food must equal the energy expended or stored in the body at equilibrium. Although the quantity of energy intake and the amount expended and stored in any 24-hour period do not correspond exactly, body weight eventually reflects the balance between energy intake and energy expenditure.
The unit of energy exchange is the calorie, which is the amount of heat required to raise the temperature of 1 mL of water 1 degree C at 1 atmosphere of pressure.
The dietary calorie equals 1,000 calories. Thus, 1,500 dietary calories are equal to a 1,500-kilocalorie diet. This notation is used to describe body stores of energy and the quantity of food ingested.
Although diets are variable, all foods are broken down through digestion into monosaccharides, amino acids, fatty acids, and glycerol. These are then redistributed to body stores or metabolized for energy.
The body stores of energy are very different from the composition of the diet. The average diet has from 30% to 50% fat calories, 40% to 60% carbohydrate calories, and 15% to 20% protein calories. Roughly 1,200 carbohydrate calories are stored as glycogen in muscle and liver, whereas 130,000 to 160,000 calories are contained in fat; one pound of fat represents 3,500 stored calories. The body also contains approximately 54,000 calories as protein in muscle and organs, but only 30% to 50% of this is available to be burned for energy. Greater than a 50% depletion of total body protein is incompatible with life (9).
Metabolism During Starvation
During starvation, the body adapts to spare vital protein stores. Carbohydrate stores are depleted within 3 days of total starvation at rest, or more rapidly if the requirements are elevated by the metabolic effects of catabolic illnesses. Many organs use glucose in large amounts, obligating the breakdown of 75 g/day of muscle early in starvation (10). If the muscle were to continue to be broken down at this rate, starvation would lead to death in 45 to 60 days, but adaptation from a fed to a fasting state over 2 to 3 days occurs instead (Fig. 19.1). In this adaptation, peripheral tissues and organs use ketone bodies, a breakdown product of fat, in place of glucose. Because the fat stores contain an average of 160,000 calories, survival can be extended to 140 to 160 days. Some muscle breakdown continues, limiting survival, because the brain and the red blood cells require glucose, necessitating the breakdown of 20 g/day of muscle even after full adaptation.
Regardless of the metabolic features of malnutrition, weight loss is usually the presenting sign. Severe malnutrition can be defined as >10% weight loss over 2 to 3 months or a history of inadequate oral intake >7 days. It is essential to know the patient's usual weight and ideal body weight (IBW).
Ideal Body Weight
For the purposes of assessment for malnutrition in gynecologic patients, a practical formula to use for determining the IBW is the following:
Hamwi equation for women: Ideal body weight = 100 lb for 5 ft + 5 lb/inch > 5 ft
Figure 19.1 The metabolic adaptation to starvation. (From Cahill GF, Owen OE. Some observations on carbohydrate metabolism in man. In: Dickens F, Randle PJ, Whelan WI, eds. Carbohydrate metabolism and its disorders. New York: Academic Press, 1968:497, with permission.)
For example, a woman whose height is 5 feet, 4 inches would have an IBW of 120 pounds. This equation has never been validated, but was compared to the body mass index of 4.2 million people from life insurance tables in 1964. Overall it is equivalent to other predictive formulas of IBW (11). Some sources recommend that small frames subtract 10 pounds and large frames add 10 pounds, although no definition of frame measurement has been made.
For many common cancers, loss of as little as 6% of usual body weight can have significant prognostic effects on survival (12). Weight loss often mirrors declining performance status. Because some patients can be 70% of ideal body weight all their lives as a result of differences in frame size or habits such as chronic smoking, knowledge about usual body weight is important.
Weight loss results from loss of body fat, body protein, or body water. Each liter of body water lost represents a weight loss of 2.2 pounds, but this weight loss can be corrected rapidly with rehydration. The degree to which losses of body protein or fat dominate the clinical picture is a reflection of the body's ability to adapt to a fat fuel economy in the face of inadequate nutrition (13). There are three basic types of malnutrition: kwashiorkor, marasmus, and a combination of the two, cachexia (Fig. 19.2).
Kwashiorkor This form of malnutrition is variously termed protein caloric malnutrition, hypoalbuminemic malnutrition, protein energy malnutrition, or kwashiorkor-like malnutrition of the adult. If malnutrition is rapid and occurs in the face of disease factors that affect nutrition, a rapid depletion of protein stores can occur out of proportion to the loss of body weight. Kwashiorkor originally referred to a tropical pediatric disease and meant “separation from the breast” in Swahili.
Figure 19.2 Classification of malnutrition.
In hospitalized patients, the major signs of protein depletion are:
It is possible for this form of malnutrition to occur in the absence of weight loss if the hypoalbuminemia leads to ascites or edema.
Marasmus The other major form of malnutrition in adults is called marasmus, starvation, or chronic inanition. Primary malnutrition due to anorexia or dietary inadequacy is the most common form. It is characterized by a depletion of fat stores and the obvious appearance of malnutrition with visible loss of muscle and fat in the arms and legs. Although weight loss is often significant in these thin patients, protein stores can be remarkably preserved. It is not uncommon for the starved patient to have normal serum albumin and transferrin levels, a normal lymphocyte count, and normal skin test responses.
Cachexia When the two major forms of malnutrition occur together in patients with advanced malnutrition, the condition is called cachexia. Cachexia is a life-threatening condition and has also been termed combined marasmic-kwashiorkor or mixed-form malnutrition of the adult.
Cancer-induced cachexia is related to proinflammatory cytokines such as IL-1, IL-2, IFNγ, and TNFα. Cytokines serve to decrease protein synthesis and increase proteolysis. Increased proteolysis releases amino acids to be utilized by the liver for energy production and as precursors in formation of C reactive protein and serum amyloid peptide. Cytokines also stimulate release of cortisol and catecholamines. Cachectic behavior further decreases patient's activity (14). In this advanced condition, there is depletion of body fat stores and body protein stores, which produce visible emaciation with loss of body muscle and fat, as well as decreased serum proteins.
The exact contribution of malnutrition to mortality in hospitalized gynecologic oncology patients is difficult to quantify. The additive effects of malnutrition include impaired immunity, poor wound healing, and cardiorespiratory dysfunction, which all impact negatively on patient survival (15).
To diagnose malnutrition, all patients should be at least minimally screened (8) or preferably assessed, for malnutrition upon diagnosis of cancer. Low levels of circulating serum proteins can reflect impaired function of the liver and other organs, even in the absence of marked depletion of visceral and muscle protein (16). This usually occurs in the setting of excessive metabolic demands caused by specific illnesses that impair the body's ability to conserve protein. Similarly, protein and fat stores can be depleted markedly, while circulating proteins remain in the normal range. This in turn reflects a gradual adaptation to starvation in adults with anorexia and primary malnutrition.
A nutritionist can provide the nutritional assessment, which should include a history, physical examination, and laboratory evaluation. The assessment should include current medical problems/treatments; social support and functional status; anthropomorphic measurements; calculation of IBW; body mass index (BMI); and visceral protein measurement.The nutritional assessment can identify the current degree of malnutrition, determine the nutritional support required, and set the goals of therapy. Assaying immune function also contributes to an understanding of the nutritional status.
Anthropometry, in which body stores are estimated by direct measurements, and biochemical markers that assess circulating proteins, must be used in concert to determine the specific type of malnutrition in any given patient (Table 19.1).
Anthropometric techniques include the measurement of body weight and height in adults. The patient's normal weight can be obtained from the history. The Hamwi formula described above is used to calculate the percentage of IBW. The BMI is calculated by dividing weight in kg by height in meters squared (kg/m2). Normal BMI is 18.5 to 25, overweight is 25 to 29.9, with obesity being >30, and underweight being <18.5.
Fat stores can be measured by assessing skin-fold thickness. The most commonly used skin fold in practice is the triceps. For this measurement, the patient sits with the right arm hanging freely at the side. For bedridden patients, the right arm is flexed at the shoulder while the forearm crosses the chest. The midpoint between the acromion and the olecranon posteriorly over the triceps muscle is marked. The skin and subcutaneous tissue at the midpoint are then pinched and pressure-regulated calipers are applied for 3 seconds before a reading is taken (17). The calipers are designed to deliver a pressure of 10 g/mm2 regardless of the fold thickness and can be used to compare the same patient's progress over time as well as to assess the severity of malnutrition.
Table 19.1 Physical/Biochemical Markers of Malnutrition
There are a number of other means of body fat assessment such as bioelectrical impedance analysis, and submersion measurements, but each institution should be capable of providing at least one type of assessment.
Protein Store Assessment
Midarm circumference and midarm muscle circumference can help estimate lean body mass/protein stores. Midarm muscle circumference = pi × triceps skin-fold thickness. It is an attempt to estimate lean body mass. Protein stores can also be assayed by a number of circulating proteins, most of which are secreted by the liver (18,19). Their synthesis and secretion are inhibited rapidly in the presence of protein malnutrition, and they decrease to a variable extent in the circulation according to their metabolic half-lives. The most widely used markers are albumin and transferrin. Each has advantages and disadvantages (18).
Albumin Albumin has a half-life of 21 days, so that significant decreases may not occur for up to 1 month after the onset of starvation. Albumin may also be decreased by rapid loss of serum proteins (e.g., excessive losses from the gastrointestinal [GI] tract) by dilution by volume resuscitation, or by fluid shifts into ascites. Restoration of the serum albumin to normal levels by nutritional means is slow and often lags behind clear improvement in nutritional status by other criteria.
Transferrin Transferrin is synthesized in the liver and other sites, where it can act as a growth-promoting peptide. In the liver, synthesis is modulated by the iron stores in the hepatocytes, as well as by the overall protein status. The half-life of the protein is 9 days, and the body pool is only 5 g. The synthetic rate is the major factor determining serum levels, and serum transferrin increases within 9 days of nutritional repletion. The problems with the interpretation of transferrin levels are that degradation rates increase during illness, and iron deficiency falsely elevates the serum levels.
For these reasons transferrin and albumin must be interpreted within the context of anthropometric determinations of body weight and triceps skin-fold thickness.
Retinol- and Thyroxine-Binding Proteins Retinol-binding protein and thyroxine-binding prealbumin also are synthesized in the liver, with half-lives of 10 hours and 2 to 3 days, respectively. Their levels drop acutely with metabolic stress, and retinol-binding protein is also filtered and broken down by the kidney. These factors complicate the interpretation of serum levels for the diagnosis of malnutrition, but they can be used in a research setting to assess more quickly the response to nutritional support.
Inflammation causes a ≥25% decrease in all of the aforementioned serum transport proteins (20). The serum half-lives of these circulating proteins are listed in Table 19.2.
The total lymphocyte count and delayed cutaneous hypersensitivity responses to skin test antigens are nonspecific markers of impaired immune function in malnourished patients(21) (Fig. 19.3). In areas of endemic starvation, malnourished patients are at increased risk of opportunistic infections in the hospital and ambulatory settings because of the following:
Table 19.2 Serum Half-Life of Circulating Proteins Decreased in Malnutrition
Figure 19.3 Immunologic alterations associated with malnutrition.
Most patients with protein and caloric malnutrition have multiple deficiencies, and almost any single nutritional deficiency, if severe enough, can affect immune function (22). Correction of malnutrition improves immune function; this is especially true in the gynecologic oncology patient, whose immune function can be impaired by therapy as well as by the tumor itself.
Absolute Lymphocyte Count (ALC) The ALC is calculated by multiplying the percentage of lymphocytes by the total white blood cell count. The ALC and skin tests are the most widely used immune markers of nutritional status. The normal lymphocyte count is greater than 2,000/mm3 in patients who are not receiving chemotherapy. The ALC is not considered valid unless the white blood cell count is normal.
Most circulating lymphocytes are T cells, and involution of the tissues producing T cells occurs early in the course of malnutrition. The delayed hypersensitivity skin test response reflects three processes:
Antigens that are frequently tested include purified protein derivative, streptokinasestreptodornase, mumps, Candida, Trichophyton, and coccidioidin. The prevalence of nonreactivity to skin test antigens is approximately 50% in patients whose serum albumin level is less than 3.0 g/dL, but it can be as high as 30% in patients whose serum albumin level exceeds 3.0 g/dL. Other problems with interpretation of skin tests include:
The delayed hypersensitivity (DH) and absolute lymphocyte count (ALC) are useful in uncomplicated nutritional deficiencies, but are not typically considered useful in this patient population.
The assessment of malnutrition by means of clinical examination in combination with routinely available laboratory tests provides an accurate estimation in more than 70% of patients (23). Difficulties with each of these tests have kept the nutritional assessment from becoming part of the routine database for every hospitalized patient.
Subjective Global Assessment (SGA) This is the most commonly utilized tool by nutritionists in both surgical and medical hospitalized patients to assess the risk for malnutrition. It is subjective in that it does not rely on calipers or laboratory values, but rather on the patient's history of weight change, dietary change, gastrointestinal symptoms, functional status, and primary disease, coupled with the nutritionist's physical examination and global rating. A variant of this, the Patient Generated SGA (PGSGA) has been developed for assessment of the oncology patient and is considered highly sensitive (>90%) and specific for detection of malnutrition (24,25).
Prognostic Nutritional Index The Prognostic Nutritional Index (PNI) combines anthropometric and laboratory tests to calculate a single index number. It is a linear predictive model of increased morbidity and mortality after surgical procedures, and uses serum albumin (A) in g/dL; triceps skin fold (TSF) in mm; serum transferrin (TFN) in mg/dL; and delayed hypersensitivity (DH) response (0-2). The formula is:
PNI % = 158 - 16.6 (A) - 0.78 (TSF) - 0.2 (TFN) - 5.8 (DH)
For example, a well-nourished patient with A = 4.8, TSF = 14, TFN = 250, and DH = 2 has a PNI of 158.0 - 152.2, or a 5.8% chance of complications. On the other hand, a malnourished patient with abnormal indexes (A = 2.8, TSF = 9, TFN = 180, and DH = 1) has a PNI of 158 - 95.3, or a 62.7% chance of complications. A PNI of <40 is taken as well nourished, whereas a PNI of >40 is taken as evidence of malnutrition. In one study of 76 gynecologic oncology patients, serum albumin could be substituted for PNI to detect malnutrition (3). The Prognostic Nutritional Index describes surgical risk reliably based on nutritional status.
Impact of Disease on Malnutrition
Many systemic illnesses, including cancer, predispose patients to malnutrition (Fig. 19.4). Although abnormalities of metabolism, digestion, absorption, and utilization of nutrients all contribute to malnutrition in such patients, decreased nutrient intake is still an almost universal finding in malnourished patients, with the exception of those with uncomplicated hyperthyroidism. Many changes that occur in cancer patients are similar to those seen in inflammatory diseases. In particular, tumor necrosis factor (TNF), interleukins 1 and 6 (IL-1 and IL-6), and interferon-γ are etiologic agents of anorexia and cachexia (23).
Figure 19.4 Impact of disease factors on nutrition.
Decreased appetite, or anorexia, is the major factor contributing to decreased intake in many disease processes. During tumor growth, anorexia and reduced food intake markedly contribute to the development of malnutrition. Serotonin plays a key role in the control of appetite, and there is evidence that administration of neutral amino acids can counteract anorexia mediated by the increased tryptophan concentrations observed in cancer patients with anorexia (16).
Although anorexia can be a feature of cancer, it can also be a side effect of many drugs, including antineoplastic drugs. A number of other commonly used drugs (e.g., anticholinergics, antihistamines, methyldopa, sympathomimetics, clonidine, and tricyclic antidepressants) may cause a dry mouth, which decreases sensation and food palatability.Another common type of anorexia is a learned aversion to food when it is known to cause adverse physical symptoms. GI diseases, including reflux esophagitis, gastritis, and peptic ulcer, frequently cause dyspepsia. Irritable bowel syndrome, food allergies, lactose intolerance, diverticulae, and biliary disease can cause diarrhea or flatulence that may contribute to anorexia.
All of these GI problems cause patients to avoid foods altogether or to ingest an unbalanced diet. Improvements in the pharmacotherapy of nausea have lessened the anorexia associated with chemotherapy. The pharmacologic classes for possible cancer cachexia treatment include appetite stimulants, metabolic inhibitors, anabolic agents, and anticytokine agents. Megestrol acetate, a progestational appetite stimulant, is an FDA-approved treatment for anorexia. This progestational steroid increases appetite through both central nervous system and peripheral mechanisms, analogous to the increased appetite that women note during the luteal phase of the menstrual cycle. Body weight gains are from fat alone and may not improve survival. Megestrol dosing begins at 160 mg/d and may advance to 480-800 mg/d. There may be a trend toward an increased risk of thromboembolism or adrenal insufficiency. ASPEN guidelines recommend consideration of megestrol as a first-line agent. If this fails, a corticosteroid trial for several weeks may be warranted (27).
Mechanical malfunction of the bowel is a particularly common problem among patients who have undergone abdominal radiation or extensive abdominal surgery. Postoperative or postirradiation adhesions can lead to partial or complete bowel obstruction. In patients with a disseminated intraabdominal malignancy such as ovarian cancer, an adynamic ileus or intestinal pseudoobstruction can result in a nonfunctional GI tract. Impaired capacity for self-feeding can also markedly decrease food intake. Imaging or exploratory laparotomy may be indicated to define the nature, severity, and location of intestinal dysfunction.
Cancer specifically affects nutrient metabolism. Patients with metastatic and localized cancer have increased rates of hepatic glucose production, insulin resistance, whole-body glucose metabolism, lipolysis, and whole-body protein breakdown (28). Improved nutrition often fails to correct such abnormalities, once severe malnutrition is present, despite continuous parenteral or enteral alimentation with adequate nutrients (28,29,30). Specific metabolic disturbances and their consequences are presented in Table 19.3.
Nutritional support is an adjunct to primary therapy for the gynecologic oncology patient. The aim is to prevent deterioration of nutritional status during planned primary therapy, such as radiation, surgery, and chemotherapy. Early initiation of nutritional support before any deterioration of nutritional status is desirable. This goal necessitates early evaluation, the proper choice of nutritional therapeutic modalities, and an accurate assessment of requirements.
Table 19.3 Metabolic Consequences of Cancer
Once protein deficiency occurs, it is difficult to reverse, inasmuch as less than 5% of the protein is replaced per day, regardless of the amount of substrate provided. Vitamins and minerals are replaced more easily, but there is no substitute for adequate planning to meet caloric and protein requirements essential for nutritional maintenance of vital functions. The first intervention is dietary counseling.
The protein and caloric requirements can be estimated at 0.8 g/kg/day and 20 to 35 kcal/kg/day for healthy adults,12 respectively. If malnutrition exists or if the patient's metabolism is elevated by infection or other metabolic stresses, then 1.5 to 2.5 g/kg/day of protein and 35 to 45 kcal/kg/day should be supplied. More exact formulas are available for pediatric patients and patients at the extremes of height and weight.
Need for Support
There are two key aspects of the patient's nutritional status that affect decisions about nutritional support:
If the degree of prior malnutrition is minimal and the patient has only mild hypermetabolism after elective surgery, a temporary form of nutritional support can be used. On the other hand, if the patient requires additional calories to restore preexisting severe malnutrition, forced intake of calories by an enteral or parenteral route must be used. The following guidelines can be used:
Method of Support
The choice between parenteral and enteral therapy should be made on the basis of the availability and functional status of the GI tract (Fig. 19.5). If the GI tract is functioning normally, the expense and complications of parenteral nutrition are not warranted. Swallowing evaluation and nutritional assessment are useful in determining whether the enteral route is the best alternative. Intake may also be improved by the pharmacologic therapies described previously. If the GI tract is functional, but oral intake remains inadequate, a feeding device should be placed to assist intake. Patients complaining of depression or pain should have these symptoms addressed concurrently.
In view of the difficulties inherent in the use of parenteral nutritional support, every effort should be made to use the enteral route whenever possible. Enteral access may be obtained at the bedside by placement of a nasal feeding tube, by a gastroenterology consultant endoscopically, by an interventional radiologist under fluoroscopic or ultrasonic guidance, or by a surgeon in the operating room, depending upon the anticipated complexity of placement. If a long-term nasal feeding tube is required, it should be changed to alternating nostrils every 4 to 6 weeks (32). If enteral access is required beyond 4 weeks, consideration should be given to a gastrostomy or jejunostomy.
The gastrostomy port can be used at night for enteral support therapy by continuous infusion of isotonic enteral supplements at a rate no greater than 100 kcal/hour. The next day, the patient can cover the port with a dressing and go through her usual daily activities. This approach is often more acceptable to patients than a nasogastric tube, which is visible and irritating.
In some patients, the gastrostomy port has the added advantage that the stomach can be used as a reservoir for bolus feeding, which is more convenient. In cases of abnormal gastric motility, esophageal reflux, or possible aspiration of gastric contents, continuous slow infusion of supplement should be used, or a tube passed beyond the pylorus into the jejunum. The gastrostomy tube may also be used as a venting port if nausea and vomiting should develop.
Figure 19.5 Parenteral versus enteral nutrition.
If the GI tract is atrophied from prior malnutrition, a period of rehabilitation with special formula diets can be used to renourish the patient gradually, so that routine formula diets can be used (33). The epithelium of the GI tract is directly nourished by the infused nutrients in the formula diet bathing these cells, and ultimately a complete formula diet can be used.
If the patient is already severely malnourished and hypermetabolic, with a nonfunctional GI tract, careful consideration should be given to initiation of concurrent parenteral nutrition to provide calories and protein during the period of nutritional rehabilitation of the GI tract. Tapering of parenteral nutrition may begin once tube feeds are between 33% and 50% of the goal for enteral feeds, and may be discontinued when tube feeds are between 50% and 75% of the goal (34).
The transition from tube feeding to oral feeding may require swallowing evaluation, holding tube feeding prior to meals, giving a bolus down the tube after each oral meal or giving nighttime feeds. When oral intake is approximately 50% for 2 days, tube feeding may be tapered by time and volume.
Total parenteral nutrition (TPN) is the provision of all required calories in an intravenous solution of dextrose, amino acids, and emulsified lipids via a centrally located catheter.Parenteral nutrition, although appearing more definitive, should not be used in the malnourished patient with a functional GI tract. In some patients receiving chemotherapy or radiation therapy, mucosal inflammation, nausea, and vomiting impair normal intake. In such patients, TPN may be needed as an adjunct to restore functional status and allow continuation of therapy. Patients with mid- to distal GI fistulae often require avoidance of enteral feeding.
Moderate to severely malnourished patients should receive more than 7 days of parenteral nutrition before surgery for the therapy to be of benefit. Additionally, life expectancy should be evaluated for those with advanced cancer. As per ASPEN guidelines, only those with a life expectancy of greater than 3 months should be considered for specialized nutritional support (35).
Peripheral parenteral nutrition (PPN) is composed of similar elements to TPN, but combined in lesser concentrations so that infusion of the less hyperosmolar (<900 to 1,000 mOsm/L) solution may be tolerated by peripheral veins. If PPN is needed for not more than 5 days, parenteral support probably is not warranted. Alternatively, if PPN is needed for 14 days or more, TPN should be given (35). Criteria for PPN administration include good peripheral access and ability to tolerate 2.5 to 3 L of fluid daily. Over time, PPNs 10% glucose solution may cause a chemical phlebitis, limiting the use of any single peripheral vein to a period of about 10 days. In patients receiving chemotherapy, peripheral veins are often sclerosed, and a central venous route for nutrition and medications must be used.
TPN is usually administered through a central venous catheter surgically placed in the subclavian vein, although other sites can be used, as described in Chapter 20. A large central vein is required for the ≥20% glucose solution plus added amino acids required for TPN. The patient must be given special training in aseptic handling of the catheter site and use of the infusion equipment required. Many medical centers also have special home parenteral nutritional support teams, and in some regions, private firms provide this service. Potential medical problems for these patients depend to a great extent on the experience of the team providing home parenteral support.
Evaluation of Response to Nutritional Support
Because the goal of nutritional support is the attainment of an anabolic state or reduction of nitrogen losses, assessment of nitrogen balance is the most useful clinical tool to determine the effectiveness of therapy. Nitrogen balance is defined as the difference between nitrogen intake and nitrogen excretion.
Because one gram of nitrogen is equivalent to 6.25 g of protein, nitrogen intake can be determined by dividing protein intake, as determined from dietary records, by 6.25.Nitrogen excretion is defined as the urinary nitrogen excreted per 24 hours, plus a fixed estimate of 4.0 g per 24 hours for unmeasured nitrogen losses from cellular sloughing into the feces (1 g); losses from the skin (0.2 g); and nonurea nitrogen losses in the urine (2 g) (36). Because nitrogen balance is most usefully applied in a serial fashion in the same patient, the particular constants used to estimate unmeasured excretion are important only for comparison of published results.
At any given level of nitrogen intake, nitrogen balance improves with increased administration of nonprotein calories. The maximum benefit is achieved when the ratio of nonprotein calories to grams of nitrogen is 150:1 (37).
To assess adequacy of protein intake, patients with stable renal function, consistent protein intake and the ability to collect a 24-hour urine sample, may benefit from a urine urea nitrogen study (UUN), where UUN = (protein (grams)/6.25) minus UUN (excretion in grams) plus 4. The goal is +2 to +4 or the least negative balance attainable. If the UUN is negative, increasing the protein delivered, assisting its absorption, and increasing the total calories given should be considered.
Proteins also vary in their biologic value, according to their mixture of essential and nonessential amino acids. Albumin has the ideal mixture of amino acids for optimal use of protein and is assigned a biologic value of 100. Casein is close to albumin in its biologic quality, whereas meat proteins, such as those found in steak or tuna, have a biologic value of 80. Corns and beans, each with biologic values of 40 or less, can be combined in a protein mixture with a biologic value of 80, because the amino acid mixtures of the two proteins are complementary. The protein requirement for normal people is 0.55 g/kg for protein with a high biologic value, such as milk or albumin, but 0.8 g/kg for the mixture of proteins found in the average American diet (38).
Effect of Nutritional Support on Prognosis
Although it is easy to demonstrate the impact of renutrition in simple starvation, it is much more difficult to demonstrate the beneficial effect of nutritional support in a patient with a chronic illness such as cancer (39). Often the course of the underlying illness masks the beneficial effects of nutritional therapy.
In patients with mild disease or elective surgery, malnutrition is relatively well tolerated from a clinical standpoint. In such cases, nutritional rehabilitation usually occurs without any special effort as the underlying medical or surgical condition runs its course. In patients with severe disease, nutrition is often relegated to the secondary list of problems, because the progress of the primary illness dictates therapeutic decisions. In both of these instances, however, nutritional therapy may play a beneficial role in either preventing or retarding malnutrition in individual patients (40). On the other hand, an extensive meta-analysis of 53 published studies of parenteral and enteral nutrition showed that survival was improved in 6 studies, unchanged in 43, and worse in 2 (41). Nonetheless, the judicious application of nutritional support for gynecologic oncology patients may lead to an improvement in the quality of life and prognosis.
Nutrition usually is an adjunct to primary medical and surgical therapy. Prior to beginning a nutritional support regimen, the patient's current clinical status and expected outcome must be discussed with the patient and her loved ones, especially in cases of end-stage disease. Broaching end-of-life topics should be done openly and early. According to the American Medical Association's Web site, the decision to use any medical therapy “should be based on the best interests of the patient (what outcome would most likely promote the patient's well-being)”. Given the social and emotional value of nutrition, ultimately the autonomy of the patient should be guided by sound advice on what benefits, potential complications, and responsibilities come with specialized nutritional support. If there is any doubt as to whether nutrition should be provided, consultation with an ethicist may be of value.
Complications can occur after either enteral or parenteral nutrition. Complications can be mechanical, infectious, or metabolic (42).
Tubes placed via the nares may cause nasal mucosal damage, septal necrosis, sinusitis, otitis, vocal cord dysfunction, and ulceration. Use of a smaller size (i.e., 5-12F) tube helps minimize complications. Overall complication rates approach 10% and include epistaxsis, aspiration, and respiratory distress (43). Cardiopulmonary complications for the transnasal route were 4%, while the transoral tubes had a 15% rate in nonintubated patients in one study. Additionally in less than 5% of patients, nasotracheal tube placement occurred. In these patients the malpositioning was unsuspected in 80%, and caused a pneumothorax in half of the patients. Dislodgement of nasoenteral tubes has been documented in 16% to 41% of placements. A nasal bridle may be useful (e.g., AMT, Brecksville, OH) to help prevent this occurrence. Tubal occlusion occurs in up to 20% of cases. Flushing regularly and using center specific protocols for declogging (e.g., viokase and sodium bicarbonate) may decrease the risk of occlusion. Finally, up to 20% of patients with enteric tubes will experience dysphagia.
The alternative approach of enterostomies may be associated with hemorrhage, perforation and bowel leakage, and bowel obstruction with necrosis. Aspiration risk may increasedue to sedation and ileus associated with the placement procedure itself. Pneumoperitoneum occurs in up to 50% of tube placements and may delay diagnosis of a perforation, if present. The ostomy site should be observed for leakage or buried bumper syndrome. Inadvertent ostomy removal may occur and must be urgently addressed.
Since enteral feeding increases the risk of aspiration, identifying patients with gastroesophageal reflux, gastric dysmotility, or progressive obstruction and intolerance can help minimize the risk. Other ways to decrease aspiration risk include head of bed elevation, evaluation of swallowing, assessment of tolerance to tube feeding, and frequent monitoring of the airway. The ASPEN guidelines for gastric residual volumes are to check every 4 to 5 hours until at goal, and to hold feeds if residual volumes are greater than 200 mL. Unfortunately, nausea and/or vomiting develop in 12% to 20% of patients receiving enteral nutrition (35).
Diarrhea is the most common complication associated with tube feeding (44) and should be assessed and treated in the following ways:
While evaluation of diarrhea is ongoing, attention should be kept on the clinical status of the patient as dehydration may rapidly occur. Dehydration with hypernatremia can be a problem in the elderly, in whom inadequate fluid intake can occur during the administration of a hypertonic enteral formula. When high-carbohydrate enteral formulas are used, glucosuria can occur even in patients without a prior history of diabetes.
The complications of parenteral nutrition are often more serious than those associated with enteral nutrition (45). Pneumothorax and subclavian venous thrombosis are the most common catheter-related complications for temporary and permanent central venous catheters (CVC). Pneumothorax should occur in only 1% to 2% of CVC insertions, but this rate is higher when transthoracic puncture is used rather than open surgical placement, or when less experienced personnel insert the catheter (46). A chest radiograph to confirm proper catheter placement and to exclude a pneumothorax is essential. A pneumothorax often resolves spontaneously, but a chest tube or pigtail catheter may be required in some cases.Peripherally inserted central catheters (PICC) are another option for TPN. The lumen for TPN should be dedicated for TPN only to minimize the risk of infection. Femoral CVCs should be avoided due to an increased risk of infection and thrombosis.
Permanent catheters, such as Hickman or Port catheters provide ready access for parenteral nutrition, blood products, and chemotherapy, but can also be malpositioned, cause thrombosis, or become infected. Thrombosis of the catheter in the central veins has been reported in 5% to 10% of patients receiving parenteral nutrition, especially with the hypercoagulable states of sepsis or cancer (47). In most patients, the catheter should be flushed with heparin solution (300 U/mL) to prevent this complication, predisposing the patient to the risk of heparin-induced thrombocytopenia (HIT). When venous thrombosis occurs, the catheter must be removed. Peripheral parenteral nutrition may be used, while a course of full intensity anticoagulation is given to treat the thrombosis and a new site for a central venous catheter is selected. A minimum of a three-month course of full-dose anticoagulation should be prescribed, and that access site should be avoided in the future.
In patients committed to lifelong parenteral nutrition, the CVC site choice must be made carefully because only nine external sites are available for central venous catheter placement: internal jugular veins, subclavian veins, femoral veins, and in some centers, the inferior vena cava.
Infections occur in 2% to 5% of central catheters placed for parenteral nutrition. Mortality of catheter related blood stream infections is 12% to 25% (48). When the patient is febrile and a peripheral source of infection is not found within 96 hours, the catheter should be removed and cultured for evidence of catheter-related infection. Infections most commonly occur from skin contaminants, such as gram-positive organisms, but can include fungi and unusual bacteria, especially if acquired during hospitalization. Fevers in patients requiring TPN should always prompt investigation of potential blood stream infection.
Infected catheters can also be a source of life-threatening septic phlebitis. Blood-borne infections from sources other than the catheter can be treated with intravenous antibiotics without removal of the catheter, but the patient should be observed carefully because the catheter may become seeded with bacteria. The subcutaneous tunnel of a permanent catheter may be a source of infection as well.
In patients treated with broad-spectrum antibiotics, systemic candidiasis can occur. The retina should be examined by an ophthalmologist for the presence of cotton-wool exudates that are pathognomonic of systemic candidiasis, and blood cultures should be sent for special fungal isolation procedures if candidiasis is suspected. Caspofungin (70 mg IV first day, then 50 mg IV daily) is a reasonable first-line agent in patients with suspected candidemia. In addition to holding TPN, the CVC should be removed and consideration given to evaluation for endocarditis (49).
A variety of metabolic complications can occur during parenteral nutrition. The most common is overfeeding, which results in excess CO2 production and occasionally hypercapniain patients with pulmonary disease (50). Blood sugars must be checked regularly as hyperglycemia or even hyperosmolar nonketotic coma can occur as a result of transient insulin resistance, relative insulin deficiency, or more rarely, chromium deficiency. Sliding scale subcutaneous insulin, an insulin drip, or insulin added to the parenteral solutions are appropriate measures (51). Hypoglycemia sometimes occurs with abrupt cessation of TPN as well. To avoid this, TPN should be tapered to half the standing infusion rate for one hour, before discontinuing it completely. Alternatively a D10W infusion can be substituted for the TPN at the same rate for one hour. Basic metabolic panels should be monitored for metabolic acidosis, a less common problem since acetate buffers have been used in parenteral solutions. Abnormalities of phosphate, potassium, calcium, and magnesium can occur because of excessive or inadequate administration, particularly in the presence of underlying disorders, such as renal failure or GI fistulae, which themselves predispose to electrolyte abnormalities (52,53).
Deficiencies of trace minerals such as zinc, copper, and chromium used to occur but are now rare, because these are now added routinely to parenteral solutions (54). Because multivitamin solutions are the same source for vitamin K, the prothrombin time and partial prothrombin time should be monitored weekly.
The most serious metabolic complication of TPN is refeeding syndrome, an acute state of electrolyte imbalance due to initiation of nutritional support. It is most likely to occur when TPN is commenced in the severely malnourished patient. Concern for this syndrome requires daily serum electrolytes initially, and often electrolyte supplementation (55).
Renal abnormalities are sometimes troubling. Azotemia may worsen in patients with renal failure or when there is excessive administration of amino acids relative to nonprotein calories, and this may treated by reduction of the amino acid load. However amino acid requirements may be higher in patients on hemodialysis. Daily weights and a strict fluid balance chart are mandatory for volume monitoring.
Hepatobiliary complications occur as well. Steatosis is associated with dextrose overfeeding, and a mild transaminitis may occur that typically resolves in 2 weeks. The latter can also reflect sepsis. Cholestasis manifests as a nonjaundiced patient (with bilirubin <2), with a mild increase in alkaline phosphatase, GGT, and direct bilirubin. Finally, gallbladder stasis occurs in almost all TPN patients, but consideration should be given to the possible development of cholangitis or cholecystitis.
Essential fatty acid (EFA) deficiency now rarely occurs because of the use of intravenous lipid emulsions (57). In animal studies, EFA deficiency occurs after 12 days without lipid supplementation. In humans this complication can be avoided by providing 1 to 3 days per week of lipid infusion. EFA deficiency clinically manifests as scaly skin, alopecia, hepatomegaly, or thrombocytopenia. To avoid hypertriglyceridemia due to lipid administration or dextrose overfeeding, weekly triglyceride levels should be checked. Rarely patients with egg allergy will react to the lipid infusion.
In most cases, the metabolic complications associated with parenteral nutrition respond to careful fluid and electrolyte management with daily monitoring of input and output. Complications can be avoided with effective communication between the physician, nutritionist, pharmacist, and patient.
Nutritional Support in Multiple Organ Failure Syndrome
Multiple organ failure syndrome (MOSF) can develop in critically ill patients secondary to a decline in cellular oxygen consumption, inflammatory cytokines, or sepsis (58). Cascading events, including at different times hypoperfusion/hypoxia, immunodysfunction, endocrine dysfunction, acute starvation, and metabolic derangements, may lead to early organ failure within 5 to 7 days after the initial insult, but can occur as late as 21 days.
The nutritional therapy provided for such patients has been called metabolic support to differentiate it from the nutritional support given to more stable patients with chronic anorexia and starvation. In nutritional support, the goals are simply to provide adequate calories and nutrients to restore nutritional deficiencies and to maintain protein synthesis, positive nitrogen balance, and lean body mass (59). Metabolic support of the critically ill patient at risk of multiple organ failure syndrome is directed at partial caloric replacement, sustenance of important cellular and organ metabolism, and the avoidance of overfeeding. Metabolic costs of overfeeding include lipogenesis, gluconeogenesis, thermogenesis, electrolyte imbalance, metabolic alkalosis, and hypervolemia. Excessive infusion rates and choice of the wrong mixture of macronutrients can be harmful in the critically ill patient (60).
A breakdown in the physical and immunologic barriers of the GI tract can promote multiple organ failure syndrome. The GI tract is particularly susceptible to ischemic and reperfusion injury. Glutamine, a preferred fuel for the gut epithelium, may promote healing of the GI tract epithelium after an injury (61). In animal studies, an enteral formula containing glutamine has been shown to maintain muscle glutamine metabolism without stimulating tumor growth, while also improving GI mucosal integrity and nitrogen balance (62). Currently there are no recommendations for glutamine outside of burn or trauma patients (63). The critical therapeutic difference between multiple organ failure syndrome and chronic malnutrition is the need to avoid overfeeding by providing a hypocaloric protein-sparing nutritional regimen in the former.
Provision of Nutritional Support
There are many methods of estimating basal energy requirements. The following are guidelines:
There are many other formulas for estimating energy requirements that take the patient's height into consideration. Taller patients have a higher resting energy expenditure at the same weight than shorter patients, because they have larger livers and other vital organs. In older people, metabolic rates tend to fall, in part because of a decrease in lean body mass. Although these equations are useful for clinical nutritional research, they are generally unnecessary for clinical management. A more practical set of guidelines is given in the following sections.
Estimation of Total Caloric Requirement
Severity of Illness
Daily Caloric Requirement
Estimation of Protein Requirement
The protein requirement can be estimated at approximately 1.0 g/kg of actual body weight per day for normal individuals or 1.0 g/kg of ideal body weight per day for obese patients. Stressed normal weight patients require 1.5 to 2.5 g/kg of actual body weight/day while stressed obese patients require 1.5 to 2 g/kg of ideal body weight/day (34).
Estimation of Nonprotein Calories
One simple method of estimating nonprotein calories is to subtract the protein calories from the total number of calories required daily. 1 gram of protein = 4 calories. The nonprotein caloric requirement may be estimated by initially estimating the amount of nitrogen administered according to the following formula: 1 g nitrogen = 6.25 g protein. By either the parenteral or the enteral route, 150 nonprotein calories must be provided for each gram of nitrogen administered. Therefore, estimation of nonprotein calories can be achieved as follows:
Determination of Carbohydrate Requirement
It is usual to give approximately half the total calories as carbohydrates. Most nutritional solutions are premixed, and the precise formulas available vary in different hospitals.Custom TPN solutions are possible and may be useful to decrease hyperglycemia. It is best to discuss custom solutions with a nutritionist and a pharmacist, as solution stability must be maintained, which limits the proportions of protein, fat, and carbohydrate that can be mixed.
Determination of Fat Requirement
The absolute fat requirement for essential fatty acids (i.e., linoleic acid and linolenic acid) is only 4% of the total calories. The amount of fat usually administered either enterally or parenterally exceeds this amount. The balance of the calories necessary to fulfill the total caloric requirement after the protein and carbohydrate calories have been calculated is often given as fat. In all cases, the number of calories given as fat should be far less than 60% of the total calories, which is the maximal fat allowance.
Sample calculations for both enteral and parenteral formulations are presented.
A 50-year-old woman who weighs 45 kg has a usual body weight of 70 kg and is severely ill with sepsis and postsurgical stress. Her GI tract is functional, and enteral formulation must be prescribed. The following steps allow calculation of the specific requirements:
A 45-kg, 70-year-old woman has lost 15 kg as a result of postirradiation changes to the bowel. In view of her poor GI function, parenteral alimentation is appropriate. The estimation of her nutritional requirements is as follows:
In this example, the intravenous fat emulsion provides needed additional calories, allowing for the more complete utilization of the administered protein. An additional reason to provide fat emulsions parenterally is the need to provide essential fatty acids at a minimum level of 4% of total calories. For example, 4% × 2,000 kcal = 80 kcal/day. One 550 kcal unit of intravenous fat emulsion per week can meet this requirement. In the absence of any fat administration, essential fatty acid deficiency develops in 4 to 6 weeks in most people, once endogenous stores of essential fatty acids are depleted. Because the cost of lipid emulsions has decreased considerably, fat is being used as a parenteral caloric source in amounts exceeding those needed to meet the minimal essential fatty acid requirements, as outlined in the previous example.
Table 19.4 Typical Parenteral Nutrition Solutions
Standard mixtures of electrolytes per liter of solution are provided by most pharmacies, and they are designed together with acetate buffers to deliver a nonacid solution with a pH of between 5.3 and 6.8. In unusual fluid and electrolyte situations, the composition of the solution can be custom designed, but this significantly increases the cost of parenteral nutrition and increases the possibility of the solution becoming insoluble or “cracking.” The use of standard fluid and electrolyte solutions with supplements as necessary is preferable. Typical parenteral nutritional solutions are shown in Table 19.4.
Osmolarity and caloric content of the parenteral solution are related to the glucose and protein concentrations. For lipid preparations, the osmolarity and caloric content are also related to the percentage of lipid in the solution (Table 19.5).
Recommended vitamins that should be provided on a daily basis in parenteral solutions are listed in Table 19.6. These substances are available in preformulated ampules, and 1 ampule per day added directly to the parenteral solution meets all the requirements in most patients. In patients who are especially stressed (e.g., septic wounds), 500 mg of vitamin C should be given. Patients receiving common medications such as phenytoin (Dilantin) may require additional specific vitamin supplements (e.g., vitamin D). The amount of vitamin K provided in daily parenteral nutrition should be routinely reviewed by a pharmacist.
Major mineral requirements are listed in Table 19.7. The daily requirement has a wide range that depends largely on the extent of GI and renal losses. In patients with an abnormally high excretion, the losses must be replaced aggressively.
Supplementation with zinc, copper, chromium, and selenium is essential in parenteral nutrition (Table 19.8). Deficiency states of these trace elements have been described in patients who have been receiving parenteral nutrition without supplementation. These patients respond to the specific replacement of deficient trace elements. Patients who require home TPN should have trace element levels measured prior to discharge.
Table 19.5 Osmolarity and Caloric Content of Glucose and Lipids in Parenteral Nutritional Solutions
Table 19.6 Guidelines for Daily Adult Parenteral Vitamin Supplementation
Iron supplementation is not recommended in the acutely ill patient. Iron levels should be documented. Manganese has not been clearly established as an essential component of TPN solutions, but it has been included in some recommended regimens. Iodine is not normally supplemented because the transdermal absorption of iodine-containing solutions that are used to clean catheter sites permits intake of the required amount of iodine. Iodine deficiency is associated with high TSH. Chromium levels may be useful in the diabetic patient as chromium is an insulin receptor cofactor and deficiency may cause hypo- or hyperglycemia.
In the presence of excessive GI losses (e.g., small bowel fistula), additional zinc should be given for replacement. It is recommended that 12.2 mg of additional zinc per liter of small bowel loss should be given.
Table 19.7 Range of Daily Requirements of Major Minerals and Electrolytes in Parenteral Solutions
Table 19.8 Suggested Daily Adult Intravenous Requirements of Essential Trace Elements and Associated Deficiency Syndromes
In patients who are being given enteral supplementation, 2 L of formula per day includes all the recommended dietary allowance for vitamins, minerals, and trace elements.
Further information regarding nutritional support may be obtained from the American Society for Parenteral and Enteral Nutrition (ASPEN) at http://www.nutritioncare.org.