Laboratory Data Vital Foundation for Therapeutic Nutrition Monitoring
Laboratory Data Vital Foundation for Therapeutic Nutrition Monitoring
By Timothy H. Carlson, RD, PhD, NRCC
When individuals hear the word "malnutrition," visions of children with blank stares and rail thin appendages or enlarged abdomens come to mind. Indeed, children from areas of the world where periodic food shortages lead to inadequate consumption of protein and calories can suffer from forms of malnutrition called marasmus and kwashiorkor.
In general, marasmus is a form of protein-energy malnutrition (PEM) characterized by a progressive loss of fat and muscle tissue because of chronic insufficiency in caloric intake. Kwashiorkor is the form of PEM that develops during relatively short-term protein and caloric deficiency. In the most severe cases, both forms of malnutrition can exist at the same time.
It was recognized more than 20 years ago that many patients in acute care settings have some of the same symptoms as kwashiorkor victims. In addition to decreases in organ function, mental and emotional vigor and immune function, this form of malnutrition is characterized by how quickly it develops in persons stressed by major illness or injury. A septic post-surgical or trauma patient who had been consuming an inadequte amount of nutrients, for example, could display lassitude, decreased immune function and compromised visceral organ function in less than a week.
In the 1970s it was estimated that from 30 percent to 50 percent of hospitalized patients suffered from PEM. Heightened awareness of this problem led to increased attention to patient nutrition needs. Intervention to supplement nutrients, or totally supplied nutrition by parenteral routes (total parenteral nutrition, TPN) or enterally via feeding tubes (enteral tube feeding1) became relatively common. Unfortunately, recent reassessment of the incidence of PEM in acute care institutions indicates that this attention to nutrition status has not eliminated the PEM problems in hospitals. A few reasons for this: resistance of the acutely ill or injured person to make improvements in nutrition status, inadequate support and a lack of objective data that correlate with needs.
While hospital-associated PEM will probably never be eliminated, improvements are still possible. The objective data provided by the laboratory already plays a significant role in the assessment and monitoring of patients with PEM, and its systematic use can contribute to future decreases in the incidence of PEM in the acute care setting.
TPN (formerly called hyperalimentation or IV hyperalimentation) was first used in the late 1960s when techniques were perfected that allowed catheter tubes to be surgically placed into large-diameter, high-flow veins for delivery of the primary nutrients. These nutrients included water, amino acids, glucose, fat emulsions, electrolytes and micronutrients (vitamins and trace minerals).
The basis for the amount of nutrients administered is estimated from the patient's age, sex, body proportions and the supposed severity of the stress caused by the patient's disease or injury. Table 1 gives the typical equations for the calculation of basal caloric needs and ranges to estimate the total requirement for protein, lipid and water.
The initial estimates of a patient's nutrition needs are necessarily crude. Monitoring response, especially through the use of lab data, allows adjustments in feeding as the patient progresses. Differences in the nutrient dynamics determines the monitoring interval for different nutrient parameters.
Venous access must be at a site where blood flow is rapid to dilute the TPN solution as it enters the circulation. For short-term parenteral support, access is via a percutaneous catheter inserted into the jugular or subclavian vein. Frequently, and especially for long-term use, central indwelling catheters made of biocompatible materials are surgically placed. Occasionally, for short-term supplementation of enteral intake, infusion of parenteral nutrition can be via a peripheral vein. Lipid emulsions can be administered by this route, but only small amounts of hypertonic glucose solutions can be infused peripherally because these damage the vein and tissue surrounding the access site.
Indications for TPN Support
Parenteral nutrition is initiated when the gastrointestinal tract is dysfunctional because of obstruction or ileus following surgery, trauma or infection. It is also used when large portions of the small intestine have been removed (short gut syndrome) or in long-term malabsorption, such as in Crohn's disease, severe cystic fibrosis or sometimes in intractable chronic pancreatitis. It is still used to provide nutrition for persons with depressed gag reflex because aspiration associated with enteral feeding often leads to pneumonia.
However, while TPN can be used to provide nutrition support to these kinds of patients, its use has decreased with improvements in enteral tube feeding technology and practice. The high cost of TPN, the importance of maintaining a functional gut because of its endocrine and immune functions, and risk of TPN-associated infections and metabolic side effects have led to the use of enteral tube feeding whenever possible.
The primary reason for giving TPN is to provide sufficient protein and calories to meet the metabolic demands of the patient. Provision of micronutrients, while essential, is of secondary importance because storage pools of many of these are present in the body and micronutrients can usually be administered by other means.
Therefore, the indications for the need for TPN (or another form of nutrition support) include data implying a deficit in protein and energy balance. A variety of data is used to make a nutritional assessment--dietary and weight history, anthropometric data (e.g., weight to height ratio and body composition indicators), diagnosis, prognosis, clinical status and laboratory data. The types of lab data most often used are low total lymphocyte count, negative nitrogen balance and low or declining serum albumin, transferrin, transthyretin (also called prealbumin or thyroxine-binding prealbumin), or retinol-binding protein levels. Serial data showing a significant fall in one or more of the proteins are more indicative than low values from a single point in time.
It is impossible to determine the need for nutrition support from any one type of data. Because plasma protein levels are affected by stress and hydration, it's not appropriate to use them as the only measurement in screening for compromised protein-energy status. While serum protein levels and other lab data contribute to the overall decision to provide nutrition support, their role is more to support the decision than to mandate it. Although screening with trans-thyretin and/or retinol-binding protein is advocated by some laboratorians and instrument/reagent manufacturers, these proteins are better used in monitoring the progress of patients. Hence, baseline serum transthyretin or retinol-binding protein levels should be determined as soon as possible after admission for patients at risk of protein-calorie malnutrition.
Except in cases where there is a history of the need for TPN, this form of nutrition support is rarely initiated immediately upon admission. This means that if a baseline set of laboratory data is obtained at admission, changes could be followed before initiating TPN. This is rarely done, but it could be cost effective. The reason for potential savings is that the above tests may be somewhat costly, but if a single day of unnecessary TPN could be avoided, a savings of >$200 could be realized. (As shown in Table 2, a panel called the Nutrition Monitoring Panel costs about $90 at the University of Washington Hospitals.)
On the other hand, failure to institute TPN when it is needed could lead to deterioration in nutrition status, which in turn contributes to complications that cost many times more than $200/day. Systematic practice guidelines need to be developed that include identification of patients who may potentially benefit from TPN, collection of baseline laboratory data, regular monitoring of laboratory indicators of nutrition status and decision points for when to initiate nutrition support.
When parenteral formulas are designed, the absence of the normal protective contributions of the GI tract that are stimulated by enteral feeding must be taken into account. The GI tract performs several important functions besides nutrient digestion and assimilation, such as secretion of hormones, control of inter-organ substrate flux and enhancement of cell-mediated immunity.
All substances entering into the circulation from the gut must first pass through the liver where >=75 percent are removed for processing, storage or detoxification. In contrast, parenterally delivered nutrients may affect a variety of organs before the liver can act to regulate their availability.
Another enteral protection against nutrient toxicity is the regulation of uptake by the mucossal cell by feedback from the level of the nutrient stored in the body. Finally, when nutrients do not pass through the gut mucossal cells the availability of nutrients to these cells is greatly reduced, leading to cell atrophy and an increase in the permeability of the gut wall to bacteria present in the lumen. This effect plays a role in reduction in the secretion of IgA by the gut, and is apparently associated with a general reduction in lymphocyte activity.
In addition to the protections resulting from enteral nutrient intake, the endocrine functions of the gut are essential for nutrient metabolism. Stimulation of pancreatic hormones by hormones released from the gut is essential for regulation of cellular glucose, amino acid and fat uptake.
The protein requirements of the TPN patient are met by infusion of a mixture of amino acids, of which about 40 percent of the total are from the nine indispensable or essential amino acids. The total amount of protein administered is >=0.8g/kg/day. To optimize the administration of protein and energy, their ratio is maintained at a level that prevents the metabolism of the amino acids to supply energy to the system. Enough energy to prevent deamination of amino acids is present when a ratio of about 150 kilocalories to 1 g of amino acid nitrogen (1 g of nitrogen is found in an average of 6.25 g of amino acids) is present in the formula.
Besides amino acids, enough lipid must be given to prevent essential fatty acid deficiency. The remaining energy needs are met by glucose. It is considered necessary that at least 30 percent of calories come from glucose in order to maintain efficient metabolism of fat. Total energy requirements are usually about 30 kcal/kg and rarely exceed 40 kcal/kg, although larger amounts are associated with some injuries or illnesses.
The amount of vitamins recommended in TPN are generally greater than the RDA. On the other hand, the amount of trace elements that must be administered in TPN is less than the RDAs because unlike in enteral intake, uptake is always complete. Table 1 compares the RDAs and recommended parenteral vitamin and trace element dosages.
The recommended parenteral do-sages for the various electrolytes are very broad--the amounts given are adjusted in response to the results of electrolyte monitoring. As indicated in Table 3, during an acute illness and immediately after beginning TPN, electrolytes should be monitored daily.
Monitoring Response to TPN
The major contribution of the clinical lab to the management of TPN is in the area of monitoring because the tests used are sensitive to changes in nutrition status but lack specificity. This characteristic of lab data is shared with the other types of data used in assessment or diagnosis of malnutrition. Therefore, assessment requires combining all of the different forms of data available, while monitoring is probably best done by concentrating on the objective, quantitative, "quality-controlled" data that come from the laboratory. Table 3 lists the laboratory results that should be monitored during TPN and gives the monitoring interval for new, stable and long-term support.
During the period immediately after initiation of TPN, blood glucose should be monitored every 6-10 hours in order to determine if the insulin release in response to the glucose in the TPN formula is stimulating cellular glucose uptake. Many conditions--diabetes mellitus, sepsis, shock, sur-gery, major trauma and advanced age-- decrease glucose tolerance. Untreated hyperglycemia due to inadequate insulin response can cause hyperglycemia, and hyperosmolar nonketotic coma, a condition that results from dehydration due to osmotic diuresis. Serum glucose can rise to >1,000 mg/dL with a parallel rise in serum osmolality.
During the initial phase of TPN therapy, serum electrolytes, phosphorous, BUN, creatinine and calcium need to be monitored daily. Potassium levels may be depressed in patients who have not been eating, or who suffer from diarrhea, intestinal, biliary or renal fluid losses, or are being treated with many commonly prescribed drugs. Clinical signs of hypokalemia occur when serum potassium levels fall below about 3 mEq/L, or when potassium excretion decreases to less than about 40 mEq/L.
Phosphate deficiency interferes with protein, ATP, DNA and membrane component synthesis. To avoid hypophosphatemia, serum phosphate should be checked and repleted before initiating TPN. It is important to closely monitor magnesium early in TPN administration because of potential hypomagnesemia and the possibility of toxic levels if dosage is in excess of needs.
Patients with impaired pulmonary function or sepsis are at risk of carbon dioxide retention. This complication is associated with increased serum or whole blood CO2 and a decrease in serum or blood pH. The patient's CO2 production can be somewhat decreased by increasing the amount of fat in the TPN formula to >=40 percent of calories.
Other blood gas parameters that are used in monitoring nutrition support are venous and arterial oxygen saturation and pO2. These are converted to oxygen concentrations (cO2) in calculations involving hemoglobin data, and then cO2 is used in the Fick equation to calculate O2 consumption. From these data, metabolic rates can be calculated from the following equation:
MR (kcal/min) = 4.86 (kcal/L O2)
x O2 consumption (liter O2/min)
The administration of calories can be adjusted to fit consumption per 24 hours. A single calculation of MR must be interpreted cautiously because of the inaccuracy that results from combining errors associated with the multiple measurements used in these calculations. As with the more indirect approaches to assessment, monitoring of oxygen consumption and calculated metabolic rate is the most appropriate use of these data.
Liver enzymes (AST, ALT and alkaline phosphatase) and bilirubin should be monitored beginning 5 to 7 days after starting TPN. These analytes warn of developing complications associated with TPN, including impaired bile flow, deficiency of specific amino acids and excessive glucose or fat administration. Administration of too many calories as glucose causes the development of hepatic steatosis (fatty liver), and this condition is exacerbated by ineffective lipid transport related to protein malnutrition. Abnormal fat metabolism can also occur following infusion of lipid emulsions, especially in sepsis and traumatic stress. Serum triglyceride and cholesterol levels, measured before and after lipid administration, are interpreted in light of the possibility of this complication.
Another lipid abnormality that may occur is essential fatty acid deficiency (EFAD). It can develop within one month of initiating TPN if no lipids are given. This condition now rarely occurs during TPN because of general awareness of its etiology. However, long term TPN patients may need to be monitored.
Serum phospholipid fatty acid levels, usually determined by GLC, are used to assess essential fatty acid status when EFAD is suspected. A ratio of fatty acids with three double bonds to those with four double bonds (the triene to tetraene ratio) >=1.0 is considered diagnostic.
Protein balance must be monitored regularly during TPN to assure that adequate protein is available to compensate for normal amino acid turnover, and to cover the extra demands of wound healing and other stress responses. This is done by measuring nitrogen excretion in 24 hour urine collections for comparison with nitrogen administration. The latter is determined by dividing the quantity of amino acids administered during the 24 hour period of the urine collection by 6.25 (the inverse of the average fraction of nitrogen in dietary protein). A positive nitrogen balance is always required in children and is essential for persons who have been through a period of negative nitrogen balance.
The nitrogen content of urine is traditionally measured by the Kjeldahl method, but this is too laborious for routine use. Many labs now measure total urinary nitrogen (TUN) by the pyrochemiluminescence procedure. In other labs, nitrogen balance is still estimated from measurement of urine urea nitrogen (UUN). The latter is much less reliable because it is difficult to accurately estimate the amount of non-urea nitrogen in urine, especially in stressed patients.
The equations used to estimate nitrogen balance are:
Estimated nitrogen balance (g) =
protein intake (g) - total urine
6.25 nitrogen + 2 g
Estimated nitrogen balance (g)=
protein intake (g) - urinary urea
6.25 nitrogen + 4 g
The 2 g correction is needed to correct TUN for sloughing of skin, hair, nails and cells from the urinary and intestinal tracts. An additional 2 g is needed to correct UUN for urinary non-urea nitrogen in urine.
It is usually not possible to produce a positive nitrogen balance in an acutely ill patient simply by increasing the amount of amino acids administered. Thus, when a larger quantity of amino acids is administered, then the patient can synthesize into protein, the excess amino acids are deaminated and the waste nitrogen is excreted as urea. Serum urea levels (BUN) monitored during TPN can be helpful because in patients with normal kidney function, BUN will indicate excessive amino acid catabolism. It must be remembered that BUN is not specific for excess protein intake, however, because when muscle protein is being hydrolyzed for energy, BUN increases even when an excess supply of amino acids is not provided.
Collection of 24 hour urine is problematic for patients whose urine is not being obtained via urinary catheter. In addition, if the patient begins some oral food intake, it is almost impossible to accurately estimate the protein consumed. Under these circumstances the use of a serum protein indicator becomes more important.
Since protein synthesis requires adequate energy, measurements of some proteins are used to monitor the adequacy of both protein and energy intake. Traditionally, serum albumin has been used to monitor protein-energy balance. However, albumin is an especially mediocre indicator of protein-energy status for several reasons: its level is affected by the degree of patient stress,2 it has a very long half-life (about 20 days) so it responds slowly to adequate nutrition, and levels vary with hydration status.
As in assessing the need for nutrition support, transferrin, trans-thyretin and retinol-binding protein are commonly used for monitoring protein-energy status. These proteins suffer from essentially the same problems that affect albumin, except that transthyretin and retinol-binding protein have the advantage of relatively short half-lives of 2 and 0.5 days and can respond more rapidly than albumin to improving protein-energy status.
For proteins like transthyretin and retinol-binding protein to be used optimally, the dietitian or physician must know if the change observed is significant. A concept known as the critical difference (CD) can be used to interpret changes in an analyte:
CD % = (2)1/2 x F x (CVa2 + CVb2)1/2
(F is a constant, CVa is coefficient of variation for analytical accuracy of the analyte, and CVb is normal individual biological or physiological variation that can be expected for the analyte.)
When a change greater than the CD percent is observed, the clinician can be sure that the change is significant. CD percent values for albumin and transthyretin have been published. If more than two serial values are available, the CD percent decreases because F decreases. More research in this area is needed to improve the utility of proteins in monitoring protein-energy status.
The concentrations of several plasma proteins increase dramatically during the inflammatory response. The most sensitive of these is C-reactive protein (CRP). The serum concentration of this can be used to help interpret changes in transthyretin, retinol-binding protein or even albumin. If the level of CRP is normal, low levels of any of these proteins is likely to be associated with protein-energy malnutrition. During monitoring, patients with decreasing levels of CRP and increasing levels of, for example, transthyretin, are likely to have improving protein-energy nutrition status. Optimally, CRP level is best measured on each of the specimens used to assay transthyretin.
The status of some micronutrients--principally ascorbic acid and zinc--should be monitored during TPN. Both substances are required for wound healing and immune function; zinc also performs many other important functions.
The other micronutrients, except perhaps vitamin A, should be assessed primarily when deficiency is suspected, particularly vitamins D, E and B12, thiamin, riboflavin, niacin, pantothenic acid, pryridoxine, folate, biotin, iron, iodine, copper, selenium, chromium and possible manganese. Of these, only iron and selenium are not included in standard TPN vitamin and trace mineral packages.
Because of its toxicity when not protein-bound, iron cannot be given intravenously. If iron deficiency develops, as demonstrated by a low serum ferritin or elevated red cell zinc protoporphyrin, iron is administered in a non-toxic iron-dextran organic complex.
Some patients must be on TPN for life. Most often, these are persons with a form of cancer or a major lower GI tract malfunction. Monitoring home parenteral nutrition requires that the list of analytes given in Table 3 be monitored several times per year.
Although laboratory data may be most useful in TPN monitoring, clinical and anthropometric data must not be neglected. Thus, vital signs, body weight and mental status and physical symptoms are important in confirming that the patient's nutrition status is improving, deteriorating or stable.
Enteral Nutrition Support
Enteral feeding by tube is any procedure in which a tube is inserted into the GI tract at or below the level of the stomach to introduce a fluid nutritional formula. The advantages of tube feeding as compared to parenteral nutrition are:
* immune function is preserved or enhanced;
* mucosal integrity and function are preserved, preventing the "trans-location" of intestinal bacteria into the circulation; and
* much more complex mixtures can be administered, e.g., extracts or homogenates containing substances of unrecognized nutritional benefit that are present in normal diets.
Enteral Tube Feeding
Tube feeding is useful in treating a wide variety of patients, including those with impaired swallowing, orophayngeal-esophageal disorders, psychotic disorders (e.g., anorexia nervosa and Alzheimer's disease), some glycogen storage diseases, increased nutrition needs (most common in acute care institutions), gastrointestinal disorders, renal failure, liver failure, chronic obstructive pulmonary disease and decubitus ulcers or risk of decubiti. Tube feeding is contraindicated in persons with intractable vomiting, intestinal obstructions, paralytic ileus, gastrointestinal hemorrhage or some fistulas. Diarrhea does not preclude enteral feeding if it can be managed by adjustment of formula type or rate of administration.
Lab data consistent with the need for nutrition support are the same for tube and parenteral feeding. Again, the primary criteria for whether to feed enterally rather than parenterally is the capacity of the GI tract to effectively assimilate nutrients.
Tube feeding products range from homogenized or "blenderized" whole foods to completely defined simple sugar, amino acid, fatty acid and micronutrient containing formulas called modular diets. Between these extremes are formulas called polymeric (containing specific homogenates and extracts), polymeric with added fiber and "elemental" (predigested carbohydrate and protein). In addition, some available specialty formulas are supplemented with amino acids, vitamins, minerals or trace elements that meet specific nutrition needs of some patients.
Several factors are considered in choosing an enteral formula. First, formula osmolality is important. Formulas with larger amounts of low molecular weight substances have a higher osmolality and have three potentially detrimental consequences: they slow gastric emptying, increasing the probability of aspiration; hyperosmolar solutions cause fluid influx into the duodenum, leading to hyperosmotic diarrhea and electrolyte depletion; and patient dehydration occurs, decreasing the ability of the kidney to dilute and excrete substances such as urea, sodium, potassium and chloride. Because of the potential for dehydration, water intake may need to be supplemented intravenously in high protein and elemental formulas to maintain a normal serum osmolality.
The macronutrient composition of an enteral formula is important, not only in meeting the needs of the patient, but because of its effect on GI tract function. Formulas that are calorie dense, especially those containing high amounts of fat, delay gastric emptying. In addition, patients who have not been fed enterally for some time may not tolerate these kinds of formulas initially.
As in TPN, the calorie to nitrogen ratio of enteral formulas is variable. For the stressed patient, formulas between 120 and 180 Kcal per gram of nitrogen are usually desirable. Lower ratios may be associated with increased amino acid deamination and elevated BUN.
The micronutrient content of most enteral formulas is known, so the patient's orders can provide for the estimated micronutrient requirements. For those patients with increased micronutrient needs, additional supplements can be administered via the feeding tube. A major problem in enteral tube feeding is that administration is often interrupted because of other procedures the patient requires. This means that less than the desired amount of micronutrients (and macronutrients) may be administered.
To Tube Feeding
As in TPN, clinical and anthropometric data are essential in monitoring the patient's response to tube feeding. Aspiration, diarrhea, bloating, constipation and the like can only be monitored clinically. Laboratory measurement of serum or urine osmolality and electrolytes may be helpful in monitoring some of these unfavorable effects.
The major contribution of the laboratory to the management of the enterally fed patients is in monitoring changes in the patient's nutrition status. Thus, laboratory monitoring of nitrogen balance, BUN and creatinine and protein-energy status by serum proteins gives the objective, quantitative data that can form the basis for effective monitoring of protein-energy status. Because of the possibility that some patients may require more or less micronutrients, and a patient may receive considerably less formula than ordered, serum vitamin C and zinc levels should be followed.
Tube feeding of patients after they leave the hospital is less hazardous than home-TPN because of the higher probability of infections in the latter. Protein-energy balance should be monitored regularly in the home tube-fed patient. The need for most other forms of monitoring should be individualized for each patient.
At the end of World War II, after prisoners of war (POWs) were liberated from concentration camps, they ate their first substantial amount of food in months. A significant number soon died.
This effect, called refeeding syndrome, can also occur in the hospital setting if patients with extremely poor protein-energy nutritional status are suddenly given nutrition support providing all the macronutrients they are calculated to need. During starvation, shortages of some minerals and vitamins (i.e., phosphorous, potassium, magnesium and thiamin) develop. Then when glucose and related compounds become available, body stores can't meet the demand for these vitamins and minerals for the production of new ATP and creatinine phosphate. This leads to redistribution of extracellular K+ into cellular fluids and ultimately to cardiac arrest. Nutrition support must be gradually introduced and K, Mg, phosphate must be frequently monitored by the lab during the first day or two of nutrition support.
While lab data is less useful or essential in nutrition screening or assessment, it provides a vital foundation for therapeutic nutrition monitoring. To improve patient nutrition care and decrease the costly effects of malnutrition in hospitalized patients, lab professionals need to become better versed in the causes of and treatment for malnutrition. The laboratory, in essence, must shift its emphasis from diagnosis to monitoring.
* About the author: Dr. Carlson manages the Clinical Nutrition Research Unit Laboratory Core, Department of Laboratory Medicine, University of Washington, Seattle.
1. Enteral tube feeding is sometimes referred to as enteral nutrition or enteral support. Technically, this terminology is incorrect because nutrients entering the body via the GI tract are forms of enteral nutrition. What is special about enteral tube feeding is that introduction of nutrient containing substances into the GI tract is via a tube connected to a syringe, pump or bag hung above the patient.
2. Inflammatory stress inhibits the synthesis of albumin and several other plasma proteins by down regulating albumin m-RNA synthesis. This is mediated by the release of cytokines from lymphocytes activated by tissue damage. The same mediators increase the synthesis of plasma proteins referred to as acute phase proteins. The latter are better termed positive acute phase proteins, and those (i.e., albumin) should be called negative acute phase proteins.