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Nutrition Support in Hospitalized Patients With Diabetes Mellitus
Concise Review for Primary-Care Physicians Nutrition Support in Hospitalized Patients With Diabetes Mellitus M. MOLLY McMAHON, M.D., AND ROBERT
A.
RIZZA, M.D.
Many physicians will manage the care of hospitalized patients with diabetes mellitus who require parenteral nutrition or enteral tube feeding. The nutritional assessment, indications for nutrition support, estimate of nutritional needs, and biochemical monitoring guidelines for critically ill patients with diabetes are similar to those for nondiabetic patients. In general, a weight loss of up to 10% of body weight is well tolerated and, in the absence of severe stress, the provision of dextrose-containing crystalloid solutions and electrolytes is adequate for as long as 7 to 10 days. Studies that demonstrate a beneficial influence of nutrition support on clinical outcome administered nutrition for a minimum of 1 week. No data have established that support for a briefer duration is of
Diabetes mellitus is a metabolic disorder caused by an absolute (insulin-dependent diabetes mellitus, type I) or a relative (non-insulin-dependent diabetes mellitus, type II, and stress diabetes mellitus) lack of insulin. Because of the prevalence of diabetes mellitus and the comorbidity of the disease, most physicians will treat hospitalized patients with diabetes. Hospitalizations are more frequent and of longer duration in patients with diabetes mellitus than in nondiabetic patients. Thus, many of these patients will require nutrition support. This review discusses the nutritional assessment, importance of glucose control, and design of nutrition programs for hospitalized patients with diabetes mellitus. BACKGROUND In nondiabetic subjects, the plasma glucose concentration is closely regulated in both the postabsorptive (overnight fasting state) and the postprandial periods. In the postabsorptive period, euglycemia is maintained because the rate of glucose release by the liver (glucose production) approximates the rate of glucose uptake (glucose utilization) by the liver, From the Division of Endocrinology/Metabolism and Internal Medicine, Mayo Clinic Rochester, Rochester, Minnesota. Address reprint requests to Dr. M. M. McMahon, Division of Endocrinology/Metabolism, Mayo Clinic Rochester, 200 First Street SW, Rochester, MN 55905. Mayo CUn Proc 1996; 71:587-594
clinical benefit. An important goal in the care of the hospitalized patient with diabetes is to avoid the extremes of hypoglycemia and hyperglycemia. Herein we provide our approach to achieving glucose control in stressed hospitalized patients with diabetes mellitus who are receiving parenteral and enteral nutrition. Although evidence is increasing that hyperglycemia impairs immune function, well-designed prospective randomized trials are needed to determine the risks, costs, and benefits of achieving glucose control and of providing nutrition support to hospitalized patients with diabetes mellitus. (Mayo Clin Proc 1996; 71:587-594) C3 =third component of complement; PN =parenteral nutrition
brain, and peripheral tissues. These rates average 2 mg/kg per minute in the nondiabetic subject or approximately 200 g per day in a 70-kg subject. After a meal (or infusion of hypertonic dextrose), the increase in plasma glucose and insulin suppresses hepatic glucose production and increases peripheral glucose uptake, a process that thereby decreases the amount of glucose that must be used by extrahepatic tissues. The postprandial glucose concentration rarely exceeds 150 mg/dL. As the plasma glucose and insulin concentrations decrease after a meal, the rates of hepatic glucose production and peripheral glucose uptake are restored to basal levels, an outcome that allows glucose production to increase and glucose uptake to decrease. The homeostatic mechanisms that maintain euglycemia in the postabsorptive state and buffer the postprandial glycemic excursion in nondiabetic subjects are impaired in patients with diabetes mellitus. These patients have both preprandial and postprandial hyperglycemia. The hyperglycemia is due to excessive hepatic glucose release, impaired glucose uptake, and decreased insulin secretion or action (or both). Severe stress can cause hyperglycemia to develop in patients without an antecedent diagnosis of diabetes mellitus. Severe stress (as during a serious illness) is accompanied by substantial increases in the plasma concentration of counterregulatory hormones (that is, glucagon, epinephrine, 587
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NUTRITION SUPPORT IN PATIENTS WITH DIABETES
cortisol, and growth hormone). These hormones cause hyperglycemia by increasing hepatic glucose production and by decreasing peripheral glucose uptake. Stress causes a greater derangement in glucose metabolism in patients with diabetes because they cannot increase insulin secretion as a compensatory response. The exaggerated glucose response after a stress dose counterregulatory hormone infusion in healthy subjects with diabetes in comparison with nondiabetic subjects is one explanation for the deterioration in glucose control that often occurs in ill patients with diabetes. Cytokines can also affect glucose homeostasis. In either instance, euglycemia can be maintained only by increasing insulin availability. NUTRITIONAL ASSESSMENT Protein catabolism (with eventual depletion of body protein) can be a consequence of starvation or severe illness. In the classic sense, malnutrition results from starvation. Nevertheless, either severe illness or illness superimposed on starvation is by far the most common cause of protein catabolism in hospitalized patients. The nutritional assessment, indications for nutrition support, and estimate of nutritional needs for critically ill patients with diabetes are similar to those for nondiabetic patients. Interpretation of the nutritional assessment of critically ill patients is enhanced by an understanding of the cytokine and hormonal milieu of sickness. Anorexia is common in patients with severe illness. Cytokine infusion has been shown to cause a considerable decrease in food intake. Of importance, illness and cytokines cause an acute decrease in plasma albumin. This decrease can be attributed to altered capillary permeability (allowing albumin to move from the intravascular to the extravascular space) and to an increase in catabolism. In addition, cytokines can downregulate the albumin gene and thereby decrease the rate of messenger RNA translation. Therefore, during severe illness, hypoalbuminemia is an excellent marker of the stress response but a poor marker of nutritional status. The importance of hypoalbuminemia is supported by studies reporting that hypoalbuminemia at hospital admission is associated with increased morbidity and mortality rates. Finally, although weight is often a key anthropometric marker, the weight of hospitalized patients must be carefully interpreted. Many critically ill patients have increased total body water and salt due to the underlying illness (for example, malnutrition or cardiac, renal, or hepatic diseases), the treatment (for example, crystalloid or colloid infusion), or the hormonal milieu of critical illness and refeeding. Thus, weight loss alone is not a requisite for initiation of nutrition support. In general, a recent (previous 3- to 6-month interval) weight loss in excess of 10% of the usual weight necessitates a thorough nutritional assessment. A recent unintentional
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weight loss of 10 to 20% of the usual weight suggests moderate protein-calorie malnutrition, and a loss of more than 20% usually indicates severe malnutrition. In addition to the magnitude of recent weight loss, the presence or absence of clinical markers of stress and the anticipated time that the patient will be unable to eat determine the need for nutrition intervention. Usually, a weight loss of up to 10% of body weight is well tolerated and, in the absence of severe stress, the provision of dextrose-containing crystalloid solutions and electrolytes is adequate for as long as 7 to 10 days. In studies that demonstrate a beneficial influence of nutrition support on clinical outcome, nutrition was administered for a minimum of 1 week. No data have established that nutrition support for a briefer duration is of clinical benefit. Identifying the functional effects of malnutrition should be emphasized. Patients with both recent weight loss and physiologic impairment of two organ systems have a significantly higher incidence of major complications, including sepsis and pneumonia, than do patients with recent weight loss but without evidence of physiologic dysfunction. In a group of patients with physiologic dysfunction, protein stores were diminished, as measured by in vivo neutron activation analysis. Once the decision has been made that nutrition support is necessary, the optimal route for nutrient delivery should be determined. In general, the enteral route is preferred for nutrient delivery if the gastrointestinal tract is functional. Advantages of enteral nutrition include lower cost, avoidance of central catheter-related complications, a more physiologic route, and its trophic effect on gastrointestinal cells. The parenteral route should be used when nutrition support is indicated in a patient with a nonfunctioning gastrointestinal tract. Parenteral nutrition (PN) may be infused peripherally or centrally. Peripheral PN avoids the risks of central venous catheterization, and it is generally used to provide up to 2 weeks of nutrition to mildly stressed, malnourished patients with low caloric requirements (for example, thin elderly patients) who can tolerate large amounts of fluid or to those in whom central access is not an option. Central PN is necessary for providing adequate nutrition to malnourished patients who are moderately or severely stressed, who require fluid-restricted nutrition programs, or who are anticipated to require PN for a long duration. A peripherally inserted central catheter (PICe) may be used to infuse central PN in selected patients if the catheter tip is in the superior vena cava. The daily energy expenditure of a hospitalized patient can be estimated by using a formula, such as the Harris-Benedict equation, by providing a certain number of kilocalories per kilogram of body weight, or by indirect calorimetry. The previous practice of estimating energy requirements of the stressed patient by multiplying the Harris-Benedict equation
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by a significant (for example, 1.5 to 1.75) "stress factor" has been challenged by studies comparing measured and estimated daily caloric expenditures. During the past decade, numerous studies have shown that the actual energy expenditure of most hospitalized patients is between 100 and 120% of predicted caloric expenditure with use of the Harris-Benedict equation (Table 1). No consensus exists about nutritional requirements of obese patients, and data are limited. Certain investigators recommend that, in obese patients, the weight used to estimate caloric requirements should be the weight halfway between the ideal and current weight. Outcome studies are needed to resolve this controversy. Avoidance of overfeeding is crucial in critically ill patients with diabetes because overfeeding can exacerbate hyperglycemia, cause abnormal liver function test results, and increase minute oxygen consumption and carbon dioxide production. The last two-mentioned factors may increase minute ventilation and the work of breathing in patients with impaired lung function. In general, the stressed patient with normal hepatic and renal function should receive approximately 1.5 g of protein per kilogram of body weight. Studies report that no greater sparing of protein occurs when exogenous protein is provided in amounts exceeding 1.5 g/kg per day. Parenteral lipids should be limited to approximately 30% of the total calories and provided continuously. Most complications (that is, impairment of the reticuloendothelial system clearance and immune function) related to the use of parenteral lipids occur at high infusion rates.
GLUCOSE GOALS A major goal in the care of the hospitalized patient with diabetes is to avoid the extremes of hyperglycemia and hypoglycemia. A reasonable goal is to attempt to maintain glucose levels between 100 and 200 mg/dL in stressed hospitalized patients. Once nutrition support has been established, more tightly regulated blood glucose concentrations (that is, 100 to 150 mg/dL) may be desirable in stable patients. Avoidance or minimization of hypoglycemia is important. Identifying neuroglycopenic and adrenergic symptoms of hypoglycemia is difficult in severely ill patients who are sedated or dependent on mechanical ventilation. In addition, patients with long-standing diabetes mellitus may experience development of hypoglycemic unawareness, a loss of the ability to recognize the warning symptoms of hypoglycemia. The physician should always attempt to identify the factor or factors responsible for hypoglycemia. Potential causes include unanticipated discontinuation of nutrition support, resolution of severe stress, discontinuation or decreased doses of corticosteroids or sympathomimetic agents, renal dysfunction, severe hepatitis, sepsis, and diabetic gastroparesis.
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Table I.-Guidelines for Calorie, Protein, and Lipid Requirements of Patients With Diabetes Calories*
Basal calories by using the Harris-Benedict equation] to Harris-Benedict plus 20%
Protein:j:
1.0 to 1.5 g/kg of body weight
Lipid
30% of total calories during 24 h
*Indirect measurement of daily caloric needs should be considered for the following groups of patients: severely stressed patients (for example, after closed-head injury, multiple trauma, severe bum), volume-overloaded patients in whom the "dry weight" estimate is uncertain, nutritionally supported patients in whom weaning from mechanical ventilation is difficult, morbidly obese patients, severely malnourished patients, or patients requiring home enteral or parenteral nutrition. tHarris-Benedict equation Men: 66.5 + (13.8 x wt [kg]) + (5.0 x ht [em]) - (6.8 x age [yr]) Women: 655 + (9.6 x wt [kg)) + (1.8 x ht [em]) - (4.7 x age [yr]) :j:Guidelines assume normal hepatic and renal function. Modified from McMahon MM, Famell MB, Murray MJ. Nutritional support of the critically ill patient. Mayo Clin Proc 1993; 68:911-920.
HYPERGLYCEMIA-EFFECTS ON FLUID BALANCE AND IMMUNE FUNCTION Avoidance or minimization of hyperglycemia is equally important. During a short-term period, hyperglycemia can adversely affect fluid balance and immune function. As the filtered load of glucose increases, it eventually exceeds tubular reabsorptive capacity. As a result, glucose remains in the tubular lumen and acts as an osmotic diuretic, increasing the urinary loss of electrolytes and water. In vitro studies confirm that hyperglycemia is associated with abnormalities in granulocyte adhesion, chemotaxis, phagocytosis, and intracellular killing. Phagocytic function can be corrected or substantially improved with control of blood glucose. Phagocytosis is a two-step process involving attachment and engulfment of the phagocytic particle. A coordinated sequence of events leads to the activation of microbicidal systems. One of the critical elements is a burst of oxidative metabolism that generates toxic products of oxygen, including hydrogen peroxide, superoxide anion, and hydroxyl radical. The respiratory burst enzyme is an NADPH (the reduced form of nicotinamide-adenine dinucleotide phosphate) enzyme that produces superoxide anion by transferring electrons from NADPH to oxygen. Neutrophils from patients with diabetes and hyperglycemia have decreased production of superoxide anion, as measured by chemiluminescence, and show improvement in superoxide production after a period of enhanced glucose control. A substantial decrease in the respiratory burst also occurs in neutrophils from healthy nondiabetic subjects after 30 minutes of in vitro exposure to glucose concentrations greater
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than 200 mg/dL. In comparison with control subjects, the basal levels of cytosolic calcium in polymorphonuclear cells of patients with diabetes are increased, whereas adenosine triphosphate content and phagocytic ability are decreased. A direct correlation was noted between cytosolic calcium concentration and fasting glucose levels. Three months of orally administered hypoglycemic agents improved glucose control, adenosine triphosphate content, and phagocytosis and decreased cytosolic calcium concentration. These results suggest that adequate glucose control is necessary for normal leukocyte function. Hyperglycemia can also impair complement function. The covalent attachment of the third component of complement (C3) to the microbial surface is a key determinant of phagocytic recognition. The opsonic process is regulated by the internal thiolester bond of C3, which connects a sulfhydryl group to an adjoining glutamyl residue. When complement is activated, a conformational change in the protein exposes the thiolester bond. If free hydroxyl or amino groups are present, the glutamyl carbonyl effects a transesterification reaction by which C3 binds in ester linkage with hydroxyl groups or in amide linkage with amino receptors. This serves as the basis for the opsonic attachment of complement to carbohydrate or amino groups on the surface of organisms. Hyperglycemia can impair the opsonic function of C3 because the binding of glucose to the biochemically active site of C3 inhibits the attachment of complement to the microbial surface and may impair opsonization. The association between hyperglycemia and infections with Candida albicans is well known. Certain unique properties of C. albicans promote its virulence in the presence of hyperglycemia. The yeast expresses a surface protein that is homologous with the a chain, but not with the ~ chain, of the neutrophil receptor for C3. Expression of the Candida surface protein increases as the glucose concentration increases from 0 to 360 mg/dL, with an abrupt increase in expression when the glucose concentration increases from 180 to 360 mg/dL. This surface protein can both impair phagocytosis by binding to the C3 ligand noncovalently and mediate adhesion of the yeast to endothelial surfaces. A growing body of clinical evidence has linked hyperglycemia to nosocomial infection in stressed hospitalized patients. First, the rate of central catheter-related infections is approximately 5 times higher in patients with diabetes receiving central PN in comparison with nondiabetic patients receiving the same nutrition. Second, hyperglycemia (plasma glucose concentration greater than 200 mg/dL) within 3 days after diagnosis is the most common risk factor for Candida infection. Third, a recent meta-analysis summarizing results from prospective randomized trials comparing parenteral with enteral nutrition in critically ill patients
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reported that significantly fewer enterally fed patients (in comparison with parenterally fed patients) experienced septic complications (16% versus 35%, respectively). Although the investigators concluded that the route of administration of nutrients was the key factor in the observed differences, hyperglycemia may have been an additional variable responsible for the increased infection rate. The mean glucose concentration at the conclusion of the study was 230 mg/dL in the parenterally fed patients in comparison with a mean of 130 mg/dL in the enterally fed group. Finally, a recent study suggested that hyperglycemia itself is an independent risk factor for the development of infection. Investigators who monitored perioperative glucose control in 100 previously uninfected patients with diabetes undergoing elective surgical treatment and the subsequent development of postoperative infection found that hyperglycemia (glucose level in excess of 220 mg/dL) on postoperative day I was associated with a high rate of infection. As with hypoglycemia, the cause or causes of hyperglycemia must be identified. Illness or infection, overfeeding (nutrition support plus dextrose-containing crystalloid plus dextrose absorption during peritoneal dialysis), medications (for example, corticosteroids, sympathomimetic infusion, and cyclosporine), insufficient insulin, or volume depletion (or some combination of these factors) can cause hyperglycemia. Because unexplained hyperglycemia may be a harbinger of infection, the central catheter should always be considered a potential source of infection. AN APPROACH TO THE MANAGEMENT OF PATIENTS WITH DIABETES MELLITUS RECEIVING PARENTERAL NUTRITION Many approaches can be used to achieve glucose control and to avoid the extremes of hypoglycemia and hyperglycemia in patients with diabetes who are receiving nutrition support. Our approach has evolved to fulfill the needs of an institution in which many physicians prescribe the nutrition. Dextrose in the PN is limited to approximately 200 g on the first day of nutrition (for example, 1L of 20% dextrose or 2 L of 10% dextrose). Most patients with diabetes require supplemental insulin when glucose is infused. For patients previously treated with insulin or oral hypoglycemic agents or for patients with a fasting glucose concentration greater than 200 mg/dL, the addition of a basal amount of human regular insulin to the dextrose-containing PN solutions is helpful. A common initial regimen is 0.1 units of insulin per gram of dextrose (for example, 15 units/L of 15% dextrose [150 gIL]; 20 units/L of 20% dextrose [200 gILD. This dose should be adjusted depending on the glucose concentrations (see sub-
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sequent discussion). In our experience, this ratio of insulin to dextrose is unlikely to cause hypoglycemia and thus minimizes the need to discard a bag of PN because it contains too much insulin. We measure glucose with use of a reflectance meter because the results are rapidly obtained and the need for venipuncture is avoided. A strenuous control program including meter calibration , personnel training, comparison measurements, and monitoring of results must be established, however, to ensure accuracy of results. Usually, we begin by measuring the glucose concentration at least every 4 to 6 hours. Subcutaneous regular insulin is typically administered on the basis of specific guidelines (Table 2) to supplement the insulin in the PN admixture. The recommended insulin dose should be doubled if the suggested dose does not result in a decrease in glucose toward goal levels. The dose of insulin in the PN admixture should be appropriately modified to maintain glucose concentrations in the goal range (see subsequent section). Once glucose concentrations are stable at the goal range (that is, 100 to 200 mg/dL), the frequency of measuring glucose concentrations often can be decreased. If during a 24-hour period, glucose values consistently exceed 200 mg/dL, the PN insulin is increased by 0.05 units of regular insulin per gram of dextrose each day. If the plasma glucose concentration remains greater than 200 mg/ dL despite insulin coverage of 0.2 units per gram of PN dextrose and adherence to the guidelines of subcutaneous administration of insulin, initiation of a separate intravenous variable insulin infusion may be helpful in achieving adequate glycemic control. Our group has found that a standardized insulin infusion order form facilitates this process (for infusion and guidelines for use, see Figure 1). In general, the dextrose content of the PN should not be increased until the glucose concentrations during the previous 24-hour period are consistently less than 200 mg/dL. Insulin in the PN should be proportionally increased or decreased when the PN dextrose content is increased or decreased. If hypoglycemia develops, parenteral dextrose should be administered (Table 3). The PN insulin content should be decreased by 50% to minimize the chance of recurrent hypoglycemia. Reductions in the PN insulin should be similar if the mean glucose concentration during a 24-hour period decreases to values below the goal range. In our experience, the incidence of symptomatic hypoglycemia after sudden discontinuation of PN is uncommon if the patient has not been infused with excess calories . Nevertheless, we recommend that, if the patient has a serum creatinine concentration greater than 2.0 mg/dL or if the PN admixture contains more than 0.2 units of insulin per gram of dextrose, the glucose concentration be monitored closely
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Table 2.- Guidelines for Subcutaneous Administration of Regular Insulin in Patients With Diabetes* Glucose (mg/dL)
Dose of regular insulin (units)
200-250 251-300 301-350 >350
2-3 4-6 6-9 8-12
*Adjustment may be necessary for differences
in patient weight, response to insulin, and treatment goals. Insulin should not be administered more often than every 4 hours.
(that is, every 10 to 15 minutes) during the first hour after discontinuation of PN.
AN APPROACH TO THE MANAGEMENT OF PATIENTS WITH DIABETES MELLITUS RECEIVING TUBE FEEDING Although subcutaneous administration of insulin aims to prevent hyperglycemia in patients receiving enteral calories, glycemic control may be difficult to achieve. Until the patient has been shown to tolerate tube feeding, intermediate-acting insulin should be used cautiously. Short-acting insulin is preferred in order to minimize the risk of hypoglycemia that could result from the continued absorption of insulin from NPH (isophane insulin suspension) or Lente (insulin zinc suspension ) preparations after unexpected discontinuation of tube feeding. Once the tube feeding infusion rate has reached 30 mL/h, the use of NPH or Lente insulin preparation intermediate-acting insulin generally is safe. If tube feedings will be administered during the day, we frequently begin by providing one-half of the patient' s preadmission morning insulin dose as intermediateacting insulin. Increases in the tube feeding infusion rate should be avoided until adequate glucose control has been achieved. Intermediate-acting insulin should be given in the evening if the tube feeding is administered during the night. Administration of intermediate-acting insulin twice daily may be necessary if the tube feedings are administered continuously for 24 hours. If the feedings are infused by gravity administration, the glucose concentration should be assessed immediately before the feeding is initiated and no sooner than 4 hours after the conclusion of the prior feeding. Although some patients receiving this type of feeding can be managed with intermediate-acting insulin alone, others will need combined treatment with intermediate-acting and short-acting insulin. The tube feeding rate should not be altered without appropriate adjustments being made in the insulin dose or doses.
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Glucose (mg/dL)
Infusion rate (mLIh)
>400 351-400 301-350 250-300 200-249 150-199 120-149 100-119 70-99 <70
8 6 4 3 2.5 2 1.5 I
0 0
Insulin infusion rate (units/h)
8 6 4 3 2.5 2 1.5 1 0 0
• Guidelines are for average 70-kg patient, and modificationmay be necessary for smaller or larger patients. Guidelines are not appropriatefor treatment of patients with diabetic ketoacidosisor hyperosmolarstates. • Glucosegoals should be determinedfor each patient. In stressed patients,glucose goal range of 100-200mg/dL is appropriate. • Glucose should be measured hourly until glucose concentrationshave stabilized in patient's goal range for 4 hours. Frequencyof testing may then be decreased to every 2 hours, and once glucose control remains stable, testing can be done every 4 hours. • If hyperglycemiapersists, for each glucose range greater than 200 mg/dL, insulin infusion may be adjusted by 50% increments. Risk of hypoglycemiamay be greater if guidelines are increased for glucose ranges less than 200 mg/dL. • In patients with hyperglycemiatreated with insulin, plasma potassium, magnesium,and phosphorusconcentrationsmay decreaserapidly and should be monitored. • At the time of conversionfrom intravenous to subcutaneousinsulin therapy, intravenousinfusion shouldbe continuedfor 1 to 3 hours after administrationof first subcutaneous insulin dose. Fig. 1. Guidelines for intravenousinsulin infusion in patients with diabetes mellitus. Gastroparesis may make tolerance of tube feeding difficult. In our experience, most patients with diabetic gastroparesis tolerate jejunal feedings when iso-osmolar formulas are initiated at a low rate (for example, 20 mL/h) and advanced slowly (for example, a 10 to 20 mL/h increment every 12 hours) to the goal infusion rate. Unexpected discontinuation of tube feeding may cause hypoglycemia in patients who are treated with subcutaneous injections of insulin. Glucose levels should be carefully monitored to determine whether intravenous infusion of a dextrose-containing solution is necessary to prevent subsequent hypoglycemia. Oral hypoglycemic agents administered by a feeding tube may be used to treat hyperglycemia in medically stable patients who have well-controlled non-insulindependent diabetes mellitus and normal renal and hepatic function. We do not recommend the use of metformin in this group of patients. A major (although very uncommon) risk of metformin is lactic acidosis, which can occur in pa-
tients with hepatic or renal disease or in patients with tissue ischemia. In patients with unstable diabetes mellitus and severe hyperglycemia, an intravenous insulin infusion may be necessary.
EFFECTS OF NEW ENTERAL FORMULAS The recent availability of enteral formulas that are lower in carbohydrates and higher in fat content than standard formulas has prompted studies examining the effects on glycemic control. Although initial studies suggested that the glycemic response to the lower carbohydrate product was blunted in comparison with standard formulas, a follow-up study indicated that the glycemic response was variable in each patient. The clinical significance of these studies is unclear because the subjects ingested very small amounts of formula over a few hours, an extremely different pattern than the usual continuous or gravity administration of tube feeding. In addition, the high fat content could impair gastric empty-
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Table 3.-Guidelines for Nurses in the Treatment of Hypoglycemia in Hospitalized Patients With Diabetes I. Presumed symptomatic hypoglycemia should be treated without waiting to determine glucose level A. If patient is able to swallow safely, approximately IS g of glucose should be given orally. Examples include the following: I. 2 sugar packets or cubes or 2. IS g of glucose tablets or gel or 3. '/2 cup (4 oz) of fruit juice B. If patient is unable to take oral feeding safely or if oral intake is restricted, the following should be administered: 1. If intravenous access is available, 1/2 ampule (12.5 g) of 50% dextrose in water intravenously 2. If no intravenous access is present, I mg of glucagon by subcutaneous or intramuscular injection C. Contact physician II. For treatment of asymptomatic hypoglycemia (glucose :0;60 mg/dL), points A through C should be followed III. Glycemic monitoring after treatment: Capillary glucose level should be reassessed in 15 minutes. If glucose concentration is <80 mg/dL, treatment should be repeated, and glucose level should be monitored. Treatment should be repeated until glucose concentration is >80mg/dL
ing in patients with gastroparesis. With regard to fiber content, the current American Diabetes Association position statement on nutrition reports that, although selected soluble fibers are capable of delaying glucose absorption from the small intestine, the effect of dietary fiber on glycemic control is probably insignificant. Therefore, the fiber intake recommendations for patients with diabetes are probably the same as for the general hospitalized population. During hospitalization, avoidance of overfeeding is likely more important than is the use of a specific enteral formula. Outcome studies are necessary to address this issue.
MONITORING The initiation of nutrition support in a malnourished patient with diabetes requires careful monitoring of vital signs, hemodynamic data, weight, fluid balance, plasma glucose and electrolytes, and acid-base status. A baseline glycated hemoglobin value is useful for establishing recent glucose control and for determining appropriate diabetic treatment after hospital dismissal. The presence of fever is always important in a patient with a central catheter. Hemodynamic data, fluid balance, creatinine, urea, and serum sodium should be reviewed to determine the appropriate volume of nutrition. Daily weight should be interpreted in light of the fluid balance. In general, a weight increase in excess of 0.25 kg during a 24-hour period should be attributed to fluid gain rather than to accretion of lean tissue.
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Knowledge of the electrolyte and mineral content of gastrointestinal and renal losses facilitates appropriate supplementation of these additives to the standard PN. PN admixtures should not, however, be used to treat acute metabolic abnormalities. Although the extent and frequency of biochemical monitoring after initiation of nutrition support should be individualized, the minimal approach is to assess plasma glucose, electrolytes, and phosphorus concentrations until stable. Hyperglycemia may cause a pseudohyponatremia. In general, every 62 mg/dL increment in the plasma glucose level will decrease the plasma sodium concentration by 1 mEq/L. Hyperkalemia, if accompanied by hyperglycemia, may be effectively treated by an increase in insulin supplementation. Hyperinsulinemia due to refeeding or insulin supplementation may lead to a decrease in the plasma levels of potassium, magnesium, and phosphorus. Hyperinsulinemia shifts potassium and magnesium into skeletal muscle and hepatic cells. Glucose- and insulin-stimulated glycolysis enhances the cellular uptake and utilization of phosphorus for the phosphorylation of glucose and fructose and for the synthesis of adenosine triphosphate. Serum potassium, magnesium, and phosphorus concentrations should be monitored daily (and appropriately managed) until the levels are in the normal range. For selected patients receiving nutrition support, triglycerides should be assessed before and after initiation of nutrition support. Monitoring is important in patients with poorly controlled diabetes mellitus, dyslipidemia, or pancreatitis. Data on infusion of lipids in patients with hypertriglyceridemia are limited. In our practice, if the plasma triglyceride concentration exceeds 400 mg/dL, the lipid infusion is discontinued or not administered. A review of the patient's medications is important to ascertain that the patient is not receiving supplemental lipids. For example, the intravenous anesthetic agent propofol is formulated in a lipid emulsion.
CONCLUSION For short-term hospitalization, the principles underlying nutritional assessment and design of nutrition programs for patients with diabetes are similar to those for nondiabetic patients. Of importance, the extremes of hypoglycemia and hyperglycemia should be avoided. Although evidence is increasing that hyperglycemia impairs immune function, well-designed prospective randomized trials are needed to determine the risks, costs, and benefits of achieving glucose control and of providing nutrition support to malnourished patients with diabetes mellitus. ACKNOWLEDGMENT We acknowledge the contributions of physicians in the nutrition and diabetes core groups.
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BIBLIOGRAPHY 1. Bagdade JD, Stewart M, Walters E. Impaired granulocyte
adherence: a reversible defect in host defense in patients with poorly controlleddiabetes. Diabetes 1978; 27:677-681 2. Baxter JK, Babineau TJ, Apovian CM, Elsen RJ, Driscoll DF, Forse RA, et al. Perioperative glucose control predicts increased nosocomial infectionin diabetics [abstract]. Crit Care Med 1990; 18(Supp1):S207 3. Bell PM, Firth RG, Rizza RA. Assessment of insulinaction in insulin-dependent diabetes mellitus using [61 4C]glucose, [33H]glucose, and [23H]glucose: differences in the apparent pattern of insulin resistance depending on the isotope used. J Clin Invest 1986;78:1479-1486 4. Hostetter MK. Handicaps to host defense: effects of hyperglycemia on C3 and Candida albicans. Diabetes 1990; 39:271-275
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5. McMahonMM. Parenteralnutrition. In: Bennett JC, Plum F, editors. Cecil Textbook of Medicine. 20th ed. Philadelphia: Saunders, 1996: 1171-1175 6. McMahon MM, Bistrian BR. Host defenses and susceptibility to infection in patients with diabetes mellitus. Infect Dis Clin North Am 1995Mar; 9:1-9 7. McMahon MM, Bistrian BR. The physiology of nutritional assessment and therapy in protein-calorie malnutrition. Dis Mon 1990; 36:373-417 8. OrtmeyerJ, MohseninV. Glucose suppressessuperoxide generation in normal neutrophils: interferencein phospholipase D activation. Am J Physio1 1993; 264:C402-C410 9. Schade DS, Santiago JV, Skyler JS, Rizza RA. Intensive Insulin Therapy. Amsterdam: Excerpta Medica, 1983: 3638
Questions About Nutrition Support in Hospitalized Patients With Diabetes (See article, pages 587 to 594)
1. Considering that a major goal in the care of the critically ill patient is to avoid the extremes of hypoglycemia and hyperglycemia, which one of the following glucose levels is most reasonable in these patients? a. b. c. d. e.
80-120 mg/dL 100-200 mg/dL 200-300 mg/dL 250-300 mg/dL 300-350 mg/dL
2. Which one of the following is a potential cause of hyperglycemia? a. b. c. d. e.
Resolution of severe stress Severe hepatitis Infection Renal dysfunction Discontinuation of corticosteroids
3. Which one of the following is most likely to occur as a result of overfeeding in critically ill patients with diabetes? a. b. c. d. e.
5. Which one of the following principles should be followed to achieve adequate glucose control in stressed patients with diabetes receiving tube feeding? a. Until the patient has been shown to tolerate tube feeding, intermediate-acting insulin is preferred rather than short-acting insulin to achieve glucose control b. Until the patient has been shown to tolerate tube feeding, short-acting insulin is preferred rather than intermediate-acting insulin to achieve glucose control c. Glucose should be routinely assessed 1 hour after initiation of gravity feeding d. The tube feeding route may be altered without appropriate adjustments being made in the insulin dose e. Oral hypoglycemic agents should never be used to treat medically stable patients with well-controlled diabetes mellitus and normal hepatic and renal function
Decreased carbon dioxide production Hypoglycemia Hyperglycemia Acid-base imbalance Decreased oxygen consumption
4. Which one of the following types of insulin should be added to parenteral nutrition admixture? a. b. c. d. e.
NPH Lente Regular Ultralente Semilente
Correct answers: 1. b, 2. c, 3. c, 4. c, 5. b
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A.
RIZZA, M.D.
Many physicians will manage the care of hospitalized patients with diabetes mellitus who require parenteral nutrition or enteral tube feeding. The nutritional assessment, indications for nutrition support, estimate of nutritional needs, and biochemical monitoring guidelines for critically ill patients with diabetes are similar to those for nondiabetic patients. In general, a weight loss of up to 10% of body weight is well tolerated and, in the absence of severe stress, the provision of dextrose-containing crystalloid solutions and electrolytes is adequate for as long as 7 to 10 days. Studies that demonstrate a beneficial influence of nutrition support on clinical outcome administered nutrition for a minimum of 1 week. No data have established that support for a briefer duration is of
Diabetes mellitus is a metabolic disorder caused by an absolute (insulin-dependent diabetes mellitus, type I) or a relative (non-insulin-dependent diabetes mellitus, type II, and stress diabetes mellitus) lack of insulin. Because of the prevalence of diabetes mellitus and the comorbidity of the disease, most physicians will treat hospitalized patients with diabetes. Hospitalizations are more frequent and of longer duration in patients with diabetes mellitus than in nondiabetic patients. Thus, many of these patients will require nutrition support. This review discusses the nutritional assessment, importance of glucose control, and design of nutrition programs for hospitalized patients with diabetes mellitus. BACKGROUND In nondiabetic subjects, the plasma glucose concentration is closely regulated in both the postabsorptive (overnight fasting state) and the postprandial periods. In the postabsorptive period, euglycemia is maintained because the rate of glucose release by the liver (glucose production) approximates the rate of glucose uptake (glucose utilization) by the liver, From the Division of Endocrinology/Metabolism and Internal Medicine, Mayo Clinic Rochester, Rochester, Minnesota. Address reprint requests to Dr. M. M. McMahon, Division of Endocrinology/Metabolism, Mayo Clinic Rochester, 200 First Street SW, Rochester, MN 55905. Mayo CUn Proc 1996; 71:587-594
clinical benefit. An important goal in the care of the hospitalized patient with diabetes is to avoid the extremes of hypoglycemia and hyperglycemia. Herein we provide our approach to achieving glucose control in stressed hospitalized patients with diabetes mellitus who are receiving parenteral and enteral nutrition. Although evidence is increasing that hyperglycemia impairs immune function, well-designed prospective randomized trials are needed to determine the risks, costs, and benefits of achieving glucose control and of providing nutrition support to hospitalized patients with diabetes mellitus. (Mayo Clin Proc 1996; 71:587-594) C3 =third component of complement; PN =parenteral nutrition
brain, and peripheral tissues. These rates average 2 mg/kg per minute in the nondiabetic subject or approximately 200 g per day in a 70-kg subject. After a meal (or infusion of hypertonic dextrose), the increase in plasma glucose and insulin suppresses hepatic glucose production and increases peripheral glucose uptake, a process that thereby decreases the amount of glucose that must be used by extrahepatic tissues. The postprandial glucose concentration rarely exceeds 150 mg/dL. As the plasma glucose and insulin concentrations decrease after a meal, the rates of hepatic glucose production and peripheral glucose uptake are restored to basal levels, an outcome that allows glucose production to increase and glucose uptake to decrease. The homeostatic mechanisms that maintain euglycemia in the postabsorptive state and buffer the postprandial glycemic excursion in nondiabetic subjects are impaired in patients with diabetes mellitus. These patients have both preprandial and postprandial hyperglycemia. The hyperglycemia is due to excessive hepatic glucose release, impaired glucose uptake, and decreased insulin secretion or action (or both). Severe stress can cause hyperglycemia to develop in patients without an antecedent diagnosis of diabetes mellitus. Severe stress (as during a serious illness) is accompanied by substantial increases in the plasma concentration of counterregulatory hormones (that is, glucagon, epinephrine, 587
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NUTRITION SUPPORT IN PATIENTS WITH DIABETES
cortisol, and growth hormone). These hormones cause hyperglycemia by increasing hepatic glucose production and by decreasing peripheral glucose uptake. Stress causes a greater derangement in glucose metabolism in patients with diabetes because they cannot increase insulin secretion as a compensatory response. The exaggerated glucose response after a stress dose counterregulatory hormone infusion in healthy subjects with diabetes in comparison with nondiabetic subjects is one explanation for the deterioration in glucose control that often occurs in ill patients with diabetes. Cytokines can also affect glucose homeostasis. In either instance, euglycemia can be maintained only by increasing insulin availability. NUTRITIONAL ASSESSMENT Protein catabolism (with eventual depletion of body protein) can be a consequence of starvation or severe illness. In the classic sense, malnutrition results from starvation. Nevertheless, either severe illness or illness superimposed on starvation is by far the most common cause of protein catabolism in hospitalized patients. The nutritional assessment, indications for nutrition support, and estimate of nutritional needs for critically ill patients with diabetes are similar to those for nondiabetic patients. Interpretation of the nutritional assessment of critically ill patients is enhanced by an understanding of the cytokine and hormonal milieu of sickness. Anorexia is common in patients with severe illness. Cytokine infusion has been shown to cause a considerable decrease in food intake. Of importance, illness and cytokines cause an acute decrease in plasma albumin. This decrease can be attributed to altered capillary permeability (allowing albumin to move from the intravascular to the extravascular space) and to an increase in catabolism. In addition, cytokines can downregulate the albumin gene and thereby decrease the rate of messenger RNA translation. Therefore, during severe illness, hypoalbuminemia is an excellent marker of the stress response but a poor marker of nutritional status. The importance of hypoalbuminemia is supported by studies reporting that hypoalbuminemia at hospital admission is associated with increased morbidity and mortality rates. Finally, although weight is often a key anthropometric marker, the weight of hospitalized patients must be carefully interpreted. Many critically ill patients have increased total body water and salt due to the underlying illness (for example, malnutrition or cardiac, renal, or hepatic diseases), the treatment (for example, crystalloid or colloid infusion), or the hormonal milieu of critical illness and refeeding. Thus, weight loss alone is not a requisite for initiation of nutrition support. In general, a recent (previous 3- to 6-month interval) weight loss in excess of 10% of the usual weight necessitates a thorough nutritional assessment. A recent unintentional
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weight loss of 10 to 20% of the usual weight suggests moderate protein-calorie malnutrition, and a loss of more than 20% usually indicates severe malnutrition. In addition to the magnitude of recent weight loss, the presence or absence of clinical markers of stress and the anticipated time that the patient will be unable to eat determine the need for nutrition intervention. Usually, a weight loss of up to 10% of body weight is well tolerated and, in the absence of severe stress, the provision of dextrose-containing crystalloid solutions and electrolytes is adequate for as long as 7 to 10 days. In studies that demonstrate a beneficial influence of nutrition support on clinical outcome, nutrition was administered for a minimum of 1 week. No data have established that nutrition support for a briefer duration is of clinical benefit. Identifying the functional effects of malnutrition should be emphasized. Patients with both recent weight loss and physiologic impairment of two organ systems have a significantly higher incidence of major complications, including sepsis and pneumonia, than do patients with recent weight loss but without evidence of physiologic dysfunction. In a group of patients with physiologic dysfunction, protein stores were diminished, as measured by in vivo neutron activation analysis. Once the decision has been made that nutrition support is necessary, the optimal route for nutrient delivery should be determined. In general, the enteral route is preferred for nutrient delivery if the gastrointestinal tract is functional. Advantages of enteral nutrition include lower cost, avoidance of central catheter-related complications, a more physiologic route, and its trophic effect on gastrointestinal cells. The parenteral route should be used when nutrition support is indicated in a patient with a nonfunctioning gastrointestinal tract. Parenteral nutrition (PN) may be infused peripherally or centrally. Peripheral PN avoids the risks of central venous catheterization, and it is generally used to provide up to 2 weeks of nutrition to mildly stressed, malnourished patients with low caloric requirements (for example, thin elderly patients) who can tolerate large amounts of fluid or to those in whom central access is not an option. Central PN is necessary for providing adequate nutrition to malnourished patients who are moderately or severely stressed, who require fluid-restricted nutrition programs, or who are anticipated to require PN for a long duration. A peripherally inserted central catheter (PICe) may be used to infuse central PN in selected patients if the catheter tip is in the superior vena cava. The daily energy expenditure of a hospitalized patient can be estimated by using a formula, such as the Harris-Benedict equation, by providing a certain number of kilocalories per kilogram of body weight, or by indirect calorimetry. The previous practice of estimating energy requirements of the stressed patient by multiplying the Harris-Benedict equation
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by a significant (for example, 1.5 to 1.75) "stress factor" has been challenged by studies comparing measured and estimated daily caloric expenditures. During the past decade, numerous studies have shown that the actual energy expenditure of most hospitalized patients is between 100 and 120% of predicted caloric expenditure with use of the Harris-Benedict equation (Table 1). No consensus exists about nutritional requirements of obese patients, and data are limited. Certain investigators recommend that, in obese patients, the weight used to estimate caloric requirements should be the weight halfway between the ideal and current weight. Outcome studies are needed to resolve this controversy. Avoidance of overfeeding is crucial in critically ill patients with diabetes because overfeeding can exacerbate hyperglycemia, cause abnormal liver function test results, and increase minute oxygen consumption and carbon dioxide production. The last two-mentioned factors may increase minute ventilation and the work of breathing in patients with impaired lung function. In general, the stressed patient with normal hepatic and renal function should receive approximately 1.5 g of protein per kilogram of body weight. Studies report that no greater sparing of protein occurs when exogenous protein is provided in amounts exceeding 1.5 g/kg per day. Parenteral lipids should be limited to approximately 30% of the total calories and provided continuously. Most complications (that is, impairment of the reticuloendothelial system clearance and immune function) related to the use of parenteral lipids occur at high infusion rates.
GLUCOSE GOALS A major goal in the care of the hospitalized patient with diabetes is to avoid the extremes of hyperglycemia and hypoglycemia. A reasonable goal is to attempt to maintain glucose levels between 100 and 200 mg/dL in stressed hospitalized patients. Once nutrition support has been established, more tightly regulated blood glucose concentrations (that is, 100 to 150 mg/dL) may be desirable in stable patients. Avoidance or minimization of hypoglycemia is important. Identifying neuroglycopenic and adrenergic symptoms of hypoglycemia is difficult in severely ill patients who are sedated or dependent on mechanical ventilation. In addition, patients with long-standing diabetes mellitus may experience development of hypoglycemic unawareness, a loss of the ability to recognize the warning symptoms of hypoglycemia. The physician should always attempt to identify the factor or factors responsible for hypoglycemia. Potential causes include unanticipated discontinuation of nutrition support, resolution of severe stress, discontinuation or decreased doses of corticosteroids or sympathomimetic agents, renal dysfunction, severe hepatitis, sepsis, and diabetic gastroparesis.
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Table I.-Guidelines for Calorie, Protein, and Lipid Requirements of Patients With Diabetes Calories*
Basal calories by using the Harris-Benedict equation] to Harris-Benedict plus 20%
Protein:j:
1.0 to 1.5 g/kg of body weight
Lipid
30% of total calories during 24 h
*Indirect measurement of daily caloric needs should be considered for the following groups of patients: severely stressed patients (for example, after closed-head injury, multiple trauma, severe bum), volume-overloaded patients in whom the "dry weight" estimate is uncertain, nutritionally supported patients in whom weaning from mechanical ventilation is difficult, morbidly obese patients, severely malnourished patients, or patients requiring home enteral or parenteral nutrition. tHarris-Benedict equation Men: 66.5 + (13.8 x wt [kg]) + (5.0 x ht [em]) - (6.8 x age [yr]) Women: 655 + (9.6 x wt [kg)) + (1.8 x ht [em]) - (4.7 x age [yr]) :j:Guidelines assume normal hepatic and renal function. Modified from McMahon MM, Famell MB, Murray MJ. Nutritional support of the critically ill patient. Mayo Clin Proc 1993; 68:911-920.
HYPERGLYCEMIA-EFFECTS ON FLUID BALANCE AND IMMUNE FUNCTION Avoidance or minimization of hyperglycemia is equally important. During a short-term period, hyperglycemia can adversely affect fluid balance and immune function. As the filtered load of glucose increases, it eventually exceeds tubular reabsorptive capacity. As a result, glucose remains in the tubular lumen and acts as an osmotic diuretic, increasing the urinary loss of electrolytes and water. In vitro studies confirm that hyperglycemia is associated with abnormalities in granulocyte adhesion, chemotaxis, phagocytosis, and intracellular killing. Phagocytic function can be corrected or substantially improved with control of blood glucose. Phagocytosis is a two-step process involving attachment and engulfment of the phagocytic particle. A coordinated sequence of events leads to the activation of microbicidal systems. One of the critical elements is a burst of oxidative metabolism that generates toxic products of oxygen, including hydrogen peroxide, superoxide anion, and hydroxyl radical. The respiratory burst enzyme is an NADPH (the reduced form of nicotinamide-adenine dinucleotide phosphate) enzyme that produces superoxide anion by transferring electrons from NADPH to oxygen. Neutrophils from patients with diabetes and hyperglycemia have decreased production of superoxide anion, as measured by chemiluminescence, and show improvement in superoxide production after a period of enhanced glucose control. A substantial decrease in the respiratory burst also occurs in neutrophils from healthy nondiabetic subjects after 30 minutes of in vitro exposure to glucose concentrations greater
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than 200 mg/dL. In comparison with control subjects, the basal levels of cytosolic calcium in polymorphonuclear cells of patients with diabetes are increased, whereas adenosine triphosphate content and phagocytic ability are decreased. A direct correlation was noted between cytosolic calcium concentration and fasting glucose levels. Three months of orally administered hypoglycemic agents improved glucose control, adenosine triphosphate content, and phagocytosis and decreased cytosolic calcium concentration. These results suggest that adequate glucose control is necessary for normal leukocyte function. Hyperglycemia can also impair complement function. The covalent attachment of the third component of complement (C3) to the microbial surface is a key determinant of phagocytic recognition. The opsonic process is regulated by the internal thiolester bond of C3, which connects a sulfhydryl group to an adjoining glutamyl residue. When complement is activated, a conformational change in the protein exposes the thiolester bond. If free hydroxyl or amino groups are present, the glutamyl carbonyl effects a transesterification reaction by which C3 binds in ester linkage with hydroxyl groups or in amide linkage with amino receptors. This serves as the basis for the opsonic attachment of complement to carbohydrate or amino groups on the surface of organisms. Hyperglycemia can impair the opsonic function of C3 because the binding of glucose to the biochemically active site of C3 inhibits the attachment of complement to the microbial surface and may impair opsonization. The association between hyperglycemia and infections with Candida albicans is well known. Certain unique properties of C. albicans promote its virulence in the presence of hyperglycemia. The yeast expresses a surface protein that is homologous with the a chain, but not with the ~ chain, of the neutrophil receptor for C3. Expression of the Candida surface protein increases as the glucose concentration increases from 0 to 360 mg/dL, with an abrupt increase in expression when the glucose concentration increases from 180 to 360 mg/dL. This surface protein can both impair phagocytosis by binding to the C3 ligand noncovalently and mediate adhesion of the yeast to endothelial surfaces. A growing body of clinical evidence has linked hyperglycemia to nosocomial infection in stressed hospitalized patients. First, the rate of central catheter-related infections is approximately 5 times higher in patients with diabetes receiving central PN in comparison with nondiabetic patients receiving the same nutrition. Second, hyperglycemia (plasma glucose concentration greater than 200 mg/dL) within 3 days after diagnosis is the most common risk factor for Candida infection. Third, a recent meta-analysis summarizing results from prospective randomized trials comparing parenteral with enteral nutrition in critically ill patients
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reported that significantly fewer enterally fed patients (in comparison with parenterally fed patients) experienced septic complications (16% versus 35%, respectively). Although the investigators concluded that the route of administration of nutrients was the key factor in the observed differences, hyperglycemia may have been an additional variable responsible for the increased infection rate. The mean glucose concentration at the conclusion of the study was 230 mg/dL in the parenterally fed patients in comparison with a mean of 130 mg/dL in the enterally fed group. Finally, a recent study suggested that hyperglycemia itself is an independent risk factor for the development of infection. Investigators who monitored perioperative glucose control in 100 previously uninfected patients with diabetes undergoing elective surgical treatment and the subsequent development of postoperative infection found that hyperglycemia (glucose level in excess of 220 mg/dL) on postoperative day I was associated with a high rate of infection. As with hypoglycemia, the cause or causes of hyperglycemia must be identified. Illness or infection, overfeeding (nutrition support plus dextrose-containing crystalloid plus dextrose absorption during peritoneal dialysis), medications (for example, corticosteroids, sympathomimetic infusion, and cyclosporine), insufficient insulin, or volume depletion (or some combination of these factors) can cause hyperglycemia. Because unexplained hyperglycemia may be a harbinger of infection, the central catheter should always be considered a potential source of infection. AN APPROACH TO THE MANAGEMENT OF PATIENTS WITH DIABETES MELLITUS RECEIVING PARENTERAL NUTRITION Many approaches can be used to achieve glucose control and to avoid the extremes of hypoglycemia and hyperglycemia in patients with diabetes who are receiving nutrition support. Our approach has evolved to fulfill the needs of an institution in which many physicians prescribe the nutrition. Dextrose in the PN is limited to approximately 200 g on the first day of nutrition (for example, 1L of 20% dextrose or 2 L of 10% dextrose). Most patients with diabetes require supplemental insulin when glucose is infused. For patients previously treated with insulin or oral hypoglycemic agents or for patients with a fasting glucose concentration greater than 200 mg/dL, the addition of a basal amount of human regular insulin to the dextrose-containing PN solutions is helpful. A common initial regimen is 0.1 units of insulin per gram of dextrose (for example, 15 units/L of 15% dextrose [150 gIL]; 20 units/L of 20% dextrose [200 gILD. This dose should be adjusted depending on the glucose concentrations (see sub-
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sequent discussion). In our experience, this ratio of insulin to dextrose is unlikely to cause hypoglycemia and thus minimizes the need to discard a bag of PN because it contains too much insulin. We measure glucose with use of a reflectance meter because the results are rapidly obtained and the need for venipuncture is avoided. A strenuous control program including meter calibration , personnel training, comparison measurements, and monitoring of results must be established, however, to ensure accuracy of results. Usually, we begin by measuring the glucose concentration at least every 4 to 6 hours. Subcutaneous regular insulin is typically administered on the basis of specific guidelines (Table 2) to supplement the insulin in the PN admixture. The recommended insulin dose should be doubled if the suggested dose does not result in a decrease in glucose toward goal levels. The dose of insulin in the PN admixture should be appropriately modified to maintain glucose concentrations in the goal range (see subsequent section). Once glucose concentrations are stable at the goal range (that is, 100 to 200 mg/dL), the frequency of measuring glucose concentrations often can be decreased. If during a 24-hour period, glucose values consistently exceed 200 mg/dL, the PN insulin is increased by 0.05 units of regular insulin per gram of dextrose each day. If the plasma glucose concentration remains greater than 200 mg/ dL despite insulin coverage of 0.2 units per gram of PN dextrose and adherence to the guidelines of subcutaneous administration of insulin, initiation of a separate intravenous variable insulin infusion may be helpful in achieving adequate glycemic control. Our group has found that a standardized insulin infusion order form facilitates this process (for infusion and guidelines for use, see Figure 1). In general, the dextrose content of the PN should not be increased until the glucose concentrations during the previous 24-hour period are consistently less than 200 mg/dL. Insulin in the PN should be proportionally increased or decreased when the PN dextrose content is increased or decreased. If hypoglycemia develops, parenteral dextrose should be administered (Table 3). The PN insulin content should be decreased by 50% to minimize the chance of recurrent hypoglycemia. Reductions in the PN insulin should be similar if the mean glucose concentration during a 24-hour period decreases to values below the goal range. In our experience, the incidence of symptomatic hypoglycemia after sudden discontinuation of PN is uncommon if the patient has not been infused with excess calories . Nevertheless, we recommend that, if the patient has a serum creatinine concentration greater than 2.0 mg/dL or if the PN admixture contains more than 0.2 units of insulin per gram of dextrose, the glucose concentration be monitored closely
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Table 2.- Guidelines for Subcutaneous Administration of Regular Insulin in Patients With Diabetes* Glucose (mg/dL)
Dose of regular insulin (units)
200-250 251-300 301-350 >350
2-3 4-6 6-9 8-12
*Adjustment may be necessary for differences
in patient weight, response to insulin, and treatment goals. Insulin should not be administered more often than every 4 hours.
(that is, every 10 to 15 minutes) during the first hour after discontinuation of PN.
AN APPROACH TO THE MANAGEMENT OF PATIENTS WITH DIABETES MELLITUS RECEIVING TUBE FEEDING Although subcutaneous administration of insulin aims to prevent hyperglycemia in patients receiving enteral calories, glycemic control may be difficult to achieve. Until the patient has been shown to tolerate tube feeding, intermediate-acting insulin should be used cautiously. Short-acting insulin is preferred in order to minimize the risk of hypoglycemia that could result from the continued absorption of insulin from NPH (isophane insulin suspension) or Lente (insulin zinc suspension ) preparations after unexpected discontinuation of tube feeding. Once the tube feeding infusion rate has reached 30 mL/h, the use of NPH or Lente insulin preparation intermediate-acting insulin generally is safe. If tube feedings will be administered during the day, we frequently begin by providing one-half of the patient' s preadmission morning insulin dose as intermediateacting insulin. Increases in the tube feeding infusion rate should be avoided until adequate glucose control has been achieved. Intermediate-acting insulin should be given in the evening if the tube feeding is administered during the night. Administration of intermediate-acting insulin twice daily may be necessary if the tube feedings are administered continuously for 24 hours. If the feedings are infused by gravity administration, the glucose concentration should be assessed immediately before the feeding is initiated and no sooner than 4 hours after the conclusion of the prior feeding. Although some patients receiving this type of feeding can be managed with intermediate-acting insulin alone, others will need combined treatment with intermediate-acting and short-acting insulin. The tube feeding rate should not be altered without appropriate adjustments being made in the insulin dose or doses.
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Glucose (mg/dL)
Infusion rate (mLIh)
>400 351-400 301-350 250-300 200-249 150-199 120-149 100-119 70-99 <70
8 6 4 3 2.5 2 1.5 I
0 0
Insulin infusion rate (units/h)
8 6 4 3 2.5 2 1.5 1 0 0
• Guidelines are for average 70-kg patient, and modificationmay be necessary for smaller or larger patients. Guidelines are not appropriatefor treatment of patients with diabetic ketoacidosisor hyperosmolarstates. • Glucosegoals should be determinedfor each patient. In stressed patients,glucose goal range of 100-200mg/dL is appropriate. • Glucose should be measured hourly until glucose concentrationshave stabilized in patient's goal range for 4 hours. Frequencyof testing may then be decreased to every 2 hours, and once glucose control remains stable, testing can be done every 4 hours. • If hyperglycemiapersists, for each glucose range greater than 200 mg/dL, insulin infusion may be adjusted by 50% increments. Risk of hypoglycemiamay be greater if guidelines are increased for glucose ranges less than 200 mg/dL. • In patients with hyperglycemiatreated with insulin, plasma potassium, magnesium,and phosphorusconcentrationsmay decreaserapidly and should be monitored. • At the time of conversionfrom intravenous to subcutaneousinsulin therapy, intravenousinfusion shouldbe continuedfor 1 to 3 hours after administrationof first subcutaneous insulin dose. Fig. 1. Guidelines for intravenousinsulin infusion in patients with diabetes mellitus. Gastroparesis may make tolerance of tube feeding difficult. In our experience, most patients with diabetic gastroparesis tolerate jejunal feedings when iso-osmolar formulas are initiated at a low rate (for example, 20 mL/h) and advanced slowly (for example, a 10 to 20 mL/h increment every 12 hours) to the goal infusion rate. Unexpected discontinuation of tube feeding may cause hypoglycemia in patients who are treated with subcutaneous injections of insulin. Glucose levels should be carefully monitored to determine whether intravenous infusion of a dextrose-containing solution is necessary to prevent subsequent hypoglycemia. Oral hypoglycemic agents administered by a feeding tube may be used to treat hyperglycemia in medically stable patients who have well-controlled non-insulindependent diabetes mellitus and normal renal and hepatic function. We do not recommend the use of metformin in this group of patients. A major (although very uncommon) risk of metformin is lactic acidosis, which can occur in pa-
tients with hepatic or renal disease or in patients with tissue ischemia. In patients with unstable diabetes mellitus and severe hyperglycemia, an intravenous insulin infusion may be necessary.
EFFECTS OF NEW ENTERAL FORMULAS The recent availability of enteral formulas that are lower in carbohydrates and higher in fat content than standard formulas has prompted studies examining the effects on glycemic control. Although initial studies suggested that the glycemic response to the lower carbohydrate product was blunted in comparison with standard formulas, a follow-up study indicated that the glycemic response was variable in each patient. The clinical significance of these studies is unclear because the subjects ingested very small amounts of formula over a few hours, an extremely different pattern than the usual continuous or gravity administration of tube feeding. In addition, the high fat content could impair gastric empty-
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Table 3.-Guidelines for Nurses in the Treatment of Hypoglycemia in Hospitalized Patients With Diabetes I. Presumed symptomatic hypoglycemia should be treated without waiting to determine glucose level A. If patient is able to swallow safely, approximately IS g of glucose should be given orally. Examples include the following: I. 2 sugar packets or cubes or 2. IS g of glucose tablets or gel or 3. '/2 cup (4 oz) of fruit juice B. If patient is unable to take oral feeding safely or if oral intake is restricted, the following should be administered: 1. If intravenous access is available, 1/2 ampule (12.5 g) of 50% dextrose in water intravenously 2. If no intravenous access is present, I mg of glucagon by subcutaneous or intramuscular injection C. Contact physician II. For treatment of asymptomatic hypoglycemia (glucose :0;60 mg/dL), points A through C should be followed III. Glycemic monitoring after treatment: Capillary glucose level should be reassessed in 15 minutes. If glucose concentration is <80 mg/dL, treatment should be repeated, and glucose level should be monitored. Treatment should be repeated until glucose concentration is >80mg/dL
ing in patients with gastroparesis. With regard to fiber content, the current American Diabetes Association position statement on nutrition reports that, although selected soluble fibers are capable of delaying glucose absorption from the small intestine, the effect of dietary fiber on glycemic control is probably insignificant. Therefore, the fiber intake recommendations for patients with diabetes are probably the same as for the general hospitalized population. During hospitalization, avoidance of overfeeding is likely more important than is the use of a specific enteral formula. Outcome studies are necessary to address this issue.
MONITORING The initiation of nutrition support in a malnourished patient with diabetes requires careful monitoring of vital signs, hemodynamic data, weight, fluid balance, plasma glucose and electrolytes, and acid-base status. A baseline glycated hemoglobin value is useful for establishing recent glucose control and for determining appropriate diabetic treatment after hospital dismissal. The presence of fever is always important in a patient with a central catheter. Hemodynamic data, fluid balance, creatinine, urea, and serum sodium should be reviewed to determine the appropriate volume of nutrition. Daily weight should be interpreted in light of the fluid balance. In general, a weight increase in excess of 0.25 kg during a 24-hour period should be attributed to fluid gain rather than to accretion of lean tissue.
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Knowledge of the electrolyte and mineral content of gastrointestinal and renal losses facilitates appropriate supplementation of these additives to the standard PN. PN admixtures should not, however, be used to treat acute metabolic abnormalities. Although the extent and frequency of biochemical monitoring after initiation of nutrition support should be individualized, the minimal approach is to assess plasma glucose, electrolytes, and phosphorus concentrations until stable. Hyperglycemia may cause a pseudohyponatremia. In general, every 62 mg/dL increment in the plasma glucose level will decrease the plasma sodium concentration by 1 mEq/L. Hyperkalemia, if accompanied by hyperglycemia, may be effectively treated by an increase in insulin supplementation. Hyperinsulinemia due to refeeding or insulin supplementation may lead to a decrease in the plasma levels of potassium, magnesium, and phosphorus. Hyperinsulinemia shifts potassium and magnesium into skeletal muscle and hepatic cells. Glucose- and insulin-stimulated glycolysis enhances the cellular uptake and utilization of phosphorus for the phosphorylation of glucose and fructose and for the synthesis of adenosine triphosphate. Serum potassium, magnesium, and phosphorus concentrations should be monitored daily (and appropriately managed) until the levels are in the normal range. For selected patients receiving nutrition support, triglycerides should be assessed before and after initiation of nutrition support. Monitoring is important in patients with poorly controlled diabetes mellitus, dyslipidemia, or pancreatitis. Data on infusion of lipids in patients with hypertriglyceridemia are limited. In our practice, if the plasma triglyceride concentration exceeds 400 mg/dL, the lipid infusion is discontinued or not administered. A review of the patient's medications is important to ascertain that the patient is not receiving supplemental lipids. For example, the intravenous anesthetic agent propofol is formulated in a lipid emulsion.
CONCLUSION For short-term hospitalization, the principles underlying nutritional assessment and design of nutrition programs for patients with diabetes are similar to those for nondiabetic patients. Of importance, the extremes of hypoglycemia and hyperglycemia should be avoided. Although evidence is increasing that hyperglycemia impairs immune function, well-designed prospective randomized trials are needed to determine the risks, costs, and benefits of achieving glucose control and of providing nutrition support to malnourished patients with diabetes mellitus. ACKNOWLEDGMENT We acknowledge the contributions of physicians in the nutrition and diabetes core groups.
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BIBLIOGRAPHY 1. Bagdade JD, Stewart M, Walters E. Impaired granulocyte
adherence: a reversible defect in host defense in patients with poorly controlleddiabetes. Diabetes 1978; 27:677-681 2. Baxter JK, Babineau TJ, Apovian CM, Elsen RJ, Driscoll DF, Forse RA, et al. Perioperative glucose control predicts increased nosocomial infectionin diabetics [abstract]. Crit Care Med 1990; 18(Supp1):S207 3. Bell PM, Firth RG, Rizza RA. Assessment of insulinaction in insulin-dependent diabetes mellitus using [61 4C]glucose, [33H]glucose, and [23H]glucose: differences in the apparent pattern of insulin resistance depending on the isotope used. J Clin Invest 1986;78:1479-1486 4. Hostetter MK. Handicaps to host defense: effects of hyperglycemia on C3 and Candida albicans. Diabetes 1990; 39:271-275
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5. McMahonMM. Parenteralnutrition. In: Bennett JC, Plum F, editors. Cecil Textbook of Medicine. 20th ed. Philadelphia: Saunders, 1996: 1171-1175 6. McMahon MM, Bistrian BR. Host defenses and susceptibility to infection in patients with diabetes mellitus. Infect Dis Clin North Am 1995Mar; 9:1-9 7. McMahon MM, Bistrian BR. The physiology of nutritional assessment and therapy in protein-calorie malnutrition. Dis Mon 1990; 36:373-417 8. OrtmeyerJ, MohseninV. Glucose suppressessuperoxide generation in normal neutrophils: interferencein phospholipase D activation. Am J Physio1 1993; 264:C402-C410 9. Schade DS, Santiago JV, Skyler JS, Rizza RA. Intensive Insulin Therapy. Amsterdam: Excerpta Medica, 1983: 3638
Questions About Nutrition Support in Hospitalized Patients With Diabetes (See article, pages 587 to 594)
1. Considering that a major goal in the care of the critically ill patient is to avoid the extremes of hypoglycemia and hyperglycemia, which one of the following glucose levels is most reasonable in these patients? a. b. c. d. e.
80-120 mg/dL 100-200 mg/dL 200-300 mg/dL 250-300 mg/dL 300-350 mg/dL
2. Which one of the following is a potential cause of hyperglycemia? a. b. c. d. e.
Resolution of severe stress Severe hepatitis Infection Renal dysfunction Discontinuation of corticosteroids
3. Which one of the following is most likely to occur as a result of overfeeding in critically ill patients with diabetes? a. b. c. d. e.
5. Which one of the following principles should be followed to achieve adequate glucose control in stressed patients with diabetes receiving tube feeding? a. Until the patient has been shown to tolerate tube feeding, intermediate-acting insulin is preferred rather than short-acting insulin to achieve glucose control b. Until the patient has been shown to tolerate tube feeding, short-acting insulin is preferred rather than intermediate-acting insulin to achieve glucose control c. Glucose should be routinely assessed 1 hour after initiation of gravity feeding d. The tube feeding route may be altered without appropriate adjustments being made in the insulin dose e. Oral hypoglycemic agents should never be used to treat medically stable patients with well-controlled diabetes mellitus and normal hepatic and renal function
Decreased carbon dioxide production Hypoglycemia Hyperglycemia Acid-base imbalance Decreased oxygen consumption
4. Which one of the following types of insulin should be added to parenteral nutrition admixture? a. b. c. d. e.
NPH Lente Regular Ultralente Semilente
Correct answers: 1. b, 2. c, 3. c, 4. c, 5. b
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