Clinical management of hyperglycaemic patients receiving total parenteral nutrition

(1996) 15:11-15 O PearsonProfessionalLtd i996 Clinical Nutrition

Clinical management of hyperglycaemic patients receiving total parenteral nutrition M. A. VALERO, E. ALEGRE*, P. GOMIS*, J. M. MORENO, S. MIGUELEZ* and M. LEON-SANZ Clinical Nutrition Unit, *Pharmacy Service, Hospital "12 de Octubre; Madrid, Spain (Reprinted requests and correspondence to P. G. Pharmacy Service, Hospital "12 de Octubre; Carretera de Andalucfa, km 5.4, 28041 Madrid, Spain) ABSTRACT--We evaluated the course of total parenteral nutrition (TPN) therapy in patients with

hyperglycaemia. We studied 1) incidence of hyperglycaemia, 2) amount of glucose and insulin provided and 3) incidence of metabolic problems in patients receiving TPN who required insulin to attain metabolic control, The group included 91 patients, 38 women (64 + 15 years) and 53 men (64 + 12 years), who developed glycaemia higher than 200 mg/dl. Nine patients had a previous diagnosis of IDDM, 36 NIDDM and 46 secondary hyperglycaemia.. Total caloric requirements were initially supplied at 132 + 20% the basal energy expenditure (Harris-Benedict formula), and 1.4 + 0,3g/kg of amino-acids. Initially, TPN provided 150-200 g/day of glucose (2.1 mg/kg/min). Regular insulin was added to the bag. The annual incidence of hyperglycaemia was estimated to be 121 per 1000 patients. Mean insulin requirements were 50 U/day (25 to 150 U/day), 0.7 + 0.3 U/kg. Comparing with prehospitalization insulin dose, 22% needed similar doses, and 11% lower doses. IDDM patients needed 1.7 times their pre-admission dose (1-4.5 times). The ratio of insulin:glucose in TPN was 0.3 + 0.1 U/g (0.1-1.2 U/g). Patients with renal failure had similar insulin requirements (56 + 26 U/day) than patients with normal renal function (49 + 19 U/day). None of the patients developed glycemic complications. In conclusion, diabetic patients receiving TPN have an acceptable metabolic control if individualized prescriptions and supplemental insulin are used.

Introduction

Hyperglycaemia is a common metabolic complication in diabetic patients receiving total parenteral nutrition (TPN) (1). It can result from diminution in insulin secretion (insulin-dependent diabetes mellitus, IDDM), from an impairment in insulin action (non-insulin-dependent diabetes mellitus, NIDDM) or from combination of both factors. Severely ill patients develop a metabolic stress response characterized by elevated concentration of counter-regulatory hormones and insulin resistance. These factors contribute to the mild to moderate hyperglycaemia observed in stressed patients. The presence of hyperglycaemia does not prevent the use of TPN. However, it may be necessary to modify the composition of TPN solutions, to institute close monitoring of blood glucose and adjust insulin requirements. The aims of this study were to estimate the incidence of hyperglycaemia in patients receiving TPN, to determine glucose and insulin requirements in these patients, to investigate the relation of insulin:glucose, and the incidence of metabolic problems in patients receiving insulin.

Material and methods

From January to December 1994, 743 patients receiving TPN were seen by our Nutritional Support Service. We identified, retrospectively, 91 patients (12.2%), who (i) had hyperglycaemia (higher than 200 mg/dl) at least once, (ii) needed insulin for more than 5 days and (iii) did not receive concurrent enteral nutrition. This group included 38 women (64 _ 15 years) and 53 men (65 _+ 12 years) (Table 1). Approximately 9.8% of patients (n = 9) had a previous

Table 1

Anthropometric and biochemical parameters Men (n = 53)

Age Weight (kg) Height (cm) BMI BEE Glucose 1 Creatinine 1 Glucose 2 Creatinine 2

65 70 168 25 1408 259 1.1 172 1.2

+ 12 + 11 _+ 6 _+ 3 + 151 _+ 62 + 0.6 + 45 _+ 0.7

Women (n = 38) 64-+ 15 63 +_ 11 156 + 6 26 _+4 1219 _+ 136 248 _+ 66 1.0 + 0.5 155 -+ 52 1.0 + 0.6

BMI (kg]m 2) = body mass index BEE (kcal/day) = basal energy expenditure (Harris-Benedict formula) Glucose 1 (mg/dl) = serum glucose levels before TPN Creatinine 1 (mg/dl) = serum creatinine levels before TPN (>2 mg/dl, n = 6, 2.8 _+0.6) Glucose 2 (mg/dl) = serum glucose levels at last day on TPN Creatinine 2 (mg/dl) = serum creatinine levels at last day on TPN (>2 mg/dl, n = 7, 3,0 + 0.8)

diagnosis of IDDM, 39.5% NIDDM (n = 36) and 50.5% hyperglycaemia secondary to catabolic illness (stress) (n = 46). The indications of nutritional support were elective surgery in 43 cases, urgent surgery in 21, pancreatitis and pancreatic pseudocyst in 14, inflammatory bowel disease in 4 and other diseases in 9 cases. Table 2 shows the underlying disease and the number of patients with severe sepsis at the end of TPN treatment. Severe sepsis was defined according to the recommendations of the ACCP/SCCM Consensus Conference (2). Individual prescriptions were assessed for all patients by members of the Nutrition Support Team. Other patients that received TPN but were not seen

12 CLINICALMANAGEMENTOF HYPERGLYCAEMICPATIENTSRECEIVINGTOTALPARENTERALNUTRITION Table 2 Underlying diagnosis according to the presence of sepsis

Pancreatitis/Pseudocyst Perforated viscera Abdominal tumour resection Gastrointestinalfistula Gastrointestinalbleeding Inflammatorybowel disease Bone marrow transplant Paralytic ileus Mesenteric ischaemia Others

No sepsis

Sepsis

11 4 29 3 5 3 2 4 3 8

3 4 3 2 0 1 0 0 0 6

'Others' comprises a heterogeneous group of patients. The non-septic group includes hepatic encephalopathy,achatasia, aortic aneurysm, incisional hernia, pyloric stenosis and brain tumour resection; the septic group includes abdominal sepsis following trauma, urologic sepsis, aspiration pneumonia, mucormicosis in renal transplant, lung cancer resection, hepatic and pleural hydatidosis.

by the Nutrition Support Team have not been included in this study. Patients were categorized according to whether the serum creatinine level was higher or lower than 1.5 mg/dl. Creatinine clearance (Clot) was estimated with the formula (140-age) x weight/72 x serum creatinine. This value was reduced by 15% in women to compensate for a lower body muscle mass (3). At the end of the TPN period, serum creatinine was 2.3 + 0.8 mg/dl (Clcr = 29.1 + 13.9 ml/min) in 15 patients, and 0.9 + 0.2 mg/dl (Clcr = 84.3 -+ 31.7 ml/ rain) in 76 patients. During the TPN period creatinine was lower than 1.5 mg/dl in 73 patients, it was always higher in 11 cases, it increased over 1.5 mg/dl in 4 cases, and it decreased in 3 patients. Among patients with a high final serum creatinine, 4 had chronic renal failure. TPN solutions were provided for 14 _+ 10 days (5 to 54 days). TPN was discontinued when the patients showed gastrointestinal tolerance to oral diets. TPN bags were centrally prepared by the Pharmacy Service. Total caloric requirements were initially supplied at 132 + 20% of the basal energy expenditure, calculated from the HarrisBenedict formula (1726 + 220 kcal/d). When the patients were obese, we used an adjusted body weight by assuming that one-fourth of weight above ideal or desirable is metabolically active (Adjusted W = [[ABW - IBW] x 0.251 + IBW, where A B W is actual body weight and I B W is ideal body weight) (4). The protein requirements were estimated at 1.4 + 0.3 g/kg weight (89 -+ 18 g/d). Volume of TPN was 1 ml/kcal, if volume restriction was not indicated. Fat was usually provided as medium and long chain triglycerides (MCT/LCT, 50/50). The composition of macronutrients in TPN solutions is shown in Table 3. Electrolytes were added as needed. Micronutrients were provided as a trace element solution (10 ml, Pharmacia, Barcelona, Spain) and vitamins

Table 3

as Cernevit (10 ml, Clintec, Madrid, Spain). Total fluid requirements were fulfilled by TPN, drug dilutions and additional IV fluids were added as needed to attain an appropriate water balance. When these fluids were given as dextrose 5%, some patients received regular insulin in a range of 0.8-1.6 U per 100 cc. This extra insulin was not added to the insulin administered in TPN bags. Patients initially received 1 5 0 - 2 0 0 g / d a y of glucose (2.1 mg/kg/min) as part of the full calorie dose, along with lipids and amino-acids. Regular human insulin was provided in the TPN bag. Capillary and serum glucose determinations were periodically assessed and the regimen adjusted to maintain glucose values between 100-200 mg/dl. Twothirds of the insulin administered subcutaneously over a 24-h period was added to the TPN the following day. When glucose values were lower than 200 mg/dl the dextrose was slowly increased adjusting the insulin dose into the bag. If hyperglycaemia occurred in spite of progressively higher doses of insulin, glucose supply in the TPN was also reduced. Statistical methods: results are expressed as mean + SD. Student's t-test was used to compare the difference of means between two groups. One-way analysis of variance, followed by the Newman-Keuls method of multiple comparisons, was employed to compare group means. A 0.05 significance level was applied for both statistical tests.

Results

The annual incidence of hyperglycaemia was estimated to be 121 per 1000 patients. The initial regular insulin provided in the TPN was 35.3 + 7.3 U/day and, when metabolic control was reached or TPN was eventually withdrawn, the amount of regular insulin administered in the bag was 50.5 + 19.6 U/day (25 to 150 U/day), equivalent to 0.7 + 0.3 U/ kg. 83% of the patients needed less than 65 U/day to obtain metabolic control. Of the patients who received insulin at home, 22% required a similar dose and 11% a lower dose. I D D M patients needed 1.7 times their pre-admission dose (1-4.5 times). The ratio between insulin and glucose in TPN solution was 0.3 _+0.1 U/g (0.10 to 1.20 U/g). The cause of the hyperglycaemia (IDDM, NIDDM, stress hyperglycaemia) was not associated with significant differences in macronutrients or of the calories supplied in the TPN. The insulin requirements gradually increased in patients with stress hyperglycaemia, to similar values to those observed in N I D D M and I D D M (0.72 + 0.32, 0.82 + 0.30, 0.96 + 0.26 U/kg, respectively). These figures represent the insulin needed to control glycaemic levels at the last day of the TPN period. Patients with renal failure had similar insulin requirements (56 + 26 U/day) to patients with normal renal function

Composition of macronutrients in TPN (3 in 1 admixtures) at day 1

Calories (kcal) Proteins (g) Glucose (g) Fat (MCT/LCT) (g)

Total

Per kg/weight

IDDM

NIDDM

Stress

1728 + 223 91 + 18 192 + 34 59 -+ 13

26.5 -+5.2 1.4 _+0.3 2.9 _+0.3 0.9 -+0.3

1593 + 113 79 _+15 169 + 24* 57 _+10

1709 + 132 89 _+18 195 + 23 57 + 10

1766 + 275 92 _+18 197 _+41 60 + 15

* = P < 0.05, IDDM vs NIDDM

CLINICALNUTRITION 13 Table 4

Characteristics of TPN according to type of diabetes mellitus at final day

IDDM (n = 7) Calories (kca]/24 h) Proteins (g/d) Glucose (g/d) Fat(g/d)

1708 ± 292 97 ± 23 170 ± 27 66±9

Normal renal function NIDDM (n = 30) Stress (n = 39) 1738 ± 96 ± 180 ± 64±

216 15 31 14

1841 ± 222 98 -+ 12 203 ± 34 62± 13

(49 + 19 U/day). The composition of TPN at the end of treatment, according to type of carbohydrate disturbance and to serum creatinine levels, is shown in Table 4. The underlying glycaemic disorder was not associated with differences in provision of macronutrients or insulin requirements. Amino-acid supply was reduced in patients with elevated serum creatinine levels. There were 19 patients with severe sepsis at the end of TPN. As a group they received TPN with a higher insulin/ glucose ratio than non-septic patients. There were 2 patients with IDDM, 8 with NIDDM and 9 with stress hyperglycaemia. The insulin/glucose ratio for those subgroups were 0.51 _+0.41, 0.48 + 0.25 and 0.33 + 0.33 U/kg, respectively. There were no differences between septic and nonseptic patients in the supply of amino-acids, lipids and total calories (Table 5). Although an increase in calorie and protein supply is recommended in septic patients, the intake in our septic and non-septic groups were similar because of the higher frequency of renal failure in septic patients that forced a restriction in the amount of nitrogen administered. On the final day of TPN, 74 patients (81%) had serum glucose levels lower than 200 mg/dl. Glycaemia was lower than 250 mg/dl in 81 patients (89%). We divided the patients into groups A and B, depending on the final glucose concentrations - lower or higher than 200 mg/dl, respectively. The amount of glucose provided in the TPN at the end of this therapy was significantly lower in group B (P = 0.0297) (Table 6). On the other hand, there were not significant differences between the amounts of insulin, calories,

Table 5

Differences between patients with and without severe sepsis No sepsis (n = 72)

Glycaemia (mg/dl) Glucose (g/24 h) Lipids (g/24 h) Amino-acids (g/kg) Calories (kcal/24 h) Insulin (U/24 h) Insulin/glucose (U/g)

169 ± 193 ± 63 ± 93 ± 1782 ± 50 ± 0.26 ±

60 33 14 18 227 16 0.12

Severe sepsis (n = 19)

P

177 ± 64 170 ± 45 66 ± 12 88 ± 21 1703 ± 235 60 ± 28 0.41 ± 0.29

0.5989 0.0441 0.3062 0.3553 0.1857 0.0754 0.0410

Table 6 Differences between patients with and without adequate glycaemic control (glycaemia < and > 200 mg/dl on the last day of TPN)

Glycaemia (mg/dl) Glucose (g/kg) Lipids (g/kg) Calories (kcal/kg) Insulin (U/kg) % BEE

Group A (n = 74)

Group B (n = 18)

148 + 31 3.1 + 0.9 1.0 +- 0.2 27.4 _+5.6 0.74 ± 0.28 135 ± 16

251 -+ 41 2.5 + 0.8 1.0 ± 0.2 25.6 ± 3.9 0.91 ± 0.39 131 ± 17

P < 0.001 0.0297 0.5034 0.2169 0.0961 0.4779

Serum creatinine _> 1.5 mg/dl IDDM (n = 2) NIDDM (n = 6) Stress (n = 7) 1625 ± 318 75 ± 14 150 ± 71 70±0

1733 + 244 75 -+ 22 179 ± 55 71 ± 16

1730 ± 65 ± 193 ± 64±

178 18 31 10

amino-acids or lipids supplied to patients in group A or B. If the cutoff level was raised to 250 mg/dl, the amount of glucose and calories provided in the TPN was significantly different between groups A and B. In group B the glucose provided on the last TPN day tended to be lower than that administered on the starting day (results not significant). The opposite trend was seen with lipids (P = 0.0021). In group A the glucose load in TPN slightly increased from the beginning to the end of TPN and lipids remained fairly similar through this period. None of the patients receiving TPN during that year developed hypoglycaemia, ketoacidosis or non-ketotic hyperosmolar coma during TPN therapy.

Discussion

The information about the actual incidence of hyperglycaemia in patients receiving TPN is rather scarce. In our series the annual incidence of hyperglycaemia was 121 per 1000 patients, but in the future, the number of diabetic patients receiving TPN will probably increase because of the growing proportion of elderly persons in the general population (5, 6). On the other hand, catabolic illness may markedly augment the underlying metabolic abnormalities of diabetic patients and of severely ill patients without an antecedent diagnosis of diabetes mellitus, who may develop hyperglycaemia during stress (7). In non-diabetic patients, glucose administered intravenously is oxidized and endogenous production is inhibited as a result of glucose-induced insulin secretion. Insulin is a strong inhibitor of protein breakdown and stimulator of protein synthesis, improving net protein balance (8, 9). These responses appear to become maximal when the glucose infusion rate reaches 4-6mg/kg/min (10, 11). Catabolic diabetic and non-diabetic patients may develop insulin resistance with increased concentration of counter-regulatory hormones, enhanced peripheral glucose uptake and utilization, hyperlactataemia, increased glucose production, depressed glycogenesis and glucose intolerance (12, 13). Therefore, it is generally prudent to limit the total daily glucose dose to 3-4 mg/kg/min in these patients. If glucose control is poor even when these precautions are taken, the quantity of glucose administered must be reduced (1) and/or insulin added to TPN solutions (14). Very often, patients with hyperglycaemia require the formulation of individualized solutions of TPN. Some authors (1) have developed guidelines for TPN administered in patients with hyperglycaemia. According to their recommendations, dextrose in the initial TPN should be restricted to 150-200 g/day. A portion, usually 1/2 of the usual daily insulin requirements, or 0.1 unit of insulin per gram of glucose, should be added to the TPN admixtures as regular

{4 CLINICALMANAGEMENTOF HYPERGLYCAEMIC PATIENTS RECEIVINGTOTAL PARENTERALNUTRITION

insulin. The amount of subcutaneously insulin administered over a 24-h period is measured. Two-thirds of this amount is added to the TPN bag during the following day if the capillary glucose concentration on the preceding day was higher than 200 mg/dl. Eventually, when at least two of the three glycaemic values are lower than 200 mg/dl, the dextrose load may be slowly augmented adjusting the TPN insulin. There are few series analyzing the experience with diabetic patients receiving TPN (15, 16) or patients with hyperglycaemia who require insulin during this therapy (17). We planned to implement the previously mentioned guidelines in our clinical setting including all TPN patients that needed insulin with TPN during 12 months. With this approach our patients did not show hypoglycaemia and 83% of them required less than 65 U/day of insulin. The individual daily dose of insulin, glucose and lipid in TPN was fairly stable when patients reached an adequate metabolic control, unless they suffered infections or other metabolic stress. An insulin to glucose ratio of 0.3 U/g was required to maintain glucose values lower than 200 mg/dl during TPN infusion. A mean of 50 U/day of regular insulin was needed to achieve metabolic control, approximately twice their pre-admission dose, figures comparable to those found by previous series (15, 16). On the other hand, our results differ from those reported by Helfel et al (17). In their study, 8 of 25 patients were included because insulin had been empirically added at the initiation of hyperalimentation without indication of need. There were no common guidelines; glucose supply was kept rather constant and not adjusted, lower doses of insulin were provided and only 12 patients (50%) had blood glucose values lower than 200 mg/dl. The formulation of TPN in our series included lipid emulsions containing MCT/LCT. Although this mixture has been recommended for diabetic patients with TPN (18), previous series of TPN treatment in hyperglycaemic patients have not used it (15-17). We have not specifically studied the lipid metabolism in our series, but we can confirm that this lipid emulsion infusion permits the glycaemic control and does not induce clinically significant ketoacidosis. There are many methods by which insulin can be administered to patients received TPN: 1. 2. 3. 4.

Administering insulin subcutaneously Using a separate insulin infusion Adding insulin to the TPN bag Combining subcutaneous or separate infusions and intraTPN insulin (19, 20).

However, there have been controversies about insulin availability in TPN solutions. A recent study, that overcomes shortcomings of previous investigations (21), shows that the recovery of regular insulin from all-in-one mixtures in ethylene vinyl acetate (EVA) bags is around 90-95% (22). In agreement with other authors (15, 16), we have obtained good results by adding insulin to TPN bags, with subcutaneous supplements as needed. In previous studies of TPN patients that develop hyperglycaemia there are no separate data about septic patients. Only Overett et al (15) reported the incidence of catheter infection in their series, but they did not provide information about their experience in sepsis. Hongsermeier & Bistrian (16) divided their patients into infected and noninfected according to a broad criteria that could include septic as well as less seriously ill patients. They did not

give information about the composition of TPN formula in infected and non-infected patients, but there were no differences in the insulin provided to both groups. We have analysed a subgroup of severe septic patients. They needed a higher insulin:glucose ratio. In practise, that implied that they received more insulin and less glucose than non-septic patients. Due to the metabolic disturbances present in these patients, the supply of amino-acids and lipids had to be restricted in some cases. Therefore, although i~. theory septic patients should have received a slightly higher amount of calories and proteins, in practise it was difficult to reach their nutritional goal. On the other hand, septic patients had an acceptable glycaemic control in spite of their serious condition. With this individualized approach our patients did not develop ketoacidosis or non-ketotic hyperosmolar coma. However, in our series 30 out of 91 patients died (33% mortality). There are no reports in the literature about the mortality of hyperglycaemic patients receiving TPN. If our findings were confirmed by others, they would suggest that such patients constitute a high risk group. Renal dysfunction is common in diabetic patients. When this complication is present, IDDM patients may experience frequent and profound hypoglycaemic episodes, because in normal conditions about one-third of exogenous insulin is metabolized by the kidney (23). However, the doses of insulin needed by our patients were slightly higher when serum creatinine was elevated. This observation can be explained in two ways: (a) renal insufficiency was mild or moderate and no patient required dialysis in our series; and (b) a larger proportion of patients with high serum creatinine were in septic shock and eventually died. Based on our experience, we disagree with the suggestion (15) that insulin requirements are lower in hyperglycaemic TPN patients with renal failure. An individual approach must be established since the requirement strongly depends on the clinical condition. In conclusion, diabetic patients receiving TPN have an acceptable metabolic control provided individualized nutritional prescriptions and supplemental insulin are used. The ratio between the insulin and glucose administered in TPN is 0.3 U/g and is unaltered by mild to moderate renal failure. Hyperglycaemia in TPN patients with sepsis and renal dysfunction is associated with an elevated mortality.

References 1. McMahon M, Manji N, Driscoll D F, Bristian B R. Parenteral nutrition in patients with diabetes mellitus: Theoretical and practical considerations. J Parenter Enteral Nutr 1989; 13:545-553 2. American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Chest 1992; 101:1644-1655 3. Cockroft D W, Grult M H. Prediction of creatinine clearance from serum creatinine. Nephron 1976; 16:3141 4. Tighe A P, Allison D B, Kral J G, Heymsfield S B. Nutritional support of obese patients. In: Rombean J L, Caldwell M D (Eds). Clinical Nutrition: Parenteral Nutrition, 2nd ed. Philadelphia: WB Saunders 1993:716-736 5. Ziegler T R, Smith R J. Parenteral nutrition in patients with diabetes mellitus. In: Rombeau J L, Caldwell M (Eds). Clinical Nutrition: Parenteral Nutrition, 2nd Edn. Philadelphia: WB Saunders 1993:649-666 6. Wingard D L, Siwsheimer P, Barrett-Conor E L, McPhillips J B.

CLINICAL NUTRITION 15

7.

8.

9.

10.

11.

12. 13. 14.

Community based study of prevalence of NIDDM in older adults. Diabetes Care 1990; 13(suppl 2): 3-8 Knape C M, Owens J P, Mirtallo J M. Management of glucose abnormalities in patients receiving total parenteral nutrition. Clin Pharm 1989; 8:136-144 Biolo G, Fleming D Y F, Maggi S P e t al. Physiologic hyperinsulinemia stimulates protein syntesis and enhances transmembrane transport of selected amino acids in human muscle. Diabetes 1993; 42: 73A Jahoor F, Shangraw R E, Miyoshi H et al. Role of insulin and glucose oxidation in mediating the protein catabolism of burns and sepsis. Am J Physiol 1989; 257:E323-E331 Wolfe R R, O'Donnell T F, Stone M D et al. Investigation of factors determining the optimal glucose infusion rate in total parenteral nutrition. Metabolism 1980; 29:892-899 Shaw J H F, Wolfe R R. An integrated analysis of glucose, fat and protein metabolism in severely traumatized patients: studies in the basal state and the response to total parenteral nutrition. Ann Surg 1989; 209:63-72 Black P R, Brooks D C, Bessy P Q et al. Mechanisms of insulin resistance following injury. Ann Surg 1991; 196:420-435 Mizock B A. Alterations in carbohydrate metabolism during stress: a review of the literature. Am J Med 1995; 98:75-84 Michae] S R, Sabo C E. Management of the diabetic patient receiving nutritional support. Nutr Clin Pract 1989; 4:179-183

Submission date: 1 July 1995 Accepted: 16 September 1995

15. Overett T K, Bistrian B R, Lowery S F et al. Total parenteral nutrition in patients with insulin-requiring diabetes mellitus. J Am Coll Nutr 1986; 5:79-89 16. Hongsermeier T, Bistrian B R. Evaluation of a practical technique for determining insulin requirements in diabetic patients receiving total parenteral nutrition. J Parenter Enteral Nutr 1993; 17:16-19 17. Helfer E, Schorr A B, Miller J L, Rose L J. Control of hyperglycemia with hyperalimentation solutions containing insulin. J Pharm Technol 1988; 4:174-178 18. Wicklmayr M, Rett K, Dietze G, Mehnert H. Comparison of metabolic clearance rates of MCT/LCT and LCT emulsions in diabetics. JPEN 1988; 12:68-71 19. Bergman M, Ravi-Kumar S, Auerhahn C, Delsavio N, Savino J, Felig P. Insulin pump therapy improves blood glucose control during hyperalimentation. Arch Intern Med 1984; 144:2013-2015 20. Sajbel T A, Dutro M P, Radway P R. Use of separate infusions with total parenteral nutrition infusions. JPEN 1987; 11: 97-99 21. Dunham B, Marcuard S F. Availability of insulin from TPN solutions. JPEN 1990; 14:434 22. Marcuard S P, Dunham D, Hobbes A, Caro J F. Availability of insulin from total parenteral nutrition solutions. JPEN 1990; 14:262-264 23. Friedman E A. Diabetic renal disease. In: Rifidn H, Porte D (Eds). Ellemberg and Rifikin's Diabetes Mellitus: Theory and Practice, 4th Edn. New York: Elsevier 1990:684-709