Serum glucose concentration in healthy people without diabetes is highly controlled through a combination of physiologic, pharmacologic, and metabolic processes. During periods of illness, however, stress increases the secretion of glucagon, catecholamines, corticosteroids, and growth hormone, leading to hyperglycemia and insulin resistance.1,2 These counterregulatory hormones all work to oppose insulin activity, resulting in increased production and decreased use (ie, peripheral uptake) of glucose. Stress may also increase the levels of cytokines, which may further contribute to hyperglycemia through their stimulation of counterregulatory hormones.2
Effects of Hyperglycemia
Hyperglycemia (defined as plasma glucose >200 mg/dL)3 with and without diabetes is associated with fluid imbalances resulting from glycosuria and dehydration, immune function disturbance, and inflammation.2,4 In vitro, it can impair white blood cell function and complement activity.2
Studies have indicated that hyperglycemia presents a risk factor for adverse outcomes during acute illness, even in patients without diabetes.2 Glucose levels greater than or equal to range 110 mg/dL to 144 mg/dL in patients who just experienced myocardial infarction were associated with a 3.9-fold increase in mortality.5 Similar mortality results (3.1-fold increase) were seen in patients who had experienced ischemic stroke and whose glucose levels were 108 mg/dL to 144 mg/dL.6
The incidence of postoperative wound infection is also significantly higher in patients with hyperglycemia, diabetes, or both.7 The results of one study suggested that hyperglycemia is an independent risk factor for the development of infection following major cardiovascular or abdominal surgery.8 The infection rate in patients with glucose levels >220 mg/dL on postoperative day 1 was 2.7 times greater than in patients with glucose levels <220 mg/dL.8
Hyperglycemia in Patients Receiving Total Parenteral Nutrition
Although total parenteral nutrition (TPN) provides necessary nutrients and calories to critically ill patients and lowers their risk of noninfectious complications, it has been shown to contribute to hyperglycemia. Patients (without diabetes) who received TPN and dextrose at rates >5 mg/kg/min had a 49% chance of developing hyperglycemia. In contrast, the risk of hyperglycemia was substantially reduced in patients who received infusions at lower rates (²4 mg/kg/min).9
Hyperglycemia resulting from excess dextrose in TPN solutions elevates the respiratory quotient in ventilated patients and increases infectious complications.10,11 Higher infection rates have been found in patients receiving TPN versus enteral nutrition; however, the serum glucose concentrations in the former group have been consistently higher, emphasizing the importance of glucose control for TPN patients.12,13
Benefits of Controlling Hyperglycemia
Controlling hyperglycemia during acute illness improves outcomes. Risk of deep sternal wound infections after coronary bypass graft surgery decreased by 66% when insulin was given to maintain glucose levels between 150 mg/dL and 200 mg/dL.14 Intensive insulin therapy for 3 months following hospitalization for myocardial infarction also reduced the 1-year mortality rate in patients with diabetes by 30% compared with standard therapy.15 Moreover, Van den Berghe and colleagues demonstrated that intensive insulin therapy (<110 mg/dL) in patients fed by TPN, combined parenteral and enteral, or total enteral feeding, reduced overall ICU mortality from 8% to 4.6% and from 20.2% to 10.6% in patients requiring more than 5 days of intensive care.16 Compared with patients receiving standard therapy, those on intensive insulin therapy also had about half the incidences of bloodstream infections, prolonged inflammation, acute renal failure requiring dialysis or hemofiltration, critical illness polyneuropathy, and transfusion requirements. Patients were also less likely to need prolonged mechanical ventilation and intensive care. A subsequent study has demonstrated that the benefits of intensive insulin control were a result of normoglycemia rather than the dose of infused insulin.17
Optimizing Glycemic Control in Patients Receiving Total Parenteral Nutrition
Since TPN is associated with dextrose overfeeding and hyperglycemia, modifications of TPN protocols should be considered in patients with baseline stress hyperglycemia to avoid exacerbation of the condition.3
Avoiding hyperglycemia during TPN administration can begin with gradual dextrose infusion, starting with 100 g to 150 g dextrose and advancing toward goal only as glucose tolerance permits. Underfeeding will not result in impaired nitrogen balance when there is adequate protein in the TPN solution (>1.2 g/kg-1.5 g/kg).3 Alternatively, TPN solutions can be formulated as 3-in-1 admixtures containing lipid emulsions as a source of calories. Incidence of hyperglycemia was significantly reduced in patients receiving a lipid-based admixture (80% nonprotein calories as lipid) compared with patients receiving a dextrose-based formulation (100% nonprotein calories as dextrose)-3.4% versus 32.3%.18 Cases of hyperglycemia were managed with insulin, which is very effective in managing hyperglycemia and should be considered a part of the TPN order.
Insulin for Managing Hyperglycemia During Total Parenteral Nutrition
Three options exist for delivering insulin to patients receiving TPN:
1. Initiate a sliding scale for constant intravenous insulin infusion that is separate from the TPN solution.19
2. Initiate a subcutaneous sliding scale with regular insulin.20
3. Add insulin to the TPN solution based on the previous 24-hour sliding scale requirement.20
Using the first method, Woolfson designed a sliding scale to change the insulin infusion based on hourly glucose measurements.21 Measurements stopped when the glucose levels stabilized. Acceptable glucose concentrations of 125 mg/dL to 200 mg/dL were achieved within 24 hours in 35 out of 39 patients. Serum glucose levels began to decrease within 8 hours in all (n=51) but 2 patients.21
The intravenous route allows for tighter glucose control than the subcutaneous method. This is true especially in patients with sepsis, congestive heart failure, edema associated with renal failure, or fluid overload, who may have compromised subcutaneous insulin absorption.1 There is also less discomfort since there are fewer injections versus the subcutaneous method. There are some disadvantages, however. Nursing time is increased, insulin may bind to the IV bag and tubing, accidental bolus insulin injections may occur, and the TPN infusion may be stopped without concomitant discontinuation of the insulin infusion.1
One way of incorporating insulin into the TPN solution is based on the previous 24-hour sliding-scale requirements. For example, two thirds of the previous day's subcutaneous insulin requirement can be included in the TPN solution and additional insulin can be provided by a subcutaneous sliding scale.20 Advantages of adding insulin in the TPN solution include reduced monitoring by the nursing staff, decreased risk of inadvertent insulin bolus doses, and concomitant discontinuation of TPN and insulin.1 Disadvantages include insulin adsorption to the bag and tubing and decreased flexibility in insulin dosage, particularly if TPN is provided in 24-hour quantities.1
Most leading centers are indeed trying to apply the Van den Berghe findings to critically ill patients receiving TPN. In practice this means that many critically ill patients receiving TPN are now often managed with insulin drips and that "acceptable" glucose control has been ratcheted down considerably. A 200 mg/dL cutoff is certainly not acceptable, though new standards or guidelines have not been widely established. There is a great need for further investigation. For example, it is not yet clear how these observations apply to patients who are not critically ill (G. L. Jensen, MD, written communication, May 2003).
Summary
Stress from illness induces a hyperglycemic state, which can be further exacerbated with TPN. Hyperglycemia is associated with adverse outcomes, including infection and mortality. Successful control of serum glucose levels below 200 mg/dL, however, can result in improved outcomes. Lower blood glucose levels (ie, <110 mg%), such as proposed by Van den Berghe and colleagues,16 may confer additional clinical benefits, but requires intensive monitoring over 24 hours to be safely applied and should only be administered as a separate infusion.22 Providing patients with insulin, either through sliding-scale intravenous infusions, sliding-scale subcutaneous administrations, or direct addition to the TPN solution are effective means of offering tight glucose control to patients receiving TPN, thereby reducing morbidity and mortality.
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