Practical Management of Diabetes in Critically Ill Patients

JEFFREY B. BOORD, ALAN L. GRABER, JOHN W. CHRISTMAN, and ALVIN C. POWERS

Department of Medicine, Divisions of Endocrinology and Allergy/Pulmonary and Critical Care Medicine, Vanderbilt University Medical Center, Tennessee Valley Veterans Affairs Medical Center, Nashville, Tennessee

	INTRODUCTION

TOP INTRODUCTION CHANGES IN DIAGNOSIS,... RECENT ADVANCES IN THERAPY... MANAGEMENT OF HYPERGLYCEMIA IN... NUTRITIONAL SUPPORT IN PATIENTS... MANAGEMENT OF DIABETIC... ACUTE CARDIOVASCULAR... CONCLUSIONS NOTE ADDED IN PROOF REFERENCES

Diabetes mellitus is a common diagnosis in patients requiring critical care. Although diabetes is sometimes the reason for admission to the intensive care unit, it is more commonly a comorbid condition that complicates patient management and may increase the severity of the primary illness. For example, in one study, up to 28% patients with sepsis syndrome carried the diagnosis of diabetes (1). This study will focus on recent advances in the diagnosis and management of diabetes and highlight certain clinical scenarios in hospitalized patients with diabetes. We believe that aggressive management of hyperglycemia, avoidance of hypoglycemia, and anticipation of the systemic complications of diabetes will improve patient outcome.

	CHANGES IN DIAGNOSIS, NOMENCLATURE, AND CLASSIFICATION OF DIABETES MELLITUS

TOP INTRODUCTION CHANGES IN DIAGNOSIS,... RECENT ADVANCES IN THERAPY... MANAGEMENT OF HYPERGLYCEMIA IN... NUTRITIONAL SUPPORT IN PATIENTS... MANAGEMENT OF DIABETIC... ACUTE CARDIOVASCULAR... CONCLUSIONS NOTE ADDED IN PROOF REFERENCES

According to the American Diabetes Association and the World Health Organization, the diagnosis of diabetes requires one of the following: (1) random plasma glucose  200 mg% with symptoms of diabetes (polyuria, polydipsia, etc.), (2) fasting plasma glucose  126 mg% (confirmed on a second occasion), or (3) plasma glucose  200 mg% 2 h after an oral glucose load (2). These criteria were developed for outpatients. Diagnostic criteria for diabetes in the hospitalized patient are not available; however, hyperglycemia (random plasma glucose > 180-200 mg%) warrants treatment. Measurement of the hemoglobin A1c, a reflection of glycemia for the prior 2-3 mo, is useful in determining the chronicity of hyperglycemia and, if elevated, indicates the presence of hyperglycemia prior to hospital admission. The nomenclature for diabetes classification is divided into type 1 diabetes (replaces insulin-dependent diabetes mellitus or IDDM), type 2 diabetes (replaces non-insulin-dependent diabetes mellitus or NIDDM), and other forms such as gestational diabetes or forms of diabetes secondary to other diseases (2).

Accurate classification of diabetes in a patient assists in glycemic management in the hospital setting and alerts the physician to associated conditions. Type 1 diabetes refers to hyperglycemia that results primarily from insulin deficiency. Although the prototypical patient is a young child or adolescent, the onset of type 1 diabetes may occur over the age of 20 yr in more than one-third of patients. Because type 1 diabetes is an autoimmune disorder, autoimmune thyroid disease (hyperthyroidism or hypothyroidism) and adrenal insufficiency should be considered in patients with unexplained hypotension, persistent tachycardia, or prolonged respiratory failure.

Type 2 diabetes results from a combination of insulin resistance and insulin deficiency with an additional contribution from increased hepatic glucose production. Although classically considered a disease of middle age, the age of onset of type 2 diabetes is declining. This is especially true in certain ethnic groups such as Native Americans, African-Americans, and individuals of Hispanic or Pacific Island background. Type 2 diabetes afflicts approximately 5% of the population and is often asymptomatic; as many as one-third of individuals with type 2 diabetes are undiagnosed. Thus, the critical care physician may "discover" diabetes in patients admitted for an unrelated illness (3, 4). Type 2 diabetes is often part of a metabolic syndrome known as "Syndrome X" or "Insulin Resistance Syndrome" that is characterized by hypertension, atherosclerosis, and central obesity. Regardless of the type of diabetes, sustained hyperglycemia over a number of years is responsible for diabetes-specific complications (retinopathy, nephropathy, neuropathy). These complications appear late in the first decade after diabetes onset. Since type 2 diabetes is often silent and undiagnosed, as many as 50% of individuals with type 2 diabetes have a diabetes-specific complication at diagnosis (2).

	RECENT ADVANCES IN THERAPY OF DIABETES MELLITUS

TOP INTRODUCTION CHANGES IN DIAGNOSIS,... RECENT ADVANCES IN THERAPY... MANAGEMENT OF HYPERGLYCEMIA IN... NUTRITIONAL SUPPORT IN PATIENTS... MANAGEMENT OF DIABETIC... ACUTE CARDIOVASCULAR... CONCLUSIONS NOTE ADDED IN PROOF REFERENCES

A brief review of advances in outpatient treatment of diabetes will facilitate the adaptation of these regimens to the intensive care setting. Type 1 diabetes requires continuous insulin treatment and even a brief period of insulin deficiency may lead to diabetic ketoacidosis (DKA). Most outpatients with type 1 diabetes are treated with two injections of long-acting insulin (ultralente, NPH, or lente insulin) and two or more injections of short-acting insulin, or receive a continuous insulin infusion via an insulin pump. Several new insulin formulations provide increased flexibility for glycemic management. Lispro is a genetically engineered derivative of human insulin that has a more rapid onset and higher peak insulin levels compared with regular insulin (5). Lispro has an onset of action of 10-15 min, peak activity at 1 h, and duration of action of 3 h after subcutaneous injection. Lispro should be given immediately prior to a meal (rather than the 30-45 min preprandial administration of regular insulin). Insulin aspart, a newly released short-acting insulin, is similar to lispro. Insulin glargine, a long-acting "basal" insulin, has two genetically engineered modifications that greatly slow absorption; insulin glargine has a duration of action of approximately 24 h, compared with 8-14 h for NPH insulin (6). In addition, insulin glargine has a very flattened plasma insulin profile compared with NPH insulin, which has a significant peak 6-12 h after injection.

Type 2 diabetes encompasses a spectrum of metabolic disorders that ranges from diet-controlled diabetes, to diabetes treated with oral medications, to diabetes that requires insulin. Although type 2 diabetes may initially be controlled with a single oral medication, it is usually progressive and eventually requires two or three oral agents and ultimately insulin for glycemic control. The growing number of oral agents available to treat the outpatient with type 2 diabetes can be broadly classified into four groups based on their site and mechanism of action (Table 1). Knowledge of these oral agents assists in management of the hospitalized diabetic who is often admitted on these agents in combination with each other and sometimes in combination with long-acting insulin. Insulin secretagogues have a rapid onset of action in contrast to metformin and thiazolidinediones, which begin to lower the blood glucose only after several weeks. Thus, metformin and the thiazolidinediones have little utility in the management of hyperglycemia in the hospitalized patient with diabetes or in the preparation of the patient with newly diagnosed diabetes for hospital discharge. Furthermore, both drugs have potential toxicity (metformin may cause lactic acidosis in patients with impaired renal function; thiazolidinediones increase plasma volume and may cause peripheral edema). Neither drug type should be used in patients with Class III-IV congestive heart failure. Insulin secretagogues will lower plasma glucose in hospitalized patients but their absorption, metabolism, and duration of action may be altered by a concurrent illness. Plus, these agents provide little option for dose adjustments to deal with changes in the plasma glucose and may cause hypoglycemia in patients who are non-per os (NPO). Oral agents should be discontinued when the patient is admitted to the intensive care unit, as these drugs are not useful for inpatient glycemic management and expose the patient to the risks of drug interactions and drug-specific side effects (Table 1). Consequently, most patients with hyperglycemia should be treated with insulin during hospitalization and then restarted on their oral medications during the transition to the outpatient setting. Many diabetic patients are taking an angiotensin-converting enzyme inhibitor because of the renoprotective activity; these drugs should be used with caution in patients with an elevated creatinine.

	MANAGEMENT OF HYPERGLYCEMIA IN CRITICAL CARE SETTING

TOP INTRODUCTION CHANGES IN DIAGNOSIS,... RECENT ADVANCES IN THERAPY... MANAGEMENT OF HYPERGLYCEMIA IN... NUTRITIONAL SUPPORT IN PATIENTS... MANAGEMENT OF DIABETIC... ACUTE CARDIOVASCULAR... CONCLUSIONS NOTE ADDED IN PROOF REFERENCES

Hospitalization of the diabetic patient interrupts the outpatient balance of medications, diet, and exercise, and may lead to hyperglycemia or hypoglycemia. Multiple factors predispose patients to both hyper- and hypoglycemia in the critical care setting (infection, drugs, reduced oral intake, etc.) (7, 8). Hospitalized patients may develop significant hyperglycemia even when there is no antecedent history of diabetes (3, 4). In fact, stress hyperglycemia is associated with increased mortality in patients with and without diabetes in the setting of acute myocardial infarction (9). Uncontrolled hyperglycemia is associated with worse clinical outcomes. For example, perioperative glycemic control correlates with postoperative risk of nosocomial infection after coronary artery bypass surgery (10). Glycemic control by continuous insulin infusion with a goal blood glucose level of < 200 mg/dl reduces the deep sternal wound infection rate for diabetic patients undergoing cardiac surgery (11). However, one must recall that there are no reliable clinical indicators for hypoglycemia; patients who have altered mental status, who are intubated, or who are severely ill may be unable to recognize or communicate hypoglycemic symptoms. Athough no clear consensus exists for the ideal level of glycemic control in the hospitalized patient, a reasonable target for glycemic control is a blood glucose of 100-200 mg/dl.

In the critically ill patient with type 1 diabetes, a continuous intravenous insulin infusion is the preferred method of hyperglycemia management. An intravenous insulin drip requires frequent blood glucose monitoring and alterations in the infusion rate, but maintains glycemic control in the setting of fluctuating clinical and metabolic status. A suggested pathway for glycemic control is shown in Table 2 (7). Unless uncontrolled hyperglycemia is present, patients receiving intravenous insulin should also receive intravenous dextrose to provide a metabolic substrate for insulin and to minimize the risk of hypoglycemia (Table 2). As an alternative to an insulin infusion, basal insulin may be provided with long-acting subcutaneous insulin (ultralente, NPH, or lente insulin). Additional short-acting insulin is given every 4-6 h to maintain glycemic control. Insulin pumps, a common outpatient therapy in type 1 diabetes, contain a reservoir of short-acting insulin and deliver a continuous infusion via a subcutaneous catheter at multiple basal rates. We generally recommend that patients admitted to the critical care unit on an insulin pump have their pump discontinued and their diabetes managed by an insulin infusion. Several practical issues support this approach: (1) most nurses and physicians are not trained to program the insulin pump (the patient may be the only person in the intensive care unit with the expertise to program the pump), (2) replacement pumps are not readily available in hospitals should the pump malfunction, and (3) infusion sets and replacement insulin reservoirs may not be routinely stocked by hospital pharmacies. As patients on insulin pumps often have a history of labile diabetes or frequent hypoglycemia, consultation with an endocrinologist may be useful.

Patients with type 2 diabetes and significant hyperglycemia (blood glucose > 180-200 mg/dl) should be managed with insulin. Oral diabetes agents should be discontinued and their use avoided in the critical care setting. Insulin regimens should provide basal insulin and short-acting insulin to cover meal-related glucose excursions and to improve glycemic control acutely. Unless the hyperglycemia is mild and expected to be transient, regular insulin sliding scales should not be used alone in hospitalized patients. Regular insulin, when given subcutaneously every 6 h without basal insulin, creates periods of insulin deficiency. Furthermore, if the blood glucose is normal, most sliding scales do not call for insulin, and thus no basal insulin is provided and hyperglycemia recurs. A continuous insulin infusion in the critically ill patient with type 2 diabetes likely provides optimal glycemic management. Alternatively, basal insulin for patients with type 2 diabetes may be provided with NPH, lente, or ultralente insulin at a starting dose of 0.4-0.6 U/kg/d in equally divided doses every 8-12 h. If the patient is relatively thin or has comorbidities that increase the risk for hypoglycemia (hepatic dysfunction or renal failure), a more conservative basal dose of 0.2 U/kg/d may be utilized. In addition to basal insulin coverage, additional short-acting insulin to manage acute hyperglycemia (given subcutaneously as regular or lispro insulin every 4-6 h) should be used. For patients who are eating, we suggest a meal dose 0.05 U/kg/meal for insulin-sensitive patients or 0.1 U/kg/meal for insulin-resistant patients. Blood glucose measurements should be reviewed at least daily and basal insulin coverage adjusted based upon the patient's level of glycemic control.

	NUTRITIONAL SUPPORT IN PATIENTS WITH DIABETES

TOP INTRODUCTION CHANGES IN DIAGNOSIS,... RECENT ADVANCES IN THERAPY... MANAGEMENT OF HYPERGLYCEMIA IN... NUTRITIONAL SUPPORT IN PATIENTS... MANAGEMENT OF DIABETIC... ACUTE CARDIOVASCULAR... CONCLUSIONS NOTE ADDED IN PROOF REFERENCES

Nutritional support with enteral or parenteral feeding, a key component in the care of critically ill patients, usually requires insulin therapy in patients with diabetes or may require insulin treatment in a patient not known to be diabetic (12, 13). Diabetic patients receiving parenteral nutrition have a 5-fold higher rate of central catheter-related infections compared with nondiabetics (13). Hypertriglyceridemia is frequent in patients with diabetes; triglyceride levels should be checked before and during parenteral lipid infusion therapy. If the patient's triglyceride levels are > 400 mg/dl, the lipid component of the parenteral nutrition should be withheld to minimize risk of uncontrolled hypertriglyceridemia, which may lead to pancreatitis (13). If the patient is not receiving a continuous insulin infusion, then regular insulin, based on the grams of carbohydrate in the infusion, may be added to the total parenteral nutrition (TPN) infusion. A reasonable initial regimen is 1 unit of insulin for every 15 g carbohydrate in the TPN infusion. The carbohydrate/insulin ratio is then adjusted based on the patient's blood glucose. Obese patients with type 2 diabetes and significant resistance may require as much as 1 unit for every 3-5 g of carbohydrate; thin type 1 diabetic patients may require only 1 unit for every 20 g of carbohydrate.

For patients receiving enteral nutrition, a continuous insulin infusion may provide optimal glycemic control. Alternatively, subcutaneous insulin may be used to provide continuous insulin coverage. Caveats about insulin coverage of enteral nutrition with subcutaneous insulin include the following: (1) Outpatient insulin regimens contain more insulin in the morning dose (for example, two-thirds of intermediate insulin in the morning and one-third in the evening dose) because of the greater oral intake during the day (2) NPH or lente insulin's peak action may vary considerably between patients; this peak is often near the mid-day or evening meal in outpatients, but complicates insulin coverage in patients receiving continuous nutritional intake. Patients receiving continuous enteral feeding require the same amount of insulin throughout the day. The use of modified enteral formulas with high monounsaturated fatty acid (MUFA) and low carbohydrate content, such as Glucerna, may improve glycemic control in patients with diabetes who require enteral nutrition (12).

	MANAGEMENT OF DIABETIC KETOACIDOSIS AND NONKETOTIC HYPEROSMOLAR SYNDROME

TOP INTRODUCTION CHANGES IN DIAGNOSIS,... RECENT ADVANCES IN THERAPY... MANAGEMENT OF HYPERGLYCEMIA IN... NUTRITIONAL SUPPORT IN PATIENTS... MANAGEMENT OF DIABETIC... ACUTE CARDIOVASCULAR... CONCLUSIONS NOTE ADDED IN PROOF REFERENCES

Patients may present with DKA as a primary diagnosis, as a complication of another diagnosis, or may develop it during the course of treatment for another condition. The most common causes of DKA are infection, noncompliance with treatment, and new-onset type 1 diabetes (14, 15). Less common precipitating events include glucocorticoids, myocardial infarction, pancreatitis, alcohol, cocaine, burns, and stroke. The mortality rate in young adults is approximately 2-4% (14, 15). However, the mortality in those over 65 yr of age may exceed 20% (14, 15). Older patients with type 2 diabetes may have hyperglycemia and hypotonic fluid loss for days or weeks as an outpatient and may present with nonketotic hyperosmolar syndrome (NKHS) with resultant hypertonicity. However, some patients with type 2 diabetes may have metabolic features of DKA; this usually occurs in Hispanic individuals and obese African-Americans (16).

DKA and NKHS should be viewed as part of a spectrum of metabolic disorders related to uncontrolled diabetes mellitus. Low dose regular intravenous insulin therapy (generally 0.1- 0.2 U/kg as a loading dose and then 5-10 units/h as an infusion) in addition to appropriate fluid and electrolyte replacement remains the mainstay of therapy for DKA and NKHS. In DKA, early institution of long-acting insulin (as soon as the acidosis begins to improve) will hasten the transition to an outpatient insulin regimen and shorten the hospital stay (8, 17). Though DKA is most commonly associated with an anion gap metabolic acidosis, some patients may present with a pure hyperchloremic metabolic acidosis or a mixed acid-base disorder (18). Hyperchloremic metabolic acidosis is commonly seen in the recovery phase of DKA due to loss of ketoacids in the urine that cannot be used to regenerate bicarbonate and infusion of fluids containing higher concentrations of chloride than plasma. Shifting to lactated Ringer's or half-normal saline (with dextrose) for intravenous fluid therapy as soon as intravascular volume is restored will minimize the development of hyperchloremia. Complications of DKA include the acute respiratory distress syndrome (ARDS), gastrointestinal (GI) hemorrhage, hypertriglyceridemia, and central nervous system disturbances. Patients with a widened alveolar-arterial O₂ gradient or rales on physical examination at presentation with DKA appear to be at increased risk for ARDS (19). A study by Faigel and Metz found a 14% incidence of upper GI hemorrhage in patients admitted to the intensive care unit with DKA (20).

In the past, bicarbonate therapy in DKA has sometimes been advocated. However, bicarbonate therapy during DKA has several potentially deleterious effects including worsening of hypokalemia, worsening of intracellular acidosis, and production of paradoxical central nervous system acidosis. A study of bicarbonate infusion in seven patients with DKA by Okuda and coworkers demonstrated a paradoxical increase in acetoacetate levels during alkali administration and a delay in the improvement of ketosis (21). A retrospective, nonrandomized study of 39 consecutive patients with DKA with an arterial pH between 6.83 and 7.08 found no difference in recovery with bicarbonate treatment (22). These authors also summarized five other trials of bicarbonate therapy in DKA and concluded that the available data do not support the use of bicarbonate in the treatment of diabetic ketoacidosis with pH values between 6.9 and 7.1. We feel that bicarbonate should not be administered during DKA for pH > 6.9; for pH < 6.9 the evidence is incomplete and does not suggest a beneficial effect.

	ACUTE CARDIOVASCULAR COMPLICATIONS IN DIABETES MELLITUS

TOP INTRODUCTION CHANGES IN DIAGNOSIS,... RECENT ADVANCES IN THERAPY... MANAGEMENT OF HYPERGLYCEMIA IN... NUTRITIONAL SUPPORT IN PATIENTS... MANAGEMENT OF DIABETIC... ACUTE CARDIOVASCULAR... CONCLUSIONS NOTE ADDED IN PROOF REFERENCES

Cardiovascular disease accounts for roughly 80% of the mortality in patients with diabetes in North America. A recent consensus statement from the American Heart Association and the American Diabetes Association designated diabetes as a major risk factor for cardiovascular disease (at the same level as hyperlipidemia, smoking, and hypertension) (23). Diabetic patients have a 1.5-2 times greater mortality risk from acute myocardial infarction (MI) than nondiabetic patients. The principal factors for this include an increased incidence of congestive heart failure, reinfarction, and recurrent ischemia (24).

Patients with diabetes and acute myocardial infarction actually derive greater absolute survival benefit from fibrinolytic therapy for acute MI than nondiabetics, but are less likely to receive fibrinolytic therapy (25). The Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO-1) trial found no significant differences in major bleeding between patients with and without diabetes and showed that the rate of ocular hemorrhage was extremely low (one ocular hemorrhage consisting of eyelid hematoma in 6,011 diabetic patients in the trial) (26). Therapy with -blockers in patients with diabetes post-MI is also clearly beneficial in terms of survival (27). However, -blockers are sometimes withheld from patients with diabetes because of concern over impairment of hypoglycemic awareness. In reality, -blockers (especially ₁-selective agents) have minimal effects on glycemic awareness and do not increase the incidence of clinically significant hypoglycemic events (28). Thus, diabetes is not a contraindication for -blockers or for fibrinolytic therapy in acute MI.

The role of catheter-based interventions such as angioplasty and stenting versus coronary artery bypass for revascularization of diabetic patients continues to evolve. Diabetic patients have a high rate of restenosis post-PTCA and the Bypass Angioplasty Revascularization Investigation (BARI) trial showed a higher mortality in patients with diabetes undergoing percutaneous transluminal coronary angioplasty (PTCA) versus coronary artery bypass (29). The weight of current evidence still favors coronary artery bypass for revascularization of patients with diabetes with multivessel disease. The SHOCK trial (SHould we emergently revascularize Occluded Coronaries for cardiogenic shocK) found that patients with diabetes have higher in-hospital mortality compared with patients without diabetes, but that patients with diabetes benefit from early revascularization (angioplasty, bypass surgery, or both) when compared to initial medical management alone (30).

The role of metabolic control in acute myocardial infarction remains controversial (28). The Diabetes Mellitus, Insulin Glucose Infusion in Acute Myocardial Infarction (DIGAMI) study found that a glucose-insulin infusion during an acute MI followed by intensive treatment with multiple daily insulin injections reduced mortality at 1-yr post-MI; the survival benefit persisted at 3.4 yr of mean follow-up (31). Melidonis and coworkers demonstrated that an insulin infusion in patients with diabetes during acute coronary syndromes improved the fibrinolytic profile (fibrinogen, t-PA, and PAI-1 levels) (32). Larger prospective trials are needed to further define the role of intensive insulin therapy in acute myocardial infarction, but significant data suggest that good glycemic control in acute MI should be the goal in patients with diabetes.

	CONCLUSIONS

TOP INTRODUCTION CHANGES IN DIAGNOSIS,... RECENT ADVANCES IN THERAPY... MANAGEMENT OF HYPERGLYCEMIA IN... NUTRITIONAL SUPPORT IN PATIENTS... MANAGEMENT OF DIABETIC... ACUTE CARDIOVASCULAR... CONCLUSIONS NOTE ADDED IN PROOF REFERENCES

Correct classification of the type of diabetes, careful attention to glycemic control, and frequent reassessment of glucose values will improve patient outcomes and reduce the length of hospital stay. Oral agents used for outpatient management of type 2 diabetes should be discontinued in the critically ill patient. Insulin regimens should provide continuous insulin coverage in the form of an insulin infusion or a combination of long- and short-acting insulin. A high suspicion and aggressive management of underlying cardiovascular disease will reduce morbidity and mortality.

	NOTE ADDED IN PROOF

TOP INTRODUCTION CHANGES IN DIAGNOSIS,... RECENT ADVANCES IN THERAPY... MANAGEMENT OF HYPERGLYCEMIA IN... NUTRITIONAL SUPPORT IN PATIENTS... MANAGEMENT OF DIABETIC... ACUTE CARDIOVASCULAR... CONCLUSIONS NOTE ADDED IN PROOF REFERENCES

A recent report of a prospective, randomized trial in hyperglycemic patients on mechanical ventilation in a surgical intensive care unit found that maintaining the blood glucose between 80 and 110 mg% by insulin infusion reduced morbidity and mortality (Van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M, Vlasselaers D, Ferdinande P, Lauwers P, Bouillon R. Intensive insulin therapy in critically ill patients. N Engl J Med 2001;345:1359-1367). Most patients had undergone cardiac surgery. This benefit, seen in patients in the intensive care unit for five or more days, included a reduction in infections, acute renal failure, and the need for transfusion.

	Footnotes

Correspondence and requests for reprints should be addressed to Alvin C. Powers, Division of Endocrinology, 715 PRB, Vanderbilt University, Nashville, TN 37232. E-mail: Al.Powers{at}mcmail.vanderbilt.edu

(Received in original form March 14, 2001 and accepted in revised form September 19, 2001).

	References

TOP INTRODUCTION CHANGES IN DIAGNOSIS,... RECENT ADVANCES IN THERAPY... MANAGEMENT OF HYPERGLYCEMIA IN... NUTRITIONAL SUPPORT IN PATIENTS... MANAGEMENT OF DIABETIC... ACUTE CARDIOVASCULAR... CONCLUSIONS NOTE ADDED IN PROOF REFERENCES

1. Moss M, Guidot DM, Steinberg KP, Duhon GF, Treece P, Wolken R, Hudson LD, Parsons PE. Diabetic patients have a decreased incidence of acute respiratory distress syndrome. Crit Care Med 2000; 28: 2187-2192 [Medline].

2. American Diabetes Association: Clinical Practice Recommendations 2001. Diabetes Care 2001;24(Suppl).

3. Graber AL, McDonald T. Newly identified hyperglycemia among hospitalized patients. South Med J 2000; 93: 1070-1072 [Medline].

4. Levetan CS, Passaro M, Jablonski K, Kass M, Ratner RE. Unrecognized diabetes among hospitalized patients. Diabetes Care 1998; 21: 246-249 [Abstract].

5. Holleman F, Hoekstra JB. Insulin lispro. N Engl J Med 1997; 337: 176-183 [Free Full Text].

6. Gillies PS, Figgitt DP, Lamb HM. Insulin glargine. Drugs 2000; 59: 253-260 [Medline].

7. Hirsch IB, Paauw DS, Brunzell J. Inpatient management of adults with diabetes. Diabetes Care 1995; 18: 870-878 [Medline].

8. Levetan CS, Magee MF. Hospital management of diabetes. Endocrinol Metab Clinics North Am 2000; 29: 745-770 . [Medline]

9. Capes SE, Hunt D, Malmberg K, Gerstein HC. Stress hyperglycaemia and increased risk of death after myocardial infarction in patients with and without diabetes: a systematic overview. Lancet 2000; 355: 773-778 [Medline].

10. Golden SH, Peart-Vigilance C, Kao WH, Brancati FL. Perioperative glycemic control and the risk of infectious complications in a cohort of adults with diabetes. Diabetes Care 1999; 22: 1408-1414 [Abstract/Free Full Text].

11. Furnary AP, Zerr KJ, Grunkemeier GL, Starr A. Continuous intravenous insulin infusion reduces the incidence of deep sternal wound infection in diabetic patients after cardiac surgical procedures. Ann Thorac Surg 1999; 67: 352-360 [Abstract/Free Full Text].

12. Coulston AM. Clinical experience with modified enteral formulas for patients with diabetes. Clin Nutr 1998;17(Suppl 2):46-56.

13. McMahon MM, Rizza RA. Nutrition support in hospitalized patients with diabetes mellitus. Mayo Clin Proc 1996; 71: 587-594 [Medline].

14. Delaney MF, Zisman A, Kettyle WM. Diabetic ketoacidosis and hyper- glycemic hyperosmolar nonketotic syndrome. Endocrinol Metab Clin North Am 2000; 29: 683-705 [Medline].

15. Lebovitz HE. Diabetic ketoacidosis. Lancet 1995; 345: 767-772 [Medline].

16. Umpierrez GE, Woo W, Hagopian WA, Isaacs SD, Palmer JP, Gaur LK, Nepom GT, Clark WS, Mixon PS, Kitabchi AE. Immunogenetic analysis suggests different pathogenesis for obese and lean African-Americans with diabetic ketoacidosis. Diabetes Care 1999; 22: 1517-1523 [Abstract/Free Full Text].

17. Fleckman AM. Diabetic ketoacidosis. Endocrinol Metab Clinics North Am 1993; 22: 181-207 . [Medline]

18. Elisaf MS, Tsatsoulis AA, Katopodis KP, Siamopoulos KC. Acid-base and electrolyte disturbances in patients with diabetic ketoacidosis. Diabetes Res Clin Pract 1996; 34: 23-27 [Medline].

19. Kitabchi AE, Wall BM. Diabetic ketoacidosis. Med Clin North Am 1995; 79: 9-37 [Medline].

20. Faigel DO, Metz DC. Prevalence, etiology, and prognostic significance of upper gastrointestinal hemorrhage in diabetic ketoacidosis. Dig Dis Sci 1996; 41: 1-8 [Medline].

21. Okuda Y, Adrogue HJ, Field JB, Nohara H, Yamashita K. Counterproductive effects of sodium bicarbonate in diabetic ketoacidosis. J Clin Endocrinol Metab 1996; 81: 314-320 [Abstract].

22. Viallon A, Zeni F, Lafond P, Venet C, Tardy B, Page Y, Bertrand JC. Does bicarbonate therapy improve the management of severe diabetic ketoacidosis? Crit Care Med 1999; 27: 2690-2693 [Medline].

23. Grundy SM, Benjamin IJ, Burke GL, Chait A, Eckel RH, Howard BV, Mitch W, Smith SC Jr,, Sowers JR. Diabetes and cardiovascular disease: a statement for healthcare professionals from the American Heart Association. Circulation 1999; 100: 1134-1146 [Medline].

24. Aronson D, Rayfield EJ, Chesebro JH. Mechanisms determining course and outcome of diabetic patients who have had acute myocardial infarction. Ann Intern Med 1997; 126: 296-306 [Abstract/Free Full Text].

25. Mak KH, Topol EJ. Emerging concepts in the management of acute myocardial infarction in patients with diabetes mellitus. J Am Coll Cardiol 2000; 35: 563-568 [Abstract/Free Full Text].

26. Mahaffey KW, Granger CB, Toth CA, White HD, Stebbins AL, Barbash GI, Vahanian A, Topol EJ, Califf RM. Diabetic retinopathy should not be a contraindication to thrombolytic therapy for acute myocardial infarction: review of ocular hemorrhage incidence and location in the GUSTO-I trial. Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries. J Am Coll Cardiol 1997; 30: 1606-1610 [Abstract].

27. Jonas M, Reicher-Reiss H, Boyko V, Shotan A, Mandelzweig L, Goldbourt U, Behar S. Usefulness of beta-blocker therapy in patients with non-insulin-dependent diabetes mellitus and coronary artery disease. Bezafibrate Infarction Prevention (BIP) Study Group. Am J Cardiol 1996; 77: 1273-1277 [Medline].

28. Paty BW. Managing myocardial infarction in the diabetic patient. Endocrinol Metab Clin North Am 2000; 29: 831-842 [Medline].

29. Influence of diabetes on 5-year mortality and morbidity in a randomized trial comparing CABG and PTCA in patients with multivessel disease: the Bypass Angioplasty Revascularization Investigation (BARI). Circulation 1997;96:1761-1769.

30. Shindler DM, Palmeri ST, Antonelli TA, Sleeper LA, Boland J, Cocke TP, Hochman JS. Diabetes mellitus in cardiogenic shock complicating acute myocardial infarction: a report from the SHOCK Trial Registry. SHould we emergently revascularize Occluded Coronaries for cardiogenic shocK? J Am Coll Cardiol 2000;36(Suppl A):1097-1103.

31. Malmberg K. Prospective randomised study of intensive insulin treatment on long term survival after acute myocardial infarction in patients with diabetes mellitus. DIGAMI (Diabetes Mellitus, Insulin Glucose Infusion in Acute Myocardial Infarction) Study Group. BMJ 1997; 314: 1512-1515 [Abstract/Free Full Text].

32. Melidonis A, Stefanidis A, Tournis S, Manoussakis S, Handanis S, Zairis M, Dadiotis L, Foussas S. The role of strict metabolic control by insulin infusion on fibrinolytic profile during an acute coronary event in diabetic patients. Clin Cardiol 2000; 23: 160-164 [Medline].