The American Journal of the Medical Sciences Hyperglycemia Correlates with Outcomes in Patients Receiving Total Parenteral Nutrition DOI: 10.1097/MAJ.0b013e3180536b26ISSN: 0002-9629Accession: 00000441-200705000-00001Full Text (PDF) 315 K Author(s): Lin, Liang-Yu MD; Lin, Han-Chieh MD; Lee, Pui-Ching MD; Ma, Wen-Ya MD; Lin, Hong-Da MD Issue:Volume 333(5), May 2007, pp 261-265 Publication Type:[Articles] Publisher:(C) Copyright 2007 Southern Society for Clinical Investigation Institution(s):From the Division of Endocrinology and Metabolism (l-yl, h-dl) and the Division of Gastroenterology (h-cl), Department of Medicine (p-cl), Taipei Veterans General Hospital, Taipei, Taiwan; the School of Medicine (h-cl, h-dl), National Yang-Ming University, Taipei, Taiwan; and the Division of Endocrinology and Metabolism (w-ym), Department of Internal Medicine, Taoyuan Veterans Hospital, Taoyuan, Taiwan. Submitted May 24, 2006; accepted in revised form December 6, 2006. Correspondence: Dr. Hong-Da Lin, Division of Endocrinology and Metabolism, Department of Medicine, Taipei Veterans General Hospital, No. 201, Section 2, Shih-Pai Road, Taipei 112, Taiwan (E-mail: hdlin@vghtpe.gov.tw). Keywords: Total parenteral nutrition, Hyperglycemia, Outcomes ---------------------------------------------- Outline ABSTRACT: Patients and Methods Study Subjects Methods Statistical Analysis Results Discussion Acknowledgments References Graphics Figure 1 Table 1 Figure 2 Table 2 ABSTRACT: Background: Hyperglycemia is associated with higher mortality rates after myocardial infarction, stroke, and in critically ill patients. This study was made to determine the associations between hyperglycemia and adverse outcomes in patients receiving total parenteral nutrition (TPN). Methods: A retrospective cohort study included total 457 patients (age, 66.4 +/- 16.3 years) receiving TPN in 2004. The patients were divided by mean glucose level into quartiles: quartile 1 (180 mg/dL, Q4). A logistic regression analysis was performed to determine whether the degree of hyperglycemia was associated with the adverse outcomes. Results: The odds ratio of death was significantly increased in quartile 2 (OR, 2.1 [95% CI: 1.1 to 4.0]) (P = 0.02), quartile 3 (OR, 2.3 [95% CI: 1.2 to 4.5]) (P = 0.01), and quartile 4 (OR, 5.0 [95% CI: 2.4 to 10.6]) (P P P P P Conclusions: Hyperglycemia in patients receiving TPN correlates with morbidities and mortality. A prospective, randomized, controlled study instituting aggressive hyperglycemic control is required to determine whether the control of blood glucose can improve outcomes in patients receiving TPN. ---------------------------------------------- It is well established that individuals with in-hospital hyperglycemia are associated with higher mortality rates after myocardial infarction, stroke, and acute exacerbations of chronic obstructive pulmonary disease as well as in critically ill patients.1-6 In addition, hyperglycemia represents an important marker of poor outcomes and mortality in general hospital ward patients.7 Moreover, hyperglycemia has been associated with increased infection rates in patients undergoing elective surgery.8 Strict glycemic control with intensive insulin therapy can reduce morbidities and mortality in medical ICU patients and coronary artery bypass graft diabetics.9,10 Total parenteral nutrition (TPN), often a lifesaving treatment, has been associated with problematic adverse effects such as infections and extremely hyperglycemia.11,12 Patients indicated for TPN therapy are usually critically ill and insulin resistant. Moreover, Overett et al 13 had reported the prevalence of central vein catheter infection is 5 times higher in diabetic patients than in the general TPN-treated population. In infants, TPN-associated hyperglycemia also correlates with prolonged mechanical ventilation and hospital stay.14 To our knowledge, there is only one report regarding the associations of hyperglycemia with adverse outcomes in patients receiving TPN.11 Furthermore, there are no reports regarding hyperglycemia with fungemia and respiratory failure, which may increase in-hospital mortality rates in TPN-treated patients. To address these questions, we performed a retrospective study to determine the associations between hyperglycemia and clinical outcomes of patients receiving TPN. Patients and Methods Study Subjects The medical records of 464 adult patients, who started receiving TPN in 498 treatment episodes between January 1, 2004, and December 31, 2004, at the Taipei Veterans General Hospital, Taipei, Taiwan were retrospectively reviewed. Of these, 7 patients (1%) in 7 treatment episodes were excluded because of a lack of detailed blood glucose measurement records during TPN treatment. In addition, patients received TPN treatment more than once during hospitalization, the first episode was included in the study, and further episodes were excluded. This retrospective cohort study was approved by the institutional review board of the hospital. Methods All of the subjects had serum glucose measurements twice a week, which were determined with the use of a Hitachi 7600 autoanalyzer (Hitachi Instruments Corp, Tokyo, Japan), whereas hyperglycemic patients would undergo capillary glucose testing every 6 hours by finger prick with a glucometer (Lifescan, CA. We estimated the capillary blood glucose as 90% of the serum glucose value.15 The number of blood glucose values per patient ranged from 1 to 207. The mean blood glucose levels were calculated according to the capillary glucose records in each TPN episode as a marker for the degree of hyperglycemia. The total caloric requirements of all patients during TPN therapy were calculated from 1.2 to 2.0 times of the estimated basal energy expenditure, using the Harris-Benedict equation, based on observations of patients undergoing treatment for a variety of medical and surgical condition. The TPN regimen consisted of protein calculated at 1.0 g/kg body weight and nonprotein energy, which was provided by dextrose, water, and fat emulsions. In addition, vitamin K1 and ferric chloride (Atofen UJI Pharmaceutical Co., Japan) are added twice a week. TPN is usually commenced at 63 mL/h, with the remaining fluid requirements from normal saline. After the first 24 hours of TPN therapy, the TPN regimen is adjusted according to the nutrition status evaluated mainly by serum albumin, transferrin, urine urea nitrogen, and enteral nutrition support. Patients receiving TPN treatment are assessed individually on a daily basis by a specialized clinical pharmacist and a clinical nurse consultant staff of the TPN group at Taipei Veterans General Hospital. A special chart with daily clinical and biochemical data recorded on a flow sheet is kept for every patient receiving TPN. The primary end point was all-cause in-hospital death. Other clinical outcome parameters as described by Cheung et al,11 including the development of any infection, cardiac complications, or acute renal failure were used in this study. In addition, bacteremia and fungemia were determined on the basis of blood culture-proven bacterial or fungal infection. Respiratory failure was defined as the clinical diagnosis of respiratory failure with the requirement of mechanical ventilatory support while receiving TPN. The accumulated outcome variables of "any complication" were based on the presence of any of the abovementioned complications. Adverse outcomes were assessed as a function of mean blood glucose levels while receiving TPN. In addition to mean blood glucose levels, other prognostic variables were examined: age, sex, body weight, prior diagnosis of diabetes, ICU stay, insulin therapy, and blood sugar readings before TPN treatment. Patients were classified as having known diabetes if they had a documented history of diabetes according to the medical records. Statistical Analysis The risk of developing adverse outcomes for different blood glucose level was determined by using univariate logistic regression, in which blood glucose level was used as a continuous variable. Multivariate logistic regressions were performed to determine the risk of obtaining adverse outcomes after adjusting for factors such as age, sex, body weight, prior diagnosis of diabetes, ICU stay, insulin therapy, blood sugar readings before TPN treatment, and frequency of blood sugar measurements. The data set was divided into quartiles according to mean blood glucose level; odds ratios for higher blood glucose groups (Q2~Q4) versus lowest one (Q1) were calculated. The Student t test was used to compare groups with normally distributed data. Where there was non-normal distribution of data, the Mann-Whitney U test was used. Differences were considered significant if the P value was Results In our series, a total of 457 study patients (mean age, 66.4 +/- 16.3 years) who received TPN treatment were included. Of the 457 treatment episodes, 291 (63.7%) were in men and 75 (16.4%) were known diabetics. Among the 75 episodes in diabetics, 67 patients were treated with insulin, 3 with oral hypoglycemic agents, and 5 with diet control alone. TPN was administrated for 397 patients (86.9%) who were under nothing per os due to primary gastrointestinal indication, including 123 cancer bleeding, 64 intestinal obstruction, 63 ulcer bleeding, 51 pancreatitis, 21 postoperative intestinal leakage, 13 intestinal perforation and others; the remaining were given as nutrition support for preoperative preparation in 28 patients (6.1%) and for other reasons in 32 episodes (7.0%). The overall mean duration of TPN treatment was 17.8 +/- 17.7 days (median [range]: 13[1-215] days). The mean blood glucose concentration was calculated during TPN therapy, and overall mean blood glucose level was 155.4 +/- 57.9 mg/dL (Figure 1). ---------------------------------------------- Figure 1. Histogram showing the mean blood glucose level calculated during TPN therapy for each of the 457 patients. ---------------------------------------------- Of the 457 treatment episodes, 298 (65.2%) were affected by one or more complication. With logistic regression analysis, the odds ratio of having "any complications" while receiving TPN was found to be 1.14 (95% CI: 1.09 to 1.20) (P P P pP P For each outcomes measure, data were also analyzed by dividing the TPN episodes into quartiles by mean glucose levels (180 mg/dL). The odds ratio of complications was analyzed by using blood glucose P P ---------------------------------------------- Table 1. Risk of Complications per Quartile of Blood Glucose Level After Adjusting for Age, Sex, Body Weight, Prior Diagnosis of Diabetes, ICU Stay, Insulin Therapy, Blood Sugar Readings Before TPN Treatment, and Frequency of Blood Sugar Measurements ---------------------------------------------- ---------------------------------------------- Figure 2. Odds ratio of adverse outcomes adjusted with sex, age, body weight, and prior diagnosis of diabetes in patients receiving TPN. Adjusted odds ratios of Q2 (blood glucose 114 to 137 mg/dL), Q3 (blood glucose 137 to 180 mg/dL), and Q4 (blood glucose >180 mg/dL) were calculated by using Q1 (blood glucose ---------------------------------------------- Patients with diabetes were significantly older (69.9 +/- 13.0 vs 65.7 +/- 16.8, P = 0.02), heavier (61.7 +/- 12.6 vs 56.8 +/- 12.4, P P P P = 0.03) than nondiabetics during TPN treatment. On the contrary, there was no significant difference in ICU stay (30.7% vs 21.5%, P = 0.11) and TPN duration (17.0 +/- 11.5 vs 17.9 +/- 18.7, P = 0.46) between these two groups. In adverse outcomes, we found that patients with diabetes mellitus had a significantly higher rate of any infection, cardiac complication, and mortality than nondiabetic patients (Table 2). ---------------------------------------------- Table 2. Differences Between Diabetic Subjects and Nondiabetic Subjects ---------------------------------------------- Discussion The salient finding of this investigation is that the degree of hyperglycemia occurring during TPN treatment is associated with increased adverse outcomes and mortality rates in patients receiving TPN. Although a strong relation between hyperglycemia and in-hospital mortality rates in critically ill patients has been well-established, our study found that the risk of death increased by a factor of 1.10 for each 10-mg/dL increase in blood glucose level as well as a 5.0-fold increase in mortality rates among subjects in the highest quartile of mean blood glucose level (>180 mg/dL). We also found an association between hyperglycemia and the development of infection, cardiac complication, acute renal failure, and respiratory failure. Therefore, the development of the increased mortality rates among patients with high mean glucose levels can be explained by the simultaneously increased potential of developing morbidities and complications in these TPN-treated patients. The Veterans Administration Cooperative Trial evaluated the clinical value of preoperative TPN in malnourished patients undergoing elective surgery.16 Despite a reduction in noninfective complications in the TPN group, the infective complications were 2.2 times more common. Recently, Cheung et al 11 conducted a retrospective study to determine whether elevated blood glucose levels were associated with adverse outcomes in patients who had TPN therapy. They found a positive correlation between the mean daily glucose level and infection and systemic sepsis. Similarly, the relation between hyperglycemia and any infection was confirmed again in our series. Our study evaluated the additional effects of hyperglycemia on bacteremia, fungemia, and respiratory failure in TPN-treated patients. As we know, mortality rate increases when bacteremia, fungemia, or respiratory failure occurs in in-hospital patients. This is first study to imply that severe hyperglycemia may be associated with respiratory failure in patients with TPN treatment. The incidence of fungemia during TPN treatment rose with the degree of hyperglycemia, even though the increase was not statistically significant. However, Bader et al 15 had proven that severe hyperglycemia was an important marker of increased mortality rates among hospitalized diabetic patients with fungemia. Although the high morbidity and mortality rates relate to the associated illness precipitating stress in such patients, hyperglycemia itself might contribute to morbidity by creating a toxic cellular milieu, causing intracellular and extracellular dehydration, inducing electrolyte abnormalities, and depressing the immune system.17,18 In this study, the incidence of any infection, cardiac complications, and death were significantly higher in diabetic patients with TPN treatment than in nondiabetic patients. These findings could partially be explained by the older age, higher blood glucose concentrations, and body weight in the diabetic group. The mean blood glucose level of nondiabetic patients receiving TPN treatment was significantly lower than that of diabetic patients (P This study has several limitations. First, patients with diabetes were significantly older, heavier, and had a relatively poorer glycemic control. Second, we did not evaluate the effect of a short period in coadministration of enteral nutrition support and TPN treatment, which may acute worse the blood sugar levels, when patients recovered from the disease for TPN treatment. Third, we did not study the effects of different treatment modalities on morbidity and mortality, and, finally, the benefit of strict glycemic control is not evaluated in this retrospective study. Van den Berghe et al 19 had shown intensive insulin therapy in the critically ill patients can improve the outcome. A prospectively controlled trial in TPN subjects is mandatory. In conclusion, this study confirmed the association between hyperglycemia and poor clinical outcomes in TPN-treated patients. Our study should prompt physicians to consider improving glycemic control for patients receiving TPN treatment. Acknowledgments The authors would like to thank the members of the clinical nurse consultant staff of the TPN group at Taipei Veterans General Hospital for their records and support for this study. References 1. Capes SE, Hunt D, Malmberg K, et al. Stress hyperglycemia and increased risk of death after myocardial infarction in patients with and without diabetes: a systemic overview. Lancet 2000;355:773-8. 2. Capes SE, Hunt D, Malmberg K, et al. Stress hyperglycemia and prognosis of stroke in patients with and without diabetes: a systemic overview. Stroke 2001;32:2426-32. 3. Baker EH, Janaway CH, Philips BJ, et al. Hyperglycemia is associated with poor outcomes in patients admitted to hospital with acute exacerbations of chronic obstructive pulmonary disease. Thorax 2006;61:284-9. 4. Van den Berghe G, Wouters P, Weeker F, et al. Intensive insulin therapy in critically ill patients. N Engl J Med 2001;345:1359-67. 5. Finney SJ, Zekveld C, Elia A, et al. Glucose control and mortality in critically ill patients. JAMA 2003;290:2041-7. 6. Krinsley JS. Association between hyperglycemia and increased hospital mortality in a heterogenous population of critically ill patients. Mayo Clin Proc 2003;78:1471-8. 7. Umpierrex GE, Isaacs SD, Bazargan N, et al. Hyperglycemia: an independent marker of in-hospital mortality in patients with undiagnosed diabetes. J Clin Endocrinol Metab 2002;87:978-92. 8. Pomposelli J, Baxter J, Babineau T, et al. Early postoperative glucose control predicts nosocomial infection rate in diabetic patients. J Parenter Enteral Nutr 1998;22:77-81. 9. Van den Berghe G, Wilmer A, Hermans G, et al. Intensive insulin therapy in the medical ICU. N Engl J Med 2006;354:449-61. 10. Lazar HL, Chipkin SR, Fitzgerald CA, et al. Tight glycemic control in diabetic coronary artery bypass graft patients improves perioperative outcomes and decreases recurrent ischemic events. Circulation 2004;109:1497-502. 11. Cheung NW, Napier B, Zaccaria C, et al. Hyperglycemia is associated with adverse outcomes in patients receiving total parenteral nutrition. Diabetes Care 2005;28:2367-71. 12. McCowen KC, Malhotra A, Bistrian BR. Stress-induced hyperglycemia. Crit Care Med 2001;17:107-24. 13. Overett TK, Bistrian BR, Lowry SF, et al. Total parenteral nutrition in patients with insulin-requiring diabetes mellitus. J Am Coll Nutr 1986;5:79-89. 14. Alaedeen DI, Walsh MC, Chwals WJ. Total parenteral nutrition-associated hyperglycemia correlates with prolong mechanical ventilation and hospital stay in septic infant. J Pediatr Surg 2006;4:239-44. 15. Bader MS, Hinthorn D, Lai SM, et al. Hyperglycaemia and mortality of diabetic patients with candidaemia. Diabet Med 2005;22:1252-7. 16. Buzby GP, Blouin G, Colling CL, et al. Perioperative total parenteral nutrition in surgical patients. N Engl J Med 1991;325:525-32. 17. Mizok BA. Alternations in carbohydrate metabolism during stress: a review of the literature. Am J Med 1995;98:75-84. 18. Khaodhiar L, McCowen K, Bristrian B. Perioperative hyperglycemia, infection or risk? Curr Opin Clin Nutr Metab Care 1999;2:79-82. 19. Van den Berghe G, Wouters PJ, Bouillon R, et al. Outcomes benefit of intensive insulin therapy in the critically ill: insulin dose versus glycemic control. Crit Care Med 2003;31:359-66. KEY INDEXING TERMS: Total parenteral nutrition; Hyperglycemia; Outcomes ----------------------------------------------