Higher dextrose delivery via TPN related to the development of hyperglycemia in non-diabetic critically ill patients

Parenteral nutrition (PN) is an important means of providing nutrition to patients with a nonfunctional gastrointestinal tract, limited absorptive capacity, or other problems that prevent enteral feeding. Although PN has improved patient outcomes, recent randomized trials and meta-analyses have raised questions about its safety and the high rate of total parenteral nutrition (TPN)-associated complications and mortality in critically ill patients [1, 2]. The current clinical guidelines for nutritional support in critically ill patients differ substantially by society. The Guidelines for the Nutrition Support Therapy in Critically Ill Patient by the American Society of Parenteral and Enteral Nutrition (ASPEN) and the Society of Critical Care Medicine (SCCM) [3] recommend early initiation of enteral nutrition but suggest that PN therapy be initiated after seven days for critically ill patients who are well nourished at baseline. In contrast, the guidelines of the European Society of Parenteral and Enteral Nutrition (ESPEN) recommended that practitioners consider initiating parenteral nutrition within two days of admission to the intensive care unit (ICU) for patients who cannot be adequately fed enterally [4].

The increased risk of TPN-associated complications can be related, among other factors, to the development of hyperglycemia [5, 6]. TPN might cause hyperglycemia in patients with no history of diabetes mellitus [7]; hyperglycemia during TPN therapy can cause a higher mortality rate and prevalence of complications, especially infectious complications. However, there have been few studies to evaluate the effects of the amount of dextrose from TPN on the development of hyperglycemia. Therefore, we conducted this study to examine whether the amount of dextrose from TPN was associated with hyperglycemia and how it affects clinical outcomes in critically ill patients with no history of diabetes mellitus.

We demonstrated that dextrose delivery from TPN and mortality were significantly higher in the hyperglycemia group during the 1^st week of ICU care, which was similar to the results of previous studies [8, 9]. Lin et al. [8] demonstrated that mortality was 2-5 times higher and the incidence of complications was 4-5.5 times higher in the group with BG ≥ 137 mg/dl than in the group with BG < 114 mg/dl. Cheung et al. [5] reported that mortality in patients with BG ≥ 9.1 mmol/l (164 mg/dl) was 11 times higher than that of patients with BG < 6.9 mmol/l (124 mg/dl), and this difference was more obvious in individuals without pre-diagnosed diabetes mellitus. Meanwhile, Pasquel et al. [9] reported that blood glucose before and within 24 h of starting TPN was associated with an increased risk of complications and mortality.

The target BG level for critically ill patients has been a controversial issue. Van den Berghe et al. [10, 11] reported that intensive insulin therapy aiming for a BG level of less than 110 mg/dl could reduce the incidence of complications and mortality in surgical and medical intensive care units. Another multicenter study [12] suggested that BG ≤ 140-150 mg/dl was the target range to improve clinical outcomes and decrease the risk of lethal hypoglycemia. However, these studies did not consider delivery of dextrose (or carbohydrate) from PN or EN, which could be closely related to the development of hyperglycemia. Our data showed that the amount of dextrose delivered via TPN was significantly higher in the hyperglycemia group, and the amount of dextrose from TPN was a significant variable upon multiple linear regression analysis. It was recommended that no more than 4 mg/kg/min of dextrose from PN be provided to the critically ill and 7 mg/kg/min for stable patients in order to prevent complications including hyperglycemia [13]. For diabetes mellitus (DM) patients, TPN should be initiated with dextrose of ≤ 100-150 g/day and then increased to the goal rate after BG level is maintained within the target range [14]. Our subjects had not been diagnosed with DM before ICU admission, and the average amount of dextrose from TPN in the hyperglycemia group was 2.6 ± 1.4 g/kg, which was within the recommended range. However, the amount of carbohydrates from EN was smaller in the hyperglycemia group than in the normoglycemia group, and the total amount of carbohydrates from EN and TPN did not differ between the two groups. EN carbohydrate delivery was not found to be associated with BG levels upon multiple regression analysis when considering EN carbohydrate delivery instead of PN dextrose.

In this study, TPN was initiated within the first week of ICU care in 75 patients (85.2%), and 61 (81.3%) of these were provided with EN within three days, suggesting that many patients were prescribed TPN despite their ability to tolerate EN. One study reported that 30-40% of the patients who were administered TPN were inadequately ordered [15], and that inadequate use of TPN could be reduced to less than 10% by implementing proper guidelines, supervision and nutrition support team activity [16]. Therefore, complications associated with hyperglycemia might be reduced by implementing guidelines for proper PN initiation and monitoring. The proper timing for TPN initiation has not yet been decided. Current clinical guidelines for nutritional support in critically ill patients differ substantially across the continents [3, 4], indicating the need for more studies. Our results support the ASPEN guidelines, which recommend early initiation of EN and delayed initiation of TPN for critically ill patients who are well-nourished at baseline.

We expected higher incidences of complications in the hyperglycemia group, but complication incidence was similar between the two groups. A higher rate of bloodstream infection was reported in the TPN treated patients [17]. A study on hematopoietic stem cell transplant recipients reported that a significantly greater number of TPN recipients required transfusion and delayed engraftment time [18]. Prospective studies will be needed to further elucidate the complications of TPN.

This study had some limitations. First, we compared the clinical outcomes on the basis of the BG concentration during the first week of ICU care. Although the mortality of the hyperglycemia group was higher than that of the normoglycemia group, we could not exclude the possibility of aggravation of the medical condition after the first week of ICU stay. However, Pasquel et al. [9] demonstrated that BG level prior to and within 24 h of PN initiation was associated with clinical outcomes rather than the average BG level during TPN therapy, emphasizing the importance of initial control of the BG level. It may be possible to overcome this limitation if we prospectively monitor the subjects' daily SOFA (sequential organ failure assessment) scores, which are used to track patients' status during their stay in an ICU [19]. Second, we considered the effect of carbohydrate on the BG level. Protein and fat, especially monounsaturated fatty acids and short chain fatty acids, can affect insulin sensitivity and/or gluconeogenesis [20-22]. Provision of protein and fat via TPN or EN might contribute to reducing the incidence of hyperglycemia by compromising the catabolic effect of body protein and body fat as the response to stress, which precluded further investigation.

In conclusion, our study showed that the amount of dextrose delivered via TPN might be associated with the development of hyperglycemia and poor clinical outcomes in critically ill patients without a history of diabetes mellitus and should be adapted carefully to maintain blood glucose within the target range.