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Inadequate glycemic control in patients receiving parenteral nutrition lowers survival: A retrospective observational trial
Clinical Nutrition Experimental xxx (2017) 1e7
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Inadequate glycemic control in patients receiving parenteral nutrition lowers survival: A retrospective observational trial Elien Coudenys a, 1, Elisabeth De Waele c, d, *, 1, Garmt Meers b, Hilde Collier b, Joeri J. Pen c, e, ** a
Department of Internal Medicine, UZ Brussel, Vrije Universiteit Brussel (VUB), Brussels, Belgium Hospital Pharmacy, UZ Brussel, Vrije Universiteit Brussel (VUB), Brussels, Belgium Department of Nutrition, UZ Brussel, Vrije Universiteit Brussel (VUB), Brussels, Belgium d Department of Intensive Care, UZ Brussel, Vrije Universiteit Brussel (VUB), Brussels, Belgium e Diabetes Clinic, Department of Internal Medicine, UZ Brussel, Vrije Universiteit Brussel (VUB), Brussels, Belgium b c
a r t i c l e i n f o
s u m m a r y
Article history: Received 14 August 2017 Accepted 6 December 2017 Available online xxx
Background & aims: Parenteral Nutrition (PN) has been shown to cause glycemic deregulation, whether patients have type 2 diabetes (T2DM) or not, causing elevated mortality, despite intensive insulin treatment. Long-term effects, however, are unclear. Methods: A retrospective observational study was performed. 226 patients of the UZ Brussel, both T2DM patients and non-diabetics, who received PN in 2013 or 2014, were analyzed on the presence of hyperglycemia and hypoglycemia, as well as mortality inhospital and after 6 months. Results: Here we show that T2DM patients displaying either hyperor hypoglycemia, had a significant higher mortality. This was the case both in-hospital and after 6 months. Non-diabetics undergoing hyperglycemia had a similar fate, but not when these patients had hypoglycemic events. Conclusion: Whether PN-receiving patients had T2DM or were non-diabetic, hyperglycemia was related to mortality, both in-
Keywords: Hyperglycemia Hypoglycemia Parenteral nutrition Mortality
List of abbreviations: PN, parenteral nutrition; T2DM, type 2 diabetes; T1DM, type 1 diabetes. * Corresponding author. Department of Nutrition, UZ Brussel, Vrije Universiteit Brussel (VUB), Brussels, Belgium. Fax: þ32 2 477 52 53. ** Corresponding author. Diabetes Clinic, Department of Internal Medicine, UZ Brussel, Vrije Universiteit Brussel (VUB), Brussels, Belgium. E-mail addresses: [email protected] (E. De Waele), [email protected], [email protected] (J.J. Pen). 1 These authors contributed equally to this work. https://doi.org/10.1016/j.yclnex.2017.12.001 2352-9393/© 2017 The Authors. Published by Elsevier Ltd on behalf of European Society for Clinical Nutrition and Metabolism. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Please cite this article in press as: Coudenys E, et al., Inadequate glycemic control in patients receiving parenteral nutrition lowers survival: A retrospective observational trial, Clinical Nutrition Experimental (2017), https://doi.org/10.1016/j.yclnex.2017.12.001
2
E. Coudenys et al. / Clinical Nutrition Experimental xxx (2017) 1e7
hospital and after 6 months, whereas hypoglycemia was only related to mortality in T2DM patients. © 2017 The Authors. Published by Elsevier Ltd on behalf of European Society for Clinical Nutrition and Metabolism. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).
1. Introduction Hyperglycemia in non-diabetics is defined as a fasting glucose >100 mg/dL or a random glucose >140 mg/dL, and is frequently present in acute or subacute ill patients [1], while T2DM is defined as a fasting glucose >125 mg/dL or a random glucose >200 mg/dL according to the WHO criteria. In patients with nutritional therapy, hyperglycemia has a higher prevalence. It is present in 30% of patients receiving enteral nutrition and in 50% of patients receiving parenteral nutrition (PN) [2e5]. Patients in need for PN are usually very ill, and PN often yields a high glucose dosage. These two factors contribute to a high frequency of hyperglycemia. Acute illness, surgery and trauma are known to cause a high secretion of stress hormones (glucagon, cortisol and catecholamines), as well as inflammatory cytokines. These, in turn, lead to a high hepatic neoglucogenesis, as well as less glucose uptake by peripheral tissue [6e8]. Ultimately, this causes metabolic disturbances, with accelerated lipogenesis in the liver and fatty tissue, augmented thermogenesis and a higher level of oxidation of glucose towards CO2, leading to a prolonged mechanical ventilation time in case of respiratory failure [9e11]. Next to these metabolic features, hyperglycemia is associated to higher mortality by complications, such as acute myocardial infarction, arrhythmia and acute renal insufficiency. Moreover, these patients are more likely to stay in the Intensive Care Unit, have a longer hospital stay and receive PN for a longer period of time, compared to patients without hyperglycemia [12e14]. A number of studies has demonstrated that the level of hyperglycemia, rather than diabetes as such, is a stronger predictor for complications. Usually, hyperglycemia in non-diabetic patients is a feature of critical illness [13,15e17]. Moreover, it has been shown that a glycemia of 180e200 mg/dL is the threshold for a much higher risk of infections [12,18]. Apart from hyperglycemia, patients receiving PN also display a higher risk for hypoglycemia, equally contributing to complications and a higher mortality rate. Causes for hypoglycemia can be inadequate dosage of insulin therapy, sudden arrest of nutritional support, recovery after acute illness, diminishing glucocorticoid treatment or even progressive multiple organ failure. Moreover, hypoglycemic symptoms are less clear in critically ill patients, causing delayed diagnosis [13]. The American Association of Clinical Endocrinologists and American Diabetes Association recommend a glycemic target of 140e180 mg/dL in critically ill patients, and a goal of 100e140 mg/dL preprandially in non-critically ill patients, but in the latter also a random glycemia of <180 mg/dL [19]. The total caloric need in the critically ill patient is about 25e30 kcal/kg/day, which translates as 2 g/ kg/day glucose, 0.7e1.5 g/kg/day lipids and 1.3e1.5/kg/day amino acids [20]. Limiting the glycemic load to 150 g/day can avoid hyperglycemia in patients receiving PN, will still fulfilling cellular metabolic needs [21]. A recent study has demonstrated that alanineeglutamine dipeptide suppletion in PN lowers insulin needs [22]. However, prospective randomized controlled trials are needed to evaluate whether a difference in glycemic load can lower the risk of hyperglycemia and, by consequence, augment survival. It is hypothesized that correct glycemic control with low glycemic variability should lead to a better prognosis. While one study using hypocaloric PN could not demonstrate better glycemic control and a lower incidence of infections [23], several observational trials as well as randomized controlled trials have shown that insulin therapy lead to better glycemic control, less complications and a lower mortality. This can be explained in part by the direct anti-inflammatory and anabolic effects of insulin [24e26]. This means that insulin remains the first choice therapy for glycemic control in patients receiving PN. There is no difference subcutaneous and intravenous insulin [27]. Despite of this, intravenous Please cite this article in press as: Coudenys E, et al., Inadequate glycemic control in patients receiving parenteral nutrition lowers survival: A retrospective observational trial, Clinical Nutrition Experimental (2017), https://doi.org/10.1016/j.yclnex.2017.12.001
E. Coudenys et al. / Clinical Nutrition Experimental xxx (2017) 1e7
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insulin is preferred in critically ill patients, due to the need of frequent dosage adaptations [28]. The place of insulin addition to PN is disputed, with contrasting results [29]. In this retrospective observational trial, the adequacy of glycemic control in patients receiving parenteral nutrition was investigated, and possible consequences and relationships with outcome parameters were evaluated. 2. Materials and methods This was a retrospective observational trial at the UZ Brussel. Adults (>18 years) receiving PN, were evaluated over a period of 6 months. Patient files were recruited in 2013 and 2014. These patients had been in a non-published observational study in 2015 (ESPEN abstract SUN-PP283). Only patients with glycemic measurements and receiving PN were included. Glycemic evaluation could be done by either capillary blood glucose or laboratory measurement of venous glucose. Glycemia was registered at 5 fixed timepoints: 3:00 h, 8:00 h, 12:00 h, 17:00 h and 22:00 h. Pathology, presence of diabetes and (if present) decease were evaluated. For practical reasons, only patients without diabetes or patients with T2DM were included. The analysis itself was conducted anonymously. Populations with and without T2DM were compared for glycemic control. Aside of that, the number of hypoglycemic and hyperglycemic events was evaluated, and correlated with mortality. Statistical analysis was performed using the Chi2-test for nominal variables. Continuous variables between groups were evaluated using an unpaired t-test or the nonparametric ManneWhitney U test. P values were set as <0.05. All analyses were performed using the Statistical Package for the Social Sciences (SPSS) program. 3. Results Table 1 shows the number of patients, admissions and PN. 4 patients were admitted twice, needing PN in both instances. In conclusion, the study yields 226 patients, needing 244 PN therapies. The group of T2DM patients consisted of 63 individuals. Because of the low numbers in type 1 diabetic patients (T1DM), they were omitted from the study. Table 2 shows the characteristics of the populations. Caloric needs were calculated using the HarriseBenedict Equation. Nutritional risk was calculated using the NRS-2002 score. Table 3 lists the measured glycemias in the two populations. In T2DM patients, average capillary glycemia at 8:00 h consists of 435 measurements, at 12:00 h of 456, at 17:00 h of 450, at 22:00 h of 475, Table 1 Number of included patients, admissions and PN.
Non-diabetics T2DM patients T1DM patients Total
Number of admissions
Number of PN therapies
Number of patients
163 63 4 230
171 68 5 244
159 63 4 226
Table 2 Characteristics of both populations. Parameter
Sex e man Average age (years) Average BMI (kg/m2) Average NRS-2002 Average caloric needs (kcal/dag) a b
T2DM patients
Non-diabetics
(n ¼ 68)
(n ¼ 171)
33 (48.52%) 70.62 (SD ¼ 9.48) 28.17 (SD ¼ 6.49) 3.91 (SD ¼ 0.82) 2097.97 (SD ¼ 487.38)
103 (60.23%) 62.22 (SD ¼ 17.52) 24.8 (SD ¼ 4.90) 4.33 (SD ¼ 1.01) 1982.35 (SD ¼ 461.32)
p value
p < 0.05a p < 0.001b p < 0.001b p < 0.5b NSb
Chi2-test. t-test.
Please cite this article in press as: Coudenys E, et al., Inadequate glycemic control in patients receiving parenteral nutrition lowers survival: A retrospective observational trial, Clinical Nutrition Experimental (2017), https://doi.org/10.1016/j.yclnex.2017.12.001
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E. Coudenys et al. / Clinical Nutrition Experimental xxx (2017) 1e7
Table 3 Average glycemia of the two populations, on 5 different, fixed timepoints. Parameter
Average Average Average Average Average Average a
glycemia glycemia glycemia glycemia glycemia glycemia
8:00 h (mg/dL) (C ¼ capillary) 12:00 h (mg/dL) (C) 17:00 h (mg/dL) (C) 22:00 h (mg/dL) (C) 3:00 h (mg/dL) (C) 8:00 h (mg/dL) (B ¼ blood sample)
T2DM patients
Non-diabetics
(n ¼ 68)
(n ¼ 171)
180.08 179.05 168.23 179.25 177.94 161.82
(SD (SD (SD (SD (SD (SD
¼ ¼ ¼ ¼ ¼ ¼
63.10) 63.00) 54.40) 56.66) 68.36) 57.31)
142.41 147.61 150.93 146.71 156.74 142.41
(SD (SD (SD (SD (SD (SD
¼ ¼ ¼ ¼ ¼ ¼
p valuea
36.44) 45.11) 46.15) 40.16) 47.77) 36.44)
p p p p p p
< < < < < <
0.001 0.001 0.001 0.001 0.001 0.001
t-test.
at 3:00 h of 167 and venous blood sample glycemia at 8:00 h of 306. In non-diabetic patients, average capillary glycemia at 8:00 h consists of 792 measurements, at 12:00 h of 703, at 17:00 h of 594, at 22:00 h of 744, at 3:00 h of 244 and venous blood sample glycemia at 8:00 h of 1061. Table 4 shows the average capillary glycemia over all timepoints, and the venous blood sample glycemia, both for non-diabetics and T2DM patients. Blood sample glycemia was only assessed at 8:00 h. Table 5 shows the average number of hyper- and hypoglycemias over all capillary measurements. In T2DM patients, 1983 capillary glycemias show 779 hyperglycemias and 31 hypoglycemias. In nondiabetic patients, 3077 capillary glycemias show 453 hyperglycemias and 29 hypoglycemias. In T2DM patients, only 4 did not have any hyperglycemic event (Table 6). Mortality after 6 months also includes patients who died during PN therapy. In non-diabetic patients, 40 did not have any hyperglycemic event (Table 7). Mortality after 6 months also includes patients who died during PN therapy.
Table 4 Average glycemia of the two populations. T2DM patients
Average glycemia (mg/dL) (C) Average glycemia (mg/dL) (B) a
Non-diabetics
(n ¼ 68)
(n ¼ 171)
162.01 (SD ¼ 54.11) 161.82 (SD ¼ 57.31)
131.49 (SD ¼ 38.24) 142.41 (SD ¼ 36.44)
p valuea
p < 0.001 p < 0.001
t-test.
Table 5 Number of hyper- and hypoglycemias in the two populations. T2DM patients
Hyperglycemia (>180 mg/dL) (C) Hypoglycemia (<80 mg/dL) (C) a
Non-diabetics
(n ¼ 68)
(n ¼ 171)
779 (39,28%) 31 (1.56%)
453 (14.72%) 29 (0.94%)
p valuea
p < 0.001 p < 0.001
Chi2-test.
Table 6 Mortality in T2DM patients, with or without hyperglycemia. Hyperglycemia
Mortality during therapy Mortality after 6 months a
No hyperglycemia
(n ¼ 59)
(n ¼ 4)
13 (22.03%) 26 (44.07%)
0 1 (25%)
p valuea
p < 0.5 p < 0.001
Chi2-test.
Please cite this article in press as: Coudenys E, et al., Inadequate glycemic control in patients receiving parenteral nutrition lowers survival: A retrospective observational trial, Clinical Nutrition Experimental (2017), https://doi.org/10.1016/j.yclnex.2017.12.001
E. Coudenys et al. / Clinical Nutrition Experimental xxx (2017) 1e7
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Table 7 Mortality in T2DM patients, with or without hypoglycemia.
Mortality during therapy Mortality after 6 months a
Hypoglycemia
No hypoglycemia
(n ¼ 23)
(n ¼ 40)
7 (30.43%) 12 (52.17%)
6 (15%) 15 (37.5%)
p valuea
p < 0.01 p < 0.05
Chi2-test.
In non-diabetic patients, 77 did not have any hypoglycemic event (Table 8). Mortality after 6 months also includes patients who died during therapy. In non-diabetic patients, 149 did not have any hypoglycemic event (Table 9). Mortality after 6 months also includes patients who died during therapy. Table 10 summarizes overall mortality, with either hyperglycemic or hypoglycemic events (although mortality was not directly due to these glycemic events). 4. Discussion In this study, glycemic control in patients receiving PN was examined, as well as its impact on survival. The nutritional risk was higher in the non-diabetic group, despite being younger and less obese, with equal caloric needs for both groups. In critically ill patients, a large glycemic variability is often observed. For T2DM patients, average glycemia and glycemic variability is higher than for non-diabetics. The current glycemic variability is 54 mg/dL, and is acceptable in our hospital. In hospital, both subcutaneous and intravenous insulin was used, but one drawback is the fact that glycemia is not continuously measured, leaving an automatic delay in insulin treatment. Glycemic control, using insulin, has previously been shown to be important Table 8 Mortality in non-diabetic patients, with or without hyperglycemia.
Mortality during therapy Mortality after 6 months a
p valuea
Hyperglycemia
No hyperglycemia
(n ¼ 86)
(n ¼ 77)
13 (15.12%) 44 (51.16%)
6 (7.79%) 33 (42.86%)
p < 0.5 p < 0.5
No hypoglycemia
p valuea
Chi2-test.
Table 9 Mortality in non-diabetic patients, with or without hypoglycemia. Hypoglycemia
Mortality during therapy Mortality after 6 months a
(n ¼ 14)
(n ¼ 149)
1 (7.14%) 5 (35.71%)
18 (12.08%) 72 (48.32%)
NS p < 0.5
Chi2-test.
Table 10 Overall mortality in non-diabetic and T2DM patients. T2DM patients
Mortality during therapy Mortality after 6 months a
Non-diabetics
(n ¼ 63)
(n ¼ 163)
13 (20.63%) 27 (42.86%)
19 (11.65%) 77 (47.23%)
p value
a
p < 0.1 NS
Chi2-test.
Please cite this article in press as: Coudenys E, et al., Inadequate glycemic control in patients receiving parenteral nutrition lowers survival: A retrospective observational trial, Clinical Nutrition Experimental (2017), https://doi.org/10.1016/j.yclnex.2017.12.001
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E. Coudenys et al. / Clinical Nutrition Experimental xxx (2017) 1e7
for prognosis [12,18]. One way glycemic variability could be improved, is the addition of insulin to the PN bag, although this remains to be proven [29]. Individualized nutritional therapy has a proven benefit in critically ill patients [30], with possible change in mortality. Optimal nutrition is requested and involves correct dosing of energy and protein. With knowledge from the available data, a benefit in mortality will be reached with a caloric target of around 80% of measured energy expenditure, and a protein load of at least 1,25 mg/kg/day [31]. The optimal way to reach caloric targets is the use of supplemental parenteral nutrition, as enteral nutrition proves to be largely inefficient [32]. As such, the potential benefit of an optimal nutritional therapy needs to be accompanied by an optimal glycemic treatment. Hyperglycemic treatment in our hospital, is performed using intravenous short-acting insulin in the Intensive Care Unit. For low-care units, at the time of the study, hyperglycemia was treated with a short-acting insulin scheme at 4-h intervals, replacing even diabetic treatment when normoglycemia was not achieved. It should, however, be notified that currently (after the trial) a basal-bolus scheme with long-acting and ultrashort-acting insulin is used for low-care units, obtaining better results. Hyper- and hypoglycemia are as expected more abundant in T2DM patients. Of note, when hyperor hypoglycemia is present, a higher mortality is observed, both in-hospital as well as 6 months afterwards. These patients are known to be more sensitive for glycemic variations, and it is unclear whether mortality after six months is still due to glycemic disturbances in hospital or later on, as no glycemia after hospitalization was included in the study. Nevertheless, both hyper- and hypoglycemia are suggested to be a predictor of both early and late mortality. Literature indeed suggests that glycemic control is needed to augment survival [24e26]. This study, being a retrospective observational trial, has its limitations. First, diagnosis of diabetes was based on medical history alone, making it unclear whether all non-diabetic patients actually were non-diabetic. Further, while hyper- and hypoglycemia within each group yield interesting results, both groups of T2DM patients and non-diabetic patients have different characteristics, as stated above. Moreover, all patients had PN and by consequence, there is no control group without PN. However, this was not the subject of the study. Finally, in patients with highly variable glycemia, more measurements than the five timepoints were done, creating a possible bias. These patients are typically Intensive Care Unit patients, who already have a higher mortality. One major confounder is obesity, defined as a BMI 30 kg/m2. T2DM patients in our study had a higher average BMI as compared to the non-diabetics. Obesity is already a contributing factor for higher mortality, and represents missing data in our study. However, within each group, there is no indication that patients with hyper- or hypoglycemia had obesity, compared to patients without these events. In conclusion, glycemic variability in patients receiving PN is an issue, both in non-diabetic and T2DM patients. Our results do suggest that in-hospital mortality is associated with glycemic variability, and T2DM patients also display a higher mortality as long as 6 months afterwards. The study suggests that better glycemic control in PN patients, either by insulin treatment combined with PN or possibly by using another composition of PN, can augment survival. Conflict of interest The authors declare no conflict of interest. Acknowledgements Each author contributed to, reviewed and approved the article. References [1] Umpierrez GE, Hellman R, Korytkowski MT, Kosiborod M, Maynard GA, Montori VM, et al. Management of hyperglycemia in hospitalized patients in non-critical care setting: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 2012;97:16e38. [2] Rosmarin DK, Wardlaw GM, Mirtallo J. Hyperglycemia associated with high, continuous infusion rates of total parenteral nutrition dextrose. Nutr Clin Pract 1996;11:151e6.
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Contents lists available at ScienceDirect
Clinical Nutrition Experimental journal homepage: http:// www.clinicalnutritionexperimental.com
Inadequate glycemic control in patients receiving parenteral nutrition lowers survival: A retrospective observational trial Elien Coudenys a, 1, Elisabeth De Waele c, d, *, 1, Garmt Meers b, Hilde Collier b, Joeri J. Pen c, e, ** a
Department of Internal Medicine, UZ Brussel, Vrije Universiteit Brussel (VUB), Brussels, Belgium Hospital Pharmacy, UZ Brussel, Vrije Universiteit Brussel (VUB), Brussels, Belgium Department of Nutrition, UZ Brussel, Vrije Universiteit Brussel (VUB), Brussels, Belgium d Department of Intensive Care, UZ Brussel, Vrije Universiteit Brussel (VUB), Brussels, Belgium e Diabetes Clinic, Department of Internal Medicine, UZ Brussel, Vrije Universiteit Brussel (VUB), Brussels, Belgium b c
a r t i c l e i n f o
s u m m a r y
Article history: Received 14 August 2017 Accepted 6 December 2017 Available online xxx
Background & aims: Parenteral Nutrition (PN) has been shown to cause glycemic deregulation, whether patients have type 2 diabetes (T2DM) or not, causing elevated mortality, despite intensive insulin treatment. Long-term effects, however, are unclear. Methods: A retrospective observational study was performed. 226 patients of the UZ Brussel, both T2DM patients and non-diabetics, who received PN in 2013 or 2014, were analyzed on the presence of hyperglycemia and hypoglycemia, as well as mortality inhospital and after 6 months. Results: Here we show that T2DM patients displaying either hyperor hypoglycemia, had a significant higher mortality. This was the case both in-hospital and after 6 months. Non-diabetics undergoing hyperglycemia had a similar fate, but not when these patients had hypoglycemic events. Conclusion: Whether PN-receiving patients had T2DM or were non-diabetic, hyperglycemia was related to mortality, both in-
Keywords: Hyperglycemia Hypoglycemia Parenteral nutrition Mortality
List of abbreviations: PN, parenteral nutrition; T2DM, type 2 diabetes; T1DM, type 1 diabetes. * Corresponding author. Department of Nutrition, UZ Brussel, Vrije Universiteit Brussel (VUB), Brussels, Belgium. Fax: þ32 2 477 52 53. ** Corresponding author. Diabetes Clinic, Department of Internal Medicine, UZ Brussel, Vrije Universiteit Brussel (VUB), Brussels, Belgium. E-mail addresses: [email protected] (E. De Waele), [email protected], [email protected] (J.J. Pen). 1 These authors contributed equally to this work. https://doi.org/10.1016/j.yclnex.2017.12.001 2352-9393/© 2017 The Authors. Published by Elsevier Ltd on behalf of European Society for Clinical Nutrition and Metabolism. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Please cite this article in press as: Coudenys E, et al., Inadequate glycemic control in patients receiving parenteral nutrition lowers survival: A retrospective observational trial, Clinical Nutrition Experimental (2017), https://doi.org/10.1016/j.yclnex.2017.12.001
2
E. Coudenys et al. / Clinical Nutrition Experimental xxx (2017) 1e7
hospital and after 6 months, whereas hypoglycemia was only related to mortality in T2DM patients. © 2017 The Authors. Published by Elsevier Ltd on behalf of European Society for Clinical Nutrition and Metabolism. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).
1. Introduction Hyperglycemia in non-diabetics is defined as a fasting glucose >100 mg/dL or a random glucose >140 mg/dL, and is frequently present in acute or subacute ill patients [1], while T2DM is defined as a fasting glucose >125 mg/dL or a random glucose >200 mg/dL according to the WHO criteria. In patients with nutritional therapy, hyperglycemia has a higher prevalence. It is present in 30% of patients receiving enteral nutrition and in 50% of patients receiving parenteral nutrition (PN) [2e5]. Patients in need for PN are usually very ill, and PN often yields a high glucose dosage. These two factors contribute to a high frequency of hyperglycemia. Acute illness, surgery and trauma are known to cause a high secretion of stress hormones (glucagon, cortisol and catecholamines), as well as inflammatory cytokines. These, in turn, lead to a high hepatic neoglucogenesis, as well as less glucose uptake by peripheral tissue [6e8]. Ultimately, this causes metabolic disturbances, with accelerated lipogenesis in the liver and fatty tissue, augmented thermogenesis and a higher level of oxidation of glucose towards CO2, leading to a prolonged mechanical ventilation time in case of respiratory failure [9e11]. Next to these metabolic features, hyperglycemia is associated to higher mortality by complications, such as acute myocardial infarction, arrhythmia and acute renal insufficiency. Moreover, these patients are more likely to stay in the Intensive Care Unit, have a longer hospital stay and receive PN for a longer period of time, compared to patients without hyperglycemia [12e14]. A number of studies has demonstrated that the level of hyperglycemia, rather than diabetes as such, is a stronger predictor for complications. Usually, hyperglycemia in non-diabetic patients is a feature of critical illness [13,15e17]. Moreover, it has been shown that a glycemia of 180e200 mg/dL is the threshold for a much higher risk of infections [12,18]. Apart from hyperglycemia, patients receiving PN also display a higher risk for hypoglycemia, equally contributing to complications and a higher mortality rate. Causes for hypoglycemia can be inadequate dosage of insulin therapy, sudden arrest of nutritional support, recovery after acute illness, diminishing glucocorticoid treatment or even progressive multiple organ failure. Moreover, hypoglycemic symptoms are less clear in critically ill patients, causing delayed diagnosis [13]. The American Association of Clinical Endocrinologists and American Diabetes Association recommend a glycemic target of 140e180 mg/dL in critically ill patients, and a goal of 100e140 mg/dL preprandially in non-critically ill patients, but in the latter also a random glycemia of <180 mg/dL [19]. The total caloric need in the critically ill patient is about 25e30 kcal/kg/day, which translates as 2 g/ kg/day glucose, 0.7e1.5 g/kg/day lipids and 1.3e1.5/kg/day amino acids [20]. Limiting the glycemic load to 150 g/day can avoid hyperglycemia in patients receiving PN, will still fulfilling cellular metabolic needs [21]. A recent study has demonstrated that alanineeglutamine dipeptide suppletion in PN lowers insulin needs [22]. However, prospective randomized controlled trials are needed to evaluate whether a difference in glycemic load can lower the risk of hyperglycemia and, by consequence, augment survival. It is hypothesized that correct glycemic control with low glycemic variability should lead to a better prognosis. While one study using hypocaloric PN could not demonstrate better glycemic control and a lower incidence of infections [23], several observational trials as well as randomized controlled trials have shown that insulin therapy lead to better glycemic control, less complications and a lower mortality. This can be explained in part by the direct anti-inflammatory and anabolic effects of insulin [24e26]. This means that insulin remains the first choice therapy for glycemic control in patients receiving PN. There is no difference subcutaneous and intravenous insulin [27]. Despite of this, intravenous Please cite this article in press as: Coudenys E, et al., Inadequate glycemic control in patients receiving parenteral nutrition lowers survival: A retrospective observational trial, Clinical Nutrition Experimental (2017), https://doi.org/10.1016/j.yclnex.2017.12.001
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insulin is preferred in critically ill patients, due to the need of frequent dosage adaptations [28]. The place of insulin addition to PN is disputed, with contrasting results [29]. In this retrospective observational trial, the adequacy of glycemic control in patients receiving parenteral nutrition was investigated, and possible consequences and relationships with outcome parameters were evaluated. 2. Materials and methods This was a retrospective observational trial at the UZ Brussel. Adults (>18 years) receiving PN, were evaluated over a period of 6 months. Patient files were recruited in 2013 and 2014. These patients had been in a non-published observational study in 2015 (ESPEN abstract SUN-PP283). Only patients with glycemic measurements and receiving PN were included. Glycemic evaluation could be done by either capillary blood glucose or laboratory measurement of venous glucose. Glycemia was registered at 5 fixed timepoints: 3:00 h, 8:00 h, 12:00 h, 17:00 h and 22:00 h. Pathology, presence of diabetes and (if present) decease were evaluated. For practical reasons, only patients without diabetes or patients with T2DM were included. The analysis itself was conducted anonymously. Populations with and without T2DM were compared for glycemic control. Aside of that, the number of hypoglycemic and hyperglycemic events was evaluated, and correlated with mortality. Statistical analysis was performed using the Chi2-test for nominal variables. Continuous variables between groups were evaluated using an unpaired t-test or the nonparametric ManneWhitney U test. P values were set as <0.05. All analyses were performed using the Statistical Package for the Social Sciences (SPSS) program. 3. Results Table 1 shows the number of patients, admissions and PN. 4 patients were admitted twice, needing PN in both instances. In conclusion, the study yields 226 patients, needing 244 PN therapies. The group of T2DM patients consisted of 63 individuals. Because of the low numbers in type 1 diabetic patients (T1DM), they were omitted from the study. Table 2 shows the characteristics of the populations. Caloric needs were calculated using the HarriseBenedict Equation. Nutritional risk was calculated using the NRS-2002 score. Table 3 lists the measured glycemias in the two populations. In T2DM patients, average capillary glycemia at 8:00 h consists of 435 measurements, at 12:00 h of 456, at 17:00 h of 450, at 22:00 h of 475, Table 1 Number of included patients, admissions and PN.
Non-diabetics T2DM patients T1DM patients Total
Number of admissions
Number of PN therapies
Number of patients
163 63 4 230
171 68 5 244
159 63 4 226
Table 2 Characteristics of both populations. Parameter
Sex e man Average age (years) Average BMI (kg/m2) Average NRS-2002 Average caloric needs (kcal/dag) a b
T2DM patients
Non-diabetics
(n ¼ 68)
(n ¼ 171)
33 (48.52%) 70.62 (SD ¼ 9.48) 28.17 (SD ¼ 6.49) 3.91 (SD ¼ 0.82) 2097.97 (SD ¼ 487.38)
103 (60.23%) 62.22 (SD ¼ 17.52) 24.8 (SD ¼ 4.90) 4.33 (SD ¼ 1.01) 1982.35 (SD ¼ 461.32)
p value
p < 0.05a p < 0.001b p < 0.001b p < 0.5b NSb
Chi2-test. t-test.
Please cite this article in press as: Coudenys E, et al., Inadequate glycemic control in patients receiving parenteral nutrition lowers survival: A retrospective observational trial, Clinical Nutrition Experimental (2017), https://doi.org/10.1016/j.yclnex.2017.12.001
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E. Coudenys et al. / Clinical Nutrition Experimental xxx (2017) 1e7
Table 3 Average glycemia of the two populations, on 5 different, fixed timepoints. Parameter
Average Average Average Average Average Average a
glycemia glycemia glycemia glycemia glycemia glycemia
8:00 h (mg/dL) (C ¼ capillary) 12:00 h (mg/dL) (C) 17:00 h (mg/dL) (C) 22:00 h (mg/dL) (C) 3:00 h (mg/dL) (C) 8:00 h (mg/dL) (B ¼ blood sample)
T2DM patients
Non-diabetics
(n ¼ 68)
(n ¼ 171)
180.08 179.05 168.23 179.25 177.94 161.82
(SD (SD (SD (SD (SD (SD
¼ ¼ ¼ ¼ ¼ ¼
63.10) 63.00) 54.40) 56.66) 68.36) 57.31)
142.41 147.61 150.93 146.71 156.74 142.41
(SD (SD (SD (SD (SD (SD
¼ ¼ ¼ ¼ ¼ ¼
p valuea
36.44) 45.11) 46.15) 40.16) 47.77) 36.44)
p p p p p p
< < < < < <
0.001 0.001 0.001 0.001 0.001 0.001
t-test.
at 3:00 h of 167 and venous blood sample glycemia at 8:00 h of 306. In non-diabetic patients, average capillary glycemia at 8:00 h consists of 792 measurements, at 12:00 h of 703, at 17:00 h of 594, at 22:00 h of 744, at 3:00 h of 244 and venous blood sample glycemia at 8:00 h of 1061. Table 4 shows the average capillary glycemia over all timepoints, and the venous blood sample glycemia, both for non-diabetics and T2DM patients. Blood sample glycemia was only assessed at 8:00 h. Table 5 shows the average number of hyper- and hypoglycemias over all capillary measurements. In T2DM patients, 1983 capillary glycemias show 779 hyperglycemias and 31 hypoglycemias. In nondiabetic patients, 3077 capillary glycemias show 453 hyperglycemias and 29 hypoglycemias. In T2DM patients, only 4 did not have any hyperglycemic event (Table 6). Mortality after 6 months also includes patients who died during PN therapy. In non-diabetic patients, 40 did not have any hyperglycemic event (Table 7). Mortality after 6 months also includes patients who died during PN therapy.
Table 4 Average glycemia of the two populations. T2DM patients
Average glycemia (mg/dL) (C) Average glycemia (mg/dL) (B) a
Non-diabetics
(n ¼ 68)
(n ¼ 171)
162.01 (SD ¼ 54.11) 161.82 (SD ¼ 57.31)
131.49 (SD ¼ 38.24) 142.41 (SD ¼ 36.44)
p valuea
p < 0.001 p < 0.001
t-test.
Table 5 Number of hyper- and hypoglycemias in the two populations. T2DM patients
Hyperglycemia (>180 mg/dL) (C) Hypoglycemia (<80 mg/dL) (C) a
Non-diabetics
(n ¼ 68)
(n ¼ 171)
779 (39,28%) 31 (1.56%)
453 (14.72%) 29 (0.94%)
p valuea
p < 0.001 p < 0.001
Chi2-test.
Table 6 Mortality in T2DM patients, with or without hyperglycemia. Hyperglycemia
Mortality during therapy Mortality after 6 months a
No hyperglycemia
(n ¼ 59)
(n ¼ 4)
13 (22.03%) 26 (44.07%)
0 1 (25%)
p valuea
p < 0.5 p < 0.001
Chi2-test.
Please cite this article in press as: Coudenys E, et al., Inadequate glycemic control in patients receiving parenteral nutrition lowers survival: A retrospective observational trial, Clinical Nutrition Experimental (2017), https://doi.org/10.1016/j.yclnex.2017.12.001
E. Coudenys et al. / Clinical Nutrition Experimental xxx (2017) 1e7
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Table 7 Mortality in T2DM patients, with or without hypoglycemia.
Mortality during therapy Mortality after 6 months a
Hypoglycemia
No hypoglycemia
(n ¼ 23)
(n ¼ 40)
7 (30.43%) 12 (52.17%)
6 (15%) 15 (37.5%)
p valuea
p < 0.01 p < 0.05
Chi2-test.
In non-diabetic patients, 77 did not have any hypoglycemic event (Table 8). Mortality after 6 months also includes patients who died during therapy. In non-diabetic patients, 149 did not have any hypoglycemic event (Table 9). Mortality after 6 months also includes patients who died during therapy. Table 10 summarizes overall mortality, with either hyperglycemic or hypoglycemic events (although mortality was not directly due to these glycemic events). 4. Discussion In this study, glycemic control in patients receiving PN was examined, as well as its impact on survival. The nutritional risk was higher in the non-diabetic group, despite being younger and less obese, with equal caloric needs for both groups. In critically ill patients, a large glycemic variability is often observed. For T2DM patients, average glycemia and glycemic variability is higher than for non-diabetics. The current glycemic variability is 54 mg/dL, and is acceptable in our hospital. In hospital, both subcutaneous and intravenous insulin was used, but one drawback is the fact that glycemia is not continuously measured, leaving an automatic delay in insulin treatment. Glycemic control, using insulin, has previously been shown to be important Table 8 Mortality in non-diabetic patients, with or without hyperglycemia.
Mortality during therapy Mortality after 6 months a
p valuea
Hyperglycemia
No hyperglycemia
(n ¼ 86)
(n ¼ 77)
13 (15.12%) 44 (51.16%)
6 (7.79%) 33 (42.86%)
p < 0.5 p < 0.5
No hypoglycemia
p valuea
Chi2-test.
Table 9 Mortality in non-diabetic patients, with or without hypoglycemia. Hypoglycemia
Mortality during therapy Mortality after 6 months a
(n ¼ 14)
(n ¼ 149)
1 (7.14%) 5 (35.71%)
18 (12.08%) 72 (48.32%)
NS p < 0.5
Chi2-test.
Table 10 Overall mortality in non-diabetic and T2DM patients. T2DM patients
Mortality during therapy Mortality after 6 months a
Non-diabetics
(n ¼ 63)
(n ¼ 163)
13 (20.63%) 27 (42.86%)
19 (11.65%) 77 (47.23%)
p value
a
p < 0.1 NS
Chi2-test.
Please cite this article in press as: Coudenys E, et al., Inadequate glycemic control in patients receiving parenteral nutrition lowers survival: A retrospective observational trial, Clinical Nutrition Experimental (2017), https://doi.org/10.1016/j.yclnex.2017.12.001
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E. Coudenys et al. / Clinical Nutrition Experimental xxx (2017) 1e7
for prognosis [12,18]. One way glycemic variability could be improved, is the addition of insulin to the PN bag, although this remains to be proven [29]. Individualized nutritional therapy has a proven benefit in critically ill patients [30], with possible change in mortality. Optimal nutrition is requested and involves correct dosing of energy and protein. With knowledge from the available data, a benefit in mortality will be reached with a caloric target of around 80% of measured energy expenditure, and a protein load of at least 1,25 mg/kg/day [31]. The optimal way to reach caloric targets is the use of supplemental parenteral nutrition, as enteral nutrition proves to be largely inefficient [32]. As such, the potential benefit of an optimal nutritional therapy needs to be accompanied by an optimal glycemic treatment. Hyperglycemic treatment in our hospital, is performed using intravenous short-acting insulin in the Intensive Care Unit. For low-care units, at the time of the study, hyperglycemia was treated with a short-acting insulin scheme at 4-h intervals, replacing even diabetic treatment when normoglycemia was not achieved. It should, however, be notified that currently (after the trial) a basal-bolus scheme with long-acting and ultrashort-acting insulin is used for low-care units, obtaining better results. Hyper- and hypoglycemia are as expected more abundant in T2DM patients. Of note, when hyperor hypoglycemia is present, a higher mortality is observed, both in-hospital as well as 6 months afterwards. These patients are known to be more sensitive for glycemic variations, and it is unclear whether mortality after six months is still due to glycemic disturbances in hospital or later on, as no glycemia after hospitalization was included in the study. Nevertheless, both hyper- and hypoglycemia are suggested to be a predictor of both early and late mortality. Literature indeed suggests that glycemic control is needed to augment survival [24e26]. This study, being a retrospective observational trial, has its limitations. First, diagnosis of diabetes was based on medical history alone, making it unclear whether all non-diabetic patients actually were non-diabetic. Further, while hyper- and hypoglycemia within each group yield interesting results, both groups of T2DM patients and non-diabetic patients have different characteristics, as stated above. Moreover, all patients had PN and by consequence, there is no control group without PN. However, this was not the subject of the study. Finally, in patients with highly variable glycemia, more measurements than the five timepoints were done, creating a possible bias. These patients are typically Intensive Care Unit patients, who already have a higher mortality. One major confounder is obesity, defined as a BMI 30 kg/m2. T2DM patients in our study had a higher average BMI as compared to the non-diabetics. Obesity is already a contributing factor for higher mortality, and represents missing data in our study. However, within each group, there is no indication that patients with hyper- or hypoglycemia had obesity, compared to patients without these events. In conclusion, glycemic variability in patients receiving PN is an issue, both in non-diabetic and T2DM patients. Our results do suggest that in-hospital mortality is associated with glycemic variability, and T2DM patients also display a higher mortality as long as 6 months afterwards. The study suggests that better glycemic control in PN patients, either by insulin treatment combined with PN or possibly by using another composition of PN, can augment survival. Conflict of interest The authors declare no conflict of interest. Acknowledgements Each author contributed to, reviewed and approved the article. References [1] Umpierrez GE, Hellman R, Korytkowski MT, Kosiborod M, Maynard GA, Montori VM, et al. Management of hyperglycemia in hospitalized patients in non-critical care setting: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 2012;97:16e38. [2] Rosmarin DK, Wardlaw GM, Mirtallo J. Hyperglycemia associated with high, continuous infusion rates of total parenteral nutrition dextrose. Nutr Clin Pract 1996;11:151e6.
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Please cite this article in press as: Coudenys E, et al., Inadequate glycemic control in patients receiving parenteral nutrition lowers survival: A retrospective observational trial, Clinical Nutrition Experimental (2017), https://doi.org/10.1016/j.yclnex.2017.12.001