Diabetes Ther (2018) 9:1359–1367 https://doi.org/10.1007/s13300-018-0433-1 BRIEF REPORT Differences in Glycemic Control in Diabetic and Non- diabetic Patients with Parenteral Nutrition Using a Basal plus Correction Insulin Regimen: An Observational, Retrospective Study . . . . Analı´a Ramos Fernanda Rabasa Lilian Mendoza Joana Cardenete . . . Pedro Gill Alba Morilla Daniel Cardona Antonio Perez Received: February 24, 2018 / Published online: May 3, 2018 The Author(s) 2018 respectively, and the target blood glucose (BG) ABSTRACT was \ 180 mg/dl. Mean BG levels, insulin total daily dose (TDD) and hypoglycemic (\ 70 mg/ Introduction: Hyperglycemia is a frequent dl) events on different days of PN were also complication of parenteral nutrition (PN) in evaluated. patients both with and without diabetes mellitis Results: Forty-one patients with previous type (DM). The aim of this study was to evaluate the 2 DM and 39 without DM were evaluated. Gly- quality of glucose control achieved with basal cemic control in both groups was as follows: plus-correction insulin in surgical patients with during the ﬁrst 48 h (230.4 ± 67 vs. and without a history of DM receiving PN. 189.4 ± 38 mg/dl, p = 0.002); at the midpoint Methods: Retrospective evaluation of a proto- (224.6 ± 58 vs. 181.3 ± 27 mg/dl, p = 0.003); col applied during the period of January 48 h before ending TPN (196.4 ± 43 vs. 2013–December 2015. The insulin dose was 169.8 ± 40 mg/dl, p = 0.004). Insulin TDD was started at 0.4 and 0.3 IU/kg/day in patients with 0.5 ± 0.3 U/kg/day in patients with DM and previous DM and without a history of DM, 0.37 ± 0.3 units/kg/day in those without DM (p \ 0.05). A total of 18 patients experienced Enhanced digital features To view enhanced digital hypoglycemic events, without differences features for this article go to https://doi.org/10.6084/ m9.ﬁgshare.6139673. between the groups. Conclusion: A basal-correction insulin regimen A. Ramos F. Rabasa L. Mendoza P. Gill is an alternative method for managing hyper- A. Morilla A. Pe´rez (&) glycemia in non-critically ill surgical patients Department of Endocrinology and Nutrition, on PN. Hospital Santa Creu i Sant Pau, Barcelona, Barcelona, Spain e-mail: firstname.lastname@example.org Keywords: Diabetic patients; Hyperglycemia; Non-diabetic patients; Parenteral nutrition J. Cardenete D. Cardona Department of Pharmacy Service, Hospital Santa Creu i Sant Pau, Barcelona, Spain INTRODUCTION A. Perez Department of Medicine, Universitat Autonoma de Hyperglycemia is an important side effect in Barcelona, Bellaterra, Spain patients receiving parenteral nutrition  A. Pe´rez because of its high prevalence and has been CIBER de Diabetes y Enfermedades Metabo´licas associated with adverse outcomes . Asociadas (CIBERDEM), Madrid, Spain 1360 Diabetes Ther (2018) 9:1359–1367 The prevalence of hyperglycemia in patients 2013–December 2015 was performed at the receiving PN is high and reported in more than Hospital de la Santa Creu i Sant Pau in Barce- 40% of these patients [3–5]. Most studies refer to lona, Spain. Data were retrieved from the hos- critically ill patients because their hyperme- pital’s electronic medical records. Patients with tabolic state makes controlling glucose levels or without a previous history of DM treated difﬁcult, and there are few studies of non-criti- with a basal plus correction insulin regimen cally ill patients, who are expected to have a were included. In the diabetic patient group, better tolerance of the glucose load. PN-related those with no record of DM but a glycated hyperglycemia is associated with poor clinical hemoglobin (HbA1c) measurement C 6.5% or outcomes in patients with and without DM as fasting plasma glucose C 126 mg/dl were also well as those who are either critically or non- included. Patients were excluded if they were critically ill [6–9]. In surgical patients, hyper- transfered to intensive care units (ICUs), the glycemia increases risks of perioperative com- duration of the PN was\5 days or[60 days, or plications, length of stay and mortality [10, 11]. they had recieved pharmacologic doses of cor- Both the consensus statement by the Amer- ticosteroids. The study was approved by the ican Diabetes Association (ADA) and the Ethics Committee of our institution, the American Association of Clinical Endocrinolo- Hospital de la Santa Creu i Sant Pau. gists (AACE) as well the clinical practice guide- line of the Endocrine Society recommend a pre- Parenteral Nutrition Administration meal BG level \ 140 mg/dl and random BG values \ 180 mg/dl [12, 13]. Furthermore, the The TPN formula was provided as a total nutri- American Society for Parenteral and Enteral ent admixture solution containing carbohy- Nutrition recommends a blood glucose goal of drates, proteins and lipids, with daily 140–180 mg/dl for hospitalized patients receiv- adjustments according to the individual caloric ing nutritional support . and nutritional requirements of the patients. Insulin is the treatment of choice to control PN administration provides approximately hyperglycemia during PN. Subcutaneous insulin 50–60% of the calculated daily carbohydrate administration, intravenous insulin infusion and caloric requirements during the ﬁrst 24 h and addition of insulin to the PN bag have been shown was increased to the desired goal during the to be effective in managing hyperglycemia in next 24 h. The glucose range administered was these patients [5, 13, 15, 16]. However, there are between 150 and 250 g. few data from clinical trials comparing different strategies , particularly in non-critically ill Blood Glucose Monitoring and Insulin patients [18, 19]. Furthermore, insulin protocols Therapy Protocol vary widely between institutions. In our hospital, a program for hyperglycemia In all patients receiving PN, capillary BG was management based on a published protocol was monitored every 6 h and was discontinued in established . For non-critically ill patients patients without a prior history of DM if glucose under continuous PN, a basal plus correction values were \ 140 mg/dl without insulin ther- insulin regimen was set up. The aim of this apy for 48 h with the desired caloric intake. study was to evaluate the quality of glucose Insulin therapy was indicated for all patients control achieved by this strategy in surgical with previous DM under pharmacologic ther- patients with and without a history of DM apy. In DM patients treated exclusively with a receiving PN. diet and in those without a history of DM, insulin therapy was indicated if blood glucose METHODS levels were [ 180 mg/dl. Patients with previous replacement insulin therapy with a basal-bolus A retrospective study of surgical patients regimen or C two doses of intermediate-acting receiving PN during the period of January or premixed insulin were started at their Diabetes Ther (2018) 9:1359–1367 1361 previous total daily dose (TDD), and in the Compliance with Ethics Guidelines remaining patients the initial TDD was esti- mated as 0.4 U/kg/day. All procedures performed in studies involving The TDD was administered as basal insulin human participants were in accordance with glargine once daily, and correction doses of the ethical standards of the institutional and/or insulin lispro were administered every 6 h if national research committee and with the 1964 glycemia remained above 180 mg/dl. The glar- Helsinki Declaration and its later amendments gine insulin dose was increased or decreased by or comparable ethical standards. Informed 10–20% every day to achieve a glycemic goal of consent was obtained from all individual par- 140–180 mg/dl. ticipants included in the study. The glycated hemoglobin (HbA1c) was determined in all patients with previous dia- RESULTS betes and in non-diabetic patients who required insulin therapy. The baseline characteristics of the 80 patients who met the eligibility criteria are shown in Outcome Measures Table 1. There were no signiﬁcant differences in age, body mass index, weight, mean LOS, type The primary outcome of this study was to of surgery or mean duration of PN between DM determine the quality of glycemic control as and non-DM patients. The most common rea- measured by mean daily BG levels 48 h after son for indicating PN was a paralytic ileus. initiation of PN treatment, at the midpoint of Patients with a prior history of DM had signiﬁ- the treatment period and 48 h before ending cantly higher admission BG and HbA1c values PN. The number of hypoglycemic (\ 70 mg/dl) (Table 2). events and TDD of insulin were also deter- mined, and information on the demographics, Glycemic Control DM characteristics, type of surgery, BG on admission and hospital length of stay (LOS) were collected. Mean daily BG concentrations during the hos- pital stay are shown in Fig. 1. In all patients the mean BG levels during the Statistical Analysis ﬁrst 48 h of PN, at the midpoint period of PN and 48 h before ending PN were 209.9 ± 58, All statistical analyses were performed with the 201.1 ± 43 and 183.1 ± 44 mg/dl, respectively. STATA 13 statistical program. Patients with previous DM had higher mean BG A p value \ 0.05 was set as statistically concentrations at the three study times (Fig. 1). signiﬁcant. There were no differences between DM patients Descriptive statistics using frequencies to with or without previous insulin therapy during summarize categorical variables (percentage) the ﬁrst 48 h of PN (230.5 ± 67 vs. and expressing quantitative variables as 221.6 ± 70 mg/dl), at the midpoint of the per- mean ± standard deviation (SD) were per- iod with PN (221.8 ± 58 vs. 233.0 ± 60 mg/dl) formed. Normal distribution of quantitative and 48 h before ending PN (196.4 ± 43 vs. data was assessed using the Shapiro-Wilk test. 193.92 ± 43 mg/dl), p [ 0.05. The proportion The univariate tests used were chi-square for of patients who achieved BG \ 180 mg/dl is categorical variables and Student’s t-test for shown in Fig. 2. quantitative variables. Paired Student’s tests Eighteen (22.5%) patients experienced mild were performed to search for statistical differ- hypoglycemic events and six (7.5%) severe ences in the variables between DM and non-DM hypoglycemic events, with no differences patients. between patients with or without previous DM. 1362 Diabetes Ther (2018) 9:1359–1367 Table 1 Clinical characteristics of the study patients (n = 80) Variables All patients Diabetic patients Non-diabetic patients p value* (n = 80) (n = 41) (n = 39) Age (years) 77.6 ± 9.1 77.6 ± 9.1 74.3 ± 10.4 0.07 Gender 0.27 Male, n (%) 50 (62.5) 28 (68.3) 22 (56.4) Female, n (%) 30 (37.5) 13 (31.7) 17 (43.6) BMI (kg/m ) 27.3 ± 4.8 26.8 ± 5.2 27.8 ± 4.4 0.16 Body weight (kg) 73.5 ± 14.2 74.8 ± 13.5 72.1 ± 14.9 0.19 HbA1c (%) 6.8 ± 1.1 7.1 ± 1.1 6.2 ± 0.9 0.003 Previous diabetes treatment Diet, n (%) – 9 (22) – – Oral agents, n (%) – 19 (46) Basal insulin ? oral agents, – 4 (10) – – n (%) Basal insulin, n (%) – 7 (17) – – Basal–bolus insulin, n (%) – 2 (5) – – Type of surgery 0.43 Non-neoplasia surgery, n (%) 24 (30) 14 (34.2) 10 (25.6) Colorectal cancer, n (%) 19 (23.8) 11 (26.8) 8 (20.5) Pancreatic cancer, n (%) 18 (22.5) 6 (14.6) 12 (30.8) Other cancer 14 (17.5) 6 (14.6) 8 (20.5) Vascular surgery, n (%) 2 (2.5) 2 (4.9) – Gynecologic cancer, n (%) 3 (3.7) 2 (4.9) 1 (2.6) TPN indication 0.09 Ileus 73 (91.3) 40 (97.6) 33 (84.6) Fistula 3 (3.7) – 3 (7.7) Wound breakdown 4 (5) 1 (2.4) 3 (7.7) Duration of PN (days) 12 ± 8 13.2 ± 8.5 10.9 ± 7.6 0.89 Length of hospital stay (days) 30.7 ± 14.5 30.8 ± 14.3 30.7 ± 14.9 0.52 Data are mean ± standard deviation *Difference between diabetic and non-diabetic patients Diabetes Ther (2018) 9:1359–1367 1363 Table 2 Difference in glycemic control, hypoglycemic events and insulin treatment (n = 80) Variables All patients Diabetic patients Non-diabetic patients p value* (n = 80) (n = 41) (n = 39) Mean BG at admission (mg/dl) 165.9 ± 63 180.7 ± 66 146.3 ± 57 0.015 Total mean insulin dose, U/day 30.2 ± 20 35.1 ± 21 25.3 ± 19 0.02 Total mean insulin dose, 0.43 ± 0.3 0.50 ± 0.3 0.37 ± 0.2 0.05 U/kg/day 48 h after start of PN Mean BG (mg/dl) 209.9 ± 58 230.5 ± 67 189.4 ± 38 0.002 Glargina insulin, U/day 11.5 ± 19 14.3 ± 20 8.5 ± 18 0.11 Lispro insulin, U/day 13.5 ± 20 16.9 ± 13 9.9 ± 8 0.007 Midpoint period of PN Mean BG (mg/dl) 201.1 ± 43 221.8 ± 58 180.1 ± 17 0.003 Glargina insulin, U/day 21.0 ± 26 26.0 ± 31 15.6 ± 18 0.03 Lispro insulin, U/day 15.4 ± 9 16.7 ± 11 14.0 ±70.12 48 h before ending PN Mean BG (mg/dl) 183.1 ± 44 196.4 ± 43 169.8 ± 40 0.004 Glargina insulin, U/day 28.2 ± 28 28.2 ± 28 15.6 ± 18 0.02 Lispro insulin, U/day 13.3 ± 9 13.3 ± 9 7.8 ± 6 0.001 Hypoglycemic events BG \ 70 mg/dl, n (%) 9 (22) 9 (22) 9 (23) 0.53 BG \ 40 mg/dl, n (%) 2 (5) 2 (5) 4 (10) Data are mean ± standard deviation BG blood glucose *Difference between diabetic and non-diabetic patients Most hypoglycemic episodes were due to Newly Diabetic Patients unplanned discontinuation of PN. We identiﬁed ﬁve newly diabetic patients, and the mean HbA1c was 7.2% ± 0.6%. At dis- Insulin Dose charge, three patients received basal insulin and two oral agents. Insulin requirements are shown in Table 2. The TDD of insulin during PN was 30.2 ± 20 units or 0.43 ± 0.3 U/kg/day. In patients with DM, DISCUSSION the TDD was 0.5 ± 0.3 U/kg/day (35.1 ± 21 U/day) and, in those with no history This retrospective study aimed to evaluate the of DM, 0.37 ± 0.3 U/kg/day (25.3 ± 19 U/day), quality of glucose control achieved by a basal p \ 0.05. The insulin glargine dose increased plus correction insulin regimen in surgical while the correctional insulin lispro decreased patients with and without a history of DM from the start until 48 h before ending the PN. receiving PN. Our study conﬁrms that 1364 Diabetes Ther (2018) 9:1359–1367 infections and mortality in surgical patients with diabetes [10, 24, 25]. Studies that evaluate hyperglycemia treat- ment in patients receiving PN are scarce and include both critically ill and non-critically ill patients. Glycemic targets are heterogeneous, and intervention includes the incorporation of insulin with PN solution  and administra- tion of long-acting insulin . Only one study has compared these strategies in surgical patients receiving PN , and the results con- ﬁrm that both glargine insulin and regular insulin in the PN are effective modalities for BG control. Moreover, a recent meta-analysis con- Fig. 1 Glycemic control in all patients, diabetic and non- ﬁrms that the most ﬁtting insulin regimen to diabetic patients in relation to the time of PN. *Difference treat hyperglycemia in hospitalized patients on between diabetic and non-diabetic patients. *p \ 0.05 nutritional support has not been established . Accordingly, there is a lack of standardized protocols for monitoring and therapy in this population, and strategies are those recom- mended for hospitalized non-critically ill patients [5, 12, 13, 20, 26]. Although there is no clear evidence for speciﬁc BG goals in non-critically ill patients, pre-meal BG targets \ 140 mg/dl with random BG \ 180 mg/dl are considered reasonable [12, 13, 20, 26]. Glucose management typically involves subcutaneous insulin administered as a basal/bolus/correction regimen with adequate adjustments as the patient’s condition changes Fig. 2 Proportion of patients with BG\180 mg/dl in the [12, 13, 20]. In patients on PN, as the rate of three study periods glucose infusion is expected to be ﬂat and remain in a postprandial state, a basal plus correction insulin regimen and a BG target \ subcutaneous insulin with basal and correction 180 mg/dl were established. components is an adequate method for achiev- The target BG \ 180 mg/dl was achieved in ing and maintaining glucose control in non- only 50% of patients, equaling overall glycemic critically ill hospitalized patients with PN and control rates obtained in a recent study with extends our knowledge as it was performed glargine insulin (52.24%) and regular insulin in during regular clinical practice. the PN bag (47.76%) . As expected, a high People with DM have a higher probability of percentage of patients with a previous history of requiring surgery during their lifetime than DM did not reach the glycemic target. The those without DM . In addition, hyper- average TDD of insulin measured 0.5 U/kg/day glycemia is a frequent complication of PN in in patients with previous DM and 0.37 U/kg/day patients both with and without DM. Develop- in those with no history of DM, in accordance ment of hyperglycemia during PN increases the with current recommendations for hospitalized risk of complications and mortality [7, 22, 23], patients as initial insulin doses [13, 27, 28]. and several studies have demonstrated that Therefore, an initial insulin dose estimated at hyperglycemia treatment reduces rates of 0.4 U/kg/day seems to be adequate for most patients, and perhaps the main reason for not Diabetes Ther (2018) 9:1359–1367 1365 achieving reasonable glycemic control was the Authorship. All named authors meet the lack of dose adjustment. International Committee of Medical Journal The prevalence of hypoglycemia in patients Editors (ICMJE) criteria for authorship of this receiving PN is not well known and has been manuscript, take responsibility for the integrity related to an increase in complications and of the work as a whole and have given ﬁnal mortality . The percentage ranges from a approval for the version to be published. low of around 4% up to 40% . In our report, Disclosures. Antonio Pe´rez has served as a 22.5% of patients experienced BG consultant for or received lecture fees or travel levels \ 70 mg/dl and 7.5% \ 40 mg/dl. Most reimbursement from Sanoﬁ-Aventis, Almirall, episodes were due to unplanned discontinua- NovoNordisk, Eli Lilly, MSD, Boehringer Ingel- tion of PN and lack of communication with the heim, Esteve, Bristol-Myers Squibb, Novartis endocrinology team, a common occurrence in and Astra Zeneca. Analı´a Ramos, Fernanda hospital wards. Rabasa, Lilian Mendoza, Joana Cardenete, Pedro The limitations of the present study include Gill, Alba Morilla and Daniel Cardona have a retrospective design that led to exclusion of nothing to disclose. subjects whose data were incomplete. As the study was performed during regular clinical Compliance with Ethics Guidelines. All practice, it provides information on the appli- procedures performed in studies involving cability of a basal-correction insulin regimen in human participants were in accordance with this context. Since our study did not aim to the ethical standards of the institutional and/or compare different strategies, conclusions national research committee and with the 1964 regarding the most appropriate method to Helsinki Declaration and its later amendments manage hyperglycemia could not be reached or comparable ethical standards. Informed based on this study. Larger studies are needed to consent was obtained from all individual par- determine the optimal glycemic control strate- ticipants included in the study. gies in patients with PN. Data Availability. The data sets generated and/or analyzed during the current study are CONCLUSIONS available from the corresponding author on reasonable request. The results of our study show that in regular clinical practice subcutaneous insulin with Open Access. This article is distributed basal and correction components is an adequate under the terms of the Creative Commons method for management of hyperglycemia in Attribution-NonCommercial 4.0 International non-critically ill hospitalized surgical patients License (http://creativecommons.org/licenses/ with PN. by-nc/4.0/), which permits any non- commercial use, distribution, and reproduction in any medium, provided you give appropriate ACKNOWLEDGEMENTS credit to the original author(s) and the source, provide a link to the Creative Commons license, We thank the study participants. and indicate if changes were made. Funding. No funding or sponsorship was received for this study or publication of this article. The article processing charges were REFERENCES funded by the authors. All authors had full access to all of the data in this study and take 1. Maroulis J, Kalfarentzos F. Complications of par- complete responsibility for the integrity of the enteral nutrition at the end of the century. 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