Strictly controlled glucose infusion rates are associated with a reduced risk of

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1 Article type : Regular Article Strictly controlled glucose infusion rates are associated with a reduced risk of hyperglycaemia in extremely low birth weight preterm infants Hans Jorgen Stensvold 1,2,3 MD; Astri M. Lang 1, MD, PhD, Kenneth Strommen 1,4, MD, Tore G. Abrahamsen 2,5, MD, PhD, Bjorn Ogland 1, MD, PhD, Are H. Pripp 6, PhD, Arild E. Ronnestad 1,2,3, MD, PhD Affiliations: 1 Neonatal Department, Division of Paediatric and Adolescent Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; 2 Faculty of Medicine, Institute for Clinical Medicine, University of Oslo, Oslo, Norway; 3 Norwegian Neonatal Network, Oslo University Hospital Rikshospitalet, Oslo, Norway; 4 Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Norway; 5 Department of Pediatrics, Division of Paediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway; 6 Oslo Centre of Biostatistics and Epidemiology, Oslo University Hospital, Oslo, Norway. Short title: Risk of hyperglycaemia in preterm infants Corresponding author: Hans Jorgen Stensvold, Neonatal Department, Oslo University Hospital Rikshospitalet, Postboks 4950 Nydalen, 0424 Oslo, Norway, [hstensvo@ous-hf.no], FINANCE This study did not receive any specific funding CONFLICTS OF INTEREST The authors have no conflicts of interest to declare This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: /apa.14164

2 Aim: We evaluated a strict strategy that aimed to avoid fluctuations in glucose infusion rates (GIRs) and assessed the independent effects of maximal daily GIRs on the hyperglycaemia risk among extremely low birth weight (ELBW) infants receiving early enhanced parenteral nutrition. Methods: This study comprised all ELBW infants admitted to the neonatal intensive care unit of Oslo University Hospital Rikshospitalet, Norway before ( ) and after ( ) implementing a strict GIR strategy. Severe hyperglycaemia was defined as two consecutive blood glucose values over12 mmol/l. Maximum daily GIRs (mg/kg/min) were categorised into low (<5.1), intermediate ( ) or high (>7.0). Mixed effects logistic regression modelling for repeated measurements was applied to investigate independent determinants of hyperglycaemia. Results: We included 1,293 treatment days for 195 infants. The maximum daily GIR decreased (6.3 versus 5.8 mg/kg/min), while mean daily glucose and energy intakes were maintained in the post strategy period. The prevalence of severe hyperglycaemia (48% versus 23%), insulin use (39% versus 16%) and mortality (26% versus 10%) fell. Intermediate GIR (odds ratio 2.11) and high GIR (odds ratio 2.85) were significant independent predictors of severe hyperglycaemia compared to low GIR. Conclusion: A strict GIR strategy reduced the risk of severe hyperglycaemia and adverse outcomes. Key Words: extremely low birth weight, glucose infusion rates, hyperglycaemia, mortality, parenteral nutrition.

3 Key notes: This study evaluated a strict strategy that aimed to avoid fluctuations in glucose infusion rates (GIRs) on extremely low birth weight (ELBW) infants receiving early enhanced parenteral nutrition. We studied 1,293 treatment days for 195 infants in a Norwegian neonatal intensive care unit before and after the strategy was introduced. Strictly controlling GIRs was associated with a reduced prevalence of hyperglycaemia and lower mortality, but total energy intake was maintained. INTRODUCTION Hyperglycaemia frequently occurs in extremely low birth weight infants (ELBW), with a birth weight of less than 1,000g, during the first days of life before enteral nutrition is established. Factors associated with hyperglycaemia include prematurity, growth restriction, parenteral nutrition (PN) with a high glucose infusion rate (GIR), clinical stress and the use of vasopressors and corticosteroids (1-4). ELBW infants have high nutritional demands and glucose is an important component of early PN (5-7). However, balancing energy supply, GIRs and blood glucose concentrations can be challenging and there is a paucity of controlled trials comparing lower and higher GIRs to inform clinical practice regarding the prevention and treatment of hyperglycaemia (8,9). The impact of GIRs on the risk of hyperglycaemia remain poorly defined, as most previous reports included small sample sizes or were performed before the current era of early PN (10-14). Hyperglycaemia in ELBW infants has been associated with increased morbidity and mortality in several observational studies (2-4,15-18). We previously reported an increased prevalence of early hyperglycaemia and higher mortality after the introduction of early enhanced PN in the neonatal intensive care unit (NICU) at Oslo University Hospital Rikshospitalet (17). Following a systematic evaluation of clinical practice, we hypothesised that iatrogenic intermittent excessive infusion rates of concentrated glucose solutions were a predominant

4 risk factor for hyperglycaemia in our NICU. Consequently, a strict strategy to avoid fluctuations in GIR was implemented to prevent hyperglycaemia, while still meeting recommended energy requirements in ELBW infants. The aim of this study was to compare the nutritional intake, insulin use, prevalence of hyperglycaemia and mortality before and after the implementation of a strict GIR strategy. Furthermore, we aimed to assess the independent effects of maximal daily GIR and selected clinical factors on the occurrence of hyperglycaemia in ELBW infants receiving early enhanced PN. METHODS Participants and setting An observational study based on prospectively collected data was performed in the level IV neonatal intensive care unit at Oslo University Hospital Rikshospitalet, Norway. All ELBW infants delivered before and after a strict GIR strategy was introduced, namely between 1 January 2007 and 31 December 2009 and 1 January 2012 and 31 December 2013, were eligible if they were alive at 12 hours of age and did not have lethal malformations or chromosomal abnormalities. There was a washout period between the two stages of the study. Glucose infusion rates and nutrition In the first period, the prescription of the daily supply of nutrients and total fluid volume was performed during the morning ward round for the coming day. This implied a risk of intermittent adjustments of GIRs if enteral feeding was reduced or stopped or if the amount of fluid or drug infusion rates were changed. The GIR strategy implemented between the two study periods aimed to keep the GIR strictly at a constant velocity in mg/kg/min and included four steps. Firstly, all changes in GIR should be re-calculated and prescribed by the attending clinician to prevent even short time excessive glucose delivery. Secondly, all glucose infusions, including those running in diluted drug infusions, should be calculated in the total GIR. Thirdly, GIRs should not be increased unless clearly tolerated. Finally, there should be

5 a rapid reduction of GIR to a minimum of 4 mg/kg/min if blood glucose values approached mmol/l. In both periods, hyperglycaemia was treated with insulin if two consecutive blood glucose values exceeded 12 mmol/l at least three hours apart. Prior to insulin treatment, a reduction of GIR was initiated, but this was not below 5 mg/kg/min during Except for the different GIR strategy, the protocol for early enhanced PN and enteral nutrition was similar in both periods. PN was started shortly after birth. GIR was initiated at a minimum of 7.2 g/kg/day on the first day, and increased by 1-2 g/kg/day up to 15 g/kg/day if tolerated. Amino acids and lipids were started at 2 g/kg/day and g/kg/day, respectively, and increased by 0.5 g/kg/day, to a maximum of and g/kg/day, respectively. Enteral nutrition was started on day one or two in all infants, and increased by ml/kg/day if tolerated. All infants received their mother s own milk or human donor milk. Data collection and definitions Patients were followed until death, discharge home or transfer to a local hospital. Demographic and anthropometric data, daily treatment modalities, the Clinical Risk index for Babies (CRIB score) (19) and the clinical outcomes were entered prospectively into the hospital s electronic database on a daily basis. Blood glucose values and daily detailed nutritional data for the first week of life were obtained from the hospital s laboratory system and medical records. The nutritional content of breast milk was based on Norwegian official standards and included for infants tolerating at least 0.5 ml/hour (20). The maximal daily GIR was defined as the highest infusion rate given continuously for at least one hour and was categorised into three groups: below 5.1 mg/kg/min (low GIR), mg/kg/min (intermediate GIR) and above 7.0 mg/kg/min (high GIR). Blood glucose values were obtained at the clinician s discretion, usually four to eight times a day from the first day of life. Blood glucose concentrations in whole blood were analysed by using the Accu-chek glucose meter

6 (Roche Diagnostics, Indiana, USA). Severe hyperglycaemia was defined as two consecutive blood glucose concentrations exceeding 12 mmol/l at least three hours apart. In addition, the prevalence of hyperglycaemia for three different thresholds was investigated: two consecutive blood glucose concentrations exceeding 10 mmol/l, 15 mmol/l and 20 mmol/l at least three hours apart. Birth weight z-scores and small for gestational age, define as a birth weight below the 10th centile, were calculated according to Norwegian growth charts (21). Severe intracranial haemorrhages were diagnosed by cranial ultrasound and defined according to Papile grade three or four (22). Necrotising enterocolitis was diagnosed according to Bell stage two or three (23). Sepsis was diagnosed as the growth of bacteria or fungi in blood culture and antibiotic treatment for at least five days or death before five days of treatment. The Privacy and Data Protection Officer at Oslo University Hospital approved the study. Statistical analyses Group differences were examined using the chi-square test and Fisher s exact test for categorical variables and Mann-Whitney U test or independent samples t test for continuous variables. Mixed effects logistic regression modelling was applied to investigate risk factors for hyperglycaemia on each separate day during the first week of life, and to account for correlations between repeated days of measurements within each patient. The crude effects of baseline characteristics, treatment modalities and nutrient intake on the outcome hyperglycaemia were explored. A composite variable of death or verified necrotising enterocolitis, sepsis or severe intracranial haemorrhage occurring on the same day as hyperglycaemia was included in the model as a marker of critical illness. The maximal daily GIR was included as a categorised variable, where intermediate GIR ( mg/kg/min) and high GIR (above 7.0 mg/kg/min), were tested against the reference value of low GIR (below 5.1 mg/kg/min). Significant covariates from the univariable analysis were included in the initial multivariable model. In cases where covariates were highly correlated, the selection of

7 only one was based on clinical judgement and whether a previous association with hyperglycaemia had been reported. When selecting variables for the final predictive model, stepwise backward analysis was performed until all remaining variables were statistically significant. The variables included in the final model were: maximal daily GIR, lipid infusion rate, mechanical ventilation, vasopressor use, gestational age (GA) and the composite variable critical illness. P values of less than 0.05 were regarded as statistically significant. Analyses were performed with Stata version 14.1 (Stata Corp, College Station, Texas, USA). RESULTS During the two study periods, 200 inborn ELBW infants were alive at 12 hours of age and we excluded five infants due to lethal malformations or chromosomal abnormalities. Of the 195 infants included in the study, 113 infants were born before the introduction of the strict GIR strategy ( ) and 82 infants were born afterwards ( ). Baseline characteristics and the total daily intake of lipids and carbohydrates during the first week of life were similar in the two study periods, while the amino acid intake and total energy intake were significantly higher in (Table 1). A significant reduction in the maximal daily GIR and in the proportion of days with a maximal daily GIR exceeding 7 mg/kg/min was observed in compared to Furthermore, the prevalence of severe hyperglycaemia (23% versus 48%), the use of insulin (16% versus 39%) and mortality (10% versus 26%) was significantly reduced in compared to Clinical predictors of hyperglycaemia The characteristics and clinical outcomes in infants with and without severe hyperglycaemia during the first week are presented in Table 2. Patients with severe hyperglycaemia were born at a lower GA, with a lower birth weight and higher CRIB score. When we investigated the prevalence and risk factors for severe hyperglycaemia during the first week of life for the total five-year study period, we included 1,293 of a total of 1,311 treatment days in the analyses. Due to missing blood glucose values, 18 treatment days were excluded. A mean of

8 4.3 blood glucose samples per patient were registered each day with a standard deviation of 2.5., However there were fewer samples on days without severe hyperglycaemia, with a mean of 3.7 and standard deviation of 2.0. Severe hyperglycaemia occurred on 170/1,293 (13%) treatment days. The daily nutritional intake and selected treatment variables during the first week of life are presented in Table 3. As shown, the mean lipid infusion rate was higher, breast milk intake was lower and maximal GIR exceeding 7 mg/kg/min occurred more frequently on days with severe hyperglycaemia than days without. Univariable multilevel mixed effects logistic regression analysis found that several clinical variables were associated with severe hyperglycaemia (Table S1). Birth weight was not selected for the multivariable model due to a highly significant correlation with GA. CRIB was excluded after stepwise backward analysis. In the final multivariable multilevel mixed effects logistic regression model (Table 4), intermediate GIR (odds ratio 2.11) and high GIR (odds ratio 2.85) were independently associated with severe hyperglycaemia compared to low GIR. Severe hyperglycaemia occurred four times more frequently on days with high GIR compared to low GIR (Figure 1). Additional independent risk factors for hyperglycaemia were lower GA, higher lipid infusion rates, mechanical ventilation, vasopressor use and the composite variable of critical illness (Table 4). DISCUSSION ELBW infants have reduced endogenous insulin production, reduced insulin sensitivity and incomplete suppression of gluconeogenesis in response to increasing GIR compared to term infants (10,24-27). Thus, excessive glucose delivery within the frames of an enhanced PN regimen is a plausible risk factor for hyperglycaemia (14,28). As a consequence of our previous study reporting increased prevalence of early hyperglycaemia after the introduction of early enhanced PN, a strict GIR practice was implemented that aimed to reduce intermittent excessive infusion rates of concentrated glucose solutions (17). The present study documents a significant reduction of the maximal daily GIR after implementing the strict GIR practice, whereas the mean daily supply of carbohydrates was maintained and total

9 energy intake increased due to the increased supply of amino acids. The strict GIR practice was followed by a decreased prevalence of severe hyperglycaemia during first week of life, reduced use of insulin and decreased mortality. After adjustment for relevant covariates, including GA and severity of illness, the maximal daily GIR was independently predictive of severe hyperglycaemia. The adjusted odds ratio for severe hyperglycaemia increased with increasing maximum GIRs, indicating a close correlation between GIR and risk of hyperglycaemia. A few clinical studies have previously reported an association between higher GIR and an increased risk of hyperglycaemia. However, most of these were performed before the current era of early PN, when only glucose was given during the first days of life (9,11-13). In a small study of eight infants below 30 weeks of gestation receiving routine PN, Chacko and Sunehag reported a direct correlation between GIR and blood glucose concentrations (10). In contrast, a study of 188 very low birth weight infants by Beardsall et al reported no association between the mean rate of glucose infused during the first week of life and the risk of hyperglycaemia (1). Our findings contribute to the existing knowledge by including a large sample size and a detailed assessment of the GIRs each day during the first week of life in a clinical relevant setting with early PN. While higher maximal GIR provided for at least one hour was independently associated with a higher risk of severe hyperglycaemia, the prevalence of severe hyperglycaemia was only 5% on days where GIRs were maintained 5.0 mg/kg/min compared to 20% on days with GIR > 7.0 mg/kg/min (Figure 1). These results suggest a narrow window of glucose tolerance in ELBW infants receiving PN and also suggest that even short-term excessive glucose delivery might cause severe hyperglycaemia. In addition to excessive infusion rates of glucose, we found that lower GA, higher lipid infusion rates, mechanical ventilation, vasopressor use and the composite marker of critical illness were independent risk factors for hyperglycaemia. Previous studies have reported

10 similar risk factors for hyperglycaemia, including GA, growth restriction, lipid infusion, sepsis and inotropic medications (1,3). Along with an immature regulation of glucose metabolism, the exogenous delivery of adrenergic vasopressors and the endogenous release of insulin counter regulatory hormones like cortisol are most likely to contribute to hyperglycaemia in critically ill premature infants (28,29). Thus, vigilance in adjusting GIRs seems particularly important in the smallest and sickest babies, especially when intensive care treatment, including vasopressor use and mechanical ventilation, is inevitable. When caring for ELBW infants, a continuous focus on preventing severe hyperglycaemia while providing a balanced nutritional supply will most likely contribute to reducing the risk of serious adverse outcomes, including mortality. Although mortality was not one of the main outcomes of this study, a significant reduction in mortality from to substantiates our previous report that hyperglycaemia was independently associated with mortality (17). While the definition of neonatal hyperglycaemia varies substantially, most studies have reported adverse outcomes if blood glucose concentrations exceeded mmol/l (4,16,17). Thus, applying an operational threshold for intervention at high blood glucose concentrations seems rational (28). Our study indicates that preventing severe hyperglycaemia is possible through strict control of GIRs, even in very sick preterm infants. In addition, we recommend a reduction of GIR to a minimum of 4 mg/kg/min as a first-line treatment once blood glucose values approach mmol/l in order to limit the need for insulin treatment. The main strength of this study was the prospective daily registration of highly detailed data on treatment modalities, nutritional intake and blood glucose values. Furthermore, applying a mixed model analysis on data from repeated measurements each day during first week of life strengthened the statistical validity, resulting in more accurate estimates and a more powerful study (30). Limitations of our study included the observational study design with two different time periods and a rather large washout period. The lower incidence of hyperglycaemia in

11 may not just be down to the strict GIR practice, as theoretically it could also have been caused by differences in the case mix or a drift in clinical practice over time. Although no significant differences in baseline characteristics, including GA and CRIB score, were seen, there were differences in both the use of vasopressors and Indomethacin between the two periods. However, in the multivariable analysis that used mixed effects modelling, days with severe hyperglycaemia were compared with days without hyperglycaemia regardless of whether the infants were born during or The maximal daily GIR remained strongly predictive of hyperglycaemia in this model and we believe that potentially confounding factors were adequately adjusted for, given the large sample size of 1,293 days, and the considerable number of characteristics and treatment data included. Since continuous blood glucose monitoring was not in use, it is possible that the frequency of sampling may have been influenced by the severity of illness. However, as 3.7 daily blood glucose samples were registered in infants with no hyperglycaemia, we find it unlikely that the lack of blood glucose sampling had any impact on the prevalence of severe hyperglycaemia. CONCLUSION A strict GIR strategy was associated with a significant reduction in the prevalence of early hyperglycaemia, while the carbohydrate and energy intakes were maintained. Our study suggests a narrow window for glucose-tolerance among ELBW infants, where excessive GIR is an important and preventable risk factor for hyperglycaemia. Strict control of GIR seems particularly important among the smallest and sickest babies, where intensive care treatment, like the use of vasopressors and mechanical ventilation, are inevitable. Randomised controlled trials are warranted that compare different GIRs for the prevention and treatment of hyperglycaemia in infants receiving early PN.

12 Acknowledgements: The authors thank Lina Merethe Knudsen Norwegian Neonatal Network, Oslo University Hospital Rikshospitalet and Eline Kjorsvik Steen, University of Oslo, Norway for assistance in retrieving the patient records. CRIB Clinical Risk Index for Babies; ELBW extremely low birth weight infants; GA gestational age; GIR glucose infusion rate; PN parenteral nutrition. REFERENCES: 1. Beardsall K, Vanhaesebrouck S, Ogilvy-Stuart AL, Vanhole C, Palmer CR, Ong K, et al. Prevalence and determinants of hyperglycemia in very low birth weight infants: cohort analyses of the NIRTURE study. J Pediatr 2010; 157(5): Alexandrou G, Skiold B, Karlen J, Tessma MK, Norman M, Aden U, et al. Early hyperglycemia is a risk factor for death and white matter reduction in preterm infants. Pediatrics 2010; 125(3): Blanco CL, Baillargeon JG, Morrison RL, Gong AK. Hyperglycemia in extremely low birth weight infants in a predominantly Hispanic population and related morbidities. J Perinatol 2006; 26(12): Kao LS, Morris BH, Lally KP, Stewart CD, Huseby V, Kennedy KA. Hyperglycemia and morbidity and mortality in extremely low birth weight infants. J Perinatol 2006; 26(12): Ehrenkranz RA. Early, aggressive nutritional management for very low birth weight infants: what is the evidence? Semin Perinatol 2007; 31(2): Harding JE, Cormack BE, Alexander T, Alsweiler JM, Bloomfield FH. Advances in nutrition of the newborn infant. The Lancet 2017; 389(10079): Koletzko B, Goulet O, Hunt J, Krohn K, Shamir R. 1. Guidelines on Paediatric Parenteral Nutrition of the European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) and the European Society for Clinical Nutrition and Metabolism (ESPEN), Supported by the European Society of Paediatric Research (ESPR). J Pediatr Gastroenterol Nutr 2005; 41 Suppl 2: S Bottino M, Cowett RM, Sinclair JC. Interventions for treatment of neonatal hyperglycemia in very low birth weight infants [Systematic Review]. Cochrane Database of Systematic Reviews 2011; (10).

13 9. Sinclair JC, Bottino M, Cowett RM. Interventions for prevention of neonatal hyperglycemia in very low birth weight infants [Systematic Review]. Cochrane Database of Systematic Reviews 2011; (10). 10. Chacko SK, Sunehag AL. Gluconeogenesis continues in premature infants receiving total parenteral nutrition. Arch Dis Child Fetal Neonatal Ed 2010; 95(6): F Cowett RM, Oh W, Pollak A, Schwartz R, Stonestreet BS. Glucose disposal of low birth weight infants: steady state hyperglycemia produced by constant intravenous glucose infusion. Pediatrics 1979; 63(3): Gilbertson N, Kovar IZ, Cox DJ, Crowe L, Palmer NT. Introduction of intravenous lipid administration on the first day of life in the very low birth weight neonate. J Pediatr 1991; 119(4): Louik C, Mitchell AA, Epstein MF, Shapiro S. Risk factors for neonatal hyperglycemia associated with 10% dextrose infusion. Am J Dis Child 1985; 139(8): Pappoe TA, Wu S-Y, Pyati S. A randomized controlled trial comparing an aggressive and a conventional parenteral nutrition regimen in very low birth weight infants. J Neonatal Perinatal Med 2009; 2: Garg R, Agthe AG, Donohue PK, Lehmann CU. Hyperglycemia and Retinopathy of Prematurity in Very Low Birth Weight Infants. J Perinatol 2003; 23(3): Hays SP, Smith EOB, Sunehag AL. Hyperglycemia is a risk factor for early death and morbidity in extremely low birth-weight infants. Pediatrics 2006; 118(5): Stensvold HJ, Strommen K, Lang AM, Abrahamsen TG, Steen EK, Pripp AH, et al. Early Enhanced Parenteral Nutrition, Hyperglycemia, and Death Among Extremely Low-Birth-Weight Infants. JAMA Pediatr 2015; 169(11): van der Lugt NM, Smits-Wintjens V, van Zwieten P, Walther F. Short and long term outcome of neonatal hyperglycemia in very preterm infants: a retrospective follow-up study. BMC pediatrics 2010; 10(1): International Neonatal Network. The CRIB (clinical risk index for babies) score: a tool for assessing initial neonatal risk and comparing performance of neonatal intensive care units. The Lancet 1993; 342(8865): Matvaretabellen. This food database shows nutrient values per 100 grams of edible food. Published February 13, http. Accessed February 28, Skjaerven R, Gjessing HK, Bakketeig LS. Birthweight by gestational age in Norway. Acta Obstet Gynecol Scand 2000; 79(6):

14 22. Papile LA, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and intraventricular hemorrhage: A study of infants with birth weights less than 1,500 gm. J. Pediatr 1978; 92(4): Bell MJM, Terberg JLM, Feigin RDM, Keating JPM, Marshall RMD, Barton LMD, et al. Neonatal Necrotizing Enterocolitis: Therapeutic Decisions Based upon Clinical Staging. Ann Surgery 1978; 187(1): Chacko SK, Ordonez J, Sauer PJ, Sunehag AL. Gluconeogenesis is not regulated by either glucose or insulin in extremely low birth weight infants receiving total parenteral nutrition. J Pediatr 2011; 158(6): Meetze W, Bowsher R, Compton J, Moorehead H. Hyperglycemia in extremely- low-birth-weight infants. Biol Neonate 1998; 74: Mitanchez-Mokhtari D, Lahlou N, Kieffer F, Magny JF, Roger M, Voyer M. Both relative insulin resistance and defective islet beta-cell processing of proinsulin are responsible for transient hyperglycemia in extremely preterm infants. Pediatrics 2004; 113(3 Pt 1): Cowett RM, Oh W, Schwartz R. Persistent glucose production during glucose infusion in the neonate. J Clin Invest 1983; 71(3): Hey E. Hyperglycaemia and the very preterm baby. Semin Fetal Neonatal Med 2005; 10(4): Lilien LD, Rosenfield RL, Baccaro MM, Pildes RS. Hyperglycemia in stressed small premature neonates. J Pediatr 1979; 94(3): Detry MA, Ma Y. Analyzing Repeated Measurements Using Mixed Models.JAMA 2016; 315(4):

15 TABLE 1. Characteristics, treatment variables and outcomes before ( ) and after ( ) the implementation of a strict GIR strategy Variables p value Characteristics Patients, No Gestational age, median (range), wk 25.6 ( ( ) 34.3) Birthweight, median (range), g 717 ( ) 790 ( ) Birthweight, z-score, mean (SD) (1.13) (1.06) 1.0 Female sex, No. (%) 58 (51.3) 31 (37.8) Singleton birth, No. (%) 77 (68.1) 59 (72.0) 0.57 Clinical Risk Index for Babies, median (range) 7 (1-19) 5 (1-17) Antenatal corticosteroid use, No. (%) 109 (96.5) 79 (96.3) 0.97 Cesarean section, No (%) 72 (63.7) 60 (73.2) 0.16 Nutritional intake first week of life Maximal daily GIR, mean (mg/kg/min), SD 6.3 (2.7) 5.8 (2.4) <0.001 Low GIR a, No. (%) 206 (28.0) 190 (34.2) Intermediate GIR b, No. (%) 274 (37.2) 230 (41.4) 0.12 High GIR c, No. (%) 257 (34.9) 135 (24.3) <0.001 Carbohydrates, mean (SD), g/kg/day 9.2 (2.2) 9.3 (2.3) 0.23 Proteins, mean (SD), g/kg/day 2.5 (0.9) 2.9 (0.8) <0.001 Lipids, mean (SD), g/kg/day 2.9 (1.6) 3.1 (1.5) 0.15 Intravenous lipids, mean (SD), g/kg/day 1.5 (1.1) 1.4 (1.0) 0.50 Breastmilk, median (range), ml/kg/day 20 (0-179) 26 (0-181) Total energy intake, mean (SD), kcal/kg/day 74.5 (23.5) 77.7 (21.7) Treatments first week of life, No (%) Mechanical ventilation 89 (78.8) 56 (68.3) Postnatal dexamethason for chronic lung 2 (1.8) 0 (0) disease Indomethacin for PDA first week 13 (11.5) 1 (1.2) Vasopressor use 28 (24.8) 11 (13.4) Intravenous antibiotics 112 (99.1) 80 (97.6) 0.38 Insulin infusion 44 (38.9) 13 (15.9) <0.001 Glycaemia first week of life, No. (%) Hyperglycaemia d > 10 mmol/l 77 (68.1) 29 (35.4) <0.001 Hyperglycaemia d > 12 mmol/l 54 (47.8) 19 (23.2) <0.001 Hyperglycaemia d > 15 mmol/l 39 (34.5) 11 (13.4) Hyperglycaemia d > 20 mmol/l 22 (19.5) 3 (3.7) Hypoglycaemia e < 2.6 mmol/l 38 (33.0) 26 (31,7) 0.88

16 Outcomes (%) Death, No. (%) 29 (25.7) 8 (9.8) Necrotising enterocolitis Bell stage 2-3, No. (%) 10 (8.9) 3 (3.7) 0.15 Intracranial haemorrhage Papile grade 3-4, No. 12 (10.6) 7 (8.5) 0.63 Culture positive sepsis, No. (%) 38 (33.6) 20 (24.4) 0.16 Growth velocity first 2 weeks f, mean (SD), g/kg/day 4.6 (7.1) 3.7 (8.3) 0.46 Abbreviations: GIR, Glucose Infusion Rate; PDA, Persistent Ductus Arteriosus; SD, Standard Deviation a Low GIR; maximal GIR below 5.1 mg/kg/min b Intermediate GIR; maximal GIR between 5.1 and 7.0 mg/kg/min c High GIR; maximal GIR exceeding 7.0 mg/kg/min d Two consecutive blood glucose concentrations exceeding the given threshold at least 3 hours apart e At least one blood glucose concentration less than 47 mg/dl f Among infants alive at two weeks of age

17 TABLE 2. Patient characteristics and outcomes among infants with and without severe hyperglycaemia a during first week of life Variables No severe hyperglycaemia a Severe hyperglycaemia a p value Characteristics Patients, No Gestational age, median (range), wk 26.4 ( ) 25.4 ( ) <0.001 Birth weight, median (range), g 814 ( ) 636 ( ) <0.001 Birth weight, z-score, mean (SD) (1.17) (0.95) 0.44 SGA, below 10th centile, No. (%) 50 (41.0) 32 (43.8) 0.70 Female sex, No. (%) 54 (44.3) 35 (48.0) 0.62 Singleton birth, No. (%) 91 (74.6) 45 (61.6) Clinical Risk Index for Babies, 4 (1-19) 8 (1-19) <0.001 median (range) Antenatal corticosteroid use, No. (%) 117 (95.9) 71 (97.3) 0.62 Cesarean section, No (%) 86 (70.5) 46 (63.0) 0.28 Outcomes first week of life, No (%) Death 5 (4.1) 8 (11.0) Necrotising enterocolitis Bell stage 0 (0) 2 (2.7) Intracranial haemorrhage Papile 8 (6.6) 10 (13.7) grade 3-4 Culture positive sepsis 6 (4.9) 5 (6.9) 0.57 Abbreviation: SD, Standard Deviation, SGA, Small for Gestational Age a Severe hyperglycaemia; two consecutive blood glucose concentrations exceeding 12 mmol/l at least 3 hours apart

18 TABLE 3. Nutrition and selected treatments in days with and without severe hyperglycaemia a during the first week of life Variables No severe hyperglycae mia a Severe hyperglyca emia a p value Total treatment days, No Maximal daily GIR, mean (mg/kg/min), SD 5.9 (2.6) 7.4 (2.5) <0.001 Low GIR b, No. (%) 375 (33.4) 21 (12.4) <0.001 Intermediate GIR c, No. (%) 435 (38.8) 69 (40.6) 0.65 High GIR d, No. (%) 312 (27.8) 80 (47.1) <0.001 Carbohydrates, mean (SD), g/kg 9.2 (2.3) 9.4 (2.2) 0.30 Proteins, mean (SD), g/kg 2.7 (0.9) 2.7 (0.8) 0.88 Lipids, mean (SD), g/kg 3.0 (1.6) 2.8 (1.4) 0.15 Intravenous lipids, mean (SD), g/kg 1.4 (1.1) 1.9 (0.9) <0.001 Breastmilk, median (range), ml/kg 24 (0-181) 13 (0-131) <0.001 Postnatal Age, mean (SD), days 3.0 (2.0) 2.9 (1.8) 0.47 Days with selected treatment variables, No (%) Mechanical ventilation 507 (45.2) 141 (82.9) <0.001 Postnatal dexamethason for chronic lung disease 2 (0.2) 4 (2.4) <0.001 Indomethacin for PDA 27 (2.4) 4 (2.4) 0.97 Vasopressor use 65 (5.8) 34 (20.0) <0.001 Intravenous antibiotics 960 (85.5) 161 (94.7) Abbreviations: GIR, Glucose Infusion Rate PDA, Persistent Ductus Arteriosus; SD, Standard Deviation a Severe hyperglycaemia; two consecutive blood glucose concentrations exceeding 12 mmol/l at least 3 hours apart b Low GIR; maximal GIR below 5.1 mg/kg/min c Intermediate GIR; maximal GIR between 5.1 and 7.0 mg/kg/min d High GIR; maximal GIR exceeding 7.0 mg/kg/min

19 TABLE 4. Final multivariable mixed effects logistic regression model for severe hyperglycaemia a during first week of life Variables Low GIR b Adjusted Odds Ratio (95% CI) 1 (reference) p value Intermediate GIR c 2.12 ( ) High GIR d 2.85 ( ) Lipid infusion, each increasing g/kg/day 1.41 ( ) Gestational age, each decreasing week 1.49 ( ) <0.001 Mechanical ventilation 2.14 ( ) Vasopressor use 2.10 ( ) Critical illness e, No (%) 3.19 ( ) Abbreviation: GIR, Glucose Infusion Rate a Severe hyperglycaemia defined as two consecutive blood glucose concentrations exceeding 12 mmol/l at least 3 hours apart b Low GIR; maximal GIR below 5.1 mg/kg/min c Intermediate GIR; maximal GIR between 5.1 and 7.0 mg/kg/min d High GIR; maximal GIR exceeding 7.0 mg/kg/min e Death, intracranial haemorrhage, culture positive sepsis or necrotising enterocolitis occurring the same day as severe hyperglycaemia

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