Early and aggressive nutritional strategy (parenteral and enteral) decreases postnatal growth failure in very low birth weight infants

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1 (2006) 26, r 2006 Nature Publishing Group All rights reserved /06 $30 ORIGINAL ARTICLE Early and aggressive nutritional strategy (parenteral and enteral) decreases postnatal growth failure in very low birth weight infants A Dinerstein, RM Nieto, CL Solana, GP Perez, LE Otheguy and AM Larguia Department of Neonatology, Hospital Sarda, Buenos Aires, Argentina Objective: To compare postnatal growth and nutritional deficits after the implementation of two different nutritional strategies in two consecutives periods of time. Methods: An early and aggressive nutritional regimen was used in a cohort of 117 very low birth weight (VLBW) infants. Amino acids were administered at the rate of 1.5 g/kg/day along with 5.6 mg/k/min of glucose flow on day 1 of life, and progressively increased to 4 g/kg/day and 13 mg/kg/min. Intravenous lipids were started at 0.5 g/kg/day at 24 h from birth, and increased to 3.5 g/kg/day; enteral feeding was begun at day 1 of life. Uni- and multivariate analyses were used to compare this group with the conventional group of 65 VLBW infants conservatively fed. Results: Univariate analysis showed that in the aggressive group there was a 66% reduction in the risk of post natal malnutrition at 40 weeks of postmenstrual age (OR 0.34; 95% CI ). This difference persisted in the multivariate analysis. Energy and protein deficits were lower in the aggressive group (P<0.001). Conclusions: Early and aggressive introduction of total parenteral nutrition and enteral feeding resulted in better growth in weight, length and head circumference, and a reduction of nutritional deficits at 40 weeks of postmenstrual age. (2006) 26, doi: /sj.jp Keywords: prematurity; nutrition; postnatal growth Introduction The first weeks of life are a critical stage for the growth and neurodevelopment of a very low birth weight (VLBW) infant. 1 This is the phase in which the nutritional requirements for an adequate growth are greater than at any other time in life. The consequences of insufficient nutrition in this critical period have yet to be determined with certainty, but there is considerable evidence that Correspondence: Dr A Dinerstein, Department of Neonatology, Hospital Sarda, Av Las Heras b, Buenos Aires, 1426, Argentina. alejandro.dinerstein@gmail.com Received 8 December 2005; revised 25 April 2006; accepted 5 May 2006 early growth failure has long-term negative effects on childhood growth and neurodevelopment, and that these effects probably persist into adulthood. 1,2 There is abundant reason to hypothesize that the rapid establishment of postnatal nutrition could be essential to attain optimal nutritional support. It is presently recommended that enough nutrients be provided so as to achieve a body composition and growth similar to those of a normal fetus of the same postmenstrual age. 3 The estimated placental transfer, in the second and the beginning of the third trimester of gestation, is 8 to 10 mg/ k/min of glucose and 3.6 to 4.8 g/k/day of amino acids; yet VLBW infants usually receive less than this postnatally. 4 In addition, these patients have poor energy stores at birth. Fat accounts for only 2% of their body weight, while glycogen for <0.5%, compared to 15 and 1.2%, respectively in the term infant. 5 Specific neonatal morbidity (ventilator and oxygen dependent infants) may also increase metabolic demands by as much as 25% compared to controls. 6,7 The Committee on Nutrition of the American Academy of Pediatrics have recommended a caloric intake of 120 kcal/kg/ day for children enterally fed and 80 to 100 kcal/kg/day for those parenterally fed, with a protein intake of 3.5 to 4 g/kg/day. 3 However, it is difficult for most VLBW infants to reach this suggested caloric and protein intake in the first two months of age. 5 This is due to the need for fluid restriction, intolerance to standard glucose infusions, tardy initiation of parenteral amino-acid solutions, feeding periods without lipids and immaturity of intestinal functions; all of which cause frequent interruptions and contribute to the slow progress of enteral feeding. This study has been designed to determine the impact of an early and aggressive nutritional regimen on postnatal growth. The hypothesis is that this early and aggressive nutritional intervention could improve the growth of VLBW infants at 40 weeks of postmenstrual age. The primary objective of the study is to compare two different nutritional interventions (conventional vs early and aggressive) in their effects on postnatal growth. The secondary objective is to assess nutritional deficits in VLBW infants

2 437 in the first 4 weeks of life when the recommended energy and protein intakes are introduced soon after birth. 3 Methods Subjects All infants with a birth weight of <1500 g and more than 750 g were eligible for the study. Infants were excluded if they had major congenital anomalies or if they died or were transferred to another hospital before seven days of age. A cohort of 117 VLBW infants was prospectively studied using an early and aggressive nutritional regimen (aggressive group). This group was compared with a retrospective cohort of 72 VLBW infants fed conservatively (conventional group). This control group was chosen from the institution s prospective data and included all infants born in the year before the beginning of the prospective cohort. For both cohorts (aggressive and conventional), all children meeting the study selection criteria were included consecutively. No infants were included in the aggressive group without a written informed consent from at least one of their parents; while not so in the conservative group as it was a historical cohort. The study was approved by the Research Ethics Committee of the Hospital Materno Infantil Ramón Sardá. Nutritional regimens group. Fluids were started at a rate of 80 ml/kg/day and increased to ml/kg/day during 7 days. Upon admission to the NICU, these infants received parenteral nutrition in the form of 10% amino-acid solution at a rate of 1.5 g/kg/day, along with 5.6 mg/k/min of glucose intake starting on day 1 of life. The amino acids were increased by 0.5 g/kg/day until reaching a total of 4 g/kg/day as long as there was no renal failure or metabolic acidosis. The glucose infusion was increased progressively by 1 mg/kg/min every 24 h to a maximum of 13 mg/ kg/min to maintain blood glucose levels between 120 and 150 mg/ dl. In the event of persistent hyperglycemia (blood glucose >150 mg/dl) a continuous insulin infusion was started at 0.02 U/ kg/h and titrated to achieve normoglycemia. A 20% lipid solution at 0.5 g/kg/day was introduced at 24 h of age and increased by 0.5 g/kg/day until reaching 3.5 g/kg/day. In the event of a high triglyceride level (between 170 and 200 mg/dl), the lipid solution was decreased by 0.5 g/kg/day. When the triglyceride level was over 200 mg/dl, the lipid infusion was discontinued until triglyceride levels normalized and was then restarted at 1 g/kg/day. Parenteral nutrition was maintained until enteral feeding reached 100 kcal/ kg/day. The aggressive group also received enteral feeding on day 1 of life, with expressed breast milk (EBM) or preterm formula (24 kcal/oz) at 10 ml/kg/day, depending on availability. Feeds were increased by 10 ml/kg/day during the first 7 days of life, and by 15 to 20 ml/kg/day thereafter until reaching 180 ml/kg/day. In the presence of progressive gastric residuals and/or abdominal distension, the volume of feeds was reduced. Enteral feeding was not administered or was suspended if gastric residuals were more than 50% of the volume of the previous feed, if there was bilious residual, or if there was any suspicion of necrotizing enterocolitis. As there were no human milk fortifiers, infants fed EBM were given 50 and 66% preterm formula when they reached 100 and 150 ml/ kg/day respectively. group These infants also received IV fluids at 80 ml/kg/day and this was increased to 150 ml/kg/day over 7 to 10 days. In accordance with the policy of the unit at that time, the infants were started at the discretion of the neonatal staff on parenteral nutrition, with a 10% amino-acids solution on day 3 of life at 0.5 g/kg/day. This was increased by 0.5 g/kg/day until reaching 3 g/kg/day. Glucose infusion was initiated at 5.6 mg/kg/min, and was increased progressively by 1 mg/kg/min every 24 h to a maximum of 8 to 9 mg/kg/min so as to maintain blood glucose below 120 mg/dl. In the event of persistent hyperglycemia the glucose infusion was progressively reduced to achieve normoglycemia. No insulin infusion was used in this group. A 20% lipid solution was started on day 3 or 4 of life at 0.5 g/kg/day, and was increased by 0.5 g/kg/day until reaching 3 g/k/day. Parenteral nutrition was maintained until enteral feeding reached 60 kcal/kg/day. Enteral feeds were not dictated by an experimental protocol but rather introduced by the attending physician when the infant was considered clinically stable. Studied variables Energy and protein intakes daily recorded in both groups for deficits calculations were those that actually occurred and not those prescribed. When the patient s condition permitted, weight was recorded daily until day 28 of life and afterwards, it was recorded weekly. Head circumference and length were measured weekly and plotted according to local tables. Small for gestational age (SGA) was defined as a birth weight below the 10th percentile of national standards; postnatal growth retardation was defined as body weight below the 10th percentile of national standards for infants of 40 weeks of postmenstrual age. 8,9 The cumulative energy and protein deficits were defined as the difference between actual and recommended energy and protein intakes. 3 Clinical outcomes Bronchopulmonary dysplasia (BPD) was defined as the need for oxygen at the 36th weeks of postmenstrual age. Necrotizing enterocolitis (NEC) was defined using Bell s classification degree 2 or more. 10 A patent ductus arteriosus (PDA), diagnosed clinically or

3 438 Early and aggressive nutrition in VLBW infants with echocardiography, was considered clinically significant when it required medical treatment. Intraventricular hemorrhage (IVH) above grade II and defined using Papile s classification, 11 as well as cystic periventricular leukomalacia (cpvl) were diagnosed with cranial ultrasonography. Late onset sepsis was defined as any positive blood culture after 72 h of life. Retinopathy of prematurity was registered when threshold stage or greater was diagnosed with indirect ophthalmoscopy. Statistical analysis Student s t-test was used for normally distributed continuous variables and Mann Whitney U-test was used when normality failed. Categorical data were analyzed using the w 2 test. Differences between protein and caloric intakes and deficits in both groups were analyzed using Mann Whitney U-test. Multivariate analysis was performed using logistic regression in order to adjust for the effects of the following contributing factors: birth weight, gestational age, multiple birth, SGA, antenatal steroids, surfactant treatment, days on mechanical ventilation and neonatal morbidity (PDA, BPD, early/late onset sepsis, IVH and cpvl). Results were expressed as adjusted odds ratios and 95% confidence intervals. The Wald test was used to test for statistical significance of the multivariance analysis (P<0.05). Calibration was evaluated with Hosmer Lemeshow test. The statistics software used was STATA7 for Windows. Results Prospective enrollment in the study was completed between 1 August 2001 and 31 July During this time, 136 infants with birth weight between 750 and 1500 g were born at our institution, and 128 of them met the inclusion criteria for the early and aggressive nutritional regimen; therefore, the informed consent was obtained. The conservative group was conformed by the 72 infants born with the same body weight range as the immediate preceding year and met the inclusion criteria. In the aggressive group, 117 out of 128 infants completed the study; six patients died (four due to late onset sepsis, one due to NEC, and one from RDS and five were transferred out of our institution before reaching their 40th weeks of postmenstrual age (three because of their health insurance and two for PDA and NEC surgery). In the conventional group 65, out of 72 infants completed the study. Three patients died (one due to late sepsis and two due to NEC) and four were transferred out of our institution before the 40th weeks of postmenstrual age (one NEC, one superior cava vein thrombosis and two because the need of ROP and PDA surgery). There were no significant differences between the two groups in terms of their clinical characteristics and morbidity (Table 1 and 2). Table 1 Clinical characteristics Gestational age in weeks median (range) 30 (26 35) 30 (24 36) 30 weeks gestational age n (%) 70 (60) 38 (58) Birth Weight (grams) median (range) 1245 ( ) 1230 ( ) Length at birth mean (SD) 37.1 (2.3) 37 (0.2) Head circumference at birth (cm) 26.3 (1.9) 26.5 (1.9) mean (SD) Small for gestational age 30 (26) 12 (18) (<10th centile) n (%) Male sex n (%) 63 (54) 37 (57) Multiple birth n (%) 23 (20) 13 (20) Maternal steroids n (%) 92 (79) 56 (86) CRIB score 0 5 n (%) 97 (83) 54 (83) >5 n (%) 13 (11) 11 (17) Surfactant treatment n (%) 23 (20) 17 (26) CRIB score clinical risk index for babies. Table 2 Clinical outcomes Days on mechanical ventilation median (range) 4 (0 86) 3 (0 95) Requiring 02 at 36 weeks post-menstrual 40 (34) 18 (28) age number (%) PDA number (%) 56 (48) 23 (35) NEC number (%) 2 (2) 3 (5) Late onset sepsis number (%) 30 (26) 15 (23) IVH>grade II number (%) 7 (6) 5 (8) cpvl number (%) 8 (7) 7 (11) Severe ROP number (%) 7 (6) 9 (14) Abbreviations: cpvl, cystic periventricular leukomalacia; IVH, Intraventricular hemorrhage more than grade II; NEC, Necrotizing enterocolitis; PDA, patent ductus arteriosus; ROP, retinopathy of prematurity. In the aggressive group, transient acute renal failure (ARF); creatinine >1.3 mg/dl in the first postnatal week; 12 was observed in five patients (4.2%) and metabolic acidosis in thirteen of them (11%), in these patients amino-acids intake was temporary reduced. Fluid intakes in the two groups were similar in the first 3 weeks of life, but the aggressive group had a slightly higher mean fluid intake in week 4 (Table 3). Significantly higher energy and protein intakes were achieved in the aggressive group in all periods (Table 4 and Figures 1 and 2). The aggressive group received TPN sooner and longer than the

4 439 Table 3 Weekly fluid intake Weekly fluid intake (ml/kg) median (DS) Week (13) 108 (13) Week (17) 145 (16) Week (25) 152 (16) Week (22)* 157 (16) Mann Withney* P ¼ Table 4 Weekly caloric and protein intake and cumulative deficits Conventiona1 Caloric intake (kcal/kg/week) Week (331/731) 351 (195/605)* Week (411/1120) 679 (348/917)* Week (333/1371) 802 (288/935)* Week (331/1159) 828 (477/932)* Figure 1 Energy intake in aggressive group was higher (P<.001) and deficit was lower from birth to day 28 (P<.001). Cumulative caloric deficit (kcal/kg) Week ( 508/13) 489 ( 726/125)* Week ( 893/18) 649 ( 1190/ 65)* Week ( 1220/506) 698 ( 1540/30)* Week (1358/627) 732 ( 1871/ 72)* Protein intake (g/kg/week) Week (12.8/25.6) 9.3 (1.8/21.3)* Week (8.7/ 33) 17.1 (6/26)* Week (1.8/31) 18.5 (2.7/27.7)* Week (7.9/34) 18.9 (12.4/24.6)* Cumulative protein deficit (g/kg) Week ( 11.6/1.44) 14.7 (22.7/ 1.5) Week ( 25/3.4) 20.9 ( 40/0.16)* Week ( 36/11.7) 27.9 (51±1.1)* Week 4 7 ( 46/14.9) 33 ( 61.6/ 0.53)* Values are median (min/max) *Mann Withney P<0.001 compared to the aggressive group. Figure 2 Protein intake was higher in aggressive group (P<.001) and deficit was lower from birth to day 28 (P<.001). conventional group. The aggressive group was not fed enterally for fewer days, and achieved full enteral feeds (120 kcal/kg/day) sooner than the conventional group (Table 5). Hyperglycemia was present and required insulin treatment in 20 patients (17%) for a median of one day (range 1 to 2). Mean triglycerides was 84 mg/dl (SD 35) on day 4 and 117 mg/dl (SD 76) on day 8. Eleven patients (9,5%) had hypertriglyceridemia during TPN and the dose of IV lipids was temporary reduced. The incidence of enteral feed interruptions was similar in both groups (25% of infants in the aggressive group for an average of 3 days with a range of 2 to 15 days and, 24% of infants in the conventional group for 4 days with a range of 2 to 21 days). Table 5 Details of nutritional intakes P-value Age TPN started (days) median (range) 1 (0 3) 3 (1 17) <0.001 Days of parenteral nutrition median (range) 10 (5 36) 4 (0 37) 0.02 Age enteral feeds started (days) median 1 (0 6) 4 (1 36) <0.001 (range) Age to achieve 120/kcal/day (days) median (range) 15 (7 52) 20 (0 62) Abbreviations: TPN, total parenteral nutrition.

5 440 Table 6 Early and late growth P-value Postnatal growth failure at 40 weeks postmenstrual age number (%) 62 (53) 50 (77) Body weight at 40 weeks postmenstrual age (kg) median (range) 2.95 ( ) 2.7 ( ) Length at 40 weeks postmenstrual age (cm) mean (s.d.) 46.6 (2.6) 45.6 (2.7) Head circumference at 40 weeks postmenstrual age (cm) mean (s.d.) 35.2 (0.17) 34.3 (0.21) Days to regain birth weight median (range) 10 (1 21) 16 (1 29) <0.001 Maximum weight loss mean (s.d.) 9 (4.9) 13.3 (6.1) <0.001 Age at maximum weight loss (days) mean (s.d.) 4.7 (2.1) 12.7 (2.3) Abbreviations: PCA, post-conceptional age. The aggressive group recovered BW sooner and its maximum percentage of weight loss was significantly lower than in the conventional group, and had higher body weight, length and head circumference at 40 weeks of postmenstrual age. The number of infants with growth retardation at 40 weeks of postmenstrual age was significantly greater in the conventional group than in the aggressive group (Table 6). Univariate analysis showed that the aggressive group had a 66% reduction in the risk of postnatal growth failure at 40 weeks (OR 0.34; 95% CI ). This difference persisted after adjusting for confounding variables (BW, gestacional age, antenatal steroids and morbidity (P<0.001). During hospitalization, the difference between actual and recommended energy and protein intakes resulted in cumulative energy and protein deficits during the first 28 days of life for both groups. These deficits were significantly greater in the conventional group caloric deficit 732 vs 295 kcal/kg and a protein deficit of 33 vs 7 g/kg (P<0.001). Infants in the aggressive group did not meet the recommended caloric and protein intake requirements during the first 2 weeks of life, but by the third and fourth week of life, caloric and protein intakes approached or surpassed the minimum requirements. By contrast, the conventional group acquired a larger deficit early in their hospitalization and continued accumulating caloric and protein deficits at 28 days of life (Table 4 and Figures 1 and 2). Discussion We compared the postnatal growth and outcomes of two groups of VLBW infants using two different types of nutritional intervention. We found that an early and aggressive parenteral and enteral nutritional regimen resulted in a significantly higher energy and protein intake without an increased incidence of adverse clinical outcomes. There were no differences in the diagnoses of NEC, PDA, BPD and ROP. Acute renal failure in the aggressive group is similar to that described in the literature. 13 The rate of hyperglycemia in the aggressive group was lower than that of other reported series. 14 This might be related to the stimulating effect on the insulin secretion that the early introduction of amino acids produces. 15 In VLBW premature infants, the incidence of hyperglycemia is frequent because the endogenous production of glucose is not suppressed either by the exogenous intakes of nutrients or by the infusion of lipids. 16 Plasmatic values of triglycerides in the aggressive group were in the normal range, similar to that found by other authors. 17 When compared with the conventional group, improved energy intake in the aggressive group was not achieved at the expense of increased fluid intake. We also found that although an early and aggressive intervention resulted in better growth and decreased the percentage of infants with postnatal growth failure, it did not completely prevent it. Although every effort was made to meet the recommended energy and protein intakes of 120 kcal/kg/day and 3.5 g/kg/day respectively, 3 most infants accumulated significant deficits in the first 2 weeks of life. Thus, on average, the infants in the aggressive group received 71 and 103 kcal/kg/day in the first and second week of life, respectively, well below the recommended energy intake, which was achieved only by the third week of life. Similarly, the recommended protein intake of 3.5 g/kg/day was not achieved until the fourth week of life. Wilson et al. in a randomized controlled trial of an aggressive nutritional regimen in sick VLBW infants, showed an improvement of growth in the early neonatal period and at hospital discharge without increasing the risk of adverse clinical or metabolic sequelae. The improved growth, however, was not associated with decreased pulmonary morbidity or shorter hospital stays. As in the present study, despite aggressive nutritional intervention, the mean energy intake was always less than the energy intake recommended for growth. 5 Similarly, Embleton et al., 18,19 in a prospective study in preterm infants <34 weeks showed significant accumulated nutritional deficits in the first few weeks of life that remained uncompensated at time of hospital discharge. Some studies have shown an association between nutrient and lipid overload and pulmonary morbidity in VLBW infants In the present study, increased energy intake resulting from an early and aggressive nutritional regimen was not associated with increased morbidity. Here, as in other studies, 23,24 there is no indication that the early introduction of enteral feeding is

6 441 associated with an increased risk of NEC (2% in the aggressive group and 5% in the conventional group). In addition, the aggressive group achieved full feeds 5 days earlier and had less feeding intolerance than the conventional group. This could be explained by the trophic effects of the early enteral feeding, nevertheless an unintentional bias, arising from the tendency of studies to improve the quality of monitoring, cannot be ruled out. The transition from fetal to extrauterine life should occur with minimal interruption to growth. This makes it essential to provide sufficient nutrients of high enough quality soon after birth so as to maintain a rate of growth similar to that of the fetus. However, most VLBW infants do not regain their birth weight before 2 weeks of age at the earliest, and many of them grow poorly or do not at all until much later. 25 Although the consequences of this early retardation in growth are not completely known, there is concern that it might contribute to long-term deleterious effects, including short stature and lower developmental indices. 1,19 Although early administration of only g/kg/day of amino acids parenterally can minimize or prevent the loss of body protein stores, significantly higher intakes are needed to promote growth and prevent increased deficits It has been estimated that, to attain intrauterine rates of protein deposition, around 4 g/kg/day of amino-acid intake may be required in the smallest VLBW infants. 30 Additional proteins and calories for catch up growth are usually necessary to compensate for any loss of lean body mass that occurred before the infant regains birth weight. Thureen et al. 27 has shown that high intravenous amino-acid intake (3 g/kg/day) was well tolerated in very low weight infants in the first days of life and resulted in increased protein accretion when compared to low intravenous amino-acid intake (1 g/kg/day). Thus, more aggressive amino-acid intakes can potentially avoid and eliminate the postnatal growth retardation that is usually observed in these infants. However, there is no clear evidence that an energy intake of more than 120 kcal/kg/day is desirable since it may do nothing more than promote higher rates of fat accretion. 31 More studies should be carried out in order to explore safe strategies for increasing protein and energy intakes during the first days of life in order to avoid deficits, because of their magnitude, cannot be compensated for before discharge. How much compensatory growth could be achieved and in what span of time? Does this compensatory growth improve neurodevelopment in the long run? Does it reduce the risk of diseases in adulthood? 32 We still have no answers to these questions, but we believe that reducing postnatal undernourishment during an early stage of development will probably improve the infant s life quality in the long run. Follow-up of the patients subjected to this study to evaluate their behavior, learning and memory alterations, renal function, metabolic dysfunctions and arterial hypertension, among others, is still in progress. Conclusion We compared two different types of nutritional intervention on postnatal growth and their outcomes in VLBW infants. Our finding was that, both in the early neonatal period and at 40 weeks of postmenstrual age, infants subjected to an early and aggressive introduction of TPN and feeding showed better growth than those of the conventional group. Despite our efforts for accomplishing with the AAP recommendations we have not been able to avoid deficits in energy and proteins intake. We speculate whether this improved early growth could be translated into a better long-term neurological outcome. A followup on the patients subjected to this study is still in progress with a view to evaluate neurodevelopment outcome, metabolic abnormalities and systemic hypertension (among others). Acknowledgment We thank Dr Ruben Alvaro, Professor of Pediatrics, University of Manitoba at Winnipeg, for help with manuscript and useful comments. References 1 Lucas A, Morley R, Cole TJ, Gore SM, Lucas PJ, Crowle P et al. Early diet in preterm babies and development status at 18 months. Lancet 1990; 335: Barker DJ. Fetal growth and adult disease. Br J Obstet Gynaecol 1992; 99: American Academy of Pediatrics. Committee on Nutrition. Nutritional needs of low birth-weight infants. Pediatrics 1985; 76: Hay Jr WW, Lucas A, Heird WC, Ziegler E, Levin E, Grave GD et al. Workshop summary: nutrition of the extremely low birth weight infant. 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