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Available online at www.sciencedirect.com

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Ongoing issues in the intensive care for the periviable infant—Nutritional management and prevention of bronchopulmonary dysplasia and nosocomial infections Richard A. Ehrenkranz, MD Department of Pediatrics and Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, PO Box: 208064, New Haven, CT 06520–8064

article info

abstra ct The focus of this paper is to describe the following: (1) the benefits of implementing feeding

Keywords:

guidelines, (2) management practices associated with the prevention of BPD, and (3)

Extremely preterm infants

management practices associated with prevention of nosocomial infection. & 2014 Elsevier Inc. All rights reserved.

Nutritional support Feeding guidelines Bronchopulmonary dysplasia Nosocomial infections

1.

Nutritional management

Extrauterine growth restriction is common among very lowbirth-weight (VLBW), and especially extremely low-birthweight (ELBW), infants.1–4 The growth of VLBW infants who experience morbidities, such as necrotizing enterocolitis (NEC), BPD, and nosocomial infection, is slower than those infants who do not experience such morbidities.1,5,6 However, did slower growth result from suboptimal nutritional support provided during the infant's neonatal intensive care unit management or due to the existence of the morbidities? Were morbidities more likely to occur in infants who were receiving suboptimal nutritional support? And, to what degree does practice variation influence nutritional support and growth rate? There are no simple answers to these questions. However, there have been some efforts to understand the factors affecting the decisions about nutritional support provided to ELBW infants.7 We previously performed a secondary analysis of the data from the parenteral glutamine supplementation trial8 conducted by the Neonatal Research Network of the Eunice Kennedy Shriver National Institute of Health and Human Development (NICHD). We sought to

determine whether early nutritional support provided to more “critically ill” ELBW infants differed from those provided to less “critically ill” infants during the first several weeks of life, and (whether such differences were associated with improved growth, reduced rates of death or decreased morbidities, the age at achieving nutritional milestones, and neurodevelopmental outcomes at 18-22 months corrected age.

Neurodevelopmental outcomes at 18–22 months corrected age For the analysis, infants were stratified by whether or not they received mechanical ventilation (MV) for the first 7 days of life. We defined “more critically ill” infants as those having received MV for the first 7 days of life, while “less critically ill” infants were defined as having received MV for less than the first 7 days of life. Appropriate-for-gestational-age (AGA) and small-for-gestational-age (SGA) infants were evaluated separately. In addition, a formal mediation framework9 was used to determine whether early nutritional support mediated the association between critical illness during the first weeks of life and later growth and other outcomes.

E-mail address: [email protected] 0146-0005/14/$ - see front matter & 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1053/j.semperi.2013.07.005

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Table 1 – Energy and fluid intake by degree of critical illness in AGA infants (unadjusted and adjusted analyses). Energy intakea (kcal/kg/d)

Critically Ill

Fluid intakea (cc/kg/d)

Less (MV o 7 days) (n ¼ 499)

More (MV days 1–7) (n ¼ 646)

p-Valuec

Days 1–7 Parenteral energy Non-protein Protein Enteral energyb Total energy Total fluid intake

46.1 38.7 7.4 3, 5.8 52.0 123

(12.5) (10.8) (2.5) (8.1) (13.8) (25)

41.1 33.3 7.8 0, 1.6 42.7 130

(12.5) (10.7) (3.2 ) (3.5) (13.1) (33)

o0.0001 o0.0001 0.34 o0.0001 o0.0001; o0.0001d 0.001; 0.09d

Days 8–14 Parenteral energy Non-protein Protein Enteral energyb Total energy Total fluid intake

62.5 52.2 10.3 24, 32.7 95.2 151

(26.4) (22.3) (5.0) (29.5) (17.0) (19)

69.5 56.5 13.0 5, 12.1 81.6 151

(18.0) (15.5) (4.6) (17.9) (19.5) (27)

0.0010 0.047 o0.0001 o0.0001 o0.0001; o0.0001d 0.89; 0.48d

Days 15–21 Parenteral energy Non-protein Protein Enteral energyb Total energy Total fluid intake

41.3 34.9 6.4 52, 58.2 99.5 139

(34.9) (29.7) (5.7) (42.4) (20.8) (27)

58.5 48.3 10.2 16, 30.7 89.2 142

(28.8) (24.4) (5.6) (35.7) (21.8) (25)

o0.0001 o0.0001 o0.0001 o0.0001 o0.0001; o0.0001d 0.068; 0.30d

Adapted from Ehrenkranz et al.7 Presented as mean (standard deviation), except where noted. b Presented as median, mean (standard deviation). c p-Values from Wilcoxon test. d p-Value after adjusting for birth weight stratum in GLM procedure.

a

Table 1 displays the weekly energy and total fluid intakes for the first 3 weeks of life by severity of critical illness for the AGA infants.7 All energy measures, except for parenteral protein energy over days 1–7, were significantly different between the more and less critically ill groups. Similar results were noted for SGA infants. Specifically, compared with more critically ill patients, less critically ill patients received more nutritional support during the first 3 weeks of life. Furthermore, the total daily fluid intake was significantly different between the more and less critically ill groups over days 1–7. Thus, the more critically ill infants received more fluid and less energy than the less critically ill infants during the first 7 days of life. In another secondary analysis of the glutamine supplementation trial,8 Oh et al.10 reported that BPD-free survivors received less daily fluid over days 1–10 than patients who died or developed BPD. Analyses performed with the mediation framework demonstrated significant differences by critical illness status, and covariate-adjusted analyses indicated that critical illness status remained an independent and statistically significant predictor of total energy intake. Table 2 displays outcome data by severity of critical illness for AGA infants.7 It is evident that more critically ill infants grew slower, were smaller at 36 weeks' PMA, experienced more morbidity, achieved nutritional milestones later, and were more likely to have adverse neurodevelopmental outcomes. Similar results were noted for SGA infants. Analyses performed with the mediation framework demonstrated that critical illness was independently and significantly associated with slower growth velocity and with significantly increased ORs for NEC or death,

late-onset sepsis or death, BPD, BPD or death, neurodevelopmental impairment (NDI), and NDI or death. The mediation framework was then used to test models containing both critical illness and energy intake variables.7 For AGA infants, these analyses demonstrated that once total daily energy was included in the model (a) the effect of critical illness on growth velocity was significantly decreased in survivors at 36 weeks' PMA; (b) the effect of critical illness on the magnitude of the ORs for NEC, NEC or death, late-onset sepsis, late-onset sepsis or death, BPD, and BPD or death were all significantly decreased; and (c) there was a significant interaction between critical illness and total daily energy intake during days 1–7 of life for NDI and NDI or death. Thus, these analyses indicated that critical illness during the first weeks of life and early nutritional practices were both independently associated with morbidity. The number of SGA infants included in the study population limited the ability to perform these analyses in that patient cohort. Since there is marked practice variation within and between centers related to nutritional practices for extremely preterm infants, the implementation of feeding guidelines has been recommended in an effort to standardize practice within a center.11,12 For example, after reviewing the published literature describing the benefits of early feeding practices,11 the neonatal staff at Yale-New Haven Children's Hospital's NICU developed a consensus, evidence-based strategy that provided both early parenteral and enteral nutrition, addressed “feeding intolerance,” and aimed to

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Table 2 – Outcome variables by degree of critical illness in AGA infants (unadjusted analyses). Variables

In-Hospital Outcomes Age when birth weight regained (days) Age when enteral nutrition started (days) Age when enteral nutrition ≥110 kcal/kg/d (days) Days of parenteral nutrition ≥ 10% total daily fluid volume (days) Number of feeding interruptions for ≥24 h Infants with at least 1 interruption (n (%)) Total number of interruptions Infants with 41 interruption (n (%)) Total number of interruptions NEC (n (%)) BPDb None (n (%)) Mild (n (%)) Moderate (n (%)) Severe (n (%)) Duration of positive pressure ventilation (days) Duration of oxygen (days) Postnatal steroids for pulmonary disease (n (%)) Severe IVH (n (%)) Late-onset sepsis (n (%)) Death (n (%)) Length of hospital stay (days) Weight at 36 weeks' PMAc (g) Weight o10th percentile at 36 weeks' PMAc (n (%)) Length at 36 weeks' PMAc (cm) Head circumference at 36 weeks' PMAc (cm) Weight gain velocity (g/kg/d), all infants Weight gain velocityd (g/kg/d) Follow-up Outcomes, 18–22 months CAe Bayley MDI o70 (n (%)) Bayley PDI o70 (n (%)) Cerebral palsy (n (%)) Bilateral blindness (n (%)) Bilateral deafness (n (%)) Neurodevelopmental impairment (n (%))

Less critically Ill (MV o 7d) (n ¼ 499)

13.3 5.4 24.9 27.5

(6.6) (3.9) (15.4) (20.7)

More critically Ill (MV days 1–7) (n ¼ 646)

12.9 10.2 35.1 36.3

p-Valuea

(7.7) (8.3) (18.4) (22.0)

0.18 o0.0001 o0.0001 o0.0001

361 (72.8) 803 205 (41.3) 647

515 (84.4) 1341 340 (55.8) 1167

o0.0001

56 (11.2)

59 (9.1)

0.24 o0.0001

o0.0001

153 158 109 51 13.5 46.7 88 42 187 35 82.6 1926 327 41.7 30.8 15.9 15.6

(32.5) (33.6) (23.1) (10.8) (16.6) (33.1) (17.6) (8.5) (37.5) (7.0) (34.9) (312) (87.2) (2.2) (1.4) (7.5) (3.0)

15 149 210 170 40.9 74.6 331 128 306 123 102.6 1781 447 40.7 30.0 13.8 14.0

(2.8) (27.4) (38.6) (31.3) (26.6) (34.5) (51.2) (19.8) (47.4) (19.0) (57.9) (340) (90.7) (2.4) (1.7) (13.6) (3.0)

o0.0001 o0.0001 o0.0001 o0.0001 0.0008 o0.0001 o0.0001 o0.0001 0.10 o0.0001 o0.0001 o0.0001 o0.0001

416 83 34 12 1 3 97

(83.4) (21.3) (8.9) (2.5) (0.2) (1) (25.3)

458 180 117 41 3 9 206

(78.6) (42.7) (27.9) (9.1) (0.7) (2.4) (48.6)

o0.0001 o0.0001 0.0002 0.63 0.12 o0.0001

Adapted from Ehrenkranz et al.7 p-Value from Wilcoxon test for continuous variables; chi-Square, or Fisher's exact test, where appropriate, for categorical variables. b Consensus definition, infants o32 GA, survived to 36 weeks' PMA; not ventilated DOL 1–7: n ¼ 472; ventilated: n ¼ 544. c Infants hospitalized at 36 weeks' PMA; not ventilated DOL 1–7: n ¼ 377; ventilated: n ¼ 496. d Infants surviving to 36 weeks' PMA; not ventilated DOL 1–7: n ¼ 472; ventilated: n ¼ 544. e Infants followed up at 18–22 months corrected age (CA); not ventilated DOL 1–7: n ¼ 416; ventilated: n ¼ 458.

a

maintain a steady rate of postnatal growth by adjusting nutritional support if growth parameters were not met. Table 3 briefly outlines our feeding guidelines. Parenteral protein (i.e., as amino acids) is initiated within hours of birth as a component of parenteral fluid support. Specifically, of the 80–100 mL/kg/d of intravenous fluids initially ordered, 50 mL/kg/d would be a “starter” (“vanilla,” “off-hours”) parenteral nutrition (PN) that would deliver 3 g protein/kg/d, 50 mg elemental calcium/kg/d in 10% glucose, minimal electrolytes, and no vitamins or other minerals. Intravenous lipid emulsion would be initiated within 24 h of birth. PN support would be optimized over the next several days, as the transition to full enteral nutrition begins and is advanced. If possible, we will deliver PN via an umbilical venous

catheter until about 14 days of age, and then, if enteral intake has reached about 120 mL/kg/d, we would discontinue the PN, remove the umbilical catheter, and alleviate the need for a central line. Once full enteral nutrition is achieved, then it is essential to monitor growth by plotting measurements on an intrauterine growth curve until 40 weeks' PMA13,14 and then on the CDC– WHO growth curves,15 identify causes of decreased rates of growth, and maintain adequate energy and protein intakes. Benefits observed following the implementation of feeding guidelines have included regaining birth weight earlier, achieving full enteral nutrition sooner, reducing the need for PN, reducing cumulative energy and protein deficits, decreasing rates of common neonatal morbidities, improving the

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Table 3 – Feeding Guidelines Initiation ● Total Fluid for first 24 hrs to provide 80-100 mL/kg/d ■ 50 mL/kg/d of a “starter” (“vanilla”, off-hrs”) parenteral nutrition (PN) ■ 30-50 mL/kg/d of glucose, minimal electrolyte solution ● Target glucose infusion rate (GIR)  6 mg glucose/kg/min ● Early initiation of parenteral protein (amino acids) ■ Start within several hours of birth ■ Provide as a “To Deliver” amount ■ 1.5 g/kg/d (minimum)- 3 g/kg/d Transition to Full Enteral Nutrition (FEN)  Optimize parenteral nutrition (PN) ■ Increase protein intake to  4 g/kg/d ○ Daily increases of 0.5-1.0 g/kg/d ■ Increase GIR to  10 mg/kg/min during first week of life ■ Initiate IFE within 24 hrs of birth ○ Start with at least 0.5 g/kg/d ○ Increase by 0.5-1.0 g/kg/d to  3.0 g/kg/d ■ Increase % Total Daily Fluids as PN over 1st 3-4 days of life  Initiate Minimal Enteral Nutrition [(MEN); trophic feeds, gi stim feeds] ■ Start within first 24 - 96 hrs of age ○ Colustrum or Donor Milk, if possible ■ Duration of MEN ○ 24 hrs vs several days ■ Volume of MEN ○ 10% total daily fluid intake ( 12 mL/kg/d) ■ Rate of advancement to FEN ○ 12 mL/kg/d ○ Fortify HM @  100 mL/kg/d Maintenance of Growth on Full Enteral Nutrition  Monitor growth ■ Weight gain 20 gm/kg/d (over 5-7 days) ■ Length  1 cm/wk ■ HC  1 cm/wk  Identify causes of decreased rates of growth ■ Energy needs 4 energy intake ○ Fluid restriction (eg, BPD) ○ Malabsorption ○ Decreased intakeduring transition to nipple feedings ■ Decreased protein content of fortified own mother’s milk (or donor milk)  Maintain adequate energy & protein intakes ■ Energy intake  120 kcal/kg/d (minimum) ■ Protein intake :  4.0 gm/kg/d o 30 wks PMA [P/E¼3.3]  3.5 gm/kg/d 4 30- 36 wks PMA [P/E¼2.9]

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Since its description in 1967 by Northway et al.,19 multiple therapies have been evaluated in attempts to reduce the incidence or severity of BPD; at best, these therapies have had limited success.20 Of the strategies and treatments listed in Table 4, vitamin A, caffeine, and corticosteroids have been shown to reduce the incidence of BPD. Compared to sham therapy, administration of vitamin A during the first month of life (5000 IU intramuscularly 3 times per week for 4 weeks) to ELBW infants who received mechanical ventilation or supplemental inspiratory oxygen at 24 h of age was associated with a significant reduction in death or BPD at 36 weeks' PMA (55% vs. 62%; RR, 0.89; 95% CI, 0.80–0.99).21 A randomized controlled trial (RCT) performed in infants with birth weights of 500–1250 g to evaluate the long-term effects of caffeine therapy for apnea of prematurity22 reported a significant reduction in the incidence of BPD from 47% to 36 % (AOR, 0.63; 95% CI, 0.52–0.76) as a secondary outcome.23 Additional analyses24 of these data suggested greater neurodevelopmental benefits from caffeine treatment in infants receiving respiratory support compared to those not receiving respiratory support and that earlier initiation of caffeine before 3 days of age was associated with a greater reduction in the duration of mechanical ventilation. Treatment in the first week of life with corticosteroids demonstrated significant reductions in the likelihood of BPD.25 However, concerns about an increased risk of cerebral palsy in infants receiving corticosteroids during the first 7 days of age to prevent BPD25,26 has tended to result in a restricted, cautious use of corticosteroids to facilitate endotracheal extubation in infants who have required prolonged mechanical ventilation.27

3.

Prevention of nosocomial infection

Table 5 displays management strategies associated with prevention of nosocomial (late-onset) infection. Infection rates as high as 50% have been reported within the last 10–15 years.17,28,29 However, during the past several years, practices aimed at reducing central line-associated blood stream infections (CLABSI) have had a major impact on reducing nosocomial infection in extremely preterm infants,30 and since 2008, it is common to go several months without new infections being reported.30 Antibiotic stewardship programs that have sought to limit prolonged and multiple courses of antibiotics have drawn attention to the risks associated with antibiotic therapy.31–33

anthropometrics at 36 weeks' and 40 weeks' PMA, mediating the severity of an infant's illness, and reducing length of stay. Table 4 – Management practices associated with prevention of BPD.

2.

Prevention of bronchopulmonary dysplasia

Bronchopulmonary dysplasia (BPD) is the most common pulmonary morbidity seen in extremely preterm infants.16,17 BPD often begins with lung injury associated with the treatment of respiratory distress syndrome, but its pathogenesis is multifactorial, involving oxygen, mechanical ventilation, and inflammation.18 Pathologically, the alveoli, airways, and vasculature are all affected by the development of BPD.

Early nutritional support and feeding guidelines DR CPAP Intubation and early surfactant Permissive hypercapnia (minimal ventilation) Extubation/re-intubation criteria Non-invasive ventilation Closure of the patent ductus arteriosus (PDA) Vitamin A Caffeine Corticosteroids

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Table 5 – Management practices associated with prevention of nosocomial infection. Early nutritional support and feeding guidelines Practices aimed at reducing CLABSI Competency-based PICC insertion team Standardized dressing management of PICC and surgically inserted central lines Prompt removal of central lines when no longer needed Antibiotic stewardship program (limit prolonged and multiple courses of antibiotics) IVIG or antistaphylococcal IgG Lactoferrin

Cotton et al.34 reported that a prolonged duration of empiric antibiotics started during the first 3 days of life was significantly associated with an increase of NEC or death, and Alexander et al.35 reported that NEC was significantly associated with the cumulative exposure to antibiotics; specifically, exposure for more than 10 days resulted in a nearly threefold increase in the risk of developing NEC. A number of therapies aimed at reducing the incidence of late-onset infection have been evaluated. A Cochrane review36 of prophylactic administration of intravenous immunoglobulin (IVIG) for the prevention of infection in VLBW infants demonstrated a 3–4% reduction in sepsis, but was not associated with reductions in mortality or other neonatal morbidities. A second Cochrane review37 analyzed the use of antistaphylococcal immunoglobulins to prevent staphylococcal infections in VLBW infants and reported no significant effects, either benefits or risks. Neither of these immunoglobulin therapies are widely used. However, a recent RCT38 has demonstrated that oral bovine lactoferrin supplementation provided during the first 4–6 weeks of life significantly reduced the incidence of late-onset sepsis in VLBW infants.

4.

Summary and conclusions

While the focus of this paper was to discuss nutritional management and the prevention of bronchopulmonary dysplasia (BPD) and nosocomial infection as part of the ongoing NICU care issues in infants born at periviable gestations discussed elsewhere in this supplement, not many infants born at o25 weeks' gestation have been included in most of the clinical studies published thus far. Therefore, one needs to acknowledge that these recommendations are an extrapolation of the practices used to manage extremely low gestational-age infants under 28 weeks, and that more studies are needed to develop the evidence-based guidelines required to manage periviable infants.

re fe r en ces

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