The Clinical Impact of Parenteral Nutrition

Details of the clinical impact of total PN and supplemental PN in preterm infants and adults.

An overview of the different routes for administration of nutritional support, including total parenteral nutrition (TPN) and supplemental parenteral nutrition (SPN), is provided in Providing Nutrition Clinically. Further details of current guidelines and recommendations in which TPN and SPN may be used for nutritional support in different patient populations and clinical settings are provided in Parenteral Nutrition Guidelines.


Details of the clinical impact of TPN and SPN in different patient populations are provided in the sections below:


Parenteral nutrition in preterm infants

Parenteral nutrition (PN) is indicated in infants and children who are unable to tolerate adequate enteral feedings to sustain nutritional requirements. Preterm infants often have a physiologically immature gastrointestinal tract. As a result, enteral nutrition alone may be insufficient to meet their nutritional needs. Therefore, these infants may require parenteral nutrition to prevent nutritional deficits and death.1,2


The importance of optimal nutritional support in preterm infants has been demonstrated by two studies.3,4 A cohort study of extremely low birth weight infants (N=124; <1000 g) showed that failure to meet nutrition recommendations for protein and energy intake in the first week of life may restrict growth and neurodevelopment at 18 months.3 Multiple linear regression analyses demonstrated that first-week energy and protein intake made a significant independent contribution to the Mental Development Index (MDI) scores (energy: b=0.46; P=0.0134; protein: b=8.21; P=0.0274) at 18 months. During week 1, every 42 kJ (10 kcal)/kg/day were associated with a 4.6-point increase in the MDI and each g/kg/day in protein intake with an 8.2-point increase in the MDI.3


A multicenter, prospective, cohort study assessed nutritional practices (nutritional intake from PN or enteral nutrition [EN]) for the first month of life (Days 7, 14, 21, and 28) in a large cohort (N=1187) of low gestational age infants (born at 23 to 27 weeks of gestation), to determine the effect on growth velocity.4 Multivariable logistic regression models estimated the contribution of limited nutrition to limited growth velocity. These models found that growth velocity in the lowest quartile (25%) was predicted by the lowest quartile of protein, carbohydrate, and fat intake on Day 7 of life. The authors concluded that early nutritional practices are an important determinant of postnatal growth.4


Two studies with 'early aggressive' PN (i.e. amino acids supplied on the first postnatal day) have demonstrated improved weight gain,5,6 and lower protein and energy deficits,5 in preterm infants (Table 1).

The first study, a prospective cohort study of very low birth weight infants, showed that an early and aggressive TPN and EN regimen (10% amino acid solution on Day 1 of life at 1.5 g/kg/day) resulted in a significantly lower energy and protein deficit (both P<0.001) compared with the conventional group (10% amino acid solution on Day 3 of life at 0.5 g/kg/day) and resulted in better weight gain and growth in length and head circumference (Table 1).5 The second study, a prospective randomized study in preterm infants <1500 g, showed that infants administered early PN (3 g/kg/day of amino acids on Day 1 of life) had significantly greater weight gains than those infants administered delayed PN (received >24 h of life) (Table 1).6

Table 1: The clinical impact effect of early aggressive PN in preterm infants

Pediatric population and Study design Nutritional outcome Clinical outcome (growth and development)
VLBW infants
<1500 g and >750 g)5

Prospective, cohort study
Aggressive PN (n=117)*
Conventional PN (n=65)**
Cumulative caloric deficit at wk 4: Aggressive PN = -295 kcal/kg
Conventional PN = -732 kcal/kg

Cumulative protein deficit at wk 4: Aggressive PN = -7 g/kg
Conventional PN= -33 g/kg

Aggressive PN = 66% reduction in risk of postnatal malnutrition at 40 wks of postmenstrual age compared with conventional PN
(OR 0.34; 95% CI 0.17–0.67)
Recovered birth weight sooner with aggressive PN than conventional PN (median: 10 days vs 16 days, respectively, P<0.001)
Maximum % of mean weight loss lower with aggressive PN than conventional PN (9% vs 13.3%, respectively, P<0.001)
Higher median body weight (2.95 kg vs 2.7 kg, p=0.002), mean length (46.6 cm vs 45.6 cm, P=0.009) and mean head circumference (35.2cm vs 34.3cm, P=0.002) at 40 wks of postmenstrual age with aggressive PN than conventional PN
Number of infants with growth retardation at 40 wks of postmenstrual age greater with conventional PN than aggressive PN (77% vs 53%; P=0.005)
Pediatric population and Study design Nutritional outcome Clinical outcome (growth and development)
Preterm infants <1500 g6

Prospective intervention: early AA supplementation
(3 g/kg/day <24 hours of life)

Retrospective cohort: late AA supplementation
(>24 hours of life)

Primary outcome variable: proportion of infants at <10th percentile at 36 wks post-conceptual age
  At 36 wks corrected GA, fewer infants below 10th percentile (P<0.001; 95% CI: -27.6 to -8.3) with early AA (23.7%) vs late AA (41.7%)
Greater weight gains with early AA than late AA (P<0.003) after adjusting for GA and time from birth to discharge

AA, amino acids; CI, confidence interval; DOL, day of life; GA, gestational age; IV, intravenous; OR, odds ratio; wks, weeks; VLBW, very low birth weight


*AAs administered at rate of 1.5 g/kg/day with 5.6 mg/k/min of glucose flow on 1st DOL, progressively increased to 4 g/kg/day and 13 mg/kg/min. IV lipids started at 0.5 g/kg/day at 24 h from birth, and increased to 3.5 g/kg/day; enteral feeding was started on 1st DOL

**10% AA solution on Day 3 of life at 0.5 g/kg/day

Parenteral nutrition in adults

TPN is a valuable treatment option for providing nutritional support when EN is contraindicated.7 SPN is a treatment option for improving protein and calorie intake when EN or oral diet is inadequate.7


As shown in a large randomized, controlled study, achieving optimal nutrition with SPN has been associated with a reduction in nosocomial infection compared with EN in intensive care unit (ICU) patients (Table 2).8 Between Days 9 and 28, 41 (27%) of 153 patients in the SPN group had a nosocomial infection compared with 58 (38%) of 152 patients in the EN group (hazard ratio 0.65, 95% CI 0.43–0.97; P=0.0338), and the SPN group had a lower mean number of nosocomial infections per patient (-0.42 [-0.79 to -0.05]; P=0.0248). The mean number of hours on mechanical ventilation was significantly reduced in patients without nosocomial infection (15 hours with SPN versus 29 hours with EN; P=0.0028).8


A multicenter, randomized, controlled trial (The Early Parenteral Nutrition Completing Enteral Nutrition in Adult Critically Ill Patients [EPaNIC] study), conducted in Belgium, determined the effects of early PN (initiated within 48 hours of ICU admission) compared with late PN (not initiated before Day 8), to supplement insufficient EN, on clinical outcomes in critically ill patients.9 Late SPN was associated with faster recovery (discharged alive earlier from ICU), and fewer ICU infections than early SPN (Table 2).9


However, since the publication of the EPaNIC study, several letters to the editor have highlighted potential limitations of the study, including the following:10–13


  • The overall calorie intake could have been excessive, reducing the benefit of SPN10,12,13
  • The early SPN group initially received a large parenteral glucose load, which is not routine practice in Europe or North America, and results in hyperglycemia and a requirement for insulin, which can ultimately cause complications and/or worse outcomes10,12,13
  • In total, 60% of patients had undergone cardiac surgery. These patients generally have a low incidence of malnutrition and tolerate EN, and would not normally be given early PN Indeed, many patients spent a short time in the ICU, and the scoring system used to evaluate risk had not been validated in ICU patients11–13
  • Finally, a large proportion (58%) of patients in the early SPN group, were exposed to only one to two days of PN. In the late SPN group, PN was initiated on day 8, and as a result, only a small portion of the late SPN patients (approximately 25%) ever received PN.13

A multicenter, randomized, single-blind trial in Australia and New Zealand studied the effects of early PN (within 24 hours of admission) versus standard care in critically ill adult patients with contraindications to EN (Table 2).14 Of 682 patients receiving standard care, 199 patients (29.2%) initially commenced EN, 186 patients (27.3%) initially commenced PN, and 278 patients (40.8%) remained unfed. Time to EN or PN in patients receiving standard care was 2.8 days (95% CI 2.3–3.4). Patients receiving early PN commenced PN a mean of 44 minutes after enrollment (95% CI 36–55).14 This study showed that the use of early PN did not result in significant differences in Day 60 mortality (P=0.60), or infection rates. Early PN resulted in a significant reduction in days of invasive mechanical ventilation compared with standard care (7.26 vs 7.73 days per 10 patient x ICU days, risk difference -0.47; 95% CI -0.82 to -0.11; P=0.01), but early PN did not result in a significant shortening of ICU or hospital length of stay.14


Table 2: The effect of PN/TPN and SPN on clinical outcomes in critically ill adults

Patient population Study design Clinical outcome (recovery) Clinical outcome (survival) Clinical outcome (LOS) Citation
Critically ill
ICU patients who had received less than 60% of their energy target from EN were expected to stay for longer than 5 days, and to survive for longer than 7 days Randomized, controlled study at two tertiary care hospitals in Switzerland153 patients received SPN
152 patients received EN only
Between Days 9 and 28, 41 (27%) of 153 patients in the SPN group had a nosocomial infection compared with 58 (38%) of 152 patients in the EN group (hazard ratio 0.65, 95% CI 0.43–0.97; P=0.0338), and the SPN group had a lower mean number of nosocomial infections per patient (-0.42 [-0.79 to -0.05]; P=0.0248) ICU mortality and general mortality at Day 28 was similar in both groups Mean length of stay in ICU and hospital was similar in both groups.Hours on mechanical ventilation were significantly reduced in patients without nosocomial infection (P=0.0028) Heidegger CP, et al. Lancet 2013; 381:385–938
ICU patients with a NRS score ≥3 and insufficient EN Randomized, controlled, multi-center study2328 patients in late-initiation group (SPN not initiated before Day 8)

2312 patients in early-initiation group (SPN initiated within 48 hours of ICU admission )
New infections: Late PN = 22.8% Early PN = 26.2%(P=0.008) Death in ICU: Late PN = 6.1% Early PN = 6.3% (P =0.76) Discharged alive from ICU: Late PN = 75.2% Early PN = 71.7%(P=0.007)Median length of stay in ICU: Late PN = 3 days Early PN = 4 days (P=0.02)Median duration of mechanical ventilation: Late PN = 2 days Early PN = 2 days Casaer MP, et al. N Engl J Med 2011; 365:506–5179
ICU patients with relative contraindications to EN and expected to remain in ICU >2 days Randomized, single-blind, multi-center study in 31 community and tertiary hospitals in Australia and New Zealand 686 patients received early PN 686 patients received standard care Any new major infection: Standard care = 11.4% Early PN = 10.9% Risk difference = -0.57% (95% CI, -5.89–4.72; P=0.80) Day 60 mortality: Standard care = 22.8% Early PN = 21.5% Risk difference = -1.26% (95% CI, -6.6–4.1; P=0.60) Days of invasive mechanical ventilation: Early PN = 7.26 days per 10 patient x ICU days Standard care = 7.73 days per 10 patient x ICU days Risk difference = -0.47; 95% CI, -0.82 to -0.11; P=0.01 Mean length of stay in ICU:
Early PN = 8.6 days
Standard care = 9.3 days(P=0.06)

Mean length of stay in hospital:
Early PN = 25.4 days
Standard care = 24.7 days (P=0.50)
Doig GS, et al. JAMA 2013; 309:2130–213814

CI, confidence interval; EN, enteral nutrition; ICU, intensive care unit; LOS, length of stay; NRS, nutritional risk screening; NS, not significant; SPN, supplemental parenteral nutrition; TPN, total parenteral nutrition

References
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  2. Koletzko B, Goulet O, Hunt J, et al. 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):S1–S87.
  3. Stephens BE, Walden RV, Gargus RA, et al. First-week protein and energy intakes are associated with 18-month developmental outcomes in extremely low birth weight infants. Pediatrics 2009;123:1337–1343.
  4. Martin C, Brown YF, Ehrenkranz R, et al. Nutritional practices and growth velocity in the first month of life in extremely premature infants. Pediatrics 2009;124:649–657.
  5. Dinerstein A, Nieto RM, Solana CL, et al. Early and aggressive nutritional strategy (parenteral and enteral) decreases postnatal growth failure in very low birth weight infants. J Perinatol 2006;26:436–442.
  6. Valentine CJ, Fernandez S, Rogers LK, et al. Early amino-acid administration improves preterm infant weight. J Perinatol 2009;29:428–432.
  7. Ukleja A, Freeman KL, Glibert K, et al. Standards for nutrition support: adult hospitalized patients. Nutr Clin Pract 2010;25:403–414.
  8. Heidegger CP, Berger MM, Graf S, et al. Optimisation of energy provision with supplemental parenteral nutrition in critically ill patients: a randomised controlled clinical trial. Lancet 2013;381:385–393.
  9. Casaer MP, Mesotten D, Hermans G, et al. Early versus late parenteral nutrition in critically ill adults. N Engl J Med 2011;365:506–517.
  10. Bistrian BR. Early or late parenteral nutrition in critically ill adults. N Engl J Med 2011;365:1840; author reply 1841–1842.
  11. Felbinger TW, Weigand MA, Mayer K. Early or late parenteral nutrition in critically ill adults. N Engl J Med 2011;365:1839; author reply 1841–1842.
  12. O'Leary MJ, Ferrie S. Early or late parenteral nutrition in critically ill adults. N Engl J Med 2011;365:1839; author reply 1841–1842.
  13. McClave SA, Heyland DK, Martindale RG. Adding supplemental parenteral nutrition to hypocaloric enteral nutrition: lessons learned from the Casaer Van den Berghe study. JPEN J Parenter Enteral Nutr 2012;36:15–17.
  14. Doig GS, Simpson F, Sweetman EA, et al.Early Parenteral nutrition in critically ill patients with short-term relative contraindications to early enteral nutrition. JAMA 2013;309:2130–2138.