Casaer MP, Mesotten D, Hermans G, Wouters PJ, Schetz M, Meyfroidt G, et al. Early versus Late Parenteral Nutrition in Critically Ill Adults. N Engl J Med. 2011 Aug 11;365(6):506–17.
Introduction
The concept of intravenous nutrition arose during World War I with the introduction of sterile glucose solutions in water (1). A decade later, intravenous protein hydrolysates were investigated, followed by the use of supplemental fat emulsions. Stanley Dudrick, during his surgical residency at the University of Pennsylvania, observed that malnutrition in the postoperative period led to poor outcomes among patients who were unable to absorb nutrients from the gut. In 1967, he tested the of feasibility of parenteral nutrition in laboratory animals (2), followed by its initial use in malnourished infants (3). The use of parenteral nutrition became more widespread with the safe and easy administration through central venous catheters. Initially, venous access was by cut down; the advent of percutaneously inserted subclavian venous catheters facilitated long-term nutritional support through the parenteral route (4).
Considering the lower risk of complications and being less expensive, enteral nutrition is the preferred route in critically ill patients. However, enteral feeding alone often fails to achieve nutritional targets. Underfeeding has been shown to be associated with adverse clinical outcomes in critically ill patients, including a higher incidence of blood stream infections(5), a longer duration of mechanical ventilation (6), and increased mortality (7). Considering the failure to achieve nutritional targets through the enteral route alone among critically ill patients, parenteral nutrition may be combined with enteral nutrition to prevent nutritional deficit. However, the parenteral route may be associated with complications, including overfeeding, preponderance to nosocomial infections, and hyperglycemia (8,9). Clinical guidelines also differed; while the European Society of Parenteral and Enteral Nutrition (E.S.P.E.N.) recommended consideration of parenteral nutrition within 2 days of ICU admission if enteral nutrition was inadequate (10), the American and Canadian guidelines suggested nutritional support through the enteral route during the first week of ICU stay (11).
The Early Parenteral Nutrition Completing Enteral Nutrition in Adult Critically Ill Patients (EPaNIC) study included adult, critically ill patients who were at risk of undernutrition, but not chronically malnourished. The study question was whether early supplemental parenteral nutrition aimed to achieve caloric targets would reduce the risk of complications compared with delayed initiation of parenteral nutrition after a week (12).
Population and design
The EPaNIC randomized controlled trial (RCT) was conducted between August 2007 and November 2010 in seven ICUs in Belgium. Eligible patients included those with a score ≥3 on nutritional risk screening (NRS), indicative of patients who were nutritionally at risk. The study excluded patients with ketoacidosis or hyperosmolar coma, a body mass index of <17, short bowel syndrome, and those who did not have a central venous catheter. Pregnant patients and those who were moribund and coded not for resuscitation were also excluded.
Early initiation group
Patients randomized to the early parenteral nutrition group received 20% glucose intravenously for a total energy intake of 400 kcal on day 1 and 800 kcal on day 2. On day 3, parenteral nutrition was commenced, combined with enteral nutrition as tolerated, aiming to achieve 100% of the caloric target. The caloric target was based on the corrected ideal body weight, age, and gender, with a maximum of 2880 kcal/day. Enteral nutrition was stepped up gradually; when the proportion of enteral nutrition had risen to 80% of the caloric target, parenteral nutrition was weaned off and ceased. If enteral nutrition dropped to below 50% of the caloric target at any stage, parenteral nutrition was recommenced.
Late initiation group
Patients assigned to the late initiation group were administered 5% glucose solution in similar volumes as the early initiation group to ensure adequate hydration. If oral intake was not feasible by day 2, enteral nutrition was commenced. After 7 days of ICU stay, if enteral nutrition was still insufficient, parenteral nutrition was initiated on day 8 to meet caloric targets.
Common management
Patients in whom oral intake was not feasible by day 2 received enteral feeding. The rate of enteral feeding was stepped up twice a day; prokinetic drugs and post-pyloric feeding tubes were employed as appropriate. Trace elements, minerals, and vitamins were routinely administered. The blood glucose level was maintained between 80 – 110 mg/dl using insulin infusions as required. Weaning from mechanical ventilation was carried out based on local guidelines. If continued ICU care was considered futile, decisions on end-of-life care were made by consensus.
Sample size calculation
The sample size was calculated to detect a 1-day difference in the duration of ICU stay with 80% power, and concurrently, a 3% difference in the ICU mortality with 70% power.
Results
The EPaNIC study assessed 8703 patients for eligibility. After the exclusion of 4063 patients, 2312 patients were assigned to receive early parenteral nutrition and 2328 to late parenteral nutrition and were included in the final analysis. Baseline characteristics were similar in both groups of patients. As envisaged in the study protocol, the caloric target of 25–30 ml/kg was achieved by day 3 in the early initiation group, and by day 8 in the late initiation group. The higher caloric target in the first 7 days resulted in a greater requirement for insulin to maintain blood glucose levels within the target range in the early initiation group. Patients in the early initiation group received a significantly higher dose of insulin – a median of 31 units (interquartile range, 19–48) per day in the early initiation compared with 58 units (interquartile range, 40–85) in the late initiation group. The levels of potassium, magnesium, and phosphorus were similar in both groups. The main clinical outcomes are summarized in Table 1.
Table 1. Main clinical outcomes
| Outcome | Late initiation (2328 patients) | Early initiation(2312 patients) | P-value |
| ICU stay (median, IQR) | 3 (2–7) days | 4 (2–9) days | 0.02 |
| ICU mortality | 141 (6.1%) | 146 (6.3%) | 0.76 |
| Hospital mortality | 242 (10.4%) | 251 (10.9)) | 0.63 |
| 90-d mortality | 257 (11.2%) | 255 (11.2%) | 1.0 |
| Mechanical ventilation >2 d | 846 (36.3%) | 930 (40.2%) | 0.006 |
| Hospital stay (median, IQR) | 14 (9–27) days | 16 (9–29) days | 0.004 |
| New infections | 531 (22.8%) | 605 (26.2%) | 0.008 |
| AKI | 104 (4.6%) | 131 (5.8) | 0.06 |
| Duration of RRT (median, IQR) | 7 (3–16) days | 10 (5–23) | 0.008 |
IQR, interquartile range; AKI, acute kidney injury; RRT, renal replacement therapy
The primary outcome
The duration of ICU stay was shorter by 1 day in the late initiation group [median: 3 days (interquartile range 2–7 days) vs. [median: 4 days (interquartile range 2–9 days), P = 0.02]. There were significantly more patients who stayed in the ICU for longer than 3 days in the early initiation group (51.3% vs. 48%, P = 0.02). Overall, patients in the late initiation group were more likely to be discharged alive from the ICU.
Safety outcomes
In the late initiation group, more patients were discharged alive from the ICU within 8 days (75.2% vs. 71.7%, P = 0.007). There were no significant differences in the ICU or hospital mortality; mortality within 90 days after enrollment was also similar. Nutrition-related complications were similar in both groups; however, hypoglycemic episodes occurred more often in the late nutrition group (3.5% vs. 1.9%).
Secondary outcomes
The overall incidence of new infections was higher in the early initiation group (26.2% vs. 22.8%, P = 0.008). Infections involving the airway or lungs, bloodstream, and wound infections were also more common in the early initiation group. There were significantly more patients in the early initiation group who required mechanical ventilation for more than 2 days (40.2% vs. 36.3%). The time to weaning from ventilator support was also longer with early initiation. The duration of hospital stay was longer in the early initiation group; furthermore, patients who required hospital admission for more than 15 days were also significantly higher with early initiation. The incidence of acute kidney injury based on the RIFLE criteria was significantly higher, and the duration of renal replacement therapy was longer in the early initiation group. Besides, early initiation of parenteral nutrition led to higher healthcare costs. The functional status at hospital discharge, assessed using the 6-minute walk test, was similar in both groups.
Subgroup analysis
The authors performed a predefined subgroup analysis of high-risk patients, including those with a body-mass index <25 or >40 and NRS score ≥5, post-cardiac surgical patients, and those presenting with sepsis. They found no difference in the duration of ICU stay or ICU mortality among these subgroups of patients.
On post hoc analysis, early vs. late initiation of parenteral nutrition was compared among patients in whom early enteral nutrition was contraindicated. Patients in this subgroup received a median of 0 calories (interquartile range, 0–163) per day until day 7. The incidence of infective complications was lower in the late initiation group; furthermore, they were more likely to be discharged alive from the ICU.
Study conclusions
The EPaNIC study did not find a significant difference in mortality between early (within 48 hours) and late initiation of parenteral nutrition (after 7 days) in ICU patients at high risk of malnutrition. Delaying parenteral nutrition for a week was associated with a lower incidence of infective complications. Late initiation of parenteral nutrition was associated with fewer days on mechanical ventilation, shorter ICU and hospital stay, lower duration of renal replacement therapy, and reduced healthcare costs. Late initiation of parenteral nutrition was associated with a higher incidence of hypoglycemia; however, the functional status at hospital discharge was comparable with early initiation.
Strengths
The EPaNIC trial was the first, large RCT that compared clinical outcomes with early versus late initiation of parenteral nutrition in critically ill patients. Analysis was by intention to treat, and allocation concealment was maintained, adding to the robustness of the trial. The findings of the study strongly supported delaying parenteral nutrition by a week; late initiation resulted in improved clinical outcomes, although mortality remained similar.
Limitations
The study was unblinded owing to its design, and hence, may have been subject to bias. The dose of amino acids administered was less than recommended in clinical guidelines. The calorie requirement was calculated based on the corrected body weight, in contrast to the generally accepted method, based on indirect calorimetry.
The difference in clinical outcomes between the two groups was minimal, although statistically significant; besides, mortality rates were similar. The large majority of participants were not severely malnourished, with a nutrition score of ≤4. Sixty percent were postoperative cardiac surgical patients; hence the results may not be extrapolatable to a general ICU setting. The study employed intensive insulin therapy aiming to maintain blood glucose levels below 110 mg/dl, in contrast to the generally accepted target of 140–180 mg/dl following the NICE-SUGAR study (13). However, the blood glucose levels in both groups were similar and may not have influenced the difference in clinical outcomes. Overall, the median duration of ICU stay was short (3 days), suggesting a low severity of illness. The study protocol was not followed after discharge from the ICU.
Subsequent analyses of EPaNIC data
De Vlieger et al. evaluated the impact of the timing of supplemental parenteral nutrition on the incidence of invasive fungal infections by univariable and multivariable analysis of data from the EPaNIC trial. They observed that delaying parenteral nutrition until day 7 reduced the incidence of invasive fungal infections (14).
In another prospectively planned sub-analysis, intensive care-acquired muscular weakness was evaluated in 600 patients; skeletal muscle biopsy was performed in 122 patients and compared with 20 matched controls. Macronutrient deficiency during the early phase of critical illness did not affect muscle wasting; furthermore, recovery of muscle weakness was more rapid with late compared with early parenteral nutrition (15).
A cost analysis of the EPaNIC trial revealed that pharmacy-related expenditure was higher with the early use of parenteral nutrition. The increased costs were related to parenteral nutrition solutions and anti-infective agents (16).
Summary
The EPaNIC investigators conducted a large, multicentric RCT to address the uncertainty regarding when parenteral nutrition should be commenced in patients who were nutritionally at risk. How does early supplemental parenteral nutrition aimed to achieve 100% of the caloric target by day 3 compared with delayed initiation of parenteral nutrition after a week of ICU stay? The study found that later initiation of parenteral nutrition led to a more rapid recovery, a shorter ICU and hospital stay, and fewer infective complications. The likely beneficial effect of late parenteral nutrition was particularly evident among patients who underwent complicated pulmonary, esophageal, and abdominal surgery in whom early enteral nutrition was contraindicated. What are the putative mechanisms behind the apparent clinical benefits associated with a strategy of late initiation of parenteral nutrition? The authors hypothesized that parenteral nutrition may inhibit autophagy, leading to inadequate clearance of damaged cells and microorganisms. The more prolonged duration of ICU and hospital stay observed among recipients of early parenteral nutrition may be related to a higher incidence of infective complications and organ dysfunction. Based on the findings of the EPaNIC trial, the Society of Critical Care Medicine (SCCM) and the American Society for Parenteral and Enteral Nutrition (ASPEN) currently recommend that parenteral nutrition be withheld for the first 7 days following ICU admission among patients who cannot tolerate oral intake and in whom enteral nutrition is not feasible (17).
References
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2. Dudrick SJ. Early developments and clinical applications of total parenteral nutrition. JPEN J Parenter Enteral Nutr. 2003;27(4):291–9.
3. Wilmore DW, Dudrick SJ. Growth and development of an infant receiving all nutrients exclusively by vein. JAMA. 1968 Mar 4;203(10):860–4.
4. Dudrick SJ, Wilmore DW, Vars HM, Rhoads JE. Can intravenous feeding as the sole means of nutrition support growth in the child and restore weight loss in an adult? An affirmative answer. Ann Surg. 1969 Jun;169(6):974–84.
5. Rubinson L, Diette GB, Song X, Brower RG, Krishnan JA. Low caloric intake is associated with nosocomial bloodstream infections in patients in the medical intensive care unit. Crit Care Med. 2004 Feb;32(2):350–7.
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10. Singer P, Berger MM, Van den Berghe G, Biolo G, Calder P, Forbes A, et al. ESPEN Guidelines on Parenteral Nutrition: intensive care. Clin Nutr Edinb Scotl. 2009 Aug;28(4):387–400.
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12. Casaer MP, Mesotten D, Hermans G, Wouters PJ, Schetz M, Meyfroidt G, et al. Early versus Late Parenteral Nutrition in Critically Ill Adults. N Engl J Med. 2011 Aug 11;365(6):506–17.
13. NICE-SUGAR Study Investigators, Finfer S, Chittock DR, Su SYS, Blair D, Foster D, et al. Intensive versus conventional glucose control in critically ill patients. N Engl J Med. 2009 Mar 26;360(13):1283–97.
14. De Vlieger G, Ingels C, Wouters PJ, Debaveye Y, Vanhorebeek I, Wauters J, et al. Impact of supplemental parenteral nutrition early during critical illness on invasive fungal infections: a secondary analysis of the EPaNIC randomized controlled trial. Clin Microbiol Infect Off Publ Eur Soc Clin Microbiol Infect Dis. 2019 Mar;25(3):359–64.
15. Hermans G, Casaer MP, Clerckx B, Güiza F, Vanhullebusch T, Derde S, et al. Effect of tolerating macronutrient deficit on the development of intensive-care unit acquired weakness: a subanalysis of the EPaNIC trial. Lancet Respir Med. 2013 Oct;1(8):621–9.
16. Vanderheyden S, Casaer MP, Kesteloot K, Simoens S, De Rijdt T, Peers G, et al. Early versus late parenteral nutrition in ICU patients: cost analysis of the EPaNIC trial. Crit Care Lond Engl. 2012 May 25;16(3):R96.
17. McClave SA, Taylor BE, Martindale RG, Warren MM, Johnson DR, Braunschweig C, et al. Guidelines for the Provision and Assessment of Nutrition Support Therapy in the Adult Critically Ill Patient: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.). JPEN J Parenter Enteral Nutr. 2016 Feb;40(2):159–211.
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