July 2011 e-Journal Club
The second article that we reviewed at our July journal club promises to be an important one, not only because of the size and quality of the study, but also because of the importance of the central question that it attempts to answer. This study provides key data about one of the major issues that divides European and North American guidelines for nutrition support - how soon to begin parenteral nutrition (PN) when nutrition goals are not met with enteral nutrition (EN). The European guidelines were based on observational studies that have demonstrated increased morbidity and decreased survival in patients that received less than estimated needs. I suspect that the current study will become an “instant classic” example of how and why observational studies should not be used to direct practice. We recommend that you obtain and read the full text, supplemental tables and the excellent editorial. The full methods and analysis plan for this study were published in a separate article (1).
Casaer MP, Mesotten D, Hermans G, Wouters PJ,et al. Early versus Late Parenteral Nutrition in Critically Ill Adults. NEJM 2011, June 29 [Epub ahead of print].
This was a randomized, multicenter, parallel-group trial of a mixed medical-surgical adult ICU population that compared the early initiation of PN per European guidelines with later initiation of PN to supplement inadequate EN as per American and Canadian guidelines. The full name of this study is the, “Early parenteral nutrition completing enteral nutrition in adult critically ill patients (EPaNIC trial).” Overall, there were 4640 patients from 7 ICU’s, with 2312 patients receiving PN within 48 hours after ICU admission (early-initiation group) and 2328 patients who received PN delayed until day 8 (late-initiation group). A protocol for the early initiation of EN and intensive insulin infusion to achieve normoglycemia (80-110mg/dl) was used in both groups. The early PN group received D20 at 45 mL/hr on the day of admission, and starting on day 2 the difference between calculated goals and the amount of EN was provided as PN. When EN provided at least 80% of nutrition needs PN was held. The late PN group received D5 to meet whatever hydration was not provided by EN, and only received PN if enteral feedings were not providing at least 80% of calculated needs by day 8.
Calorie needs were calculated based on corrected ideal body weight (see online supplemental tables) with 24 kcals/kg for females > 60 years, 30 kcals/kg for females < 60 years, 30 kcals/kg for males > 60 years and 36 kcals/kg for males < 60 years.
Enteral nutrition orders for all patients specified a twice-daily increase in the feeding rate and the use of prokinetic agents; duodenal feeding tubes were used where indicated. Patients in both study groups received parenteral trace elements, minerals (potassium, phosphate, and magnesium), and vitamins early in their ICU stay.
The primary outcome of the study was number of ICU days (for survivors and nonsurvivors) and the time to discharge from the ICU. This study also had “safety endpoints” that were monitored which included the proportion of patients who were alive at discharge from the ICU in ≤ 8 days, the rates of death in the ICU and the hospital, the rates of survival up to 90 days, regardless of ICU and hospital discharge status and the rates of complications and hypoglycemia.
An extensive number of secondary endpoints were also monitored including the number of patients with new infections, infection site, duration of antibiotic therapy, inflammation (C-reactive protein), time to vent wean, need for tracheostomy, acute kidney injury, need for and duration of pharmacologic or mechanical hemodynamic support, liver dysfunction, duration of the hospital stay and time to discharge from the hospital, functional status according to the distance walked in 6 minutes and the proportion of patients who were independent in all activities of daily living, and the total incremental health care costs from randomization to hospital discharge.
Inclusion and Exclusion Criteria:
Admission to a participating ICU, a nutritional risk screening (NRS) score of 3 or more (on a scale of 1 to 7, with a score ≥3 indicating that the patient was nutritionally at risk) and did not meet any of the exclusion criteria.
Patients with a "do not resuscitate" code at the time of ICU admission, patients expected to die within 12 hours, patients readmitted to the ICU after randomization to the EPaNIC trial, patients enrolled in another trial, patients transferred from another ICU after a stay of more than 7 days, patients suffering from ketoacidotic or hyperosmolar coma on admission, patients with a BMI <17 (kg/m2), patients with short bowel syndrome treated with home-PN, patients on home mechanical ventilation, pregnant or lactating women, patients without a clinical indication or with a contra-indication for a central venous catheter, and patients who are still able to take oral nutrition on ICU admission or with an NRS score lower than 3.
Major Results reported by authors:
The primary outcome result was that median stay in the ICU was 1 day shorter in the late-initiation group than in the early-initiation group. There was a statistically significant increase in the likelihood of earlier discharge alive from the ICU (hazard ratio, 1.06; 95% confidence interval [CI], 1.00 to 1.13; P=0.04). There were no significant differences in ICU, hospital or 90-day mortality between the groups.
The median duration of hospitalization was 2 days shorter in the late-initiation group than in the early-initiation group, which was reflected in a relative increase by 6.4% in the likelihood of earlier discharge from the hospital (hazard ratio, 1.06; 95% CI, 1.00 to 1.13; p = 0.04). There were significantly fewer patients that developed new infections in the late-initiation initiation group, and the subgroups of airway, bloodstream and wound infections were also significantly less in the late-initiation group. Additionally, the duration of mechanical ventilation and the course of renal-replacement therapy were significantly shorter in the late-initiation group.
Functional status (6-minute walk distance and activities of daily living at the time of hospital discharge) were not significantly different between the two study groups. Late initiation of PN resulted in a mean reduction in total health care costs of €1,110 (about $1,600) per patient.
Interestingly, the late-initiation group had significantly more hypoglycemia than the early PN group, as well as a greater peak C-reactive protein level during the ICU stay. Significantly more patients in the late-initiation group had hyperbilirubinemia (> 3 mg per deciliter), and fewer had a clinically important increase in levels of γ-glutamyltransferase or alkaline phosphatase.
There were no significant changes in the results in any of the pre-defined subgroup analyses, including those patients with more severe malnutrition (NRS > 5). A post-hoc subgroup analysis was done with those patients where EN was surgically contraindicated (meaning that the late-initiation group received insignificant nutrition X 7 days). Among these patients, the rate of infection was lower in the late-initiation group (29.9%) than in the early-initiation group (40.2%, p = 0.01). In the late-initiation group, there was a relative 20% increase in the likelihood of earlier discharge alive from the ICU (hazard ratio, 1.20; 95% CI, 1.00 to 1.44; P=0.05; p = 0.11 for interaction)
“Early initiation of PN to supplement insufficient EN during the first week after ICU admission in severely ill patients at risk for malnutrition appears to be inferior to the strategy of withholding PN until day 8 while providing vitamins, trace elements, and minerals. Late parenteral PN was associated with fewer infections, enhanced recovery, and lower health care costs.”
This study is exceptional for a nutrition support study due to it’s size and rigorous methodology. The decision to study primarily patients at nutrition risk and the use of a validated score of clinical nutrition risk (rather than something that is not a valid marker of nutrition status like albumin) strengthens the results and impact of this study (2).
This study demonstrates that even in the setting of tight blood glucose control and providing some amount of enteral support (to “protect the gut”) that even/only 7 days of PN results in significantly increased infectious complications. More impressive is the fact that even mild to moderately malnourished patients appeared to be better off without any nutrition X 7 days than to receive early PN.
Although there were no significant differences in mortality between the groups, it is very interesting to note that there was significantly greater hypoglycemia in the late-initiation group. The NICE-SUGAR study demonstrated that mortality was significantly increased when intensive insulin therapy to achieve normoglycemia was provided to patients that are not yet receiving full nutrition (3). It is conceivable that any possible mortality difference between these groups was masked by the potential negative effects of enforcing normoglycemia in critically ill patients that had not yet received full feedings. The significantly greater hypoglycemia seen in the late-initiation group may also explain the increased C-reative protein, since hypoglycemia can release vasoactive substance and increase C-reative protein (4).
One limitation of this study is that patients with a BMI < 17 were excluded, so it is possible that the results may not apply to the most severely malnourished patients. There was no interaction with malnutrition (NRS > 5) identified in the subgroup analysis, but we do not have any information on how many of the most severely malnourished patients were available for analysis (NRS of 7). Another unknown is that there is no data presented on how many patients in the late-initiation group actually received PN. Additionally, in practice, we would not have started patients that are receiving 50-75% of their estimated needs from EN by day 8. It is possible that there would be an even greater difference between the groups if PN was not started until day 10-12 in the late-initiation group.
The other potential implication of this study that we discussed is the possibility that it is not necessarily just the negative effects of PN that were demonstrated. One possibility is that it could be undesirable to provide full calorie needs within the first week of critical illness from parenteral or enteral nutrition. There is an undeniable need to study how much nutrition should be provided to ICU patients in the early portion of their admission. At the risk of provoking the ire of nutrition support professionals everywhere, it would be correct to say that based on the limited data that we have to date, there is still a need to study if any nutrition should be provided in the early portion of an ICU stay (i.e., we need an unfed group—zip, zilch, zero, nada, nyet).
The one issue clouding the results that we identified in this study was the routine use of parenteral trace elements, minerals, and vitamins in both groups. While supplemental micronutrients was a great idea to make sure that there were no negative effects from deficiencies until patients received full nutrition, this is generally not a standard practice (at least in the US). While it would be easy to marginalize the importance of micronutrient supplements, it is possible that in the early ICU period, these nutrients may play a more important role than is generally appreciated. Given the limited data that we have, there is no way to know for sure if patients receiving limited amounts of EN would have the same outcomes if they did not receive full micronutrient supplements.
One last point that needs to be made is how the calculation of energy requirements delivered from EN were determined, and then PN calories were supplemented:
“For calculation of the energy requirements, 50% of the gastric residual volume (GRV), which is being discarded by the bedside nurses, is considered to be EN calories not absorbed by the patient.”
This practice has never been validated as a means to determine calories delivered. It presumes that EN is the only fluid found in the stomach, when from a physiological standpoint, we know that is not the case. GRV IS the sum of its components (saliva, gastric secretions, reflux of duodenal contents in addition to EN, medications and water flushes (5,6). Although this would be unlikely to affect the overall results of the study due to the large number of patients randomized, as both groups would have been treated equally, we could not let this point go unnoticed.
Our Take Home messages:
1) Late parenteral nutrition in adult ICU patients at nutrition risk or malnutrition was associated with fewer infections, enhanced recovery, and lower health care costs.
2) Early parenteral nutrition in the first 7 days of ICU admission results in significantly increased infections even in the setting of tight glucose control and concomitant enteral feeding.
1. Casaer MP, Hermans G, Wilmer A, Van den Berghe G. Impact of early parenteral nutrition completing enteral nutrition in adult critically ill patients (EPaNIC trial): a study protocol and statistical analysis plan for a randomized controlled trial. Trials. 2011 Jan 24;12:21.
2. Kondrup J, Allison SP, Elia M, Vellas B, Plauth M. ESPEN guidelines for nutrition screening 2002. Clin Nutr 2003;22:415-21.
3. Finfer S, Chittock DR, Su SY, et al. Intensive versus conventional glucose control in critically ill patients. N Engl J Med. 2009;360:1283-1297.
4. Wright RJ, Newby DE, Stirling D, Ludlam CA, Macdonald IA, Frier BM. Effects of acute insulin-induced hypoglycemia on indices of inflammation: putative mechanism for aggravating vascular disease in diabetes. Diabetes Care. 2010;33(7):1591-1597.
5. Chang WK, Chao YC, Mcclave SA, Yeh MK. Validation the use of refractometer and mathematic equations to measure dietary formula contents for clinical application. Clin Nutr. 2005 Oct;24(5):760-7.
6. Parrish CR, McClave S. Checking Gastric
A Practice in Search of Science? Practical Gastroenterology 2008; XXXII(10):33.
See our website: www.ginutrition.virginia.edu for:
Upcoming Webinars for Fall 2011:
- September 20: Making Sense of Fluid Management: ICU and Acute Care
- October 13: The Basics of Gastrointestinal Anatomy
- November 15: Vitamin and Mineral Issues in Gastric Bypass
- December 6: The Basics of GI Anatomy, Part II: The Malabsorption Workup
Latest Practical Gastroenterology Nutrition Series Article:
Stout SM, Cober MP. Cyclic Parenteral Nutrition Infusion: Considerations for the Clinician. Practical Gastroenterology 2011;XXXV(7):11.
Joe Krenitsky MS, RD
Carol Rees Parrish MS, RD
PS – Please feel free to forward on to friends and colleagues.