We are experiencing “Summer Relativity” where time flies because of vacations and working in the hubris of covering for team members that are away on vacation – in a teaching hospital with new house officers. It is this “time dilation” that is responsible for our June e-journal club appearing in late July (1). We hope you are all having a great summer and catching up on your vitamin D requirements!
Doig GS, Simpson F, Sweetman EA, et al. Early parenteral nutrition in critically ill patients with short-term relative contraindications to early enteral nutrition: a randomized controlled trial. JAMA. 2013;309(20):2130-2138.
This was a randomized, single-blind, multi-center trial of early parenteral nutrition (PN) in mixed critically ill adult patients (63% surgical) with a “relative contraindication” to early enteral nutrition (EN). Early PN patients received PN on day 1 of the study and reached goal calories by day 3. Early PN patients were re-evaluated for initiating EN starting day #3.
Control patients received a variable amount and type of nutrition based on the usual practices of the individual hospital and attending physician. The primary endpoint of the study was 60-day mortality. The secondary endpoints were quality of life and physical function measures. There were a host of tertiary endpoints including organ failure, infection rates, ICU and hospital stay, vital status at ICU and hospital discharge, days of mechanical ventilation, days of renal replacement therapy, days of treatment for pressure ulcers, days of antibiotic usage, muscle wasting (as determined by mid-arm muscle circumference), fat loss (as determined by Subjective Global Assessment), plus others.
Inclusion and Exclusion Criteria were:
Adults in the ICU < 24 hours, expected to be in the ICU the next day after enrollment, and not expected to receive enteral, parenteral or oral nutrition the day after enrollment.
Expected survival <24 hours, brain death, palliative care only, previously in an ICU or the study, known long-term contraindication to enteral or oral nutrition, burn injury > 20% BSA, pregnant or breastfeeding, weight < 35 kg, height < 140 cm, malnutrition as the primary reason for admission, contraindication or allergy to TPN components.
The investigators randomized 1372 patients over 5.8 years, and analysis was completed on 1358 patients. The number of patients screened was not reported.
The early PN group received PN an average of 44 minutes after randomization (amazing in itself), vitamins on day 2.8 and trace elements on day 2.2. Ultimately, 40.2% of the early PN group received EN at some point in the ICU. The early PN group received PN for a mean of 6 days and EN for 3.1 days.
A proportion (29.2%) of the standard care group started EN within 1.98 days after randomization and ultimately, 43.7% of the standard care group received EN at some point in the study. PN was started in 27.3% of the standard care group within 1.99 days, and 37% of the standard care group received PN at some point in the study. Standard care patients received an average of 2.9 days of PN and 4.0 days of EN.
There was no significant difference in the primary outcome of 60 day mortality between the 2 groups. There was a statistically significant increase in the quality of life measurement in the PN group, however, the magnitude of the difference did not meet the pre-established definition of a difference that would be clinically meaningful to patients.
There were no significant differences in infection rates between the two groups.
After adjusting for length of ICU stay, there were significantly fewer days of mechanical ventilation (1.07 fewer days) and significantly fewer days with coagulation failure (0.43 days) in the early PN group.
The early PN had significantly less muscle wasting and fat loss as reported by SGA scores. Mid-arm muscle circumference (MAMC) reflected statistically significantly more muscle loss in the standard group on day 2 of the study, but MAMC did not remain significantly different throughout the ICU stay.
“The use of early parenteral nutrition did not result in significant differences in day-60 mortality or infection rates. Early parenteral nutrition resulted in a significant reduction in days of invasive mechanical ventilation, but this did not result in a significant shortening of ICU or hospital length of stay. No harm was associated with the use of early parenteral nutrition in this trial.”
This study focused on a narrow population that was not considered eligible for early EN because a systematic review suggested that there may be a survival advantage of early PN use in this population. The investigators utilized a “real-world” pragmatic approach for the control group, so they could see if there was an advantage of very early initiation of PN, compared to the usual practices. The editorial to this article (2) points out the one obvious issue with using this approach–just because the primary team did not think the patient was a candidate for enteral/oral nutrition, does not really mean that the patient was not an appropriate candidate for enteral/oral nutrition. The discussion section of the article points out another other obvious limitation of this study – in a single blind study, the investigators are aware of group allocation, and especially when there are subjective outcomes, there is room for the inadvertent introduction of bias.
Our group spent some time discussing the actual differences in the timing and amount of nutrition provided to both groups. Although there was a statistical difference in the amount/timing of nutrition between the groups, we noted that the standard group actually received nutrition relatively soon. Importantly, a lot of the standard patients received PN, and they received it early in their stay. More than 25% of standard patients received PN in < 2 days, and more than 1/3 of controls received PN. Unless we were dealing with severely malnourished patients, we would never “pull the trigger” on PN this early, and on this many people. The early PN group received PN for a mean of only 6 days, which means there were only really 3 days of difference of PN use between groups. It is not surprising that there was no difference in infections complications between two groups of patients – they both received short-term PN with similar use of EN between groups. Considering the relatively small number of patients that had clinically different nutrition regimens, this paper does not provide strong evidence that early PN is safe in the adult ICU.
Considering the number of tertiary outcomes, there was at least a 40% chance of finding something that was statistically different. The investigators mention that although there was a 1 day difference in weaning time, there were no other more meaningful (ICU or hospital stay, survival) outcome differences. We were pleased to see that evaluation of body composition was included in the study. However, we were astounded that there was no disclosure of the grievous limitations associated with the methods used for assessment of body composition. Subjective global assessment is, well,…subjective. SGA is validated for assessment of overall nutrition status, but it was never designed for, or validated as a tool to quantify fat and muscle changes over time in critically ill patients. In critically ill patients with varying degrees of fluid resuscitation, third spacing and then diuresis it is not feasible to accurately discern body compartments by observation.
Anyone that has ever attempted to get accurate upper arm and skinfold measurements in a bedbound patient (especially with multiple different users at different hospitals) would be disinclined to use this in a ICU study. Arm measurement and skinfolds lack the accuracy to reliably detect small changes in muscle mass that would occur over the relatively short duration of this study. These methods used are completely inadequate to make any conclusions about the effects of early PN on muscle and fat stores.
Our Take Home Message (s)
1. Early PN in patients not deemed to be candidates for early EN did not improve mortality or other major outcomes.
2. Be wary of presenters who use his study as good evidence that early PN does not increase infections, or is effective in preserving body cell mass.
3. Interventions that are expensive (and in the US in limited supply), but do not offer tangible benefits can be viewed as injurious overall until proven otherwise.
1. Einstein, A. (1907) “Über eine Möglichkeit einer Prüfung des Relativitätsprinzips”, Annalen der Physik.
2. Ochoa Gautier JB, Machado FR. Early nutrition in critically ill patients: feed carefully and in moderation. JAMA. 2013;309(20):2165-2166.
Other News on the UVAHS GI Nutrition Website: (www.ginutrition.virginia.edu):
Upcoming Webinars 2013
- September: Clinical Cases for the Nutrition Support Clinician
- October: Small Bowel Follow Through, Barium Swallow, Enteroclysis—What Does it All Mean? Radiology for the Nutrition Support Clinician
- November: Nutrition in ALS
- December: Clinical Cases, Part II: GI Nutrition Cases
Check out What’s New:
–“Nutrition Support Blog”
Latest Practical Gastroenterology articles
–Duggan SN, Conlon KC. A Practical Guide to the Nutritional Management of Chronic Pancreatitis. Practical Gastroenterology 2013;XXXVII(6):19.
–Walia R, Mulheran N, Khan R, Cuffari C. Chronic Constipation in Children: An Overview. Practical Gastroenterology 2013;XXXVII(7):19.
–Glassman K. Adult Enteral Product Guide For Selected Allergies–Table. Practical Gastroenterology 2013;XXXVII(7):35.
Joe Krenitsky MS, RD
Carol Rees Parrish MS, RD
PS – Please feel free to forward on to friends and colleagues.