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University of Virginia Health System

Nutrition Support E-Journal Club

October 2008



October is often Charlottesville at its best, with warm days, cool nights, and glorious Fall foliage.  The start of our traineeship week felt more like summer, however, but our trainees from Missouri, Indiana, Florida and Sydney Australia had more seasonal weather by week's end.  This month was also our semi-annual Nutrition Support Forum where professionals from surrounding hospitals join us to share cases and journal critiques - so we have 2 article summaries in this newsletter.


October Citation 1: 

Collier BR, Giladi A, Dossett LA, et al.  Impact of high-dose antioxidants on outcomes in acutely injured patients.  J Parenter Enteral Nutr. 2008 Jul-Aug;32(4):384-8.


A retrospective cohort study in which 2272 patients admitted to a trauma unit after the start of an antioxidant protocol (AO+) were compared with 2022 patients that were admitted in the year prior to the start of the antioxidant protocol (AO-).

The AO+ group received a 7-day antioxidant protocol comprised of 1000 mg intravenous vitamin C q 8 hrs, 200µg intravenous selenium q d, and 1000 IU vitamin E (DL-a-tocopherol acetate) via enteral feeding tube q 8 hours.  Vitamin C and Se could be changed to enteral delivery once access was achieved.

The primary outcome studied was hospital mortality.  Other outcomes monitored were hospital days, ICU days, ventilator days, and ventilator-free days.

The investigators grouped patients into Expected Survivors and Expected Deaths based on the Trauma Related Injury Severity Score (TRISS) score, in order to determine if the effect of antioxidant supplementation was different in the sickest patients. Information such as age, gender, race, and injury scores including initial Glasgow Coma Scale (GCS), weighted Revised Trauma Score (w-RTS), and Injury Severity Score (ISS) were obtained from the trauma registry so that differences in these factors could be adjusted between the two cohorts.  Patients that received enteral nutrition received an immunonutrition formula that contains supplemental fish oil, arginine and glutamine.-

Inclusion and Exclusion Criteria were:

Inclusion criteria were acutely injured patients admitted to the trauma unit.

Exclusion criteria were patients that were pregnant or had a serum creatinine > 2.5 mg/dl.

Major Results reported by authors:

The investigators reported that hospital mortality was significantly less in the AO+ group compared to AO- group (139 out of 2272, 6.1% versus 171 out of 2022, 8.5%, respectively, p < 0.001).  In addition, median ICU length of stay and hospital length of stay were also significantly less in the group that received antioxidants (p < 0.001).

The patients in the AO+ group were statistically more likely to be male, older, and have a lower calculated probability of survival (based on the TISS score).  The unadjusted relative risk indicated that the AO+ patients had a 30% less risk of dying during their hospitalization (OR 0.70, 95% confidence interval (CI), 0.56-0.88).  Adjustment for age, gender and probability of survival resulted in a further improvement in the relative risk of in-hospital mortality (OR 0.32, 95% CI 0.22-0.46).

The separation of the patients into expected survivors and expected deaths revealed that there was no significant difference between the AO+ and AO- groups among the expected survivors (OR 1.0, 95% CI 0.70-1.4, P = .98).  The hospital cost for the 7-day antioxidant treatment was $11.00 per patient.

Author's Conclusions:

The authors concluded that a high-dose antioxidant protocol resulted in a 28% relative risk reduction in mortality and a significant reduction in both hospital and ICU length of stay.  Additionally, the authors concluded that this benefit appears to be primarily in those patients who are less likely to survive their acute injury.


There is accumulating evidence that antioxidant supplementation may have beneficial effects in the critically ill population.  The virtue of the present study is that the antioxidant supplements, as part of a unit protocol, were provided to a very large number of patients.  Randomized studies of similar size are expensive, time consuming and rarely undertaken with products that do not offer the possibility of patents and commercial sales.

The primary limitations of this study are well described in the discussion section.  A retrospective study has inherent limitations that can never be fully accounted for with statistical control.  For example, use of historic controls offers too much possibility for other changes, within or without the hospital environment that could influence any outcome differences. 

One factor that we discussed, in addition to the limitations of non-randomized studies was the fact that enterally-fed patients also received a feeding supplemented with fish-oil, glutamine and arginine.  Animal studies of fish oil supplementation have demonstrated increased production of certain oxidative products; therefore, there is the possibility that supplemental antioxidants only benefit patients that are concurrently receiving fish oil or immunonutrition containing fish oil.

Our Take Home message:

This study provides evidence that antioxidant supplementation could offer substantial benefit in an extremely cost effective manner.  However, considering that the current level of evidence (no large, double-blind randomized trials), would not be adequate to justify routine use of a medication, it follows logically that the current level of evidence is not adequate to advocate routine clinical use of a "neutraceutical."   The lessons learned from studies of arginine in sepsis, beta-carotene in smokers, probiotics in severe pancreatitis and vitamin E in cardiovascular disease have certainly left us wiser about the potential harm from large doses of nutrients in pathologic states.   The results of this study certainly justify large randomized trials to fully establish risks vs. benefits and to study optimum doses and combinations of antioxidants in patients receiving standard enteral feeding formulas.


October Citation #2: 

Desachy A, Clavel M, Vuagnat A, et al.  Initial efficacy and tolerability of early enteral nutrition with immediate or gradual introduction in intubated patients. Intensive Care Med. 2008 Jun;34(6):1054-9.


This is a prospective, randomized, non-blinded study comparing the efficacy and feeding tolerance of starting gastric enteral nutrition (EN) at full goal rate, as compared to a gradual introduction and advancement of feeding.  The population was 100 consecutive patients intubated > 72 hours in two medical-surgical ICUs.  Goal calories were based on 25 Kcal/kg per day for all patients.  EN was provided within 24 hours following intubation with a standard polymeric 1 calorie/mL formula fed through a 16 or 18 Fr gastric placed "salem sump" type tube. 

The immediate optimal flow group started EN at the full 25 Kcal/kg rate, while the slow advance group began at 25 mL/hour, advancing every 24 hours by an increment of 25mL/hr.  Gastric residual volume (GRV) was measured every 8 hours, and prokinetic medication (erythromycin or metoclopramide) started if the GRV was greater than 300mL.  If the GRV remained > 300mL, the EN rate was reduced by 25mL per hour q 8 hours.  Once flow rate was reduced, the protocol was to wait until GRVs were below 300mL on 3 occasions before the rate could be advanced again. 

The primary outcome of the study was the calorie supply actually delivered to the patient compared with the prescribed supply (differed between the two arms, based on advancement protocol) and with the theoretical optimal calorie provision (25 Kcals/kg).  EN intolerance was defined as the onset of abdominal distension, suspected aspiration (tracheal aspirates looking digestive fluid), regurgitation (digestive fluid in the oropharynx), or vomiting.  Outcomes were evaluated at day 7 of EN, or at the time that EN was discontinued if < 7 days.

Inclusion and Exclusion Criteria were:

Inclusion criteria were adult patients in two medical-surgical ICUs intubated greater than 72 hours.

Exclusion criteria were pregnancy, malnourished patients, those with a direct contraindication to EN (occlusion, ileus, or gastrointestinal ischemia), contraindications to gastric access (esophageal stenosis, surgery, recent gastroesophageal trauma, or hematemesis), and shock.

Major Results reported by authors:

Sixty-nine men and 31 women were enrolled in the study. There were 50 patients in each group. The reasons for ICU admission were 68 medical, 11 surgical, and 21 trauma. 

Age, length of hospitalization, length of ICU and hospital stay and Simplified

Acute Physiology Score 2 were similar between the two groups, but a randomization bias resulted in:

  • Significantly more patients being admitted after surgery in the gradual group, and,
  • More patients being admitted for trauma in the immediate optimal flow group.

Caloric delivery was significantly less in the gradual group compared to the immediate full flow group, 76% vs. 95%, (p < 0.0001).  The cumulative and daily calorie deficiency were also significantly less in the immediate full flow group compared the gradual advance group (p < 0.0001). 

The study protocol was stopped before day 7 in 55 patients because of extubation (n = 32), serious adverse events (n = 15), or death (n = 8), with no significant difference between the groups.  Serious adverse events during the protocol requiring EN to be discontinued were not significantly different between the two groups, 8 (16%) vs 7 (14%) patients in the gradual group and immediate optimal flow group respectively (p = 0.65).  There were no clinically suspected episodes of aspiration pneumonia.

At least one episode of GRV > 300 mL was reported in 18 patients, with significantly more patients with GRV > 300mL in the immediate full flow group (5 patients in gradual, 13 in full flow, p = 0.04).

There were also significantly greater total episodes of elevated GRV in the immediate full group (11 in gradual group, 29 in the immediate full flow group p = 0.037).  Prokinetic medication tended to be administered more frequently to patients in the immediate full flow group (9 gradual vs 12 full flow), but this did not reach significance.

Author's Conclusions:

The authors concluded that early enteral nutrition (EEN) can be started in shock-free patients intubated for mechanical ventilation.  Furthermore, if GRV is regularly measured and prokinetic agents are used, EEN can be introduced at the goal flow identified to meet 25 kcal/kg, thereby improving overall calorie supply.


This was a randomized, but unblinded study since there is no way to make a study of this nature double-blind when the caregivers must be aware of the feeding protocol that the patient is receiving.  One limitation of this study was the relatively modest size of the study.  The realization that there was an unequal distribution of surgical and trauma patients between groups from the outset underlies the possibility that the sample size was too small for the groups to become homogenous.

Another limitation was that only "clinically suspected" aspiration was monitored, not the actual diagnosis of aspiration pneumonia (although the sample size was likely far too small for any meaningful evaluation of patient outcomes).

This study does call into question the practice of starting EN at a marginal rate with subsequent graded advancement based on GRV.  Ultimately, there was no significant difference in adverse events such as regurgitation, emesis, or distention between the two groups.  In addition, starting EN at goal flow rate is clearly an asset for improving nutrition delivery to the patient.

Of course, there is still the fact that increased GRV occurred in significantly more patients in the full flow group, with an increased use of prokinetic medications.  Considering that there is no good data that GRV are a valid marker of EN tolerance, one must ask, "how meaningful are increased GRV in the setting of no increase in adverse events?"

Our Take Home message:

It may not be necessary or desirable to start EN at reduced rates with a slow advancement.  Larger outcome studies will be necessary to know if starting EN at goal flow rate has a positive, negative or neutral effect on patient outcomes.


Other News:

  • Our first WEBINAR is scheduled for Tuesday, December 2nd (2:00 - 3:30 pm). The topic is Enteral Nutrition presented by Carol Parrish, MS, RD. Please tell your friends and colleagues about this new opportunity! 
  • Our next Weekend Warrior 2 day mini-traineeship program is scheduled for Saturday and Sunday, March 7th & 8th, 2009. If you know anyone who might not be able to get away for our full week traineeship, please let them know about our weekend program, and to check out our website for full information.
  • Check out the latest Practical Gastroenterology articles/info at:


  • Parrish CR, McClave S. Checking Gastric Residual Volumes: A Practice in Search of Science? Practical Gastroenterology 2008; XXXII(10):33.


Joe Krenitsky MS, RD

Carol Parrish RD, MS


PS - Please feel free to forward this on to friends and colleagues.