Sep06.html

University of Virginia Nutrition Support
E-Journal Club
September 2006 

Greetings,

It is finally starting to feel like Fall here in Virginia, and although our trainees had a damp start, by week's end we were treated to sunny skies, cool mornings, and comfortable days.  This month our trainees hailed from South Bend, Indiana and just down the road in Richmond, Virginia.

 

This month's study was completed at the Fernandes Tavora Hospital in Fortaleza, Brazil.  I have never visited that part of the world, but a website about Fortaleza reported that it is, "a coastal city with most sunny days throughout the year.  Party is the permanent state of spirit of the people and the city."  The city is known for having the "wildest Monday nights in the world, and at the same time has a strong history of education and culture.  We have decided that we need to do our next journal club there, on a Monday night!  :):)

Because we have had several emails already about the particulars of omega-3 versus omega-6 fats, so we are going to include a sort section on fatty acids before the journal club proper.

Lipids and immune function

This is a VERY casual review of lipid sources and their relation to nutrition support in the critically ill population. The issue is more complex than can be covered adequately here, but we have received several emails from past trainees, so we just wanted to include a brief review.

Normal (American) diets normally contain a mix of all types of fat, but only modest amounts of polyunsaturated omega-6 fatty acids (such as linoleic) when compared to the amount of saturated and total fat that is consumed.

The early enteral formulas provided almost all fat as omega-6, but currently most are combinations of different fats, with canola and high-oleic safflower oil being quite popular because they consist primarily of monounsaturated fatty acids.

Fatty acids are precursors for prostaglandins, leukotrienes and thromboxanes, and when a diet/feeding has 100% of the fat source as omega-6 fatty acids (such as the current intravenous lipid emulsions or the early enteral formulas), the phospholipids of cell membranes are altered to mirror the fat provided.  Changing the lipid profile of cell membranes affects production of prostaglandins, leukotrienes and thromboxanes that play a role in inflammation and immunity.

The rationale for avoiding high-fat formulas is based on the idea of avoiding excessive omega-6 fatty acids, which can lead to increased production of pro-inflammatory cytokines, prostaglandins, and thromboxanes.  There is no evidence at present that enteral feedings low in omega-6 fatty acids, but rich in monounsaturates (such as canola oil, or high-oleic safflower oil), have any detrimental effects in critically ill patients.  There is evidence that supplemental linoleic acid increases arachidonic acid in cell membranes.  However, a-Linolenic acid supplementation appears to be relatively neutral in terms of cytokine production from stimulated cells (1). 

Borage oil, a component of Oxepa, is rich in Gamma-linolenic acid (GLA).  Although borage oil is rich in omega-6 PUFA, the GLA is converted to DGLA, which competes with arachadonic acid products.

Increasing levels of dietary linoleic acid (omega-6 PUFA) suppresses the linolenic (omega-3) products.  Conversely, when levels of dietary linoleic acid were held constant, an increase in omega-3 fats suppressed the omega-6 products.  However, it is important to know that it takes considerably less omega-3 fats to suppress the products of omega-6 fats, than the amount of omega-6 fats required to inhibit omega-3 metabolism.

One study found that suppression of 50% of omega-6 metabolism by dietary omega-3 fats was achieved by ~0.5% of calories from linolenic acid.  The same level of suppression of omega-3 metabolism by omega-6 required approximately 7% of calories from linoleic acid (2).  A full review of fatty acids can be found in the August 2006 issue of Nutrition in Clinical Practice (3).

  • 1. Thies F, Nebe-von-Caron G, Powell JR, et al. Dietary supplementation with g-linolenic acid or fish oil decreases T lymphocyte proliferation in healthy older humans. J Nutr. 2001;131:1918-1927
  • 2. Rahm J, Holman R. Effect of linoleic acid upon the metabolism of linolenic acid. J. Nutr. 84:1964; 15-19.
  • 3. Lee S, Gura KM, Kim S, et al. Current clinical applications of omega-6 and omega-3 fatty acids. Nutr Clin Pract. 2006;21:323-41.

And now for our...

September Citation: 

  • Pontes-Arruda A, Aragao AM, Albuquerque JD.   Effects of enteral feeding with eicosapentaenoic acid, gamma-linolenic acid, and antioxidants in mechanically ventilated patients with severe sepsis and septic shock.  Crit Care Med. 2006;34(9):2325-33.

Summary: 

This was a randomized, double-blind, placebo-controlled study designed to test the effect of enteral feeding enriched with eicosapentanoic acid (EPA) and docosahexanoic acid (DHA) from fish oil, gamma-linolenic acid (GLA) from borage oil, and antioxidants in patients with sepsis or septic shock.  The primary outcome was mortality over 28 days, and secondary outcomes were change in oxygenation, time on mechanical ventilation, ICU length of stay, and new organ dysfunction.

Initially 165 patients were randomized to receive Oxepa or Pulmocare.  Patients were fed within 6 hours via NG, ND or jejunal tube for minimum of 4 days.  Feeding goal was REE (via Harris-Benedict) X 1.3. 

Major Results reported by authors:

The investigators reported a significant reduction in 28-day mortality in the Oxepa group compared to the control group (18 out of 55 [33%] versus 25 out of 48 [52%], p = 0.037).

The authors also reported that the Oxepa group had significantly more ventilator-free days than the control group (13.4 ± 1.2 vs. 5.8 ± 1.0, respectively, p < 0.001), and significantly more ICU-free days than the control group (10.8 ± 1.1 vs. 4.6 ± 0.9, respectively, p < 0.001).  The Oxepa group was also reported to have significantly less new organ dysfunction compared to the control group (38 vs. 81%, respectively, p < 0.001).

Author's Conclusions:

The investigators concluded that a diet enriched with EPA, GLA, and elevated antioxidants contributed to better ICU and hospital outcomes and was associated with lower mortality rates.  In addition, they concluded that, "the effect of this diet on the overall population of septic patients needs further investigation."

Evaluation:

Overall, the group thought that this was a very well designed study.  The decision to exclude patients receiving any parenteral nutrition is particularly notable (if only this could be made a universal protocol when studying enteral nutrition!).  Another very positive aspect of this study was that patients started feeding very quickly (approx. 3 hrs after study entry) and patients achieved 75% of their goal feedings in a little over 24 hours (approx. 26 hrs) - Wow!!

The Oxepa and control groups appeared to be similar at baseline, although the Oxepa group did have somewhat more patients with septic shock than the control group (27.3% versus 12.5%).  However, this was not significantly different (p = 0.063) than the control group, and if anything, would appear to favor a better outcome in the control group.  Additionally, if you compare more than 20 baseline characteristics, as was done in this study, there is a 64% chance of having a "significant" imbalance between groups (at two-sided p < 0.05) by chance alone! (1)

One aspect of this study that did raise concern was the relatively large number of patients dropped from the analysis after randomization, and that there was no intention-to-treat analysis.  Although 165 patients were enrolled, analysis was completed on only 103 patients that fulfilled the protocol requirements.  The authors DID provide details about why patients were dropped from the study in the first 4 days.  In reviewing the reasons for dropouts, there did not appear to be any glaringly obvious bias in favor of the Oxepa group, because there was 38.2% mortality in control dropouts, and only 28.5% mortality in Oxepa group dropouts.

Carol contacted the principal investigator and he graciously provided us with additional details of the study, including the fact that they had completed a post-hoc intention to treat analysis.  They reported that based on intention to treat (all 165 randomized patients) there was still a significant improvement in survival in the Oxepa group compared to the control group (68.68% versus 53.66% respectively, p = 0.0039 via the log-rank test). 

The other factor discussed was the use of a high-fat (55% total calories) enteral formula as a control.  Although high-fat formulas are not considered ideal in a critically ill population, it should be remembered that the rationale for avoiding high-fat formulas is based on the idea of avoiding excessive omega-6 fatty acids, which can lead to increased production of pro-inflammatory cytokines, prostaglandins, and thromboxanes.  The control feeding used in this study provided approximately 10-11% of total calories as omega-6 fatty acids (19% of fat calories), and the rest of the fat was either MCT or canola oil (primarily omega-9).  There is no evidence that enteral feeding low in omega-6 fatty acids, but rich in omega-9 fatty acids, has any detrimental effects in critically ill patients. 

The experimental and the control formulas were isocaloric, isonitrogenous, and had the same percentage of total calories derived from fat.

Another factor that must be considered is the relatively small sample size of this study.  It must be remembered that small studies can exaggerate the treatment effect.  Studies as "large" as 200 patients have described interventions that halved mortality in critically ill patients, but larger follow-up studies with over 600 patients reported an 11% increase in mortality (not statistically significant).2,3

Take home message: 

This is a promising study, but the results will need to be reproduced in studies with a larger sample size with all analysis based on intention to treat before use of a substantially more expensive enteral product could be endorsed.  In addition, cost-analysis and further studies comparing Oxepa to low-fat enteral feedings should be completed.

  1. Burgess DC, Gebski VJ, Keech AC.  Baseline data in clinical trials.  Medical Journal of Australia 2003;179(2):105-107.
  2. Ziegler EJ, Fisher CJ Jr, Sprung CL, et al, the HA-1A Sepsis Study Group. Treatment of gram-negative bacteremia and septic shock with HA-1A human monoclonal antibody against endotoxin: a randomized, double-blind, placebo-controlled trial. N Engl J Med. 1991;324:429-436.
  3. McCloskey RV, Straube RC, Sanders C, Smith SM, Smith CR.  Treatment of septic shock with human monoclonal antibody HA-1A. A randomized, double-blind, placebo-controlled trial. CHESS Trial Study Group.   Ann Intern Med. 1994;Jul 1;121(1):1-5.

Other News:

Check out the latest Practical Gastroenterology articles/info at:

http://www.uvadigestivehealth.org/  
Scroll down to GI Nutrition on the far left column and click on link
Then scroll down to box with links within the nutrition site
Nutrition Articles in Practical Gastroenterology is in the right column:

Joe Krenitsky MS, RD

Carol Parrish RD, MS

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