University of Virginia
Our trainees for May were able to experience the full range Charlottesville spring weather - from cool and windy on Monday, to fair and sunny by the end of the week. These are the days when it takes more than a bit of discipline to head to work, rather than to a mountain trail in the Blue Ridge! Our trainees this month hailed from Tennessee, Michigan, Pennsylvania, and New Hampshire.
Kuhls DA, Rathmacher JA, Musngi MD, et al. Beta-hydroxy-beta-methylbutyrate supplementation in critically ill trauma patients. J Trauma 2007;6(1):125-31;discussion 131-2.
This was a randomized, double-blind study comparing 3 groups (beta-hydroxy-beta-methylbutyrate (HMB) against HMB plus l-arginine and l-glutamine (Juven), or an isocaloric, isonitrogenous control) and the different effects on nitrogen balance and muscle proteolysis in critically ill trauma patients. Patients received either:
- 3g HMB calcium salt
- 3g HMB calcium salt with 14g arginine and 14g glutamine, or
- Isonitrogenous control composed of gelatin plus alanine, glycine, serine, and glutamic acid.
All patients received enteral feedings with a polymeric 1.2 calorie/mL formula plus protein powder with the goal of providing 25 calories and 1.5g protein per kg. Patients were given the supplements for 14 days, and were followed for 28 days or until hospital discharge.
The investigators collected continuous 24-hr urine collections for the first 14 days for nitrogen balance, monitored 3-methylhistidine (3-MH) excretion as a marker of muscle proteolysis, and measured prealbumin on days 0,1,3,7 and 14.
The researchers enrolled 100 patients over 1 year, but analysis was completed on only the 72 patients that were able to complete the 14-day protocol and who were at least 50% compliant with the supplementation.
Inclusion Criteria were:
Trauma patients with an injury severity score (ISS) of at least 18, survival estimated > 48 hours, age 18-65 years, who were candidates for enteral feeding.
Exclusion criteria included pregnancy, renal insufficiency, genetic or immune disorder, malignancy, HIV infection, congestive heart failure, inflammatory bowel disease, hepatic dysfunction, or implanted defibrillator or pacemaker.
Major Results reported by authors:
Ultimately, 28 patients in the HMB group, 22 patients in the Juven group, and 22 control patients completed the study. The amount of enteral feeding received was similar between the groups. Nitrogen balance was negative on every day during the first 14 days in all three groups. However, the HMB group had a 14 day average nitrogen balance (-6.5 +/- 1.2) that was significantly less negative than the Juven group (-10.9 +/- 1.3, p < 0.02) and the control group (-9+/- 1.3, p < 0.05). When nitrogen balance was viewed as the change in values from day 7 to day 14, the value was -4.3 for HMB, -5.6 for Juven and -8.9 for the control (p < 0.05 HMB compared to control). There were no significant differences in 3-MH at any point, or a change in prealbumin values between the groups. The authors reported that there were no significant differences between the groups in any patient outcome including mortality, 28-day antibiotic use, hospital length of stay, ICU stay, ventilator days, or number of infections.
The author's conclusions were that supplementation with HMB alone may improve nitrogen balance in critically injured adult patients and that this effect is not a result of lowered muscle protein turnover as originally hypothesized.
This was an ambitious and well-designed study. The daily nitrogen collections allowed them to avoid any criticism related to normal daily swings in nitrogen balance. Indeed, a close look at the daily variation in nitrogen balances in figure 3 of the article will make any clinician give pause before putting too much faith in a single nitrogen balance study (note shameless prompt to encourage everyone to read the whole article).
Despite the sound design, the study is limited by a small number of patients - only 28 patients in the HMB group, and 22 patients in each of the other groups that completed the protocol. Despite the fact that they did not achieve the final number of patients indicated in their power calculations, they did find statistical difference in nitrogen balance. We also noted that the results were not presented as intention-to-treat. Those patients that died, dropped out, or did not otherwise receive the full doses of study supplement were dropped from the analysis.
What is surprising is that the HMB group had a significantly higher nitrogen balance than the group that received the same dose of HMB plus arginine and glutamine (Juven). There was little discussion in the paper or commentary that follows about why HMB alone might influence nitrogen balance, but the addition of glutamine and arginine would eliminate this effect. It is surprising that the Juven group actually had a trend towards a more negative nitrogen balance than the placebo group during the first 7 days of the study. The abstract mentions that the change in nitrogen balance in the HMB and Juven groups was better from the first 7 days until the last 7 days (-4.3 HMB, -5.6 Juven, -8.9 control), but this only reached statistical difference between HMB and control. The Juven group had a numerically lower nitrogen balance than the control on 9 out of 14 days.
It was also surprising that there was no change in 3-MH excretion between the groups. HMB was thought to have a positive effect on nitrogen balance via a reduction in proteolysis, but this did not appear to be the case based on the 3-MH excretion.
Another point we discussed was the applicability of the results to our patients. The researchers excluded patients with hepatic failure, renal insufficiency, known insulin-dependent diabetes, corticosteroid use, HIV infection and malignancy, (hence a more homogenous population), which is important considering the relatively small groups. However, there is no way to know if the results are generalizable to ALL trauma patients without a larger study that includes these patients.
One last point was that the results were not presented as intention-to-treat. Those patients that died, dropped out, or did not otherwise receive the full doses of study supplement were dropped from the analysis.
Take home message:
HMB appears to reduce the negative nitrogen balance after trauma, (within the confines of exclusion criteria - see evaluation). Further study, with a larger number of subjects, is required to establish if the addition of arginine and glutamine to HMB has a negative effect on nitrogen balance. A MUCH larger study would be required to establish if there is any outcome benefit to the patient from the addition of HMB to trauma patients. In fact, this outcome data would be absolutely necessary before routine use of HMB could be recommended.
1) Our first Weekend Warrior Mini-Nutrition Support Traineeship was a great success! Check out our website for the dates of our next one:
2) Check out the latest Practical Gastroenterology articles/info at:
Scroll down to GI Nutrition on the far left
column and click on link
This leads to a pull down menu with links within the GI nutrition site including the Nutrition Articles in Practical Gastroenterology. May's articles are:
1) Pagano A. The Gluten Free Vegetarian Practical Gastroenterology 2007:XXXI(5):94.
•2) Leising L, McCathy P, Hahn T, Dunford L, McKernon M. Bottled Water Myths: Separating Fact from Fiction Practical Gastroenterology 2007:XXXI(5):87.
Joe Krenitsky MS, RD
Carol Parrish RD, MS
PS - Please feel free to forward this on to friends and colleagues.