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Excerpt
Numerous studies have examined whether chemicals, provided parenterally or enterally, that have metabolic and/or immunologic effects favorably alter the outcome of critically ill patients. In this issue of Critical Care Medicine, Drs. Hirokawa and Walser [1] provide interesting data that mortality may be influenced by infusing ketone body substrate enterally. In an animal model of sepsis, where endotoxin was injected into rats, they demonstrated that animals fed with ketoisocaproate (KIC) had improved survival compared with animals fed enterally with pyruvate or bicarbonate. As discussed by these authors, previous studies with intravenously administered KIC generally did not find protein sparing. Other possible mechanisms of action include scavenging of hydrogen peroxide or improved energy metabolism through the increased generation of ketone bodies. The current study supports the latter mechanism.
The primary result from this study is provocative. The mortality rate was reduced from 74.2% to 46.9%. However, several issues need to be considered when interpreting these results. First is the choice of sepsis model. Intravascular endotoxin models may be useful to examine pathophysiology, but have not been predictive of treatment effects in clinical practice [2]. These results should therefore be confirmed in a more appropriate model before clinical testing. Another flaw in this study is that different doses of endotoxin were used in study 1 (15 mg/kg) compared with studies 2 and 3 (3 mg/kg). A five-fold difference in dose can be expected to have qualitative and quantitative differences in the response. Thus, the results from each study appear valid on their own, but associating results derived from studies 2 and 3 with the mortality study is tenuous.
The data presented in this study by Dr. Hirokawa and colleagues [1] need to be considered in the light of clinical studies that examine the role of nutritional support in septic patients. There are no placebo-controlled trials evaluating the effect of any form of enteral or parenteral nutrition on clinically important outcomes in septic, critically ill patients. One study [3] of septic patients compared standard enteral nutrition with total parental nutrition and found no difference in clinical outcomes. Recent studies of specialized nutritional support with immunomodulating properties have included large subsets of septic patients. In these randomized trials [4,5] that compared products supplemented with arginine, glutamine, and omega-3 fatty acids with standard enteral nutrition, the enriched formulas did not demonstrate a consistent benefit in clinically important outcomes. A recent, placebo-controlled trial of Impact[registered sign] (Sandoz Nutrition, Minneapolis, MN) in surgical patients demonstrated that patients fed with this enriched formula had similar outcomes as those receiving intravenous crystalloid only [6].
Assuming KIC provided enterally is of benefit in the experimental models, such benefit is based on the immediate delivery of enteral nutrition after the onset of experimentally induced sepsis and assumes that all patients will tolerate sufficient amounts of nutrients provided enterally. In clinical practice, this is not the case. Nutritional support delivered enterally is often started 3 to 4 days after intensive care unit admission, and not all patients tolerate enteral feedings [7,8]. Reasons for delays in providing enteral nutrition include oversight, logistical problems, and problems obtaining and maintaining enteral access.
Mortality is the ultimate arbitrator of success. Nutritional support may affect mortality by directly supporting metabolic requirements but also by effects on immune function, complications directly related to the administration of nutritional support, and the maintenance of bowel wall integrity. The benefit of enteral nutrition may be indirect, by avoiding the complications associated with parenteral nutrition [9,10]. Use of the gut may also increase splanchnic blood flow, prevent mucosal atrophy, and thus decrease bacterial or endotoxin translocation [11].
