SHOCK, Vol. 41, No. 1, pp. 87Y88, 2014

Editorial Comment NUTRITIONAL SUPPORT IN CRITICALLY ILL PATIENTS: ENTERAL, PARENTERAL, OR NOT AT ALL? Mark G. Clemens,* Peter Radermacher,† and Christoph Thiemermann‡ *Department of Biology, University of North Carolina at Charlotte, Charlotte, North Carolina; †Sektion Ana¨sthesiologische Pathophysiologie und Verfahrensentwicklung, Klinik fu¨r Ana¨sthesiologie, Universita¨tsklinikum, Ulm, Germany; and ‡Centre for Translational Medicine and Therapeutics, William Harvey Research Institute, Charterhouse Square, London, United Kingdom

Shock, Vanwijngaerden et al. (12) brought several new ideas to this ongoing debate. They report an interesting animal model, propose potential regulatory mechanisms for controlling bile transporter expression, and offer the novel concept of using fasting as an alternative to PN in critically ill patients. Appropriate animal models are essential to study mechanisms of disease. Vanwijngaerden et al. (12) use a rabbit burn model of prolonged critical illness. Being physically larger than conventional rodent models (rat/mouse), the rabbit model used here allows for more intensive monitoring for a prolonged period, while being much less expensive and more manageable than large animal models (swine/sheep). There are, however, disadvantages. Most noteworthy in this report was the need to limit the assessment of some transporter and nuclear receptor expressions to mRNA levels due to the unavailability of antibodies directed against the relevant rabbit proteins. There are many examples of situations in which steady-state mRNA levels are not representative of protein expression, so these results need to be interpreted very cautiously. Nevertheless, they do suggest novel targets for the development of therapies to treat cholestasis in critically ill patients. The primary focus of research and clinical application with respect to PN has been manipulation of the composition of the PN solution, as well as resumption of enteral feeding as quickly as possible. A very interesting component of this report is the conclusion that fasting is superior to PN in preserving bile excretory function. Clearly, recent subgroup analyses of the EPaNIC trial by the Leuven group support the notion of caloric restriction in the acute phase of critical illness: early (within 48 h) initiation of PN increased the amount of adipose tissue within the muscle compartments (13) and was associated with marked catabolism of the additional amino acids and a consecutive increase in both blood urea nitrogen and urinary nitrogen excretion (14), as compared with late (not before day 8) start. Nevertheless, this conclusion must be viewed very cautiously. First, early caloric restriction while maintaining (even insufficient) enteral nutrition does not equal complete starvation. Moreover, sepsis and burns are marked by a prolonged hypermetabolic state with increased glucose turnover and negative nitrogen balance. These derangements are associated with increased organ failure, impaired immunity, and increased mortality (15). In fact, one fifth of the patients studied in the EPaNIC trial had sepsis, and consequently, prolonged starvation of patients is not likely to receive widespread clinical

The problem of providing nutritional support for critically ill patients who could not tolerate enteral feeding is a long-standing one. For decades, the use of parenteral nutrition (PN) has been an essential means for providing nutritional support to patients unable to tolerate enteral nutrition (1). Nevertheless, PN also has its dark side. Since the mid-1970s, it has been recognized that long-term PN is associated with its own pathologies. The liver is a major site of PN-mediated organ dysfunction. This includes the development of fatty liver, as well as cholestasis [reviewed by Carter and Shulman (2)]. In the setting of sepsis or related systemic inflammation syndromes (burn, trauma, etc.), this issue is further complicated by the fact that sepsis and related conditions themselves lead to cholestasis (3). Today, 37 years later, the mechanisms leading to cholestasis are still not completely clear. Bile secretion is an active, energy-requiring process involving specific transporters on both the apical and basolateral membranes of the hepatocytes. As such, bile secretion depends on delivery of the secreted substances to the hepatocyte (i.e., blood flow), maintenance of adequate ATP levels in the hepatocytes, and expression of transporters on the appropriate membranes. Impaired blood flow leading to energetic deficiencies is a common event in most systemic inflammatory conditions and almost certainly makes some direct contribution to cholestasis. However, sepsis is also associated with downregulation of specific bile transporters (4). This scenario is further complicated by some reports of upregulation of some transporters ostensibly to compensate for the downregulation of others (5). Nevertheless, this failure of bile transport appears to be an important determinant of outcome. For example, Kortgen et al. (6) showed that while conventional markers failed to predict outcome, indocyanine green excretion [a marker of liver excretory function (7)] of less than 8% per minute showed high sensitivity and specificity for outcome prediction. The cellular mechanisms responsible for downregulation of bile transporters are not clearly understood, but certainly complex. Although cytokines such as interleukin 6 have been shown to be involved (8), this may be model specific. Recknagel et al. (9) have shown that whereas a lipopolysaccharide model produces greater cytokine response and oxidative stress compared with a septic peritonitis model, impaired bile secretion was less than that in the peritonitis model. Nitric oxide has also been implicated as a possible contributor to cholestasis in sepsis working via s-nitrosylation of transporters (10). Similarly, oxidative stress is a likely contributor (11). In this issue of 87

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SHOCK VOL. 41, NO. 1

acceptance for sepsis and/or burn injury. The absence of baseline values from fed control animals also makes interpretation of the article of Vanwijngaerden et al. (12) difficult. It is not clear whether fasting restores function to close to normal or just less severely dysfunctional. Likewise, because the study focused specifically on the liver, we do not know if there were improvements in function of other organs. These weaknesses notwithstanding, the report is provocative and offers insights into new ways to look at PN in critical illness. Even if fasting is not a viable clinical approach, the mechanistic insights gained from this study may lead to practical approaches. Clearly, much more study is needed to answer these questions. REFERENCES 1. Dudrick SJ, Wilmore DW, Vars HM, Rhoads JE: Long-term total parenteral nutrition with growth, development, and positive nitrogen balance. Surgery 64(1):134Y142, 1968. 2. Carter BA, Shulman RJ: Mechanisms of disease: update on the molecular etiology and fundamentals of parenteral nutrition associated cholestasis. Nat Clin Pract Gastroenterol Hepatol 4(5):277Y287, 2007. 3. Miller DJ, Keeton DG, Webber BL, Pathol FF, Saunders SJ: Jaundice in severe bacterial infection. Gastroenterology 71(1):94Y97, 1976. 4. Kim PK, Chen J, Andrejko KM, Deutschman CS: Intraabdominal sepsis downregulates transcription of sodium taurocholate cotransporter and multidrug resistance-associated protein in rats. Shock 14(2):176Y181, 2000. 5. Wauters J, Mesotten D, van Zwam K, van Pelt J, Thiessen S, Dieudonne´ AS, Vander Borght S, van den Berghe G, Wilmer A: The impact of resuscitated fecal peritonitis on the expression of the hepatic bile salt transporters in a porcine model. Shock 34(5):508Y516, 2010.

EDITORIAL COMMENTS 6. Kortgen A, Paxian M, Werth M, Recknagel P, Rauchfuss F, Lupp A, Krenn CG, Mu¨ller D, Claus RA, Reinhart K, et al.: Prospective assessment of hepatic function and mechanisms of dysfunction in the critically ill. Shock 32(4): 358Y365, 2009. 7. Stehr A, Ploner F, Traeger K, Theisen M, Zuelke C, Radermacher P, Matejovic M: Plasma disappearance of indocyanine green: a marker for excretory liver function? Intensive Care Med 31(12):1719Y1722, 2005. 8. Andrejko KM, Raj NR, Kim PK, Cereda M, Deutschman CS: IL-6 modulates sepsis-induced decreases in transcription of hepatic organic anion and bile acid transporters. Shock 29(4):490Y496, 2008. 9. Recknagel P, Gonnert FA, Halilbasic E, Gajda M, Jbeily N, Lupp A, Rubio I, Claus RA, Kortgen A, Trauner M, et al.: Mechanisms and functional consequences of liver failure substantially differ between endotoxaemia and faecal peritonitis in rats. Liver Int 33(2):283Y293, 2013. 10. Schonhoff CM, Ramasamy U, Anwer MS: Nitric oxideYmediated inhibition of taurocholate uptake involves S-nitrosylation of NTCP. Am J Physiol Gastrointest Liver Physiol 300(2):G364YG370, 2011. 11. Cai W, Wu J, Hong L, Xu Y, Tang Q, Shi C: Oxidative injury and hepatocyte apoptosis in total parenteral nutrition-associated liver dysfunction. J Pediatr Surg 41(10):1663Y1668, 2006. 12. Vanwijngaerden YM, Langouche L, Derde S, Liddle C, Coulter S, van den Berghe G, Mesotten D: Impact of parenteral nutrition versus fasting on hepatic bile acid production and transport in a rabbit model of prolonged critical illness. Shock 41:48Y54, 2013. 13. Casaer MP, Langouche L, Coudyzer W, Vanbeckevoort D, de Dobbelaer B, Gu¨iza FG, Wouters PJ, Mesotten D, van den Berghe G: Impact of early parenteral nutrition on muscle and adipose tissue compartments during critical illness. Crit Care Med 41(10):2298Y2309, 2013. 14. Gunst J, Vanhorebeek I, Casaer MP, Hermans G, Wouters PJ, Dubois J, Claes K, Schetz M, van den Berghe G: Impact of early parenteral nutrition on metabolism and kidney injury. J Am Soc Nephrol 24(6):995Y1005, 2013. 15. Williams FN, Branski LK, Jeschke MG, Herndon DN: What, how, and how much should patients with burns be fed? Surg Clin North Am 91(3):609Y629, 2011.

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Nutritional support in critically ill patients: enteral, parenteral, or not at all?

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