Editorials
REFERENCES 1. Frith D, Davenport R, Brohi K: Acute traumatic coagulopathy. Curr Opin Anaesthesiol 2012; 25:229-234 2. Hiippala ST, Myllylä GJ, Vahtera EM: Hemostatic factors and replacement of major blood loss with plasma-poor red cell concentrates. Anesth AnaIg 1995; 81:360-365 3. Grottke O, Braunschweig T, Henzler D, et al: Effects of different fibrinogen concentrations on blood loss and coagulation parameters in a pig model of coagulopathy with blunt liver injury. Crit Care 2010; 14:R62 4. Fries D, Krismer A, Klingler A, et al: Effect of fibrinogen on reversal of dilutional coagulopathy: A porcine model. Br J Anaesth 2005; 95:172-177 5. Rahe-Meyer N, Solomon C, Hanke A, et al: Effects of fibrinogen concentrate as first-line therapy during major aortic replacement surgery: A randomized, placebo-controlled trial. Anesthesiology 2013; 118:40-50 6. Karlsson M, Ternström L, Hyllner M, et al: Prophylactic fibrinogen infusion reduces bleeding after coronary artery bypass surgery. A prospective randomised pilot study. Thromb Haemost 2009; 102:137-144 7 Fenger-Eriksen C, Jensen TM, Kristensen BS, et al: Fibrinogen substitution improves whole blood clot firmness after dilution with hydroxyethyl starch in bleeding patients undergoing radical cystectomy: A
8.
9.
10.
11.
12.
13.
randomized, placebo-controlled clinical trial. J Thromb Haemost 2009; 7:795-802 Martini J, Cabrales P, Fries D, et al: Effects of Fibrinogen Concentrate After Shock/Resuscitation: A Comparison Between In Vivo Microvascular Clot Formation and Thromboelastómetry. Crit Care /Wed2013;41:e301-e308 Weber CF, Görlinger K, Meininger D, et al: Point-of-care testing: A prospective, randomized clinical trial of efficacy in coagulopathic cardiac surgery patients. Anesthesiology 2012; 117:531 -547 Honickel M, Rieg A, Rossaint R, et al: Prothrombin complex concentrate reduces blood loss and enhances thrombin generation in a pig model with blunt liver injury under severe hypothermia. Thromb Haemosi 2011; 106:724-733 Grottke O, Braunschweig T, Spronk HM, et al: Increasing concentrations of prothrombin complex concentrate induce disseminated intravascular coagulation in a pig model of coagulopathy with blunt liver injury. Blood 2011 ; 118:1943-1951 Rossaint R, Bouillon B, Cerny V, et al; Task Force for Advanced Bleeding Care in Trauma: Management of bleeding following major trauma: An updated European guideline. Crit Care 2010; 14:R52 Murakawa M, Okamura T, Kamura T, et al: Diversity of primary structures of the carboxy-terminal regions of mammalian fibrinogen A alphachains. Characterization of the partial nucleotide and deduced amino acid sequences in five mammalian species; rhesus monkey, pig, dog, mouse and Syrian hamster. Thromb Haemost 1993; 69:351-360
A Little Fat Every Day Keeps the Doctor Away' David J. van Westerloo, MD, PhD Hendrik J. Heimerhorst, MD Department of Intensive Care Medicine Leiden University Medical Centre Leiden, The Netherlands
T
he autonomie nervous system, and especially the vagus nerve, has been identified as a crucial mediator of the inflammatory response (1). In vivo studies have shown that electrical stimulation of the efferent vagus nerve inhibits pro-inflammatory cytokine release and prevents endotoxic shock (2, 3). The vagus nerve releases acetylcholine (Ach) through its nerve endings and Ach interacts with nicotinic Ach receptors of the alpha 7 subtype on mononuclear cells. Upon binding of Ach specific anti-inflammatory pathways are stimulated in these monocytes resulting in a decreased inflammatory response (4). This so-called cholinergic anti-inflammatory pathway can be stimulated by electrical or mechanical activation of the vagus nerve and also through the use of ligands for the alpha 7 subunit of the Ach receptor, and the use of such
*See also p. e361. Key Words: neuroimmunology; nutrition; vagus nerve The authors have disclosed that they do not have any potential conflicts of interest. • Copyright © 2013 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins
agents decreased the severity of experimental peritonitis and pancreatitis (5,6). In 2005, the group of Luyer et al (7) showed that another way to stimulate the cholinergic anti-inflammatory pathway is by the use of dietary fat. In this study, feeding animals a high-fat diet resulted in diminished release of interleukin 6 and tumor necrosis factor in an animal model of hemorrhagic shock. The authors further showed that this antiinflammatory phenotype was reversed when the vagus nerve was cut. Additionally, the immune-modulating effects of fat disappeared when either nicotinic Ach receptors or cholecystokinin receptors were blocked. Taken together adding fat to the diet of animals resulted in activation of the cholinergic antiinflammatory pathway and an anti-inflammatory phenotype. In this issue of Critical Care Medicine, de Haan et al (8) significantly expand on their previous data. They report that nutritional activation of the vagal anti-inflammatory reflex by the addition of dietary fat preserves tissue integrity and attenuates systemic inflammation in a rodent model of acute hemolysis. Although massive hemolysis, such as during malaria or sickle cell crisis, is a disease entity that is not all too frequently encountered in the ICU setting, milder forms or hemolysis is frequently seen mainly after patients have been subjected to an extracorporeal circulation. The hemolysis model used in this study resulted in free hemoglobin levels that are comparable to those seen after cardiopulmonary bypass of autoimmune hemolysis and is therefore of relevance to clinical practice. The authors describe several interesting findings. Eirst, they show that infusion of lysed erythrocytes results in an inflammatory response, multiple organ damage, and a decreased
DOI:10.1097/CCM.0b013e3182963e7c 2662
www.ccmjournal.org
November 2013 • Volume 41 • Number 11
Editorials
microcirculation specifically through impairment of the availability of nitric oxide. The authors postulated that this loss of nitric oxide and the resultant impairment of regional blood flow could potentially be compensated by stimulating the release of Ach through by the addition of dietary fat. Enterai lipid-rich nutrition indeed significantly abrogated inflammation as well as reduced organ damage, and in several lines of well-performed control and blocking experiments the authors convincingly show that the beneficial effects of fatty feeding are mediated through a cholecystokinin receptor 1 and nicotinic Ach receptor-dependent pathway. The report is interesting because of several reasons. First, the authors show that in a model that is totally dissimilar to previously used animal models in this field of research, the addition of dietary fat reduces inflammation and organ injury. Second, they also show that the microcirculation and regional blood flow to key organ systems can be enhanced by adding some fat to the food of animals. Whether this is a direct effect of fat-induced Ach release on the microcirculation or endothelium or an indirect result of a reduction in the inflammatory response remains to be elucidated, but clearly the effects of fat supplementation go far beyond the previously described effects on inflammation alone. This is a novel finding of great interest and of potential clinical significance. During critical illness, the stress response to injury results in hypermetabolism, loss of protein synthesis, and a catabolic state. Appropriate nutritional support should be giveni to counteract this preferably by feeding via the enterai route (9). In recent years, many groups have tried to develop additional supplements to standard nutrition with the goal to modulate the immune response and therewith improving patient outcome. Studies have been performed with formulas supplemented with arginine, glutamine, and fish oil or combinations of these, and an immune-modulating diet containing a formula supplemented with fish oil (omega 3 fatty acids) reduced infection rates, mortality, and length of stay in selected patient populations (10). The current report suggests that supplementation of fat in the nutritional support of our patients could not only activate an endogenous
Critical Care Medicine
anti-inflammatory pathway but also significantly enhance the microcirculation of key organs affected during critical illness. It is even tempting to speculate whether prophylactic feeding with adequate fat contents would benefit those patients who will undergo an intervention associated with hemolysis such as during major (elective) cardiothoracic surgery. It is conceivable that the detrimental effects of even low levels of hemolysis could be averted if a prophylactic fatty feeding regimen would be instituted before surgery. In those patients, this study suggests that it might not be the apple but rather a little fat every day that keeps the doctor away.
REFERENCES 1. Tracey KJ: understanding immunity requires more than immunology. Wai Immunol 2010; 11:561 -564 2. van Westerloo DJ, Giebelen IA, Meijers JC, et al: Vagus nerve stimulation inhibits activation of coagulation and fibrinolysis during endotoxemia in rats. J Thromb Haemost 2006; 4;1997-2002 3. Tracey KJ: The inflammatory reflex. Nature 2002; 420;853-859 4. de Jonge WJ, van der Zanden EP, The FO, et al: Stimulation of the vagus nerve attenuates macrophage activation by activating the Jak2STAT3 signaling pathway. Nat Immunol 2005; 6;844-851 5. van Westerloo DJ, Giebelen IA, Florquin S, et al: The oholinergic antiinflammatory pathway regulates the host response during septic peritonitis. J Infect Dis 2005; 191:2138-2148 6. van Westerloo DJ, Giebelen IA, Florquin S, et al: The vagus nerve and nicotinic receptors modulate experimental pancreatitis severity in mice. Gastroenterology 2006; 130;1822-1830 7 Luyer MD, Grève JW, Hadfoune M, et al: Nutritional stimulation of oholecystokinin receptors inhibits inflammation via the vagus nerve. J Exp Med 2005; 202:1023-1029 8. de Haan JJ, Windsant IV, Lubbers T, et al: Prevention of HemolysisInduced Organ Damage by Nutritional Activation of the Vagal AntiInfiammatory Reflex. Orit Oare Med 2013; 41 :e361 -e367 9. Martindale RG, McClave SA, Vanek VW, et al; American College of Critical Care Medicine; A.S.P.E.N. Board of Directors: Guidelines for the provision and assessment of nutrition support therapy in the adult critically ill patient: Society of Critical Care Medicine and American Society for Parenteral and Enterai Nutrition: Executive Summary. Orit Care Med 2009; 37:1757-1761 10. Beale RJ, Sherry T, Lei K, et al: Early enterai supplementation with key pharmaconutrients improves Sequential Organ Failure Assessment score in critically ill patients with sepsis: Outcome of a randomized, controlled, double-blind trial. Crit Care Med 2008; 36:131-144
www.ccmjournal.org
2663
Copyright of Critical Care Medicine is the property of Lippincott Williams & Wilkins and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
REFERENCES 1. Frith D, Davenport R, Brohi K: Acute traumatic coagulopathy. Curr Opin Anaesthesiol 2012; 25:229-234 2. Hiippala ST, Myllylä GJ, Vahtera EM: Hemostatic factors and replacement of major blood loss with plasma-poor red cell concentrates. Anesth AnaIg 1995; 81:360-365 3. Grottke O, Braunschweig T, Henzler D, et al: Effects of different fibrinogen concentrations on blood loss and coagulation parameters in a pig model of coagulopathy with blunt liver injury. Crit Care 2010; 14:R62 4. Fries D, Krismer A, Klingler A, et al: Effect of fibrinogen on reversal of dilutional coagulopathy: A porcine model. Br J Anaesth 2005; 95:172-177 5. Rahe-Meyer N, Solomon C, Hanke A, et al: Effects of fibrinogen concentrate as first-line therapy during major aortic replacement surgery: A randomized, placebo-controlled trial. Anesthesiology 2013; 118:40-50 6. Karlsson M, Ternström L, Hyllner M, et al: Prophylactic fibrinogen infusion reduces bleeding after coronary artery bypass surgery. A prospective randomised pilot study. Thromb Haemost 2009; 102:137-144 7 Fenger-Eriksen C, Jensen TM, Kristensen BS, et al: Fibrinogen substitution improves whole blood clot firmness after dilution with hydroxyethyl starch in bleeding patients undergoing radical cystectomy: A
8.
9.
10.
11.
12.
13.
randomized, placebo-controlled clinical trial. J Thromb Haemost 2009; 7:795-802 Martini J, Cabrales P, Fries D, et al: Effects of Fibrinogen Concentrate After Shock/Resuscitation: A Comparison Between In Vivo Microvascular Clot Formation and Thromboelastómetry. Crit Care /Wed2013;41:e301-e308 Weber CF, Görlinger K, Meininger D, et al: Point-of-care testing: A prospective, randomized clinical trial of efficacy in coagulopathic cardiac surgery patients. Anesthesiology 2012; 117:531 -547 Honickel M, Rieg A, Rossaint R, et al: Prothrombin complex concentrate reduces blood loss and enhances thrombin generation in a pig model with blunt liver injury under severe hypothermia. Thromb Haemosi 2011; 106:724-733 Grottke O, Braunschweig T, Spronk HM, et al: Increasing concentrations of prothrombin complex concentrate induce disseminated intravascular coagulation in a pig model of coagulopathy with blunt liver injury. Blood 2011 ; 118:1943-1951 Rossaint R, Bouillon B, Cerny V, et al; Task Force for Advanced Bleeding Care in Trauma: Management of bleeding following major trauma: An updated European guideline. Crit Care 2010; 14:R52 Murakawa M, Okamura T, Kamura T, et al: Diversity of primary structures of the carboxy-terminal regions of mammalian fibrinogen A alphachains. Characterization of the partial nucleotide and deduced amino acid sequences in five mammalian species; rhesus monkey, pig, dog, mouse and Syrian hamster. Thromb Haemost 1993; 69:351-360
A Little Fat Every Day Keeps the Doctor Away' David J. van Westerloo, MD, PhD Hendrik J. Heimerhorst, MD Department of Intensive Care Medicine Leiden University Medical Centre Leiden, The Netherlands
T
he autonomie nervous system, and especially the vagus nerve, has been identified as a crucial mediator of the inflammatory response (1). In vivo studies have shown that electrical stimulation of the efferent vagus nerve inhibits pro-inflammatory cytokine release and prevents endotoxic shock (2, 3). The vagus nerve releases acetylcholine (Ach) through its nerve endings and Ach interacts with nicotinic Ach receptors of the alpha 7 subtype on mononuclear cells. Upon binding of Ach specific anti-inflammatory pathways are stimulated in these monocytes resulting in a decreased inflammatory response (4). This so-called cholinergic anti-inflammatory pathway can be stimulated by electrical or mechanical activation of the vagus nerve and also through the use of ligands for the alpha 7 subunit of the Ach receptor, and the use of such
*See also p. e361. Key Words: neuroimmunology; nutrition; vagus nerve The authors have disclosed that they do not have any potential conflicts of interest. • Copyright © 2013 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins
agents decreased the severity of experimental peritonitis and pancreatitis (5,6). In 2005, the group of Luyer et al (7) showed that another way to stimulate the cholinergic anti-inflammatory pathway is by the use of dietary fat. In this study, feeding animals a high-fat diet resulted in diminished release of interleukin 6 and tumor necrosis factor in an animal model of hemorrhagic shock. The authors further showed that this antiinflammatory phenotype was reversed when the vagus nerve was cut. Additionally, the immune-modulating effects of fat disappeared when either nicotinic Ach receptors or cholecystokinin receptors were blocked. Taken together adding fat to the diet of animals resulted in activation of the cholinergic antiinflammatory pathway and an anti-inflammatory phenotype. In this issue of Critical Care Medicine, de Haan et al (8) significantly expand on their previous data. They report that nutritional activation of the vagal anti-inflammatory reflex by the addition of dietary fat preserves tissue integrity and attenuates systemic inflammation in a rodent model of acute hemolysis. Although massive hemolysis, such as during malaria or sickle cell crisis, is a disease entity that is not all too frequently encountered in the ICU setting, milder forms or hemolysis is frequently seen mainly after patients have been subjected to an extracorporeal circulation. The hemolysis model used in this study resulted in free hemoglobin levels that are comparable to those seen after cardiopulmonary bypass of autoimmune hemolysis and is therefore of relevance to clinical practice. The authors describe several interesting findings. Eirst, they show that infusion of lysed erythrocytes results in an inflammatory response, multiple organ damage, and a decreased
DOI:10.1097/CCM.0b013e3182963e7c 2662
www.ccmjournal.org
November 2013 • Volume 41 • Number 11
Editorials
microcirculation specifically through impairment of the availability of nitric oxide. The authors postulated that this loss of nitric oxide and the resultant impairment of regional blood flow could potentially be compensated by stimulating the release of Ach through by the addition of dietary fat. Enterai lipid-rich nutrition indeed significantly abrogated inflammation as well as reduced organ damage, and in several lines of well-performed control and blocking experiments the authors convincingly show that the beneficial effects of fatty feeding are mediated through a cholecystokinin receptor 1 and nicotinic Ach receptor-dependent pathway. The report is interesting because of several reasons. First, the authors show that in a model that is totally dissimilar to previously used animal models in this field of research, the addition of dietary fat reduces inflammation and organ injury. Second, they also show that the microcirculation and regional blood flow to key organ systems can be enhanced by adding some fat to the food of animals. Whether this is a direct effect of fat-induced Ach release on the microcirculation or endothelium or an indirect result of a reduction in the inflammatory response remains to be elucidated, but clearly the effects of fat supplementation go far beyond the previously described effects on inflammation alone. This is a novel finding of great interest and of potential clinical significance. During critical illness, the stress response to injury results in hypermetabolism, loss of protein synthesis, and a catabolic state. Appropriate nutritional support should be giveni to counteract this preferably by feeding via the enterai route (9). In recent years, many groups have tried to develop additional supplements to standard nutrition with the goal to modulate the immune response and therewith improving patient outcome. Studies have been performed with formulas supplemented with arginine, glutamine, and fish oil or combinations of these, and an immune-modulating diet containing a formula supplemented with fish oil (omega 3 fatty acids) reduced infection rates, mortality, and length of stay in selected patient populations (10). The current report suggests that supplementation of fat in the nutritional support of our patients could not only activate an endogenous
Critical Care Medicine
anti-inflammatory pathway but also significantly enhance the microcirculation of key organs affected during critical illness. It is even tempting to speculate whether prophylactic feeding with adequate fat contents would benefit those patients who will undergo an intervention associated with hemolysis such as during major (elective) cardiothoracic surgery. It is conceivable that the detrimental effects of even low levels of hemolysis could be averted if a prophylactic fatty feeding regimen would be instituted before surgery. In those patients, this study suggests that it might not be the apple but rather a little fat every day that keeps the doctor away.
REFERENCES 1. Tracey KJ: understanding immunity requires more than immunology. Wai Immunol 2010; 11:561 -564 2. van Westerloo DJ, Giebelen IA, Meijers JC, et al: Vagus nerve stimulation inhibits activation of coagulation and fibrinolysis during endotoxemia in rats. J Thromb Haemost 2006; 4;1997-2002 3. Tracey KJ: The inflammatory reflex. Nature 2002; 420;853-859 4. de Jonge WJ, van der Zanden EP, The FO, et al: Stimulation of the vagus nerve attenuates macrophage activation by activating the Jak2STAT3 signaling pathway. Nat Immunol 2005; 6;844-851 5. van Westerloo DJ, Giebelen IA, Florquin S, et al: The oholinergic antiinflammatory pathway regulates the host response during septic peritonitis. J Infect Dis 2005; 191:2138-2148 6. van Westerloo DJ, Giebelen IA, Florquin S, et al: The vagus nerve and nicotinic receptors modulate experimental pancreatitis severity in mice. Gastroenterology 2006; 130;1822-1830 7 Luyer MD, Grève JW, Hadfoune M, et al: Nutritional stimulation of oholecystokinin receptors inhibits inflammation via the vagus nerve. J Exp Med 2005; 202:1023-1029 8. de Haan JJ, Windsant IV, Lubbers T, et al: Prevention of HemolysisInduced Organ Damage by Nutritional Activation of the Vagal AntiInfiammatory Reflex. Orit Oare Med 2013; 41 :e361 -e367 9. Martindale RG, McClave SA, Vanek VW, et al; American College of Critical Care Medicine; A.S.P.E.N. Board of Directors: Guidelines for the provision and assessment of nutrition support therapy in the adult critically ill patient: Society of Critical Care Medicine and American Society for Parenteral and Enterai Nutrition: Executive Summary. Orit Care Med 2009; 37:1757-1761 10. Beale RJ, Sherry T, Lei K, et al: Early enterai supplementation with key pharmaconutrients improves Sequential Organ Failure Assessment score in critically ill patients with sepsis: Outcome of a randomized, controlled, double-blind trial. Crit Care Med 2008; 36:131-144
www.ccmjournal.org
2663
Copyright of Critical Care Medicine is the property of Lippincott Williams & Wilkins and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
![[An avocado a day keeps the doctor away].](/assets/img/hold.png)
