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adenosine diphosphate and thrombin receptor activating peptide, although modest, differentiated between survivors and nonsurvivors (6). These preliminary studies demonstrating platelet inhibition were further reinforced byfindingsfrom field blood samples that underwent TEG platelet mapping, which demonstrated significant ADP inhibition if 86.1% (interquartile range [IQR], 38.6-97.7%) versus 4.2% (IQR, 0-182.2%) in healthy controls (7). Lastly, decreased admission platelet aggregation to arachidonic acid and collagen were sensitive and independent predictors of both early and late mortality postinjury (8). More prospective studies are needed to define platelet function following injury. 5) There is still heterogeneity with regard to platelet dosing and standards have not been evaluated which should take into account either the patient weight or surface area. 6) The authors have included statements with regard to other plasma-based therapies that drastically affect coagulation, namely, the use of cryoprecipitate which is the optimal source for b = fibrinogen and factor XIII. The use of cryoprecipitate and specific fibrinogen and factor XIII concentrates needs to be considered in any RCTs on platelet dosing and liberal versus conservative platelet:RBC transfusions. In short. Hallet et al have provided a detailed systematic review on the use of higher platelet:RBC transfusion ratios in the acute phase of trauma resuscitation with appropriate guidelines

to be followed in the formulation of needed RCTs on this subject. The initiation of such RCTs is sorely needed as is extramural funding to complete these very important studies.

REFERENCES 1. Hallet J, Lauzier F, Mailloux G, et al: The Use of Higher Platelet:RBG Transfusion Ratio in the Acute Phase of Trauma Resuscitation: A Systematic Review. Crit Care Med 2013; 41:2800-2811 2. Phan HH, Wisner DH: Should we increase the ratio of plasma/platelets to red blood cells in massive transfusion: What is the evidence? Vox Sang 201 0; 98(3, Part 2):395-402 3. Silliman GG, Moore EE, Le T, et al: Gne to one to what? Transfusion 2010; 50:2066-2067 4. Brown LM, Gall MS, Margaret Knudson M, et al; Trauma Gutcomes Group: A normal platelet count may not be enough: The impact of admission platelet count on mortality and transfusion in severely injured trauma patients. J Trauma 2011 ; 71 :S337-S342 5. Jacoby RG, Gwings JT, Holmes J, et al: Platelet activation and function after trauma. J Trauma 2001 ; 51:639-647 6. Solomon G, Traintinger S, Ziegler B, et al: Platelet function following trauma. A multiple electrode aggregometry study. Thromb Haemost 2011; 106:322-330 7. Wohlauer MV, Moore EE, Thomas S, et al: Early platelet dysfunction: An unrecognized role in the acute coaguiopathy of trauma. J Am Coii Surg 20^2; 214:739-746 8. Kutcher ME, Redick BJ, McGreery RG, et al: Gharacterization of platelet dysfunction after trauma. J Trauma Acute Care Surg 2012; 73:13-19

Is the Time Right to Fight Global Warming in Sepsis?* Sven Laudi, MD Department of Anesthesioiogy and Intensive Care Medicine University of Leipzig Medical Faculty Leipzig, Germany Wolfgang Steudel, MD Anesthesioiogy Services Lowell General Hospital Lowell, MA epsis and septic shock are characterized by severe organ and s circulatory dysfunction due to arterial and venous vasodi-.,„. lation. Massive production of the vasodilator nitric oxide. 'Seealso p. e401. Key Words: cooling; hyperthermia; hypothermia; oxygen consumption; sepsis This work was done at the author's institutions. The authors have disclosed that they do not have any potential conflicts of interest. Gopyright © 2013 by the Society of Gritical Gare Medicine and Lippincott Williams & Wilkins DOI:10.1097/CCM.0b013e31829cb357

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produced by the inducible nitric oxide synthase, overwhelms most endogenous vasoregulatory systems. This leads to shunting and hypoperfusion. Clotting cascades are activated by inñammatory mediators, and blood clots further worsen vascular perfusion. Although cardiac output in patients with sepsis is increased, hypotension and the lack of an intact microcirculation lead to a cellular nutrient and oxygen deprivation. Therapies such as nitric oxide antagonists, heparin, antithrombin, and activated protein C with the goal to improve the microcirculation in sepsis have been tested but were clinically not successful (1). If adequate tissue oxygen delivery has been established by reversing the shock state, mortality of septic shock can be lowered by more than 30% (2). Lowering oxygen demand of cells by hypothermia might be advantageous if perfusion (supply) cannot be established adequately. More than half a century ago, in 1961, Blair et al (3) reported in a case series of 33 patients that therapeutic hypothermia (32°C) lowered the expected mortality in severe septic shock. They hypothesized that hypothermia decreased oxygen consumption by one third, and hypothermia induced bradycardia (and vasoconstriction), and they concluded this to be responsible for the reduction in mortality. Over the years, the role of thermorégulation in sepsis has been studied in various settings. Spontaneous hypothermia in sepsis has been found to www.ccmjournal.org

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consumption and improved hemodynamics induced by dialysisinduced normothermia. The first randomized trial yielding normothermia was promising, showing a survival advantage when patients were cooled in the first 48 hours of septic shock (14). However, is this knowledge sufficient to implement active cooling into treatment protocols of patients with sepsis? Not yet, we believe. Given the history of initially promising but then often ineffective or even harmful therapies in sepsis, premature conclusions should not be made. There are still confiicting animal data showing deleterious effects of mild hypothermia in septic rats (15). It is still poorly understood if just prevention of In this issue of Critical Care Medicine, Schwarzl et al ( 11 ) reporthyperthermia, and/or treatment of high fever, is enough, or the effects of mild hypothermia (33°C) induced by endovascular (more sophisticated and invasive) induction of hypothermia cooling of septic pigs. Sepsis was provoked by an IV infusion of (with the subsequent need of rewarming) is needed. The best Escherichia coli lipopolysaccharide (LPS), and cardiopulmonary, cooling devices, the optimal cooling time, inclusion/exclusion hemodynamic, and gas exchange measurements were taken over criteria, and the mode of rewarming have not even been prelimthe course of 8 hours after LPS challenge. They report an increase inarily studied. The time is right to fight global warming, but we in oxygen consumption by 22% (at 38°C = normothermia) in need to be well prepared. Strong experimental and convincing sepsis which could be lowered by 37% if pigs were cooled to 33°C. clinical data should be present before we turn the cooler on. Cardiac output changes had a biphasic pattern: within the first 2 hours, hypothermie pigs had a lower cardiac output REFERENCES than their normothermic counterparts; again, at the end of the 1. Dellinger RP, Levy MM, Rhodes A, et al; Surviving Sepsis Campaign experiments (8 hr), cardiac output of the hypothermie pigs was Guidelines Committee including the Pédiatrie Subgroup: Surviving lower. Both cold and warm septic pigs were profoundly hyposepsis campaign: International guidelines for management of severe tensive but not significantly different. Sepsis induced tachysepsis and septic shock: 201 2. Crit Care Med 2013; 41:580-637 cardia at normal body temperature. This started at a baseline 2. Rivers E, Nguyen B, Havstad S, et al; Early Goal-Directed Therapy Collaborative Group: Early goal-directed therapy in the treatment of average heart rate of -100 beats per minute (bpm) before LPS severe sepsis and septic shock. N Engi J Med 2001 ; 345:1368-1377 and went up to ~ 130 bpm after 8 hours. Cooled pigs dropped 3. Blair E, Buxton RW, Cowley RA, et al: The use of hypothermia in septheir heart rats after 2 hours from 100 bpm to ~ 70-80 bpm tic shock. JAMA 1961 ; 178;916-919 and remained there. Schwarzl et al (11) followed up and 4. Clemmer TP, Fisher CJ Jr, Bone RC, et al: Hypothermia in the sepanalyzed this heart rate response using heart rate variability sis syndrome and clinical outcome. The Methylprednisolone Severe Sepsis Study Group. Crit Care Med 1992; 20:1395-1401 analysis. This technique supposedly helps "to mathematically 5. Peres Bota D, Lopes Ferreira F, Mélot C, et al: Body temperature dissect" the effect of the autonomous nervous system on heart alterations in the critically ill. intensive Care Med 2004; 30:811-816 rate. Diminished norepinephrine levels and a stable low heart 6. de Pont AC: Does cold-bloodedness protect against sepsis? Crit rate in hypothermia go hand in hand with the theory of supCare Med 2006; 34:2692-2693 pression of the sympathetic (low-frequency band) and stimu7. Gilston A: Induced hypothermia for sepsis? Crit Care Med 1993; lation of the parasympathetic (high-frequency band) nervous 21:1247-1248 system. It is reassuring that in vivo left ventricular contractility 8. LHer E, Amerand A, Vettier A, et al: Effects of mild induced hypothermia during experimental sepsis. Crit Care Med 2006; 34:2621-2623 and in vitro left ventricular muscle strip contractility were not 9. Chang YT, Wann SR, Tsai JS, et al: The role of autonomie nervous impaired by hypothermia and that despite the depressed carsystem function in hypothermia-mediated sepsis protection. Am J diac output (function) during profound hypotension, no aciEmerg Med 2013; 31:375-380 dosis occurred. This may be indeed due to the overall reduced 10. Rim KP, Kim K, Jo YH, et al: Effect of therapeutic hypothermia oxygen need and an advantageous oxygen balance. Of some according to severity of sepsis in a septic rat model. Cytokine 201 2; 60:755-761 concern is that the tumor necrosis factor -a and interleukin-6 11. Schwarzl M, Seiler S, Wallner M, et al: Mild Hypothermia Attenuates levels in hypothermia exceeded the ones in normothermia. Circulatory and Pulmonary Dysfunction During Experimental Schwarzl et al ( 11 ) were not really able to explain this finding. Endotoxemia. Crit Care Med 2013; 41 :e401 -e410

be associated with increased mortality (4). Fever in the severely ill patient may cause harm by increasing metabolic demands (5, 6), and high fever (> 40°C) has been linked to increased mortality (7). Several animal studies suggest a survival advantage by active cooling in sepsis. Septic rats after cecal ligation and perforation had reduced mortality when cooled to 32°C compared with normothermic or febrile rats (8). Chang et al (9) reported decreased mortality in hypothermie (34°C), immunosuppressed, and bacteremic rats compared with a 37°C group. Rim et al (10) were able to demonstrate that cooling to 30-32°C increased survival of severely septic rats.

Based on the study by Schwarzl et al (11), and historical data, it appears safe to conclude that therapeutic cooling lowers increased oxygen demand induced by sepsis-associated hyperthermia, and as far as we can tell, it does not damage the heart. Furthermore, it seems that h'ypothermia reduces mortality in, at least, some animal models of septic shock. In addition, there is clinical evidence that suggests that preventing hyperthermia in sepsis may be of benefit. Vular and Slutsky (12) studied septic patients with acute respiratory distress syndrome and report reduced mortality in the hypothermia group. Rokyta et al (13) demonstrated decreased oxygen 2836

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12. Villar J, Slutsky AS: Effects of induced hypothermia in patients v\iith septic adult respiratory distress syndrome. Resuscitation 1993; 26:183-192 13. Rokyta R Jr, Matejovic M, Krouzecky A, et al: Effects of continuous venovenous haemofiltration-induced cooling on global haemodynamics, splanchnic oxygen and energy balance in critically ill patients. Nephroi Diai Transpiant 2004; 19:623-630 14. Schortgen F, Clabault K, Katsahian S, et al: Fever control using external cooling in septic shock: A randomized controlled trial. Am J Respir Crit Care Med 2012; 185;1088-1095 15. Torossian A, Ruehlmann S, Middeke M, et al: Deleterious effects of mild hypothermia in septic rats are ameliorated by granulocyte colonystimulating factor. Anesthesioiogy 2003; 99:1087-1 092 December 2013 »Volume 41 • Number 1 2

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Is the time right to fight global warming in sepsis?

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