rials Towards changing the definition of the acute respiratory distress syndrome: One step forward* aving a common and reli- able definition for the acute respiratory distress syn- drome (ARDS) or acute lung injury is very important for the manage- ‘ment of this severe respiratory complica- tion. Ata full stage, this syndrome corre- sponds to diffuse alveolar damage, but lung pathology is usually not available except at autopsy (1). There is no vali dated biomarker, even in bronchoalveolar lavage fluid, which could improve our ability for an early recognition of in- creased lung permeability. An accurate definition is required for clinical trials or epidemiologic studies, with sufficient specificity to reduce the noise-to-signal ratio and good sensitivity to avoid miss- ing patients. An accurate definition can also greatly help clinicians to define which patients may benefit from precise ventilatory strategies, diagnostic proce- dures, or drug therapy. Our current def- inition, coming from a consensus (2), hhas been extremely useful, especially for clinical trials. It combines simple parameters that are available at the bedside and a clinical assessment of the patient. The cornerstone of this defini- tion is the Pa0,/Fio, ratio. This ratio has become the most popular way to quantify oxygenation defects. Several factors greatly influence the value of the Pa0,/Fi0, ratio, indepen- dently from lung pathology, but are often ignored at the bedside. Mixed venous ox- ygenation is a crucial one and is influ- enced by cardiac output. For a given lung status, varying cardiac output and arteri- al-to-venous difference in oxygen content heavily influences the Pa0,/Fi0, ratio (3). *See also p. 2025. Key Words: acute lng injury, acute respiratory distress syndrome; oxygenation; positive end iar pressure; ventlton The autor as not disclosed any potential con fl of intrest. Copyright © 2011 by the Society of citcal Care Medicine and Uppncot Wiliams & Wikins Dok: 10.1097/0C¥.0b013e3182266078 Crit Care Med 2011 Vol. 38, No. 9 For this reason, it was advocated in the 1980s to calculate shunt using the Berg- ‘ren equation instead of relying on Pa0, and Fog alone (4). The decline in the use ‘of the pulmonary artery catheter, neces- sary to get mixed venous blood, is one of, the reasons why this approach is not used anymore. A second determinant is the pressure delivered by the ventilator. For this reason, pediatricians have intro- duced mean airway pressure in their as- sessment of oxygenation and calculation ‘of the oxygenation index. Although this approach makes good sense, a clear clin- ical advantage over the Pa0,/Fi0, ratio alone has not been clearly demonstrated. ‘Along the same line, several investigators have argued thatthe level of positive end- expiratory pressure (PEEP), a major de- terminant of oxygenation, needed to be taken into account, either by introducing the PEEP level into an oxygenation equ- ation or by imposing a fixed level of PEEP to make calculations (5,6). Itis possible, however, that the vast majority of pa- tients in whom the Pad,/Fidg ratio is cal- culated are already on a “moderate,” av- erage level of PEEP. How frequently adding a requirement for a given PEEP level would change the definition has not been clearly evaluated. This was the first ‘question addressed in the work done by Britos and colleagues (7) in this issue of Gritical Care Medicine, who explored the influence of the initial PEEP level on mortality across different ranges of Pat! Fic». They used the data collected during conduct of the ARDS Network trials, ‘when patients were enrolled in clinical trials, making a total of 2,312 patients with acute lung injury/ARDS available. ‘They tested if, for a given range of Paoy/ Fio, values, mortality was different ac- cording to the PEEP level, which would suggest that patients with very different disease severity were enrolled under the ‘same oxygenation criterion, It is remark- able, however, to see in the results of Britos etal, how consistent the mortality is between a PEEP at 5 cm H,0 or below and a PEEP at 11 em H,0 or above. This suiggests that adding PEEP to the defini- tion would not help in better character- izing the disease severity of the patients. Several reasons may explain this. First, ‘when clinicians increase PEEP they prob- ably also often increase Fios, which by itself decreases the Pa0,/Fing ratio. Sec- ond, clinicians may vary the PEEP set- tings over a relatively narrow range. In- deed, in the ARDS Network hospitals, very few patients (13%) were ventilated vith PEEP levels below 5 cm H,0. At the opposite, only 11% of patients had PEEP at 15 cm HzO or higher before enroll ment in the trials. Therefore, their results may not apply to ICUs where the PEEP level is frequently under 5 cm H,0 or above 14 cm H,0 to calculate the initial Pao2/Fi0» ratio. A last issue is the effect of the Flo, level on the Paog/Fiog ratio itself. This is often ignored because it sounds as coun- terintuitive. Clinicians may think that normalizing Pad, to Fid, is possible be- cause a linear relationship exists between the two. This is not the case, however, and several experimental or clinical stud- ies have clearly shown that there is a nonlinear relationship between Pao, and ios, and consequently between Pa02 and Pa0,/Fi0, (8-10). The shape of the oxyhe- moglobin dissociation curve describing the relationship of the percentage of he- ‘moglobin saturation to the blood Po. and the equation for human blood oxygen dis- sociation explains this relationship (11). This relationship is difficult to predict because it depends on the cardiac output, the arterial-to-venous difference in oxy- gen content, and the shunt fraction (8). In patients with a relatively high shunt, the curve will often display a U shape, with an increase in the Pa02/Fi0, ratio ‘when Fog is raised from around 50% or 60% up to 100%. This means that a given Pa0,/Fi0, value measured in a patient at Fio, 1.0 will reflect a more severe impair- ment of oxygenation than in another pa- tient with the same Pa0,/Fing ratio at a Fio2 of only 50%, It also means that for a given patient, changing Fio, modifies the a7Pa0,/F'0, value. As an illustration, a study performed in 14 patients with acute lung injury or ARDS showed that decreasing Fio, from 1.0 to 0.6 over 15 mins led to a reduction of the Pao,/Fi0, ratio from a ‘median of 223 mm Hg toa median of 158 ‘mm Hg at the same high PEEP level; the same change was reproduced from 171 to 115 at a lower PEEP level (12). Therefore, taking into account the Fids in the defini- tion may help to better identify the disease severity of the patients. This is what was found in a second part of the analysis by Britos et al (7). Contrasting with the lack of influence of PEEP, they found that the ‘mortality rate significantly increased at cach range of Pao,/Fi0y values for Fi vary- ing from 0.50 or less to 0.70 or more. ‘These results are important because they confirm physiologic observations on a large scale and may need to be taken into account for a revision of the current definition of ARDS. Although the PEEP level was not found to influence the re- sults, calculating the Pao,/Fi0» ratio for a PEEP level of at least 5 cm H,0 and no ‘more than 15 cm H,0 may be reasonable. big step forward can be to introduce the Burn fluid resuscitation: Let the autopilot do efore the recognition of the magnitude of fluid shifts and the massive fluid require- ‘ments of severe burn patients, hypovolemia, hypoperfusion, and organ failure was the leading cause of death. Investigations in the 1960s led to the widely accepted Parkland formula (1). Despite controversy and debate over amounts, algorithms, and fluid mixes, the Parkland formula is still the most widely used (2). From 1970 to 2000, burn. fluid resuscitation science was dominated by the fear of hypovolemia, hypoperfu- sion, shock, and organ damage. Fluids hhave been generously administered, far *See also p. 2031. Key Words: bum; clinical decision support sy tems; ical care automation; tid ree, fu ress ciation; oper-lop system The autor as not disclosed any potent con fl of intrest. Copyright © 2011 by the Society of citcal Care Medicine and ppineat Wiliams & Wikins Dok: 10.1097/0c¥.obot3e3182110300 2178 level of Fo, in the definition of ARDS, which could help to better stratify the disease severity of patients Laurent J. Brochard, MD Department of Intensive Care Geneva University Hospital University of Geneva Geneva, Switzerland REFERENCES 1. Bstehan A, Perinde-Segoviano P, ruts Vvar F, et ak Comparison of clinical criteria forthe atu respiratory distress syndrome with autopsy findings Arn tern Med 200; 14140-—145, 2. Bernard GR, Artigas A, Brigham KL, et a: ‘The American-Buropean Consensus Canfer- ence on ARDS, Definitions, mechanisms, rel fant outcomes, and clinical tral coordina: Lion. Am J Respir Crit Care Med 108; 149: sis—s24 Lemaire F,Teisssire B, Harf A: [Assessment fof acute respiratory failure: Shunt versus al- veolar arterial exygen diference|- re Ar Jinestls Reanim 1982; 150-64 4. Berggren Si The oxygen deficit of arterial blood caused by non ventilating pars of the lung. Aeta Physiol Scand 1942; 111-92 Villar J, Pérez-Méndez L, Lopez J, et al: An carly PEEP/FIO2 trial identifies different de- frees of lung injury in patients with acute beyond the original recommendations. In 2000, the Seattle team showed that 58% of the patients received more fluid than predicted (3). A similar observational study from Toronto (4) showed that pa- tients received on average 6.7 mL/kg burn surface area (instead ofthe original 4 mL/kg/¥), and 84% of the patients received more than predicted compared to 12% in the original study (1). Sadly, too much fluid, a phenomenon called fluid creep, can lead to "Michelin Man" patients and organ failure (5, 6). Awareness of the side effects ‘of fluid over-resuscitation has increased cover the last decade. The most significant effect of fluid over-resuscitation in burn patients is edema of the stasis area sur- rounding the deeper burned coagulation area, This leads to necrosis of just viable tissue yielding to a secondary deepening and extension of the burn area. Abdominal ‘compartment syndrome, frequent in over- resuscitation trauma (7), is a classic prob- lem in massive burns (8). In burn patients, decreased urine output is often used to respiratory distress syndrome. Am J Respir Crit Care Med 2007 176-795-804 6. Villa J, Pérez-MéndezL, Kacmarek RM: Cue rent definitions of acute lung injury and the acute respiratory distress syndrome do not reflect their true severity and outcome, tensive Care Med 1009; 25:130-95 7 Britor M, Smoot E, Lit KD, etal: The value of positive end-expiratory pressure and Finy criteria in the definition ofthe acute respi ratory distress syndrome. Crit Care Med 20; 36:3025-030 8. Aboah J, Louis B, Jonson B, et al: Relation between Pa02/P102 ratio and F ematical description, fens 2006; 3214041497 8. Govada MS, Klocke RA: Variabiliy of indices syndrome. Crit Care Med 1007; 25:81-45 10, Whiteley JP, Gavaghan DJ, Hahn CE: Vari tion of venous admisture, SP6 shunt, Pa02, and the PaO2/PIO2 ratio with FIO Br J Anaesth 2002; 8871-778 11. Severinghaus JW: Simple, accurate equa tions for human blood 02 dissociation com- ulations. J App! Physiol 1970; 46:590~602 12 Aboab J Jonson B, Kouatchet A, et al: fect. of inspired oxygen fraction on alveolar dere cruitment in acute respiratory distress syn rome, Intensive Care Med 2006; ¥2: 1979-1986, it!* dictate more fluids, but may also reflect cver-resuscitation and the onset of abdom- inal compartment syndrome (9). Despite awareness of the problem (10), the pendu- lum is still above Baxter’s original recom- ‘mendations (11). ‘The fine balance between too little or too much fluid is hard to maintain and requires clinicians with extensive burn experience. In this context, the paper in is issue of Critical Care Medicine by Salinas and colleagues (12) is very wel- come. They showed that using an algo- rithm programmed in Java they were able to suggest the right amount of fluid to maintain an adequate urine output with- out polyuria while limiting hypoperfu- sion and fluid creep in burn patients. The same investigators previously published a full closed-loop system in experimental sheep burn (13). The present paper is an interesting application, but is not yet a full closed-loop system. The system gives the clinician advice, which can be followed or ignored (Fig. 1) Crt Care Med 2011 Vol. 38, No. 9‘A Open loop system ||P Ciinician Uf tse foce owe me ones Ssene soapstone f= cine a ‘Seppor <_—— SS Ue ut B Closed loop system =a, 7S == ‘ine ut C Integrated system Matte opts ‘cyst Cotas Sezaton computer as owas and computer D Artificial neural network system ‘esr en Ty tip prystene Utne opt HRVEIS. Cucoee Nomina tie density tpl outputs wate Figure 1. Various concept in systems. , An open-loop system. The computer analyzes the input and makes suggestions tothe clinician The system presented by Salinas etal in the present issue bears this concept. 8, In closed-loop systems, Une computer directly adapts the pump rates to achieve a desired input In integrated systems (C) the computer combines several forms of information to program the pump rates or olher typeof information. In neural network type systems (D), the sstem adapts through several hidden layer “neurons” the output from various inpuls. The system “learns" from previous situations BP, blood pressure; HR, heat rate; BIS, bispectral index seale. ‘The first autopilot in aviation was in- vented by Lawrence Sperry one century ago (1912). Based on a gyroscope and an altimeter, the system was able to main. Crit Care Med 2011 Vol. 38, No. 9 tain a constant heading and altitude. The system was connected hydraulically to the elevators and rudder. With the evolu- tion of technology and computer science, systems are now able to control all plane systems, including engine thrust, and perform a complete flight plan. Typically several hundred thousand lines of com- puter code are required to fly actual planes. Flight management systems have been shown to provide a smoother ride with lower fuel consumption compared to manual flight. In a parallel manner, Salinas et al (12) showed that patients managed following the advice of the de- cision support system performed better. ‘They had a smoother ride, as shown by less wobbling in terms of both fluid ad- ministration and urine output, and they reduced the fuel consumption, i.e., the total fluid needed for the same - or even better - result, There are two components in the approach. First there is an algo- rithm, a set of rules, which define a re- sponse (fluid administration) to an input (urine production). The second is embed- ded in the software. Strategy makes the difference in outcome, as shown in septic shock or burn resuscitation (14), and soft- ‘ware makes it easy to apply. An algorithmic approach to bum fluid resuscitation was proposed 20 yrs ago by Miller etal (15). The concept of closed loop in medicine is not new. A Society of Critical Care Medicine task force pioneered the assessment of closed-loop technologies 16 yrs ago (16). In aviation, the development of flight ‘management systems was welcomed by pilots, having more time and mind to focus on the navigation and safety rather than the flying process. Interestingly, al- though the clinical decision system pre- sented here gives “sound” fluid resuscita- tion advice, the advice was frequently not applied. Interestingly, when clinicians fol- Towed the advice of the decision system, they were more often in the target in terms of urine output, than when >100 mL/hr off the computer decision support system. De- cision systems often act more quickly than the clinician and avoid overreacting when late. For example, closed-loop ventilation systems adapt each breath based on the previous one (17), a process that can only be done by a computer. Closed-loop systems are not in their infancy in critical care. Several closed- loop systems managing heparin during hemodialysis (18) or lidocaine infusion to contol premature ventricular contrac- tions (19) have been developed but did not reach widespread clinical use. Clini- cians aim at personally controlling all pa- rameters of patient care. With the develop- ment of critical care and scarcity of resources, this will not be possible. Avail- 2179able systems can not only manage fluid resuscitation, but also glucose level (20), anesthesia (21), or ventilation weaning (17). Future systems will be integrated and able to adapt dynamically to the changing situation. A significant part of today’s clini- cians are reluctant to give away the control stick to a computer. Clinicians should not, reject these system (or their advice), hiding behind the arf of critical care or burn fluid ‘management. These decision support sys- tems are here to do your basic job. The new role for clinicians will be to focus on clini- cal strategy while overlooking the systems, taking over in case of unplanned situations. Similarly, autopilots and flight manage- ‘ment systems have not and will not replace pilots in airplanes; autopilots will never be able to land on the Hudson River with both, engines out (22). They are our assistants, ‘our helpers, and can extend the burn in- tensive care unit expertise outside the burn unit walls to remote hospitals, austere en- vironments, transport situations, disaster situations, and less wealthy counties. David Bracco, MD, PhD, FCCM Associate Professor of ‘Anesthesia Critical Care and Trauma McGill University Montreal General Hospital, ‘Montreal Quebec, Canada REFERENCES 1 Boater CR, Shires 7: Physiological response to entalloid resuscitation of severe burns. lnm NV Acad Sci 1968; 150:874-804 2. Greenhalgh DG: Bur resuscitation: The results of the ISBUABA survey. Bua 2010; 36176182 3. Bngrav LH, Colescolt PL, Kemalyan N, etal: A biopsy of the use of the Baxter formula to resuscitate burns or do we do it like Charlie did iJ Burm Care Rehabil 2000; 2101-95 4. Cartotto RC, Innes M, Musgrave MA, eta: How wel does the Parkland formula estimate actual fd resuscitation volumes? J Burm Care Rehabil 2002; 23:258-285 5. Saffe J: The phenomenon of fui excep” in cute burn resuscitation. J Bum Care Res 2007; 28:382-295 6. Chung KK, Wolf SB, Cancio Le, ea: Resus- ciation of severely Bumed military caulies Fd begets more id. J Pama 2000; 67: aL 1. Balogh Z, MeKinley BA, Cocanour CS, et a: Supranormal trauma resuscitation causes more cases of abdominal compartment syn- drome. Arch Surg 2003; 138:637-642; dis cussion 642-682 8, Burke BA, Latenser BA: Defining intra: abdominal hypertension and abdominal compartment syndrome in acute thermal in- jury: A multicenter survey. J Burm Care Res 2s, 20:580-584 9. Azzopardi EA, MeWilliams B, Iyer S, et ab Fluid resuscitation in adults with severe burns at risk of secondary abdominal com- partment syndrome-an evidence based sy tematic review, Burns 2000; 95:911-920 10, Pruitt BA Jr: Protection from excessive re- suscitation: “Pushing the pendulum back" J Trauma 2000; 49:567-568 11, Carttto R, Zhou A: Fluid erep: The pendu- lum hasnt swung back yell J Burm Care Res 2010; 31:551-558 12, SlinasJ, Chung KK, Mann BA, eal Comput- erized decision support sistem improves Mid resuscitation following severe burns: An org nal study. rt Care Med 2011; 38281-2038 1, Salina J, Drew G, Gallagher J, et al: Closed Toop and deision-assst resuscitation of burn patients. J Trauma 2008; 64:S321-$332 1M Chung KK, Blackbourne LH, Wolf SE, et ak Evolution of bur resuscitation in operation rai freedom, J Br Care Res 2006; 2708-611 15, Miler 1G, Carruthers HR, Burd DA: An algo rithmic approach to the management of cu taneous burns. Bums 100; 18200211 165, Jastremski M, Jastremski C, Shepherd M, et al: A model for technology assessment 35 applied to closed loop infusion systems. Technology Assessment Task Porce of the Society of Critical Care Medicine. Crit Care ‘Med 1905; 2%:1745-1755 117, Burns KE, Lellouche P, Lessard MR: Auto rating the weaning process with advanced closed-loop systems. Infensive Care Med 2008; 24:1757-1765 18, Jannett TC, Wise MG, Sanders PN: An adaptive control system for delivering heparin to pro vide antinoguton during hemos. Can? Proc BBE Brg Me Biol Soc 02; 4207-2208 10, Jannett TC, Kay GN, Sheppard LC: Auto rated administration of lidocaine for the treatment of ventricular arrhythmias. Med Prog Technol 19; 1653-50 2, Yatabe 7, Yamazaki R,Kitagva Hy et ak The cation ofthe ability of losed-oop glycemic control device to maintain the blood glucose concentration in intensive care unit patients, Chit Care Med 2011; 20875-578 21, Absalom AR, De Keyser R,Struys MM: Closed loop anesthesi Are we geting lose to finding the holy rail dest Analy 2011; 112516-518 2 Pederal vation Administration. Accident and Incident Data: USAinvays 1549 (AWEIS40), January 15, 2000, 2000, Available at htt ve fan gouldata_resarchiaccident incident! 1540, Accessed April 1, 2011 Acute kidney injury: Clear the kidney of apoptotic debris!* ccute kidney injury (AKI) is a major clinical problem in in- tensive care units. Sepsis- induced AKI is the most com- ‘mon form of AKI observed in critically ill patients, but ischemia-reperfusion (U/R) “See also p. 2039. Key Words: cut kidney injury apoptosis ct hein; mik fat looule-epidermal growth factor 8; phagocytic clearance ‘The authors have not isclsed any potential con- fl of interest Copyright © 2011 by the Society of citeal Care Medicine and Uppineat Wiliams & Wikins ok: 10.1097/0C¥.000136318726619 2180 injury play a crucial role in the develop- ment of AKI in all types of shock, trauma, and transplantation. Similar to sepsis, UR injury is accompanied by an intense sys- temic inflammatory response, which may induce organ damage at a distance from the initial ischemic insult site, Accumu- lating evidence highlights the crucial role of effective clearance of apoptotic cells after ischemia to prevent the accumula tion of inflammatory apoptotic cells, hy- percoagulable state, and impaired tissue repair (1, 2). Effective clearance of apo- ptotic cells requires bridging molecules, which recognize apoptotic cells and facil- itate apoptotic target-phagocyte effector juxtaposition, thereby enabling phagocy- tosis. Milk fat globule-epidermal growth factor 8 (MFG-E8)lactadherin is one of these bridging molecules (3-6). MPG-ES is a glycoprotein originally found in milk-fat globules and mammary epithelial cells. MPG-ES is expressed in several epithelial cells and in immune cells involving macrophages and den- dritic cells. MFG-ES has a domain struc- ture of epidermal growth factor (EGF) L-EGF2.C1-C2 in which EGF indicates EGF homology domains, and the C do- mains share homology with the phos- phatidylserine-binding domains of blood coagulation factors Vand VIIL. The sec- Crit Care Med 2011 Vol. 38, No. 9ond EGF-like domain binds to the av83 and a5 integrins. The second C do- ‘main binds to phospholipids. MFG-E8 promotes phagocytosis of apoptotic cells by establishing a bridge between phos- phatidylserine on apoptotic cells and in- tegrins on phagocytes (6, 7), modulates downstream inflammatory. signaling pathways, promotes vascular endothelial growth factor and neovascularization via the induction of integrin-dependent Akt phosphorylation in endothelial cells (8), and promotes cellicell adhesion such as that during sperm-oocyte interaction (9). In this context, an interesting manu- script in the current issue of Critical Care Medicine provides useful new informa- tion. In this issue, Matsuda and col- leagues (10) described that, while the ex- pression of MGF-ES was reduced after renal UR injury in mice, intraperitoneal administration of MGF-ES attenuates tu- bular UR injury and improves the survival rate of renal VR mice. This renal- protective effect appears to be mediated through anti-inflammatory and antiapo- ptotic effects of recombinant murine MEG-E8 and improvement of capillary functions (recovery of vascular endothe- lial growth factor expression and suppres- sion of endothelin-1 overexpression) in the kidney. This study confirms previous results of the same group reporting an attenuation of inflammation and acute lung injury by MFG-E8 after mesenteric VR (11). Alter superior mesenteric artery ‘occlusion for 90 mins followed by reper- fusion for 4 hrs, MFG-E8 levels decreased in the spleen and lungs by 50% to 60%. ‘Treatment with recombinant murine MPG-E8 significantly suppressed inflam- ‘mation (tumor necrosis factor-a, inter- leukin-6, interleukin-18, and myeloper- oxidase) and injury of the lungs, liver, and kidneys, with a significant improve: ‘ment in survival of wild-type mice These two stutdies suggest that the de- creased production of MFG-E8 in the dis- tant organ may be one of the possible ‘mechanisms for distant organ injury after UR injury. ‘These studies lend credence to the no- tion that inflammation and uncleared de- bris from dying cells play a major role in the UR injury. This role is not only lim- ited to the ischemic organ (renal UR in- jury in the Matsuda study), but is also important in the nonischemic organs (liver injury induced by renal ischemia in the Matsuda study). Recent studies have Crit Care Med 2011 Vol. 38, No. 9 clearly shown that efficient phagocytosis of apoptotic debris is critical to the main- tenance of an ant-inflammatory milieu. Phagocytic clearance of apoptotic debris is beneficial because it removes toxic or inflammatory stimuli and avoids an exag- gerated immune response with down- stream effects, such as secretion of cyto- kines and a production of reactive oxygen species. Fast removal of apoptotic cells by phagocytes in tissues and circulation may prevent a secondary (postapoptotic) ne- crosis of apoptotic cells with leakage of toxic or inflammatory debris, Ait-Oufella et.al 2) reported a marked acceleration of atherosclerosis in MGF-E8-deficient mice, with substantial accumulation of apoptotic debris, both systemically and within the developing lipid lesions. This accumulation of apoptotic debris was as- sociated with a reduction in interleu- kin-10 in the spleen and an alteration of natural regulatory T-cell function, but an increase in interferon-y production in both the spleen and the atherosclerotic arteries. Miksa et al (12), in a cecal ligs- tion and puncture model, found a reduc- tion of MFG-E8 protein levels in the spleen and liver by 48% and 70%, respec- tively. Peritoneal macrophages from MFG-E8-treated rats displayed a 2.8fold increased ability to phagocytose apoptotic cells with an attenuation of the systemic inflammatory response. ‘As mentioned by Matsuda etal (10), the observed beneficial effect of MBC-ES in their renal UR model satributed tothe fact that MPG-ES accelerates the phagocytosis of apoptotic cells based on several studs 3, 4, 12,13), However, the authors reported that recombinant murine MFG.BS decreases apo- plotc cells in the kidney after UR injury, but there sno direct data showing that clearance ‘of apoptotic cell is impaired ater renal UR. It is plausible that the MFC-E8-mediated pro- tection after renal UR results from an im- provement of the MPC.BS-meiated apopto- tic cell phagocytosis, but this hypothesis has to be demonstrated in further investigations. Matsuda et al (10) provide new in- sights into the field of AKI therapy. This study suggests that recombinant MFG-E8 may be beneficial for the treatment of tubular UR injury and could be a novel treatment option for AKI. This therapeu- tic hypothesis must be confirmed by other teams, but it is obviously an excit- ing therapeutic approach that must be actively investigated. Anatole Harrois, MD Jacques Duranteau, MD, PRD Assistance Publique - Hopitaux de Paris Hopital Bicétre Département d'Anesthésie- Réanimation. Université Paris, Sud XI Le Kremlin-Bi , France REFERENCES 1. Thorp EB: Mechanisms of failed apoptotic cell clearance by phagocyte subsets in car Aiovascular disease. Apoptosis 2010; 15: 124-1136, 2. AiLOufella H, Kinugawa K, Zll Je al: Lac: tadherin deficieney leads to apoptotic cell accumulation and accelerated atheroscero fis in mice, Circulation 2007; 115: 2168-2177 3 Hanayama R, Tanaka M, Miyasaka K, et al Autoimmune disease and impaired uptake of apoptotic cells in MPG-ES-deficient mice. ‘Sconce 2004; 204:1147-1150 4. Hanayama R, Tanaka M, Miva K, eta: Ken: tiation ofa factor that links apoptotic ells to phagocytes, Nature 2002; 417:182-187 5. Bu HP, Zuo XL, Wang X, et al: Mik fat slobule-EGP factor Slactadhern pays a cr ‘ial role in maintenance and repair of mu rine intestinal epithelium. J Clin Invest 2007; 117:3673-2683 6. Fens MH, Mastrobaltsta Bde Graaff AM, et al: Angiogenic endothelium shows lactad- hherin-dependent phagocytosis of aged ery rocytes and apoptotic cells. Blood 2008; 111: 4512-4550 7. Leonardi-Essmann F, Emig M, Kitamura Y, ef ak: Fractalkine-upregulated milla glob tule EGF factor8 protein in cultured rat mi crogia. J Neurotmmunol 2005; 1602-101 & Silvestre JS, Théry C, Hamard G, etal: Lac: tadherin promotes VEGP-dependent neovas- culaization, Nat Med 2008; 11:499-506 9, Ensslin MA, Shur BD: Identification of rouse sperm SEDI, a bimotif EGF repeat and discoidin domain protein involved in sperm-egg binding. Cell 2008; 11:405~A17 1, Matsuda A, We R, Jacob A, etal: Protective effect of milk fat globule-epidermal growth factor-factor VIII after renal ischemia reperfusion injury in mice. Crit Care Med 201; 362039 2087 1. CT, Miksa M, Wa R, etal: Mil ft globule epidermal growth factor 8 altenuates acute Jung injury in mice aftr intestinal ischemia and reperfusion. Am J Respir Crit Care Med 2010; 181-228-246 12, Miksa M, Wu R, Dong W, et al: Dendritic cellderived exosomes containing milk ft lobule epidermal growth factor factor VU altenuate proinflammatory responses in sep sis, Shock 2006; 25:586-303 13, Dasgupta SK, Abdel-Monem H, Guchhait P, tt a: Role of lactadherin in the clearance of phosphatidyserine-expressing red blood cells. Transfusion 2008; 48:2370-2376 2181Too much of a good thing is not necessarily better* na situation of emerging multi- drug resistance among important pathogens and a very high (too high?) use of very-broad-spectrum antibiotics in the intensive care units (ICUs) worldwide, the importance of an- timicrobial stewardship is increasingly necessary and action is urgently needed (1), At the same time, sepsis is a contin- uous risk for patients in the ICUs and because delay to appropriate antimicro- bial therapy in severe bacterial infections is related to mortality (24), itis recom- ‘mended in guidelines to initiate antimi- crobial therapy within I hr (5). The diag- nosis of sepsis is hampered, however, by its nonspecific presentation because the systemic inflammatory response syn- drome is common not only in severe infection, but also in various noninfec- tious conditions of inflammation. The clinician needs help to rational use of potent antimicrobial therapy if we should not give way to blind very broad- spectrum antibiotic exposure to every- fone, which will be the way directly to untreatable infections resulting from multiresistant organisms (6). Its also a fact that only a minority of septic patients will have a microbiologi- cally documented bloodstream or other- wise serious infection, so most patients are treated on clinical Suspicion based on altered organ functions, radiologic imag- ing, biochemistry, and biomarkers such as C-reactive protein or procalcitonin (PCT). In several infectious diseases, the application of PCT guidance for decisions oon antibiotic therapy has proven helpful to support antibiotic stewardship and a reduction in exposure to antibiotics is usually possible without adverse out- comes (7). This principle can work in the critically ill population of the ICU from a stepdown perspective as shown in the “See also p. 2048. Key Words: antes; clinica ta inesiv care; procactonin The author has not disclosed any potent con fl of intrest. Copyright © 2011 by the Society of citcal Care Medicine and Uppincat Wiliams & Wikins ok: 10.1097/0C¥.ob013e3182207613 2182 French Procalcitonin to Reduce Patients’ Exposure to Antibiotics in Intensive Care Units (PRORATA) trial (8) and to reduce antibiotic exposure in ventilator-associ- ated pneumonia (9), but the question re- mains if itis possible to initiate antibiotic therapy with less extensive antimicrobial spectrum and then use PCT guidance to escalate when necessary. ‘The study by Jensen and coworkers published in this issue of Critical Care Medicine (10) is so far the largest multi- center randomized clinical trial exploring a biomarker-guided strategy of antibiotic therapy in the ICU setting. The study conclusion challenges the dogma that es- calation from target-directed to very broad-spectrum ("blind") antibiotics be- fore a microbiologic diagnosis increases survival in the ICU. The trial was con- ducted in nine multidisciplinary ICUs in Denmark with a randomization of 1200 patients to daily PCT guidance or stan- dard of care. Consequently, the escalation, to broad-spectrum piperacillin/tazobac- tam or meropenem was significantly more prevalent in the PCT group, but disappointingly, no survival benefit was demonstrated. The results were robust because several subanalyses on stratifica- tion of the cohort confirmed the outcome to be nondifferent. The study confirms previous observations (11) that the sen- sitivity of baseline PCT is low and thus cannot be used to rule out infection, whereas the changes in PCT concentra tion on repeated measurements predicts prognosis. An unexpected finding for patients on the PCT strategy was increased time on mechanical ventilation and longer time with renal failure, Increased morbidity associated with a PCT strategy was also suggested in the PRORATA trial (8). Ad- ditionally, the length of stay in the ICU. was prolonged in the PCT-guided strat- egy. These findings are a strong reminder that new diagnostics and new therapies should not be introduced to routine care without prior rigorous scientific evalua- tion because unexpected adverse events may occur. Too much of a good thing is not necessarily better. ‘The strengths of the study were the design, the large sample size, inclusion of multiple centers, rigorous statistical analysis, and the complete follow-up un- til the primary end point. The authors should be congratulated with the efforts to report 28-day mortality as the pre- ferred outcome, superior to inhospital mortality often reported in such studies. ‘The limitations of the study include the mononational design because all cen- ters in Denmark had a low prevalence of multiresistant organisms in contrast to most other countries, which reduce the predictive value ofa positive PCT alert. In the Scandinavian countries with a rela- tively low incidence of multiresistant pathogens, the study results are reassur- ing that it is safe to continue with a restrictive antibiotic policy in the ICUs without escalating to very broad-spec- trum agents unless supported by micro- biologic findings. The proportional expo- sure in the standard-of-care group to piperacillin/tazobactam or meropenem ‘was as low as 0.07 and yet the survival was not adversely affected. However, for countries with a higher prevalence of multidrug resistance, the results may not apply, so generalization is maybe not pos- sible. Another parameter, which may dif- fer among centers, is fungal infections in the ICU because PCT response to Candida species is considerably weaker as com- pared with bacterial infections (12). Fur- thermore, the mortality in ICU patients is multifactorial and intervention within a single area of treatment (e.g, antibiotics) rarely results in substantial mortality reduction, As reported, biomarkers cannot sub- stitute for good microbiologic data in the ICU (13), but admittedly, the turnaround time is a problem. Although we still wait for that “superior sensitive bedside, 1-hr, broad-range pathogen test covering all relevant organisms with a very high spec- ificity to rule out infection in the septic patient,” the clinician is dependent on microbiologic findings, biochemistry of acute-phase reactants, and careful obser- vations of patient physiology responses. ‘The hope for PCT guidance to improve outcome is unclear, and the study by Jen- Crt Care Med 2011 Vol. 38, No. 9sen and coworkers may not apply to all, countries. We are eagerly awaiting the results of ongoing clinical trials on PCT guidance in ICU patients (14, 15). Henrik Nielsen, MD, DMSci Department of Infectious Diseases Aalborg Hospital ‘Aarhus University Hospitals Aalborg, Denmark REFERENCES 1, Dellit TH, Owens RC, MeGowan JE, etal: Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America guidelines for developing an inst- tutional program to enhance antimicrobial stewardship. Clin Infect Dis 2007: 44: 159-177 Leibovic L, Shraga L, Drucker M, et al: The benefit of appropriate empirical antibiotic treatment in patients with bloodstream in- fection, J Intern Med 1098; 244:379 386 2, Ibyahim EH, Sherman G, Ward S, et a: The influence of inadequate antimicrobial treatment of bloodstream infections on pa- tient outcome in the ICU selling. Chest 2000; 118146155 Take a deep breath. atient care isan art directed by science. New discoveries from good clinical research often prompt changes in patient care or in the way clinicians think about dis- ease. But by shifting their focus to the latest topic in the literature, clinicians may ignore more mundane problems. When an old problem comes back into focus, there is an opportunity for new insight. In this issue of Critical Care Medicine, Schmidt and colleagues (1) refocus on dyspnea in mechanically ventilated pa- tients. Their findings suggest that dys- pea is common, often severe, is associ- ated with anxiety, responds to basic ventilator changes in a third of cases, and “See also p, 2059. Key Wore breathing pattem; dyspnea; mechari- cal entation; patient amet; replay sensations The author has not disclosed any potential con Als of interest. Copyright © 2011 by the Society of citeal Care Medicine and Uppincat Wiliams & Wikins ok: 10.1097/C0M obot3es182217442 Crt Care Med 2011 Vol. 38, No. 9 4. Kumar A, Roberts D, Wood KE, etal: Dura. tion of hypotension before initiation ofeffec- tive antimicrobial therapy is the critical de- terminant of survival in human septic shock, (Grit Care Med 2006; 24:1580-1596 5. Dellinger RP, Carlet JM, Masur H, et a Sur- viving Sepsis Campaign guidelines for man- agement of severe sepsis and seplic shock. (Grit Care Med 2008; 323858883, 6. Nordmann P, Poire L, Toleman MA, etal: Does broad-spectrum’ Brlactam resistance due to NDI herald the end ofthe antibi- otic era for treatment of infections caused by Gram-negative bacteria? J’ Antimicrob (Cheather 2011; 66680692 7. Simon L, Gauwin P, Amre DR, et a: Serum procakitonin and C-reactive protein levels as ‘markers of bacterial infection: systematic review and meta-analysis. Clin Infect Dis 2008; 30:206-217 8. Bouadima L, Luyt CE, Tubach F, tal: Use of procaeitonin to reduce patients exposure to Antibiotics in intensive care units (PRORATA tral: A milticentre randomised controlled tral, Lancet 2010; 375462474 9. Stolz D, Smyrnios N, Bggimann P, etal: Procalcitonin for reduced antibiotic expo- sure in ventilator associated pneumonia: A randomised study. Eur Respir J 2000; 34: 1364-1275, correlates with time on mechanical ven- tilation, They conclude that more re- search is needed to evaluate whether the benefits of modern therapies for respira- tory failure “... are worth their dyspnea- related ransom.” This conclusion reso- nates at a scientific level. At the same time, it suggests that there are times when the science applied fails an individ ual patient. When clinical research uncovers a dramatic finding, the natural tendency is. to apply it. Low tidal volumes.prevent lung injury in the acute respiratory dis- tress syndrome (2); they might be helpful with other forms of respiratory failure as well (3). Limiting (4) or avoiding (5) some forms of sedation might reduce the incidence of delirium or the time spent ‘on mechanical ventilation. Of course, ‘good clinical research tends to be carried ‘out under tightly controlled conditions ‘ona specific group of patients. One of the difficult questions an astute clinician must ask when applying scientific data to a patient is: do the patients in the study reflect the patient I am caring for right 20. Jensen JU, Hein L, Lundgren B, et a: Pro caletonin’guided interventions’ against in fection to increase erly appropriate anti oes and improve survival in the intensive care unit: A randomized trial. Crit Care Med 2011; 382048 2058 11, Jensen JU, Hest L, Jensen TH, et a: Pro calitonin inerease in early identification of critically ill patients at high risk of mor tality. Crit Care Med 2006; 38:2506— 2602 12 Charles PE, Dalle F, Abo S, et al: Serum procalitonin measurement contribution to the carly diagnosis of candidemia in evitically il patients. Intensive Care Med 2006; 32: 1577-1588 13 Jung B, Embriaco N, Roux P, etal Microbio. logical data, but not procaleitinin improve the accuracy of the clinical pulmonary infection score, intensive Care Med 2010, 36:790-708 14 Placeho controlled tial of sodium selenite and procaletonin guide antimicrbial therapy in se vere sepsis (SISPCT), Availabe a: liivne cliicaltvials gov/e2/chowNCTOOS2039, Ac cessed Apel 27,2011 15. Safety and eticacy of procaleitonin guided an Uiiotc therapy in adult intensive care units UcUs) (SAPS). Available at: http:/hwwew. cliicaltrial geslct2howNCTOL139489, Ac cessed April 27,2011 now? Understanding the mechanisms of the disease and the therapy helps answer this question, but no mechanistic mode! is complete. Ultimately, the clinician must look for reasons to accept or reject the application of clinical science to his patient. In the case of respiratory failure, the focus on therapy (mechanical ventilation) has shifted from how best to support a patient's breathing to how to avoid harm. Changes in ventilation strategies, seda- tion regimens, and bundled-care proto- cols for ventilated patients (6) reflected a desire to minimize complications. As ventilator-induced lung injury, delirium, and ventilator-associated pneumonia be- came the focus, the discomfort of dys- pnea receded. In their study, Schmidt et al surveyed intubated critically ill patients for dys- pnea. Dyspnea is a distressing symptom, worse than pain for some patients (7). Pain is frequently a target for interven- tion, yet dyspnea is rarely discussed out- side of the literature of palliative care. When it is described, data suggest the 2183sensation is severe and uncomfortable (8). ‘Schmidt et al point out that dyspnea de- serves attention. It is common (47% of pa- tients studied) and severe enough (median visual analog scale of 5) to merit a discus- sion about the benefits and hazards of me- chanical ventilation and sedation strate- gies. Regarding therapies, this study suggests some proportion of dyspnea could be treated by ventilator changes. Further- more, lack of improvement in dyspnea cor- related with increased time on mechanical ventilation, raising the possibility that dys- pnea-focused therapies, at least in some patients, might improve critical outcomes. ‘The association of dyspnea with anxiety adds to a growing literature on the psycho- logical burden of critical illness, including the risks of posttraumatic stress disorder (9) and depression (10). Shifting the focus from mechanics and complications to the sensation of breathlessness, the authors hhave uncovered a new therapeutic target. Itis refreshing to think that a classic model of symptom and therapy might improve outcomes, but too much must not be extrapolated from this initial of- fering. The study subjects are not rep- resentative of all mechanically venti- lated patients. The study patients were responsive and able to answer questions about dyspnea. Few, if any, had delir- ium. A large number were ventilated for neurologic conditions, especially motor weakness, and extrapolation to patients without these disorders will be specu- lative. Nevertheless, this study chal- lenges conventional thinking. It should drive the exploration of new hypothe- ses. Not wanting to let a good answer go unquestioned, we can speculate around these findings. How often do ventilator settings contribute to dyspnea? When can it be treated without doing harm? How can we use it to predict patient ‘outcomes? ‘Schmidt et al raise a hypothesis that is not yet disproven. To help patients in respiratory failure, dyspnea may be the price. The possibility isa cold reality, one that should not remain on the periphery. ‘This paper helps refocus the discussion, along such lines. Mark E. Nunnally, MD University of Chicago, Department of Anesthesia and Critical Care, Chicago, IL REFERENCES 1, Schmidt M, Demoule A Polito A, etal Dys- pea in mechanically ventilated critically ll Patients. Cit Care Med 2011; 3020592065 2, Ventilation with lower tidal volumes as com- pared with traditional tidal volumes for acute Tung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. V Bgl J Med 2000; 382: 1201-1308 3. Kilpatrick B, Slinger P: Lung protective strategies in anaesthesia. BJ Anaesth 2010; 105(Suppl1):108-i116 4. Kress JP, Pohlman AS, O'Connor ME, et al: Daily interruption of Sedative infusions in critically ill patents undergoing mechanical ventilation. NV Engl J Med 2000; 342: wna? 5. Strom, Martinussen T, Toft PA protocol of po sedation fr critically il patients receiving ‘mechanical venilalion: A randomised tral. Lancet 2010; 375:75-80 6. Zilberberg MD, Shorr AP, Kollet MH: Implementing quality improvements in the intensive eare unit: Ventilator bun- dle as an example. Crit Care Med 2009; 7205-200 7. Banzett RB, Pedersen SH, Schwarlasein RM, tak: The affective dimension of laboratory dyspnea: Air hunger is more unpleasant than worketort. lm J Respir Crit Care Med 2008; 7rlast—1390 8 Rolondi AJ, Chelluri L, Siri C, et ak Pa tients recollections of stressful experiences while receiving prolonged mechanical vent Tation in an intensive care unit. Crif Care ‘Med 2002; 90:746-752 8. de Miranda S, Pochard F, Chaize M, et al Postintensive care unit psychological burden in patients with chronic obstructive pulmo: rary disease and informal caregivets:A mul ticenter study. Crit Care Med 2011; 2 12s 20. Jubran A, Lawn G, Kelly J, et al: Depressive tisorders during weaning from prolonged rechanical ventilation, Jntensive Care Med 2010; 26828-895, Antibiotics in sepsis: Timing, appropriateness, and (of course) timely recognition of appropriateness* ach year approximately 500,000, severe sepsis or septic shock pa- tients will present to US. emer- gency departments (1). The un- fortunate realities are that as many as 150,000 of them will die during their hos- pitalization and the incidence of sepsis is steadily increasing (2,3). Evidence suggests, *See also p. 2066. Key Words: appropriate ntibiates; emergency medicine; goal-irecled resusctson; seplo shock, severe sepsis; be to antiotes The autars have not dslsed any potential con- fl of interest. Copyright © 2011 by the Society of citcal Care Medicine and Uppineat Wiliams & Wikins Dok: 10.1097/0cM.obot3e3182226H 2184 that outcomes are improved with early goal-directed therapy (EGDT) (4) and prompt, effective antibiotic administration (6, 6) during the most proximal phase of critical illness. In this issue of the Critical Care Med- icine, Puskarich et al (7) examine the relationship between time to antibiotics and mortality using data obtained from their parent, randomized, multicentered clinical trial, which compared lactate clearance to central venous oxygen satu ration as goals of early severe sepsis ther- apy (8). Experimental data support this investigation: in the murine surgical implantation model of septic shock of Kumar et al (9), when antibiotics were initiated before shock onset, mortality ‘was =20%, and if they were delayed >3 hrs after shock onset, mortality was 85%. However, to date, only two hu- ‘man studies have examined this impor- tant question. In 2006, Kumar and colleagues (5) examined the relationship between the duration of hypotension before the ini- tiation of effective antimicrobial ther- apy and mortality in septic intensive care unit patients, In this large, retro- spective, multicentered study, in- hospital mortality was 58% and the me- dian time to effective antimicrobials was 6 hrs (interquartile range 2-15 hrs). If appropriate antimicrobials were Crt Care Med 2011 Vol. 38, No. 9given in the first hour of hypotension, mortality was 20.1%; for each hour's delay over the next 6 hrs, mortality increased by an average of 7.6%. The message to critical care clinicians was Toud and clear: do not delay effective antimicrobial therapy in patients with septic shock as every hour matters. In 2010, we presented our experience from a single academic emergency de- partment with a mature EGDT protocol (6). We sought to determine whether time to antibiotics was associated with ‘mortality in patients receiving EGDT in the emergency department. We studied 261 patients with severe sepsis (48! of the cohort) or septic shock (the remain. ing 52%) over a 2-yr interval. The median. time from triage to antibiotics was <2 hrs (119 mins, interquartile range 76— 192 mins), and from EGDT qualification to antibiotics was 42 mins (interquartile range 0-93 mins). In-hospital mortality was 31%, consistent with the interven- tion arm of the original EGDT trial (4). We found that time from triage to appro- priate antibiotics and time from qualifi- cation to appropriate antibiotics, not simply time to inifial antibiotics, were associated independently with in-hospital ‘mortality. Our results supported the gen- eral principle that timely, goal-directed resuscitation and timely, effective antimi- crobials save lives independent of each other. Admittedly, our study warranted confirmation. We were excited to read that Puskar- ich and colleagues took the baton to fur- ther our understanding of this compli- cated relationship. In this multicentered cohort study, the median time from tri age to antibiotics was 115 mins (inter- quartile range 65-175 mins). Despite 81% of the patients fulfilling hemody- namic criteria for septic shock, in- hospital mortality was only 18.996. Simi- lar to our study (6), they found no significant relationship between time from triage to initial antibiotics and in- hospital mortality; however, a delay in antibiotics until after shock’ recognition, was independently associated with mor- tality. In effect, at highly experienced centers where the time to antibiotics has been minimized and care delivery opti- ‘mized, hourly delays in antibiotic admin. istration are not associated with mortal- ity—unless the patient either presents in shock or is initially not recognized as being at risk for the development of shock and his/her antibiotics are not ad- ministered until after shock ensues. This Crit Care Med 2011 Vol. 38, No. 9 latter observation is consistent with Ku- mar’s murine model of septic shock and challenges sepsis management guide- lines, which recommend administering effective antimicrobials within 1 hr of recognition of severe sepsis or septic shock (9, 10) ‘The strengths of the present study are numerous. First, given the prospective, prespecified proposal to study this ques- tion within the framework of a clinical trial, the authors were able to accurately and precisely capture the time variables. Second, the exclusion criteria were sparse, permitting wide generalizability of the results. Third, the authors should be commended for the use of institu. tion-specific antibiograms, allowing cli- nicians to select the appropriate antibi- otic in 91% of blood-culture-positive patients. Nevertheless, while assur- ances are given that the remaining pa- tients received appropriate, antibi ‘ogram-based antibiotics, the potential for residual confounding exists. ‘The study's limitations, in contrast, are few. First, while the multicentered design of the study is meritorious, the potential for center effects confounding the relationship between time to antibi- otics and mortality exists (11) and was not examined in the current study. This is a result of the highly standardized re- suscitation protocol, which, by design, did not standardize antibiotic administra- tion but rather noted only that “antibiot- ics were administered as soon as practi- cal” (8). Second, the authors did not test for interaction between the two resusci- tation protocols studied in the parent trial and the relationship between timing of antibiotics and mortality. Although unlikely given that there were no differ- ‘ences observed in other co-interventions, it is conceivable that behavior regarding the timing of emergency department co- interventions (e., antibiotic administra- tion) could have been influenced by the tunblinded treatment assignment. Third, they only report the appropriateness of an- tibiotis for blood-culture-positive patients (4.4%), whereas other studies have re- ported the results of positive cultures from all sources, with percentages ranging from. 56.7% to 82.2% (5, 6, 12). This limits the ‘generalizations that can be made about the ‘overall appropriateness of initial antibiot- ies, Finally, these three centers managed to achieve a mortality rate of 18.9% and to deliver antibiotics effectively in <2 hrs, which may have limited the power to detect a relationship between time to antibiotics ‘and mortality. Despite these limitations, the study by Puskarich et al is the largest to date on the relationship between the timing of antibiotics and mortality in patients re- ceiving goal-directed resuscitation and furthers our understanding of this impor- tant question. Now all we need to do is learn how to predict which septic patients will rapidly deteriorate to fulfil criteria for severe sepsis and septic shock and administer appropriate antibiotics before they do. Let’s get to work. ‘Mark E. Mikkelsen, MD, MSCE Pulmonary, Allergy, and Critical Care Division Department of Medicine University of Pennsylvania School of Medicine Philadelphia, PA David P. Gaieski, MD Department of Emergency Medicine University of Pennsylvania School of Medicine Philadelphia, PA REFERENCES 1. Wang HE, Shapiro NI, Angus DC, tal: Na tional estimates of severe sepsis in United States emergency departments. Crit Care ‘Med 2007; 25:1028-1096 2 Angus DC, Linde-2wirble WT, Lidicker J, et al: Epidemiology of severe sepsis in the United States: Analysis of incidence, out come, and associated costs of ere. Crt Care ‘Med 2001; 2:1303-1310 ‘3. Martin GS, Mannino DM, Eaton S, et al: The epidemiology of sepsis in the United States from 1979 through 2000.1V Engl J Med 2003; 248 1546-1554 A. Rivers E, Nguyen B, Hovstad S, et al: Early goal-directed therapy in the treatment of se ‘vere sepsis and septic shock.’ Bn J Med 2001; 245:1268-1377 5. Kumar A, Roberts D, Wood KB, et a: Dura tion of hypotension before initiation of effec tive antimicrobial therapy isthe critical de terminant of survival in human septic shock, Crit Care Med 2006; 24:1589-1596 6. Gaieski DF, Mikkelsen ME, Band RA, et al: Impact of time to antibiotics on survival in patients with severe sepsis or septic shock in whom early goal-directed therapy was init ated in the emergency department. rit Care ‘Med 2010; 2:1045-1053 7. Paskarch MA, TraciakS, Shapiro NI, al Association beeen timing of antibiotic admin ‘tration and mortality frm septic shock in tints treated with a quantitative resuscitation protocol. Chit Cae Med 2011; 2066-2071 ‘8. Jones AE, Shapiro NI, TrasciakS, etal: Lactate clearance vs central venous omen saturation 2185as goals of early spss therapy: A randomized clinical til. JA 2010; 308730746 9, Kumar A, Haery ¢, Paladug B, et als The uation of hypotension before the initiation of antibiotic teatment isa critical determi ‘nant of survival in a muine model of sch erichia coli septic shock: Association with serum lactate and inflammatory cytokine levee, J dnect Dis 2006; 192251258 10. Delnger RP, Lewy MM, Care JM, et ak Sunis- ing Sepsis Carpaig International guidelines for management of severe sepsis and seplic shock: 208, Crt Care Med 2008 25206 -277 11, Locaio AR, Berlin JA, Ten Have TR, et al: Adjustments fr center in mulicenter studies: “Am overview Aon intern Med 2001 8112-123, 12, Kumar A, Elis P, Avabi ¥, etal: Initiation of inappropriate antimicrobial therapy re sults in fivefold reduction of survival in hhuman septic shock. Ches? 2009; 136: 237-1248 Myocardial infarction complicated by cardiogenic shock: A possible role for the Impella device?* ardiogenic shock (CS) is the leading cause of mortality in patients hospitalized for myo- cardial infarction (Ml). Due to better infarct management, the incidence cof CS complicating MI has decreased and prognosis has improved in recent years (1). Nevertheless, with hospital mortality rates up to 50%, the outcome of pa- tients with CS is still poor. Although it hhas been acknowledged recently that CS cannot be seen as a sole mechanistic model, and that an accompanying sys- temic inflammatory response contrib- utes to the disease entity, the severity of the left ventricular function depression and the grade of mitral regurgitation at the initial echocardiographic assessment are significantly linked to worse prognosis, (2). In most severe cases, despite successful ‘opening of the infarct-related artery, treat- ment with high-dose vasopressors/ino- tropes, and intra-aortic counterpulsation, hemodynamics cannot be stabilized and let ventricular assist devices are seen as the last therapeutic option. In this context, the retrospective analysis of Engstrim and colleagues (3) in this issue of Critical Care Medicine, describes the use of the Impella 2.5/5.0, devices in patients with profound CS deemed to be refractory to conventional, inotropic and vasopressor support. The clear strength of this study is that it provides a real-world scenario, with de- tailed case-to-case descriptions. Some important clinical issues concerning “See also p. 2072. Key Wards: catogenc shock: Impala device; et ventricular asist devices; myocardial infarction The autors have not disclosed any potential con- fl of interest. Copyright © 2011 by the Society of citcal Care Medicine and Uppincat Wiliams & Wikins ok: 10.1097/60¥.ob01363182217475, 2186 the patient population in this series should be considered. Close to 60% of patients were resuscitated before arrival to hospital, which implies that CS was associated also with the systemic postresuscitation syndrome in many patients. Although no clear distinctions of these two components can be made in terms of hemodynamic sequelae, it seems obvious that a combination of these syndromes yields a unique and very poor prognosis, Regarding the MI characteristics, itis noteworthy that al- though the total ischemic time avail- able in 27 out of 34 patients (symptoms to balloon time) was low when com- pared with the landmark SHOCK trial (4), a coronary stent was implanted in only 73% of patients, and normal cor- ‘onary flow was present in only 58% of patients at the end of the procedure! According to the case descriptions, pos- sible causes include that a substantial proportion of patients had never gained an adequate hemodynamic response to sustain sufficient coronary perfusion pressure, either because of the severity ‘of the shock itself or because of ongo- ing malignant arrhythmias. Interest- ingly also is the high proportion of pa- tients with triple-vessel coronary artery disease, which is in contrast with other series of patients with MI complicated by CS. In light of these specific patient characteristics, what conclusions upon the feasibility, safety, and efficacy of the Impella pump system in patients with CS can be drawn from this series? The priming and insertion of the Impella 2.5 device that can be inserted percuta- neously through a 12.5F sheet via the common femoral artery seems to be possible in a dedicated catheterization lab. However, the hemodynamic re- sponse to the 2.5 device was classified as insufficient in 32% of patients within the first 48 hrs, and these patients were upgraded to a 5.0 Impella device that requires a surgical cutdown of the fem- oral artery and usually the use of a Dacron tube. Considering safety issues during the extended use of both the 2.5 and 5.0 systems, several issues have to be addressed. Three of 34 patients ex- perienced potential embolic events (two strokes, one bowel ischemia) in the course ‘of or after Impella treatment. One additional patient experienced se- vere limb ischemia after removal of the 2.5 Impella device, which required sur- gical intervention. It should be also kept in mind that, as with other extra- corporeal life support systems, patients with the Impella system have to be deeply sedated, prolonging the inten- sive care unit stay even after successful weaning of the device. Although the ease of use of the Impella 2.5 pump is attractive, its hemodynamic support seems inadequate in patients with pro- found CS. Only two of 25 patients who ‘were solely treated with the 2.5 Impella system survived the hospital stay. In line with the obvious inadequate hemodynamic support observed in this series, are data from the ISAR-SHOCK study where in- creases of the cardiac power index were not significantly different in comparison with patients with conventional therapy, includ- ing an intra-aortic balloon pump, beyond 2 hrs (5). The Impella 5.0 pump seems to provide adequate hemodynamic support ‘and could be an attractive device in patients ith profound CS, possibly also in those with ventricular septal defects as a conse- quence of MI as a bridge to surgery. The safety issues, especially with regard to bleeding and hemolysis, seem to compare ‘well with other emergency assist devices. However, prospective data, in particular in Crt Care Med 2011 Vol. 38, No. 9comparison with extracorporeal life sup- port systems, are missing. This study adds important institutional experiences to the growing dataset regard ing the use of left ventricular assist devices in patients with CS. Nevertheless, such ex- periences are no substitute for properly de- signed prospective trials. In patients profound CS, such trials could adopt the ‘growing experience with the Impella device and opt for an initial strategy with the 5.0 Impella pump. Before the results of those trials are available, the decision to use this device must be taken in a multiprofessional healthcare team ap- proach on an individualized and stan- dardized basis. Lisa Krenn, MD Georg Delle Karth, MD Medical University of Vienna, Department of Cardiology, Vienna, Austria REFERENCES 1. Goldberg BI, Spencer FA, Gore JM, et al: ‘Thirty year trends (1975 to 2005) in the magni- tue of management of and hospital deh ates assocaed wilh cardiogenic shock inpatients with fscute myocar infarction: A population-based perspective Coulton 2008; 110-1211-1219 2, Pat MH, Davidoff R Sleeper LA, eta: Echo cardiographic predictors of sural and re- sponse to early revasularizalion in cardiogenic shock, Circulation 20; 10729-2584 ‘8 Engstrim AE, Coccier R, Driessen AH, et a ‘The Impella 25 and 5.0 devices for ST: elevation myocardial infarction patients pre senting with severe and profound cardio genic shock: The Academic Medical Center intensive care unit experience. Crit Care Med 2011; 39:2072-2079 44. Hochman J, Sleeper LA, Webb 36, ta: Early revascuarization in acute myocardial infarction complicated by cardiogenic shock. SHOCK In vtigators, Should We Emergenly Revascuar iae Occluded Coronaries for Cardingenic Shock N Brg J Med 1000; 3812625-634 5. Seyfarth M,Sibbing D, Bauer I eal: A random: iaed clinical trial to evaluat the safety and eff cacy of a percutaneous lef ventricular asst, device versus intra-aortic balloon pumping for twealment of cardiogenic shock caused by nyo cardial inortion, J im Coll Cardiol 2008; 52: 1584-1588 Electrocardiogram interpretation for ischemia in patients with septic shock: A disheartening exercise* ike many diagnostic tests, elec- trocardiogram (ECG) interpre- tation requires a combination of knowledge, skill, and practi- cal clinical experience. Knowledge of the pathophysiology of electrocardiographic abnormalities, skill in recognizing com- ‘mon abnormal BCG patterns, and experi- ence in relating the result of the ECG to a patient's clinical situation are all com- ponents of successful interpretation, The principal goals of ECG monitoring in the intensive care unit (ICU) are to alert staf to changes in cardiac rhythm, which may herald life-threatening events, to alert staff to sudden changes in cardiac rhythm, which are themselves life- threatening, and to identify silent isch- emia. Like most clinical tests, the ECG yields both false-positive and false- negative results. For example, the routine ECG surveillance in the ICU, which usu- ally includes continuous two-lead moni- toring, has been shown to have a very low sensitivity for myocardial ischemia (1). “See also p. 2080. Key Words agreement; electocardagram; ist emi: relabiy sepss; topo The autor as not dscosed any potential con fl of intrest. Copyright © 2011 by the Society of citcal Care Medicine and Uppincot Wiliams & Wikins ok: 10.1097/60¥.0b01363182266035, Crit Care Med 2011 Vol. 38, No. 9 It is of great importance in clinical practice to be aware of the diagnostic limitations of any clinical test. Reliable knowledge of test characteristics, such as sensitivity and specificity, indifferent test situations are essential, as well as an un- derstanding of the population character istics in which the testis performed (e.g., pretest probability ofa certain condition). ‘The most important questions for a diag- nostic ECG in the ICU are—and this hholds true for most tests in medicine— what are the clinical consequences for the patient? Has an abnormal ECG prog- nostic value? What additional tests are required? Can we influence the abnor- mality by a therapeutic intervention that thas been shown to be effective in well- designed trials and which does not lead to further harm? Test results are not absolute, and (mis-) interpretation of test values can lead to significant problems, as the his- tory of the pulmonary artery catheter has shown us. The proper use of the pulmo- nary artery catheter requires a perfect knowledge of the numerous pitfalls and difficulties in interpretation of its me surements (2). The same applies for BCG interpretation in intensive care patients. ‘The level of agreement in ECG interpre- tation among clinicians has to be accept- able to provide reliable diagnostic and prognostic information. In this issue of Critical Care Medicine, Mehta and colleagues (3) present a sub- study of the Vasopressin and Septic Shock Trial (VASST), in which the intra- and inter-rater agreement of ECG inter- pretation with and without knowledge of troponin values in adult septic patients is investigated. A total of 373 ECGs were obtained from 121 septic patients and in- dependently and nonsequentially inter- preted by an intensivist and a cardiologist using a checklist to standardize interpre- tation. Appropriate statistical methods ‘were used to describe intra- and inter- rater agreement with and without know!l- edge of troponin values for each of seven categories: normal, ischemia, atrial ar- rhythmias, bundle branch block, ST ele- vation, T-wave inversion, and Q waves. As could be expected, both intra- and inter- rater agreement for specific ECG pat- terns, such as atrial arrhythmias and bundle branch block, were good to very good. However, intrarater agreement was only moderate for ischemia, and the in- ter-rater agreement for ischemia im- proved from fair to moderate when the readers were unblinded to troponin. ‘These results are important and in- crease our understanding of the limita- tions of ECG interpretation, especially for the diagnosis of ischemia in patients with septic shock. Specific strengths of this study include the large number of ECGs, 2187the standardization of the interpretation, and the very specific cohort of patients with septic shock. The ECGs were inter- preted nonsequentially for patient and time, which prevents so-called coupling of images (the interpretation of the next ECG is influenced by the previous ECG). Unfortunately, at the same time this technique limits generalizability and ex- trapolation to real-life practice. Interpre- tation of serial or sequential ECGs and comparison with patients’ old ECGs is likely to improve the real accuracy of interpretation of abnormalities (e.g, typ- ical dynamic changes over time as seen in new ischemia or infarction as opposed to fixed abnormalities in patients with pre- vious cardiac “insults"). In addition, the pretest probability for detection of isch- emia in this cohort of patients was influ- enced by the exclusion of patients with acute coronary syndrome or severe heart failure, Another limitation of the current study is the lack of a gold standard for ECG interpretation. Agreement between both readers does not automatically ‘mean their interpretation was correct. One common feature of most ECG inter- pretation studies is the use of an expert, electrocardiographer “gold standard,” typically a consensus panel of cardiolo- gists. These panels have shown to have good intrarater agreement (4). The results of the current study are consistent with what has been shown pre- viously, which is that ECG detection of ischemia in intensive care patients in general is not as straightforward as it may be in a pure cardiac population. For ex- ample, in a recent observational cohort analysis of ST elevation in critically ill patients, 85% of patients with electrocar- diographic ST-segment elevation myo- cardial infarction (STEMI) had peak tro- ponin elevation <5 ng/mL, which made clinically “real” STEMI in these patients unlikely (5). This means that in ICUs, the BCG has a poor predictive value for acute ‘myocardial infarction and lacks the spec- ificity compared with non-ICU patients. Correlation with clinical symptoms and signs is essential but unfortunately often, not contributory in ICU patients. For ex- ample, only 14% of patients who experi- ence a perioperative myocardial infarc- tion will have chest pain, and only 53% of patients will have clinical signs or symp- toms (6). The BCG, therefore, which is the gold standard for diagnosing clinical ‘STEMI in patients who present with chest, pain, may be a poor diagnostic modality to indicate STEMI in critically ill patients 2188 in ICUs, Twelve-lead ECGs in the ICU are often obtained for reasons other than cchest pain, stich as arrhythmias, hypoten- sion, agitation, pulmonary edema, a sud- den change in the vital signs, or simply as workup for weaning failure. Under these circumstances, a bedside transthoracic or transesophageal echocardiogram may help increase or decrease the likelihood of ischemia or STEMI (7). Emergent car- diac catheterization should probably be reserved for a very small number of cases in which the clinical picture and another imaging study, such as the echocardio- gram, independently indicates a high likelihood of STEMI, Another important issue raised by the current study is the effect of knowledge of troponin levels to ECG interpretation. ‘The authors report that knowledge of tro- ponin levels improved the inter-rater agreement for myocardial ischemia in their study. Interestingly however, knowledge of troponin levels caused an increase in the number of ECGs reported as normal by Reader 1, but a decrease in this number reported by Reader 2. Both changes were statistically significant and the inter-rater agreement for normality decreased from moderate to fair. How can wwe explain these discrepancies? Bearing in mind that one reader was an intensiv- ist and the other reader a cardiologist, it is not unreasonable to hypothesize that both readers, working in different clinical environments, interpret troponin levels differently. In cardiology clinical practice, elevated troponin levels are often strongly correlated with myocardial isch- emia, The new generation of sensitive assays for troponin are highly sensitive but not very specific for the diagnosis of myocardial infarction (8, 9). This repre- sents a true clinical problem in intensive care patients, where troponin elevations ‘can occur in settings other than myocar- dial infarction, the most common being tachycardia, right ventricular strain and failure in the setting of pulmonary em- boli or exacerbation of chronic obstruc- tive pulmonary dysfunction, and myocar- dial necrosis caused by neurohumoral changes and/or elevated left ventricular end-diastolic pressure in the setting of congestive heart failure, head injury, or subarachnoidal bleeding. An increased troponin measurement has been shown to be an independent predictor of mortal- ity after noncardiac surgery as well as following cardiac surgery (10, 11). Fi- nally, and relevant to the current study, elevated troponin concentrations have also been reported in patients with sepsis and septic shock without indication of significant coronary artery disease (12, 13). It has been demonstrated that tro- ponin elevations occur far more often than ischemia, even in patients with known or high probability for coronary artery disease in a general ICU, and that necrosis but not detectable ischemia is related to mortality (14). Unfortunately it is not possible to reliably discriminate ischemic from nonischemic causes of tro- ponin elevation by simply changing the cutoff value, However, a rising or falling pattern of troponin values could be help- ful in discriminating acute injury from some other causes, such as end-stage re- nal disease (15). Where to go from here? Should all ECGs be interpreted by cardiologists as discussed by the authors? In addition to being unpractical, the literature shows that this may not improve the number of false-positive and -negative ECGs for ischemia. The interpretation by several cardiologists reading the same ECG often varies substantially. Even one cardiolo- gist reading the same ECG on separate occasions may have substantially differ- ent interpretations (4, 16). In the current study, both readers - one of whom is an experienced cardiologist - showed only moderate intrarater agreement for isch- emia. In the abovementioned cohort analysis in critically ill patients, a cardi- ologist agreed with the computer inter- pretation of ST-elevation myocardial in- farction in 39% of cases, but of those patients, only 33% showed a significant rise in the troponin level (5). Physicians ofall specialties and levels of training, as well as computer software for interpret ing ECGs, frequently make ervors in in- terpreting ECGs when compared to ex- pert electrocardiographers. Adverse patient outcomes, however, occurred in- frequently when ECGs were incorrectly interpreted, typically in <19% of interpre- tations (17), Currently there is no evi dence-based minimum number of ECG interpretations that is ideal for attaining or maintaining competency in ECG inter- pretation skills (18). Since ECG monitor- ing is an integral and essential part of the intensive care environment, formal in- tensivist training on ECG interpretation should be a standardized and compulsory part of any intensive care curriculum. In conclusion, the current study con- firms that, in septic shock patients, sig- nificant variability of ECG interpretation of myocardial ischemia exists. Correla- Crt Care Med 2011 Vol. 38, No. 9tion with all other pieces of the diagnos- tic puzzle is essential, and this includes the clinical context, interpreting serial ECGs, the serial measurement of cardiac biomarkers despite their known limita tions in the ICU, and bedside echocardi- ography, to prevent both over- and un- derdiagnosis of myocardial ischemia in ICU patients. Frank van Haren, MD, PhD Waikato Hospital Hamilton, New Zealand REFERENCES 1, Martinez BA, Kim LJ, araday N, et ak: Sen- sitivity of routine intensive care unit survell- Tance for detecting myocardial ischemia. Crt Care Med 2002; 31:2302-2308 Richard C, Monnet X, Teboul JL: Pulmonary artery catheler monitoring in 2011, Curr Opin Crit Care 2011; 17:206-302 3. Mehla S, Granton J, Lapinsky SE, et a: Agresment in eletrocardiogram interprta- lion in patients with septic shock. Crit Care ‘Med 2011; 32080-2086 4 Holmvang L, HasbakP, Clemmensen P, etal: Ditferences between local investigator and core laboratory interpretation of the admis- sion electrocandiogram inpatients with un- stable angina pectoris or non-Qave myo- cardial infarction (a Thrombin Inhibition in Myocardial Ischemia [TRIM] substudy). Am J Cardio! 1908; 8235460 5. Rennyson SL, Hunt J Haley MW, eal lec- trocardiographic ST-segment elevation myo- cardial infarction in citcally il patients: An ‘observational cohort analysis. Crit Care Med 2010; 38:2804-2209, 6. Devereaux PJ, Goldman L, Cook DJ, etal: Perioperative cardiac events in patients un- dergoing noncardiac surgery A review ofthe ‘magnitude ofthe problem, the pathophysiol- ‘ogy of the events and methods to estimate land communicate risk, CMAJ 2005; 173 27-64 7 Pooler: Use of ultrasound inthe ICU. Best Pract Res Clin Anaesthesiol 200%; 23: 249-261 8. Keller, Zeller T, Peetz D, etal: Sensitive troponin I assay in early diagnosis of acute myocardial infarction. 4” Engl J Med 2000; 361:868-877 9, Reichlin T, Hochholzer W, Basset S, eta: Early diagnosis of myocardial infarction with sensitive cardiac troponin assays. Engl J Med 2009; 3613858857 10. Levy M, Heels Ansdell D, Hiralal R, et al: Prognostic value of troponin and creatine kinase muscle and brain isoenzyme messure- ment afer noncardie surgery: A systematic review and meta-analysis. Anesthesiology 2011; 114:796-—806 11, Januzsi JL: What is the role of biomarker measurement after cardia surgery? Minera Anestesiol 2011; 72834241 12, Ammann P, Fehr T, Minder El, e al: Eleva tion of troponin Ii sepsis and septic shock, Intensive Care Med 2001; 27:965-069 13, Ammann P, Maggiorini M, Bertel 0, etal Troponin a6 a risk factor for mortality in critically ill patients without acute coronary syndromes. J Am Coll Cardiol 2003; Al: 2004-2000 14 Landesberg G, Vesselow Y, Binay S, etal Myocardial ischemia, cardiac troponin, and long-term survival of high-cardiae risk ei cally ill intensive care unit patints, Crt Care Med 2005; 32:1281-1287 15, Thygesen K, Alpert JS, Jaffe AS, et a: Di agnostic application of the universal det nition of myocardial infaretion in the in tensive care unit, Curr Opin Crit Care 2008; 1542-548 16, Massel D, Davdy JA, Melendez LJ: Strict re liance on a computer algorithm of measur able ST segment criteria may lead to errors in thrombolytic therapy eligibility. Am Hart J 2000; 140:221-226 17, Salerno SM, Alguire PC, Watman HS: Com petency in interpretation of 12-lead electro fardiggrams: A summary and appraisal of published evidence. Ann Intern Med 2003: 138:751-760 18, Salerno SM, Alguire PC, Waxman HS: Trin ing and competency evaluation for interpre tation of12-lead electrocardiograms: Recom- mendations fom the American College of Physicians. inn Intern Med 2003; 128 147-750 Danger at the doorstep: Regulation of bacterial translocation across the intestinal barrier by nitric oxide* he ability of the host to regu- late the permeability of the in- testinal barrier represents a major determinant of disease vs, health. This is particularly relevant to the critically il surgical patient, in whom intestinal obstruction — be it due to me- chanical causes or in the setting of ileus — is associated with an increase in infec- tious complications (1, 2). The fact that such infections are seen to be caused *See also p. 2087. Key Words: bacterial translocation; epithelial per- ‘meabilty, intestinal obstruction nic axe; signal transduction; tight junctions The author as not disclosed any potential con fl of intrest. Copyright © 2011 by the Society of citcal Care Medicine and ppncat Wiliams & Wikins ok: 10.1097/60¥.06013631822661ad Crit Care Med 2011 Vol. 38, No. 9 predominantly by enteric microbes has led to the widespread notion that intesti- nal barrier dysfunction develops as a con- sequence of intestinal obstruction, re- sulting in the translocation of enteric bacteria (3). It therefore stands to reason that an understanding of the factors that regulate normal barrier function during health and in the presence of disease may provide important insights into enhanc- ing care of the critically il patient. It has been known for some time that there are several pathways by which en- teric microbes or their microbial-derived antigenic ligands can access the circula- tion. The intestinal mucosa is lined by a tightly interconnected layer of epithelial cells over which a layer of mucus exists that together represent the first line of defense against bacterial passage (4, 5). To transit across the normally imper- ‘meant intestinal mucosal barrier, bacte- ria can either transit directly through the intestinal epithelial cells (IECs, ie, tran- scellular passage), pass between the IECs (paracellular passage), or they can be ac- tively internalized by dendritic cells and macrophages that lie within the lamina propria with the capacity to extend cellu- lar processes between the IECs that can internalize the bacteria and deliver them to the Iymph nodes and circulation (6). While IECs have been shown to have the ability to internalize whole bacteria both, in vitro and in vivo (7), the effect of in- testinal obstruction on transcellular bac- terial internalization by IBCs remains un- known. By contrast, itis well known that adjacent IECs are interconnected by tight junctions that determine the extent to ‘which large molecules, and possibly bac- teria, can pass between the adjacent IECs 2189(8). Recent studies have demonstrated that circulating cytokines and other pro- inflammatory molecules can cause an in- crease in the permeability of the intesti- nal barrier by causing tight junction dysfunction or internalization (5, 9). However, the precise role of tight junc- tion dynamics in the maintenance of bar- rier integrity in the setting of intestinal obstruction, and the molecular mecha- nisms involved in the regulation of tight junctions in this setting, remain largely unexplored, In this issue of Critical Care Medicine, Wu and colleagues (10) now attempt to solve this riddle. Using an elegant model, fof mechanical intestinal obstruction in mice, this group demonstrates that the presence of intestinal obstruction leads to an increase in permeability across the intestinal barrier and an increase in bac- terial translocation, and that these changes are associated with a disruption, in tight junctions (10). In seeking to identify the molecular mechanisms in- volved, Wu et al now also show that in- testinal obstruction is associated with an inerease in inducible nitric oxide synthase, \which led to disruptions in tight junctions, likely through a pathway that involved the intermediates myosin light chain, myosin phosphatase target subunit 1, and protein kinase C { (10). Although the precise dy- namics of this pathway in vivo are un- clear, the authors show that at least iv vitro, there is an apparent role for nitric, oxide signaling leading to a Rho-depen- dent phosphorylation in myosin light chain that was required for the reduction, in tight junctions (10). Taken together, these findings place the spotlight on the role of nitric oxide signaling in the path- ways by which tight junctions may be disrupted in intestinal obstruction. Itis useful to consider these findings in the broad context of bacterial translo- cation in general, and in the role of tight, junctions in the setting of intestinal obstruction in particular. In this vein, it should be mentioned that while it is accepted that a disruption in tight june- tions can lead to the transepithelial pas- sage of large solutes and other macro- molecules, it is unclear whether disruptions in tight junctions have direct, effects on the translocation of entire bac- teria, In support of an argument against the role of tight junctions in regulating bacterial translocation, mice lacking my- osin light chain kinase, which have a baseline instability in tight junctions, did 2190 not demonstrate any spontaneous evi- dence of sepsis (11). However, these same mice did demonstrate an increase in mu- cosal immune activation. It is thus pos- sible that the findings of increased mu- cosal permeability that Wu et al now ‘observe may in fact represent the effects of increased local inflammation involving increased activity of lamina propria den- dritic cells and macrophages, which could then primarily mediate the trans- location of bacteria as was measured. In support of this possibility, nitric oxide release by enterocytes may directly ac- tivate subepithelial dendritic cells or macrophages, which could potentiate these effects, and the broad use of the inducible nitric oxide synthase global knockout mice, as well as the pharma- cologic reagents utilized, are entirely consistent with this possibility (12). It is also worth mentioning that the above findings have direct relevance to the situation in which the intestinal harrier is largely intact, yet may have little impact under conditions in which the intestinal barrier is severely damaged (13). The gut barrier is known to be broadly susceptible to injury in the setting of nitrosative stress, leading to cell death via apoptosis resulting in broad gaps in the intestinal epithe- lium, which would allow for direct access to the underlying dendritic cells and macrophages for bacterial delivery to lymph nodes and the systemic circula- tion. The degree to which epithelial loss ‘occurs in the model presented by Wu and colleagues, or in the clinical setting of intestinal ‘obstruction, still remains an ‘open question. In summary, the current findings pro- vide important insights into how the in- testinal barrier can be transformed from an intact, protective shield to a semiper- meant membrane can occur in the set- ting of intestinal obstruction. The study also suggests the possibility that the local delivery of nitric oxide regulators within the gut epithelium may modulate the ex- tent of bacterial translocation and poten- tially prevent septic complications from occurring in critically ill patients with intestinal obstruction. While further studies are necessary to discern in greater detail the precise cellular site of action at which bacterial translocation occurs, these studies represent an important first step in recognizing how danger on the mucosal doorstep can be kept at bay, and the ill effects that can transpire if such bacteria are allowed passage into the po- tentially damaging world of the subepi- thelial immune system. David J. Hackam, MD, PhD Division of Pediatric Surgery Children’s Hospital of Pittsburgh Department of Surgery University of Pittsburgh ‘School of Medicine Pittsburgh, PA REFERENCES 1, Madi C, Druml W: Gastrointestinal disorders ofthe critically il Systemic consequences of ileus. Best Pract Res Clin Gastroenterol 20005 1745-456 2 Deitch BA, Xu D, Kaise Vz Role ofthe gut in the development of injury and shock induced SIRS and MODS: The gul-mph hypothesis, a review. rant Biase 2006, 11520528 4. Swank GM, Deitch EA: Role of the gut in ‘multiple organ failure: Bacterial translocs tion and permeability changes, World J Surg 1996; 2011-417 4. Tumer HL, Turmer JR: Good fences make food neighbors: Gastrointestinal mucosal Structure. Gut Microbes 2010; 12: 5. Tumer JR: Intestinal mucosal barter func tion in health and disease. Nat Rep Immunol 2000 9700-809 5, Asis D: Bpithelal-cell recognition of com: ‘mensl bacteria and maintenance of immune homeostasis in the gut. Nat Rev Immunol 2008; #411-420 17 Neal MD, Leaphart C, Levy R, etal Enter cote TLR mediates phagocytosis and trans location of hactria across the intestinal bar ier J bmmumol 2006; 17630702079 8. Shen L, Weber CR, Raleigh DR, etal Tight junction pore and leak pathways: A dynamic «duo. Arm Rew Physiol 2011; 73:283-200 8, Han X, Fink MP, Yang R, etal: Increased INOS activity is essential fr intestinal ep thelial tight junction dysfunction in endo- toxemie mice. Shock 2004; 21:261-270 20, Wu Ls Chiu H-D; Peng WH, et al Epithelial inducible nitric oxide symthase causes hicteril translocation by impairment of enterocytic tight junctions via intracellular signal of Rho: associated kinase and protein kinase C zeta, Grit Care Med 2011; 29:2087-2008 11. SuL, Shen L, Clayburgh DR, etal: Targeted epithelial tight junction dysfunction causes jmmune activation and contributes to devel lopment of experimental clits. Gastraenter- ‘ology 2008 136:551-563 12, Anand RU, Dai S,RipelC, et a: Activaled mac rophages inhibit eneroot gap junctions va the release frit nie. J Pil Gastrotest Liver Physiol 208; 24:6100-G119 13. Gribar SC, Richardson WM, Sodhi CP, ta No longer an innocent bystander: Epithelial toll-ike receptor signaling in the develop rent of mucosal inflammation, Mol Med 2008; 14645-650 Crt Care Med 2011 Vol. 38, No. 9Beneficial effects of carbamylated erythropoeitin on trauma- induced brain edema: Proposed molecular mechanisms of action* tythropoietin (EPO), in addi tion to its known function in erythropoiesis, is an impor- tant mediator of the adaptive response to metabolic stress. In response to brain trauma, as is the case in the report of Bouzat and colleagues (1) in this issue of Critical Care Medicine, blood-brain barrier dysfunction ensues due to the breakdown of various endathe- lial junction proteins/mechanisms. This process allows for the passage of immune cells and water into the cerebral paren- chyma. This type of edema is generally referred to as vasogenic edema. Another type of brain edema, termed cytotoxic, occurs from dysfunctional energy-driven sodium/potassium pumps in glial cell membranes, resulting in edematous- swollen astrocytes. It is conceivable that both types of edema exist in this model of brain trauma and that temporal events are characterized by an initial vasogenic ‘component followed by a cytotoxic effect. Carbamylation (homocitrullination) of proteins is a nonenzymatic reaction of the cyanate ion with the free Epsilon NH2 group of lysines. This process, in vivo, can be facilitated by the presence of my: celoperoxidase (2). Carbamylation of pro- teins is known to occur in vivo in uremic patients through the formation of the turea-derived cyanate ion. Carbamylated erythropoietin (CEPO) is a nonerythro- poietic species/modification of EPO that does not bind to the EPO receptor (3). ‘The classic homodimeric EPO receptor is not the transducer of the tissue-protec- tive effects of CEPO. It has been sug- *See also p. 2098. Key Words: aquaporin 4; brain edema: carbamy- lated erythropoietin, carbamiatio; erythropoietin, soc hedgehog; trauma The aubors have not dslosed any potential con fl of interest. Copyright © 2011 by the Society of citcal Care Medicine and Uppincot Wiliams & Wikins Dok: 10.1097/0C¥.0b013e3187204a9e Crit Care Med 2011 Vol. 38, No. 9 gested that at least one of the EPO recep- tor chains, CD131, complexed with others is responsible for the neuro- and tissue-protective effects of CEPO (3, 4). A positive correlation between the expres- sion of the EPO receptor in tissue and the protective effects of EPO and CEPO are ‘evident and support this notion. CEPO was also found to modulate the Sonic hedgehog (Shh) pathway. Wang et al (5) elegantly demonstrated that block- age of the Shh pathway with cyclopamine or specific siRNA abolished some of CEPO beneficial effects. In the brain, Shh binds to the transmembrane receptor protein Patched. Patched, in the absence of Shh, has an inhibitory effect on the transmem- brane receptor Smoothened. Shh binding to Patched blocks this inhibitory effect. Activated Smoothened results in the ini- tiation of transcription factor GLI sig- naling in neural cells. This mechanism might be involved in the edema/inflam- mation reduction reported by Bouzat et al (1). The decreased extracellular signal- regulated kinase 1/2 phosphorylation ob- served appears to be a downstream event, perhaps mediated by a CEPO-induced up- regulation of the Shh pathway. ‘Aquaporin 4 isa water channel protein heavily expressed in the brain, particu- larly in astrocytes. Clearance of excess water in the brain is possibly mediated through this protein. Water uptake by astrocytes through aquaporin 4 is impor- tant in the mechanism of astrocyte water permeability and subsequent cell swelling (cytotoxic edema) encountered in isch- emia and trauma. EPO (and potentially ‘CEPO) has been shown to antagonize the effects of group I metabotropic glutamate receptor agonists on water permeability (6). EPO and now CEPO may directly reduce cytotoxic edema of astrocytes via aquaporin 4 water transport. ‘This therapeutic window of treating tyauma-induced brain edema with CEPO needs further exploration into the molec- ular mechanisms as well as the temporal relationships of acute and repeat admin- istration effects on brain edema and other functional outcomes. ‘The important observations of re- duced brain edema and improved func- tional recovery in an animal model of traumatic brain injury reported by Bou- zat (1) could lead to a novel clinical path in the treatment of this deleterious con- dition. Conferring tissue protection with- ‘out cross talk with the hematopoietic sys- tem and its associated serious adverse events could be ideal for treating this condition, David Bar-Or, MD Gregory Thomas, BSC ‘Swedish Medical Center St. Anthony Central Hospital ‘Trauma Research Department Englewood, CO REFERENCES 1. Bouzat P, Prancony S, Thomas $, et al: Re dlced brain edema and functional deiits af ter treatment of difuse traumatic brain injury by carhamslated erythropoietin derivative. Gritical Care Med 2011; 30:2000-2108 2, Wang Z, Nicholls SJ, Rodrigues ER, etal: Protein carbamlation links inflammation, smoking, uremia and atherogenesis. Nal Med 2007; 13176-1184 4. Lest M, Ghezz P, Grasso G, tal: Derivatives of enthropoietin that are issue protective But not exythropoietic. Seience 2004; 305: 239-20 4. Brines M, Graso G, FordalisoP, et al Eryth ropoietin mediates tissue protection through an enthropoietin and common beta-subunit heteroreceptor. Proc Nall cad Sci U SA 2004; L01:14907-14912 5. Wang L, Zhang 26, Gregg SR, et al: The Sonic hedgehog pathway mediates carbamylated exythropoietin-enhanced proliferation and dit ferentiation of adult neural progenitor cells 4 Biol Chem 2007: 282:22482-22470 6. Gunnarson £, Song ¥, Kovalewski JM, et al: Enthropoietin modulation of astrocyte water permeabilily asa component of neuroprotec tion. Proc Natl Acad Sci U $A 200%: 106: 1602-1607 2191Globalization of ejection fraction: The pulmonary artery catheter has been outsourced* nan elegant study by Trepte and colleagues (1) in this issue of Crit ical Care Medicine, we discover how the less invasive transpulmo- ‘nary measurement of cardiac physiology compares to pulmonary arterial catheter- ization in a variety of shock states (1). AS their reference measurement, they offer ventricular pressure-time measures, long considered the gold standard for cardiac function. Due to survival concerns, they chose to measure the rate of rise in left ventricular pressure at a single preload. While this clearly limits the reader's abil ity to infer true cardiac contractility it does reflect clinical practice in that the clinician must make decisions at a single point, which in the final analysis may actually strengthen this study's util Estimating preload, global ejection frac tion (GEF), and more controversially, ex- travascular lung water using peripheral arterial sensing of a centrally injected ‘molecular tracer or thermal dilution has great intuitive appeal given the ubiqui- tous nature of central venous and arterial catheters in shock states (2-5). The key questions confronting clinicians are: can transpulmonary data yield information equivalent to that derived from pulmo- nary arterial catheterization while avoid- ing its small but significant increase in ‘morbidity (6), and secondly, in whom is it worth measuring? thas long been appreciated that indi ces of cardiac function derived from ther- modilution are inexact. Statistically, if fone Uses a single measure of cardiac out- put, the minimum detectable true differ- ence must be at least 22% (3). This study (1) provides us valuable information in “See also p. 2106. Key Words cardiac function index; loal econ fraction; heart fale: hemodynamics: pulmonary ar- tery catheter, stock; tanspumonary cardiac output The author has not disclosed any potential con Alcs of interest Copyright © 2011 by the Society of citcal Care Medicine and Uppincot Wiliams & Wikins Dok: 1.1097/0cM.oboraest8z1f0248 2192 that we discover that neither indices of right heart function nor transpulmonary measurements correlate particularly well with the direct measurement of the rate of rise in left ventricular pressure. This is not to say that transpulmonary GEF and cardiac function index (CFI) are unable to detect impaired cardiac function, but rather that they do so much more reliably in very low output states. This is evi- denced by an increase by 40% in the correlation between the rate of rise in let ventricular pressure and GEF/CFI when cardiac output was highly suppressed by calcium channel blocker infusion com- pared to normal cardiac function (Fig. 3, B and D in [1)). According to this study, the main utility of transpulmonary mea- sures would appear to be the identifica tion of those with severely compromised cardiac output (corresponding to a car- diac index of well under 2.0 Limin/m?).. Given its performance characteristics as, outlined above, GEFICFI should also serve to identify a large subsequent im- provement in output. Once in the normal range, GEF and CF! appear rather insen- sitive to changes in cardiac function. In whom might measurement of GEF and CFI be useful? This study (1), along with recent observational data (7, 8), pro- vides us some guidance. Most ‘patients with septic shock, regardless of their pre- senting left ventricular ejection fraction, experience an augmentation of cardiac ‘output following fluid resuscitation and treatment with noradrenaline (8). There are however a subset of patients in whom. cardiac output declines significantly de- spite normalization of blood pressure (8). ‘These patients are at great risk of unrec- ognized shock and subsequent organ fail- ure. Routine clinical use of a screening GERICFI following stabilization of blood pressure would serve both to identify these patients and to guide subsequent titration of inotropes. While the same role could be envisioned for the pulmo- nary arterial catheter, the added morbid- ity (6) and physician time spent upon this procedure could only be justified if itis obviously superior to transpulmonary measures. This study provides good evi- dence that this is not the case, and adds pressure to continue the clinical shift away from pulmonary artery catheters. John H. Boyd, MD Critical Care Research Laboratories Heart + Lung Institute St. Paul's Hospital University of British Columbia Vancouver BC, Canada REFERENCES 1. Treple CJ, Eichhorn V, Haas SA, et al: Ther: rodilution-derived indices for assesiment of lef and right ventricular eardiae function in normal and impaired cardiac function. Crit (Care Med 2011; 32106-2112 2, Stetz CW, Miller RG, Kelly GE, et al: Relibil ity of the thermodiution method in the de termination of cardiac output in clinical prac Lice Am Rev Respir Dis 1982; 126:1001-1008 3 Pernindez-Mondejar B, Castafo-Pérez J, Ri vera-Fernindez R, et al: Quantification of lung water by transpulmonary thermodilu tion in normal and edematous lung. J Crit Care 4. Combes A, Berneat JB, Luyt CE, et ak: Bt ‘mation of left ventricular systolic function by single transpulmonarythermodilution. den sive Care Med 2004; 30:1377-1382 5. Pemindez-Mondéjar B, Rivera-Pernindez R, Carcia-Delgado M, et a Small increases in extravascular lung water are accurately de tected by transpulmonary thermodilution. J Trauma 2005; 59:1420-142%, discussion 2a 6. Sandham JD, Hull RD, Brant RP, et al: A randomized, controlled trial ofthe use of ul rmonary-artery catheters in high-risk surgical patients. Engl J Med 2008; 348:5-14 7. Ritter S, Rudiger A, Maggiorini MM Transpl ‘monary thermodilution-derived cardiac fune tion index identifies cardiac dystunetion in acute heat failure and septic patients: An ob- servatinal study. Crit Care 2000; 138133 8, Hamzaoui 0, Georger JF, Monnet X, et a: Early administration of norepinephrine in- creases cardiac preload and cardiac output in septic paints with life-threatening hypoten sion, Crit Care 2010; M4:R142 Crt Care Med 2011 Vol. 38, No. 9Pseudomonas aeruginosa: So many virulence factors, so little time espite 60 yrs of intensive an- timicrobial development, bacterial infections remain an important cause of mor- bidity and mortality. The ever-increasing burden of resistance erodes the efficacy of conventional antibiotics, while critically ill patients frequently fail to respond to appropriate agents, even when infected with susceptible organisms. To improve upon the current situation, attempts are being made to leverage our impressive knowledge of bacterial pathogenesis for development of novel therapeutics that block virulence mechanisms rather than simply kill or inhibit growth of bacteria. ‘The thought is that such agents could be used by themselves or as adjuncts that would boost the efficacy of conventional antibiotics. But which virulence determi- nants should be targeted? A factor that is, highly critical to the organism's patho- genesis, of course. In some cases, the choice is straightforward. For example, tetanus toxin is the major virulence de- terminant of Clostridium tetani, and ad- ministration of human tetanus immune globulin attenuates the course of tetanus (1). In other cases, however, the choice is less clear. The problem is compounded by the current emphasis on reductionist ap- proaches in microbiology. To test the im- portance ofa particular bacterial factor in pathogenesis, scientists usually disrupt the gene encoding the factor in a well- characterized laboratory strain, and the virulence of the mutant is compared to that of the parental strain in an estab- lished animal model of infection. This powerful approach has the benefit of demonstrating a causal relationship be- “See asp p 2118 ey Word elsae; xl, O-anige:Psuzomo- as serugoss, quorum sean; pel sereton vlree This wok was supported. in part, by oans aorAOsoe7 and ROMANS helen Inte o Hel The aur has an gpg casting agreement with Mab Cort © 201 by te Say of Ct Care edie ard Lppnest Wians & Wikis ok: 10.1097/60M.oboT36318221742d Crit Care Med 2011 Vol. 38, No. 9 tween the factor and disease in the model used, and has become the gold standard for identification of virulence factors (2). However, it leaves unanswered two im- portant questions: Is the factor critical for virulence in most clinical isolates, and how important is the factor relative to other virulence determinants made by the same bacterium? In this issue of Crit- ical Care Medicine, Le Berre and col- leagues (3) address these questions in re- lation to Pseudomonas aeruginosa. P. aeruginosa is an opportunistic pathogen familiar to every hospitalist and intensivis. It is a frequent cause of nos- ‘ocomial infections, many of which are responsible for substantial mortality even when treated with appropriate antibiot- ics. Thus, novel agents that target viru- lence determinants would be a welcome addition to our antipseudomonal arma- mentarium, But which virulence deter- minants should be targeted? P. aerugi- nnosa produces a potpourri of pathogenic factors, any one of which might or might not be a worthy target for inhibition. Le Berre and colleagues focused on three extensively studied virulence determi- nants: quorum-sensing (QS), the type III secretion (TTS) system, and lipopolysac- ccharide (LPS) O-antigen. QS allows bac teria to respond to their own population density by coordinately regulating their gene expression patterns (4). For exam- ple, in the presence of high bacterial numbers, QS signaling leads to produc- tion of two P. aeruginosa toxins, elastase and pyocyanin. TTS is a mechanism by which bacteria inject a set of toxins di- rectly into the cytosol of host cells. Two P. aeruginosa proteins secreted by this mechanism are Exol and ExoS; both have been previously linked to virulence (6). LPS O-antigen is a variable polysac- charide that decorates the outer surfaces of many bacteria and protects against complement-mediated lysis (6); differ- ences in O-antigens are the basis for se- rolyping P. aeruginosa strains, Each of these three factors has been studied ex- tensively and conclusively shown to be pathogenic in animal models of infection. Importantly, P. aeruginosa strains also differ in their production of each of these factors. Le Berre and colleagues characterized the QS, TTS, and LPS O-antigen proper- ties of 56 nonclonal P. aeruginosa iso- lates from patients with ventilator. associated pneumonia. The severity of pneumonia caused by each isolate was quantified by measuring alveolar-capil- lary barrier permeability, lung wet/dry ‘weight ratios, and bacterial dissemina- tion from the lungs in a mouse model of pneumonia. The QS, TTS, and LPS O-an- tigen properties of each strain were then compared to the severity of pneumonia it caused. Univariate analysis indicated an association between lung injury and elas- tase production (and by inference QS), O11 O-antigen serotype, and TTS-positive phenotype. However, it had been shown previously that QS, TTS, and LPS O-an- tigen type are not independent variables. For example, O11 serotype strains more commonly secrete the potent TTS toxin Exo (7), and QS regulates TIS (8). To account for this, a multivariate analysis was performed, which showed that TTS (espe- cially secretion of ExoU) was most highly cor- related with lung injury and that secretion of, elastase was associated to a lesser degree. ‘The approach used by Le Berre and colleagues has several limitations. As ac- knowledged by the authors, the produc- tion of virulence factors in vitro may not mimic expression in vivo, and virulence ‘meastirements at a single time point may not adequately capture the true extent of disease. The measurement of QS was in- direct, using elastase and pyocyanin se- cretion as surrogate markers. Also, al- though inbred mice offer the advantage of a uniform host model, their vulnera- bility to particular virulence determi- nants may not reflect that of humans. In this regard, it is reassuring that several studies have also found associations be- tween P. aeruginosa TTS and poor out- comes in humans with acute respiratory infections (911). Perhaps the most sig- nificant limitation is that this study does not show a causal relationship between severe disease and TTS or QS, but only an association. However, when viewed to- gether with previously published reports 2198describing conventional mutational ap- proaches, the paper by Le Berre and col- leagues provides a compelling argument in favor of an important role for these two factors in acute pneumonia. Studies such as this one are especially relevant given the current emphasis on translational research and the develop- ‘ment of novel therapeutic agents. Since $800 million is required to bring a new drug to market, it is essential that due diligence is performed to maximize the chances of success before costly clinical tials are begun. In this regard, the study by Le Berre and colleagues bodes well for ‘ongoing preclinical and clinical trials ex- amining the efficacy of inhibitors of TTS and QS in infections caused by P. aerugi- rosa (12-14). When possible, this ap- proach should be considered as well for other virulence factors that are candidate drug targets (15, 16). ‘Alan R. Hauser, MD, PhD Departments of Microbiology/ Immunology and Medicine Northwestern University Chicago, IL REFERENCES 1, Blake PA, Feldman RA, Buchanan TM, et al: Serologic therapy of tetanus in the United ‘States, 1965-1071, JAMA 1976; 235.4248 2, Falkow S: Molecular Koch's postulates ap- plied to microbial pathogenicity. Rev Infect Dis 1988; 1:s274-S276 3. Le Berre R, Nguyen S, Nowak B, et al: Relative contribution of three main viru: lence factors in Pseudomonas aeruginosa pneumonia. Crit Care Med 2011; 39: 211-2120 4 JuhasM, Eber L, Tummlr B: Quorum sens- ing: The power of cooperation in the wold of Pseudomonas, Environ Microbiol 2005; e547] 5. Hauser AR: The type II secretion system of Pseudomonas aeruginosa: Infection by in- jection, Nat Rev Microbiol 200%; 73654 565, 6. Pier GB: Pseudomonas aeruginos lpopoly- saccharide: A major virulence factor, inti tor of inflammation and target for effective immunity. int J Med Microbiol 2007; 207: 277-2085, 7. Faure K, Shimabukuro D, Ajayi 7, et a O- antigen Serotypes and type II secretory tox- ins in clinical isolates of Pseudomonas ‘aeruginosa. Clin Microbiol 200 Al: 258-2160 8. Bleves 8, Sosia C, Nogueira-Orlandi P, etal: Quorum sensing negatively controls type I secretion regulon expression in Preudomo- nas aeruginosa PAOL.J Bacteriol 2005; 187 3898-2002 9. EI Soh AA, Akinnusi ME, Wiener-Kronish {Peta Persistent infection with Pseudomo- nas aeruginosa in. ventilator-associated pneumonia. Am) Respir Crit Care Med 2008; 17s513-519 10. Hauser AR, Cobb , Bodi M, eta: Type IIL protein secretion is associated with poor elin- cal outcomes in patients with ventilator sociated prcumonia caused hy Pseudomonas ‘aeraginasa. Crit Care Med 2002; 3521-528 1. Roy-Burman A, Savel RH, Racine S, etal Type IU protein secretion is associated with death in lower respiratory and systemic Pseudomonas aeruginosa inections.J Infect Dis 2001; 188:1767-1774 12 Prank DW, Vallis A, Wiener-Kronish JP, a Generation and characteriation of a protec tive monoclonal antibody to Pseudomonas ‘aeruginosa Pew. J Infect Dis 2002; 186: 6173 13, Hentzer M, Wu H, Andersen JB, et a: Aten uation of Pseudomonas aeruginosa virulence by quorum sensing inhibitors. £MBO J 2003; 22:3800-3815 1M, Aiello D, Williams JD, Majgier-Baranowska H, etal: Discovery and characterization of inhibitors of Pseudomonas aeruginosa type UL secretion. Antimicrob Agents Chemother 2010; 5419851999 15, Veesenmeyer JL, Hauser AR, Lisboa T, ta: Pseudomonas aeruginosa’ virulence and therapy: Evolving translational strategies. Crit Care Med 2008; 27:1777-1786 16, Kipnis B, Sawa 7, Wiener-Kronish J: Tar. geting mechanisms of Pseudomonas ‘aeruginosa pathogenesis. Med Mal Infect 2006; 26:78-91 How alcohol impairs the granulocyte expansion during septicemia* pidemiologic studies indicate that chronic alcohol abuse is associated with high morbid. ity and mortality in critically ill patients, particularly those with sepsis, and septic shock (1, 2). Chronic alcohol abuse also increases the risk of develop- ing several acute insults that may lead to acute respiratory distress syndrome (1, 2), Thus, many experimental and clinical studies Rave been conducted to elucidate the mechanisms underlying the detri- ‘mental impact of chronic alcohol abuse “See also p. 2121. Key Words: leohosm: grawopdesis; hema oleic lem cal lem call ntigen-1 Te utors have not cisclsed any potential con- Als of interest. Copyright © 2011 by the Society of citcal Care Medicine and ppincat Wiliams & Wikins ok: 10.1097/C0M.ob01363182217400 2194 ‘on patients with sepsis (1, 2). Por exam- pile, excessive alcohol consumption in- duces the dysfunction of epithelial barvi- ers of the airway or gut, disrupts the antioxidant system, and impairs immu- nologic function, leading to both the predisposition to bacterial infection and increased severity of endotoxemia (1 4). During bacterial infection, granulo- poiesis in bone marrow is enhanced to increase the number of circulating granulocytes for host defense (5). Alco- hol is known to have direct toxic effects ‘on bone marrow, resulting in granulo- ccytopenia in patients with alcohol abuse (6, 7). Currently, the exact molecular mechanisms underlying the disability of granulocyte expansion in patients with alcohol abuse are incompletely under- stood. Hematopoietic stem cells are broadly classified into lymphoid hematopoietic stem cells and myeloid hematopoietic stem cells, both of which have the capac- ity of self-renewal and the potential to differentiate into in a variety of mature blood cells in bone marrow (8). Under normal conditions, hematopoiesis in bone marrow is tightly controlled by a complex mechanism to regulate the turn- cover of different blood cell lineages. Upon bacterial infection, however, the homeo- stasis of hematopoiesis is altered and pre- dominantly shifted toward the expansion of granulocyte lineage, which serves as the first line of phagocytic defense for invading bacteria (9). In the regulation of hematopoiesis, stem cell antigen-1 (Sca-1) is a phosphatidylinositol-an- chored glycoprotein of the lymphocyte activation protein-6 gene family found on. the surface of several murine marrow stem cell subtypes and it serves as an important regulator for the proliferation Crt Care Med 2011 Vol. 38, No. 9of early hematopoietic precursors (10, 1). In mice, bone marrow lineage (lin) ckit+Sca-1+ cells are highly purified hematopoietic stem cells (12). Upon stimulation, lin-c-kit+Sca-1- cells rap- idly transform into lin-c-kit+Sca-1+ cells that contain more committed my- eloid progenitors, such as granulocyte progenitors (12). In this issue of Critical Care Medicine, Melvan and colleagues (13) investigated the involvement of Sca-1 expression of granulocyte lineage-committed progeni- tors in the granulopoietic response to septicemia, and how acute alcohol treat- ‘ment affected this response in a mouse model with Escherichia coli insult. Two previous studies from this group (14, 15) reported that enhanced Sca-1 expression, promoted the conversion of bone marrow lin-cit+-Sea-1- cells to linckit+Seal-+ cells, which play an essential role in di- recting lineage commitment of primitive precursors toward myeloid lineage de- velopment in mice during septicemia, Additionally, acute alcoho! intoxication, retarded this initial step of the granulo- poietic response to the challenge with E. coli (15). This elegantly designed investi- gation (13) appears to be a logical exten- sion of these two studies (14, 15), and focuses on the functional significance of enhanced Sca-1 expression in down- stream granulocyte lineage-committed progenitor cells. Several important find- ings were reported. Firstly, they em- ployed an in vivo model to demonstrate that the level of Sca-1 expression of im- ‘mature granulocyte differentiation anti- gen-1 precursors was highly linked to the expansion of granulopoietic precursors during septicemia, suggesting that these two events might have a cause-effect re- lationship. Indeed, they found that alco- hl treatment was able to downregulate the response of Sca-1 expression, maturation of granulocyte differentiation antigen-1 pre- cursors, and mobilization of mature granulocytes from bone marrow into the Circulation. Secondly, it is known that the function of certain granulopoietic mediators, stuch as granulocyte colony stimulating factor, play a crucial role in the maturation and mobilization of bone ‘marrow granulocytes upon bacterial in- Crit Care Med 2011 Vol. 38, No. 9 fection (9). They showed that alcohol treatment decreased the activity of gran- tlocyte colony-stimulating factor elicited by the B. coli challenge in the Sca-1+ ‘granulocyte differentiation antigen-1 pre- ‘cursors in mice, a result that is in line with their finding regarding the suppres- sive effect of alcohol on granulocyte ex- pansion. Thirdly, they employed an in vitro model to reveal that exposure to lipopolysaccharide could upregulate the expression of Sca-1 in granulocyte differ- entiation antigen-1+Sca-1~ cells via the activation of c-Jun N-terminal kinase, a crucial signaling pathway for several LPS-induced responses. Importantly, al- cohol treatment inhibited the activation of this signaling pathway. Lastly, they found that Sca-I-deficient mice in fact exhibited a defect in the expansion of ‘granulopoietic precursors in response to E. coli challenge, a result that was similar to the situation in alcohol-treated ani- mals, Thus, their i vivo and in vitro data provide solid evidence suggesting that al- cohol treatment attenuates the Sca-l re- sponse in granulocyte precursors leading to a restriction of granulocyte expansion during septicemia. Although data of this investigation (13) were obtained from a murine model with acute alcohol treatment, the find- ings may serve as one of the plausible mechanisms to explain the impaired host defense in alcohol abusers. Whether the same concept applies to an experimental model with chronic alcohol ingestion (3) warrants investigation. Granulocytes are an important player for innate immune responses in critically ill patients with various etiologies. Particularly, granulo- cytopenia is an indicator of bad prognosis, for these patients. Since alcohol abuse produces many complications in these patients (1, 2), the findings of this study may also provide important information for potential therapeutic targets to en- hance host defense in critically ill pa- tients with alcohol abuse, ‘Tzong-Shyuan Lee, DVM, PhD Yu Ru Kou, PhD Department of Physiology ‘School of Medicine National Yang-Ming University ‘Taipei, Taiwan REFERENCES 1. Joshi PC, Guidot DM: The alcoholic lung: Epidemiology, pathophysiology, and poten tial therapies. Am J Physiol Lang Cell Mol Physiol 2007; 202:.813-1823 2. de Wit M, Jones DG, Sessler CN, etal: Alco: hol-se disorders in the citically ill patient, Chest 2010; 138:994-1003 3. Guidot DM, Roman J: Chronic ethanol inges: tion increases susceptibility to acute lung injury: Role of oxidative stress and tissue remodeling. Chest 2002; 122:3008-3148 4. Keshavarian A, Farhad A Poroyth CB, etal Evidence that chronic aleohol exposure pro ‘motes intestinal oxidative stress, intestinal hyperpermeabilty and endotoxemia prior to development of alcoholic steatohepatitis in als. J Hepatol 2009; 5038-547 5. Ueda ¥, Kondo M, Kelsoe C: Inflammation and the reciprocal production of granulo tes and lymphocytes in hone marrow. J Exp Med 2005; 201:1771-1780 6. MichotF, Gut J: Alcohol-induced bone mar: row damage. A hone marrow study in alco hol-dependent individuals. Acta Haematol 187; 7252-257 1 Ballard HS: Hematological complications of aleoholism. Alcohol Clin Exp Res 1989; 1: 706-720 8. Cronkite EP: Analytical review of structure and regulation of hemopoiesis. Blood Cells 198s; 1431-228 8, Terashima T, Wiggs B, English D et al: Poly: rmorphonuclear leukocyte transit times in bone marrow during streplococcal pneumo- nia. Am J Physiol 1006; 271:1587-1502 10, Holmes ‘C, Stanford WL: Concise review: Stem cell antigen-1: Expression, function, and enigms. Slem Cells 2007; 25:1290-1247 1 Trumpp A, Essers M, Wilson A: Awakening dormant haematopoitic stem ells. Nat Rev Jmmunol 2010; 10201-2009 12, Okada S, Nakauchi H, Nagayoshi K, etal In vivo and in vitro stam eel funtion of eit and Sca-L-postive murine hematopoietic cells. Blood 1902; 80:3044~-3050, 18, Mean JN, Siggins RW, Bagby GJ, etal ‘Suppression of stem cell antigen-1 response and granulocyte lineage expansion by alcohol during septicemia, Crit Care Med 2011; 39: 2121-2100 14. Zhang P, Nelson S, Bagby GU, et al: The lineage-c Kit +-Sca-1+ cell response to Esch: trichia coi bacteremia in Babe mice, Sem cells 2008; 26:1778-1785 15. Zhang P, Welsh DA, Siggins RW 2nd, etal ‘Acute alcohol intoxication inhibits the lin age: cit+ Sca-l+ cell response to Esche richia coli bacteremia, J mmol 2009; 182 1568-1576, 2195Plumbing the depths of blood pressure: Hypotensive hemorrhage and acute kidney injury* n abrupt decline in kidney function, now termed acute kidney injury (AKI), occurs commonly in hospitalized pa- tients (1, 2). Even mild forms of AKI are independently associated with significant, ‘morbidity and mortality, and more severe forms are associated with mortality in excess of 50% (1, 2). Despite advances in the care of seriously ill patients, out- comes associated with AKI have not sig- nificantly improved over several decades. AKI is usually diagnosed when either an increase in serum creatinine concen- tration (which is an insensitive and time- delayed marker for AKI) or a decrease in urine output (which often does not ac- company AKI) is observed (3, 4). Thus, diagnosis of AKI is usually delayed until after a substantial reduction in kidney function, and perhaps nonreversible re- nal cellular damage, has been initiated. Also, despite many studies, there is cur- rently no specific treatment that has been shown to either attenuate the severity or speed recovery from AKI. The complex. and dynamic nature of the clinical setting in which clinical AKI is encountered of- ten renders conduct and interpretation of clinical studies difficult. Finally, many of the animal models developed for study of AKI may not be relevant (5). Collec tively, these observations demonstrate a need for better models with which to study AKI, potentially leading to earlier diagnosis and tailored interventions that attenuate AKI. Renal ischemia occurs in several set- tings, including hemorrhagic hypoten- sion, and is one of the most common. factors predisposing to AKI. Pioneering \whole-animal work by Henrich et al (6, 7), published more than 3 decades ago, “See also p. 2131. Key Words: acute kidney injury, emorhape hem othage shock hypotensive hemorhage The author as not disclosed any potential con- fl of intrest. Copyright © 2011 by the Society of citcal Care Medicine and ppincat Wiliams & Wikins ok: 10.1097/60¥.0b01363182217465, 2196 delineated a delicate interplay between neurohumoral factors to acutely regulate renal blood flow and glomerular filtration rate in response to hemorrhage. Removal of vasodilatory eicosanoids (which en- hance renal blood flow) and angiotensin, I (hich increases glomerular capillary hydrostatic pressure by constricting the efferent arteriole), and the presence of intact renal adrenergic neural pathways (which decrease renal blood flow), mark- edly enhance the effect of hemorrhage to induce renal ischemia and decrease glo- merular filtration rate. These observa- tions provided a physiologic explanation for the now well-known effects of non- steroidal anti-inflammatory drugs and drugs that impair angiotensin II forma- tion and action to induce AKI in hemo- dynamically compromised states. In this issue of Critical Care Medicine, ‘Mayeur and colleagues (8) extend our in- sights into kidney responses to ischemia by providing a comprehensive short- and longer-term evaluation of the functional and morphologic response of the mouse kidney to hemorrhagic hypotension. This study is of interest because AKI occurring in the context of hypotension may more closely mimic clinical AKI than widely used models, such as warm ischemia- reperfusion induced by short-term renal artery occlusion. It is likely that the mul- tiorgan hypoperfusion that occurs with hypotension induces systemic responses that contribute to altered function of sev- eral organs, including the kidney. Also, the multiple genetic alterations that are possible to induce in mice provide a potentially rich opportunity to analyze the pathogenetic role of several path- ways in AKL Mayeur et al demonstrate a time- dependent effect of controlled hypoten- sion to induce increasing degrees of AKI. ‘The AKI is characterized by decreased ‘glomerular filtration rate, impaired tubu- lar resorption of sodium and water, and the presence of tubular lesions that are most marked in the outer medulla and cortex. Mayeur et al also find an increase in kidney injury molecule-1 and hypoxia- inducible factor-a _mRNA, beginning shortly after induction of hypotension and persisting for up to 6 days. The renal functional and histologic abnormalities are maximal 2-6 days after the induction, of hypotension and much less prominent 21 days later. However, impaired renal tubular sodium resorption and mild peri- tubular fibrosis are observed 21 days fol- lowing induction of AKI. The finding of mild fibrosis several days after develop- ment of AKI is of note with regard to increasing reports of lack of complete re- covery from AKI in selected cases (9). Collectively, these results suggest that the model described by Mayeur and oth- ers share many characteristics with clin- ical AKI. ‘The hope is that with further study, relevant animal models, such as that characterized by Mayeur et al, will be utilized to provide pathogenetic insights leading to prevention, earlier diagnosis, and attenuation of AKI. While awaiting real-time methods to diagnose and more specific pathophysiologic-based methods to attenuate AKI, the prudent clinician will use tested prophylactic methods to protect the kidneys in response to expo- sure to potential nephrotoxins, and will identify patients at high risk for develop- ment of AKI and monitor renal function closely in these patients (1, 2) Robert J. Anderson, MD Clinical Professor of Medicine Department of Medicine New York University Medical Center New York, NY REFERENCES 1. Walker 8S, Lin KD, Chertow GME Diagnosis, epidemiology and outcomes of acute kidney injury. Clin J Am Soc Nephrol 2008; 844-861 2 Dennen P, Douglas 1S, Anderson R: Acute kidney injury in the intensive care unit: An update and primer forthe intensivst. Crit Care Med 2010; 38261-273 {3 RiceiZ, Cruz DN, Ronco C: Classifation and staging of acute kidney injury: Beyond the Crt Care Med 2011 Vol. 38, No. 9RIFLE and AKIN criteria. Nat Rev Nephrol 2011; 2201-208; 4, Kellum JA: Acute kidney injury. Orit Care ‘Med 2008; 36141-8145 5. Lieberthal W, Nigam SK: Acute renal failure. I. Expevimental models of acute eral fuilure: Imperfect hut indispensable. cm J Physiol Renal Physiol 2000 278P1-12 6. Henrich WL, Anderson RJ, Bers AS, et a The Pediatric brain death* he history of brain death dates to the mid-1950s. Although not using the term, Pope Pius XII when asked to opine oon the timing of death said in an ad- dress to an International Congress of Anesthesiologists on November 24, 1957, “[the timing of death] does not fall within the competence of the Church ... But considerations of a gen- eral nature allow us to believe that hu- man life continues for as long as its vital functions— distinguished from the simple life of organs—manifest them- selves spontaneously or even with the help of artificial processes” (1). Electro- encephalographers in France in the late 1950s recognized “coma depasse” or “beyond coma”, which described a state now consistent with brain death (2). A 1964 report from the United States sug- gested the electroencephalogram be used to declare death (3), but it was the Harvard Criteria for “irreversible coma,” published in 1968, in which the line in the sand was drawn formally demarcating the concept of a neurologic based definition of death to supplement cardiorespiratory death (4). That this era also saw the introduction of solid organ transplants is not coincidental 6,6). In the work after publication of the Harvard Criteria and then incorporated by experts from the 1981 President's Commission (7), refinements were not added to the conceptual definition of brain death (still fundamentally whole “See also p. 2138. Koy Wr: ran deh checks pais; ei The autors have not disclosed any potential con- fl of interest. Copyright © 2011 by the Society of citcal Care Medicine and ppincat Wiliams & Wikins Dok: 10.1097/0C¥.0b013e3182226467 Crit Care Med 2011 Vol. 38, No. 9 role of renal nerves and prostaglandins in con- tool of renal hemodynamics and plasma renin activity daring hypotensive hemorshagein the dog. J Clin est 1978, 61:-744-750 7. Henrich WL, Berl T, MeDonald KM, et al: Angiotensin Il renal nerves and prostaglan- dins in renal hemodynamics during hemor- rhage. Am J Physiol 1078; 235:P46-51 8. Mayeur N, Minville V, Jaafar A eta: Morpho- brain death [8]), but substantial changes were made to the operational definition (e.g., more precision in the neurologic reflex examination and the apnea test requirements). With no ad- ditional data, a pediatric version of the brain death guidelines was published in 1987 (9). It is reassuring the current guidelines change only procedural as- pects of the declaration of brain death, maintaining the conceptual and the most central aspects of the operational definition (10). Although variability in the declaration, of death led to a memorable quote in an 1844 story by Edgar Allen Poe ("The boundaries hetween life and death are at best shadowy and vague. Who shall say where one ends and where the other be- sgins?"), variability in the criteria used for the declaration of death is unacceptable in 2011. The guideline authors reference a number of studies that demonstrate this point, but the magnitude of the prob- lem must be re-emphasized. In 1995, Me- jia and Pollack (11) reported that no ap- nea testing was performed in 25% of brain death declarations and incomplete apnea testing practices were documented in another 22%, A small, but real, per- centage of patients had brain death eval- uations within hours of discontinuing barbiturate infusions. In 2003, Chang et al (12) reported a small but telling survey in which four of 10 centers and none of the eight surveyed neurosurgeons an- swered "yes" to the question “Do you follow guidelines/waiting periods ex- actly?” Finally, Mathur et al (13) reported the mean number of the requisite 14 ex- amination elements for 142 brain dead children at well <50% by neurologists, pediatric intensivists, and neurosur- ‘geons. No apnea testing was recorded in {60% of brain death confirmations. While publication of consensus guidelines for logic and functional renal impact of acute kidney injury after prolonged hemorrhagic shock in mice. Crif Care Med 2011; 3: 211-2138, 8. Joanidis M, Philipp GH: Long-term outcome fof acute kidney injury. dn: Management of Acute Kidney Problems, Jores A, Ronco C, Kellum JA Jr (Eds). Springer-Verlag Berlin Heidlburg, 2010, pp 260-278 determining brain death is of great in- terest to clinicians and also has signif- icant applicability, it should be ex- pected that the revised guidelines will improve this variability. To be purpose- fully redundant, in 2011, variability in the declaration ‘of brain death in chil- dren must be obliterated. ‘The inclusion of a checklist in the revised guidelines is a great concept and should have widespread appeal and appli- cability (10). Similarly, clearly defined components of the neurologic examina- tion for neonates, infants, and children, including a standardized procedure for apnea testing, will be of significant help to clinicians in assuring consistent, in- clusive, and reproducible results when performing the examinations both be- tween physicians and over time. Given the complexity of the different parts of a pediatric neurologic examination, the po- tential for ancillary testing, and the is- sues related to repeated testing and as- sessments, the potential for variability simply due to diagnostic errors is real. Many high-risk, high-reliability profes- sions, such as airline pilots and nuclear plant operators, have reduced errors by using checklists (14). Checklists are gaining increasing acceptance and use in medicine, especially in complex areas stich as operating rooms and intensive care units (14). The use of a standard- ized checklist for determination of pe- diatric brain death may assist the phy- sician to optimize their cognitive approach, avoid diagnostic errors, and improve evaluation of the neurologic injury. While most checklists have not been subjected to rigorous evaluation, this type of organized approach may he analogous to the implementation of sepsis bundles in the care of patients with septic shock to improve outcomes (15) or a multidisciplinary daily quality 2m7checklist that was shown to correlate with decreased infection rates in a trauma intensive care unit (16). We strongly suggest that this checklist be incorporated into the patient's medical record as it will guide clinicians during a high-stress period and provide defin- itive documentation of the specific steps and timeline followed for determi- nation and declaration of brain death for clinical and medical legal purposes. Finally, we support the authors’ sug- gestions for the future directions that re- search and policy in this field should take (10). In particular, development of a na- tional database to track pediatric patients who are diagnosed as brain dead could provide a valuable source of data for future investigations and queries that multiple users could take advantage of—clinicians, researchers, transplant organizations, and state and federal fund- ing health agencies, to name a few. Such. a repository of data could also be re- viewed in a timely fashion for future re- visions of the pediatric guidelines for brain death, The Task Force, the Society of Critical Care Medicine (Mount Prospect, IL), and the American Academy of Pediatrics (Elk Grove Village, IL) should be congratu- lated on compiling such a timely and comprehensive review of the 1987 guide- lines and the evidence review of the med- ical literature. James Packler, MD Anesthesiology and Critical Care Medicine The Johns Hopkins University School of Medicine Baltimore, MD Brahm Goldstein, MD, MCR Clinical Development Ikaria, Inc. Clinton, NI REFERENCES 1, Pope Pius XIL: To an International Congress of Anesthesiologsts, Nov. 24, 1957. Pope ‘Speaks 1958; 4393-308 2, Mollaret P, Bertrand 1, Mollaret H: Coma dépassé et nécrosesnerveusescentales mas- sives. Reo Neural 1950; 10L 116-139 3. Hamlin H: Life or death by BEG. JAMA 1068; 00:1 12-14 4A definition of irreversible coma, Report of the Ad Hoc Committe of the Harvard Med- ical School to Examine the Definition of Brain Death, JAMA 1968; 205:297-340 5. Giacomini Mt A change of heat and a change ‘of mind? Technology and the redefinition of death in 1968, Soe Sci Med 1007; 4 1485-1482 6. Spoor MT, Sutherland FR: The evolution of the cancept of brain death, An R Coll Phy- cians Surg Can 1995; 2830-34 7. Guidelines for the determination of death Report of the medical consultants on the Aiagnosis of death to the President's Com- mission forthe Study of Ethical Problems in Medicine and Biomedical and Behavioral Re search, AM 1981; 246:2184-2185 8. Truog RD, Packler JC: Rethinking brain death, Cri Care Med 1992; 20:1705-1713 8, Report of special Task Force. Guidelines for the determination of rain death in children, American Academy of Pediatrics Task Force fon Brain Death in Children, Pediatrics 1087; 80:208-200 1. Nakagawa TA, Ashwal S, Mathur M, etal Guidelines for the determination of brain death in infants and children: An update of the 1987 Task Force recommendations. Crt Care Med 2011; 39:2130-2155 11. Mejia RE, Pollack MM: Variability in brain death determination practices in children, JAM 1998 2743550853 12. Chang MY, MeBride LA, Ferguson MA: Var ability in brain death declaration practices in petri head trauma patients. Pediatr New- rasurg 2008; 3057-9 1%, Mathur M, Petersen L, Statler M,et a: Vari ability in pediatric brain death determination and documentation in southern California, Paiiatrcs 2008; 121:988-003 14 Bly JW, Graber ML, CroskerryP: Checklists to reduce diagnostic errors. Acad Med 2011 s607-a13 15, Borochia AV, Cul X, Vtherg D, etal: Bundled care for seplic shock: An analysis of clinical Urals. Crit Care Med 2010; 38:658-678 16, Chua C, Wisniewski , Ramos A, et als Ml tidisciplinary trauma intensive care unit checklist: Impact on infection rates J Traurna Nurs 2010; V7A63-166 Opening our eyes to postoperative pulmonary complications* ulmonary complications are ‘common after surgery due to the unigue stresses that are placed on the patient during the perioperative period, such as general anesthesia, the surgical stress response, and postoperative pain (1). Patients with pulmonary complications experience lon- ger hospital stays, are more likely to be discharged to a skilled nursing facility and have increased rates of mortality (2). *See also p. 2163. Key Words: healincare: outsome assessment (peat cae); postoperative complialins, quay I cas; respiratory nsuffieney The autors have not disclosed any potential con fl of interest. Copyright © 2011 by the Society of citcal Care Medicine and Uppincat Wiliams & Wikins Dok: 10.1097/¢c¥.obot3e3182226"%6 2198 Pulmonary complications have been de- fined in a diverse manner, making mea- surement and improvement difficult. ‘Thus, improving the care of the postop- erative patient requires a valid and reli- able definition, In this issue of Critical Care Medicine, Shander et al (3) have presented a sage discussion of the burden postoperative pulmonary complications create through increasing morbidity and mortality and thus increasing resource utilization. ‘These authors were part of a patient safety summit consisting of a multidisci- plinary group that included health policy researchers, patient safety and quality ex- perts, and intensivist physicians repre- senting a broad background of primary specialties. They believe that increased awareness of both the scope of the prob- lem of postoperative pulmonary compli- cations and strategies to reduce these complications can lead to improved pa- tient care, better resource utilization, and overall cost savings for the health system asa whole, Recommendations were based on the expert clinical experience of the group and evidence collected from a lim- ited literature search. Proper application of resources is de- pendent upon accurate assessment of the prevalence of pulmonary complications. Given the heterogeneity of existing data, the authors’ have done a commendable job of characterizing the scope and im- portance of postoperative pulmonary complications and have set a framework for future discussions. Measuring the burden of postoperative pulmonary com- plications is contingent on standardized Crt Care Med 2011 Vol. 38, No. 9definitions of disease, and there is no better example of this dilemma than ventilator- associated pneumonia. Ambiguities as to what constitutes ventilator-associated pneumonia exist internally within individ ual published definitions and vary by defin- ing group (4). When compared to autopsy as.a gold standard, our ability to accurately diagnose or exclude ventilator-associated pneumonia is poor (5). Improving our un- derstanding of the scope and burden of postoperative pulmonary complications in the future will require standardization of disease definitions for proper data collec- tion, aggregation, and analysis. Postoperative pulmonary complica tions encompass a spectrum of processes such as bronchospasm, pneumonia, and respiratory failure. As such, there is no single modality that is likely to reduce complication rates, but instead a multi- faceted approach or “bundle” of interven- tions aimed at reducing complications will likely be required. The authors pro- pose a number of evidence-based inter- ventions that may be used to reduce com- plication rates. Given the complexity and ‘magnitude of the problem, eliminating postoperative pulmonary complication may seem to be an impossible goal using only standardization of best practices, yet this approach has already been proven success ful in the dramatic reductions in catheter- related bloodstream infections (6). ‘There is currently no standard by Which we are able to ascertain the quality of postoperative care as it relates to pul- ‘monary complications. Calculating post operative rates of mechanical ventilator support in excess of 48 hrs is an enticing proposal for this new metric, but we must, tread cautiously. It is true that these data should be easy to obtain through existing collection mechanisms; however, the va- lidity of this metric is unclear at this time. A more rigorous analysis of current evidence using standard principles such as systematic literature review should be used to determine the validity of this rec- ‘ommendation, Furthermore, rigorous testing for reliability and accuracy needs tobe performed before introduction as an accepted quality measure, ‘There is the inherent danger that pub- lic reporting performance measures may drive practice to comply with the mea- sure without actually improving delivery of care. Emergency department best practice, as judged by the Centers for Medicare & Medicaid Services (Balti- more, MD), required antibiotic adminis- Crit Care Med 2011 Vol. 38, No. 9 tration to any patient with community. acquired pneumonia within 4 hrs of presentation (7). Desire to comply with this publicly reported measure ultimately led to antibiotic administration, in the face of diagnostic uncertainty, which many times was unnecessary (8). Similarly, man- dated reporting ofthe rates of postoperative mechanical ventilator use in excess of 48 hrs could create incentive for early termi- nation of a necessary treatment. ‘Metrics that are outcome hased, such as duration of mechanical ventilation, in the setting of external reporting for benchmarking, can create unforeseen in- centives. To lower the reported rates of complications, hospitals may “cherry pick” patients who are least likely to have complications, thereby improving the measured outcome to be reported with- ‘out ever having improved the quality of care. Conversely, hospitals that improve delivery of best practices while serving a higher risk population may not show the same improvement (9, 10). Quality im- provement projects, especially when tied to pay for performance, may also draw re- sources from other health initiatives, re- sulting in an overall negative health effect, despite producing improvements in the de- sired indicator (11). Thus, metrics that track delivery of best practices may ulti- mately have the best potential to improve ‘outcomes across the system as a whole. ‘There is a growing list of stakeholders that utilize quality metrics for a variety of, requirements. They are used by individ- ual institutions for internal quality im- provement and external benchmarking, regulatory agencies for monitoring, and third-party payers for pay-for-perfor- mance incentives. Premature adoption of, ‘a metric has the potential for harm with- ‘out offering improvement in care. Reductions in postoperative pulmo- nary complications will require develop- ment and consensus acceptance of diag- nostic criteria and creation of a valid standard of measurement and ultimately care guidelines. Successful implementa- tion of such a quality improvement ini- tiative will require input from multiple stakeholders in the delivery process, in- cluding caregivers and their professional societies, hospital systems, government and regulatory bodies, and third-party payers. Inadequate consideration of any component in this process may under- mine the capability to significantly re- duce postoperative pulmonary infections. We applaud the efforts of Dr. Shander and colleagues in taking the first substantive steps toward advancing our understand- ing of this important clinical entity. ‘Mark C. Romig, MD Department of Anesthesiology & Critical Care Medicine Johns Hopkins University School of Medicine Baltimore, MD ‘Todd Dorman, MD, FCCM Department of Anesthesiology & Critical Care Medicine Joint Appointments in Medicine, Surgery, and the School of Nursing Johns Hopkins University School of Medicine Baltimore, MD REFERENCES 1. Perreyra G, Long Y, Ranieri VM: Respiratory complications after major surgery. Curr Opin Crit Care 2000; 15:342-348 2. Thompson DA, Makary MA, Dorman T, etal: Clinical and economic outcomes of hospital acquired pneumonia in intra-abdominal sur ery patients. Amn Surg 2006; 243:547-552 ‘3% Shander A, Fleisher LA, Bari PS, etal Clinical ani econamic burden of postoperative pulmo- ‘ary complication Patient sey summit on det inition, risk-educng interventions and preven tie strategies Cif Care Med 2011; 302163-2172 4. Klompas M, Platt R: Ventilator associated peumonia—The wrong quality measure for benchmarking. Arm Intern Med 2007; 147 03-805, 5. Tejerna B, Esteban A, Fersndes-Segoviano P, et als Accuracy of clinical definitions of vent Ibtorassocated pneumonia: Comparison with autopsy findings. J Crit Care 2010; 2532-68 6, Pronovost PI, Goeschel CA, Colantuoni Ee a: Sustaining ructions in catheter related Hood stream infections in Michigan intensive cate nits: Observational study. AW 2010, 340300 7. Wachter RM, landers SA. Fee C etal: Public reporting of antibiotic timing in patients with Pricumeonis: Lessons from a faved performance ‘measure. Ar Idem Med 208; 14820-22 Nicks BA, Manthey DE, Fitch MT: The Cen- ters for Medicare and Medicaid Services (CMS) community-acquired pneumonia core seasures lead to unnecessary antibiotic ad ‘ministration by emergency physicians. Acad Emerg Med 2009; 16:184-187 8. Dranove D, Kessler D, McClellan M, etal Is ‘more information helter? The effects of re port cards on health care providers. J Poli ‘Econ 20013; 111:555-588 1, Shen Ys Selection incentives in a perfor. rmance-hased contracting system. Health Soro Res 2008; 38:535-552 11. Mullen 10, Frank RG, Rosenthal MB: Can You get what you pay for? Payfor-perfor ‘mance and the quality of healthcare provid crs, Rand J Econ 2010; 4164-01 2199Just fastening the belt! Is it the future measure for assessing fluid responsiveness?* bserving the respiratory vari- ation of hemodynamic sig- nals has emerged as a valt- able tool for assessing volume responsiveness in mechanically ventilated patients (1, 2). The concept is, based on the assumption that the cyclic changes in right ventricular preload in- duced by mechanical ventilation should result in greater cyclic changes in left ventricular stroke volume when both ventricles operate on the steep rather than on the flat portion of the Frank- Starling curve, ie, in the case of biven- tricular preload dependency (3). ‘This concept has gained great popularity in recent years for at least three reasons. First, the heart-lung interaction indices have’ been reported to reliably predict, fluid responsiveness in patients who are fully adapted to their ventilator and do rot experience cardiac arrhythmias (4). Second, classic markers of preload, such. as cardiac filling pressures, have been demonstrated to be poor predictors of fluid responsiveness (5, 6). Third, new hemodynamic monitors that provide au- tomatic calculation and real-time display of heart-lung interaction indices have been developed and are now available at the bedside. Most of these monitors, eg. PiCCO (Pulsion Medical Systems, “Mu- nich, Germany), LiDCO (LiDCO Ltd, Lon- don, UK), FloTracVigileo (Irvine, CA), use the arterial pressure waveform ob- tained from a peripheral artery catheter to derive heart-lung interaction indices. Pulse pressure variation (PPV) is probably the most popular dynamic parameter of fluid responsiveness since it is obtained from a simple algorithm (7). Stroke vol- *See also p. 2173. Key Words: cardiac preload; electrical impedance ‘omogray, it responsieness,puse pressure vari- ation, stoke volume vation Dr. Teboul consulted for Psion Medial Systems. Dr, Monnet is @ member ofthe Advisory Board for Paision Medial Systems. Copyright © 2011 by the Society of Citcal Care Medicine and Uppineat Wiliams & Wikins ok: 10.1097/60¥.0b01363187266080 2200 lume variation (SVV) is another dynamic parameter derived from the arterial pres- sure waveform analysis that, unlike PPV, can only be provided by hemodynamic devices that monitor stroke volume from. the arterial pressure waveform. Because of its denomination, SV sounds like a better reflection of the respiratory vari- ability of stroke volume than PPV. How- fever, a recent meta-analysis in mechani- cally ventilated patients showed that PPV is actually a better predictor of fluid re- sponsiveness than SVV (4), maybe be- cause the calculation of stroke volume from the arterial pressure waveform anal- ysis is based on mathematical assump- tions, which are not always applicable in critically ill patients. In addition, because of the pulse wave amplification phenom- enon, leading to a higher pulse pressure in the periphery than in the ascending aorta, PPV and SVV measured at the pe- riphery could differ from the correspond- ing indices, if measured in the ascending aorta. The magnitude of this difference is variable from patient to patient since the degree of the pressure wave amplification phenomenon depends on numerous fac- tors, such as age, height, arterial compli- ance, and vasomotor tone. In any case, because the femoral artery pressure is closer to the aortic pressure than the radial artery is (8), SVW measured at the femoral artery level should be a better reflection of the respiratory variation of, the left ventricular stroke volume than ‘SW if measured at the radial artery level. ‘Measuring the respiratory variability of the stroke volume at the level of aortic annulus is indisputably the best method, and it is feasible using ultrasound de- vices. Accordingly, the respiratory vari- ability of the aortic blood velocity mea- sured at the aortic annulus using echocardiography (9) has been demon- strated to be a good predictor of fluid responsiveness in mechanically venti- lated patients. The advantages of this technique are its low invasiveness and its ability to track the respiratory changes in stroke volume at the appropriate (cen- tral) level for minimizing the pulse wave amplification phenomenon and hence for ‘an adequate interpretation of heart-lung interaction indices in the perspective of as- sessing fluid responsiveness. Nevertheless, because echocardiography is an operator- dependent technique unable to provide a continuous monitoring of the hemody. namic variables, its widespread use is re- grettably still limited in the perspective of the prediction of fluid responsiveness. In this issue of the Critical Care Medi- cine, Maisch and co-workers (10) present interesting results of an experimental study in which SWV was assessed neither by ul- trasound techniques nor by arterial pres- sure waveform analysis but by an innova- tive technology. The electric impedance tomography continuously tracks the changes in intrathoracic volumes by mea- suring the changes in electric impedance of the thorax obtained from a thoracic belt applied around the thorax. The authors de- veloped a new analysis ofthe electric aortic impedance signal that allows assessment of, the volume-related changes in impedance induced by the beating heart, which leads toa continuous estimation of SW. In this preliminary validation study in animals, the authors found a good correlation between, SSW assessed by electric impedance tomog. raphy and the reference technique, ie., SW. measured by an ultrasound probe placed directly around the aortic annulus. These positive results must be, however, tem- pered by the fact that the limits of agree- ‘ment between SW assessed by electric im- pedance tomography and the reference method were (unacceptably?) large, sug- gesting that the technology is still imper- fect and should further be improved before being applied to patients. Surprisingly, the authors did not test whether SW estimated by the new technique actually predicted fluid responsiveness, ie., whether cardiac output significantly increased in response toa systematic volume challenge. Beyond the limitations of this preliminary study, electric impedance tomography should be regarded as a promising technology. Ifim- proved and applied to humans, this method Crt Care Med 2011 Vol. 38, No. 9would have the great advantage to be non- invasive and to assess on a real-time basis, the variations of stroke volume at the “cen- tral” level. Jean-Louis Teboul, MD, PhD Xavier Monnet, MD, PhD. AP-HP Service de Réanimation Médicale Hopitaux Universitaires Paris- ‘Sud and Faculté de Médecine Paris-Sud Université Paris-Sud Le Kremlin-Bicétre, France REFERENCES 1 Marik PE, Monnet X, Teboul JL: Dynamic parameters to guide Muid therapy. Ann Jn lensive Care 2011; Ll Crit Care Med 2011 Vol. 38, No. 9 Monnet X, Teboul JL: Volume responsive: ness. Curr Opin Cri Care 2007; 13:549-$53 Michard F, Teboul JL: Using heart-lung in- teractions to assess hid responsiveness dur- ing mechanical ventilation. Crit Care 2000; 4282-280 Marik PE, Caallazai R, Vasu T, et al: Dy- namie changes in arterial waveform derived variables and fuid responsiveness in me- chaniclly ventilated patients: A systematic review ofthe literature, Cif Care Med 200%; 37:2642-2647 (Osman D, Ride C, Ray , et al Cardiac fling pressures are not appropriae to predict he- ‘modynamic response to volume challenge. (Grit Care Med 2007; 5:64-68 Marik PE, Baram M, Vahid B: Does central venous pressure predict fuid responsive- ness? A systematic review of the literature and the tale of seven mares. Ches! 2008; 134172178 1. Michard F, Boussat S, Chemla D, et a: Relation between respiratory changes in arterial pulse pressure and uid respon- siveness in seplic patients with acute cir culatory failure. Am J Respir Crit Care Med 2000; 1622134138, Dufour N, Chemla D, Teboul JL, et al: Changes in pulse pressure following uid loading: A comparison between aortic root (non-invasive tonometry) and femoral artery (invasive recordings) Intensive Care Med 2011; 742-049 Feisel M, Michard P, Mangin I, et al: Resp ratory changes in aortic blood velocity as an indicator of uid responsiveness in ventilated patients with septic shock. Chest 2001 19867-8732 Mash, Bohm SH, Sola J, et a: Hear-lung inleractions measured by electrical imped ance tomography. Crit Care Med 2011; 39% 21n-2176, 2201