Towards changing the definition of the acute respiratory distress syndrome. one step forward...

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Editorials

Towards changing the definition of the acute respiratory distress

syndrome: One step forward*

Having a common and reli-able definition for the acuterespiratory distress syn-drome (ARDS) or acute lung

injury is very important for the manage-ment of this severe respiratory complica-tion. At a full stage, this syndrome corre-sponds to diffuse alveolar damage, butlung pathology is usually not availableexcept at autopsy (1). There is no vali-dated biomarker, even in bronchoalveolarlavage fluid, which could improve ourability for an early recognition of in-

creased lung permeability. An accuratedefinition is required for clinical trials orepidemiologic studies, with sufficientspecificity to reduce the noise-to-signalratio and good sensitivity to avoid miss-ing patients. An accurate definition canalso greatly help clinicians to definewhich patients may benefit from preciseventilatory strategies, diagnostic proce-dures, or drug therapy. Our current def-inition, coming from a consensus (2),has been extremely useful, especiallyfor clinical trials. It combines simple

parameters that are available at thebedside and a clinical assessment of thepatient. The cornerstone of this defini-tion is the PaO2/FIO2 ratio. This ratiohas become the most popular way toquantify oxygenation defects.

Several factors greatly influence thevalue of the PaO2/FIO2 ratio, indepen-dently from lung pathology, but are oftenignored at the bedside. Mixed venous ox-ygenation is a crucial one and is influ-enced by cardiac output. For a given lungstatus, varying cardiac output and arteri-

al-to-venous difference in oxygen contentheavily influences the PaO2/FIO2ratio (3).

For this reason, it was advocated in the1980s to calculate shunt using the Berg-gren equation instead of relying on PaO2and FIO2alone (4). The decline in the useof the pulmonary artery catheter, neces-sary to get mixed venous blood, is one ofthe reasons why this approach is not usedanymore. A second determinant is thepressure delivered by the ventilator. Forthis reason, pediatricians have intro-duced mean airway pressure in their as-sessment of oxygenation and calculationof the oxygenation index. Although this

approach makes good sense, a clear clin-ical advantage over the PaO2/FIO2 ratioalone has not been clearly demonstrated.Along the same line, several investigatorshave argued that the level of positive end-expiratory pressure (PEEP), a major de-terminant of oxygenation, needed to betaken into account, either by introducingthe PEEP level into an oxygenation equ-ation or by imposing a fixed level of PEEPto make calculations (5, 6). It is possible,however, that the vast majority of pa-tients in whom the PaO2/FIO2ratio is cal-

culated are already on a moderate, av-erage level of PEEP. How frequentlyadding a requirement for a given PEEPlevel would change the definition has notbeen clearly evaluated. This was the firstquestion addressed in the work done byBritos and colleagues (7) in this issue ofCritical Care Medicine, who explored theinfluence of the initial PEEP level onmortality across different ranges of PaO2/FIO2. They used the data collected duringconduct of the ARDS Network trials,when patients were enrolled in clinical

trials, making a total of 2,312 patientswith acute lung injury/ARDS available.They tested if, for a given range of PaO2/FIO2 values, mortality was different ac-cording to the PEEP level, which wouldsuggest that patients with very differentdisease severity were enrolled under thesame oxygenation criterion. It is remark-able, however, to see in the results ofBritos et al, how consistent the mortalityis between a PEEP at 5 cm H2O or belowand a PEEP at 11 cm H2O or above. This

suggests 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 FIO2, which byitself decreases the PaO2/FIO2 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 (1.3%) were ventilatedwith PEEP levels below 5 cm H2O. At theopposite, only 11% of patients had PEEP

at 15 cm H2O or higher before enroll-ment in the trials. Therefore, their resultsmay not apply to ICUs where the PEEPlevel is frequently under 5 cm H2O orabove 14 cm H2O to calculate the initialPaO2/FIO2 ratio.

A last issue is the effect of the FIO2level on the PaO2/FIO2 ratio itself. This isoften ignored because it sounds as coun-terintuitive. Clinicians may think thatnormalizing PaO2 to FIO2 is possible be-cause a linear relationship exists betweenthe two. This is not the case, however,

and several experimental or clinical stud-ies have clearly shown that there is anonlinear relationship between PaO2 andFIO2, and consequently between PaO2andPaO2/FIO2(810). The shape of the oxyhe-moglobin dissociation curve describingthe relationship of the percentage of he-moglobin saturation to the blood PO2andthe equation for human blood oxygen dis-sociation explains this relationship (11).This relationship is difficult to predictbecause 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 PaO2/FIO2 ratiowhen FIO2 is raised from around 50% or60% up to 100%. This means that a givenPaO2/FIO2 value measured in a patient atFIO21.0 will reflect a more severe impair-ment of oxygenation than in another pa-tient with the same PaO2/FIO2 ratio at aFIO2of only 50%. It also means that for agiven patient, changing FIO2modifies the

*See also p. 2025.Key Words: acute lung injury; acute respiratory

distress syndrome; oxygenation; positive end-expiratory pressure; ventilation

The author has not disclosed any potential con-flicts of interest.

Copyright 2011 by the Society of Critical CareMedicine and Lippincott Williams & Wilkins

DOI: 10.1097/CCM.0b013e318226607a

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PaO2/FIO2value. As an illustration, a studyperformed in 14 patients with acute lunginjury or ARDS showed that decreasingFIO2from 1.0 to 0.6 over 15 mins led to areduction of the PaO2/FIO2 ratio from amedian of 223 mm Hg to a median of 158mm Hg at the same high PEEP level; thesame change was reproduced from 171 to115 at a lower PEEP level (12). Therefore,taking into account the FIO2 in the defini-

tion may help to better identify the diseaseseverity of the patients. This is what wasfound in a second part of the analysis byBritos et al (7). Contrasting with the lack ofinfluence of PEEP, they found that themortality rate significantly increased ateach range of PaO2/FIO2values for FIO2vary-ing from 0.50 or less to 0.70 or more.

These results are important becausethey confirm physiologic observations ona large scale and may need to be takeninto account for a revision of the currentdefinition of ARDS. Although the PEEP

level was not found to influence the re-sults, calculating the PaO2/FIO2ratio for aPEEP level of at least 5 cm H2O and nomore than 15 cm H2O may be reasonable.A big step forward can be to introduce the

level of FIO2 in the definition of ARDS,which could help to better stratify thedisease severity of patients.

Laurent J. Brochard, MD

Department of Intensive Care

Geneva University HospitalUniversity of Geneva

Geneva, Switzerland

REFERENCES

1. Esteban A, Fernandez-Segoviano P, Frutos-VivarF, et al: Comparison of clinical criteria for the

acute respiratory distress syndrome with autopsy

findings.Ann Intern Med2004; 141:440 445

2. Bernard GR, Artigas A, Brigham KL, et al:

The American-European Consensus Confer-

ence on ARDS. Definitions, mechanisms, rel-

evant outcomes, and clinical trial coordina-

tion. Am J Respir Crit Care Med1994; 149:

818824

3. Lemaire F, Teisseire B, Harf A: [Assessment

of acute respiratory failure: Shunt versus al-

veolar arterial oxygen difference]. Ann Fr

Anesth Reanim 1982; 1:5964

4. Berggren S: The oxygen deficit of arterialblood caused by non ventilating parts of the

lung.Acta Physiol Scand1942; 11:192

5. Villar J, Perez-Mendez L, Lopez J, et al: An

early PEEP/FIO2 trial identifies different de-

grees of lung injury in patients with acute

respiratory distress syndrome. Am J Respir

Crit Care Med2007; 176:795804

6. Villar J, Perez-Mendez L, Kacmarek RM: Cur-

rent definitions of acute lung injury and the

acute respiratory distress syndrome do not

reflect their true severity and outcome. In-

tensive Care Med1999; 25:930935

7. Britos M, Smoot E, Liu KD, et al: The value

of positive end-expiratory pressure and FiO2criteria in the definition of the acute respi-

ratory distress syndrome. Crit Care Med

2011; 39:302530308. Aboab J, Louis B, Jonson B, et al: Relation

between PaO2/FIO2 ratio and FIO2: A math-

ematical description. Intensive Care Med

2006; 32:1494 1497

9. Gowda MS, Klocke RA: Variability of indices

of hypoxemia in adult respiratory distress

syndrome.Crit Care Med1997; 25:4145

10. Whiteley JP, Gavaghan DJ, Hahn CE: Varia-

tion of venous admixture, SF6 shunt, PaO2,

and the PaO2/FIO2 ratio with FIO2. Br J

Anaesth2002; 88:771778

11. Severinghaus JW: Simple, accurate equa-

tions for human blood O2 dissociation com-

putations.J Appl Physiol1979; 46:599602

12. Aboab J, Jonson B, Kouatchet A, et al: Effect

of inspired oxygen fraction on alveolar dere-

cruitment in acute respiratory distress syn-

drome. Intensive Care Med 2006; 32:

19791986

Burn fluid resuscitation: Let the autopilot do it!*

Before the recognition of themagnitude of fluid shifts andthe massive fluid require-ments of severe burn patients,

hypovolemia, hypoperfusion, and organfailure was the leading cause of death.Investigations in the 1960s led to thewidely accepted Parkland formula (1).Despite controversy and debate overamounts, algorithms, and fluid mixes,the Parkland formula is still the mostwidely used (2). From 1970 to 2000, burnfluid resuscitation science was dominatedby the fear of hypovolemia, hypoperfu-

sion, shock, and organ damage. Fluidshave been generously administered, far

beyond the original recommendations. In2000, the Seattle team showed that 58%of the patients received more fluid thanpredicted (3). A similar observationalstudy from Toronto (4) showed that pa-tients received on average 6.7 mL/kg/%burn surface area (instead of the original 4mL/kg/%), and 84% of the patients receivedmore than predicted compared to 12% inthe original study (1). Sadly, too muchfluid, a phenomenon calledfluid creep, canlead to Michelin Man patients and organfailure (5, 6). Awareness of the side effects

of fluid over-resuscitation has increasedover the last decade. The most significanteffect of fluid over-resuscitation in burnpatients is edema of the stasis area sur-rounding the deeper burned coagulationarea. This leads to necrosis of just viabletissue yielding to a secondary deepeningand extension of the burn area. Abdominalcompartment 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

dictate more fluids, but may also reflectover-resuscitation and the onset of abdom-inal compartment syndrome (9). Despiteawareness of the problem (10), the pendu-lum is still above Baxters original recom-mendations (11).

The fine balance between too little ortoo much fluid is hard to maintain andrequires clinicians with extensive burnexperience. In this context, the paper inthis issue of Critical Care Medicine bySalinas and colleagues (12) is very wel-come. They showed that using an algo-

rithm programmed in Java they were ableto suggest the right amount of fluid tomaintain an adequate urine output with-out polyuria while limiting hypoperfu-sion and fluid creep in burn patients. Thesame investigators previously published afull closed-loop system in experimentalsheep burn (13). The present paper is aninteresting application, but is not yet a fullclosed-loop system. The system gives theclinician advice, which can be followed orignored (Fig. 1).

*See also p. 2031.Key Words: burn; clinical decision support sys-

tems; critical care automation; fluid creep; fluid resus-citation; open-loop system



DOI: 10.1097/CCM.0b013e31821f030d

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The first autopilot in aviation was in-vented by Lawrence Sperry one centuryago (1912). Based on a gyroscope and analtimeter, the system was able to main-

tain a constant heading and altitude. Thesystem was connected hydraulically tothe elevators and rudder. With the evolu-tion of technology and computer science,

systems are now able to control all planesystems, including engine thrust, andperform a complete flight plan. Typicallyseveral hundred thousand lines of com-puter code are required to fly actualplanes. Flight management systems havebeen shown to provide a smoother ridewith lower fuel consumption comparedto 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 byless wobbling in terms of both fluid ad-ministration and urine output, and theyreduced the fuel consumption, i.e., thetotal fluid needed for the same - or evenbetter - result. There are two componentsin 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 thedifference in outcome, as shown in septicshock or burn resuscitation (14), and soft-ware makes it easy to apply. An algorithmicapproach to burn fluid resuscitation wasproposed 20 yrs ago by Miller et al (15). Theconcept of closed loop in medicine is notnew. A Society of Critical Care Medicinetask force pioneered the assessment ofclosed-loop technologies 16 yrs ago (16).

In aviation, the development of flightmanagement systems was welcomed bypilots, having more time and mind tofocus on the navigation and safety ratherthan the flying process. Interestingly, al-

though the clinical decision system pre-sented here gives sound fluid resuscita-tion advice, the advice was frequently notapplied. Interestingly, when clinicians fol-lowed the advice of the decision system,they were more often in the target in termsof urine output, than when100 mL/hr offthe computer decision support system. De-cision systems often act more quickly thanthe clinician and avoid overreacting whenlate. For example, closed-loop ventilationsystems adapt each breath based on theprevious 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 duringhemodialysis (18) or lidocaine infusion tocontrol premature ventricular contrac-tions (19) have been developed but didnot 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 ofresources, this will not be possible. Avail-

Figure 1. Various concepts in systems.A, An open-loop system. The computer analyzes the input andmakes suggestions to the clinician. The system presented by Salinas et al in the present issue bears thisconcept. B, In closed-loop systems, the computer directly adapts the pump rates to achieve a desiredinput. In integrated systems (C) the computer combines several forms of information to program thepump rates or other types of information. In neural network type systems (D), the system adaptsthrough several hidden layer neurons the output from various inputs. The system learns fromprevious situations. BP, blood pressure; HR, heart rate; BIS, bispectral index scale.



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able systems can not only manage fluidresuscitation, but also glucose level (20),anesthesia (21), or ventilation weaning(17). Future systems will be integrated andable to adapt dynamically to the changingsituation. A significant part of todays clini-cians are reluctant to give away the controlstick to a computer. Clinicians should notreject these system (or their advice), hidingbehind theart of critical careor burn fluid

management. These decision support sys-tems are here to do your basic job. The newrole 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 replacepilots in airplanes; autopilots will never beable to land on the Hudson River with bothengines out (22). They are our assistants,our helpers, and can extend the burn in-tensive care unit expertise outside the burnunit walls to remote hospitals, austere en-vironments, transport situations, disastersituations, and less wealthy countries.

David Bracco, MD, PhD, FCCM

Associate Professor ofAnesthesia

Critical Care and Trauma

McGill University

Montreal General Hospital,Montreal

Quebec, Canada

REFERENCES

1. Baxter CR, Shires T: Physiological response

to crystalloid resuscitation of severe burns.

Ann N Y Acad Sci1968; 150:874894

2. Greenhalgh DG: Burn resuscitation: The results

of the ISBI/ABA survey.Burns 2010; 36:176182

3. Engrav LH, Colescott PL, Kemalyan N, et al:

A biopsy of the use of the Baxter formula to

resuscitate burns or do we do it like Charlie

did it? J Burn Care Rehabil2000; 21:9195

4. Cartotto RC, Innes M, Musgrave MA, et al:

How well does the Parkland formula estimate

actual fluid resuscitation volumes? J Burn

Care Rehabil2002; 23:258265

5. Saffle JI: The phenomenon of fluid creep in

acute burn resuscitation. J Burn Care Res2007; 28:382395

6. Chung KK, Wolf SE, Cancio LC, et al: Resus-

citation of severely burned military casualties:

Fluid begets more fluid. J Trauma 2009; 67:

231237

7. Balogh Z, McKinley BA, Cocanour CS, et al:

Supranormal trauma resuscitation causes

more cases of abdominal compartment syn-

drome. Arch Surg 2003; 138:637642; dis-

cussion 642 643

8. Burke BA, Latenser BA: Defining intra-

abdominal hypertension and abdominal

compartment syndrome in acute thermal in-

jury: A multicenter survey. J Burn Care Res

2008; 29:5805849. Azzopardi EA, McWilliams B, Iyer S, et al:

Fluid resuscitation in adults with severe

burns at risk of secondary abdominal com-

partment syndromean evidence based sys-

tematic review. Burns 2009; 35:911920

10. Pruitt BA Jr: Protection from excessive re-

suscitation: Pushing the pendulum back.

J Trauma2000; 49:567568

11. Cartotto R, Zhou A: Fluid creep: The pendu-

lum hasnt swung back yet! J Burn Care Res

2010; 31:551558

12. Salinas J, Chung KK, Mann EA, et al: Comput-

erized decision support system improves fluid

resuscitation following severe burns: An origi-

nal study.Crit Care Med2011; 39:20312038

13. Salinas J, Drew G, Gallagher J, et al: Closed-

loop and decision-assist resuscitation of burn

patients.J Trauma 2008; 64:S321S332

14. Chung KK, Blackbourne LH, Wolf SE, et al:

Evolution of burnresuscitation in operation Iraqi

freedom. J Burn Care Res2006; 27:606611

15. Miller JG, Carruthers HR, Burd DA: An algo-

rithmic approach to the management of cu-

taneous burns. Burns 1992; 18:200211

16. Jastremski M, Jastremski C, Shepherd M, et

al: A model for technology assessment as

applied to closed loop infusion systems.Technology Assessment Task Force of the

Society of Critical Care Medicine. Crit Care

Med1995; 23:17451755

17. Burns KE, Lellouche F, Lessard MR: Auto-

mating the weaning process with advanced

closed-loop systems. Intensive Care Med

2008; 34:17571765

18. Jannett TC, Wise MG, Sanders PN: An adaptive

control system for delivering heparin to pro-

vide anticoagulation during hemodialysis. Conf

Proc IEEE Eng Med Biol Soc 1992; 14:22972298

19. Jannett TC, Kay GN, Sheppard LC: Auto-

mated administration of lidocaine for the

treatment of ventricular arrhythmias. Med

Prog Technol1990; 16:5359

20. Yatabe T, Yamazaki R, Kitagawa H, et al: The

evaluation of the ability of closed-loop glycemic

control device to maintain the blood glucose

concentration in intensive care unit patients.

Crit Care Med2011; 39:575578

21. Absalom AR, De Keyser R, Struys MM: Closed

loop anesthesia: Are we getting close to finding

the holy grail?Anesth Analg2011; 112:516518

22. Federal Aviation Administration. Accident and

Incident Data: USAirways 1549 (AWE1549),

January 15, 2009. 2009. Available at: http://

www.faa.gov/data_research/accident_incident/

1549/.Accessed April 1, 2011

Acute kidney injury: Clear the kidney of apoptotic debris!*

Acute kidney injury (AKI) is amajor clinical problem in in-tensive care units. Sepsis-induced AKI is the most com-

mon form of AKI observed in critically illpatients, but ischemia-reperfusion (I/R)

injury play a crucial role in the develop-ment of AKI in all types of shock, trauma,and transplantation. Similar to sepsis, I/Rinjury is accompanied by an intense sys-

temic inflammatory response, which mayinduce organ damage at a distance fromthe initial ischemic insult site. Accumu-lating evidence highlights the crucial roleof effective clearance of apoptotic cellsafter ischemia to prevent the accumula-tion of inflammatory apoptotic cells, hy-percoagulable state, and impaired tissuerepair (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 growthfactor 8 (MFG-E8)/lactadherin is one ofthese bridging molecules (36).

MFG-E8 is a glycoprotein originallyfound in milk-fat globules and mammaryepithelial cells. MFG-E8 is expressed inseveral epithelial cells and in immunecells involving macrophages and den-dritic cells. MFG-E8 has a domain struc-ture of epidermal growth factor (EGF)1-EGF2-C1-C2 in which EGF indicatesEGF homology domains, and the C do-mains share homology with the phos-phatidylserine-binding domains of bloodcoagulation factors V and VIII. The sec-

*See also p. 2039.Key Words: acute kidney injury; apoptosis; lactad-

herin; milk fat globule-epidermal growth factor 8;phagocytic clearance

The authors have not disclosed any potential con-flicts of interest.


DOI: 10.1097/CCM.0b013e318226619c

http://www.faa.gov/data_research/accident_incident/1549/http://www.faa.gov/data_research/accident_incident/1549/http://www.faa.gov/data_research/accident_incident/1549/http://www.faa.gov/data_research/accident_incident/1549/http://www.faa.gov/data_research/accident_incident/1549/http://www.faa.gov/data_research/accident_incident/1549/http://www.faa.gov/data_research/accident_incident/1549/


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ond EGF-like domain binds to the v3and v5 integrins. The second C do-main binds to phospholipids. MFG-E8promotes phagocytosis of apoptotic cellsby establishing a bridge between phos-phatidylserine on apoptotic cells and in-tegrins on phagocytes (6, 7), modulatesdownstream inflammatory signalingpathways, promotes vascular endothelialgrowth factor and neovascularization via

the induction of integrin-dependent Aktphosphorylation in endothelial cells (8),and promotes cell/cell adhesion such asthat during sperm-oocyte interaction (9).

In this context, an interesting manu-script in the current issue ofCritical Care

Medicine provides useful new informa-tion. In this issue, Matsuda and col-leagues (10) described that, while the ex-pression of MGF-E8 was reduced afterrenal I/R injury in mice, intraperitonealadministration of MGF-E8 attenuates tu-bular I/R injury and improves the survival

rate of renal I/R mice. This renal-protective effect appears to be mediatedthrough anti-inflammatory and antiapo-ptotic effects of recombinant murineMFG-E8 and improvement of capillaryfunctions (recovery of vascular endothe-lial growth factor expression and suppres-sion of endothelin-1 overexpression) inthe kidney. This study confirms previousresults of the same group reporting anattenuation of inflammation and acutelung injury by MFG-E8 after mesentericI/R (11). After superior mesenteric artery

occlusion for 90 mins followed by reper-fusion for 4 hrs, MFG-E8 levels decreasedin the spleen and lungs by 50% to 60%.Treatment with recombinant murineMFG-E8 significantly suppressed inflam-mation (tumor necrosis factor-, inter-leukin-6, interleukin-1, and myeloper-oxidase) and injury of the lungs, liver,and kidneys, with a significant improve-ment in survival of wild-type mice.

These two studies 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 afterI/R injury.These studies lend credence to the no-

tion that inflammation and uncleared de-bris from dying cells play a major role inthe I/R injury. This role is not only lim-ited to the ischemic organ (renal I/R in-jury in the Matsuda study), but is alsoimportant in the nonischemic organs(liver injury induced by renal ischemia inthe Matsuda study). Recent studies have

clearly shown that efficient phagocytosisof apoptotic debris is critical to the main-tenance of an anti-inflammatory milieu.Phagocytic clearance of apoptotic debrisis beneficial because it removes toxic orinflammatory stimuli and avoids an exag-gerated immune response with down-stream effects, such as secretion of cyto-kines and a production of reactive oxygenspecies. Fast removal of apoptotic cells by

phagocytes in tissues and circulation mayprevent a secondary (postapoptotic) ne-crosis of apoptotic cells with leakage oftoxic or inflammatory debris. Ait-Oufellaet al (2) reported a marked acceleration ofatherosclerosis in MGF-E8-deficientmice, with substantial accumulation ofapoptotic debris, both systemically andwithin the developing lipid lesions. Thisaccumulation of apoptotic debris was as-sociated with a reduction in interleu-kin-10 in the spleen and an alteration ofnatural regulatory T-cell function, but anincrease in interferon- production inboth the spleen and the atheroscleroticarteries. Miksa et al (12), in a cecal liga-tion and puncture model, found a reduc-tion of MFG-E8 protein levels in thespleen and liver by 48% and 70%, respec-tively. Peritoneal macrophages fromMFG-E8-treated rats displayed a 2.8-foldincreased ability to phagocytose apoptoticcells with an attenuation of the systemicinflammatory response.

As mentioned by Matsuda et al (10), theobserved beneficial effect of MFG-E8 intheir renal I/R model is attributed to the fact

that MFG-E8 accelerates the phagocytosis ofapoptotic cells based on several studies (3, 4,12, 13). However, the authors reported thatrecombinant murine MFG-E8 decreases apo-ptotic cells in the kidney after I/R injury, butthere is no direct data showing that clearanceof apoptotic cells is impaired after renal I/R. Itis plausible that the MFG-E8mediated pro-tection after renal I/R results from an im-provement of the MFG-E8mediated apopto-tic cell phagocytosis, but this hypothesis hasto be demonstrated in further investigations.

Matsuda et al (10) provide new in-

sights into the field of AKI therapy. Thisstudy suggests that recombinant MFG-E8may be beneficial for the treatment oftubular I/R injury and could be a noveltreatment option for AKI. This therapeu-tic hypothesis must be confirmed byother teams, but it is obviously an excit-ing therapeutic approach that must beactively investigated.

Anatole Harrois, MD

Jacques Duranteau, MD, PhD

Assistance Publique - Hopitauxde Paris

Hopital Bicetre

Departement dAnesthesie-Reanimation

Universite Paris, Sud XI

Le Kremlin-Bicetre, France

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1. Thorp EB: Mechanisms of failed apoptoticcell clearance by phagocyte subsets in car-

diovascular disease. Apoptosis 2010; 15:

11241136

2. Ait-Oufella H, Kinugawa K, Zoll J, et al: Lac-

tadherin deficiency leads to apoptotic cell

accumulation and accelerated atherosclero-

s is i n m ic e. Circulation 2007; 115:

21682177

3. Hanayama R, Tanaka M, Miyasaka K, et al:

Autoimmune disease and impaired uptake of

apoptotic cells in MFG-E8-deficient mice.

Science2004; 304:11471150

4. Hanayama R, Tanaka M, Miwa K, et al: Iden-

tification of a factor that links apoptotic cells

to phagocytes. Nature 2002; 417:1821875. Bu HF, Zuo XL, Wang X, et al: Milk fat

globule-EGF factor 8/lactadherin plays a cru-

cial role in maintenance and repair of mu-

rine intestinal epithelium.J Clin Invest2007;

117:36733683

6. Fens MH, Mastrobattista E, de Graaff AM, et

al: Angiogenic endothelium shows lactad-

herin-dependent phagocytosis of aged eryth-

rocytes and apoptotic cells. Blood2008; 111:

45424550

7. Leonardi-Essmann F, Emig M, Kitamura Y,

et al: Fractalkine-upregulated milk-fat glob-

ule EGF factor-8 protein in cultured rat mi-

croglia.J Neuroimmunol2005; 160:92101

8. Silvestre JS, Thery C, Hamard G, et al: Lac-

tadherin promotes VEGF-dependent neovas-

cularization.Nat Med2005; 11:499506

9. Ensslin MA, Shur BD: Identification of

mouse sperm SED1, a bimotif EGF repeat

and discoidin-domain protein involved in

sperm-egg binding. Cell2003; 114:405417

10. Matsuda A, Wu R, Jacob A, et al: Protective

effect of milk fat globule-epidermal growth

factor-factor VIII after renal ischemia-

reperfusion injury in mice. Crit Care Med

2011; 39:2039 2047

11. Cui T, Miksa M, Wu R, et al: Milk fat globule

epidermal growth factor 8 attenuates acute

lung injury in mice after intestinal ischemiaand reperfusion. Am J Respir Crit Care Med

2010; 181:238246

12. Miksa M, Wu R, Dong W, et al: Dendritic

cell-derived exosomes containing milk fat

globule epidermal growth factor-factor VIII

attenuate proinflammatory responses in sep-

sis. Shock 2006; 25:586593

13. Dasgupta SK, Abdel-Monem H, Guchhait P,

et al: Role of lactadherin in the clearance of

phosphatidylserine-expressing red blood

cells.Transfusion 2008; 48:23702376



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Too much of a good thing is not necessarily better*

In a situation of emerging multi-drug resistance among important

pathogens and a very high (toohigh?) use of very-broad-spectrumantibiotics in the intensive care units(ICUs) worldwide, the importance of an-timicrobial stewardship is increasinglynecessary and action is urgently needed(1). At the same time, sepsis is a contin-uous risk for patients in the ICUs andbecause delay to appropriate antimicro-bial therapy in severe bacterial infectionsis related to mortality (2 4), it is recom-mended in guidelines to initiate antimi-crobial therapy within 1 hr (5). The diag-nosis of sepsis is hampered, however, byits nonspecific presentation because thesystemic inflammatory response syn-drome is common not only in severeinfection, but also in various noninfec-tious conditions of inflammation. Theclinician needs help to rational use ofpotent antimicrobial therapy if weshould not give way to blind very broad-spectrum antibiotic exposure to every-one, which will be the way directly tountreatable infections resulting frommultiresistant organisms (6).

It is also a fact that only a minority of

septic patients will have a microbiologi-cally documented bloodstream or other-wise serious infection, so most patientsare treated on clinical suspicion based onaltered organ functions, radiologic imag-ing, biochemistry, and biomarkers suchas C-reactive protein or procalcitonin(PCT). In several infectious diseases, theapplication of PCT guidance for decisionson antibiotic therapy has proven helpfulto support antibiotic stewardship and areduction in exposure to antibiotics isusually possible without adverse out-

comes (7). This principle can work in thecritically ill population of the ICU from astepdown perspective as shown in the

French Procalcitonin to Reduce PatientsExposure to Antibiotics in Intensive Care

Units (PRORATA) trial (8) and to reduceantibiotic exposure in ventilator-associ-ated pneumonia (9), but the question re-mains if it is possible to initiate antibiotictherapy with less extensive antimicrobialspectrum and then use PCT guidance toescalate when necessary.

The study by Jensen and coworkerspublished in this issue of Critical Care

Medicine(10) is so far the largest multi-center randomized clinical trial exploringa biomarker-guided strategy of antibiotictherapy in the ICU setting. The study

conclusion challenges the dogma that es-calation from target-directed to verybroad-spectrum (blind) antibiotics be-fore a microbiologic diagnosis increasessurvival in the ICU. The trial was con-ducted in nine multidisciplinary ICUs inDenmark with a randomization of 1200patients to daily PCT guidance or stan-dard of care. Consequently, the escalationto broad-spectrum piperacillin/tazobac-tam or meropenem was significantlymore prevalent in the PCT group, butdisappointingly, no survival benefit was

demonstrated. The results were robustbecause several subanalyses on stratifica-tion of the cohort confirmed the outcometo be nondifferent. The study confirmsprevious observations (11) that the sen-sitivity of baseline PCT is low and thuscannot be used to rule out infection,whereas the changes in PCT concentra-tion on repeated measurements predictsprognosis.

An unexpected finding for patients onthe PCT strategy was increased time onmechanical ventilation and longer time

with renal failure. Increased morbidityassociated with a PCT strategy was alsosuggested in the PRORATA trial (8). Ad-ditionally, the length of stay in the ICUwas prolonged in the PCT-guided strat-egy. These findings are a strong reminderthat new diagnostics and new therapiesshould not be introduced to routine carewithout prior rigorous scientific evalua-tion because unexpected adverse eventsmay occur. Too much of a good thing isnot necessarily better.

The strengths of the study were thedesign, the large sample size, inclusion of

multiple centers, rigorous statisticalanalysis, and the complete follow-up un-til the primary end point. The authorsshould be congratulated with the effortsto report 28-day mortality as the pre-ferred outcome, superior to inhospitalmortality often reported in such studies.

The limitations of the study includethe mononational design because all cen-ters in Denmark had a low prevalence ofmultiresistant organisms in contrast tomost other countries, which reduce thepredictive value of a positive PCT alert. Inthe Scandinavian countries with a rela-tively low incidence of multiresistantpathogens, the study results are reassur-ing that it is safe to continue with arestrictive antibiotic policy in the ICUswithout escalating to very broad-spec-trum agents unless supported by micro-biologic findings. The proportional expo-sure in the standard-of-care group topiperacillin/tazobactam or meropenemwas as low as 0.07 and yet the survivalwas not adversely affected. However, forcountries with a higher prevalence ofmultidrug resistance, the results may not

apply, so generalization is maybe not pos-sible. Another parameter, which may dif-fer among centers, is fungal infections inthe ICU because PCT response to Candidaspecies is considerably weaker as com-pared with bacterial infections (12). Fur-thermore, the mortality in ICU patients ismultifactorial and intervention within asingle area of treatment (e.g., antibiotics)rarely results in substantial mortalityreduction.

As reported, biomarkers cannot sub-stitute for good microbiologic data in the

ICU (13), but admittedly, the turnaroundtime is a problem. Although we still waitfor that superior sensitive bedside, 1-hr,broad-range pathogen test covering allrelevant organisms with a very high spec-ificity to rule out infection in the septicpatient, the clinician is dependent onmicrobiologic findings, biochemistry ofacute-phase reactants, and careful obser-vations of patient physiology responses.The hope for PCT guidance to improveoutcome is unclear, and the study by Jen-

*See also p. 2048.

Key Words: antibiotics; clinical trial; intensive care;procalcitonin



DOI: 10.1097/CCM.0b013e3182207c13



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sen and coworkers may not apply to allcountries. We are eagerly awaiting theresults of ongoing clinical trials on PCTguidance in ICU patients (14, 15).

Henrik Nielsen, MD, DMSci

Department of InfectiousDiseases

Aalborg HospitalAarhus University Hospitals

Aalborg, Denmark

REFERENCES

1. Dellit TH, Owens RC, McGowan JE, et al:

Infectious Diseases Society of America and

the Society for Healthcare Epidemiology of

America guidelines for developing an insti-

tutional program to enhance antimicrobial

stewardship. Clin Infect Dis 2007; 44:

159177

2. Leibovici L, Shraga I, Drucker M, et al: The

benefit of appropriate empirical antibiotic

treatment in patients with bloodstream in-

fection. J Intern Med1998; 244:379386

3. Ibrahim EH, Sherman G, Ward S, et al: The

influence of inadequate antimicrobialtreatment of bloodstream infections on pa-

tient outcome in the ICU setting. Chest

2000; 118:146155

4. Kumar A, Roberts D, Wood KE, et al: Dura-

tion of hypotension before initiation of effec-

tive antimicrobial therapy is the critical de-

terminant of survival in human septic shock.

Crit Care Med2006; 34:15891596

5. Dellinger RP, Carlet JM, Masur H, et al: Sur-

viving Sepsis Campaign guidelines for man-

agement of severe sepsis and septic shock.

Crit Care Med2004; 32:858883

6. Nordmann P, Poirei L, Toleman MA, et al:

Does broad-spectrum -lactam resistance

due to NDM-1 herald the end of the antibi-otic era for treatment of infections caused by

Gram-negative bacteria? J Antimicrob

Chemther2011; 66:689692

7. Simon L, Gauvin F, Amre DR, et al: Serum

procalcitonin and C-reactive protein levels as

markers of bacterial infection: A systematic

review and meta-analysis. Clin Infect Dis

2004; 39:206217

8. Bouadma L, Luyt CE, Tubach F, et al: Use of

procalcitonin to reduce patients exposure to

antibiotics in intensive care units (PRORATA

trial): A multicentre randomised controlled

trial. Lancet 2010; 375:463474

9. Stolz D, Smyrnios N, Eggimann P, et al:

Procalcitonin for reduced antibiotic expo-sure in ventilator-associated pneumonia: A

randomised study. Eur Respir J 2009; 34:

13641375

10. Jensen JU, Hein L, Lundgren B, et al: Pro-

calcitonin-guided interventions against in-

fections to increase early appropriate antibi-

otics and improve survival in the intensive

care unit: A randomized trial. Crit Care Med

2011; 39:2048 2058

11. Jensen JU, Heslet L, Jensen TH, et al: Pro-

calcitonin increase in early identification

of critically ill patients at high risk of mor-

tality. Crit Care Med 2006; 34:2596

2602

12. Charles PE, Dalle F, Aho S, et al: Serumprocalcitonin measurement contribution to

the early diagnosis of candidemia in critically

ill patients. Intensive Care Med 2006; 32:

15771583

13. Jung B, Embriaco N, Roux F, et al: Microbio-

logical data, but not procalcitonin improve the

accuracy of the clinical pulmonary infection

score.Intensive Care Med 2010; 36:790798

14. Placebo controlled trial of sodium selenite and

procalcitonin guided antimicrobial therapy in se-

vere sepsis (SISPCT). Available at: http://www.

clinicaltrials.gov/ct2/show/NCT00832039. Ac-

cessed April 27, 2011

15. Safety and efficacy of procalcitonin guided an-

tibiotic therapy in adult intensive care units(ICUs) (SAPS). Available at: http://www.

clinicaltrials.gov/ct2/show/NCT01139489. Ac-

cessed April 27, 2011

Take a deep breath*

Patient care is an art directed byscience. New discoveries from

good clinical research oftenprompt changes in patient care

or in the way clinicians think about dis-ease. But by shifting their focus to thelatest topic in the literature, cliniciansmay ignore more mundane problems.When an old problem comes back intofocus, there is an opportunity for newinsight.

In this issue ofCritical Care Medicine,Schmidt and colleagues (1) refocus ondyspnea in mechanically ventilated pa-tients. Their findings suggest that dys-

pnea is common, often severe, is associ-ated with anxiety, responds to basicventilator changes in a third of cases, and

correlates with time on mechanical ven-tilation. They conclude that more re-

search is needed to evaluate whether thebenefits of modern therapies for respira-tory failure are worth their dyspnea-related ransom. This conclusion reso-nates at a scientific level. At the sametime, it suggests that there are timeswhen the science applied fails an individ-ual patient.

When clinical research uncovers adramatic finding, the natural tendency isto apply it. Low tidal volumes preventlung injury in the acute respiratory dis-tress syndrome (2); they might be helpful

with other forms of respiratory failure aswell (3). Limiting (4) or avoiding (5)some forms of sedation might reduce theincidence of delirium or the time spenton mechanical ventilation. Of course,good clinical research tends to be carriedout under tightly controlled conditionson a specific group of patients. One of thedifficult questions an astute clinicianmust ask when applying scientific data toa patient is: do the patients in the studyreflect the patient I am caring for right

now? Understanding the mechanisms ofthe disease and the therapy helps answer

this question, but no mechanistic modelis complete. Ultimately, the clinicianmust look for reasons to accept or rejectthe application of clinical science to hispatient.

In the case of respiratory failure, thefocus on therapy (mechanical ventilation)has shifted from how best to support apatients breathing to how to avoid harm.Changes in ventilation strategies, seda-tion regimens, and bundled-care proto-cols for ventilated patients (6) reflected adesire 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 surveyedintubated 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

*See also p. 2059.

Key Words: breathing pattern; dyspnea; mechani-cal ventilation; patient anxiety; respiratory sensations



DOI: 10.1097/CCM.0b013e3182217442

http://www.clinicaltrials.gov/ct2/show/NCT00832039http://www.clinicaltrials.gov/ct2/show/NCT00832039http://www.clinicaltrials.gov/ct2/show/NCT00832039http://www.clinicaltrials.gov/ct2/show/NCT01139489http://www.clinicaltrials.gov/ct2/show/NCT01139489http://www.clinicaltrials.gov/ct2/show/NCT01139489http://www.clinicaltrials.gov/ct2/show/NCT01139489http://www.clinicaltrials.gov/ct2/show/NCT00832039http://www.clinicaltrials.gov/ct2/show/NCT00832039


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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 (medianvisual 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 studysuggests some proportion of dyspnea couldbe treated by ventilator changes. Further-

more, lack of improvement in dyspnea cor-related with increased time on mechanicalventilation, raising the possibility that dys-pnea-focused therapies, at least in somepatients, might improve critical outcomes.The association of dyspnea with anxietyadds to a growing literature on the psycho-logical burden of critical illness, includingthe risks of posttraumatic stress disorder(9) and depression (10). Shifting the focusfrom mechanics and complications to thesensation of breathlessness, the authorshave uncovered a new therapeutic target.

It is refreshing to think that a classicmodel of symptom and therapy mightimprove outcomes, but too much mustnot be extrapolated from this initial of-fering. The study subjects are not rep-resentative of all mechanically venti-lated patients. The study patients wereresponsive and able to answer questionsabout dyspnea. Few, if any, had delir-ium. A large number were ventilated forneurologic conditions, especially motor

weakness, and extrapolation to patientswithout these disorders will be specu-lative. Nevertheless, this study chal-lenges conventional thinking. It shoulddrive the exploration of new hypothe-ses. Not wanting to let a good answer gounquestioned, we can speculate aroundthese findings. How often do ventilatorsettings contribute to dyspnea? Whencan it be treated without doing harm?

How can we use it to predict patientoutcomes?Schmidt et al raise a hypothesis that is

not yet disproven. To help patients inrespiratory failure, dyspnea may be theprice. The possibility is a cold reality, onethat should not remain on the periphery.This paper helps refocus the discussionalong such lines.

Mark E. Nunnally, MD

University of Chicago,Department of Anesthesiaand Critical Care,Chicago, IL

REFERENCES

1. Schmidt M, Demoule A, Polito A, et al: Dys-

pnea in mechanically ventilated critically ill

patients.Crit Care Med 2011; 39:20592065

2. Ventilation with lower tidal volumes as com-

pared with traditional tidal volumes for acute

lung injury and the acute respiratory distress

syndrome. The Acute Respiratory Distress

Syndrome Network.N Engl J Med2000; 342:

13011308

3. Kilpatrick B, Slinger P: Lung protective

strategies in anaesthesia. Br J Anaesth2010;

105(Suppl 1):i108i116

4. Kress JP, Pohlman AS, OConnor MF, et al:

Daily interruption of sedative infusions in

critically ill patients undergoing mechanical

ven tila tio n. N E ng l J M ed 2000; 342:

14711477

5. Strm T, Martinussen T, Toft P: A protocol of

no sedation for critically ill patients receiving

mechanical ventilation: A randomised trial.

Lancet2010; 375:4754806. Zilberberg MD, Shorr AF, Kollef MH:

Implementing quality improvements

in the intensive care unit: Ventilator bun-

dle as an example. Crit Care Med 2009;

37:305309

7. Banzett RB, Pedersen SH, Schwartzstein RM,

et al: The affective dimension of laboratory

dyspnea: Air hunger is more unpleasant than

work/effort.Am J Respir Crit Care Med2008;

177:13841390

8. Rotondi AJ, Chelluri L, Sirio C, et al: Pa-

tients recollections of stressful experiences

while receiving prolonged mechanical venti-

lation in an intensive care unit. Crit CareMed2002; 30:746752

9. de Miranda S, Pochard F, Chaize M, et al:

Postintensive care unit psychological burden

in patients with chronic obstructive pulmo-

nary disease and informal caregivers: A mul-

ticenter study. Crit Care Med 2011; 39:

112118

10. Jubran A, Lawm G, Kelly J, et al: Depressive

disorders during weaning from prolonged

mechanical ventilation. Intensive Care Med

2010; 36:828835

Antibiotics in sepsis: Timing, appropriateness, and (of course)

timely recognition of appropriateness*

Each year approximately 500,000severe sepsis or septic shock pa-tients will present to U.S. emer-gency departments (1). The un-

fortunate realities are that as many as150,000 of them will die during their hos-

pitalization and the incidence of sepsis issteadily increasing (2, 3). Evidence suggests

that outcomes are improved with earlygoal-directed therapy (EGDT) (4) and

prompt, effective antibiotic administration

(5, 6) during the most proximal phase ofcritical illness.

In this issue of the Critical Care Med-

icine, Puskarich et al (7) examine therelationship between time to antibiotics

and mortality using data obtained from

their parent, randomized, multicenteredclinical 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 ofKumar et al (9), when antibiotics were

initiated before shock onset, mortalitywas 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 antimicrobialswas 6 hrs (interquartile range 215

hrs). If appropriate antimicrobials were

*See also p. 2066.Key Words: appropriate antibiotics; emergency

medicine; goal-directed resuscitation; septic shock;severe sepsis; time to antibiotics



DOI: 10.1097/CCM.0b013e3182226ffa



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given in the first hour of hypotension,mortality was 20.1%; for each hoursdelay over the next 6 hrs, mortalityincreased by an average of 7.6%. Themessage to critical care clinicians wasloud and clear: do not delay effectiveantimicrobial therapy in patients withseptic shock as every hour matters.

In 2010, we presented our experiencefrom a single academic emergency de-

partment with a mature EGDT protocol(6). We sought to determine whethertime to antibiotics was associated withmortality in patients receiving EGDT inthe emergency department. We studied261 patients with severe sepsis (48% ofthe cohort) or septic shock (the remain-ing 52%) over a 2-yr interval. The mediantime from triage to antibiotics was 2hrs (119 mins, interquartile range 76 192 mins), and from EGDT qualificationto antibiotics was 42 mins (interquartilerange 093 mins). In-hospital mortalitywas 31%, consistent with the interven-tion arm of the original EGDT trial (4).We found that time from triage toappro-priateantibiotics and time from qualifi-cation to appropriate antibiotics, notsimply time to initial antibiotics, wereassociated independently with in-hospitalmortality. Our results supported the gen-eral principle that timely, goal-directedresuscitation and timely, effective antimi-crobials save lives independent of eachother. Admittedly, our study warrantedconfirmation.

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 multicenteredcohort study, the median time from tri-age to antibiotics was 115 mins (inter-quartile range 65175 mins). Despite81% of the patients fulfilling hemody-namic criteria for septic shock, in-hospital mortality was only 18.9%. Simi-lar to our study (6), they found nosignificant relationship between timefrom triage to initial antibiotics and in-hospital mortality; however, a delay in

antibiotics until after shock recognitionwas independently associated with mor-tality. In effect, at highly experiencedcenters where the time to antibiotics hasbeen minimized and care delivery opti-mized, hourly delays in antibiotic admin-istration are not associated with mortal-ityunless the patient either presents inshock or is initially not recognized asbeing at risk for the development ofshock and his/her antibiotics are not ad-ministered untilaftershock ensues. This

latter observation is consistent with Ku-mars murine model of septic shock andchallenges sepsis management guide-lines, which recommend administeringeffective antimicrobials within 1 hr ofrecognition of severe sepsis or septicshock (9, 10).

The strengths of the present study arenumerous. First, given the prospective,prespecified proposal to study this ques-

tion within the framework of a clinicaltrial, the authors were able to accuratelyand precisely capture the time variables.Second, the exclusion criteria weresparse, permitting wide generalizabilityof the results. Third, the authors shouldbe commended for the use of institu-tion-specific antibiograms, allowing cli-nicians to select the appropriate antibi-otic in 91% of blood-culture-positivepatients. Nevertheless, while assur-ances are given that the remaining pa-tients received appropriate, antibi-

ogram-based antibiotics, the potentialfor residual confounding exists.

The studys limitations, in contrast,are few. First, while the multicentereddesign of the study is meritorious, thepotential for center effects confoundingthe relationship between time to antibi-otics and mortality exists (11) and wasnot examined in the current study. Thisis 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 testfor interaction between the two resusci-tation protocols studied in the parenttrial and the relationship between timingof antibiotics and mortality. Althoughunlikely given that there were no differ-ences observed in other co-interventions,it is conceivable that behavior regardingthe timing of emergency department co-interventions (e.g., antibiotic administra-tion) could have been influenced by theunblinded treatment assignment. Third,

they only report the appropriateness of an-tibiotics for blood-culture-positive patients(34.4%), whereas other studies have re-ported the results of positive cultures fromall sources, with percentages ranging from56.7% to 82.2% (5, 6, 12). This limits thegeneralizations that can be made about theoverall appropriateness of initial antibiot-ics. Finally, these three centers managed toachieve a mortality rate of 18.9% and todeliver antibiotics effectively in 2 hrs,which may have limited the power to detect

a relationship between time to antibioticsand mortality.

Despite these limitations, the study byPuskarich et al is the largest to date onthe relationship between the timing ofantibiotics and mortality in patients re-ceiving goal-directed resuscitation andfurthers our understanding of this impor-tant question. Now all we need to do islearn how to predict which septic patients

will rapidly deteriorate to fulfill criteriafor severe sepsis and septic shock andadminister appropriate antibiotics beforethey do. Lets get to work.

Mark E. Mikkelsen, MD, MSCE

Pulmonary, Allergy, andCritical Care Division

Department of Medicine

University of PennsylvaniaSchool of Medicine

Philadelphia, PADavid F. Gaieski, MD

Department of Emergency

MedicineUniversity of PennsylvaniaSchool of Medicine

Philadelphia, PA

REFERENCES

1. Wang HE, Shapiro NI, Angus DC, et al: Na-

tional estimates of severe sepsis in United

States emergency departments. Crit Care

Med2007; 35:19281936

2. Angus DC, Linde-Zwirble WT, Lidicker J, et

al: Epidemiology of severe sepsis in the

United States: Analysis of incidence, out-

come, and associated costs of care. Crit CareMed2001; 29:13031310

3. Martin GS, Mannino DM, Eaton S, et al: The

epidemiology of sepsis in the United States

from 1979 through 2000.N Engl J Med2003;

348:15461554

4. Rivers E, Nguyen B, Havstad S, et al: Early

goal-directed therapy in the treatment of se-

vere sepsis and septic shock. N Engl J Med

2001; 345:13681377

5. Kumar A, Roberts D, Wood KE, et al: Dura-

tion of hypotension before initiation of effec-

tive antimicrobial therapy is the critical de-

terminant of survival in human septic shock.

Crit Care Med2006; 34:1589 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 initi-

ated in the emergency department. Crit Care

Med2010; 38:10451053

7. Puskarich MA, Trzeciak S, Shapiro NI, et al:

Association between timing of antibiotic admin-

istration and mortality from septic shock in pa-

tients treated with a quantitative resuscitation

protocol. Crit Care Med2011; 20662071

8. Jones AE, Shapiro NI, Trzeciak S, et al: Lactate

clearance vs central venous oxygen saturation



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as goals of early sepsis therapy: A randomized

clinical trial.JAMA2010; 303:739746

9. Kumar A, Haery C, Paladugu B, et al: The

duration of hypotension before the initiation

of antibiotic treatment is a critical determi-

nant of survival in a murine model ofEsch-

erichia coli septic shock: Association with

serum lactate and inflammatory cytokine

levels.J Infect Dis 2006; 193:251258

10. Dellinger RP, Levy MM, Carlet JM, et al: Surviv-

ing Sepsis Campaign: International guidelines for

management of severe sepsis and septic shock:

2008.Crit Care Med2008; 36:296327

11. Localio AR, Berlin JA, Ten Have TR, et al:

Adjustments for center in multicenter studies:

An overview.Ann Intern Med2001; 13:112123

12. Kumar A, Ellis P, Arabi Y, et al: Initiation

of inappropriate antimicrobial therapy re-

sults in a fivefold reduction of survival in

human septic shock. Chest 2009; 136:

12371248

Myocardial infarction complicated by cardiogenic shock: A possiblerole for the Impella device?*

Cardiogenic shock (CS) is theleading cause of mortality inpatients hospitalized for myo-cardial infarction (MI). Due to

better infarct management, the incidenceof CS complicating MI has decreased andprognosis has improved in recent years

(1). Nevertheless, with hospital mortalityrates up to 50%, the outcome of pa-tients with CS is still poor. Although ithas been acknowledged recently thatCS cannot be seen as a sole mechanisticmodel, and that an accompanying sys-temic inflammatory response contrib-utes to the disease entity, the severity ofthe left ventricular function depressionand the grade of mitral regurgitation atthe initial echocardiographic assessmentare significantly linked to worse prognosis(2). In most severe cases, despite successfulopening of the infarct-related artery, treat-

ment with high-dose vasopressors/ino-tropes, and intra-aortic counterpulsation,hemodynamics cannot be stabilized and leftventricular assist devices are seen as thelast therapeutic option.

In this context, the retrospectiveanalysis of Engstrom and colleagues (3)in this issue of Critical Care Medicine,describes the use of the Impella 2.5/5.0devices in patients with profound CSdeemed to be refractory to conventionalinotropic and vasopressor support. Theclear strength of this study is that it

provides a real-world scenario, with de-tailed case-to-case descriptions. Someimportant clinical issues concerning

the patient population in this seriesshould be considered. Close to 60% ofpatients were resuscitated before arrivalto hospital, which implies that CS wasas sociat ed al so wi th t he s yst emi cpostresuscitation syndrome in manypatients. Although no clear distinctions

of these two components can be madein terms of hemodynamic sequelae, itseems obvious that a combination ofthese syndromes yields a unique andvery poor prognosis. Regarding the MIcharacteristics, it is noteworthy that al-though the total ischemic time avail-able in 27 out of 34 patients (symptomsto balloon time) was low when com-pared with the landmark SHOCK trial(4), a coronary stent was implanted inonly 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 substantialproportion of patients had never gainedan adequate hemodynamic response tosustain sufficient coronary perfusionpressure, either because of the severityof the shock itself or because of ongo-ing malignant arrhythmias. Interest-ingly also is the high proportion of pa-tients with triple-vessel coronary arterydisease, which is in contrast with otherseries of patients with MI complicated

by CS. In light of these specific patientcharacteristics, what conclusions uponthe feasibility, safety, and efficacy of theImpella pump system in patients withCS can be drawn from this series? Thepriming and insertion of the Impella2.5 device that can be inserted percuta-neously through a 12.5F sheet via thecommon femoral artery seems to bepossible in a dedicated catheterizationlab. However, the hemodynamic re-sponse to the 2.5 device was classified

as insufficient in 32% of patients withinthe first 48 hrs, and these patients wereupgraded to a 5.0 Impella device thatrequires a surgical cutdown of the fem-oral artery and usually the use of aDacron tube. Considering safety issuesduring the extended use of both the 2.5

and 5.0 systems, several issues have tobe addressed. Three of 34 patients ex-perienced potential embolic events (twostrokes, one bowel ischemia) in thecourse of or after Impella treatment.One additional patient experienced se-vere limb ischemia after removal of the2.5 Impella device, which required sur-gical intervention. It should be alsokept in mind that, as with other extra-corporeal life support systems, patientswith the Impella system have to bedeeply sedated, prolonging the inten-

sive care unit stay even after successfulweaning of the device. Although theease of use of the Impella 2.5 pump isattractive, its hemodynamic supportseems inadequate in patients with pro-found CS. Only two of 25 patients whowere solely treated with the 2.5 Impellasystem survived the hospital stay. In linewith the obvious inadequate hemodynamicsupport observed in this series, are datafrom the ISAR-SHOCK study where in-creases of the cardiac power index were notsignificantly different in comparison with

patients with conventional therapy, includ-ing an intra-aortic balloon pump, beyond 2hrs (5). The Impella 5.0 pump seems toprovide adequate hemodynamic supportand could be an attractive device in patientswith profound CS, possibly also in thosewith ventricular septal defects as a conse-quence of MI as a bridge to surgery. Thesafety issues, especially with regard tobleeding and hemolysis, seem to comparewell with other emergency assist devices.However, prospective data, in particular in

*See also p. 2072.

Key Words: cardiogenic shock; Impella device; leftventricular assist devices; myocardial infarction



DOI: 10.1097/CCM.0b013e3182217476



11/25

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 devicesin patients with CS. Nevertheless, such ex-

periences are no substitute for properly de-

signed prospective trials. In patients withprofound CS, such trials could adopt the

growing experience with the Impella device

and opt for an initial strategy with the5.0 Impella pump. Before the results of

those trials are available, the decisionto 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, MDMedical University of Vienna,

Department of Cardiology,Vienna, Austria

REFERENCES

1. Goldberg RJ, Spencer FA, Gore JM, et al:

Thirty-year trends (1975 to 2005) in the magni-

tude of, managementof, andhospitaldeathrates

associated with cardiogenic shock in patients withacute myocardial infarction: A population-based

perspective. Circulation2009; 119:12111219

2. Picard MH, Davidoff R, Sleeper LA, et al: Echo-

cardiographic predictors of survival and re-

sponse to early revascularization in cardiogenic

shock. Circulation 2003; 107:279284

3. Engstrom AE, Cocchieri R, Driessen AH, et al:

The Impella 2.5 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; 39:20722079

4. Hochman JS, Sleeper LA, Webb JG, et al: Early

revascularization in acute myocardial infarction

complicated by cardiogenic shock. SHOCK In-

vestigators. Should We Emergently Revascular-

ize Occluded Coronaries for Cardiogenic Shock.

N Engl J Med 1999; 341:6256345. Seyfarth M, Sibbing D, Bauer I, et al: A random-

ized clinical trial to evaluate the safety and effi-

cacy of a percutaneous left ventricular assist

device versus intra-aortic balloon pumping for

treatment of cardiogenic shock caused by myo-

cardial infarction. J Am Coll Cardiol2008; 52:

15841588

Electrocardiogram interpretation for ischemia in patients with

septic shock: A disheartening exercise*

Like many diagnostic tests, elec-trocardiogram (ECG) interpre-tation requires a combinationof knowledge, skill, and practi-

cal clinical experience. Knowledge of thepathophysiology of electrocardiographicabnormalities, skill in recognizing com-mon abnormal ECG patterns, and experi-ence in relating the result of the ECG to

a patients clinical situation are all com-ponents of successful interpretation. Theprincipal goals of ECG monitoring in theintensive care unit (ICU) are to alert staffto changes in cardiac rhythm, which mayherald life-threatening events, to alertstaff to sudden changes in cardiacrhythm, which are themselves life-threatening, and to identify silent isch-emia. Like most clinical tests, the ECGyie lds both fal se- pos iti ve and fal se-negative results. For example, the routineECG surveillance in the ICU, which usu-ally includes continuous two-lead moni-toring, has been shown to have a very lowsensitivity for myocardial ischemia (1).

It is of great importance in clinicalpractice to be aware of the diagnosticlimitations of any clinical test. Reliableknowledge of test characteristics, such assensitivity and specificity, in different testsituations are essential, as well as an un-derstanding of the population character-istics in which the test is performed (e.g.,pretest probability of a certain condition).

The most important questions for a diag-nostic ECG in the ICU areand thisholds true for most tests in medicinewhat are the clinical consequences forthe patient? Has an abnormal ECG prog-nostic value? What additional tests arerequired? Can we influence the abnor-mality by a therapeutic intervention thathas been shown to be effective in well-designed trials and which does not lead tofurther 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 hasshown us. The proper use of the pulmo-nary artery catheter requires a perfectknowledge of the numerous pitfalls anddifficulties in interpretation of its mea-surements (2). The same applies for ECGinterpretation in intensive care patients.The level of agreement in ECG interpre-tation among clinicians has to be accept-able to provide reliable diagnostic andprognostic information.

In this issue ofCritical Care Medicine,Mehta and colleagues (3) present a sub-study of the Vasopressin and SepticShock Trial (VASST), in which the intra-and inter-rater agreement of ECG inter-pretation with and without knowledge oftroponin values in adult septic patients isinvestigated. A total of 373 ECGs wereobtained from 121 septic patients and in-

dependently and nonsequentially inter-preted by an intensivist and a cardiologistusing a checklist to standardize interpre-tation. Appropriate statistical methodswere used to describe intra- and inter-rater agreement with and without knowl-edge of troponin values for each of sevencategories: normal, ischemia, atrial ar-rhythmias, bundle branch block, ST ele-vation, T-wave inversion, and Q waves. Ascould be expected, both intra- and inter-rater agreement for specific ECG pat-terns, such as atrial arrhythmias and

bundle branch block, were good to verygood. However, intrarater agreement wasonly moderate for ischemia, and the in-ter-rater agreement for ischemia im-proved from fair to moderate when thereaders were unblinded to troponin.

These results are important and in-crease our understanding of the limita-tions of ECG interpretation, especially forthe diagnosis of ischemia in patients withseptic shock. Specific strengths of thisstudy include the large number of ECGs,

*See also p. 2080.

Key Words: agreement; electrocardiogram; isch-emia; reliability; sepsis; troponin



DOI: 10.1097/CCM.0b013e3182266036



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the standardization of the interpretation,and the very specific cohort of patientswith septic shock. The ECGs were inter-preted nonsequentially for patient andtime, which prevents so-called couplingof images (the interpretation of the nextECG is influenced by the previous ECG).Unfortunately, at the same time thistechnique limits generalizability and ex-trapolation to real-life practice. Interpre-

tation of serial or sequential ECGs andcomparison with patients old ECGs islikely to improve the real accuracy ofinterpretation of abnormalities (e.g., typ-ical dynamic changes over time as seen innew ischemia or infarction as opposed tofixed abnormalities in patients with pre-vious cardiac insults). In addition, thepretest probability for detection of isch-emia in this cohort of patients was influ-enced by the exclusion of patients withacute coronary syndrome or severe heartfailure. Another limitation of the currentstudy is the lack of a gold standard forECG interpretation. Agreement betweenboth readers does not automaticallymean their interpretation was correct.One common feature of most ECG inter-pretation studies is the use of an expertelectrocardiographer gold standard,typically a consensus panel of cardiolo-gists. These panels have shown to havegood intrarater agreement (4).

The results of the current study areconsistent with what has been shown pre-viously, which is that ECG detection ofischemia in intensive care patients in

general is not as straightforward as it maybe in a pure cardiac population. For ex-ample, in a recent observational cohortanalysis of ST elevation in critically illpatients, 85% of patients with electrocar-diographic ST-segment elevation myo-cardial infarction (STEMI) had peak tro-ponin elevation 5 ng/mL, which madeclinically real STEMI in these patientsunlikely (5). This means that in ICUs, theECG has a poor predictive value for acutemyocardial infarction and lacks the spec-ificity compared with non-ICU patients.

Correlation with clinical symptoms andsigns is essential but unfortunately oftennot 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% ofpatients will have clinical signs or symp-toms (6). The ECG, therefore, which isthe gold standard for diagnosing clinicalSTEMI in patients who present with chestpain, may be a poor diagnostic modalityto indicate STEMI in critically ill patients

in ICUs. Twelve-lead ECGs in the ICU areoften obtained for reasons other thanchest pain, such as arrhythmias, hypoten-sion, agitation, pulmonary edema, a sud-den change in the vital signs, or simply asworkup for weaning failure. Under thesecircumstances, a bedside transthoracic ortransesophageal echocardiogram mayhelp increase or decrease the likelihoodof ischemia or STEMI (7). Emergent car-

diac catheterization should probably bereserved for a very small number of casesin which the clinical picture and anotherimaging study, such as the echocardio-gram, independently indicates a highlikelihood of STEMI.

Another important issue raised by thecurrent study is the effect of knowledge oftroponin levels to ECG interpretation.The authors report that knowledge of tro-ponin levels improved the inter-rateragreement for myocardial ischemia intheir study. Interestingly however,knowledge of troponin levels caused anincrease in the number of ECGs reportedas normal by Reader 1, but a decrease inthis number reported by Reader 2. Bothchanges were statistically significant andthe inter-rater agreement for normalitydecreased from moderate to fair. How canwe explain these discrepancies? Bearingin mind that one reader was an intensiv-ist and the other reader a cardiologist, itis not unreasonable to hypothesize thatboth readers, working in different clinicalenvironments, interpret troponin levelsdifferently. In cardiology clinical practice,

elevated troponin levels are oftenstrongly correlated with myocardial isch-emia. The new generation of sensitiveassays for troponin are highly sensitivebut not very specific for the diagnosis ofmyocardial infarction (8, 9). This repre-sents a true clinical problem in intensivecare patients, where troponin elevationscan occur in settings other than myocar-dial infarction, the most common beingtachycardia, right ventricular strain andfailure in the setting of pulmonary em-boli or exacerbation of chronic obstruc-

tive pulmonary dysfunction, and myocar-dial necrosis caused by neurohumoralchanges and/or elevated left ventricularend-diastolic pressure in the setting ofcongestive heart failure, head injury, orsubarachnoidal bleeding. An increasedtroponin measurement has been shownto be an independent predictor of mortal-ity after noncardiac surgery as well asfollowing cardiac surgery (10, 11). Fi-nally, and relevant to the current study,elevated troponin concentrations have

also been reported in patients with sepsisand septic shock without indication ofsignificant coronary artery disease (12,13). It has been demonstrated that tro-ponin elevations occur far more oftenthan ischemia, even in patients withknown or high probability for coronaryartery disease in a general ICU, and thatnecrosis but not detectable ischemia isrelated to mortality (14). Unfortunately it

is not possible to reliably discriminateischemic from nonischemic causes of tro-ponin elevation by simply changing thecutoff value. However, a rising or fallingpattern of troponin values could be help-ful in discriminating acute injury fromsome other causes, such as end-stage re-nal disease (15).

Where to go from here? Should allECGs be interpreted by cardiologists asdiscussed by the authors? In addition tobeing unpractical, the literature showsthat this may not improve the number offalse-positive and -negative ECGs forischemia. The interpretation by severalcardiologists reading the same ECG oftenvaries substantially. Even one cardiolo-gist reading the same ECG on separateoccasions may have substantially differ-ent interpretations (4, 16). In the currentstudy, both readers - one of whom is anexperienced cardiologist - showed onlymoderate intrarater agreement for isch-emia. In the abovementioned cohortanalysis 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 thosepatients, only 33% showed a significantrise in the troponin level (5). Physiciansof all specialties and levels of training, aswell as computer software for interpret-ing ECGs, frequently make errors in in-terpreting ECGs when compared to ex-pert electrocardiographers. Adversepatient outcomes, however, occurred in-frequently when ECGs were incorrectlyinterpreted, typically in1% of interpre-tations (17). Currently there is no evi-dence-based minimum number of ECG

interpretations that is ideal for attainingor maintaining competency in ECG inter-pretation skills (18). Since ECG monitor-ing is an integral and essential part of theintensive care environment, formal in-tensivist training on ECG interpretationshould be a standardized and compulsorypart of any intensive care curriculum.

In conclusion, the current study con-firms that, in septic shock patients, sig-nificant variability of ECG interpretationof myocardial ischemia exists. Correla-



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tion with all other pieces of the diagnos-tic puzzle is essential, and this includesthe clinical context, interpreting serialECGs, the serial measurement of cardiacbiomarkers despite their known limita-tions in the ICU, and bedside echocardi-ography, to prevent both over- and un-derdiagnosis of myocardial ischemia inICU patients.

Frank van Haren, MD, PhD

Waikato HospitalHamilton, New Zealand

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Danger at the doorstep: Regulation of bacterial translocation

across the intestinal barrier by nitric oxide*

The ability of the host to regu-late the permeability of the in-testinal barrier represents amajor determinant of disease

vs. health. This is particularly relevant tothe critically ill surgical patient, in whomintestinal 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 thatsuch infections are seen to be caused

predominantly by enteric microbes hasled to the widespread notion that intesti-nal barrier dysfunction develops as a con-sequence of intestinal obstruction, re-sulting in the translocation of entericbacteria (3). It therefore stands to reasonthat an understanding of the factors thatregulate normal barrier function duringhealth and in the presence of disease may

provide important insights into enhanc-ing care of the critically ill patient.It has been known for some time that

there are several pathways by which en-teric microbes or their microbial-derivedantigenic ligands can access the circula-tion. The intestinal mucosa is lined by atightly interconnected layer of epithelialcells over which a layer of mucus existsthat together represent the first line ofdefense against bacterial passage (4, 5).To transit across the normally imper-

meant intestinal mucosal barrier, bacte-ria can either transit directly through theintestinal epithelial cells (IECs, i.e., tran-scellular passage), pass between the IECs(paracellular passage), or they can be ac-tively internalized by dendritic cells andmacrophages that lie within the laminapropria with the capacity to extend cellu-lar processes between the IECs that can

internalize the bacteria and deliver themto the lymph nodes and circulation (6).While IECs have been shown to have theability to internalize whole bacteria bothin vitro and in vivo (7), the effect of in-testinal obstruction on transcellular bac-terial internalization by IECs remains un-known. By contrast, it is well known thatadjacent IECs are interconnected by tightjunctions that determine the extent towhich large molecules, and possibly bac-teria, can pass between the adjacent IECs

*See also p. 2087.Key Words: bacterial translocation; epithelial per-

meability; intestinal obstruction; nitric oxide; signaltransduction; tight junctions



DOI: 10.1097/CCM.0b013e31822661ad



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(8). Recent studies have demonstratedthat circulating cytokines and other pro-inflammatory molecules can cause an in-crease in the permeability of the intesti-nal barrier by causing tight junctiondysfunction or internalization (5, 9).However, the precise role of tight junc-tion dynamics in the maintenance of bar-rier integrity in the setting of intestinalobstruction, and the molecular mecha-

nisms involved in the regulation of tightjunctions in this setting, remain largelyunexplored.

In this issue ofCritical Care Medicine,Wu and colleagues (10) now attempt tosolve this riddle. Using an elegant modelof mechanical intestinal obstruction inmice, this group demonstrates that thepresence of intestinal obstruction leads toan increase in permeability across theintestinal barrier and an increase in bac-terial translocation, and that thesechanges are associated with a disruptionin tight junctions (10). In seeking toidentify the molecular mechanisms in-volved, Wu et al now also show that in-testinal obstruction i

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