Blood transfusion and the development of acute respiratorydistress syndrome: More evidence that blood transfusion in theintensive care unit may not be benign*
T ransfusion practice remainsan area of fertile ground forboth inquiry and improve-ment in critical care. Recent
investigations have established that a re-strictive transfusion strategy is safe (1)and that injudicious transfusion may beassociated with development of ventila-tor-associated pneumonia (2), nosoco-mial infection (3, 4), and organ dysfunc-tion (5). These potential risks fortransfusion are of course additive to thewell-defined concerns of transmissible in-fection and hemolytic reactions. Further-more, the immunomodulatory effects oftransfusion may be particularly poorlytolerated in the critically ill, where a myr-iad of states such as sepsis, trauma, pneu-monia, or respiratory failure may stimu-late an initial proinflammatory responsethat is adversely complemented by bloodproducts through means not yet fully elu-cidated (6). This interaction is of partic-ular interest in acute lung injury (ALI),where both direct pulmonary and ex-trapulmonary insults can prime an organthat is sensitive to transfusion compo-nents and potentially propagate furtherdamage. The development of transfusion-related ALI (TRALI) (7, 8) represents theclassic example of this phenomenon, andfortunately recognition of and interest inTRALI are increasing. However, givenwhat is now known about immunomodu-lation after blood product administration,the possibility that transfusion mightpredispose a patient to development of
ALI independent of the distinct pathogen-esis described for TRALI requires consid-eration. This hypothesis was recentlygiven additional credibility in a retrospec-tive chart review by Gajic et al. (9), whoreported transfusion to be an indepen-dent risk factor for development of ALI inmechanically ventilated patients.
In this issue of Critical Care Medicine,Dr. Gong and colleagues (10) provide in-sight into this possibility and add to theburgeoning literature relentlessly estab-lishing the deleterious effects of bloodtransfusion in the critically ill. These au-thors prospectively examined a sizeablecohort of intensive care unit (ICU) pa-tients who developed acute respiratorydistress syndrome (ARDS) after admis-sion and performed multivariate analysisto identify risk factors for developmentand subsequent mortality. Most notablyand originally, the authors found thatpacked red blood cell transfusion signifi-cantly increased the risk both of develop-ing and of dying from ARDS, with thelatter effect dose-dependent. Strengths ofthis study include rigorous patient selec-tion, multifaceted attempts at quality as-surance, and a reasonably blinded appli-cation of the consensus definition forARDS. In addition, some of the clinicalpredictors elicited, such as trauma, directpulmonary injury, and acidemia, havebeen reasonably well established by priorstudy and experience and lend credenceto the authors’ methodology.
Unfortunately, the timing of transfu-sion relative to development of ARDS wasnot reported, limiting the ability to dis-cern whether episodes of ALI were dis-tinctly “primed” by transfusion. Assess-ment of the temporal relationship wouldbe helpful in determining if massivetransfusion is a risk factor because ofblood product “burden” or because mas-sive transfusion provides multiple oppor-tunities for TRALI. Also, although pro-spective in design, the analysis by Dr.Gong and colleagues is limited in that
their study was observational in nature.Hence, the association between transfu-sion and ARDS that they noted can onlysuggest causation. But if the question ispatient safety and adverse outcomes, as itis in this case, many would agree that ourthreshold for taking action and for reeval-uating our practice is lower than what wewould require for the adoption of a noveltechnology for critical care.
In that vein, the results of Dr. Gongand colleagues, when combined with re-cent studies documenting the potentiallyinjurious effects of blood products (2–5,11), call into serious question the statusquo of liberal transfusion, particularlygiven that anemia may be well toleratedin both the ICU and perioperative arenas(1, 12). Unfortunately, the clinical rea-soning behind transfusion remains re-markably ill-defined (13, 14). Specifically,often clinicians transfuse purely to alterthe hemoglobin level and do not act witha clear objective in mind. Resuscitation ofovert hemorrhage and temporal supportof exsanguinating traumatic injury whilepursuing definitive source control are es-tablished indications for blood transfu-sion. Although conceptually attractive,evidence that transfusion augments oxy-gen delivery has been elusive to establishin ICU practice, and purported beneficialeffects may in fact be considerably atten-uated or even harmful (15, 16). Otherindications, including those thought tobe conventionally acceptable—such as inthe setting of acute coronary syndromes(17) and perioperative cardiovascular sur-gery (12)—are in fact not clearly estab-lished and require further study. Indeed,given the lack of efficacy and potential forharm currently demonstrated in the trans-fusion literature, benefit in the form of tan-gible, clinically relevant end points shouldbe a requisite for investigations promotinguse of transfusion in specific critically illpopulations. In other words, intensivistsneed to view the choice to transfuse as we
*See also p. 1191.Key Words: acute respiratory distress syndrome;
packed red blood cells; transfusion; transfusion-related acute lung injury
The opinions or assertions contained herein arethe private views of the authors and are not to beconstrued as official or as reflecting the views of theDepartment of the Army or the Department of Defense.
do decisions regarding other interven-tions—a balancing of risks and benefits.
In sum, continued disregard for the ev-idence (18) in the form of an uncritical,uninformed approach to transfusion prac-tice can no longer be tolerated. Althoughthe safety achieved in minimizing risks ofovert compatibility errors and direct trans-mission of infectious agents is truly impres-sive, ironically, these advances may have en-couraged complacency about the negativeeffects of transfusion (19). Moreover, limita-tion of blood draws, judicious administrationof erythropoietin where established indica-tions exist, and continued prudent search forcommercially useful red blood cell substi-tutes, although reasonable interventions,should be considered mere adjuncts to auniversal, fundamental change in what weas intensivists consider acceptable practice.Only a paradigm shift that views red bloodcell transfusion not as an “outcome-neutral” necessity of ICU care, but insteadas a potentially harmful intervention to beavoided as assiduously as possible, is com-patible with current evidence. Adherence to“primum non nocere” demands no less.
William L. Jackson Jr, MDCritical Care Medicine ServiceDepartment of SurgeryWalter Reed Army Medical CenterWashington DC
Andrew F. Shorr, MD, MPHPulmonary and Critical Care
Medicine ServiceDepartment of MedicineWashington Hospital CenterWashington, DC
REFERENCES
1. Hebert PC, Wells G, Blajchman MA, et al: Amulticenter, randomized, controlled clini-cal trial of transfusion requirements incritical care. N Engl J Med 1999; 340:409 – 417
2. Shorr AF, Duh MS, Kelly KM, et al: Red bloodcell transfusion and ventilator-associatedpneumonia: A potential link? Crit Care Med2004; 32:666–674
3. Leal-Noval SR, Rincon-Ferrari MD, Garcia-Curiel A, et al: Transfusion of blood compo-nents and postoperative infection in patientsundergoing cardiac surgery. Chest 2001;119:1461–1468
4. Taylor RW, Manganaro L, O’Brien J, et al:Impact of allogenic packed red blood celltransfusion on nosocomial infections rates inthe critically ill patient. Crit Care Med 2002;30:2249–2254
5. Vincent JL, Baron JF, Reinhart K, et al: ABC(Anemia and Blood Transfusion in CriticalCare) Investigators: Anemia and blood trans-fusion in critically ill patients. JAMA 2002;288:1499–1507
6. Raghavan M, Marik PE: Anemia, allogenicblood transfusion and immunomodulationin the critically ill. Chest 2005; 127:295–307
8. Silliman CC, Boshkov LK, MehdizadehkashiZ, et al: Transfusion-related acute lung in-jury: epidemiology and a prospective analysisof etiologic factors. Blood 2003; 101:454–462
9. Gajic O, Dara SI, Mendez JL, et al: Ventilator-associated lung injury in patients withoutacute lung injury at the onset of mechanicalventilation. Crit Care Med 2004; 32:1817–1824
10. Gong MN, Thompson BT, Williams P, et al:Clinical predictors of and mortality in acuterespiratory distress syndrome: Potential roleof red cell transfusion. Crit Care Med 2005;33:1191–1198
12. Jackson WL Jr: Prospective studies are re-quired prior to revision of perioperativetransfusion guidelines. Arch Intern Med2003; 163:2396
13. Corwin HL, Parsonnet KC, Gettinger A: RBCtransfusion in the ICU. Is there a reason?Chest 1995; 108:767–771
14. Levy MM, Abraham E, Zilberberg M, et al: Adescriptive evaluation of transfusion prac-tices in patients receiving mechanical venti-lation. Chest 2005; 127:928–935
15. Marik PE, Sibbald WJ: Effect of stored-blood transfusion on oxygen delivery inpatients with sepsis. JAMA 1993; 269:3024 –3029
16. Walsh TS, McArdle F, McLellan SA, et al:Does the storage time of transfused redblood cells influence regional or global in-dexes of tissue oxygenation in anemic crit-ically ill patients? Crit Care Med 2004; 32:364 –371
17. Rao SV, Jollis JG, Harrington RA, et al:Relationship of blood transfusion and clin-ical outcomes in patients with acute coro-nary syndromes. JAMA 2004; 292:1555–1562
18. Shorr AF, Jackson WL: Transfusion practicein the ICU: When will we apply the evidence?Chest 2005; 127:702–705
Nearly 80 yrs ago, as the sci-ence of quantum mechanicswas evolving, many compet-ing theories and ideas were
proposed. Whether the physics of elec-trons was best explained by wave theoryor matrix mechanics was hotly debated.During these discussions, Albert Einstein
reportedly told Werner Heisenberg,“. . .what can be observed is really deter-mined by the theory. . .you cannot firstknow what can be observed, but you mustfirst know a theory, or produce a theory,and then you can define what can beobserved. . . (http://www.aip.org/history/heisenberg/voice1.htm).
In this issue of Critical Care Medicine,Ms. Pun and colleagues (1) present sem-inal work on the introduction of theCAM-ICU (before this used only as a re-search tool) for routine bedside docu-mentation by nurses in two different in-tensive care units (ICU). This work is
important for several reasons, includingits potential to guide implementation inother ICUs, the incidence of delirium re-ported, varying agreement between bed-side nurses and expert assessment, andthe perceptions by nurses regarding im-pediments to using these tools.
This study encompassed assessmentsby 40 nurses in the medical ICU of auniversity hospital during a 12-monthperiod and by 24 nurses in a Veterans’Administration hospital during a5-month period. Details of the planning,baseline, educational, and maintenancephases of this implementation among 64
*See also p. 1199.Key Words: delirium; sedation; nursing assess-
nurses are provided in the manuscript,which may serve as a model to otherunits planning similar introductions. Atbaseline, agreement between study staffand bedside nurses using the CAM-ICUwas very poor, with kappa scores of 0.20and 0.03. Agreement improved greatlyfollowing the educational phase but asshown in Figure 2, fluctuated signifi-cantly over time and differed between thetwo units (0.92 at Vanderbilt and 0.75 atthe VA). All ICU clinicians must remem-ber that we need reminders and updatesto perform at our best. The work by Dr.Pun and colleagues highlights this point;when spot-checking was discontinued,compliance rates dropped.
Among the 614 patients studied atVanderbilt, 65% developed delirium atsome point and 28% were never deliri-ous. Of the 97 patients studied at the VA,41% were delirious at some point and47% were never delirious. This incidenceof delirium is quite different from priorreports using the CAM-ICU when 87% ofstudied patients developed this condition(2). The experimental design differs inthese studies, and perhaps the currentnumbers of 41% and 65% better reflectreal-life experience with an “all-comers”enrollment approach.
Nearly a third of responding nursesinvolved in this study reported the majorimpediment to use of the CAM-ICU wastime. This is somewhat surprising sinceresearchers in prior studies reported thatonly 2–3 mins were required to perform
and document the CAM-ICU (2). Perhapsit takes longer for less experienced nursesto perform the assessment and documentit in appropriate bedside documents, orperhaps it seems longer than a few min-utes to utilize another assessment tool,especially one that is new to us. Of addi-tional concern, physicians were listed asthe second most significant impediment by21% and 26% of the participating nurses.This must be interpreted with some cau-tion, but the message is clear: We caneither be team players and work togetherto help improve outcomes for our pa-tients, or we can be obstructionist with anegative impact on improvement efforts.
As we move the science of ICU seda-tion and delirium forward in the early21st century, many aspects remain hotlydebated and controversial. Can detectionof ICU delirium affect patient outcome? Isthe association between delirium andbenzodiazepine or opiate use causal (3)?How does symptomatic treatment withantipsychotic medications affect out-comes (4)? This work from Ms. Pun andcolleagues builds on prior efforts fromtheir group and others to develop toolswe can use when searching for delirium(1, 2, 5). As with early quantum physics,the theories we propose guide what welook for and how we interpret what wesee. As we learn more about delirium andhow to diagnose it, and hopefully soonhow to treat and prevent it, unexpectedanswers may occur. As Heisenberg andEinstein taught us, we need to remember
to question the theories that prompt ourstudies as rigorously as we question thedesign of our studies and their results. Ifour model of what causes delirium, whatevents predispose to it, and how best toprevent and treat it in the ICU is mark-edly different 10 yrs from now, we maytruly have succeeded.
Richard R. Riker, MDGilles L. Fraser, PharmD, FCCM
Department of MedicineDivision of Pulmonary/Critical
Care MedicineMaine Medical CenterPortland, ME
REFERENCES
1. Pun BT, Gordon SM, Peterson JF, et al: Large-scale implementation of sedation and deliriummonitoring in the ICU: A report from twomedical centers. Crit Care Med 2005; 33:1199 –1205
2. Ely EW, Margolin R, Francis J, et al: Evalua-tion of delirium in critically ill patients: Vali-dation of the Confusion Assessment Methodfor the Intensive Care Unit (CAM-ICU). CritCare Med 2001; 29:1370–1379
3. Dubois MJ, Bergeron N, Dumont M, et al:Delirium in an intensive care unit: A study ofrisk factors. Intensive Care Med 2001; 27:1297–1304
4. Skrobik YK, Bergeron N, Dumont M, et al:Olanzapine vs haloperidol: Treating deliriumin a critical care setting. Intensive Care Med2004; 30:444–449
5. Bergeron N, Dubois MJ, Dumont M, et al:Intensive Care Delirium Screening Checklist:Evaluation of a new screening tool. IntensiveCare Med 2001; 27:859–864
Glutamine and heat shock proteins: One more approach to lunginjury*
Acute lung injury and acute re-spiratory distress syndrome(ARDS) remain importantcauses of mortality and mor-
bidity in critically ill patients (1, 2).These entities contribute to prolongedlength of intensive care unit and hospi-
tal stay and, in part, are responsible forthe staggering cost of intensive careunit care. Despite increasing under-standing of the pathology, pathophysi-ology, and pathogenesis of acute lunginjury and ARDS, therapy at this timeis, by and large, supportive. However, itis clear that these disorders, at leastinitially, involve overexuberant inflam-mation, protein degradation, and pul-monary epithelial cell loss via necrosisor apoptosis. Thus, therapy that directlyaddresses any or all of these abnormal-ities might be of value in acute lunginjury and ARDS.
Along these lines, it is well establishedthat the heat shock response, a phyloge-netically conserved response to a numberof noxious stimuli, may be protectiveagainst these very abnormalities (3). Theheat shock response involves the elabora-tion of a series of proteins (heat shockproteins [HSPs]), each of which may havespecific cytoprotective effects. Of particu-lar interest is the 70-kD HSP-70 family.Studies in cells and intact animals havedemonstrated that hyperthermia is pro-tective against damage to pneumocytes(4, 5). Unfortunately, one effect of ARDS
*See also p. 1206.Key Words: septic shock; metabolism; rat; animal
may be an inability to mount an adequateheat shock response. Using an animalmodel of sepsis-induced lung injury (ce-cal ligation and puncture [CLP]), we haveshown a failure to up-regulate HSP-70expression (6). Fortunately, this defect isamenable to correction. Villar et al. (4)found that total-body hyperthermia effec-tively increased HSP-70 expression in thelung after CLP. This improved outcome.Unfortunately, this approach is not clin-ically applicable, and it is unclear if aspecific HSP in a specific tissue type con-tributed to increased survival. To addressthis, we used intratracheal administra-tion of an adenovirus expressing HSP-70to enhance expression in the lungs afterCLP (7). This approach has the advantageof ensuring that only HSP-70 is expressedand only in the lung. Our studies dem-onstrate a near-complete amelioration oflung injury and attenuation of 48-hrmortality. However, we are left with theproblem of clinical utility. Adenoviralgene therapy has been problematic andmust be approached with great caution inhumans.
In this issue of Critical Care Medicine,Singleton and colleagues (8) provide anapproach that may be more therapeuti-cally useful. They have shown previouslythat glutamine is capable of inducingHSP-70 elaboration in cells and in ani-mals treated with endotoxin (9). Further,they have attenuated injury in this man-ner. Because glutamine is a naturally oc-curring substance, it can be administeredsafely. Indeed, it has been used in themetabolic support of the critically ill.Thus, these investigators tested the hy-potheses that post-CLP administration ofglutamine would increase HSP-70 ex-pression, improve cellular energetics, at-tenuate lung injury, and improve out-come. Their results, presented here, arequite impressive.
There are several important caveatsthat require discussion. First, there areno controls receiving glutamine alone.Although this amino acid has been ad-ministered to achieve physiologic levels,Singleton and colleagues (8) make thepoint that they are testing glutamine inpharmacologic doses. It has been shownthat high levels of HSP-70 may be toxic tonormal cells and that circulating HSP-70may be proinflammatory. Because glu-tamine presumably would be given to pa-tients at risk in anticipation of impendinglung injury, this may be problematic.Further, because Singleton and col-
leagues (8) show that glutamine altersheat shock factor-1 phosphorylation, fac-tors other than HSP-70 may be altered.Indeed, HSP-25 is altered in these stud-ies. As a result, it is unclear what HSP isresponsible for the changes observed. Theeffects may also be indirect, resultingfrom a change somewhere other than thelung that affects acute lung injury/ARDSsecondarily. In this sense, these data areanalogous to those presented by Villar etal. (4) and are less clear than the resultsafter adenoviral enhancement of HSP-70in lung alone (7). It would have beenuseful to examine glutamine content inthe lung and to search for a direct inter-action between glutamine, HSP-70 (orsome other HSP), or heat shock factor-1.
Effects other than outcome were ex-amined at a single time point (24 hrspost-CLP) only. Although we have shownan improvement 48 hrs after CLP usinggene enhancement, it is possible that therespite is temporary (7). There is stillsubstantial mortality, even in glutamine-treated animals, and it is possible thatthis may result from reactivation of lunginjury.
Most importantly, the cause of deathin sepsis remains unclear. Five-day mor-tality is improved by glutamine after CLP,but longer time frames remain unexam-ined. It may be that early, lung-injuryinduced mortality is reduced but thatlater death from other causes is un-changed. These issues require further in-vestigation.
Finally, the question of cellular ener-getics remains controversial. Studieshave reported that adenosine 5'-triphos-phate (ATP) levels may be reduced ormaintained in sepsis (10). The demon-stration of an altered ATP/adenosine 5'-diphosphate ratio and nicotinamide ade-nine dinucleotide levels after CLP andattenuation of this by glutamine is diffi-cult to interpret. Recent studies have fo-cused not on the levels of ATP but on theprocess of ATP synthesis and its utiliza-tion. We and others have demonstratedthat sepsis is associated with specific de-fects in oxidative phosphorylation (11–13). The cells seem to respond by reduc-ing cellular activity, oxygen consump-tion, and ATP demand. A similar processin cardiomyocytes after ischemia or hyp-oxia has been termed myocardial hiber-nation and may underlie changes in ATPoxidation in sepsis (14). In the data pre-sented by Singleton and colleagues (8),correction of a deficit may reflect im-proved ATP generation or a reduction in
Overall, however, this is an importantstudy. It adds to our understanding of themechanisms by which glutamine en-hancement may work and suggests otherpotential studies. Most importantly, thesedata support further investigations intothe use of glutamine in the therapy ofinflammatory states.
Clifford S. Deutschman, MS, MD,FCCM
Department of AnesthesiaUniversity of Pennsylvania School
of MedicinePhiladelphia, PA
Richard J. Levy, MDDepartment of Anesthesiology
and Critical Care MedicineChildren’s Hospital of
PhiladelphiaPhiladelphia, PA
Yoram G. Weiss, MDDepartment of Anesthesia and
Critical Care MedicineHadassah Hebrew University
Medical CenterJerusalem, Israel
REFERENCES
1. Ware LB, Matthay MA: The acute respiratorydistress syndrome. N Engl J Med 2000; 342:1334–1349
2. Rubenfeld GD: Epidemiology of acute lunginjury. Crit Care Med 2003; 31:276S–S284
3. De Maio A: The heat shock response. NewHoriz 1997; 3:198–207
4. Villar J, Ribeiro SP, Mullen JBM, et al: In-duction of the heat shock response reducesmortality rate and organ damage in a sepsis-induced acute lung injury model. Crit CareMed 1994; 22:914–922
5. Wong HR, Menendez IY, Ryan MA, et al:Increased expression of heat shock pro-tein-70 protects A549 cells against hyperoxia.Am J Physiol 1998; 275:L836–L841
6. Weiss YG, Bouwman AR, Gehan B, et al:Cecal ligation and double puncture impairsheat shock protein 70 (HSP-70) expression inthe lungs of rats. Shock 2000; 13:19–23
7. Weiss YG, Maloyan A, Tazelaa RJ, et al: Ad-enoviral transfer of HSP-70 into pulmonaryepithelium ameliorates experimental acuterespiratory distress syndrome. J Clin Invest2002; 110:801–806
8. Singleton KD, Serkova N, Beckey VE, et al:Glutamine attenuates lung injury and im-proves survival after sepsis: Role of enhancedheat shock protein expression. Crit Care Med2005; 33:1206–1213
9. Wischmeyer PE, Kahana M, Wolfson R: Glu-
1423Crit Care Med 2005 Vol. 33, No. 6
tamine induces heat shock proteins and pro-tects against endotoxin shock in the rat.J Appl Physiol 2001; 90:2403–3410
10. Levy RJ, Deutschman CS: Myocardial depres-sion in sepsis. Shock 2004; 22:1–10
11. Levy RJ, Vijayasarathy C, Raj NR, et al: Com-petitive and noncompetitive inhibition of
myocardial cytochrome C oxidase in sepsis.Shock 2004; 10:110–114
12. Brealey D, Karyampudi S, Jacques TS, et al:Mitochondrial dysfunction in a long-term ro-dent model of sepsis and organ failure. Am JPhysiol 2004; 286:R491–R497
13. Chen HW, Hsu C, Lu TS, et al: Heat shock
pretreatment prevents cardiac mitochondrialdysfunction during sepsis. Shock 2003; 20:274–279
14. Budinger GR, Duranteau J, Chandel NS, etal: Hibernation during hypoxia in cardiomy-ocytes: Role of mitochondria as the O2 sen-sor. J Biol Chem 1998; 273:3320–3326
Fast hug, Cartesians, and the World Series*
No game in the world is as tidy and dramatically neat. . .with cause and effect, crime and punishment, motive and result, socleanly defined. The consequences of a single error or failure pyramid inexorably as the game goes on and finally prove to be theevents that have won or lost the day, exactly as the minor unnoticed incidents unfolded at the beginning of a well-constructedplay suddenly loom as prime and all-important to the climax.—Paul Gallico
T his was how Paul Gallico,journalist and novelist (ThePoseidon Adventure), oncedescribed baseball. His de-
scription came to mind as I first readDr. Vincent’s manuscript, “Give yourpatient a fast hug (at least) once a day,”which is published in this issue of Crit-ical Care Medicine (1). Although I’membarrassed to admit it, I happened tobe reviewing the article while watchingthe 2004 World Series between the Bos-ton Red Sox and the St. Louis Cardi-nals. What initially caught my attentionwas not anything in the manuscript;rather, it was the way St. Louis wasplaying—making embarrassingly ama-teurish mistakes at bat, in the field, andwhile running the bases. No self-respecting bunch of Little Leaguerswould be caught dead committing thekind of fundamental errors these highlypaid professionals were making on thebiggest stage of their sport.
Returning to the article, somethinggelled right then and there. Had it beenanother time or place, I do not know if Iwould have appreciated the erudition ofFast Hug (an acronym for a protocol offeeding, analgesia, sedation, thromboem-bolic prophylaxis, head elevation, ulcerprevention, and glucose control). WithGallico’s words as a backdrop, the Cardi-
nals were blowing the World Series sim-ply because they failed to execute thebasics—and in the process, making Dr.Vincent’s case. As far as I’m aware, Dr.Vincent has no more reason to know any-thing about America’s National Pastimethan I know about fine French cuisine(which is to say precious little). Yet hispoint was the essence of lucidity: makesure, above all else, the simple things aredone correctly. Essentially, practicinggood critical care is analogous to playinggood baseball.
Too many patients survive the slingsand arrows of critical illness only tosuccumb to pulmonary emboli, stressulcers, aspiration, or secondary infec-tions abetted by a hyperglycemic envi-ronment. (It would be nice if there weremore studies documenting preciselyhow often these complications are ter-minal pathways). Fast Hug tells us thatprevention, a word not commonly asso-ciated with critical care, has its place inthe intensive care unit.
None of the Fast Hug protocol inter-ventions are complicated (then again,neither are bunting, base running, po-sitioning, or pitch selection, the thingsa casual baseball fan may not notice).And doing these things right doesn’tguarantee a good outcome for a partic-ular patient; it simply makes a goodoutcome more likely. Therein lies thesubtle edge every critical care practitio-ner must constantly strive for.
Essayist and occasional political col-umnist George Will cites an earlier, fel-low countryman of Dr. Vincent in de-scribing baseball in a way that relates toFast Hug philosophy:
The best baseball people are Cartesians.That is, they apply Descartes’ methodsto their craft, breaking it down intobite-size components, mastering themand then building the craft up bit bybit. . .. Master enough little problemsand you will have few big problems.
In that sense, the best intensivists arealso Cartesians.
It is popular today for observers ofthe medical scene to cite medical mis-takes and analogize that taking care ofcritically ill patients should be akin toflying jets. Why, they ask, cannot themedical profession duplicate the suc-cess of the airline industry, which has aremarkably low rate of disasters? Theanalogy is facile and, like most facileanalogies, does more to obscure thanclarify. Airplanes fly according to wellunderstood scientific principles ofphysics and engineering. The flight of aplane involves a number of variables,but except in the most unusual circum-stances, those variables are predictableand easy to compensate for, a fact that makes99.99% of all flights routine.
Critical illness, be it septic shock,acute respiratory distress syndrome, orpancreatitis, is rarely routine (just asthere is no such thing as a “routine”baseball game). Medicine operates ac-cording to abstruse interactions be-tween biology, physiology, genetics,etc. There are virtually an infinite num-ber of variables involved in the care of acritically ill patient, many of which can-not be predicted. The same infection intwo individuals may present completelydifferently. The same medication, at thesame dose, may also have radically dif-
*See also p. 1225.The author has no financial interests to disclose.Key Words: intensive care; prophylaxis; thrombo-
ferent effects on two individuals. Na-ture always has the final word. And inthe face of Nature’s vagaries and vicis-situdes, the best we can do is controlthat which is under our control. Hence,Fast Hug.
In conclusion, there is a verse from awell-known old song that goes like this:
Oh, it’s fine to be a genius, of course, Butkeep that old horse before the cart.
Good critical care occasionally re-quires superb diagnostic acumen orsome brilliant insight. As the song cau-tions, genius is nice, and its value shouldcertainly never be underestimated. Butit’s not the basis of critical care medicine.What’s essential is putting the horse be-fore the cart, i.e., ensuring everything isput in its proper order. In the long run,that will save more lives in the intensivecare unit than genius will. This is themessage of Fast Hug. Incidentally, that
well-known song verse happens to befrom a 1950s Broadway musical, DamnYankees, whose plot is about a man whomakes a deal with the devil—so his teamcan play in the World Series.
Cory M. Franklin, MDCook County HospitalChicago, IL
REFERENCE
1. Vincent JL: Give your patient a fast hug (at least)once a day. Crit Care Med 2005; 33:1225–1229
Real-time ultrasonography—Should this be available to everycritical care physician?*
T here is a growing body of lit-erature demonstrating thevalue of real-time ultrasonog-raphy in the care of critically
ill patients. This literature also suggeststhat ultrasonography can be of equalvalue when performed by the clinician atthe patient’s bedside. It is well knownthat ultrasound-guided thoracentesisperformed by interventional radiology isassociated with low complication ratescompared with published literature forthoracentesis performed without ultra-sound guidance (1). Similarly low com-plication rates are found when ultra-sound-guided thoracentesis is performedby critical care physicians on patients re-ceiving mechanical ventilation (2). Ultra-sonography of the anterior neck per-formed by an anesthesiologist beforepercutaneous dilation tracheostomy canreveal vasculature that may be at risk ofinjury during the procedure, potentiallyimproving the safety of this technique(3). Central venous cannulation is alsomore successful, requires fewer cannula-tion attempts, and results in fewer arte-rial punctures when real-time ultrasoundguidance is used instead of anatomicallandmarks alone (4, 5). Real-time ultra-sound guidance improved outcomes mostconvincingly for those clinicians least ex-perienced at central catheter placement
and presumably ultrasonography as well(6). Furthermore, ultrasonography per-formed by clinicians with 2 hrs of specificultrasonography training can be used toconfirm proper catheter placement andrule out postprocedure pneumothorax fol-lowing central venous cannulation (7). Sur-geon-performed ultrasonography has alsobeen used to detect pneumothorax in thebedside evaluation of trauma patients (8).
Knudtson and colleagues (9) demon-strated the high accuracy of surgeon-performed ultrasonography at the patient’sbedside for detection of pneumothorax.They presented a prospective analysis of328 consecutive trauma patients who un-derwent thoracic ultrasonography by theattending surgeon for detection of pneu-mothorax before chest radiography. Chestultrasonography consisted of placing theprobe over the second intercostal space atthe midclavicular line for five respiratorycycles and noting the presence or absenceof “lung sliding.” The absence of lung slid-ing using this simple sonographic evalua-tion had a sensitivity of 92.3% and a spec-ificity of 99.6% for the detection ofpneumothorax visible by plain chest radi-ography. Similar sensitivities for ultrasono-graphic detection of radiographic apparentpneumothorax have been shown by others(10, 11).
In this issue of Critical Care Medicine,Dr. Lichtenstein and colleagues (12) de-scribe several key sonographic features ofpneumothorax and clearly demonstratethe value of clinician-performed, bedsidechest ultrasonography for identificationof occult pneumothorax—defined as apneumothorax not visualized by plain
chest radiography but apparent on tho-racic computed tomography. This studyincluded 200 consecutive medical andsurgical intensive care unit patients whounderwent routine supine chest radiogra-phy without definitive evidence of pneumo-thorax, with computed tomography of thechest and chest ultrasonography performedwithin 120 mins. Forty-seven patients werefound to have occult pneumothorax. Theabsence of anterior lung sliding on ultra-sonography was 100% sensitive and 78%specific for the detection of radiographi-cally occult pneumothorax. The absence ofanterior lung sliding plus the “A line sign”was 95% sensitive and 94% specific. Thepresence of a “lung point” was 79% sensi-tive and 100% specific.
Dr. Lichtenstein and colleaguespresent a systematic and clinically usefulapproach to ultrasonography of the chestfor the detection of pneumothorax. Theyalso clearly define and delineate the use-ful sonographic features of pneumotho-rax. Their use of time-motion mode todemonstrate the presence of lung slidingand lung point likely improves both thenovice and experienced sonographer’sability to correctly identify these features.The authors also add clarity to the some-times confusing and overly inclusiveterm “comet tail” artifact. By differenti-ating “B-lines” from other comet tail fea-tures, they make it possible for ultra-sound to rule out pneumothorax with anexceptionally high degree of confidence.
Dr. Lichtenstein and colleagues’ arti-cle further supports the use of ultrasoundfor the detection of pneumothorax andclearly demonstrates that ultrasonogra-phy performed by the clinician at the
*See also p. 1231.Key Words: ultrasound; pneumothorax; occult
patient’s bedside can accurately and reli-ably detect occult pneumothorax. Occultpneumothorax is a relatively commonproblem in trauma patients, being foundin 7.9% of those who underwent abdom-inal computed tomography scans (13).Although several authors (14, 15) haveobserved that patients with occult pneu-mothoraces are managed successfullywith observation alone, Enderson andcolleagues (16) found that eight of 15patients with occult pneumothorax whorequired positive pressure ventilation anddid not have a chest tube in place hadprogression of their pneumothorax, andthree of the same 15 developed tensionpneumothorax. Given that a delay in appro-priate therapy for tension pneumothorax isassociated with a four-fold increase in mor-tality rate (17), Enderson and colleagues(18) suggest that all patients with occultpneumothorax who require positive pres-sure ventilation should undergo tube tho-racostomy. It therefore seems that early,reliable detection is needed for those pa-tients at risk of occult pneumothorax.
Dr. Lichtenstein and colleagues’ arti-cle also adds to the growing body of lit-erature demonstrating the value of clini-cian-performed ultrasonography at thepatient’s bedside. Widespread adaptationof clinician-performed ultrasonographyin the critical care unit may allow de-creased complication rates for proceduressuch as thoracentesis, central venouscannulation, and percutaneous dilationtracheostomy. Additionally, clinician-performed ultrasonography in the criticalcare unit may allow rapid confirmation ofclinically suspected pneumothorax,
thereby expediting appropriate therapy. Itmay allow early detection of occult pneu-mothorax in patients at risk who are un-dergoing positive pressure ventilation,thereby allowing appropriately height-ened vigilance or tube thoracostomy toprotect the patient. This growing body ofevidence raises the question, should real-time ultrasonography be readily availableto every clinician in every critical care unit?
Martin L. Mayse, MDWashington University School of
MedicineDivision of Pulmonary and Critical
Care MedicineSt. Louis, MO
REFERENCES
1. Jones PW, Moyers JP, Rogers JT, et al: Ultra-sound-guided thoracentesis: Is it a safermethod. Chest 2003; 123:418–423
2. Mayo PH, Goltz HR, Tafreshi M, et al: Safetyof ultrasound-guided thoracentesis in pa-tients receiving mechanical ventilation.Chest 2004; 125:1059–1062
3. Hatfield A, Bodenham A: Portable ultrasonicscanning of the anterior neck before percu-taneous dilation tracheostomy. Anaesthesia1999; 54:660–663
4. Keenan SP: Use of ultrasound to place cen-tral lines. J Crit Care 2002; 17:126–137
5. Hind D, Calvert N, McWilliams R, et al: Ultra-sonic locating devices for central venous can-nulation: meta-analysis. BMJ 2003; 327:361
6. Keenan SP: Use of ultrasound to place cen-tral lines. J Crit Care 2002; 17:126–137
7. Maury E, Guglielminotti J, Alzieu M, et al:Ultrasonic examination: An alternative tochest radiography after central venous cath-eter insertion? Am J Respir Crit Car Med2001; 164:403–405
8. Knudtson JL, Dort JM, Helmer SD, et al:Surgeon-performed ultrasound for pneumo-thorax in the trauma suite. J Trauma 2004;57:527–530
9. Knudtson JL, Dort JM, Helmer SD, et al:Surgeon-performed ultrasound for pneumo-thorax in the trauma suite. J Trauma 2004;56:527–530
10. Dulchavsky SA, Schwarz KL, KirkpatrickAW, et al: Prospective evaluation of thoracicultrasound in the detection of pneumotho-rax. J Trauma 2001; 50:201–205
11. Rowan KR, Kirkpatrick AW, Liu D, et al:Traumatic pneumothorax detection withthoracic US: Correlation with chest radiog-raphy and CT—Initial experience. Radiology2002; 225:210–214
12. Lichtenstein DA, Mezière G, Lascols N, et al:Ultrasound diagnosis of occult pneumotho-rax. Crit Care Med 2005; 33:1231–1238
13. Hill SL, Edmisten T, Holtzman G, et al: Theoccult pneumothorax: An increasing diag-nostic entity in trauma. Am Surg 1999; 65:254–258
14. Wolfman NT, Meyers WS, Glauser SJ, et al:Validity of CT classification on managementof occult pneumothorax: A prospective study.Am J Roentgenol 1998; 171:1317–1320
15. Brasel KJ, Stafford RE, Weigelt JA, et al:Treatment of occult pneumothoraces fromblunt trauma. J Trauma 1999; 46:987–990
16. Enderson BL, Abdalla R, Frame SB, et al:Tube thoracostomy for occult pneumotho-rax: A prospective randomized study of itsuse. J Trauma 1993; 35:726–729
17. Baumann MH, Sahn SA: Tension pneumo-thorax: Diagnostic and therapeutic pitfalls.Crit Care Med 1993; 21:177–178
18. Enderson BL, Abdalla R, Frame SB, et al:Tube thoracostomy for occult pneumotho-rax: a prospective randomized study of itsuse. J Trauma 1993;35: 726–729
Jumpers, fallers, and stumblers: Children should not drop andelders should not trip*
I n this issue of Critical CareMedicine, Dr. Lapostolle and as-sociates (1) bring us an unusualperspective of falls from heights.
The unique feature of this report isthe retrospective and prospective look
at prognostic factors after falls from thenonpareil French emergency medicalsystem. The French system, with itsinimitable physician presence in theambulance, allowed the authors togather all pertinent information of pa-tients falling from height (�3 m or onefloor). The physicians had a unique ac-cess to the events surrounding the fall:the conditions of the fall, the nature ofimpact before or after the final destina-tion of the fall, and the impacting sur-face of the body. Patients with cardiac
arrest at the scene were not excludedtill the ambulance and the physiciancould attend the scene. These unparal-leled observations set this article apartfrom the crowded literature repletewith postmortem and clinical studiesbut seldom a combination of the two.
Several studies (2–5) are availablefrom postmortem analyses of fatal falls,all documenting that the head is the mostfrequently injured body region (70%),followed by the chest, abdomen, extrem-ities, and neck (19%) (2). Two autopsy
*See also p. 1239.Key Words: falls; jumpers; free falls; ground level
studies from Germany (3, 4) also empha-sized that the primary cause of death wascraniocerebral trauma and that the vastmajority of skull injuries associated withfalls down stairs were found above the“hat brim line.” Aortic lacerations andvertebral compression fractures were alsofrequent.
Even though one retrospective clinicalstudy from Australia (6) tried to arguethat the height of fall had poor sensitivityand specificity for serious injury, manyother clinical studies in the past decade,also retrospective, agreed that the sever-ity of injury was primarily dependent onthe height of the fall, the nature of thecontact surface, body orientation on im-pact, body mass, the victim’s ability todistribute the impact forces efficiently,and the victim’s age (7–10). From theUnited Kingdom, The and associates (8)analyzed 342 fallers and 57 jumpers andconcluded that the two caused differentinjury patterns, jumpers tending to landfeet first and sustain more injuries ontheir dominant side.
The nature of injuries associated withfree falls in children is considerably differ-ent from that in adults. Children �3 yrs aremuch less likely to have serious injuriesthan older children who fall the same dis-tance. It is thought that because youngerchildren have more fat and cartilage andless muscle mass than older children, theydissipate the energy transferred by the fall(9, 10). In the study by Yagmur et al. (11),young children who fell from �3 m sus-tained only minor injuries, such as contu-sions, abrasions, and lacerations. Fractureswere the most common of their seriousinjuries, and the radius, ulna and femurwere the most frequent sites. Mortality rateincreased in falls from �6 m. Wang et al.(12) also emphasized that children withlow-level falls had a similar risk for intra-cranial and abdominal injury as those whofell from greater heights. It is estimatedthat 58,000 fall-related hospitalizations andthe 130 deaths below the age of 15 are mostoften associated with falls �10 m (13).Other facts of importance: Nearly threequarters of falls from heights in childrenare unintentional, and the circumstances ofinjury should always be investigated for in-flicted trauma, especially in children �5yrs (14). One shining beacon for us to fol-low is the “Children Can’t Fly” programstarted by Barlow in New York City in 1979.This was instrumental in legally requiringwindow guards in all family houses withchildren �10 yrs old. The results werenothing short of spectacular: Accidental
falls decreased by 96% in 4 yrs (9). It isdisheartening, therefore, to note that 98children were injured during a 3-yr periodfrom 1997 to 1999 in Dallas, because ofinadequate balcony rails (distance betweenrails �4 inches) and windows positionedlow on the floor, an injury-prone situationpermitted by older building codes (15).
The most disturbing group in relationto falls is the elderly (14, 16, 17). Alarm-ingly, nearly one third of individuals �65yrs of age fall each year with a dispropor-tionately high injury severity (16). Same-level falls cause serious injury 30% of thetime in people older than 65 comparedwith 4% in the younger group. Falls wereseven times more likely to be the cause ofdeath compared with the younger group,55% vs. 7.5% (16). In a prospective studyfrom Scotland (17), 51 patients with amean age of 68.9 yrs died after slippingdown stairs. Death was due to brain orspinal cord injury. Multiple comorbiditiesas well as environmental factors such asslippery floors and stairs without safetyrails predispose these frail, aged individ-uals to what frequently is the last straw,”their last fall. Another beacon is beckon-ing us, however. Unlike the disappoint-ingly poor results of preventive efforts inearlier studies, Tinnetti and associates(18) presented a more optimistic assess-ment of strategies to reduce falls amongthe elderly. In a study of 301 patients ofage �70 yrs, the intervention group par-ticipants, randomly assigned, were givenan adjustment in their medications, be-havioral instructions, and exercise pro-grams aimed at modifying their risk fac-tors. The control group received theusual health care plus social visits. Dur-ing 1 yr of follow-up, 35% of the inter-vention group fell compared with 47% ofthe control group (p � .04). In at-riskpeople living at home, Clemson et al. (19)conducted a multifaceted community-based program using a learning environ-ment in reducing falls for small groups.This intervention group experienced a31% reduction in falls (relative risk, 0.69;95% confidence interval, 0.50–0.96; p �.025). Despite these encouraging reports,a systematic database review by Cochranecorporation (20) concluded that interven-tions to prevent falls are now availablebut their effectiveness in preventing fall-related injuries is yet not firmly estab-lished. Nevertheless, both the NationalCenter for Injury Prevention and Controlin the United States (21) and the NationalInstitute for Clinical Excellence branch ofNational Health Service in the United
Kingdome (22) have issued fall preven-tion guidelines in the elderly. Thesemerit our careful attention.
The prognostic factors described byDr. Lapostolle and colleagues (1) in theircarefully performed study will be hard tochallenge for eons. The alarmingly highmortality rate (34%) they describe shouldbe a clear message to intensify our pre-vention efforts.
Rao R. Ivatury, MDVirginia Commonwealth
UniversityMedical College of VirginiaRichmond, VA
REFERENCES
1. Lapostolle F, Gere C, Borron SW et al: Prog-nostic factors in victims of falls from height.Crit Care Med 2005; 33:1239–1242
2. Li L, Smialek JE: The investigation of fatalfalls and jumps from heights in Maryland(1987–1992). Am J Forensic Med Pathol1994; 15:295–299
3. Turk EE, Tsokos M: Pathologic features offatal falls from height. Am J Forensic MedPathol. 2004; 25:194–199
4. Preuss J, Padosch SA, Dettmeyer R, et al:Injuries in fatal cases of falls downstairs. Fo-rensic Sci Int. 2004; 141:121–126
5. Goren S, Subasi M, Tyrasci Y, et al: Fatal fallsfrom heights in and around Diyarbakir, Tur-key. Forensic Sci Int 2003; 14:137:37–40
6. Goodacre S, Than M, Goyder RC, et al: Canthe distance fallen predict serious injuryafter a fall from a height? J Trauma 1999;46:1055–1058
7. Agalar F, Cakmakci M, Sayek I: Factors ef-fecting mortality in urban vertical free falls:Evaluation of 180 cases. Int Surg 1999; 84:271–274
8. The J, Firth M, Sharma A, et al: Jumpers andfallers: A comparison of the distribution ofskeletal injury. Clin Radiol 2003; 58:482–486
9. Barlow B, Niemirska M, Gandhi RP, et al: Tenyears of experience with falls from a height inchildren. J Pediatr Surg 1983; 18:509–511
10. Lallier M, Bouchard S, St-Vil D, et al: Fallsfrom heights among children: A retrospec-tive review. J Pediatr Surg 1999; 34:1060–1063
11. Yagmur Y, Guloglu C, Aldemir M, et al: Fallsfrom flat-roofed houses: A surgical experi-ence of 1643 patients. Injury 2004; 35:425–428
12. Wang MY, Kim KA, Griffith PM, et al: Inju-ries from falls in the pediatric population: Ananalysis of 729 cases. J Pediatr Surg 2001;36:1528–1534
13. Rivara FP, Alexander B, Johnston B, et al:Population-based study of fall injuries inchildren and adolescents resulting in hospi-talization or death. Pediatrics 1993; 92:61–63
14. Schermer CR: Injuries due to falls from
1427Crit Care Med 2005 Vol. 33, No. 6
heights. Available at: http://www.facs.org/trauma/falls/html
15. Istre GR, McCoy MA, Stowe M, et al: Childhoodinjuries due to falls from apartment balconiesand windows. Inj Prev 2003; 9:349–52
16. Sterling DA, O’ Connor JA, Bonadies J: Geri-atric falls: Injury severity is high and dispro-portionate to mechanism. J Trauma 2001;50:116–119
18. Tinetti ME, Baker DI, McAvay G, et al: Amultifactorial intervention to reduce therisk of falling among elderly people livingin the community. N Engl J Med 1994;331:821– 827
19. Clemson L, Cumming RG, Kendig H, et al:The effectiveness of a community-based pro-
gram for reducing the incidence of falls inthe elderly: A randomized trial. J Am GeriatrSoc 2004; 52:1487–1494
20. Gillespie LD, Gillespie WJ, Robertson MC, etal: Interventions for preventing falls in el-derly people. Cochrane Database Syst Rev2001; (3):CD000340
Water, water, everywhere. . .But how do we measure it?*
T he advances made in our un-derstanding of the pathophys-iology of acute lung injury andthe physiology and pathophys-
iology of the movement of water in thelung, and the conjunction between thetwo, have led to a greater understandingof the changes that occur in acute lunginjury, the timing of those changes, themonitoring of those changes, and thetreatments to modify those changes.
One of the areas that has continued toraise questions is the bedside measure-ment of extravascular lung water(EVLW). The gold standard for EVLWmeasurement is the comparison of wet-to-dry weight of the lung, which, ofcourse, is not practical for human appli-cation. Standard clinical approaches suchas the chest radiograph are neither sen-sitive nor specific indicators of lung wa-ter. The double-indicator dilution tech-nique has been the standard forrepeatable measurements since it wasfirst described �50 yrs ago (1). The stan-dard indicators for the past few decadeshave been indocyanine green dye for theintravascular indicator and cold solutionfor the thermal or extravascular indica-tor. This technique in itself has been thesubject of numerous studies in the pastfew years, primarily because it is perfu-sion dependent and is therefore affectedby a variety of conditions that alter re-gional perfusion in the lung (2–4). Thistechnique also has not gained widespreadclinical use, in part because it is expen-sive and more complicated to use thanthe common thermal techniques to mea-
sure cardiac output, despite the develop-ment of commercial systems that sim-plify its use. Some 20 yrs ago, Elings andLewis (5) and Baudendistel et al. (6)proposed using only the thermal indi-cator to reflect extravascular lung wa-ter. The application of the single-indicator method requires twoassumptions. The first is that the down-slope time of the thermal decay curvetimes the cardiac output is the totalpulmonary thermal volume. This calcu-lation can then give the total blood inthe four heart chambers, or the globalend-diastolic volume. The second as-sumption is that the ratio between theglobal end-diastolic volume and thepulmonary blood volume is always 4:1.
Anytime one has an estimation withsuch significant assumptions, concern israised about the precision and accuracyof the estimation. The initial studies byElings and Lewis (5) and Baudendistel etal. (6) did not have acceptable correla-tions with the double-indicator method,mostly due to technical and mathemati-cal problems. Specifically, the single-indicator values were systematically un-derestimated by the equipment they wereusing. More recently, Sakka et al. (7, 8),using more rapidly responding ther-mistors and a fiberoptic system, evalu-ated this estimation in 266 critically illadults in a surgical ICU. They found acloser correlation between the two tech-niques in these patients, using a smallcorrection factor. They initially evaluated57 patients, 23 with multiple organ sys-tem dysfunction and 17 with acute respi-ratory distress syndrome and derived theequation describing the relationship be-tween the intrathoracic blood volumeand the global end-diastolic volume.These authors subsequently furthertested this equation on another 209 pa-tients in a surgical ICU (99 with sepsis, 31
with acute respiratory distress syndrome,19 with hemorrhagic shock, and 60 withhead trauma or other intracranial pathol-ogy). The authors found that the EVLWindex (indexed to body surface area) de-termined by the two methods had a cor-relation coefficient of .96 with a SD of 1.4mL/kg and that the SD as a percentage ofthe EVLWI decreased at the higher levelsof EVLW index (as would be expected).But they also pointed out that furthervalidation of this technique was needed.
In this issue of Critical Care Medicine,Dr. Michard and colleagues (9) have donejust that. They evaluated a number offactors that could affect the accuracy ofthe single-indicator dilution technique.This was done in 48 postoperative pa-tients who were on mechanical ventila-tion and who had a variety of conditionsrequiring hemodynamic monitoring, in-cluding sepsis (n � 29), nosocomialpneumonia (n � 29), and hemorrhage (n� 3). The authors then used linear re-gression analysis to evaluate factors thatmight influence the single-dilution mea-surement. They found that the PaO2, theintrathoracic blood volume, and the car-diac output had no influence, at least inthe range measured. They did find thatthe amount of the EVLW, the tidal vol-ume, the positive end-expiratory pressurelevel, and the PaO2/FIO2 level did affectEVLW, probably by reducing perfusion toareas of the lung so that the intrathoracicblood volume was overestimated, leadingto an underestimation of EVLW. Thesefindings are not surprising, given the per-fusion dependence of these techniques.However, as the authors point out, thebias remained �10% in the conditions ofthe study, well within clinically accept-able variance.
This study and others on both thedouble-indicator and single-indicatortechniques still leave significant ques-
*See also p. 1243.Key Words: acute lung injury; extravascular lung
tions. One persisting question has to dowith the clinical implications of theEVLW measurement. How important isit to have an accurate measurement ofEVLW in clinical care? There are stud-ies indicating that using the EVLWmeasurement to direct therapy can leadto improved outcomes (10, 11). How-ever, using EVLW, even with the sim-plification of using a single indicator,adds complexity and expense to the careof the critically ill patient. It remains tobe seen if the advantages of havingknowledge of the EVLW are sufficient tojustify the additional complexity. Thisis especially important as other nonin-vasive measures of hemodynamic per-formance, such as the transthoracicechocardiogram, are being increasinglyused to evaluate and guide therapy, al-beit not EVLW. The technique itselfmust continue to be evaluated in moresevere circumstances of perfusion alter-ation than were present in this study.
Thus, the most important clinical ques-tions remain to be answered.
D. Robert McCaffree, MDUniversity of Oklahoma College
of MedicineOklahoma City, OK
REFERENCES
1. Chinard FP, Enns T: Transcapillary pulmo-nary exchange of water in the dog. Am JPhysiol 1954; 178:197–199
2. Bock JC, Lewis FR: Clinical relevance of lungwater measurement with the thermal-dye dilu-tion technique. J Surg Res 1990; 48:254–265
3. Carlile PV, Beckett RC, Gray BA: Relation-ship between CO and transit times for dyeand thermal indicators in central circulation.J Appl Physiol 1986; 60:1363–1372
4. Beckett RC, Gray BA: Effect of atelectasis andembolization on extravascular thermal vol-ume of the lung. J Appl Physiol 1982; 53:1614–1619
5. Elings VB, Lewis FR: A single indicator tech-nique to estimate extravascular lung water.J Surg Res 1982; 33:375–385
6. Baudendistel LJ, Kaminski DL, Dahms TE:
Evaluation of extravascular lung water bysingle thermal indicator. Crit Care Med1986; 14:52–58
7. Sakka SG, Reinhart K, Meier-Hellman A: Com-parison of pulmonary artery and arterial ther-modilution cardiac output in critically ill pa-tients. Intensive Care Med 1999; 25:843–846
8. Sakka SG, Rühl CC, Pfeiffer UJ, et al: Assess-ment of cardiac preload and extravascular lungwater by single transpulmonary thermodilu-tion. Intensive Care Med 2000; 26:180–187
9. Michard F, Schachtrupp A, Toens C: Factorsinfluencing the estimation of extravascularlung water by transpulmonary thermodilu-tion in critically ill patients. Crit Care Med2005; 33:1243–1247
10. Eisenberg PR, Hansbrough JR, Anderson D,et al: A prospective study of lung water mea-surements during patient management in anintensive care unit. Am Rev Respir Dis 1987;136:662–668
11. Mitchell JP, Schuller D, Calandrino FS, et al:Improved outcome based on fluid manage-ment in critically ill patients requiring pul-monary artery catheterization. Am Rev Re-spir Dis 1992; 145:990–998
Slow response times: Is it the pneumonia or the physician?*
Pneumonia remains one of themost serious complications ofmechanical ventilation (1). De-spite significant research at-
tention and clear financial incentives, ef-forts to avoid or treat ventilator-associated pneumonia (VAP) moreeffectively have not had the success thatfollowed attention to another early com-plication of mechanical ventilation—stress-induced gastric mucosal hemor-rhage. The latter has become so rare thatmany younger critical care physicianshave never seen a clinically significantcase, much less a death, from this com-plication. Were that true of VAP!
The initial focus in VAP was improvingdiagnostic accuracy, with the naïve as-sumption that if the clinician couldclearly define which patient had pneumo-nia, correct treatment would follow logi-cally based on antibiotic sensitivities of
the cultured pathogen. Although moreaccurate diagnostic techniques do lead tolower mortality rates, the benefit appearsto be due to prevention of infections withmultiple-drug-resistant microorganismsby decreasing excessive antibiotics (2, 3).Meanwhile, emphasis was shifting to therole of initial empirical antibiotic ther-apy. Inappropriate initial empirical ther-apy is consistently associated with an in-creased mortality rate (1), no matterwhat the culture method used to deter-mine appropriateness of therapy. Al-though clearly important in improvingoutcome, appropriate initial empiricaltherapy alone may still not be sufficientto decrease mortality rates (4). Increasingevidence suggests that antibiotic therapyis often ineffective for certain types ofVAP, especially those due to Pseudomo-nas (5) and oxacillin-resistant Staphylo-coccus aureus (6–8). The clinical failurerates for Pseudomonas VAP are com-monly 50%, whereas 40% failure of ther-apy for oxacillin-resistant S. aureus VAPis the norm.
Recognition of failure of antibiotictherapy therefore becomes critically im-portant to improve outcome of VAP. Un-
fortunately, clinicians have a difficulttime recognizing failure. The article byDr. Vidaur and colleagues (9) in this issueof Critical Care Medicine adds furtherdata to this complex issue. Other studieshave examined the routine clinical vari-ables used by most clinicians to assessresponse to therapy. Several studies havesuggested that the improvement in oxy-genation is the most reliable criteria todistinguish patients who are respondingto antibiotic treatment from those whoare not (10). Dr. Vidaur and coworkers’contribution to the increasing body ofliterature is to demonstrate that improve-ment in oxygenation is unreliable in pa-tients with the acute respiratory distresssyndrome (ARDS) (9). Only fever, of theusual five clinical criteria for response,distinguished those with successful fromthose with poor response, and even reso-lution of fever was delayed compared withnon-ARDS patients. At days 7–8 of treat-ment, when antibiotics for VAP should bestopped (11), 35% of ARDS patients withVAP were still febrile.
Unfortunately, tracking fever in ARDSpatients is probably also unreliable. Pre-vious studies have demonstrated that two
*See also p. 1248.Key Words: pneumonia; mechanical ventilation;
or more potential causes of fever can bedemonstrated in each ARDS patient sus-pected of VAP if a diagnostic algorithm isfollowed (12). Any of these additional oralternative diagnoses can be the cause ofpersistent fever and other signs of pneu-monia but require different antibiotictherapy or additional therapeutic proce-dures for optimal management.
Clinical response is not the only wayto assess response to therapy. Microbio-logical response has only been usedrarely. Disappearance of bacterial fromsputum cultures has been used to assessresponse (13). However, tracheal aspi-rates in intubated patients are probablyless reliable because of persistent coloni-zation, possibly due to viable bacteria em-bedded in the glycocalyx on the endotra-cheal tube (14). Serial quantitativecultures from a variety of techniqueshave been demonstrated to correlate withoutcome (8, 15, 16), often clarifying re-sponse earlier than clinical variables.
Molecular markers may also be morereliable than clinical response. Luyt et al.(17) recently demonstrated that the pro-calcitonin level at day 3 of therapy dis-criminates between clinical success andfailure with an area under the receiveroperating curve of 0.87. Other markersmay function as well (18). Unfortunately,none of the markers is specific for VAP,and most will be elevated in ARDS.Therefore, although a persistently highlevel may indicate that problems exist,the elevated marker may be caused byother infections or causes of inflamma-tion as well. Further testing is needed todefine the cause of persistent mediatoractivation (18).
As critical care physicians, we havebeen slow to respond to the evidence re-garding poor outcomes from VAP. Part ofthat slow response has been a sense thatpatients are dying with VAP, rather thandying of VAP, and that mortality directlyattributable to VAP is very low. The factthat differences in diagnostic strategies(2, 3) or appropriate antibiotics (6) leadto mortality differences suggests that anattributable mortality rate for VAP existsand that this therapeutic nihilism is notwarranted. Clinical failure is consistentlyassociated with increased mortality fromVAP, particularly in non-ARDS patients(9, 10, 15).
So what can clinicians do now? Firstof all, heightened awareness of the fre-
quency of antibiotic failure in itself maylead to a lower threshold to change ther-apy or conduct more tests. Second, pro-longing the duration of therapy for pa-tients who do not seem to be respondingappears to be a futile response (11). If �8days of antibiotic therapy for an episodeof VAP is believed to be needed, changingto a different antibiotic regimen has agreater probability of improving outcomethan continuing what is most likely afailing regimen.
Prospective trials are clearly needed todetermine whether a diagnostic or treat-ment algorithm leads to improved out-come when criteria for failure are met,whether clinical, microbiological, or mo-lecular. Classification schemes and diag-nostic algorithms have already been pub-lished (18). The study of Dr. Vidaur andcolleagues (9) adds another piece to thepuzzle of poor response to therapy ofVAP.
Richard G. Wunderink, MDDivision of Pulmonary and Critical
CareNorthwestern University Feinberg
School of MedicineChicago, IL
REFERENCES
1. Guidelines for the management of adultswith hospital-acquired, ventilator-associ-ated, and healthcare-associated pneumo-nia. Am J Respir Crit Care Med. 2005; 171:388 – 416
2. Fagon JY, Chastre J, Wolff M, et al: Invasiveand noninvasive strategies for managementof suspected ventilator-associated pneumo-nia. A randomized trial. Ann Intern Med2000; 132:621–630
3. Singh N, Rogers P, Atwood CW, et al: Short-course empiric antibiotic therapy for patientswith pulmonary infiltrates in the intensivecare unit. A proposed solution for indiscrim-inate antibiotic prescription. Am J RespirCrit Care Med 2000; 162:505–511
4. Ibrahim EH, Ward S, Sherman G, et al: Ex-perience with a clinical guideline for thetreatment of ventilator-associated pneumo-nia. Crit Care Med 2001; 29:1109–1115
5. Brun-Buisson C, Sollet JP, Schweich H, etal: Treatment of ventilator-associatedpneumonia with piperacillin-tazobactam/amikacin versus ceftazidime/amikacin: Amulticenter, randomized controlled trial.VAP Study Group. Clin Infect Dis 1998;26:346 –354
6. Wunderink RG, Rello J, Cammarata SK, et al:Linezolid vs vancomycin: analysis of twodouble-blind studies of patients with methi-cillin-resistant Staphylococcus aureus noso-
comial pneumonia. Chest 2003; 124:1789–1797
7. Fagon J, Patrick H, Haas DW, et al: Treat-ment of Gram-positive nosocomial pneumo-nia. Prospective randomized comparison ofquinupristin/dalfopristin versus vancomycin.Nosocomial Pneumonia Group. Am J RespirCrit Care Med 2000; 161:753–762
8. Baughman RP, Kerr MA: Ventilator-associ-ated pneumonia patients who do not reducebacteria from the lungs have a worse prog-nosis. J Intensive Care Med 2003; 18:269–274
9. Vidaur L, Gualis B, Rodriguez A, et al: Clin-ical resolution in patients with suspicion ofventilator-associated pneumonia: A cohortstudy comparing patients with and withoutacute respiratory distress syndrome. CritCare Med 2005; 33:1248–1253
10. Luna CM, Blanzaco D, Niederman MS, et al:Resolution of ventilator-associated pneumo-nia: Prospective evaluation of the clinicalpulmonary infection score as an early clinicalpredictor of outcome. Crit Care Med 2003;31:676–682
11. Chastre J, Wolff M, Fagon JY, et al: Compar-ison of 8 vs 15 days of antibiotic therapy forventilator-associated pneumonia in adults: Arandomized trial. JAMA 2003; 290:2588–2598
12. Meduri GU, Mauldin GL, Wunderink RG, etal: Causes of fever and pulmonary densitiesin patients with clinical manifestations ofventilator-associated pneumonia. Chest1994; 106:221–225
13. Schentag JJ: Correlation of pharmacoki-netic parameters to efficacy of antibiotics:Relationships between serum concentra-tions, MIC values, and bacterial eradicationin patients with Gram-negative pneumo-nia. Scand J Infect Dis 1991; 74:218 –234
14. Sottile FD, Marrie TJ, Prough DS, et al: Nos-ocomial pulmonary infection: Possible etio-logic significance of bacterial adhesion toendotracheal tubes. Crit Care Med 1986; 14:265–270
15. Montravers P, Fagon JY, Chastre J, et al:Follow-up protected specimen brushes to as-sess treatment in nosocomial pneumonia.Am Rev Respir Dis 1993; 147:38–44
16. A’Court CH, Garrard CS, Crook D, et al: Micro-biological lung surveillance in mechanicallyventilated patients, using non-directed bron-chial lavage and quantitative culture. QuartJ Med 1993; 86:635–648
17. Luyt CE, Guerin V, Combes A, et al: Procal-citonin kinetics as a prognostic marker ofventilator-associated pneumonia. Am J Re-spir Crit Care Med 2005; 171:48–53
18. Ioanas M, Ferrer M, Cavalcanti M, et alCauses and predictors of nonresponse totreatment of intensive care unit-acquiredpneumonia. Crit Care Med 2004; 32:938 –945
1430 Crit Care Med 2005 Vol. 33, No. 6
Lower cortisol concentrations in patients with liver disease: Moreadrenal failure or more confusion?*
I n this issue of Critical CareMedicine, Dr. Marik and colleagues(1) categorize 340 liver disease pa-tients and claim that 72% have ad-
renal failure. Adrenal failure was defined asa random cortisol �20 �g/dL in patientswith systolic blood pressure �90 mm Hgrequiring vasopressor agents or with hy-poxemic respiratory failure, or a randomcortisol �15 �g/dL in patients not needingvasopressor support. Using this criterion,the authors reported that 72% of the pop-ulation met their criteria for adrenal fail-ure. In an earlier study, two thirds of pa-tients with a cortisol concentration �15�g/dL stimulated �19.9 �g/dL after 250�g of adrenocorticotropic hormone(ACTH). These septic patients did not haveadrenal failure (2). Therefore, true adrenalfailure may have been seen in only onethird of Dr. Marik and colleagues’ patientswith cortisol �15 �g/dL (one third of the174 nonvasopressor-supported patients,which would total 58). This would repre-sent 17% of the total population since noneof the patients with a cortisol �14.9 �g/dLshould have been considered to have adre-nal failure. For adrenal failure to be seen in72% of patients, this would have to be anunrecognized epidemic, or should we ques-tion the criteria used in this study for thediagnosis of adrenal failure?
Could the common occurrence of areduced total serum cortisol concentra-tion in patients with liver disease be dueto reduced binding proteins? An exampleof this possibility has been seen with thethyroid binding-protein deficiency. Pa-tients with this autosomal dominant dis-order have severely reduced thyroid bind-ing-protein and, because it binds 60% ofthyroxin (T4), a severely reduced T4 con-centration. However, their free-T4 serumconcentration is normal. These patients
are commonly diagnosed as hypothyroidbecause of the severely reduced total T4concentration. Could a reduced bindingprotein in liver disease cause a similarproblem?
Chronic liver disease patients who arenot critically ill have a reduced cortisol-binding globulin (CBG) by 13–30% (3, 4).During acute illness, the concentration ofCBG is also reduced. In patients withoutliver disease, critical illness reduces CBGby approximately 25% (5). In septic shockpatients, CBG is reduced by 36% (6). In amixture of critically ill patients, somewith liver disease, CBG was reduced by55% (7).
The reduced CBG is likely due to anincreased degradation of CBG and a re-duced synthesis. The shorter half-life isdue to removal by neutrophil elastase atthe site of injury, and a reduced hepaticsynthesis is likely related to the elevatedinterleukin-6 concentration. In liver dis-ease patients with sepsis, interleukin-6concentration increases five-fold greaterthan in non-liver disease patients withsepsis (8). Interleukin-6 diminishes CBGsynthesis by reducing the stability of themessenger RNA (9). The higher interleu-kin-6 concentration seen in liver diseasepatients with sepsis likely plays a role inreduction of CBG concentration. The ma-jority of the total cortisol concentrationis bound to CBG (80%), with only 14%bound to albumin and 6% unbound orfree (10). When CBG concentration de-creases, free cortisol concentration in-creases. This was shown nicely in patientswith reduced CBG concentrations, whereCBG was inversely related to their freecortisol concentration (r � �.74, p �.01) (11).
Free cortisol concentration is the bio-logically active agent that regulates pitu-itary secretion of ACTH (5). Families thathave a mutation in the CBG proteinwhere cortisol cannot bind to CBG have anormal diurnal variation and free cortisolACTH concentrations (10). In critical ill-ness and in postoperative recovery, freecortisol concentration is increased ap-
proximately seven- to eight-fold despitethe fact that total cortisol concentrationis only increased two- to three-fold (5,12). Unfortunately, total serum cortisolconcentration does not reflect the freehormone concentration.
Selecting a random cortisol concen-tration �15 �g/dL to indicate adrenalfailure is like selecting a total T4 concen-tration of 4.5 �g/dL and calling it hypo-thyroidism in a family with thyroid bind-ing-protein deficiency. Furthermore,defining adrenal failure at this thresholdappears counterintuitive since mortalityrate was reduced in patients with adrenalfailure (39 vs. 56%, p � .005). If hepato-adrenal failure increases risk, like thatassociated with hepato-renal failure, thenthe overall mortality rate should havebeen greater. Dr. Marik and colleagues’data support the opposite (1).
Since those with a “normal” adrenalfunction had the higher mortality rate,the authors may want to consider a dif-ferent cutoff for adrenal failure. Maybe arandom cortisol cutoff of �5 �g/dL, or�10 �g/dL with hypotension, would be amore reasonable approach. Using thiscutoff, the incidence may be in the 10–20% range. One wonders that if this cut-off were used, what would be the mortal-ity rate in those who met the stricterclinical criteria of adrenal failure.
These authors did demonstrate thatpatients with a serum cortisol concentra-tion �15 �g/dL on vasopressors, or �20�g/dL not on vasopressors, derived somebenefit from hydrocortisone treatment asevidenced by a reduced mortality rate (26vs. 46% mortality; treated vs. nontreated,p � .002). However, this was nonblindedand nonrandomized and may have en-tirely been due to patient selection andphysician-driven efforts to improve out-come.
Maybe total cortisol concentration isnot related to benefit from hydrocorti-sone treatment. We need a better way toidentify those who will benefit from hy-drocortisone therapy. Blood pressure re-sponse to the use of hydrocortisone may
*See also p. 1254.Key Words: liver disease; adrenal failure; serum
be one specific situation. In Dr. Marik andcolleagues’ study, hydrocortisone was as-sociated with a reduced need for vaso-pressor support as measured by 24-hrnorepinephrine dose. With the highermortality rate in the “normal” adrenalgroup (cortisol �19.9 and on vasopressorsupport), one wonders if they would havehad the same benefit for vasopressor re-sponse.
Why was the mortality rate higher inthose with “normal” adrenal function de-spite the fact that age, vasopressor usage,mechanical ventilation, liver function, al-bumin, and renal function were similar?Terms used to define adrenal failure ordysfunction must be standardized be-cause of the paradox seen in this study. Ahigher mortality rate was seen in patientswith a “normal” adrenal function, andthese patients had a higher baseline cor-tisol concentration (30 � 19 vs. 9 � 4�g/dL, mean � SD, p � .001). Many stud-ies have demonstrated that mortality rateis increased as baseline cortisol concen-tration increases (13).
Until studies are completed using freecortisol concentration, errors will bemade in deciding who to treat for adrenalfailure. A cortisol response of 9 or 13�g/dL after 250 �g of ACTH may identifythose who are at risk of not having anadequate adrenal reserve (2, 13–15). Infact, mortality has been inversely linkedwith the delta cortisol response to 250 �gof ACTH (r � �.727, p � .01) (13). Theuse of the smaller 1-�g dose of ACTHresults in a small change in total cortisolconcentration and may add more confu-sion to this area. Having a 9–13 �g/dLincrease in serum cortisol after 250 �g ofACTH helps in identifying adrenal dys-function (relative adrenal insufficiency)since a reduced response has been asso-ciated with an increased mortality rate (2,14, 15).
If we are going to use the delta re-sponse, until a free cortisol assay be-comes available, then this response mayrepresents something other then adrenalfailure. In a recent study, patients withreduced binding proteins (CBG and albu-
min) had a 7.6-�g/dL response and a hos-pital mortality rate of 33% (5). Thosewith higher binding proteins had agreater response (11.8 �g/dL) and aslightly lower hospital mortality rate(23%). Since both of these groups hadsimilar free cortisol concentrations be-fore and after the ACTH test, the deltacortisol response should be viewed as amarker of adrenal dysfunction and notadrenal failure.
There has been one prospective studyproviding hydrocortisone to patients withblunted responses to 250 �g of ACTH(14). This study demonstrated an im-proved survival in patients with �9�g/dL response to a 250-�g ACTH ad-ministration (53% vs. 63% 28-day mor-tality, p � .05). There was no survivaladvantage of hydrocortisone treatment inpatients who had a normal adrenal re-sponse to ACTH (61 vs. 53% mortalityrate, steroid treated vs. placebo). Untilstudies are available to evaluate thechange in free cortisol during the con-ventional ACTH testing, criteria based onthe adrenal response to a 250-�g dose ofACTH are required to help identify thosewith a blunted adrenal response. Theterm “hepato-adrenal” should be reservedfor those few who have a total cortisolconcentration of �5 �g/dL without vaso-pressor support or �10 �g/dL with vaso-pressor support. A potential seven- toeight-fold increase in free cortisol con-centration seen in sepsis and after injuryis unlikely to represent a widespread ep-idemic of cortisol deficiency (5, 12).
John A. Tayek, MDLos Angeles Biomedical Research
Institute at Harbor-UCLAMedical Center
Torrance, CA
REFERENCES
1. Marik PE, Gayowski T, Starzl TE: The hepa-toadrenal syndrome: A common yet unrec-ognized clinical condition. Crit Care Med2005; 33:1254–1259
2. Manglik S, Flores E, Lubarsky L, et al: Glu-cocorticoid insufficiency in patients whopresent to the hospital with severe sepsis: A
prospective clinical trial. Crit Care Med 2003;31:1668–1675
4. Doe RP, Fernandez R, Seal US: Measurementof corticosteroid-binding globulin in man.J Clin Endocrinol 1964; 24:1029–1039
5. Hamrahian AH, Oseni TS, Arafah BM: Mea-surements of serum free cortisol in criticallyill patients. N Engl J Med 2004; 350:1629–1638
6. Perrot D, Bonneton A, Dechaud H, et al:Hypercortisolism in septic shock is not sup-pressible by dexamethasone infusion. CritCare Med 1993; 21:396–401
7. Beishuizen A, Thijs LG, Vermes I: Patterns ofcorticosteroid-binding globulin and the freecortisol index during septic shock and mul-titrauma. Intensive Care Med 2001; 27:1584–1591
8. Bly B, Roucloux I, Crusisux A, et al: Tumornecrosis factor alpha and interleukin 6plasma levels in infected cirrhotic patients.Gastroenterology 1993; 104:1492–1497
9. Bartalena L, Hammond GL, Farsetti A, et al:Interleukin-6 inhibits corticosteroid-bindingglobulin synthesis by human hepatoblas-toma-derived (Hep G2) cells. Endocrinol 133:291–296
10. Emptoz-Bonneton A, Cousin P, Seguchi K, etal: Novel human corticosteroid-binding glob-ulin variant with low cortisol-binding affin-ity. J Clin Endocrinol Met 2000;85:361–367
11. Bernier J, Jobin N, Emptoz-Bonneton A, etal: Decreased corticosteroid-binding globulinin burn patients: Relationship with interleu-kin-6 and fat in nutritional support. CritCare Med 1998; 26:452–460
12. Vogeser M, Groetzner J, Kupper C, et al: Freeserum cortisol during the postoperativeacute phase response determined by equilib-rium dialysis liquid chromatography-tandemmass spectrometry. Clin Chem Lab Med2003; 41:146–151
14. Annane D, Sebille V, Charpentier C, et al:Effect of treatment with low dose of hydro-cortisone and fludrocortisone on mortality inpatients with septic shock. JAMA 2002; 288:862–871
15. Moran JL, Chapman MJ, O’Fathartaigh MS,et al: Hypocortisolaemia and adrenocorticalresponsiveness at onset of septic shock. In-tensive Care Med 1994;20:489–495
1432 Crit Care Med 2005 Vol. 33, No. 6
Delirium: Out of one, many. . .*
W e have learned muchabout delirium and inten-sive care unit (ICU) pa-tients in the last few
years. In this issue of Critical Care Med-icine, Dr. Micek and colleagues (1) reporttheir results assessing delirium for 6months in the medical ICU at a majorteaching hospital. Excluding patientswith a history of psychosis or neurologicdisease (the number excluded is not re-ported), the research team used the Con-fusion Assessment Method for the ICU(CAM-ICU) once each day until ICU dis-charge in 93 mechanically ventilated pa-tients. Of this cohort, 29% remained co-matose during their entire ICU stay, 24%remained cognitively intact during theirentire ICU stay, and 47% developed delir-ium on �1 day during their ICU stay.Mortality rate was greater for comatosepatients (70%) than for either the deliri-ous (32%) or intact (36%) patients. Onlyone third of the delirious patients had �1day of normal cognition during their ICUstay, and 75% spent �1 day comatose(median of 2.5 days).
As with most well-conducted clinicalstudies, this report raises many morequestions than it answers. We will focusattention on only two: Why is the inci-dence of ICU delirium so variable fromstudy to study? What is the role of drug-induced alteration of consciousness onthe incidence and diagnosis of deliriumand adverse outcomes?
Why Is the Incidence of ICU DeliriumSo Variable From Study to Study? At thehigh end, Ely et al. (2, 3) reported adelirium incidence of 83% and 87% withthe CAM-ICU when patients with demen-tia, psychosis, or neurologic disease wereexcluded. At the low end, Lin et al. (4)reported an incidence of 22% using theCAM-ICU and excluding the same pa-tients, and Bergeron et al. (5) reported anincidence of 19% using the IntensiveCare Delirium Screening Checklist and
enrolling all except patients admitted tothe ICU with delirium. Dr. Micek andcolleagues (1) identified delirium in 47%of patients in their ICU, excluding thosewith psychosis or neurologic disease. Pa-tient heterogeneity and varying protocolsfor their care may contribute to the dif-ferent results reported, but it is difficultto identify a clear trend or signal. Four ofthese studies (and all reported studies forthe CAM-ICU) were performed in medicalICU patients with the reported incidenceof delirium ranging from 22% to 87%.None of the reports using the CAM-ICUhave employed bedside nurse assessment;rather, all have used dedicated researchpersonnel. Severity of illness may in-crease the incidence of delirium (6), butthe median Acute Physiology andChronic Health Evaluation II scores weresimilar in the delirious and intact groupin this study (21 vs. 21.5) and also similarto the CAM-ICU validation studies (2, 3).
The criteria and methods to define de-lirium (and the features of delirium em-phasized in that diagnosis) vary signifi-cantly between two ICU-specificassessment tools first reported in 2001,the CAM-ICU and the Intensive Care De-lirium Screening Checklist (2, 5). Asshown in Table 1, the CAM-ICU is a 2-minassessment of the patient, whereas theIntensive Care Delirium ScreeningChecklist reflects observations by thebedside nurse over the course of the en-tire shift. No direct comparison has beenreported between these two scales, butwhen the CAM-ICU was compared withthe Confusion Assessment Method (thescale from which it was derived) in acohort of nonintubated awake ICU pa-tients, significant differences in the inci-
dence of delirium occurred (7). The CAMclassified 68% of the cohort as deliriouscompared with 50% for CAM-ICU, whichhad a false-negative rate of 27% (7). In aneffort to explain the disagreement, theauthors suggested that the brief periodassessed by the CAM-ICU may underesti-mate the incidence of delirium, whichoften fluctuates significantly over time.To improve the sensitivity of diagnosingdelirium, especially among those withmilder symptoms, the authors stress thatmore time and additional detail may im-prove sensitivity (7). These scales appearto be assessing different things, yet bothshowed excellent agreement with expertsacting as the gold standard. How can wereconcile this apparent paradox?
What Is the Role of Drug-Induced Al-terations of Consciousness on the Inci-dence and Diagnosis of Delirium and Ad-verse Outcomes? The most strikingfinding of Dr. Micek and colleagues (1)relates to the doubling of mortality ratefor the persistently comatose patientscompared with those who awakened withor without delirium. Whether the “coma”described in this study is drug-induced ordue to an underlying disease process isunclear. Similarly, the CAM-ICU consid-ers fluctuations in mental status and al-tered level of consciousness as meetingcriteria for the diagnosis of deliriumwhether these are due to sedative admin-istration or an underlying disease pro-cess. Does it make a difference? Deepsedation has been associated with adverseoutcomes in studies by Kress et al. (8)and Brook et al. ( 9), and a recent study of820 patients during 4,707 patient-days atthe University of Montreal identified astrong relationship between “coma” and
Table 1. Comparison of the Confusion Assessment Method for the Intensive Care Unit (CAM-CIU) andthe Intensive Care Delirium Screening Checklist (ICDSC)
CAM-ICU (2) ICDSC (5)
Time of assessment 2–3 mins 8-hr nursing shiftExcluded patients Dementia, psychosis, neurologic disease Admitting diagnosis of deliriumDuration of study Hospital stay ICU stay (up to 5 days)Type of ICU Medical Medical-surgicalGold standard Board-certified psychiatrist or geriatrician Board-certified psychiatristPatients studied, n (%) 38/86 (44) 93/99 (94)
1433Crit Care Med 2005 Vol. 33, No. 6
the incidence of delirium (6). Is deep se-dation resulting in a coma-like stateworse than less sedation complicated bydelirium, or does deep sedation reducethe incidence of unpleasant recall andposttraumatic stress disorder? Are the re-duced rates of delirium after cardiac sur-gery reported with dexmedetomidinecompared with midazolam or propofol aresult of avoiding oversedation or due toadministering drugs that avoid the�-aminobutyric acid pathway? (10)
Many questions remain unasked andunanswered in this complex area of pa-tient sedation and delirium. Cliniciansand researchers are working hard to im-prove our ability to detect deliriumamong ICU patients. Delirium in itsmany forms and various definitions has astrong association with negative out-comes including mortality, longer ICUand hospital lengths of stay, and persis-tent cognitive impairments. The newtools available to help identify this syn-drome should improve patient care, butthere is a great deal more we need tolearn. The pivotal work by the groups atVanderbilt and the University of Montreal
and the follow-up work by groups such asDr. Micek and colleagues are helping tomove us all forward in this challengingtask.
Richard R. Riker, MDGilles L. Fraser, PharmD, FCCM
Division of Pulmonary/CriticalCare Medicine
Department of MedicineMaine Medical CenterPortland, ME
REFERENCES
1. Micek ST, Anand NJ, Laible BR, et al: Delir-ium as detected by the CAM-ICU predictsrestraint use among mechanically ventilatedmedical patients. Crit Care Med 2005; 33:1260–1265
2. Ely EW, Margolin R, Francis J, et al: Eval-uation of delirium in critically ill patients:Validation of the Confusion AssessmentMethod for the Intensive Care Unit (CAM-ICU). Crit Care Med 2001; 29:1370 –1379
3. Ely EW, Inouye SK, Bernard GR, et al: De-lirium in mechanically ventilated patients:Validity and reliability of the Confusion As-sessment Method for the Intensive Care Unit(CAM-ICU). JAMA 2001; 286:2703–2710
4. Lin SM, Liu CY, Wang CH, et al: The impactof delirium on the survival of mechanicallyventilated patients. Crit Care Med 2004; 32:2254–2259
5. Bergeron N, Dubois MJ, Dumont M, et al:Intensive Care Delirium Screening Check-list: Evaluation of a new screening tool. In-tensive Care Med 2001; 27:859–864
6. Skrobik Y, Dumont M, Ouimet S: Risk fac-tors, coma, and consequences of intensivecare unit delirium. Abstr. Crit Care 9:S58
7. McNicoll L, Pisani MA, Ely EW, et al: Detec-tion of delirium in the intensive care unit:Comparison of confusion assessment methodfor the intensive care unit with confusionassessment method ratings. J Am GeriatrSoc 2005; 53:495–500
8. Kress JP, Pohlman AS, O’Connor MF, et al:Daily interruption of sedative infusions incritically ill patients undergoing mechanicalventilation. N Engl J Med 2000; 342:1471–1477
9. Brook AD, Ahrens TS, Schaiff R, et al: Effectof a nursing-implemented sedation protocolon the duration of mechanical ventilation.Crit Care Med 1999; 27:2609–2615
10. Maldonado JR, van der Starre PJ, Wysong A:Post-operative sedation and the incidence ofICU delirium in cardiac surgery patients. An-esthesiology 2003; 99:A-465
The importance of understanding the costs of critical care andmechanical ventilation*
U nderstanding the daily costsof care in the intensive careunit (ICU), and particularlythe incremental cost of me-
chanical ventilation, is important forboth macro-level health policy and forhospital-level evaluation of individualICUs. In this issue of Critical CareMedicine, Dr. Dasta and colleagues (1)help advance our understanding of thisissue. They calculated costs related to thedaily care of ICU patients and, in partic-ular, costs related to mechanically venti-lated patients, including adjustments forimportant patient and hospital character-
istics. Analysis was performed on a largesample of �50,000 adults in �250 hos-pitals throughout the United States dur-ing a 3-month period in autumn 2002.
The database used for this studycomes from NDCHealth, a health careinformation service business that pro-vides support to approximately 300 for-profit hospitals in the United States. Thepatient characteristics and duration ofmechanical ventilation in this researchare remarkably similar to those observedin a population-based study of mechani-cal ventilation (2). This similarity pro-vides some assurance of the representa-tiveness of the patient sample, eventhough smaller-sized, nonteaching, andrural hospitals were underrepresentedand seasonal variation may have affectedthe study findings. Despite this similarity,the use of a proprietary database and thefor-profit status of all hospitals in thisstudy may affect the research results andtheir generalizability.
Calculation of the cost data in thisresearch was based on individual hospitalcost-to-charge ratios applied to hospital-reported charge data. As the authors dis-cuss, this approach is commonly usedand currently the only feasible way toobtain cost data on a large sample of U.S.hospitals. Such data should be viewed ascomplementary to microcosting data thatmay provide more detailed, patient-specific cost information (3, 4).
Dr. Dasta and colleagues demon-strated that the mean ICU cost and lengthof stay (LOS) were approximately $31,000and 14 days for ventilated patients and$13,000 and 8 days for nonventilated pa-tients. Thus, the mean cost and LOS formechanically ventilated patients are ap-proximately 2.5 and 1.7 times greaterthan for nonventilated patients. Themean incremental cost for mechanicalventilation was approximately $1,500 perday. Costs for the first day of ICU care forboth ventilated and nonventilated pa-
*See also p. 1266.Key Words: mechanical ventilation; length of stay;
survival; costs and cost analysis; critical care; inten-sive care units; critical illness; health policy
tients were more than two times higherthan for subsequent days. However, asdiscussed by the authors, non-ICU costscould have potentially inflated this costestimate for the first day of ICU care.
This research provides important newinformation for economic analyses ofcritical care and mechanical ventilation.Particularly within publicly fundedhealth care systems like Medicare andMedicaid, which were payers for �50% ofpatients in this study, it is important tohave accurate and timely cost data. Thesedata are needed to assist with macro-leveldecision-making related to resource allo-cation within overall health care services(e.g., critical care vs primary care) andbetween health care and other nonmedi-cal services (e.g., public education) (5).
We also believe that this research isnoteworthy for specifically studying me-chanically ventilated patients. The researchfindings reflect the high cost and mortalityrate of these patients and justify the impor-tance of using mechanically ventilated pa-tients as a specific focus for research withincritical care medicine (6, 7).
At the individual hospital or ICU level,the research findings also have impor-tance. The stability of ICU costs after day2 provides further evidence that ICU LOSand duration of mechanical ventilationmay be simple proxies for ICU costs andappropriate means of measuring effi-ciency at the ICU level (8, 9).
Furthermore, the dramatically in-creased costs associated with the first day ofICU care may help explain increasing totaland average patient costs in ICUs that areactually reducing patient LOS but main-taining occupancy rates by providing careto a larger number of patients. Hospitalleaders must understand that as ICUs re-duce length of stay by improving safety andreducing complications (10–12), averagedaily costs for ICU patients will increasebecause of the greater proportion of morecostly patients with a 1- or 2-day LOS. Es-timates used to compare the efficiency ofICUs should differentially weight the pro-portion of patients with an ICU LOS of 1, 2,and �3 days. Hospital leaders should alsoaccount for the incremental revenue fromincreased throughput of efficient ICUswhen evaluating ICU financial perfor-mance.
This study has raised at least two im-mediate questions for future research.First, transferred patients numbered al-most 4,000 in this study. These patients
are known to have a higher risk-adjustedLOS and mortality rate than patients nottransferred from an outside hospital intothe ICU (13, 14). Cost information onthese patients, from a large multiple-center study, would complement priorresearch and expand our knowledge inthis area. Second, the hospital character-istics considered in this study did notprovide data on ICU physician and nursestaffing—factors that have an impact onpatient complications, survival, LOS, andcost (15–17). Financial modeling indi-cates that intensivist staffing may reducehospital costs (18). Further empirical re-search using cost data from a large sam-ple of hospitals would build on the exist-ing research in this field.
In summary, this study of �250 hospi-tals has provided new and important infor-mation on the costs associated with ICUcare and mechanical ventilation. Within anenvironment of fiscal constraint, thesefindings can help with decision making atboth a macro and an individual ICU level.This research reinforces the importance ofstudying mechanically ventilated patientsas a large and important subgroup withinthe ICU. Furthermore, future analyses ofNDCHealth or similar databases have thepotential to help elucidate the importantcost implications of patient transfer andICU staffing issues.
Dale M. Needham, MAcc, CA, MDDivision of Pulmonary and Critical
Care MedicineJohns Hopkins UniversityBaltimore, MDDepartment of MedicineUniversity of TorontoToronto, Canada
Peter J. Pronovost, MD, PhDDepartments of
Anesthesiology/Critical CareMedicine, Surgery, and HealthPolicy and Management
Johns Hopkins University
REFERENCES
1. Dasta JF, McLaughlin TP, Mody SH, et al:Daily cost of an intensive care unit day: Thecontribution of mechanical ventilation. CritCare Med 2005; 33:1266–1271
2. Needham DM, Bronskill SE, Sibbald WJ, etal: Mechanical ventilation in Ontario,1992–2000: Incidence, survival, and hospitalbed utilization of noncardiac surgery adultpatients. Crit Care Med 2004; 32:1504–1509
3. Noseworthy TW, Konopad E, Shustack A, etal: Cost accounting of adult intensive care:
Methods and human and capital inputs. CritCare Med 1996; 24:1168–1172
4. Doyle JJ, Casciano JP, Arikian SR, et al: Full-cost determination of different levels of carein the intensive care unit. An activity-basedcosting approach. Pharmacoeconomics1996; 10:395–408
5. Teres D, Rapoport J, Jacobs P: Affordablehealth care for all Canadians? Crit Care Med2004; 32:1614–1615
6. Needham DM, Bronskill SE, Calinawan JR, etal: Projected incidence of mechanical venti-lation in Ontario to 2026: Preparing for theaging baby boomers. Crit Care Med 2005;33:574–579
7. Shorr AF, Jackson WL: Transfusion practicein the ICU: When will we apply the evidence?Chest 2005; 127:702–705
8. Wong DT, Gomez M, McGuire GP, et al:Utilization of intensive care unit days in aCanadian medical-surgical intensive careunit. Crit Care Med 1999; 27:1319–1324
9. Rapoport J, Teres D, Zhao Y, et al: Length ofstay data as a guide to hospital economicperformance for ICU patients. Med Care2003; 41:386–397
10. Berenholtz SM, Pronovost PJ, Lipsett PA, etal: Eliminating catheter-related bloodstreaminfections in the intensive care unit. CritCare Med 2004; 32:2014–2020
11. Pronovost P, Berenholtz S, Dorman T, et al:Improving communication in the ICU usingdaily goals. J Crit Care 2003; 18:71–75
12. Pronovost P, Weast B, Rosenstein B, et al:Implementing and validating a comprehen-sive unit-based safety program. J PatientSafety 2005; 1:1–8
13. Rosenberg AL, Hofer TP, Strachan C, et al:Accepting critically ill transfer patients: Ad-verse effect on a referral center’s outcomeand benchmark measures. Ann Intern Med2003; 138:882–890
14. Durairaj L, Will JG, Torner JC, et al: Prog-nostic factors for mortality following inter-hospital transfers to the medical intensivecare unit of a tertiary referral center. CritCare Med 2003; 31:1981–1986
15. Pronovost PJ, Angus DC, Dorman T, et al:Physician staffing patterns and clinical out-comes in critically ill patients: A systematicreview. JAMA 2002; 288:2151–2162
16. Amaravadi RK, Dimick JB, Pronovost PJ, etal: ICU nurse-to-patient ratio is associatedwith complications and resource use afteresophagectomy. Intensive Care Med 2000;26:1857–1862
17. Dimick JB, Swoboda SM, Pronovost PJ, et al:Effect of nurse-to-patient ratio in the inten-sive care unit on pulmonary complicationsand resource use after hepatectomy. Am JCrit Care 2001; 10:376–382
18. Pronovost PJ, Needham DM, Waters H, et al:Intensive care unit physician staffing: Finan-cial modeling of the Leapfrog standard. CritCare Med 2004; 32:1247–1253
1435Crit Care Med 2005 Vol. 33, No. 6
Limitation and withdrawal practice patterns in India*
T echnological advances in thepast 40 yrs have had an enor-mous impact on the way med-icine is delivered today. This is
particularly true in our specialty, whereintensivists possess the knowledge andtools to prolong life in many situationswhere patients would have died in thepast. Our increasing ability to sustainphysiologic function through the use oftechnology has forced the issue of with-holding (WH) and withdrawal (WD) oftreatment to the forefront of discussion(1). A recent publication noted that22.4% of all deaths occurred after an in-tensive care unit (ICU) admission in theUnited States (2). The concepts of futilityand end-of -life care are important topics,with ongoing publications and researchin North America. In North America, theWH and WD of life support are beingincreasingly used (1, 3). Great variationin practices regarding the WD and WH oflife support are noted even within theUnited States depending on the geo-graphic, regional, disease type, and payermix. European nations are also evaluat-ing the different patterns of care providedin their ICUs across the union and havefound that considerable practice varia-tions exist regarding end-of-life deci-sions. Many of these discussions, re-search, publications, active interventions,and educational campaigns via the mediahave improved care for patients and uti-lization of resources for the commonbenefit. However, these practices are notwidely disseminated, used, or endorsed inmany developing countries.
India is the largest democratic coun-try and is the second most populous na-tion in the world. It has less than onehospital bed per 1,000 people, comparedwith more than seven beds in the first-world countries. Most of these beds areprovided by the private health care sec-
tor. Medical care in India is rapidly ad-vancing and rivaling that of some of Eu-ropean nations. Of late, patients fromsome European and African countries aretraveling to private medical centers inIndia to obtain specialized care like trans-plantation, cardiovascular, orthopedic,and ophthalmic surgeries (4). The careand performance of these centers arecomparable to those of developed coun-tries. Despite these advances, there isgreat disparity in access to care amongthe rich, the middle class, and the poor.
In this issue of Critical Care Medicine,Dr. Kapadia and colleagues (5) are to becommended for examining the sensitivesubject of WD and WH practices in twopublic and two private ICUs in Mumbai, alarge metropolitan city in India. This isthe first peer-reviewed publication fromthe Indian subcontinent addressing end-of-life practices and patterns. The ICUbeds in a public hospital are a preciousresource, and patients are triaged by thephysicians from medical floors, takinginto consideration the severity of illnessand the likelihood of return to function.The WH and WD rates were 19% to 50%,which are much less than those pub-lished from the United States and Europe(6, 7). The WD rates are much closer tothose of a recent study from Israel (8).This needs further exploration to exam-ine if it is related to the lack of judicialapproval, lack of understanding from so-ciety, or lack of understanding by healthcare personnel. The study from Israel didnot demonstrate any significant changein their WD and WH patterns despite adirective from the Ministry of Health per-mitting WD and WH, as WH and WD areperceived differently in the Jewish reli-gion (8). Given the scarcity of resourcesand growing needs in India, it is the righttime for physicians and allied health caresocieties to educate the government andpublic about the magnitude of the prob-lem and to start a healthy dialogue toreach a constitutional and legal directivein regard to WH and WD of care.
It would have been interesting to notethe range and averages for age, AcutePhysiology and Chronic Health Examina-tion score at admission, and disease cat-
egories of the ICU patients at each center.Furthermore, in those who died, identi-fying factors like age, reversibility of theunderlying illness, and public vs. privatehospital would have been helpful. Onemay presume that in the public hospitals,the scarcity of ICU beds will demandmore rigorous criteria for triaging. With-out the Acute Physiology and ChronicHealth Examination and the disease cat-egory data, it is very difficult to draw anymeaningful comparisons and conclusionsamong the various ICUs in the study. Inthis study, the cancer center patient pop-ulation is primarily a referral populationfor the entire country. Once the diseasehas been deemed terminal and chancesfor reasonable prognosis are poor, oneassumes that these patients would returnto their home or primary physicians,which could account for less overall mor-tality at this facility, despite catering topublic patients. More research needs tobe done with regard to the extent of in-volvement of patients, their families, andthe health care team in the decision pro-cess. Enhancing opportunities for betterpatient-physician-family communication,although advocated as the major methodfor improving patient outcomes, may stillbe inadequate to change established prac-tice pattern (9).
There are only a handful of publica-tions on end-of-life care from the Asiancontinent (10). This is an important issuethat needs further intense exploration asthere are vast differences due to religious,cultural, social, and political factors be-tween the East and the West (10–14).
The SUPPORT study, among others,has illustrated that end-of-life careshould be improved for all ICU patients,not just for those who are likely to die (9).When adequate resources are availableand the disease process is reversible, allcritically ill patients should receive atherapeutic trial of intensive care, unlessthey or their surrogates specify other-wise. When restorative efforts fail, physi-cians and health care personnel shouldgive way to palliative approach, and pal-liation will be of the greatest benefit re-gardless of its impact on health carecosts. Palliative end-of-life care has been
*See also p. 1272.Key Words: withholding of treatment; withdrawal
of treatment; end-of-life care; intensive care unit, In-dia; palliative care
ignored in India for lack of judicial, po-litical, and legal support (15). Hence, pal-liative care and its delivery need to befostered. We hope that this article leadsto healthy debate and discussion, pavingway to changes in the constitution andenhanced judicial interpretation by thecourts of law. That said, we stress thatproviding timely and appropriate pallia-tive care throughout the health care sys-tem is desirable in its own right, indepen-dent of religious, cultural, political, andpotential economic implications.
Venkata Bandi, MDKalpalatha K. Guntupalli, MD
Ben Taub General HospitalBaylor College of MedicineHouston, TX
REFERENCES
1. McLean RF, Tarshis J, Mazer CD, et al: Deathin two Canadian intensive care units: Insti-tutional difference and changes over time.Crit Care Med 2000; 28:100–103
2. Angus DC, Barnato AE, Linde-Zwirble WT, et
al: Use of intensive care at the end of life inthe United States: An epidemiologic study.Crit Care Med 2004; 32:638–643
3. Teres D: Trends from the United States withend of life decisions in the intensive careunit. Intensive Care Med 1993; 19:316–322
4. Medical Tourism 2005 Available at: http://www.cbc.ca/news/background/healthcare/medicaltourism.html
5. Kapadia F, Singh M, Divatia J, et al: Limita-tion and withdrawal of intensive therapy atend of life: Practices in intensive care unitsin Mumbai, India. Crit Care Med 2005; 33:1272–1275
6. Prendergast TJ, Claessens MT, Luce JM: Anational survey of end-of-life care for criti-cally ill patients. Am J Respir Crit Care Med1998; 158:1163–1167
7. Sprung CL, Cohen SL, Sjokvist P, et al: End-of-life practices in European intensive careunits: The Ethicus Study. JAMA 2003; 290:790–797
8. Jakobson DJ, Eidelman LA, Worner TM, et al:Evaluation of changes in forgoing life-sustaining treatment in Israeli ICU patients.Chest 2004; 126:1969–1973
9. A controlled trial to improve care for seri-ously ill hospitalized patients. The study to
understand prognoses and preferences foroutcomes and risks of treatments (SUP-PORT). The SUPPORT Principal Investiga-tors. JAMA 1995; 274:1591–1598
10. Buckley TA, Joynt GM: Limitation of life sup-port in the critically ill: The Hong Kongperspective. Ann Acad Med Singapore 2001;30:281–286
11. Ip M, Gilligan T, Koenig B, et al: Ethicaldecision-making in critical care in HongKong. Crit Care Med 1998; 26:447–451
12. Oppenheim A, Sprung CL: Cross-culturalethical decision-making in critical care. CritCare Med 1998; 26:423–424
13. Pochard F, Abroug F: End-of-life decisions inICU and cultural specificities. Intensive CareMed 2005; 31:506–507
14. Yazigi A, Riachi M, Dabbar G: Withholdingand withdrawal of life-sustaining treatmentin a Lebanese intensive care unit: A prospec-tive observational study. Intensive Care Med2005; 31:562–567
15. Ghooi RB, Ghooi SR: Freedom from pain—Amirage or a possibility? Experience in at-tempts to change laws and practices in India.J Pain Palliat Care Pharmacother 2003; 17:1–9
Catheter-related infection can be prevented. . .If we take thearterial line seriously too!*
T oday most intensive care pa-tients will have two intravas-cular catheters in place. Thearterial catheter (AC) is often
the first catheter to be inserted because itallows the physician to analyze arterialblood gases repeatedly. AC-related infec-tion has generated much less attention inthe medical literature than central ve-nous catheter (CVC) infection. As a re-sult, the exact incidence of AC-relatedinfection has remained a matter of de-bate. This controversy is well illustratedin the guidelines of the Centers for Dis-ease Control and Prevention for theprevention of catheter-related infec-tion. In Table 1 of these guidelines (1),ACs are considered to be related to a“low infection rate; rarely associated
with bloodstream infection.” However,on page 11 of the same guidelines, onecan read that “the rate of AC-relatedbloodstream infection is comparable tothat of temporary CVCs (2.9 vs. 2.3 per1,000 catheter days)” (1).
Every AC manipulation carries therisk of development of a microbial huband eventually endoluminal catheter col-onization. A guidewire accidentally con-taminated during catheter insertion isanother cause of endoluminal coloniza-tion. The outer surface (exolumen) be-comes colonized when skin microfloramigrate from the insertion site to theintravascular part of the catheter or at-tach to the exolumen during insertion.How colonization leads to symptomaticcatheter infection in some but not allpatients is an important but largely un-resolved issue. It is a multifactorial pro-cess during which a quantitative thresh-old or a changing microenvironmenttriggers the switch from colonization toinfection (2). Quorum sensing mecha-nisms and a change in gene expression
patterns are crucial steps in this process(3). Local host immunodeficiency andcatheter design are other key factors (4).
Why has the role of the AC as a sourceof infection remained a matter of debatefor many intensive care physicians? Theincidence of AC infection in part dependson the patient population studied. Mostpostoperative patients, for instance, arenot critically ill and have an AC in placefor only 1 or 2 days. These patients are ata low risk of AC infection, and the inci-dence (the fraction of all inserted cathe-ters that causes infection, e.g., 1 per 350)will be very small. This might lead to thefalse impression that ACs do not causeinfection. However, we should keep inmind that the risk for a catheter to be-come colonized and infected increaseswith the time the catheter remains inplace. In a recent study on AC-relatedinfection, up to 38% of the ACs that re-mained in place for �14 days (15 of 39)were colonized at removal (Fig. 1) (5).
In this issue of Critical Care Medicine,Traore et al. (6) compare the incidence of
*See also p. 1276.Key Words: arterial catheter; intensive care; cen-
CVC and AC tip colonization and infec-tion in critically ill patients. For obviousreasons, the ideal study design—a ran-domized, controlled trial in which pa-tients are randomized to have an AC orCVC inserted—is not possible. The au-thors in part circumvented this problemof allocation bias (due to which the pref-erential allocation of the sickest patientsto one of both study groups will lead tobias) by including only patients who hadboth an AC and CVC inserted during theirintensive care unit stay. Both catheterswere inserted by means of the sameSeldinger technique, and comparablestate-of-the art infection prevention mea-sures were taken during insertion (full-sterile barrier precautions with a cap,gown, mask, sterile gloves, and chlo-rhexidine 0.5% in alcohol as disinfec-tant). As a result, baseline characteristicsand risk of catheter infection were com-parable for both catheters. The authorsfound a comparable incidence of tip col-onization for both types of catheters andtherefore conclude that when the sameprevention measures are taken during in-sertion, no difference in catheter tip col-onization and infection is seen.
At first glance the study methodologyseems original and straightforward, butthis study has its limitations. Althoughpatients needed to have a CVC and ACinserted during their intensive care unitstay to be included in the study, bothcatheters were inserted on the same dayin only 114 of the 212 patients. Becausedisease status changes over time, differ-
ences in severity of illness at the time theAC and the CVC were inserted can lead todifferences in baseline characteristics be-tween groups. Also, after insertion the ACand CVC are not used in the same man-ner. In the most severely ill patients, ar-terial blood gases will be measured (andthe AC manipulated) up to 10 times a day,whereas the CVC is used for continuousinfusion only. The epidemiology of CVCand AC infection in patients recoveringfrom an uncomplicated surgical interven-tion could therefore differ considerablyfrom the observations concerning the se-verely ill patient population (33% mortal-ity) studied by Traore et al. (6). Finally, asample size of 607 catheters might im-press readers, but only two catheter-related bloodstream infections were diag-nosed during the study, which is mostlikely the result of the state-of-the artcatheter insertion and management pro-tocol. Traore et al. therefore had to useAC tip colonization as a surrogate endpoint for AC-related bloodstream infec-tion. Semiquantitative and quantitativecolonization cut-offs have been relativelywell validated for CVCs, and a good cor-relation between incidence of coloniza-tion and bloodstream infection was re-cently shown (7–10). Whether similarcut-offs are suitable for the prediction ofAC-related infection has not been studiedin great detail.
Despite the limitations of the study,the authors have, to some extent, tackledthe allocation bias issue. Also, their studyadds to a growing body of evidence that
we should take ACs as a source of infec-tion more seriously and that measures toprevent catheter-related infection shouldaddress ACs and CVCs simultaneously (5,11). For skin disinfection, chlorhexidine2% is the preferred antiseptic agent.When a guidewire is used during AC in-sertion, we should apply the same full-sterile barrier precautions that have beenshown to prevent CVC-related infection,because contamination of the guidewireduring the procedure will lead to coloni-zation of the endolumen (12). Sterilegloves alone will probably suffice whenno guidewire is used (5). The applicationof a chlorhexidine-impregnated sponge(Biopatch, Johnson & Johnson Medical,Cincinnati, OH) around the insertion siteof the catheter might help to preventexoluminal AC infection, as was shown ina randomized clinical trial (13). We ea-gerly await the full publication (and pref-erably confirmation) of this logical andstraightforward concept. Also, ACs im-pregnated or coated with an antibioticbut preferably antiseptic agent wouldbe a welcome addition to our defensivearmature but are as yet unavailable and,as far as I know, not in the pipeline. Inthe meantime the least we can do istake arterial catheters seriously.
Bart J. A. Rijnders, MD, PhDInternal Medicine and
Infectious DiseasesErasmusRotterdam, The Netherlands
REFERENCES
1. Centers for Disease Control and Prevention:Guidelines for the prevention of intravascu-lar catheter-related infections. MMWR MorbMortal Wkly Rep 2002; 51(RR-10)
3. Vandecasteele S, Peetermans W, Merckx R, etal: Expression of biofilm associated genes inStaphylococcus epidermidis during in vitroand in vivo foreign body infections. J InfectDis 2003; 188:730–737
4. Zimmerli W, Lew PD, Waldvogel FA: Patho-genesis of foreign body infection: Evidencefor a local granulocyte defect. Clin Invest1984; 73:1191–1200
5. Rijnders BJ, Van Wijngaerden E, Wilmer A,et al: Use of full sterile barrier precautionsduring insertion of arterial catheters: A ran-domized trial. Clin Infect Dis 2003; 36:743–748
6. Traoré O, Loitier J, Souweine B: Prospectivestudy of arterial and central venous cathetercolonization and of arterial- and central venouscatheter-related bacteremia in intensive careunits. Crit Care Med 2005; 33:1276–1280
Figure 1. Influence of catheterization time (days) on the proportion of catheter tips that areculture-positive following removal.
1438 Crit Care Med 2005 Vol. 33, No. 6
7. Maki DG, Weise CE, Sarafin HW: A semi-quantitative culture method for identifyingintravenous-catheter-related infection.N Engl J Med 1977; 296:1305–1309
8. Sherertz RJ, Heard SO, Raad II: Diagnosis oftriple-lumen catheter infection: comparisonof roll plate, sonication, and flushing meth-odologies. J Clin Microbiol 1997; 35:641–646
9. Sherertz RJ, Raad II, Belani A, et al: Three-year experience with sonicated vascular cath-eter cultures in a clinical microbiology lab-oratory. J Clin Microbiol 1990; 28:76–82
10. Rijnders BJ, Van Wijngaerden E, PeetermansWE: Catheter-tip colonization as a surrogate
end point in clinical studies on catheter-related bloodstream infection: How strong isthe evidence? Clin Infect Dis 2002; 35:1053–1058
11. Kluger D, Maki D: The relative risk of in-travascular device-related bloodstream in-fections with different types of intravascu-lar devices in adults: A meta-analysis of 206published studies. In: Programs and Pro-ceedings of the Fourth Decennial Interna-tional Conference on Nosocomial andHealthcare-Associated Infections. Atlanta,GA, 2000, p 95
12. Raad II, Hohn DC, Gilbreath BJ, et al: Pre-
vention of central venous catheter–relatedinfections by using maximal sterile barrierprecautions during insertion. Infect ControlHosp Epidemiol 1994; 15:231–238
13. Maki DG, Mermel LA, Kluger D, et al: Theefficacy of a chlorhexidine impregnatedsponge (Biopatch) for the prevention of in-travascular catheter–related infection: A pro-spective, randomized, controlled, multi-center study. Abstract 1430. In: Program andAbstracts of the 40th Interscience Confer-ence on Antimicrobial Agents and Chemo-therapy. Washington, DC, American Societyfor Microbiology, 2000, p 422
Determination of troponin in the intensive care unit patient:Please avoid “troponinitis”!*
T he determination of the car-diac isoforms of troponin Tand troponin I as rapidly re-leased specific and sensitive
markers of myocardial injury by highlysensitive and specific immunoassays ledto a redefinition of myocardial infarction,with emphasis on cardiac marker eleva-tion (1). All patients with troponin eleva-tions as a result of cardiac ischemia arenow considered to have an acute myocar-dial infarction. This has simplified thedefinition of myocardial infarction, butthe implications on patients, their care,and the use of healthcare resources aresubstantial. While aggressive antiplateletand antithrombotic therapy as well asearly coronary angiography and percuta-neous coronary intervention are recom-mended for troponin-positive patientswith an acute coronary syndrome, itmust be stressed that singular troponinelevations, although clearly indicatingmyocyte injury (because there is no evi-dence of false-positive test results, e.g., inthe setting of renal failure with the cur-rently available new generation tests), donot automatically equate with an acutemyocardial infarction. In fact, troponinelevations can occur in settings otherthan myocardial infarction, the mostcommon being tachycardia, right ven-tricular strain/failure in the setting of
pulmonary emboli (2) or exacerbation ofchronic obstructive pulmonary dysfunc-tion (3), and myocardial necrosis causedby neurohumoral changes and/or ele-vated left ventricular end-diastolic pres-sure in the setting of congestive heartfailure, head injury, or subarachnoidalbleeding (4). In addition, troponin eleva-tions have been shown to be of particularprognostic significance in surgical inten-sive care unit (ICU) patients, after generalsurgery (including neurosurgery) (5),major vascular surgery (6), and coronaryartery bypass grafting (7, 8). Finally, ele-vated troponin concentrations have alsobeen reported in patients with sepsis/septic shock without indication of signif-icant coronary artery disease (CAD) (9,10). Given the fact that administration ofendotoxin to healthy volunteers causedincreases in plasma levels of cytokinesbut no increase in serum troponin (11), itis unlikely that elevated troponin concen-trations in the septic patient without sig-nificant CAD are caused by cytoplasmaticleakage of troponins following exposureto cytokines instead of myocardial necro-sis, inasmuch as troponin I levels in sep-tic patients were found to correlate withan increased use of vasopressors/ino-tropes (12) and more severe hypotensiveepisodes (13, 14). Therefore, there are anumber of causes of troponin elevationsin the ICU patient that are not necessarilyrelated to myocardial ischemia in con-junction with demonstrable CAD but nev-ertheless are clearly related to prognosis.
However, what are the exact signifi-cance and therapeutic implication of tro-
ponin elevations in patients with knownor high probability for CAD admitted toan ICU for reasons other than myocardialdisease? Given an aging population in de-veloped countries with an increased like-lihood for CAD, this is or will be a cardi-nal question in our ICUs.
In the current issue of Critical CareMedicine, Landesberg and colleagues (15)report that elevated troponin concentra-tions during the ICU stay of patients witha high probability for or a known historyof CAD admitted to a general ICU forreasons other than myocardial disease areindependently associated with increasedlong-term (2-yr) mortality, whereas de-tectable ischemia in continuous 12-leadECG monitoring was not associated withincreased mortality. Whereas only 21% ofpatients had detectable episodes of silentischemia (mostly ST depression) in thecontinuous 12-lead ECG monitoring(myocardial infarction has been clinicallysuspected in only a minority of them),38% of the patients had troponin eleva-tions above the chosen cut-off levels dur-ing the course of their ICU stay, and onlyone third of these 38% with troponinelevations had detectable ischemia oncontinuous ECG monitoring, reflectingeither a nonischemic etiology of myocar-dial injury or the failure to detect isch-emia. The authors conclude that silentmyocardial injury, as evidenced by serumtroponin elevation, is common amongpatients in the noncoronary ICU and isassociated with markedly increased mor-tality and that transient ischemia per semay not predict mortality unless myocar-
The study is important because itdemonstrates that troponin elevationsoccur far more often than ischemia inpatients with known or high probabilityfor CAD in a general ICU and that necro-sis but not detectable ischemia is relatedto mortality. Given the patient mix in thestudy (sepsis, 57%; postsurgical, 22%;multiple trauma, 8%; and other admis-sion diagnoses [COPD exacerbation,acute pancreatitis, etc.], 14%), however,there are some limitations. The prognos-tic significance of troponin elevationsmight be completely different for patientswith sepsis than for patients with rightventricular strain (COPD, pulmonary em-bolism) or following trauma (cardiac con-tusion), even if all patients had at leasttwo risk factors for or a known history ofCAD. Furthermore, even within the sep-tic population (as the largest subgroup ofthe patients studied), we do not knowwhether the prognostic implication oftroponin elevation is similar between pa-tients with increased right ventricularwall strain following pulmonary failure/acute respiratory distress syndrome withmore invasive/aggressive mechanicalventilation (if this causes troponin eleva-tion at all) and those septic patientswhose troponin elevations are possiblyrelated to more severe hypotension, co-agulation abnormalities, or temporarilydecreased oxygen supply.
In addition, with respect to long-termmortality, only limited data are providedon the treatment of patients after the ICUstay. Three patients underwent coronaryangiography right away during the ICUstay because of severe CAD (!), but howmany patients underwent coronary an-giography simply because they were tro-ponin-positive during the ICU course?This might have influenced long-termprognosis. Therefore, the cardinal practi-cal question—whether there is an indica-tion for “routine” coronary angiographyfollowing recovery from acute illness forpatients with known or high suspicion ofCAD because of troponin-positivity dur-ing ICU stay—remains unresolved.Should coronary angiography be reservedfor those patients with electrocardio-graphically detectable ischemia and tro-ponin elevations because the associationof ischemia with elevated troponin con-centrations might carry a higher riskthan elevated troponin concentrationsalone? Should we try to identify cut-offlevels for troponin elevations in the crit-
ical care setting that might help us toguide the decision for coronary angiogra-phy after ICU stay? Should septic ICUpatients with per example in whom CADis highly suspected and who have elevatedtroponin concentrations and hemody-namic instability related to an inade-quately low cardiac output undergo im-mediate coronary angiography, whetheror not wall motion abnormalities are de-tectable during echocardiography? Fi-nally, is there indication for a specificpharmacologic therapy in troponin-positive ICU patients with a high likeli-hood of CAD? In pulmonary embolism,troponin elevations might guide the de-cision for thrombolysis (16), but it is un-clear which therapy is indicated for tro-ponin-positive ICU patients after surgeryor with sepsis. Should we treat troponinelevations in high-cardiac-risk patients inthe ICU at all? Should these patients (notthe ones in whom significant CAD is un-likely) receive the same amount of anti-thrombotic and antiplatelet therapy thanpatients with acute coronary syndromes,consisting not only of aspirin—which hasbeen shown to be beneficial in the post-surgical patient with troponin elevation(5)—but also full anticoagulation withheparin or low-molecular-weight heparinand a thienopyridine (ticlopidine or clo-pidogrel)?
Given the potential adverse events offull, not completely reversible anticoagu-lation/antiplatelet therapy (thienopyri-dines) in a critical care setting, we defi-nitely need studies that address the issueof antiplatelet and antithrombotic ther-apy for critically ill patients with a highlikelihood of CAD and troponin eleva-tions. On the other hand, activated pro-tein C therapy is recommended for pa-tients with sepsis. Is it less dangerous totreat septic patients with activated pro-tein C in terms of bleeding complicationsthan to treat patients with a combinationof aspirin-heparin and perhaps a thien-opyridine? Is it possible that therapy withactivated protein C, because of its antico-agulant properties, might be especiallybeneficial for septic patients with CADand troponin elevations? Finally, shouldwe avoid dobutamine therapy for criti-cally ill patients with CAD and elevatedtroponin levels, given the potential forincreased myocardial oxygen consump-tion, and should we prefer other positiveinotropic drugs that appear to cause lessincrease in myocardial oxygen consump-tion, such as the calcium sensitizer levo-simendan?
Therefore, with the exception of spe-cial circumstances such as acute pulmo-nary embolism, where troponin eleva-tions might guide the decision tosystemic thrombolysis, there is presentlyno absolute need for daily troponin mon-itoring in our ICUs outside of clinicalresearch situations, as long as there is nouniversal consensus on treatment ofthese patients. Just knowing that the pa-tient has a higher risk of dying within thefollowing 2 yrs is of little help to thepatient and the treating physician. How-ever, work like this is important in orderto stimulate research in this field andinterdisciplinary communication.
Alexander Geppert, MDProfessor of MedicineDirector, Cardiovascular Intensive
Care UnitThird Department of Medicine
with Cardiology andEmergency Medicine
Wilhelminenhospital, Vienna,Austria
REFERENCES
1. Myocardial infarction redefined: A consensusdocument of The Joint European Society ofCardiology/American College of CardiologyCommittee for the Redefinition of Myocar-dial Infarction. Eur Heart J 2000; 21:1502–1513
2. Giannitsis E, Muller-Bardorff M, Kurowski V,et al: Independent prognostic value of car-diac troponin T in patients with confirmedpulmonary embolism. Circulation 2000; 102:211–217
3. Baillard C, Boussarsar M, Fosse JP, et al:Cardiac troponin I in patients with severeexacerbation of chronic obstructive pulmo-nary disease. Intensive Care Med 2003;29:584–589 (E-pub 2003 Feb 13)
4. French JK, White HD: Clinical implicationsof the new definition of myocardial infarc-tion. Heart 2004; 90:99–106
5. Relos RP, Hasinoff IK, Beilman GJ: Moder-ately elevated serum troponin concentra-tions are associated with increased morbidityand mortality rates in surgical intensive careunit patients. Crit Care Med 2003; 31:2598–2603
6. Landesberg G, Shatz V, Akopnik I, et al: As-sociation of cardiac troponin, CK-MB, andpostoperative myocardial ischemia withlong-term survival after major vascular sur-gery. J Am Coll Cardiol 2003; 42:1547–1554
7. Salamonsen RF, Schneider HG, Bailey M, etal: Cardiac troponin I concentrations, butnot electrocardiographic results, predict anextended hospital stay after coronary arterybypass graft surgery. Clin Chem 2005; 51:40–46
8. Lasocki S, Provenchere S, Benessiano J, et al:
1440 Crit Care Med 2005 Vol. 33, No. 6
Cardiac troponin I is an independent predic-tor of in-hospital death after adult cardiacsurgery. Anesthesiology 2002; 97:405–411
9. Ammann P, Fehr T, Minder EI, et al: Eleva-tion of troponin I in sepsis and septic shock.Intensive Care Med 2001; 27:965–969
10. Ammann P, Maggiorini M, Bertel O, et al: Tro-ponin as a risk factor for mortality in criticallyill patients without acute coronary syndromes.J Am Coll Cardiol 2003; 41:2004–2009
11. van Bockel EA, Tulleken JE, Muller KoboldAC, et al: Cardiac troponin I release and
cytokine response during experimental hu-man endotoxaemia. Intensive Care Med2003; 29:1598–1600
12. Turner A, Tsamitros M, Bellomo R: Myocar-dial cell injury in septic shock. Crit Care Med1999; 27:1775–1780
13. Guest TM, Ramanathan AV, Tuteur PG, et al:Myocardial injury in critically ill patients: Afrequently unrecognized complication. JAMA1995; 273:1945–1949
14. Arlati S, Brenna S, Prencipe L, et al: Myocar-dial necrosis in ICU patients with acute non-
cardiac disease: A prospective study. Inten-sive Care Med 2000; 26:31–37
15. Landesberg G, Vesselov Y, Einav S, et al:Myocardial ischemia, cardiac troponin, andlong-term survival of high-cardiac risk criti-cally ill intensive care unit patients. CritCare Med 2005; 33:1281–1287
16. Konstantinides S, Geibel A, Olschewski M, etal: Importance of cardiac troponins I and T inrisk stratification of patients with acute pul-monary embolism. Circulation 2002;106:1263–1268
Peptidoglycan: Just another marker of postoperative infections or amediator of disease?*
Even though lipopolysaccha-ride is still the gold standardin endotoxin research, it hasbecome clear that lipopolysac-
charide, being confined to Gram-negativebacteria, is not the only endotoxin. Pep-tidoglycan is a structural component ofthe cell wall of both Gram-positive andGram-negative bacteria, which undercertain conditions is released into theblood from infectious foci or by translo-cation from the intestine (1, 2).
A number of studies have demon-strated that peptidoglycan has endotoxicproperties (3–5) and that it can causeorgan dysfunction and injury when in-jected into rats (6). Furthermore, in ex-perimental models, peptidoglycan and itsstructural monomer muramyl dipeptidecan enhance inflammation and toxicityinduced by other bacterial components(3, 7, 8). These studies have suggestedthat peptidoglycan is involved in delete-rious systemic inflammation in patientsdeveloping septic complications. How-ever, one major criticism of experimentalpeptidoglycan research has been the lackof evidence for the presence of pepti-doglycan in the blood of patients.
In this context, the article by Dr.Shimizu and colleagues (9) in this issueof Critical Care Medicine is important.These authors demonstrate that an in-creased plasma level of peptidoglycan, de-
termined by the silkworm larvae plasmatest, is a better predictor of infectiouscomplications than C-reactive proteinfollowing gastrointestinal surgery (9). Inpatients with infectious complications,peptidoglycan was detected in the plasmaimmediately following surgery, and pep-tidoglycan levels remained elevated in pa-tients with severe infections such as in-tra-abdominal abscess, anastomoticleakage, and sepsis (9). These observa-tions represent a novel aspect of pepti-doglycan research in the context of postop-erative infectious complications and arepotentially important in understanding thecomplex mechanisms underlying systemicinflammation in these patients. However,the group of patients with severe infectionscounted only seven, and they differed fromthe others with respect to age, blood loss,and operation time. Therefore, the findingsby Dr. Shimizu and coworkers need to beconfirmed in comparable patient groupsbefore any firm conclusions can be drawn.Nevertheless, the study demonstrates thatpeptidoglycan is indeed released into thecirculation during infectious complicationsafter surgery, justifying studies exploringthe effect of systemic peptidoglycan in ex-perimental models.
In addition to indicating bacterial pep-tidoglycan, the silkworm larvae plasma testrecognizes the fungal component �-glucan(1). Hence, it is important to clarifywhether the activity detected in the patientplasmas by Dr. Shimizu and colleagues isdue to peptidoglycan or �-glucan. This testis not readily available but can be achievedby combining the silkworm larvae plasmatest with a limulus amebocyte lysate test(detecting lipopolysaccharide and �-glu-
can) and a lipopolysaccharide-specificlimulus amebocyte lysate test where thefactor G responsible for recognition of�-glucan has been deleted. This approachwas recently used to measure peptidogly-can in cerebrospinal fluid in the diagnosisof bacterial meningitis (10). A similar ap-proach may be useful in distinguishing be-tween bacterial and nonbacterial postoper-ative complications in surgical patients.
Another important aspect in interpret-ing the data presented by Dr. Shimizuand colleagues is to determine whetherthe detected peptidoglycan is biologicallyactive (inflammatory). The activity ofpeptidoglycan is totally dependent on itsmacrostructure. Whereas native pepti-doglycan is inflammatory and patho-genic, disruption of the sugar backboneabrogates its inflammatory properties(11) as well as its ability to cause organinjury/dysfunction (12).
In addition to acting as a mediatorand/or marker of the systemic inflamma-tory response, peptidoglycan has beenshown to be involved in the pathogenesis ofsuch diverse conditions as rheumatoid ar-thritis (13), Crohn’s disease (14), and sterileperitonitis following peritoneal dialysis(15). We believe that by bridging the pro-cess of disease with the presence of pepti-doglycan in human blood, Dr. Shimizu andcolleagues have promoted the interest offurther studies of the many aspects of pep-tidoglycan in human health and disease.
Jacob E. WangAnders E. MyhreAnsgar O. Aasen
Institute for Surgical ResearchRikshospitalet University HospitalOslo, Norway
*See also p. 1288.Key Words: lipopolysaccharide; endotoxin; pepti-
1. Kobayashi T, Tani T, Yokota T, et al: Detec-tion of peptidoglycan in human plasma usingthe silkworm larvae plasma test. FEMS Im-munol Med Microbiol 2000; 28:49–53
2. Shimizu T, Tani T, Endo Y, et al: Elevation ofplasma peptidoglycan and peripheral bloodneutrophil activation during hemorrhagicshock: Plasma peptidoglycan reflects bacte-rial translocation and may affect neutrophilactivation. Crit Care Med 2002; 30:77–82
3. Oken MM, Peterson PK, Wilkinson BJ: En-dogenous pyrogen production by humanblood monocytes stimulated by staphylococ-cal cell wall components. Infect Immun1981; 31:208–213
4. Timmerman CP, Mattsson E, Martinez-Martinez L, et al: Induction of release of tumornecrosis factor from human monocytes bystaphylococci and staphylococcal peptidogly-cans. Infect Immun 1993; 61:4167–4172
5. Kengatharan KM, De Kimpe S, Robson C, etal: Mechanism of Gram-positive shock: Iden-tification of peptidoglycan and lipoteichoic
acid moieties essential in the induction ofnitric oxide synthase, shock, and multipleorgan failure. J Exp Med 1998; 188:305–315
6. Wang JE, Dahle MK, Yndestad A, et al: Pep-tidoglycan of Staphylococcus aureus causesinflammation and organ injury in the rat.Crit Care Med 2004; 32:546–552
7. Takada H, Galanos C: Enhancement of endo-toxin lethality and generation of anaphylac-toid reactions by lipopolysaccharides in mu-ramyl-dipeptide-treated mice. Infect Immun1987; 55:409–413
8. Wang JE, Jorgensen PF, Ellingsen EA, et al:Peptidoglycan primes for LPS-induced releaseof proinflammatory cytokines in whole humanblood. Shock 2001; 16:178–182
9. Shimizu T, Endo Y, Tabata T, et al: Diagnos-tic and predictive value of the silkworm lar-vae plasma test for postoperative infectionfollowing gastrointestinal surgery. Crit CareMed 2005; 33:1288–1295
10. Inada K, Takahashi K, Ichinohe S, et al: Asilkworm larvae plasma test for detecting pep-tidoglycan in cerebrospinal fluid is useful for
the diagnosis of bacterial meningitis. MicrobiolImmunol 2003; 47:701–707
11. Majcherczyk PA, Langen H, Heumann D, etal: Digestion of Streptococcus pneumoniaecell walls with its major peptidoglycan hy-drolase releases branched stem peptides car-rying proinflammatory activity. J Biol Chem1999; 274:12537–12543
12. Myhre AE, Stuestol JF, Dahle MK, et al: Or-gan injury and cytokine release caused bypeptidoglycan are dependent on the struc-tural integrity of the glycan chain. InfectImmun 2004; 72:1311–1317
13. Liu ZQ, Deng GM, Foster S, et al: Staphylo-coccal peptidoglycans induce arthritis. Ar-thritis Res 2001; 3:375–380
14. Bonen DK, Ogura Y, Nicolae DL, et al:Crohn’s disease-associated NOD2 variantsshare a signaling defect in response to li-popolysaccharide and peptidoglycan. Gas-troenterology 2003; 124:140 –146
15. Martis L, Patel M, Giertych J, et al: Asepticperitonitis due to peptidoglycan contamina-tion of pharmacopoeia standard dialysis so-lution. Lancet 2005; 365:588–594
Sepsis and vascular dysfunction: Connections with endothelialconnexin 40*
Microvascular endothelial in-jury is one of the keyevents during the earlyphase of sepsis (1–3). If the
endothelium cannot repair itself moresites of damage will develop, ultimatelycontributing to the development of multi-ple organ failure. Cellular coordination iscentral to maintaining cardiovascular func-tion, and many cardiovascular diseasesarise and/or are aggravated when coordina-tion fails. However, several questions aboutthe molecular mechanisms of action re-main. In the present issue of Critical CareMedicine, Dr. Rignault and colleagues (4)describe a potential link between endothe-lial connexin (Cx) 40 expression and endo-thelial function in a rat model of sepsis.
Intercellular communication is medi-ated via secreted mediators, such as nitricoxide, and through direct transfer of signalsbetween neighboring cells through trans-
membrane gap junctional assemblies com-posed of connexin (Cx) proteins (5, 6). Gapjunctions are clusters of transmembranechannels that link the plasma membrane ofadjacent cells, permitting direct flow ofsmall solutes and electrical current (5).Each channel consists of two hemichannels(termed connexons), and each connexon isa hexamer of connexin subunits. Currentevidence indicates that connexins governnormal heart rhythm and that altered ex-pression of connexins is a potential proar-rhythmic factor in the diseased heart (7).Less well known is the fact that gap junc-tions also integrate the functions of thecells of the vessel wall (6).
Endothelial cells express Cx37, Cx40,and Cx43, of which the most prominentconnexin in vitro is Cx43 (8). Indeed, dis-turbed hemodynamic forces (e.g., flow sep-aration and/or recirculation) may compro-mise intercellular communication throughthe expression, organization, and functionof Cx43 (9). Bacterial lipopolysaccharidewas reported to increase Cx43 gene expres-sion in the rat kidney and lung (10) and todecrease it in the heart (11). Althoughthese observations suggested a role for con-nexins in sepsis, there have been no studies
on the relationships between sepsis and en-dothelial gap junction expression and func-tion. To fill gaps in our knowledge, Dr.Rigault and colleagues investigated endo-thelial connexin expression and function inthe cecal ligation and perforation model ofsepsis.
Dr. Rignault and colleagues (4) reportenhanced Cx40 expression (detected atboth the protein and messenger RNA level)in the aortic endothelium of septic rats,coinciding with blunted endothelium-dependent relaxation. Among endothelialconnexins, only Cx40 expression was al-tered, and Cx40 appeared to demonstrate anormal subcellular distribution. Interest-ingly, up-regulation of Cx40 expression wasnot associated with detectable changes ininterendothelial gap junctional communi-cation, as assessed by the scrape-loadingtechnique. These observations raise the in-triguing possibility that endothelial dys-function induced by sepsis may be associ-ated with endothelial cell-specific increasesin expression of Cx40, but not Cx37 orCx43. However, to firmly establish a causalrelationship, additional studies are neededto assess the impact of endothelium-specific silencing or overexpression of Cx40
*See also p. 1302.Key Words: gap junctions; connexins; endothelial
on endothelial function. The cecal ligationand perforation model used by Dr. Rigaultand colleagues more appropriately mimicsclinical sepsis than lipopolysaccharide ad-ministration. The different experimentalmodels may also explain the apparently dis-cordant results on connexin expression ob-tained in this and previous studies (10, 11).
With every new observation, more ques-tions emerge. For instance, it would beimportant to know whether changes de-tected in the aorta are representative ofthose that can be observed in resistancevessels. Do regional differences exist in en-dothelial Cx40, Cx37, or Cx43 expression?Does sepsis affect connexin expression dif-ferently in endothelial and vascular smoothmuscle cells? Could the regional connexinexpression profile explain the differences invascular reactivity of small pulmonary andsystemic arteries in hyperdynamic sepsis?The findings of Dr. Rignault and colleagues(4) suggest that inflammation precedes in-creased Cx40 expression, although the mo-lecular signals are unknown. A role for tu-mor necrosis factor- appears to beunlikely, because tumor necrosis factor-was found to down-regulate Cx40 expres-sion in human umbilical vein endothelialcells (12). Therefore, the balance betweenopposing signals, rather than any mediatorper se, may determine CX40 expression.Clearly, additional work is needed to clarifyhow Cx40 could affect vascular reactivitywhen gap junctional communications ap-pear to be intact.
These concerns notwithstanding, thestudy by Dr. Rignault and colleagues (4)lends support to the notion that gap junc-tions, and Cx40 in particular, may play animportant role in integrating endothelial(and perhaps smooth muscle cell) func-tions in sepsis. The connexin-vascular func-tion connection continues to unravel. Thefinding that sepsis enhances endothelialCx40 expression is a novel step in this di-rection. Now, uncovering the molecularmechanisms behind this interaction andconfirming altered Cx40 expression in sep-tic patients are more important. Further-more, it remains to be seen whether target-ing interendothelial cell communicationcan effectively be used to restore endothe-lial function in animal models of sepsis and,ultimately, in patients with sepsis.
János G. FilepResearch CenterMaisonneuve-Rosemont HospitalUniversity of MontrealMontreal, QC, Canada
REFERENCES
1. Parillo JE: Pathogenetic mechanisms of sep-tic shock. N Engl J Med 1991; 328:1471–1477
2. Riedemann NC, Guo RF, Ward PA: Novelstrategies for the treatment of sepsis. NatureMed 2003; 9:517–524
3. Marshall JC: Such stuffs as dreams are madeon: Mediator-directed therapy in sepsis. NatRev Drug Discov 2003; 2:391–405
4. Rignault S, Haefliger J-A, Gasser D, et al:Sepsis up-regulates the expression of con-
nexin 40 in rat aortic endothelium. Crit CareMed 2005; 33:1302–1310
5. Bruzzone R, White TW, Paul DL: Connec-tions with connexins: The molecular basis ofdirect intercellular signaling. Eur J Biochem1996; 238:1–27
6. Figueroa XF, Isakson BE, Duling BR: Connex-ins: Gaps in our knowledge of vascular func-tion. Physiology (Bethesda) 2004; 19:277–284
7. Dupont E, Ko Y-S, Rothery S, et al: The Gap-junctional protein connexin40 is elevated inpatients susceptible to postoperative atrial fi-brillation. Circulation 2001; 103:842–849
8. Bruzzone R, Haefliger J-A, Gimlich RL, et al:Connexin 40, a component of gap junctionsin vascular endothelium, is restricted in itsability to interact with other connexins. MolBiol Cell 1993; 4:7–20
9. DePaola N, Davies PF, Pritchard WF Jr, et al:Spatial and temporal regulation of gap junc-tion connexin 43 in vascular endothelial cellsexposed to controlled disturbed flows in vitro.Proc Natl Acad Sci U S A 1999; 96:3154–3159
10. Fernandez-Cobo M, Gingalewski C, De MaioA: Expression of the connexin 43 gene isincreased in the kidneys and the lungs of ratsinjected with bacterial lipopolysaccharide.Shock 1998; 10:97–102
11. Fernandez-Cobo M, Gingalewski C, DrujanD, et al: Downregulation of connexin 43 geneexpression in rat heart during inflammation.The role of tumor necrosis factor. Cytokine1999; 11:216–224
12. Ouellette Y, Liddington D, Keet M: Modula-tion of endothelial cell connexin expressionand regulation of connexin trafficking by cy-tokines. Abstr. Am J Respir Cell Mol Biol2003; 167:A566
Toward directed therapy for amphetamine-mediated hyperthermia:Is carvedilol worth raving about?*
Amphetamine intoxication is anincreasingly common problemfor the intensivist, the enormityand complexity of which are
most clearly manifested by the growing
popularity and consequences of 3,4-meth-ylenedioxymethamphetamine (MDMA, “ec-stasy”) use (1–3). Recreational consump-tion of MDMA in association with“clubbing” or “rave” parties has developedinto a cultural phenomenon among adoles-cents and young adults, and this environ-ment may potentiate the pleasant neuro-psychological and sympathomimeticproperties of the drug (4, 5). However, thesocial disinhibition, sensory arousal, andexpansive mood that MDMA users initiallyexperience in the loud, hot, overcrowdedvenues of clubs and raves often progress toinclude deleterious systemic signs andsymptoms, necessitating medical attention.
The sympathomimetic and serotoner-gic effects resulting from MDMA-inducedcatecholamine release are well describedand include hypertension, tachycardia,agitation, delirium, and hyperthermia (6,7). In the setting of volume depletion,hypotonic fluid intake, increased ambienttemperature, and prolonged physical ex-ertion, organ dysfunction arising from ahyperthermic and hyperdynamic statemay rapidly evolve into a complex clinicalpicture that includes rhabdomyolysis, hy-ponatremia, hepatotoxicity, metabolic ac-idosis, acute renal failure, seizures, dis-seminated intravascular coagulation, andcoma. Current treatment for clinical se-
*See also p. 1311.Key Words: amphetamine; carvedilol; creatine ki-
The opinions or assertions contained herein arethe private views of the author and are not to beconstrued as official or as reflecting the views of theDepartment of the Army or the Department of Defense.
quelae of amphetamine intoxication is es-sentially supportive, consisting primarilyof volume repletion, antihypertensives,sedatives such as benzodiazepines andbutyrophenones, and active cooling mea-sures when indicated. Recent animal in-vestigations of directed pharmacologictherapy, including dantrolene (8), ba-clofen (9), and agents affecting serotoninpathways (10), have yielded encouragingfindings. Despite these results, given thegrowing enormity of this problem, addi-tional studies exploring the pathophysi-ology and treatment of amphetamine in-toxication are sorely needed.
In this issue of Critical Care Medicine,Dr. Sprague and colleagues (11) add totheir considerable work in this field and setthe foundation for pharmacotherapy tar-geted directly at the cellular mechanismsresponsible for hyperthermia and rhabdo-myolysis in MDMA intoxication. The samegroup has previously reported on the mul-tifaceted pathophysiology observed withMDMA toxicity (encompassing not just se-rotonergic and sympathomimetic pathwaysbut also the hypothalamic-pituitary-thyroidaxis) (12) as well as the role of MDMA-specific activation of both the thermogenicprotein UCP-3 (found within skeletal mus-cle mitochondria) and peripheral 1- and�3-adrenergic receptors in mediating heatgeneration and creatine kinase release (13–16). Moreover, these authors have shownthat the degree of hyperthermia and rhab-domyolysis seen after MDMA ingestion maybe reduced by the respectively selective 1-and �3-adrenergic receptor antagonistsprazosin and SR59230A (16). In this con-text, the pharmacologic effects of carve-dilol, a relatively novel nonselective 1- and�123-adrenergic receptor with additionalantioxidant, antiapoptotic, and anti-inflam-matory properties (17), would appear tooffer promise.
In the current study (11), the authorsexamined the effects of both carvediloland nonselective �-blockers through adetailed series of experiments in ratstreated with thermogenic doses ofMDMA. In one group of studies, subjectswere pretreated with either nonselective�-adrenergic receptor antagonists (pro-pranolol or nadolol) or their vehicle be-fore administration of MDMA. Plasmalevels of norepinephrine, epinephrine,dopamine, and the norepinephrine me-tabolite dihydroxyphenylglycol andtrends in core temperature and creatinekinase levels were measured at predeter-mined intervals thereafter. A secondgroup of rats received carvedilol or vehi-
cle pre- or post-MDMA at 15- and 60-minintervals. These intervals were derivedfrom the magnitude of catecholamine in-creases observed in the group treatedwith nonselective agents. Not surpris-ingly, large elevations in catecholaminelevels were seen in all rats receivingMDMA. However, whereas rats pretreatedwith propranolol or nadolol uniformly ex-hibited marked hyperthermia afterMDMA treatment, those pretreated withcarvedilol evidenced an initial hypother-mic effect without subsequent thermo-genesis. More important from a potentialmanagement perspective, rats treatedwith carvedilol 60 mins after MDMA ex-posure displayed both a complete reversalto baseline temperature and a markedattenuation in creatine kinase levels. In-triguingly, despite the fact that hyper-thermia was not attenuated in rats pre-treated with propranolol, none of thesubjects receiving this agent died.The authors reasonably concluded thatthe unique pharmacologic profile ofcarvedilol, combined with its beneficialeffects on the double product, make this aparticularly appealing candidate for fur-ther study. They also plausibly suggestedthat �3-agonistic effects of nadolol mightaccount for the increased mortality ratein this group relative to propranolol, al-though objective evidence of the in-creased skeletal muscle thermogenesisthat would be expected to account for thisdifference was lacking.
Despite the impressive findings of thisstudy (11), some caution is warranted.First, as the authors acknowledged, theusual clinical scenario observed withMDMA intoxication does not involve largequantities of ingested drug but insteadconsiderably smaller relative doses in thesetting of strenuous physical activity. Ac-cordingly, it should be appreciated thatthe mechanism of rhabdomyolysis andclinical course observed in sedentary, eu-volemic patients with an overdose ofMDMA parallel to the amount used in thisstudy may differ from that seen when thedrug is taken after exertion (18). Themagnitude of muscle damage demon-strated following exercise may be greater,independent of the degree of hyperther-mia (19). Additionally, the required doseof carvedilol to duplicate these findings inclinical care might be considerablyhigher than that currently administeredfor cardiovascular indications in humans,the vagaries of extrapolating animal datanotwithstanding.
These concerns aside, Dr. Sprague andcoworkers have contributed an intriguingreport in an area of increasing clinicaland public health interest and they are tobe commended for their ingenuity. Tothe toxicologists and intensivists whomanage life-threatening complications ofamphetamine intoxication, these resultsoffer considerable hope that agent-specific therapy might one day be avail-able at the bedside.
William L. Jackson Jr, MDWalter Reed Army Medical CenterDepartment of SurgeryWashington, DC
REFERENCES
1. Landry MJ: MDMA: A review of epidemio-logic data. J Psychoactive Drugs 2002; 34:163–169
2. Green AR: MDMA: Fact and fallacy, and theneed to increase knowledge in both the sci-entific and popular press. Psychopharmacol-ogy (Berl) 2004; 173:231–233
3. Schifano F: A bitter pill. Overview of ecstasy(MDMA, MDA) related fatalities. Psychophar-macology (Berl) 2004; 173:242–248
4. Parrott AC: MDMA (3,4-Methylenedioxymeth-amphetamine) or ecstasy: The neuropsycho-biological implications of taking it at dancesand raves. Neuropsychobiology 2004; 50:329–335
5. Parrott AC: Human psychopharmacology ofEcstasy (MDMA): A review of 15 years ofempirical research. Hum Psychopharmacol2001; 16:557–577
6. Zimmerman JL: Poisonings and overdoses inthe intensive care unit: General and specificmanagement issues. Crit Care Med 2003; 31:2794–2801
7. Green AR, O’Shea E, Colado MI: A review ofthe mechanisms involved in the acute MDMA(ecstasy)-induced hyperthermic response.Eur J Pharmacol 2004; 500:3–13
8. Fiege M, Wappler F, Weisshorn R, et al: In-duction of malignant hyperthermia in sus-ceptible swine by 3,4-methylenedioxymeth-amphetamine (“ecstasy”). Anesthesiology2003; 99:1132–1136
9. Bexis S, Phillis BD, Ong J, et al: Baclofenprevents MDMA-induced rise in core bodytemperature in rats. Drug Alcohol Depend2004; 74:89–96
10. Mechan AO, Esteban B, O’Shea E, et al: Thepharmacology of the acute hyperthermic re-sponse that follows administration of 3,4-methylenedioxymethamphetamine (MDMA,“ecstasy”) to rats. Br J Pharmacol 2002; 135:170–180
11. Sprague JE, Moze P, Caden D, et al: Carve-dilol reverses hyperthermia and attenuatesrhabdomyolysis induced by 3,4-methyl-enedioxymethamphetamine (MDMA, Ec-stasy) in an animal model. Crit Care Med2005; 33:1311–1316
1444 Crit Care Med 2005 Vol. 33, No. 6
12. Sprague JE, Banks ML, Cook VJ, et al: Hypotha-lamic-pituitary-thyroid axis and sympathetic ner-vous system involvement in hyperthermia in-duced by 3,4-methylenedioxymethamphetamine(Ecstasy). J Pharmacol Exp Ther 2003; 305:159–166
13. Mills EM, Banks ML, Sprague JE, et al: Phar-macology: Uncoupling the agony from ec-stasy. Nature 2003; 426:403–404
14. Mills EM, Rusyniak DE, Sprague JE: Therole of the sympathetic nervous system anduncoupling proteins in the thermogenesis
induced by 3,4-methylenedioxymetham-phetamine. J Mol Med 2004; 82:787–799
15. Rusyniak DE, Tandy SL, Hekmatyar SN, etal: The role of mitochondrial uncoupling in3,4-methylenedioxymethamphetamine me-diated skeletal muscle hyperthermia andrhabdomyolysis. J Pharmacol Exp Ther2005 (Epub)
16. Sprague JE, Brutcher RE, Mills EM, et al:Attenuation of 3,4-methylenedioxymetham-phetamine (MDMA, Ecstasy)-induced rhab-domyolysis with alpha1- plus beta3-adreno-
19. Duarte JA, Leao A, Magalhaes J, et al: Stren-uous exercise aggravates MDMA-inducedskeletal muscle damage in mice. Toxicology2005; 206:349–358
Carbon monoxide and ileus: Inhaled gas to prevent retained gas?*
I ntestinal ileus is a common com-plication in critically ill patientsand surgical patients undergoingmajor abdominal surgery (1). In-
testinal ileus can lead to significant com-plications, including intestinal ischemia,perforation, intraabdominal hyperten-sion, abdominal compartment syndrome,and other complications that prolonghospital stay, including the need for in-testinal decompression and intravenoushydration, inability to resume oral intake,abdominal pain, and distention.
The pathophysiology of ileus in thecritically ill patient is multifactorial,likely related to a number of factors, in-cluding immobility, ischemia and reper-fusion injury, medications, and lack ofenteral nutrition stimulation. Further-more, other potential contributingcauses of intestinal ileus in critically illhumans, including sepsis and multipleorgan dysfunction syndrome, are not wellstudied.
Animal studies have confirmed a num-ber of contributing factors in the patho-physiology of intestinal ileus, includingactivation of inhibitory neural reflexpathways, activation of inflammatoryprocesses, opioid receptor activation, sur-gical manipulation of the intestine, anes-thesia and other myogenic, neural, and,hormonal mechanisms (2, 3).
Heme oxygenase (a cytoprotectiveheme-degrading enzyme that is rate-limiting in the conversion of heme to
bilirubin, iron, and carbon monoxide) hasrecently been identified as an importantmediator of intestinal injury and ileus.The induction of intestinal production ofheme oxygenase by intravenous glu-tamine has recently been documented toprotect against lipopolysaccharide-in-duced mucosal injury, inflammation, andapoptotic cell death in the ileum and co-lon in a rat model (4). Heme-oxygenase-1induction by hemin also protectedagainst gut ischemia/reperfusion injuryand improved intestinal transit in a ratmodel (5). Similarly, regional hypother-mia and hypertonic saline resuscitationwere protective against gut ischemia/reperfusion-induced injury and impairedintestinal transit by induction of intesti-nal (ileal) heme oxygenase-1 in a ratmodel (6, 7).
In this issue of Critical Care Medicine,Dr. Moore and colleagues (8) present theresults of their intriguing experimentsusing a rodent and swine model of post-operative ileus with administration ofopioid analgesia to mimic the clinical sit-uation. They determined that inhaledcarbon monoxide (CO) at a low dose (75ppm) or higher dose (250 ppm) for 3 hrspretreatment and up to 24 hrs after sur-gery treatment ameliorated delayed gas-trointestinal transit in vivo and improvedintestinal circular muscle contractility invitro.
There are, however, some limitationsto these studies. First, none of the exper-imental groups had CO exposure in thepostoperative period only, and pretreat-ment of at least 3 hrs was required toensure maximal improvement in gastro-intestinal transit. This limits the applica-bility of this treatment strategy to elec-tive surgical cases only, and this strategy
could not be utilized in cases in whichemergency surgery is required. Second,no data are yet available regarding thedurability of this improvement in gastro-intestinal transit with inhaled CO, andwhether continued inhaled CO treatmentwould be warranted to sustain this effecthas not yet been determined. Finally, thelowest concentration that was efficaciousin the rat model was a 3-hr pretreatmentwith 75 ppm inhaled CO, but Dr. Mooreand colleagues (8) chose to study a 3-hrpretreatment with 250 ppm inhaled COin the swine model to evaluate any po-tential toxicity. This resulted in a car-boxyhemoglobin concentration of ap-proximately 6%. Additional studiesregarding the efficacy of the lower COconcentration (75 ppm) in the swinemodel are necessary.
Most importantly, the applicability ofanimal models of postoperative ileus tothe ileus associated with critical illnessand injury is unclear. Animal studiescommonly use models of postoperativeileus and ileus associated with ischemia/reperfusion injury as described above.There may, however, be significant differ-ences in the pathophysiology of ileus as-sociated with sepsis, compared with ileusthat occurs postoperatively or in shockstates. A recent study in a murine septicmodel demonstrated an important rolefor activation of inducible nitric oxidesynthase in the endotoxin-induced delayin gastric emptying and small intestinaltransit, in part related to the activation ofguanylyl cyclase leading to the produc-tion of cyclic guanosine monophosphateand smooth muscle relaxation (9). Incontrast, mechanical gut stimulationtriggered enhanced nitric oxide synthesis
*See also p. 1317.Key Words: ileus; intestine; carbon monoxide;
by constitutive nitric oxide synthase in arat postoperative ileus model (10).
Are animal studies investigating intes-tinal ileus in rodents and swine applicableto humans? There are significant speciesdifferences in intestinal anatomy, perfu-sion, and physiology that are well recog-nized. The porcine stomach and smallintestine are similar to human, but thececum and colon are sacculated, whichmay serve to prolong the retention ofingesta. Rodents possess a large cecumthat is important in cellulose digestion.Therefore, results of animal studies inileus may not be directly applicable tohumans.
In critically ill humans, the systemicconsequences of ileus can be significant(11). Current methods for prevention andtreatment of ileus include limitation ofnarcotic use by substitution of alternativemedications such as nonsteroidals or re-gional anesthetics for postoperative paincontrol such as epidural anesthesia andanalgesia (12). The selective use of gastricdecompression and vigorous correctionof electrolyte abnormalities are also im-portant factors to consider (13). The pro-vision of early enteral nutrition, earlyambulation, and the use of prokineticagents and bowel regimens has alsoshown clinical benefit (14). The efficacyof these individual treatment strategiesis, however, limited (15).
Neostigmine has been documented toresolve critical illness–related colonic il-eus in a single prospective, randomized,double-blind, placebo-controlled trial in30 patients with multiple organ failurerequiring mechanical ventilation. In thisstudy, neostigmine was administered as acontinuous intravenous infusion at adose of 0.4–0.8 mg/hr over 24 hrs (16).
A new treatment strategy for postop-erative ileus is currently under investiga-tion. ADL 8-2698 (alvimopan) is an opioidantagonist with limited oral absorptionthat does not readily cross the blood–brain barrier, resulting in selective inhi-bition of gastrointestinal opioid recep-tors. It therefore reverses opioid-inducedinhibition of gastrointestinal motilitywithout antagonizing the analgesic ef-fects of opioids. Clinical studies (double-blind, placebo-controlled, multiple center
trials) have confirmed the efficacy of thisdrug in prevention of postoperative ileusin surgical patients. Enteral administra-tion of this drug initiated preoperativelyresulted in significantly faster recovery ofgastrointestinal function and reducedhospital length of stay, and submission ofa New Drug Application to the Food andDrug Administration has been completed(17, 18).
There is a significant need for addi-tional preclinical and clinical studies in-vestigating the pathophysiology of ileusin both postoperative and critically ill pa-tients, concurrent with clinical studiesfocused on treatment strategies. A morecomprehensive understanding of thecomplex interplay of the numerous fac-tors that result in intestinal ileus is re-quired, and development of an animalmodel of critical illness–associated intes-tinal ileus would be a great advance inthis area of investigation.
Lena M. Napolitano, MD, FACS,FCCP, FCCM
University of Michigan School ofMedicine
Surgical Critical CareDepartment of SurgeryUniversity of Michigan Health
2. Jones MP, Wessinger S: Small intestinal mo-tility. Curr Opin Gastroenterol 2005; 21:141–146
3. Huge A, Kreis ME, Jehle EC, et al: A model toinvestigate postoperative ileus with straingauge transducers in awake rats. J Surg Res1998; 74:112–118
4. Uehara K, Takahashi T, Fujii H, et al: Thelower intestinal tract-specific induction ofheme oxygenase-1 by glutamine protectsagainst endotoxemic intestinal injury. CritCare Med 2005; 33:381–390
5. Attuwaybi BO, Kozar RA, Moore-Olufemi SD,et al: Heme oxygenase-1 induction by heminprotects against gut ischemia/reperfusion in-jury. J Surg Res 2004; 118:53–57
6. Attuwaybi BO, Hassoun HT, Zou L, et al:Hypothermia protects against gut ischemia/reperfusion-induced impaired intestinaltransit by inducing heme oxygenase-1.J Surg Res 2003; 115:48–55
7. Attuwaybi B, Kozar RA, Gates KS, et al: Hy-pertonic saline prevents inflammation, in-jury, and impaired intestinal transit after gutischemia/reperfusion by inducing heme oxy-genase 1 enzyme. J Trauma 2004; 56:749–758
8. Moore BA, Overhaus M, Whitcomb J, et al:Brief inhalation of low-dose carbon monoxideprotects rodents and swine from postoperativeileus. Crit Care Med 2005; 33:1317–1326
9. De Winter BY: Study of the pathogenesis ofparalytic ileus in animal models of experi-mentally induced postoperative and septicileus. Verh K Acad Geneeskd Belg 2003; 65:293–324
10. Korolkiewicz RP, Sein-Anand J, Ruczynski J,et al: The role and interactions of nitric oxide(NO), carbon monoxide (CO), and prosta-noids in the pathogenesis of postoperativeileus in rats. J Gastrointest Surg 2004;8:346–357
11. Madl C, Druml W: Gastrointestinal disordersof the critically ill: Systemic consequences ofileus. Best Pract Res Clin Gastroenterol2003; 17:445–456
12. Miedema BW, Johnson JO: Methods for de-creasing postoperative gut dysmotility. Lan-cet Oncol 2003; 4:365–372
13. Luckey A, Livingston E, Tache Y: Mecha-nisms and treatment of postoperative ileus.Arch Surg 2003; 138:206–214
15. Chen JY, Wu GJ, Mok MS, et al: Effect ofadding ketorolac to intravenous morphinepatient-controlled analgesia on bowel func-tion in colorectal surgery patients: A pro-spective, randomized, double-blind study.Acta Anaesthesiol Scand 2005; 49:546–551
16. van der Spoel JI, Oudemans-van StraatenHM, Stoutenbeek CP, et al: Neostigmine re-solves critical illness-related colonic ileus inintensive care patients with multiple organfailure: A prospective, double-blind, placebo-controlled trial. Intensive Care Med 2001;27:822–827
17. Taguchi A, Sharma N, Saleem RM, et al:Selective postoperative inhibition of gastro-intestinal opioid receptors. N Engl J Med2001; 345:935–940
18. Wolff BG, Michelassi F, Gerkin TM, et al:Alvimopan, a novel, peripherally acting muopioid antagonist: Results of a multicenter,randomized, double-blind, placebo-con-trolled, phase III trial of major abdominalsurgery and postoperative ileus. AlvimopanPostoperative Ileus Study Group. Ann Surg2004; 240:728–734
1446 Crit Care Med 2005 Vol. 33, No. 6
Renal-dose dopamine: Another nail in the coffin*
Acute renal failure is a signifi-cant problem in hospitalizedpatients, particularly in thosewho have undergone cardiac
surgery (1). Given the correlation ofacute renal failure with adverse outcome,it is understandable that clinicians em-braced a therapy that appeared to holdpromise as a “magic bullet” in the battleagainst this entity. Indeed, followingGoldberg’s 1963 discovery of the natri-uretic effect of dopamine in patients withrefractory congestive heart failure (2), aseries of animal experiments and clinicalstudies investigating its use in both med-ical and surgical patients appeared in the1970s and 1980s. These studies led to theconsensus that dopamine in low dosescould improve renal blood flow and func-tion in patients at risk for renal failure.Administration of “low-dose” or “renal-dose” dopamine became standard for theprevention and treatment of renal failurein hospitals around the world.
With the increased emphasis on evi-dence-based medicine in the 1990s, arti-cles questioning the validity of this ther-apy were published in the perioperativeand critical care literature (3, 4) Theseinitial reports cited a lack of adequatelypowered randomized, controlled trialsaddressing the utility of renal-dose dopa-mine and called into question the endpoints used to assess its effectiveness. In2000, these arguments were bolstered bythe publication of the first adequatelypowered, prospective, randomized, dou-ble-blind, placebo-controlled study of do-pamine’s ability to prevent renal failure(5). This study of 328 ICU patients withearly evidence of renal failure showed nodifference between the dopamine and pla-cebo groups with regard to peak serumcreatinine, increase in serum creatininefrom baseline, or mortality. In 2001, ameta-analysis of 17 underpowered ran-
domized clinical trials addressing the useof dopamine in the prevention and/ortreatment of renal dysfunction concludedthat the drug offered no benefit in theprevention of death, acute renal failure,or need for hemodialysis (6). There fol-lowed in 2003 and 2004 two comprehen-sive reviews presenting evidence regard-ing many adverse side effects of thedopamine (7, 8). Emphasizing the unfa-vorable risk/benefit profile of low-dosedopamine, both reviews called for theabandonment of its prophylactic use.
The study by Argalious et al. (9) in thisissue of Critical Care Medicine raises an-other red flag in the low-dose dopaminecontroversy. Although the arrhythmo-genic properties of dopamine in patientsundergoing cardiac surgery have beennoted previously (10), Argalious et al.demonstrate an interesting correlationbetween intraoperative administration ofrenal-dose dopamine and postoperativeincidence of atrial arrhythmia, with re-nal-dose dopamine independently in-creasing the odds of new-onset postoper-ative atrial fibrillation or flutter by 74%.
Since postoperative atrial fibrillation orflutter is a major reason for delayed dis-charge, this finding is important. However,since this is a retrospective data-base re-view, the study design reduces the possibil-ity of meaningful mechanistic assessmentof the described phenomenon.
The reader should question why pa-tients in this study were given renal-dosedopamine, since there appears to be nodifference in the preoperative creatininelevels between the dopamine group and thematched controls. It would be interestingto look at the use of dopamine at the Cleve-land Clinic by surgeon and by anesthesiol-ogist and to query the dopamine propo-nents as to the indications for therapy.
A possible explanation for the persis-tence of renal-dose dopamine use is thefervent hope that a simple, proactive, pre-ventive treatment for renal failure exists.Uninspiring yet potentially more effectivestrategies for renal protection such asmaintenance of normal hydration and he-modynamics, avoidance of renal toxins,and the resurgent use of antiquated drugssuch as N-acetylcysteine and sodium bi-
carbonate should be studied by hospitalsystems interested in lowering costs andimproving outcomes.
Unfortunately a simple approach to re-nal protection may prove elusive, giventhe complex physiology of the outer med-ullary area of the kidney, the region inwhich acute tubular necrosis occurs. Theouter medullary renal tubules are oxygensupply– dependent during normal ho-meostasis and have evolved a mechanismfor staving off hypoxia that does not relyupon an increase in extraction or a sig-nificant increase in regional blood flow(9). Instead, oxygen demand is down-regulated through the process of tubulo-glomerular feedback, which limits tubu-lar work by decreasing solute delivery tothese cells. The occurrence of acute tu-bular necrosis is thus a “demand” prob-lem and is a result of the breakdown ofthe tubulo-glomerular feedback mecha-nism caused by one or multiple diseaseprocesses or toxins (10). Dopamine ago-nizes both D1 (renal vasodilation) and D2(renal vasoconstriction) receptors. Fur-thermore, the proteonomics of D1 recep-tors result in individual variation in D1agonist/effect relationships (11). Thus,depending on the phenotype of the D1receptor, dopamine may have a positiveor a negative impact in the face of im-paired tubulo-glomerular feedback in anygiven individual. No clinical studies havetaken D1 phenotype into consideration,and studies of new D1 agonists will beconfounded if this cannot be done.
Recently, however, a facile transitionfrom dopamine to fenoldopam as the newrenal magic bullet has occurred despitethe mechanistic similarity between thetwo agents. No definitive trials have beenperformed involving the use of fenoldo-pam in cardiac surgery, but the suspen-sion of disbelief in the face of no negativetrials allows those seeking the magic bul-let to hold out hope. This hope was di-minished significantly with the publica-tion of the CONTRAST trial report inNovember 2003 (12). The most importantaspect of the study by Argalious et al. (9)is that it will support robust power cal-culations for future safety studies of dopa-
*See also p. 1327.Key Words: renal-dose dopamine; acute renal fail-
minergic agonists. It is time for physiciansas a group to require manufacturers ofagents like fenoldopam to conduct ade-quately powered, prospective, double-blind,randomized, controlled trial studies onperioperative safety and effectiveness insurgical patients. Until such studies arepublished, the prudent perioperative physi-cian may conclude that dopaminergic ago-nists are most likely not the answer.
Furthermore, known adverse safetyand effectiveness considerations, includ-ing the data presented by Argalious et al.(9), are sufficient to warrant abandon-ment of prophylactic renal-dose dopa-mine in cardiac surgery.
Andrew D. Friedrich, MDElmer K. Choi, MD, PhDMichael N. D’Ambra, MD
Brigham and Women’s HospitalBoston, MA
REFERENCES
1. Mangano CM, Diamonstone LS, Ramsay JG,et al: Renal dysfunction after myocardial re-vascularization: Risk factors, adverse out-comes and hospital utilization. Ann InternMed 1998; 128:194–203
2. Goldberg LI, McDonald RH, ZimmermanAM: Sodium diuresis produced by dopaminein patients with congestive heart failure.N Engl J Med 1963; 269:1060–1064
4. Perdue PW, Balser JR, Lipsett PA, et al: “Renaldose” dopamine in surgical patients: Dogma orscience? Ann Surg 1998; 227:470–473
5. ANZICS Clinical Trials Group: Low dose do-pamine in patients with early renal dysfunc-tion: a placebo-controlled randomized trial.Lancet 2000; 356:2139–2143
6. Kellum JA, Decker JM: Use of dopamine inacute renal failure: A meta-analysis. CritCare Med 2001; 29:1526–1530
7. Holmes CL, Walley KR: Bad medicine: Low-dose dopamine in the ICU. Chest 2003; 123:1266–1275
8. Debaveye YA, Van den Berghe GH: Is therestill a place for dopamine in the modernintensive care unit? Anesth Analg 2004;98:461– 468
9. Argalious M, Motta P, Khandwala F, et al:“Renal dose” dopamine is associated with therisk of new-onset atrial fibrillation after cardiacsurgery. Crit Care Med 2005; 33:1327–1332
10. Chiolero R, Borgeat A, Fisher A: Postopera-tive arrhythmias and risk factors after openheart surgery. Thorac Cardiovasc Surg 1991;39(2):81–84
11. Sato M, Soma M, Nakayama T, et al: Dopa-mine D1 receptor gene polymorphism is as-sociated with essential hypertension. Hyper-tension 2000; 36:183–186
12. Schlichtig R, Kramer DJ, Boston JR, et al:Renal O2 consumption during progressivehemorrhage. J Appl Physiol 1991; 70:1957–1962
The answer is always NO*
T he role of nitric oxide (NO) inacute lung injury after sepsisremains controversial andconfusing. Hypotension dur-
ing sepsis is probably secondary to NOderived from type 2 or inducible NO syn-thase (iNOS), and inhibition with a non-specific NOS inhibitor improves hypoten-sion during sepsis (1). However, the effectof NO inhibition on mortality rates insepsis has been disappointing. The mostrecent multiple-center, randomized, pla-cebo-controlled, double-blind humanstudy using a nonspecific NOS inhibitorin septic shock actually found increasedmortality rates (2). Animal studies havebeen equally puzzling, with iNOS defi-ciency either worsening or improvingmortality rates in septic mice (3, 4).
A role for iNOS has also been proposedin the all-too-frequent sequela of sepsis,acute lung injury (5). Although investi-gations in humans into the role of iNOSas a sequela to sepsis are limited, iNOS-
deficient mice have usually been reportedresistant to acute lung injury during sep-sis. Yet, as noted, the effect of iNOS defi-ciency on overall mortality rates in mu-rine models of sepsis is unclear. Theseobservations raise a number of questions:Are other enzymatic sources (such astype 3 or endothelial NOS) important? Isthe amount of NO important? Since NOcan interact with other oxidants, are theyalso important? What is the specific cel-lular source for NO?
Dr. Razavi and colleagues (6), in thisissue of Critical Care Medicine, have ad-dressed some of these questions.Through an elegant set of experiments,they were able to manipulate the cellularsource of iNOS by performing bone mar-row transplants on iNOS knockout mice.Marrow from iNOS sufficient mice wastransplanted into iNOS knockout mice,producing chimeric mice whose solesource of iNOS was bone marrow-derivedinflammatory cells (called /� in thearticle). The authors also reversed theprocedure by transplanting marrow fromthe iNOS knockout mice into iNOS-sufficient mice, producing chimeric ani-mals whose sole source of iNOS was re-cipient parenchymal cells (called �/ inthe article). After animals recovered fromthe transplant, sepsis was produced by
cecal ligation and perforation in fourgroups of animals, iNOS-sufficient orwild-type mice (/), iNOS-deficient orknockout mice (�/�), and the two chi-meric groups of animals. Previous exper-iments in this model by this group ofinvestigators have revealed that the ma-jor source of NO (as measured by the NOend products nitrite and nitrate in theblood) are the parenchymal cells (7), yetmicrovascular protein leak is totally de-pendent on iNOS in inflammatory cellsand not the major source of iNOS andNO, the pulmonary parenchymal cells(8).
Dr. Ravazi and colleagues (7) extendedthese investigations by examining pulmo-nary oxidant stress as measured by 8-iso-prostane concentrations and tyrosine ni-tration in the murine lung in sepsis. Thelatter is formed when NO combines withsuperoxide, forming peroxynitrite thatcan then interact with tyrosine formingthe stable end product 3-nitrotryosine(9). Compared with iNOS-sufficient mice,pulmonary oxidant stress was abolishedin iNOS knockout mice, despite similarseptic increases in pulmonary myeloper-oxidase activity. In chimeric mice whoseiNOS was localized only to donor bonemarrow-derived inflammatory cells, sep-sis resulted in pulmonary oxidant and
*See also p. 1333.Key Words: nitric oxide; acute lung injury; inducible
nitrosative stress similar in degree to sep-tic iNOS-sufficient or wild-type mice. Incontrast, pulmonary oxidant and nitrosa-tive stresses were absent in septic chi-meric mice whose iNOS was localizedonly to recipient parenchymal cells, sim-ilar to iNOS-deficient knockout mice.These results suggest that in this murinemodel of sepsis, the relatively minor con-tribution to total body NO from iNOSlocalized to inflammatory cells is impor-tant in producing pulmonary oxidant andnitrosative stress, whereas the muchlarger amounts of NO produced by thepulmonary parenchymal cells are not.
Although these studies indicate thatinflammatory cell expression of iNOS isclearly important in producing acutelung injury in this murine model of sep-sis, several cautions and limitations ofthe study preclude directly applying theseresults to human sepsis and lung injury.First, although the study was not de-signed to test the effect of modulation ofNO production on mortality in sepsis, thesurvival rates of the four groups of septicmice were all similar. Second, cellularsources of NO vary between species. Forexample, NO is produced abundantly bymurine cells but less vigorously by hu-man cells (10). However, as pointed outin the present article, the total amount ofNO may not be so important in producinglung injury. Third, iNOS regulation iscomplex. The inflammatory milieu in thelung and NO itself may enhance or de-crease NO production and might affectacute lung injury (10, 11). Fourth, thetiming of NO production, the interaction
with other oxidants such as superoxide,and the subsequent interaction of oxi-dants such as peroxynitrite with inflam-matory proteins may also be important(12).
Despite these limitations, Dr. Razaviand colleagues have made an importantcontribution. Their work suggests thatinvestigations into the pathophysiologyof human sepsis should take into accountiNOS from bone marrow-derived cellsand lung oxidative stress.
Richard A. Robbins, MDClement Singharajah, MD
Pulmonary and Critical CareMedicine
Carl T. Hayden VA MedicalCenter
University of Arizona Collegeof Medicine
Phoenix, AZ
REFERENCES
1. Watson D, Grover R, Anzueto A, et al: GlaxoWellcome International Septic Shock StudyGroup. Cardiovascular effects of the nitricoxide synthase inhibitor NG-methyl-L-arginine hydrochloride (546C88) in patientswith septic shock: Results of a randomized,double-blind, placebo-controlled multicenterstudy (study no. 144-002). Crit Care Med2004; 32:13–20
2. Lopez A, Lorente JA, Steingrub J, et al: Mul-tiple-center, randomized, placebo-con-trolled, double-blind study of the nitric oxidesynthase inhibitor 546C88: Effect on survivalin patients with septic shock. Crit Care Med2004; 32:21–30
deficiency increases the mortality of sepsis inmice. Surgery 1999; 126:438–442
4. Hollenberg SM, Broussard M, Osman J, et al:Increased microvascular reactivity and im-proved mortality in septic mice lacking in-ducible nitric oxide synthase. Circ Res 2000;86:774–778
5. Kristof AS, Goldberg P, Laubach V, et al: Roleof inducible nitric oxide synthase in endotox-in-induced acute lung injury. Am J RespirCrit Care Med 1998; 158:1883–1889
6. Razavi HM, Wang L, Weicker S, et al: Pul-monary oxidant stress in murine sepsis isdue to inflammatory cell nitric oxide. CritCare Med 2005; 33:1333–1339
7. Wang LF, Mehta S, Weicker S, et al: Relativecontribution of hemopoietic and pulmonaryparenchymal cells to lung inducible nitricoxide synthase (iNOS) activity in murine en-dotoxemia. Biochem Biophys Res Commun2001; 283:694–699
8. Wang LF, Patel M, Razavi HM, et al: Role ofinducible nitric oxide synthase in pulmonarymicrovascular protein leak in murine sepsis.Am J Respir Crit Care Med 2002; 165:1634–1639
10. Pitt BR, St Croix CM: Complex regulation ofiNOS in lung. Am J Respir Cell Mol Biol2002; 26:6–9
11. Connelly L, Madhani M, Hobbs AJ: Resis-tance to endotoxic shock in endothelial ni-tric-oxide synthase (eNOS) knock-out mice:A pro-inflammatory role for eNOS-derivedNO in vivo. J Biol Chem 2005; 280:10040–10046
12. Robbins RA, Hadeli K, Nelson D, et al: Nitricoxide, peroxynitrite, and lower respiratorytract inflammation. Immunopharmacology2000;48:217–221
Early induction of hypothermia: Will sooner be better?*
I n recent years, there has been anincreasing awareness of potentialmedical applications of inducedhypothermia. Interest increased
significantly when the results of threerandomized, controlled trials suggestedthat mild-to-moderate hypothermiacould improve neurologic outcome and
survival in selected patients after cardiacarrest (1–3). A meta-analysis of thesestudies published recently in CriticalCare Medicine concluded that in the cat-egory of patients studied (witnessed car-diac arrest, short ambulance responsetimes, ventricular fibrillation or tachy-cardia on arrival of the ambulance), thenumber needed to treat to achieve favor-able neurologic outcome in one addi-tional patient was 6, with a range of 4–13(4). The odds ratio for survival and goodneurologic outcome at 6 months was1.44 (95% confidence interval, 1.11–1.76). It should be noted that cooling
rates in these clinical studies were rela-tively low, with target temperatures be-ing reached only after an average of 8 hrsin the largest study (1). Animal studiesand some clinical data strongly suggestthat protective effects of hypothermiamay increase significantly when thetreatment is initiated in the very earlystages after the occurrence of injury (5).
Many animal studies assessing protec-tive effects of induced hypothermia havefocused on one specific underlying mech-anism for cellular injury after ischemiaand reperfusion, which can be modifiedby hypothermia. This mechanism, known
*See also p. 1340.Key Words: hypothermia; cardiac arrest; neuro-
as the neuroexitotoxic cascade, involves asevere disturbance of intracellular ionhomeostasis induced by accumulation ofexcitatory neurotransmitters such as glu-tamate around the cell after an ischemicevent. This excess of neurotransmitterscauses prolonged and excessive influx ofCa2 into the cell, inducing a permanentstate of hyperexcitability and hyperactiv-ity that can lead to additional cell injuryand death (5–7).
In this issue of Critical Care Medicine,Dr. Takata and colleagues (8) report theresults of an animal study assessing theeffects of very short-term (20 mins) mod-erate hypothermia (31°C) on extracellu-lar glutamate release and the degree ofhistologic injury in a rat cardiac arrestmodel. The authors also measured direct-current potentials, which is a sensitivemeasure for the functional status of neu-rons. Cold saline nasopharyngeal coolingwas used for selective brain cooling,which was initiated either before initia-tion of cardiac arrest, at the onset ofresuscitation, immediately after the com-pletion of direct-current recovery, or 10
or 20 mins after the onset of resuscita-tion. The authors observed that histo-logic injuries were significantly decreasedby hypothermia if this was initiated be-fore injury (94% reduction), at the onsetof resuscitation (65% reduction), or im-mediately after direct-current recovery(�5 mins after start of resuscitation, 29%reduction). Excessive glutamate releasewas prevented or mitigated if hypother-mia was initiated before cardiac arrest orat the onset of resuscitation but not inlater stages (8).
These observations would seem tosuggest that the therapeutic time windowfor the application of therapeutic hypo-thermia, at least for very brief periods, isvery short: about 10 mins after the onsetof ischemia in this study. However, hypo-thermia has been shown to improve neu-rologic outcome in numerous animal andclinical studies even when its applicationwas delayed for prolonged periods oftime, up to 8 hrs in one clinical study (1).How can this apparent discrepancy beexplained?
First, hypothermia influences not justone but many destructive mechanismsthat can develop after ischemic or trau-matic injury. Some of these mechanismsare listed in Table 1; all are stimulated byfever and blocked or inhibited by hypo-thermia (5). Affecting the glutamate con-centration and the neuroexitotoxic cas-cade is just one of these mechanisms. Therelative importance of these differentmechanisms is very difficult to determineand may vary both in time and betweendifferent types of injury (traumatic, focalischemic, global ischemic, and a “second-hit” ischemic episode in already injuredneurons). In addition, the relative impor-tance of destructive mechanisms mayvary between different species. The ro-dent brain is comparatively small and lis-sencephalic; its rheologic and metabolicproperties are different from those of thelarger mammalian brain, which is muchmore complex, comparatively enormous,and gyrencephalic. Although the neuro-exitotoxic cascade appears to be a cru-cial mechanism in the development ofbrain injury in rodents, its relative im-
Table 1. Destructive mechanisms after ischemia/reperfusion that are all favorably influenced by hypothermia
Mechanism Explanation Time Frame After Injury
Ion homeostasis/neuroexitotoxiccascadea
Ischemia induces accumulation of excitatory neurotransmitters such asglutamate and prolonged excessive influx of Ca2 into the cell. Thisinduces a state of permanent excitability (exitotoxic cascade) that canbe attenuated by hypothermia.
First minutes to 72 hrs
Free radical production andreperfusion injury
Production of free radicals such as superoxide, peroxynitrite, hydrogenperoxide and hydroxyl radicals occurs during ischemia and (especially)reperfusion. Hypothermia blocks or mitigates free-radical production.
Hours to days
Coagulation activation andformation of microthrombi
Coagulation and blockage of small vessels may occur in the brain aftertrauma or ischemia. Hypothermia has a mild anticoagulatory effect.
Hours to days
Apoptosis Ischemia can induce apoptosis (i.e., programmed cell death).Hypothermia can prevent this.
Hours to many days or even weeks
Permeability of the blood—brainbarrier and the vascular wall;reduced edema formation
Both the blood—brain barrier and the walls of blood vessels becomemore permeable after trauma or ischemia. These effects are moderatedby hypothermia.
Hours to days
Cellular membrane permeability Hypothermia can decrease the leakage of cellular membranes, therebyimproving cell function and cellular homeostasis and decreasingintracellular acidosis.
Hours to days
Mitochondrial injury anddysfunction
Intracellular energy stores are quickly depleted after ischemia;mitochondrial dysfunction prevents rapid repletion and preventsrecovery. The recovery process can be favorably affected byhypothermia.
Minutes to hours (days?)
Metabolic rates Hypothermia reduces oxygen and glucose requirements by �7% perdegree of temperature decrease.
Hours to days
Inflammatory response After ischemia, there is a sustained destructive inflammatory reactionwith secretion of large amounts of proinflammatory cytokines. Thiscan be blocked or mitigated by hypothermia.
First hour to 5 days
Cerebral thermopooling There are areas in the brain with higher temperatures than thesurrounding brain areas and measured core temperature. Thesedifferences increase dramatically (up to 2–3°C) in injured brains, withhigher temperatures in injured areas. Hyperthermia can increasedamage to injured brain cells, whereas hypothermia can mitigate suchdamage.
Minutes to many days
aSubject of the study by Takata et al (8).
1450 Crit Care Med 2005 Vol. 33, No. 6
portance may be less in mammals (in-cluding humans).
Second, the time during which hypo-thermia is applied is important. The ef-fects of excessive glutamate begin almostimmediately after injury but may persistfor several hours, especially in energy-deprived cells; even after glutamate levelsreturn to normal shortly after reperfu-sion, glutamate receptor activation maypersist. Some of the other injuriousmechanisms, such as inflammatory re-sponses and apoptosis, begin much later(hours after injury) and continue formany hours to several days. Thus, pro-longed hypothermia may be required toimprove outcome in these situations.However, in the study by Dr. Takata andcolleagues (8), positive effects were seenin some animals when hypothermia wasinitiated before or immediately after in-jury, despite its extremely brief applica-tion. This suggests that perhaps the ini-tiation of some of these other harmfulprocesses could be largely or wholly pre-vented by very early initiation of hypo-thermia. If this observation holds true forlarge mammalian brains (including thehuman brain), this may imply that thebeneficial effects of hypothermia on neu-rologic and overall outcome after resto-ration of spontaneous circulation in car-diac arrest patients could be furtherenhanced by (much) earlier application ofhypothermia. Techniques such as rapidinfusion of refrigerated saline and ice-pack cooling at the scene or in the am-bulance may allow us to achieve suchrapid induction of hypothermia.
Based on their observations, Dr.Takata and colleagues (8) suggest thatmoderate induced hypothermia of briefduration may be helpful for neurosurgi-cal procedures. However, a recently pub-lished large clinical study assessing theeffects of mild intraoperative hypother-mia on neurologic outcome after intra-cranial aneurysm surgery found no or, atbest, only marginal benefits on neuro-logic outcome compared with normo-thermia (9). One reason for the apparentdiscrepancy may be the use of more pro-found hypothermia in the animal study(31.0°C) compared with the clinical study(33.0°C). However, the risk of side effectsmay increase at lower temperatures. Inhumans, at temperatures �35°C, there isa significant impairment of neutrophiland macrophage functions and suppres-sion of proinflammatory mediator re-lease. When temperatures drop to �33°C,white blood cell count also decreases,
which leads to a further increase in in-fection risks, especially for airway andwound infections (10). Clinically signifi-cant arrhythmias may develop if coretemperatures decrease below 28°C–30°C.This risk may be increased further if elec-trolyte disorders develop, a complicationthat can also be induced by hypothermia(10–12). Apart from arrhythmias, elec-trolyte disorders (particularly loss ofmagnesium) can have many other seriousconsequences, especially in patients withneurologic injuries (13). Although manyof these problems and side effects can beprevented or well managed with properintensive care treatment (10, 11, 14), thepotential risks should be outweighed byclear and proven benefits. All this under-scores that translating the results of thestudy by Dr. Takata and colleagues (8)into clinical practice will not be easy andthat further studies will be required toaddress issues such as the required depthand duration of hypothermia in varioustypes of neurologic injury. At this mo-ment, the overall evidence suggests thattemperatures of 32–33°C should be re-garded as the lower limit for use in theclinical setting. We recommend thatlower temperatures should not be usedoutside the context of clinical trials, andthen, only in centers with a great deal ofexperience in applying induced hypother-mia and in managing its potential sideeffects and risks.
Regarding interruption of the neuro-exitotoxic cascade that was the aim of thestudy by Dr. Takata and colleagues (8),some additional strategies may shortlybecome available to achieve this goal.Various studies have shown that gluta-mate transporters play an important rolein preventing glutamate neurotoxicity;the most important glutamate trans-porter is GLT1, the physiologically dom-inant astroglial protein. Recently, Roth-stein et al. (15) reported that �-lactamantibiotics (in contrast to several otherclasses of antibiotics) reduce extracellularglutamate levels and stimulate GLT1 ex-pression. Thus, in theory, combining hy-pothermia with �-lactam antibioticscould have synergistic effects, and using�-lactam antibiotics to treat infections inpatients with neurologic injuries may bea good choice.
In conclusion, hypothermia (even ifinitiated several hours after injury) hasbeen shown to improve outcome in pa-tients who remain comatose after cardiacarrest. The study by Dr. Takata and col-leagues (8) suggests that perhaps even
greater benefits could be achieved, or re-quired cooling periods reduced, if coolingcould be initiated in the very early stagesafter cardiac arrest. The next step shouldbe the confirmation of these findings inother animal models, specifically inlarger mammalian brains, which can bemore easily translated to the humanbrain. In the end, clinical studies will berequired to determine both optimumtemperature levels and optimum dura-tion of hypothermia therapy.
Arthur R. H. van Zanten, MDDepartment of Intensive CareGelderse Vallei HospitalEde, The Netherlands
Kees H. Polderman, MD, PhDDepartment of Intensive CareVU University Medical CenterAmsterdam, The Netherlands
REFERENCES
1. The Hypothermia after Cardiac Arrest StudyGroup: Mild therapeutic hypothermia to im-prove the neurologic outcome after cardiacarrest. N Engl J Med 2002;346:549–556
2. Bernard SA, Gray TW, Buist MD, et al: Treat-ment of comatose survivors of out-of-hospital cardiac arrest with induced hypo-thermia. N Engl J Med 2002; 346:557–563
3. Hachimi-Idrissi S, Corne L, Ebinger G, et al:Mild hypothermia induced by a helmet de-vice: A clinical feasibility study. Resuscita-tion 2001; 51:275–281
4. Holzer M, Bernard SA, Hachimi-Idrissi S, etal: Hypothermia for neuroprotection aftercardiac arrest: Systematic review and indi-vidual patient data meta-analysis. The Col-laborative Group on Induced Hypothermiafor Neuroprotection After Cardiac Arrest.Crit Care Med 2005;33:414–418
5. Polderman KH: Application of therapeutichypothermia in the ICU: Opportunities andpitfalls of a promising treatment modality.Part 1: Indications and evidence. IntensiveCare Med 2004; 30:556–575
6. Siesjo BK, Bengtsson F, Grampp W, et al:Calcium, excitotoxins, and neuronal deathin brain. Ann NY Acad Sci 1989; 568:234 –251
7. Dietrich WD, Busto R, Alonso O, et al: In-traischemic but not postischemic brain hy-pothermia protects chronically followingglobal forebrain ischemia in rats. J CerebBlood Flow Metab 1993; 13:541–549
8. Takata K, Takeda Y, Sato T, et al: Effects ofhypothermia for a short period on histologicoutcome and extracellular glutamate con-centration during and after cardiac arrest inrats. Crit Care Med 2005; 33:1340–1345
9. Todd MM, Hindman BJ, Clarke WR, et al:Mild intraoperative hypothermia during sur-gery for intracranial aneurysm. Intraopera-tive Hypothermia for Aneurysm Surgery
1451Crit Care Med 2005 Vol. 33, No. 6
Trial (IHAST) Investigators. N Engl J Med2005;352:135–145
10. Polderman KH: Application of therapeutic hy-pothermia in the intensive care unit: Opportu-nities and pitfalls of a promising treatmentmodality. Part 2: Practical aspects and side ef-fects. Intensive Care Med 2004; 30:757–769
11. Polderman KH, Tjong Tjin Joe R, PeerdemanSM, et al: Effects of artificially induced hypo-thermia on intracranial pressure and out-come in patients with severe traumatic head
injury. Intensive Care Med 2002; 28:1563–1567
12. Polderman KH, Peerdeman SM, GirbesARJ: Hypophosphatemia and hypomag-nesemia induced by cooling in patientswith severe head injury. J Neurosurg 2001;94:697–705
13. Polderman KH, van Zanten AR, Girbes AR:The importance of magnesium in criticallyill patients: A role in mitigating neurolog-ical injury and in the prevention of vaso-
spasms. Intensive Care Med 2003; 29:1202–1203
14. Polderman KH, Ely EW, Badr AE, et al: In-duced hypothermia in traumatic brain in-jury: Considering the conflicting results ofmeta-analyses and moving forward. IntensiveCare Med 2004; 30:1860–1864
In search of the silver bullet: Fast and safe cooling for braininjury?*
Experimentally, hypothermia isby far the most effective neu-roprotective method afterbrain injury such as stroke,
head trauma, and global cerebral isch-emia (1). So far, it has been successful ina subgroup of patients who remain coma-tose after witnessed cardiac arrest (2, 3).Results of brain trauma and ischemicstroke are limited to feasibility and safety,but neuroprotective effects were notshown up to now (4, 5). It is generallyaccepted that the dimension of protectiondepends on how fast and effective coolingis induced (1). However, there are manycofactors that influence effectiveness ofhypothermia when the goal temperatureis reached (6, 7). These include safety ofthe cooling method, optimal goal tem-perature itself, ventilation management(8), duration, rewarming (9), infections,electrolyte disturbances, and arrhythmias(6). All these factors directly influencethe potential success of hypothermia inpatients with acute brain injury. How-ever, most of them are not clarified—neither experimentally nor clinically.
In this issue of Critical Care Medicine,Dr. Holzer and colleagues (10) report theresults of an experimental study investi-gating effectiveness, safety, and feasibilityof venovenous vs. endovascular coolingin human-sized swine. Ventilated swinewere cooled to a goal brain temperatureof 33°C as fast as possible. Venovenous
cooling cooled the animals within 41 �17 mins in contrast to the endovasculartechnique, which took 126 � 37 mins. Inother words, venovenous cooling led to acooling rate of 8.2 � 2.8°C per hour vs.2.6 � 0.8°C per hour in endovascularcooling. Obviously, the speed of cooling isimpressing and seems to be the majoradvantage of the venovenous approach.No serious side effects occurred.
It is important to mention that hu-man-sized swine were used because eval-uating cooling techniques in smaller an-imals is not appropriate for transferringresults to the patient. The issue of thesuitable cooling technique was neglectedfor a certain time, but recent investiga-tions focus on this problem. The majorcooling techniques are listed and well dis-cussed in a recent editorial of Polderman(7) in Critical Care Medicine. The au-thors of the recent study conclude thatvenovenous cooling might be a promis-ing technique to be evaluated in brain-injured patients. There are at least somedisadvantages of the method itself andaccomplished study design. The aim ofthe study was to investigate coolingspeed. However, a suitable techniquemust ensure that the goal temperaturecan be maintained at the desired levelwithout major fluctuations, which is of-ten the case in external cooling (7). More-over, the issue of rewarming was disre-garded. The animals were rewarmed “asfast as possible” within 10 mins. Furtherinvestigations must show that slower re-warming can be performed in a con-trolled manner because patient data showdisadvantages of uncontrolled and fast re-warming (9). Although the speed of thevenovenous technique is impressing,
other factors might interfere with it inthe emergency situation. Similar to en-dovascular techniques, the required in-sertion procedure and its risks might beassociated with a significant time loss.Moreover, as the authors indicate, the useof heparin to avoid clotting of the extra-corporeal cooling system might be aproblem in patients with traumatic braininjury and focal neurologic signs indicat-ing a possible stroke. In these situations,cranial computed tomographic scanningor magnetic resonance imaging is re-quired to rule out intracerebral hemor-rhage. Therefore, the time loss fromsymptom onset to the diagnostic proce-dure must be added to the velocity ofcooling. Taking these disadvantages to-gether, venovenous cooling might be re-served for cardiac arrest patients and pa-tients with trauma and stroke in whichthe diagnosis was confirmed by neurora-diology.
In conclusion, different cooling tech-niques, or even their combination, mightbe suitable for different kinds of braininjury. For patients with cardiac arrest,fast techniques such as intravascularcatheters, infusion of ice-cold fluids, andextracorporal circulation might be appro-priate. For brain trauma and stroke, com-binations of different techniques mightbe suitable in the emergency situation.External cooling and ice-cold infusionsmight serve as a “bridging therapy” untilthe diagnosis is confirmed. In the sub-acute stage, more convenient techniquessuch as endovascular catheters and extra-corporal circulation might be appropri-ate. Again, it must be underlined thatmajor points need to be clarified in thefuture before hypothermia will be a suc-
*See also p. 1346.Key Words: hypothermia; brain temperature; car-
cess in brain-injured patients (5–7, 11).The critical evaluation of different goaltemperatures in animal experiments andpatients is necessary to define the optimaldepth of hypothermia.
Rainer KollmarStefan Schwab
Department of NeurologyUniversity of HeidelbergHeidelberg, Germany
REFERENCES
1. Corbett D, Thornhill J: Temperature modu-lation (hypothermic and hyperthermic con-ditions) and its influence on histological andbehavioral outcomes following cerebral isch-emia. Brain Pathol 2000; 10:145–152
2. Bernard SA, Gray TW, Buist MD, et al:Treatment of comatose survivors of out-of-
hospital cardiac arrest with induced hypo-thermia. N Engl J Med 2002; 346:557–563
3. Hypothermia after Cardiac Arrest StudyGroup. Mild therapeutic hypothermia toimprove the neurologic outcome aftercardiac arrest. N Engl J Med 2002; 346:549 –556
4. Clifton GL, Miller ER, Choi SC, et al: Lack ofeffect of induction of hypothermia after acutebrain injury. N Engl J Med 2001; 344:556–563
5. Polderman KH: Application of therapeutichypothermia in the ICU: Opportunities andpitfalls of a promising treatment modality.Part 1: Indications and evidence. IntensiveCare Med 2004; 30:556–575
6. Polderman KH: Application of therapeutichypothermia in the intensive care unit: Op-portunities and pitfalls of a promising treat-ment modality. Part 2: Practical aspects andside effects. Intensive Care Med 2004; 30:757–769
7. Polderman KH: Keeping a cool head: How toinduce and maintain hypothermia. Crit CareMed 2004; 32:2558–2560
8. Kollmar R, Frietsch T, Georgiadis D, et al:Early effects of acid–base management dur-ing hypothermia on cerebral infarct volume,edema, and cerebral blood flow in acute focalcerebral ischemia in rats. Anesthesiology2002; 97:868–874
9. Steiner T, Friede T, Aschoff A, et al: Effectand feasibility of controlled rewarming aftermoderate hypothermia in stroke patientswith malignant infarction of the middle ce-rebral artery. Stroke 2001; 32:2833–2835
10. Holzer M, Behringer W, Janata A, et al: Ex-tracorporeal venovenous cooling for induc-tion of mild hypothermia in human-sizedswine. Crit Care Med 2005; 33:1346–1350
11. Schwab S, Kollmar R: Rise of the machines:Controlling the body temperature of criti-cally ill patients by endovascular catheters.Neurocritical Care 2004; 1:127–130
Immunosuppression after trauma*
I n this issue of Critical CareMedicine, the report by Dr. Perl andcolleagues (1) indicates, as in manyearlier publications (involving ther-
mal trauma, smoke inhalation, hemor-rhagic shock, etc.), that an insult such ascontusive chest trauma can cause a state ofimmunosuppression. In this context, im-munosuppression has been defined by thereduced ability of tissue cells (CD3splenocytes, splenic macrophages, andperitoneal macrophages) to produce a vari-ety of cytokines (tumor necrosis factor-,interleukin (IL)-6, IL-10, interferon-�). Itshould be noted that different stimuli (con-canavalin A, lipopolysaccharide, anti-CD3)were employed, but they were not uni-formly used with each cell type. Neverthe-less, defective cytokine production has beendescribed in many other reports after theinsults described above (2–4). It is not es-pecially surprising that a “double hit”(chest contusive injury followed by cecalligation and puncture CLP) results ingreatly increased lethality. Although it isassumed that the double-injury model re-sults in high mortality due to uncontrolled
bacterial invasion in the peritoneal cavityand elsewhere as a result of the state ofimmunosuppression, this remains to bedemonstrated. In other studies, a doubleinsult (hemorrhagic shock and nonlethallipopolysaccharide injection) has also in-duced a high rate of lethality (5), suggest-ing that intervening bacterial infection maynot necessarily be the cause of the lethaloutcome. In other words, in these models,multiple organ failure and death can occurin the absence of overt bacterial invasion.
An important aspect of the study by Dr.Perl and colleagues (1) is the “disconnect”between in vitro cell production of cyto-kines and those that occur in the plasmaand those produced by anti-CD3–stimu-lated blood mononuclear cells. For thesame cytokines for which there is defectiveproduction by splenic cells and peritonealmacrophages, blood mononuclear cellsfrom chest-contusive animals show en-hanced (not diminished) production, andserum levels of tumor necrosis factor-,IL-6, and IL-10 are greatly enhanced afterchest trauma. Obviously, the data indicatethat cells producing cytokines in the post-contusive state demonstrate quite differentresponsiveness. It is likely that othersources of cytokines (such as liver) are re-fractory to whatever leads to the immuno-suppressed state involving tissue macro-phages, as defined by criteria in the studyby Dr. Perl and colleagues (1). It may also
be the case that selection of the in vitro cellstimulus will greatly bias the results.
An important unanswered question isthe cause of the multiple organ dysfunctionin cytokine production as demonstrated byreduced cytokine release from stimulatedperitoneal macrophages and splenic cells. Itseems likely that there two possibilities.The first is the presence of a circulatinginhibitor of cytokine synthesis. There areseveral suggestions that circulating NO,granulocyte colony-stimulating factor,IL-4, and IL-10 may account for immuno-suppressive effects (6, 7). There is also areport suggesting that after thermal injury,macrophages become refractory to the sup-pressive effects of IL-10 (8). A dilemma hereis why in the chest trauma model an inhib-itor would target splenic and peritonealmacrophages but not CD3 blood mono-nuclear cells and whatever are the othercellular sources of tumor necrosis factor-,IL-6, and IL-10. The second possibility fordevelopment of the state of immunosup-pression is the potential for triggering ofthe autonomic nervous system (involvingthe vagus nerve), causing stimulation ofnicotinic acetyl choline receptors on tissuemacrophages with resultant inhibition ofmacrophage production of cytokines (9,10). Determining the cause of multiple or-gan dysfunction of cytokine production af-ter the various insults (as described above)might result in a therapeutic intervention
*See also p. 1351.Key Words: trauma; immunosuppression; cyto-
that could prevent the onset of immuno-suppression that occurs so commonly inhumans after trauma or surgery (11) andalso develops in experimental animals afterthe various conditions listed above. Cer-tainly, we now know that immunosuppres-sion is a rather common condition in hu-mans and correlates with a bad prognosis ifnot rapidly reversed. Trying to define thecause of the immunosuppression state is anurgent priority.
Peter A. Ward, MDDepartment of PathologyUniversity of Michigan Medical
SchoolAnn Arbor, MI
REFERENCES
1. Perl M, Gebhard F, Brückner UB, et al: Pul-monary contusion causes impairment of
macrophage and lymphocyte immune func-tions and increases mortality associated witha subsequent septic challenge. Crit Care Med2005; 33:1351–1358
2. Xu YX, Ayala A, Chaudry IH: Prolonged im-munodepression after trauma and hemor-rhagic shock. J Trauma 1998; 44:335–341
3. Schwacha MG, Chaudry IH: The cellular basis ofpost-burn immunosuppression: macrophagesand mediators. Int J Mol Med 2002; 10:239–243
4. Shelley O, Murphy T, Paterson H, et al: In-teraction between the innate and adaptiveimmune systems is required to survive sepsisand control inflammation after injury. Shock2003; 20:123–129
5. Anaya-Prado R, Ramos-Kelly JR, Toledo-Pereyra LH, et al: Multiple selectin blockadewith a small-molecule selectin inhibitor doesnot affect survival after a second inflamma-tory challenge with nonlethal LPS. J InvestSurg 2002; 15:171–180
6. Hoffmann G, Schobersberger W: Anti-inflam-
matory and nitric oxide-inhibiting properties ofgranulocyte colony-stimulating factor. Zhong-guo Yao Li Xue Bao 1999; 20:673–681
7. Junger WG, Hoyt DB, Liu FC, et al: Immu-nosuppression after endotoxin shock: the re-sult of multiple anti-inflammatory factors.J Trauma 1996; 40:702–709
8. Schwacha MG, Schneider CP, Bland KI, et al:Resistance of macrophages to the suppres-sive effect of interleukin-10 following ther-mal injury. Am J Physiol Cell Physiol 2001;281:C1180–C1187
9. Pavlov VA, Tracey KJ: Neural regulators ofinnate immune responses and inflammation.Cell Mol Life Sci 2004; 61:2322–2331
10. Czura CJ, Tracey KJ: Autonomic neural reg-ulation of immunity. J Intern Med 2005; 257:156–166
11. Mannick JA, Rodrick ML, Lederer JA: Theimmunologic response to injury. J Am CollSurg 2001;193:237–244
Caught in the act: Observation of polymorphonuclear neutrophilsfor the regulation of tumor necrosis factor- release by tumornecrosis factor- converting enzyme in patients with secondaryperitonitis*
T umor necrosis factor (TNF)-converting enzyme (TACE,ADAM17, CD156b), a memberof the A disintegrin and met-
alloproteinase (ADAM) family, is the firstdescribed (1, 2) and best characterizedsecretase (i.e., an enzyme that releasesthe extracellular domains of transmem-brane proteins by proteolytical cleavage).This limited proteolysis, called shedding,is a tightly regulated process importantfor growth factor and cytokine signaling.Besides TNF-, several other TACE sub-strates were identified. These proteinscan be mainly categorized in those with arole in development and differentiationand those involved in the modulation ofimmune responses (3). The transmem-brane precursor of the TNF- molecule is
cleaved by TACE into membrane-boundTNF- (mTNF-) and the soluble form ofTNF- (sTNF-), recently confirmed asan important mediator of inflammation(4). The proinflammatory mediatorTNF- has been implicated in the patho-physiology of several acute states andcontributes to cell death, apoptosis, andorgan dysfunction. Using sophisticatedmouse models and in vitro assays, thecomplex mechanism of inflammatorymodulation, in which TACE and TNF-are key players, becomes more and moreunderstood. However very few data areavailable about the role of TACE and itssubstrates in acute human inflammation.
In the study in this issue of CriticalCare Medicine by Dr. Kermarrec and col-leagues (5), secondary peritonitis wasused as model for acute inflammation,and they investigated the role of TACE inthe modulation of acute inflammation fo-cusing on the cell population of polymor-phonuclear neutrophils (PMN). They as-sessed TACE expression on PMN and thesubstrates TNF-, L-selectin, and solubletype 1 and 2 TNF- receptors in blood
and peritoneal fluid. Via FACS analysis,Dr. Kermarrec and colleagues (5) de-tected elevated TACE expression on thePMN surface, and mTNF- expressionwas decreased when compared with PMNisolated from healthy donors. Levels ofsTNF-, L-Selectin, and soluble type 1and 2 TNF- receptors were highly ele-vated in the serum and in the peritonealfluid of the patients. When Dr. Kermarrecand colleagues (5) stimulated PMN iso-lated from the peritonitis patients invitro, they observed an impaired capacityto synthesize TNF-. Finally, they wereable to show a correlation of increasedTACE expression and poor outcome ofthe patients with secondary peritonitis.
This work by Dr. Kermarrec and col-leagues (5) is intriguing because it con-centrates on PMN as a source of TNF- ina specific state of inflammatory disease.Furthermore, this study suggests a roleof TACE in the pathophysiology of peri-tonitis and points to this molecule astarget for new therapeutic strategies.This is important because clinical resultsadministering anti-TNF- antibodies to
*See also p. 1359.Key Words: peritonitis; sepsis; polymorphonuclear
patients with sepsis were disappointing sofar (6, 7), and inhibitors of TACE to treatinflammatory diseases are under develop-ment (8, 9).
However, two caveats toward the studyshould be mentioned. The authors per-formed no experiments to prove the as-sociation between increased TACE ex-pression on PMN and its elevated solublesubstrates on a molecular level. Also, ex-perimental data on the biological activityof increased TACE are missing. A secondpoint is the choice of the control groupused by the researchers. Because onlyhealthy donors were compared with pa-tients with sepsis who had all undergonelaparotomy, the authors cannot differen-tiate between the effects on modulationof TACE and its substrates by peritonitisand surgical incision alone as this wasshown to be as effective in increasingTNF- levels as trauma and shock (10).
In conclusion, the data of this carefulobservational study adds new and inter-esting information on the role of PMNand TACE and its substrates in the con-text of sepsis and peritonitis. It shouldprompt researchers in the field to per-
form similar studies addressing the mo-lecular aspects and the biological activityof TACE up-regulation to gain a deeperunderstanding of the molecular mecha-nisms of peritonitis and acute inflamma-tion in humans.
Wolfram Trudo Knoefel, MD, FACSDepartment of SurgeryHeinrich-Heine-University
DuesseldorfDuesseldorf, Germany
REFERENCES
1. Black RA, Rauch CT, Kozlosky CJ, et al: Ametalloproteinase disintegrin that releasestumour-necrosis factor-alpha from cells. Na-ture 1997; 385:729–733
2. Moss ML, Jin SL, Milla ME, et al: Cloning ofa disintegrin metalloproteinase that pro-cesses precursor tumour-necrosis factor-alpha. Nature 1997; 385:733–736
3. Mezyk R, Bzowska M, Bereta J: Structure andfunctions of tumor necrosis factor-alphaconverting enzyme. Acta Biochim Pol 2003;50:625–645
4. Mohammed FF, Smookler DS, Taylor SE, etal: Abnormal TNF activity in Timp3-/- miceleads to chronic hepatic inflammation and
failure of liver regeneration. Nat Genet 2004;36:969–977
5. Kermarrec N, Selloum S, Plantefeve G, et al:Regulation of peritoneal and systemic neu-trophil-derived tumor necrosis factor- re-lease in patients with severe peritonitis: Roleof tumor necrosis factor- convertingenzyme cleavage. Crit Care Med 2005; 33:1359–1364
6. Abraham E, Anzueto A, Gutierrez G, et al: Dou-ble-blind randomised controlled trial of mono-clonal antibody to human tumour necrosis fac-tor in treatment of septic shock: NORASEPT IIStudy Group. Lancet 1998; 351:929–933
7. Fisher CJ Jr, Agosti JM, Opal SM, et al: Treat-ment of septic shock with the tumor necrosisfactor receptor: Fc fusion protein. The Solu-ble TNF Receptor Sepsis Study Group.N Engl J Med 1996; 334:1697–1702
8. Black RA: Tumor necrosis factor-alpha con-verting enzyme. Int J Biochem Cell Biol2002; 34:1–5
9. Levin JI, Du MT: Sulfonate ester hydroxamicacids as potent and selective inhibitors of TACEenzyme. Drug Des Discov 2003; 18:123–126
10. Davidson MT, Deitch EA, Lu Q, et al: A studyof the biologic activity of trauma-hemor-rhagic shock mesenteric lymph over timeand the relative role of cytokines. Surgery2004; 136:32–41
Heparins in sepsis-induced disseminated intravascular coagulation:Low weight—high impact?*
T he coagulation cascade, en-dogenous anticoagulants, andthe fibrinolytic system arecritically balanced to maintain
blood fluidity and prevent hemorrhage inresponse to vascular insults. This homeo-static mechanism can be compromised byimbalances of clotting factors or inhibi-tors due to congenital or acquired causes.Inflammation related to sepsis is onesuch acquired state of deregulated coag-ulation (1, 2).
Consequently, coagulation abnormali-ties occur in nearly all patients with sep-sis or septic shock (once more confirmedby the PROWESS data, in which patients
with apparent coagulopathies were ex-cluded (3)). The range varies from a sim-ple decrease in platelet count and sub-clinical prolongation of clotting times tofull-blown disseminated intravascular co-agulation (DIC), characterized by simul-taneous widespread microvascularthrombosis and profuse bleeding fromvarious sites (4). The clinical significanceof DIC with severe thrombocytopenia andlow levels of coagulation factors is indis-putable. However, major bleeding occursonly in a small minority (�5%) of pa-tients with DIC. Much more commonthan hemorrhage is the occurrence ofmultiple organ failure, but there is con-siderable debate about the contributionof vascular fibrin deposition to its devel-opment.
Several lines of evidence support animportant role of DIC in the pathogenesisof multiple organ failure. Extensive datahave been reported from postmortemfindings in DIC patients (5). The observed
diffuse bleedings, hemorrhagic necrosisof tissue, and intravascular thrombi for-mation seem to be specifically related tothe clinical dysfunction of the involvedorgans. Similarly, experimental bactere-mia or endotoxemia in animal studiescause intravascular and extravascular fi-brin deposition (e.g., in kidneys, lungs,liver, and brain) (6). Finally, DIC hasbeen shown to be an independent predic-tor of mortality in patients with sepsisand septic shock (7).
Therefore, manipulation of the coagu-lation system to improve outcome in sep-sis seems to be an obvious therapeuticgoal. However, clinical trials aiming at aninterruption of “latent coagulation” insepsis by administration of coagulationinhibitors, such as antithrombin or tissuefactor pathway inhibitor, have so farfailed to demonstrate a statistically sig-nificant clinical benefit concerning sur-vival, despite the indisputable effect onlaboratory indicators of blood coagula-
*See also p. 1365.Key Words: disseminated intravascular coagula-
tion; low molecular weight heparin; sepsis; organ fail-ure; inflammation; coagulation
tion activation or score systems based onsuch variables (8). An exception seems tobe recombinant human activated proteinC, in which the clinical benefit seems tobe produced by effects other than justinhibition of coagulation (9).
In this issue of Critical Care Medicine,Slofstra and colleagues (10) address thequestion of whether a more conventionalanticoagulant like (low molecularweight) heparin would have beneficial ef-fects in experimental sepsis and multipleorgan failure. In the first part of thestudy, mice were subjected to two injec-tions of Serratia marcescens lipopolysac-charide, resulting in the generalizedShwartzman’s reaction—a widely usedmodel for DIC. Before each lipopolysac-charide injection and 10 hrs after the firstexposure to lipopolysaccharide, low mo-lecular weight heparin was administered.Multiple organ failure was significantlyreduced as determined by reduction ofhepatic necrosis, lung epithelial proteinleakage, and creatinine concentration inplasma.
To further elucidate the effects ofLMWH on inflammation, the authorsperformed a second (in vitro) part of thestudy. A co-culture system with humanumbilical vein endothelial cells incubatedwith isolated human monocytes was em-ployed. Human umbilical vein endothe-lial cells were stimulated with lipopoly-saccharide and monocytes in the absenceor presence of LMWH. Interestingly,LMWH administration did not affectmonocyte-dependent E-selectin expres-sion—as marker for monocyte-endothe-lial interaction. The in vitro results con-firmed the findings of their own animalexperiments, in which LMWH adminis-tration neither diminished the level ofsystemic inflammatory mediators nor af-fected the influx of granulocytes in lung,liver, or kidney during severe sepsis/DIC.In Critical Care Medicine, Derhaschnigand colleagues (11) presented similardata in human endotoxemia, in whichheparins displayed only little effects oncytokine production and on endothelialcell or platelet activation.
The latter findings are in contrast toprevious reports, which support the con-cept that heparins exert anti-inflamma-tory actions such as suppression of se-lected leukocyte functions or inhibitionof inflammatory mediators release (12).However, despite the lack of activatedprotein C–like side effects in regard toanti-inflammation, LMWH attenuatedmultiple organ failure in this model of
DIC. Thus, the study of Slofstra and col-leagues (10) challenges the significanceof the coagulation/inflammation positivefeedback loop in sepsis and multiple or-gan failure. One explanation of these con-flicting results may be that the contrib-uting effect of blood coagulation onorgan function and survival in sepsis washitherto underestimated. Another impor-tant point might be the observation thatLMWH increases fibrinolysis in vitro (13).As the pathophysiology of septic DIC ischaracterized by enhanced coagulationand impaired fibrinolytic potential, in-creased fibrinolytic activity could be anadditional favorable property of LMWH inthis model.
Nevertheless, the crosstalk betweeninflammation and coagulation is an in-controvertible fact—it represents a phy-logenetically ancient host response to tis-sue injury and has become the primarysurvival strategy throughout the longhistory of vertebrate evolution (14). Mul-tiple mechanisms are at play, includinginflammation-induced tissue factor ex-pression in monocytes (via nuclear factorkappa-B activation) or thrombin-relatedactivation of platelets and endothelium,increasing the surface expression of P-selectin—a prerequisite of leukocyte ad-hesion (1, 2, 15).
This combined response is useful indelimited injury but may be detrimentalin systemic inflammation. Unfortunately,simple inhibition of microthrombosisand consumptive coagulopathy by selec-tive blockade of thrombin generation didnot prevent lethality in a model of septicshock (16). The actual findings stronglysuggest that the initiation phase of thecoagulation pathways can sustain an in-flammatory lethal response, independentof the downstream effector proteasethrombin and coagulation-related effects(17). Slofstra and colleagues (10) couldalso not show a significant effect on sur-vival, despite of a reduction of DIC-induced organ damage. Another limita-tion of the presented study is thepretreatment approach in the animal ex-periments. Furthermore, LMWH requiresantithrombin, and the possible enhanceddepletion of that inhibitor with anti-inflammatory properties raises new ques-tions in the setting of sepsis.
However, the study of Slofstra and col-leagues (10) provides a solid backgroundfor further experimental research in thefield of anticoagulant intervention withheparins in sepsis-related DIC. The clin-ical effectiveness of this strategy remains
unclear, unless controlled trials wouldindicate any survival benefit in patients.Because the bioavailability of unfraction-ated heparin is reduced in the presence ofhigh levels of acute phase proteins,LMWH should be preferred in those trials(18). Regrettably, although LMWH mayhave a high effect in the prevention ofmultiple organ failure in septic patientswith DIC, the funding of such a study hasnot yet gained its supporters. The scien-tific community is on call!
Christian Lehmann, MDTaras I. Usichenko, MDDragan Pavlovic, MD
Klinik für Anästhesiologie undIntensivmedizin
Ernst-Moritz-Arndt-UniversitätGreifswald
Greifswald, Germany
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1. Jagneaux T, Taylor DE, Kantrow SP: Coagu-lation in sepsis. Am J Med Sci 2004; 328:196–204
2. Amaral A, Opal SM, Vincent JL: Coagulationin sepsis. Intensive Care Med 2004; 30:1032–40
3. Kinasewitz GT, Yan SB, Basson B, et al: Uni-versal changes in biomarkers of coagulationand inflammation occur in patients with se-vere sepsis, regardless of causative micro-organism. Crit Care 2004; 8:R82–R90
4. Levi M, de Jonge E, van der Poll T: Sepsisand disseminated intravascular coagulation.J Thromb Thrombolysis 2003; 16:43–47
5. Shimamura K, Oka K, Nakazawa M, et al:Distribution patterns of microthrombi in dis-seminated intravascular coagulation. ArchPathol Lab Med 1983; 107:543–547
6. Scherer RU, Giebler RM, Schmidt U, et al:Short-time rabbit model of endotoxin-induced hypercoagulability. Lab Anim Sci1995; 45:538–546
7. Dhainaut JF, Yan SB, Joyce DE, et al: Treat-ment effects of drotrecogin alfa (activated) inpatients with severe sepsis with or withoutovert disseminated intravascular coagula-tion. J Thromb Haemost 2004; 2:1924–1933
8. Freeman BD, Zehnbauer BA, Buchman TG: Ameta-analysis of controlled trials of antico-agulant therapies in patients with sepsis.Shock 2003; 20:5–9
9. Bernard GR, Vincent JL, Laterre PF, et al:Efficacy and safety of recombinant humanactivated protein C for severe sepsis. N EnglJ Med 2001; 344:699–709
10. Slofstra SH, van ’t Veer C, Buurman WA, etal: Low molecular weight heparin attenuatesmultiple organ failure in a murine model ofdisseminated intravascular coagulation. CritCare Med 2005; 33:1365–1370
11. Derhaschnig U, Pernerstorfer T, Knechtels-dorfer M, et al: Evaluation of antiinflamma-tory and antiadhesive effects of heparins in
1456 Crit Care Med 2005 Vol. 33, No. 6
human endotoxemia. Crit Care Med 2003;31:1108–1112
12. Elsayed E, Becker RC: The impact of heparincompounds on cellular inflammatory re-sponses: A construct for future investigationand pharmaceutical development. J ThrombThrombolysis 2003; 15:11–18
13. Lisman T, Adelmeijer J, Nieuwenhuis HK, etal: Enhancement of fibrinolytic potential invitro by anticoagulant drugs targeting acti-vated factor X, but not by those inhibiting
thrombin or tissue factor. Blood Coagul Fi-brinolysis 2003; 14:557–562
14. Opal SM, Esmon CT: Bench-to-bedside re-view: Functional relationships between coag-ulation and the innate immune response andtheir respective roles in the pathogenesis ofsepsis. Crit Care 2003; 7:23–38
15. Esmon CT: Interactions between the innateimmune and blood coagulation systems.Trends Immunol 2004; 25:536–542
16. Taylor FB Jr, Chang ACK, Peer GT, et al:DEGR-factor Xa blocks disseminated intra-
vascular coagulation initiated by Escherichiacoli without preventing shock or organ dam-age. Blood 1991; 78:364–368
17. Riewald M, Ruf W: Science review: Role ofcoagulation protease cascades in sepsis. CritCare 2003; 7:123–129
18. Cosmi B, Fredenburgh JC, Rischke J, et al:Effect of nonspecific binding to plasma pro-teins on the antithrombin activities of un-fractionated heparin, low-molecular-weightheparin, and dermatan sulfate. Circulation.1997;95:118–24
Dementia: A justification for limiting intensive care?*
T here are currently 2.2 millionAmericans living with demen-tia (1). Projections suggestthat this number will grow to
�10 million by 2040 (2) due to the agingof the population and increasing life ex-pectancy among those affected (3). It isessential that we provide critical care tothose who desire aggressive interventionand who might reasonably be expected tobenefit from it, not only to be good stew-ards of our finite health care resourcesbut also to prevent the needless pain andsuffering that can result from medicallyinappropriate or unwanted care. Al-though there are no data to support it,there is a prevailing notion in the medicalcommunity that patients with dementiahave worse outcomes from intensive carethan those without dementia. This hasled some to suggest that the use of crit-ical care services be restricted for de-mented patients (4).
In this issue of Critical Care Medicine,Dr. Pisani and colleagues (5) present astudy that challenges this notion. Using aprospective cohort study design, they ex-amined 395 consecutive patients aged�65 yrs admitted to the medical inten-sive care unit (ICU) of an academic med-ical center. Patients were categorized ashaving moderate to severe dementia (n �66) or not (n � 329) using the ModifiedBlessed Dementia Rating Scale (6), a val-idated proxy-administered tool with gooddiscrimination (receiver operating char-
acteristic curve area 0.95). The primaryoutcome was ICU length of stay, and thestudy was powered to detect a 1-day dif-ference in this outcome. Secondary out-comes included duration of mechanicalventilation, hospital length of stay, newdischarge to a nursing home, and mor-tality.
The first interesting finding is thatphysicians were only aware of the diag-nosis of moderate or severe dementia in43% of the cases. Despite the fact thatpatients with dementia were older,slightly sicker, and more likely to have ado-not-resuscitate/do-not-intubate orderon admission, there were no differencesin outcomes between demented and non-demented patients. In fact, ICU and hos-pital mortality rates were actually lowerin patients with dementia, although thesedifferences were not statistically signifi-cant. Not surprisingly, patients with de-mentia were more likely to have theircode status changed to less aggressivecare. Yet, overall aggressiveness of ICUcare, as measured by the use of ICU in-terventions, was not different betweengroups. The authors conclude that pre-sumptions of less favorable outcomes ofcritical care in patients with dementiashould not drive treatment decisions inthe ICU, with the possible exception ofcode status determinations.
This was a very well done study andthe first to show equivalent short-termoutcomes for older ICU patients with andwithout dementia. However, a few limi-tations deserve consideration. Since thiswas a study of patients admitted to theICU, we know nothing of the outcomes ofthose who never made it to the ICU in thefirst place. It is conceivable that only lessseverely demented patents with few co-
morbidities were considered for intensivecare. Indeed, as the authors point out,there was a nonsignificant trend towardfewer comorbidities in patients with de-mentia. However, the prevalence of de-mentia seen in this ICU cohort waswithin the range of cognitive impairmentand dementia seen in community-dwell-ing seniors (7) and medical inpatients (8).To better understand the severity of de-mentia in this cohort and whether thesefindings apply to other patient popula-tions, it would have been helpful for theauthors to present measures of centraltendency and dispersion of ModifiedBlessed Dementia Rating Scale scores inthose with dementia. Similarly, becauseonly medical ICU patients were studied, itis unclear if these results would apply tosurgical ICU patients. Finally, althoughthere were no short-term outcome differ-ences, there may have been importantlong-term differences, such as quality oflife or functional decline, which the au-thors note deserve further study.
As the paradigm for the managementand prognosis of patients with dementiachanges, the focus moves increasingly toproviding what might be many years ofcare for the wide variety of health condi-tions that they, just like other elderlysubjects, are likely to suffer. An entrainedconsequence of this changing paradigmwill be the need, often frequent, for ICUadmission (9). This, of course, raisessome interesting ethical challenges. Mostcritically, how does one elicit the prefer-ences of these subjects for aggressivecare? Terry Fried and colleagues recentlyreported in the New England Journal ofMedicine that 89% of Americans wouldnot wish to be kept alive if they hadsevere, irreversible neurologic damage
*See also p. 1371.Key Words: dementia; critical care; outcome as-
(10). One can imagine clear-cut but rarescenarios where honoring this desirewould be possible and straightforward.But Alzheimer’s disease and other de-mentias often involve a long, slow de-cline. Patients may or may not haveclearly articulated their preferences be-fore cognitive impairment became too se-vere. Dr. Pisani and colleagues show thatthere are ample opportunities for patientswith dementia to survive intercurrent ep-isodes of critical illness, which presum-ably means they can wean from mechan-ical ventilation, recover from acuteillness, and so on. But for how long?
It seems that those with dementia are avulnerable population with special needs,not necessarily because of poor prognosis,as we now know from Dr. Pisani, but be-cause we may not know their care prefer-ences. Furthermore, with less than half ofdementia cases being recognized by physi-cians, one can envision scenarios wheredecision-making ability is presumed, yetnot present. Previously, it has been easy toassume, given a poor prognosis, that ag-gressive care would not be wanted—butwhat now? Should we manage these pa-tients as if they would always want aggres-sive care? This is more aggressive than thecare plan for patients without dementia—and, by extension, it likely flies in the face ofFried’s findings. It would be easy in theearly years to say “manage aggressively.”But what about the subject who has livedwith dementia for many years and has ex-perienced several admissions and/or man-
agement crises for underlying medical con-ditions? When is it time to say, “enough isenough”? How can we try to help this pro-cess along, and what is the role of theintensivist? A good place to start might beto engage in ICU exit interviews to helpfamilies think about what they would dothe next time their loved one becomes ill.Better yet would be to get patients betteroriented to their potential future and moreinvolved in advanced decision making wellbefore dementia has become too advancedand the window of opportunity has closed.
This study has profound implicationsfor patients with dementia, their families,and the physicians caring for them. Pre-sumptions that these patients do not farewell with critical care should not drivetreatment decisions. Instead, decisions re-garding the use of life-sustaining therapiesshould be made only after considering thecomplete picture and, ideally, with an un-derstanding of patient preferences.
Eric B. Milbrandt, MD, MPHThe CRISMA Laboratory (Clinical
Research, Investigation, andSystems Modeling of AcuteIllness)
Department of Critical CareMedicine
University of Pittsburgh Schoolof Medicine
Pittsburgh, PA
REFERENCES
1. Pisani MA, Redlich C, McNicoll L, et al: Un-derrecognition of preexisting cognitive im-
pairment by physicians in older ICU patients.Chest 2003; 124:2267–2274
2. U.S. Congress. Losing a Million Minds: Con-fronting the tragedy of Alzheimer’s Diseaseand Other Dementias. Report number OTA-BA-324. Washington, DC, U.S. GovernmentPrinting Office, 1987
4. Murphy DJ, Barbour E. GUIDe (Guide-lines for the Use of Intensive Care in Den-ver): A community effort to define futileand inappropriate care. New Horiz 1994;2:326 –331
5. Pisani MA, Redlich CA, McNicoll L, et al:Short-term outcomes in older intensive careunit patients with dementia. Crit Care Med2005; 33:1371–1376
6. Blessed G, Tomlinson BE, Roth M: The asso-ciation between quantitative measures of de-mentia and of senile change in the cerebralgrey matter of elderly subjects. Br J Psychi-atry 1968; 114:797–811
7. Graham JE, Rockwood K, Beattie BL, et al:Prevalence and severity of cognitive impair-ment with and without dementia in an el-derly population. Lancet 1997; 349:1793–1796
8. Fields SD, MacKenzie CR, Charlson ME, etal: Cognitive impairment. Can it predict thecourse of hospitalized patients? J Am GeriatrSoc 1986; 34:579–585
9. Iwashyna TJ: Critical care use during thecourse of serious illness. Am J Respir CritCare Med 2004; 170:981–986
10. Fried TR, Bradley EH, Towle VR, et al: Un-derstanding the treatment preferences of se-riously ill patients. N Engl J Med 2002; 346:1061–1066
Should we add stem cells to the code cart in resuscitation ofheatstroke?*
Stem cell researchers haveshown promising break-throughs that may ultimatelyenhance the quality of lives of
victims who suffer devastating chronicdiseases. However, because of the timeneeded for migration and differentiation
by these cells, many scholars and scien-tists doubt if stem cells have any practicalvalue to save lives in resuscitation. Inresuscitation medicine and often in theintensive care unit, time is most critical.Either conventional or novel treatmentsdelivered in a timely fashion are crucialto maximize outcome. Although the po-tential use of therapies such as with stemcells may have tremendous value acrossrehabilitation settings, with current tech-nologies, resuscitation results are stillcritically limited by a very narrow timeframe: an approximately 5-min no-flowduration in cardiopulmonary resuscita-
tion, a “golden hour” for traumatic andhemorrhagic shock, and a possible 2-hrwindow in the treatment of heatstroke (1,2). Presumably, this is not a race that onecan win with cellular pseudopodia.
Although this assumption may havekept stem cells out of resuscitation med-icine, in this issue of Critical CareMedicine, Dr. Chen et al. (3) revealed tous that stem cells—or, more precisely, astem cell preparation— could surpris-ingly improve acute survival in an exper-imental animal model of heatstroke.Although the magnitude of the improve-ment in survival by the cell treatment is
*See also p. 1377.The authors have no financial interests to disclose.Key Words: stem cell research; heatstroke; resus-
dwarfed by the findings of their priorstudies using conventional drugs, such asdexamethasone (4) or an oral dose of aChinese herbal compound (5), the studyremains particularly interesting in that itmay challenge the doubt about the valueof stem cell preparations in acute resus-citation medicine.
Chen and his colleagues previously es-tablished special heatstroke models inrats (4–6). In spite of slight technicalmodifications and changes in the defini-tion of “the onset of heatstroke” over theyears, the models appear to be reproduc-ible. They found that administration ofhuman umbilical cord blood cells(HUCBCs) either intravenously or intothe cerebral ventricle 68 mins after heatexposure significantly extended the sur-vival time and preserved the brain histo-logically. In contrast, rats treated withvehicle died in approximately 22 mins,and brain histology revealed severe neu-ronal injury (3).
Treatment with peripheral bloodmononuclear cells (PBMCs) also failed toproduce any significant improvement.The authors attributed the discrepancybetween PBMC and HUCBC treatments tothe lack of pleuropotential of PBMCs (3).
Could the pleuropotential of HUCBCsbe critical to this beneficial effect in re-suscitation from heatstroke? We believethat cellular plasticity may be of limitedimportance in the current experimentalparadigm. First, in such a short time (12mins), it is inconceivable that therewould be any functional differentiation,and if there were any, that it would affecthemodynamics or acute survival. Second,since no immunosuppression treatmentwas given, any functional and sustainabledifferentiation may not be possible withxenotransplantation, although this maynot be a major issue in the acute situa-tion. The speculation that the observedbeneficial effects may be attributed to thechanges in cytokines and nitric oxide pro-duction by the HUCBCs is more plausible(3). Indeed, something rapidly elaboratedby the HUCBCs or released in response totheir injection seems to be a likely medi-ator of these effects.
The biochemical and molecular mech-anisms leading to improved survival andbrain histologic findings with HUCBCs inthe model need additional clarification.However, physiologically, it is appropri-ate to attribute the “neuroprotective ef-fects” of HUCBC preparations to the he-modynamic improvement in the currentstudy. Previously, this group has demon-
strated increased lipid peroxidation in thebrain during heat exposure (6), but moredramatic biochemical changes in thebrain coincided with systemic hypoten-sion after heat exposure was terminated.Therefore, brain injury is probably sec-ondary to systemic circulatory collapse(5) or to a combination of hemodynamicsand the direct central effect of hyperther-mia. This assumption is also supported by astudy of dogs by Oglesbee et al. (7) in whichheat exposure at 42.5°C for 90 mins, whichdid not cause significant reduction in arte-rial blood pressure, did not produce anyabnormalities in cerebral morphology orneurologic function after 8 days (7).
Although this study may be thought-provoking and define heretofore unrecog-nized potential hemodynamic effects ofHUCBC preparations, there are severalfactors that may limit its implications.
First, many potential experimental ar-tifacts may be operating. As stated inMethods, mean arterial pressure (MAP)decreased to 25 mm Hg at 68 � 3 mins ofheat exposure in the normal saline–treated group. As shown in Figure 1,however, MAP in both the HUCBC-treated and PBMC-treated groups wasgreater than 90 mm Hg at 68 mins ofheat exposure, which suggests that thesegroups may have been less insulted thancontrols before cell injections. Similarly,the lack of full randomization of thestudy is a pitfall. In addition to theseissues with study design, the findings ofthe neuropathological evaluation (60% ofneurons were damaged over 12 mins) arerather unexpected. Neuronal damagegenerally takes time to mature and beseen with conventional histopathology.The findings in many animal studies sug-gested that the acute central nervous inju-ries may be very subtle, even in animalswith lethal heatstroke (8). Few previousstudies had examined the short-term histo-logic effects on the brain immediately afterheat exposure (8), and the differences inheatstroke models confound the interpre-tation of their brain histologic findings.
Second, as a general principle, noveldrugs/compounds should not be tested inan “underresuscitated” model. Otherwise,one might target a problem that actuallyis not a clinical concern, or the effective-ness of the experimental treatments be-comes ineffective when conventionaltreatments are provided. Unfortunately,this principle was not followed in thecurrent study. Clinically, the conven-tional treatment of heatstroke (systemichyperthermia) includes aggressive cool-
ing and support of vital organs (1, 2, 9).Central nervous system functions are dis-turbed, but the brain is not the first or-gan at risk (8). If circulatory, hepatic, andrenal dysfunction and hematologic disor-ders are prevented, brain injury can oftenbe avoided.
In summary, there may be some ben-eficial ingredients in the HUCBC prepa-ration, but it remains to be determinedwhether this must be delivered with in-tact cells. Local versus systemic deliveryis also a logistic concern. Finally, it isimportant to note that cooling and sup-port of extracerebral organs are critical inthe initial treatment of heatstroke. Al-though this study by Chen et al. is pro-vocative and stem cell therapies may havegreat promise in the rehabilitation ofcentral nervous system injury, it is un-clear whether they will ever find a placein the code cart for resuscitation.
Xianren Wu, MDPatrick M. Kochanek, MD, FCCM
Departments of Critical CareMedicine and Anesthesiology
2. Heled Y, Rav-Acha M, Shani Y, et al: The“golden hour” for heatstroke treatment. MilMed 2004; 169:184–186
3. Chen S, Chang F, Tsai Y, et al: Resuscitationfrom experimental heatstroke by transplanta-tion of human umbilical cord blood cells. CritCare Med 2005; 33:1377–1383
4. Liu CC, Chien CH, Lin MT: Glucocorticoidsreduce interleukin-1 concentration and resultin neuroprotective effects in rat heatstroke.J Physiol 2000; 527 Pt 2:333–343
5. Wang NL, Liou YL, Lin MT, et al: Chineseherbal medicine, shengmai san, is effective forimproving circulatory shock and oxidativedamage in the brain during heatstroke.J Pharmacol Sci 2005; 97:253–265
6. Yang CY, Lin MT: Oxidative stress in rats withheatstroke-induced cerebral ischemia. Stroke2002; 33:790–794
7. Oglesbee MJ, Alldinger S, Vasconcelos D, et al:Intrinsic thermal resistance of the caninebrain. Neuroscience 1905; 113:55–64
Lung injury and renal failure: From protective ventilation to renalprotection*
Lung dysfunction is a commonproblem in intensive care set-tings. Since there are currentlyno specific measures to correct
either the abnormality in permeability orinjurious inflammatory reaction in pa-tients with acute respiratory distress syn-drome (ARDS), the overall goal of me-chanical ventilation is to maintainacceptable gas exchange with minimalcomplications, while the acute lung in-jury resolves. Despite advances in venti-lation strategies based on recent trials,ARDS remains associated with mortalityrates ranging from 40% to 70% (1). Out-come depends not only on factors presentwhen initiating mechanical ventilationbut mainly on the development of com-plications, changes in monitored vari-ables, and patient management duringthe subsequent course (2). In particular,a negative effect of mechanical ventila-tion on the kidney is speculated. Thequestion is relevant since the incidence ofacute renal failure (ARF) remains high(3–25%) in patients admitted to intensivecare unit. The mortality rate of ARF, evena modest degree not resulting in dialysistreatment (3), varies from 20% to 50%,despite advances in renal replacementtherapy (4, 5). It is now well establishedthat patients die of, and not just with,ARF (6). Thus, improvements in outcomein adult patients receiving mechanicalventilation might be achieved by betterunderstanding the involved disturbancesto limit the risk of renal impairment.
In this issue of Critical Care Medicine,Dr. Kuiper and colleagues (7) summarizethe pathophysiology of mechanical venti-lation-induced acute renal failure. Threedifferent mechanisms that may impair re-nal function are developed: first, strate-
gies of acute lung injury or ARDS venti-lation; second, a change of cardiac outputthat may affect systemic and renal hemo-dynamics; and third, mechanical ventila-tion-induced biotrauma, defined as a pul-monary inflammatory reaction that maygenerate systemic release of inflamma-tory mediators. The authors concludethat the development of ARF during me-chanical ventilation likely represents amultifactorial process that may becomemore important in the presence of co-morbidities, as shown in Figure 1 in theirarticle. Despite difficulties in distinguish-ing the effects of mechanical ventilationfrom those of the underlying disorder,Dr. Kuiper and colleagues provide impor-tant information to minimize renal in-jury during mechanical ventilation in pa-tients with ARDS.
Regarding ventilation strategies, it isunclear whether the ventilatory modemay influence outcome in patients withARDS. In a randomized trial comparingvolume-controlled ventilation with pres-sure-controlled ventilation in patientswith ARDS, factors independently associ-ated with an increased risk of death werethe presence of two or more extrapulmo-nary organ failures and acute renal fail-ure, but not the ventilatory mode used(8). However, a volume-cycled mechani-cal ventilator in the assist-control modeis usually recommended to avoid expos-ing the lung to overdistension and thento ventilator-induced lung injury. Recentstudies have contributed to improveARDS management. On one hand, theconcept of protective ventilation was de-veloped during the past decade with adramatic decrease in tidal volumes from12 to 6 mL/kg. The negative impact ofmoderately high tidal volume on out-come and organ function was clearlypointed out by the results of the multiple-center trial of the ARDS network (9). Onthe other hand, the optimal level of pos-itive end-expiratory pressure (PEEP) isnot clearly determined. In a randomizedcontrolled trial also initiated by the ARDSnetwork, the use of higher PEEP added to
a strategy of low tidal volume, in an at-tempt to prevent derecruitment at end-expiration, did not result in a statisticallysignificant survival benefit (10). In thislatter study, the number of days withoutorgan failures, including renal failure,was not influenced by the PEEP regimen.Finally, a recent meta-analysis based onfive trials with a total of 1,202 patientsfavored protective ventilation on 28-dayoutcome, and the treatment effect de-pended on threshold levels of tidal vol-ume �7.7 mL/kg, plateau pressure �30cm H2O, and plateau pressure difference�5–7 cm H2O between protective andstandard ventilation (11).
As extensively examined in animalmodels and summarized by Dr. Kuiperand colleagues, mechanical ventilationand PEEP induce hemodynamic effects,such as alteration of venous return, car-diac preload, pulmonary vascular resis-tance, and cardiac afterload. PEEP in-duces a decrease in glomerular filtrationrate, renal blood flow, and free waterclearance, and the effect may be wors-ened by concurrent volume depletion. Adecrease in renal dopamine productionand an increase in antidiuretic hormoneand aldosterone levels are involved in re-nal function impairment, as well as achange in the sympathetic tone mediatedby an increase in the release of cat-echolamines or vasoactive peptides. Theadequate strategy of ventilation in acutelung injury or ARDS is still controversial,since ventilation strategies that limit air-way pressure and volume often result inhypercapnia and respiratory acidosis,which can be deleterious to renal func-tion by direct and indirect hemodynamiceffects (12). Thus, the relevant issue maybe to define the best strategy to limithemodynamic effects of mechanical ven-tilation. A recent retrospective studycomparing two ventilation strategies(ventilation with 12 mL/kg predictedbody weight vs. the lung-protective 6mL/kg predicted body weight tidal vol-ume protocol, with the same level ofPEEP used for both strategies) failed to
*See also p. 1408.Key Words: acute respiratory distress syndrome;
acute renal failure; mechanical ventilation; nephropro-tection; intensive care unit
find a difference in body weight, urineoutput, and fluid balance or in patientsupportive care requirements, includingvasopressors, intravenous fluids, or di-uretics (13). These data fill a gap in theARDS network trials that did not examinein detail the direct effects of low tidalvolume ventilation strategy on hemody-namics or urine output.
Mechanical ventilation can increasealveolar capillary permeability and aug-ment the pulmonary inflammatory re-sponse, leading to overproduction of cy-tokine-mediated inflammation. Then arelease of these mediators into the sys-temic circulation induces multiple organdysfunction syndrome. This mechanismmay be involved in the ARDS-inducedrisk of death. Ischemia remains the majorcause of ARF in the intensive care unit.Animal studies have reported an associa-tion between mechanical ventilation; cellapoptosis in the kidney; changes in in-flammatory molecules in kidney, such astumor necrosis factor-, interleukin-6, orvascular endothelial growth factor; andorgan dysfunction (14, 15); whereas ex-perimental models have shown that renalinjury is related to increase in circulatingcytokines, such as tumor necrosis fac-tor- and growth factors. In an effort toclarify the message, Table 1 in the articlesummarizes the potential effects on ARFof a mechanical ventilation-induced in-crease in inflammatory mediators. An im-portant chapter in the field was the studyof Ranieri and colleagues (16), whichdemonstrated that cytokine response(e.g., interleukin-6, soluble tumor necro-sis factor- receptor 75, and interleu-kin-1 receptor antagonist) to mechanicalventilation may be attenuated by a strat-egy to minimize overdistension and re-cruitment/derecruitment of the lung.
In conclusion, this remarkable reviewon interactions between the lung and kid-ney provides new insight into the delete-rious effects of mechanical ventilation onrenal function. Mechanical ventilation isessential for patients with ARDS. How-ever, it can worsen preexisting lung in-jury and produce ventilator-induced lung
injury and then multiple organ dysfunc-tion syndrome by an increase in systemicinflammatory mediator release. The im-pact of protective ventilation (low tidalvolume and elevated level of PEEP) mustnot be limited to the lung but has to takeinto account nephroprotection. As statedby Dr. Kuiper and colleagues, the devel-opment of optimal intervention strategiesrequires scientific advances in immunol-ogy, in particular the precise molecularand cellular mechanisms that may play arole in renal function impairment. Forthe purpose of intervening therapeuti-cally in ventilator-induced lung injuryand multiple organ dysfunction syn-drome and modulating the entire cyto-kine network, nuclear factor-�B, which isrequired for maximal transcription ofmany cytokines and growth factors, maybe the right target in the future. Morespecific inhibitors than corticosteroids orantioxidants could be clinically useful intreating acute lung injury/ARDS, in addi-tion to providing protective ventilation.
D. du Cheyron, MDDepartment of Medical Intensive
CareCaen University HospitalCaen, France
REFERENCES
1. Krafft P, Fridrich P, Pernerstorfer T, et al:The acute respiratory distress syndrome:Definitions, severity and clinical outcome.An analysis of 101 clinical investigations. In-tensive Care Med 1996; 22:519–529
2. Esteban A, Anzueto A, Frutos F, et al: Char-acteristics and outcomes in adult patientsreceiving mechanical ventilation: A 28-dayinternational study. JAMA 2002; 287:345–355
3. Martin C, Viviand X, Leone M, et al: Effect ofnorepinephrine on the outcome of septicshock. Crit Care Med 2000; 28:2758–2765
4. Ronco C, Bellomo R, Homel P, et al: Effectsof different doses in continuous veno-venoushaemofiltration on outcomes of acute renalfailure: A prospective randomised trial. Lan-cet 2000; 356:26–30
5. Schiffl H, Lang SM, Fischer R: Daily hemo-dialysis and the outcome of acute renal fail-ure. N Engl J Med 2002; 346:305–310
6. Metnitz PG, Krenn CG, Steltzer H, et al:
Effect of acute renal failure requiring renalreplacement therapy on outcome in criticallyill patients. Crit Care Med 2002; 30:2051–2058
7. Kuiper JW, Groeneveld ABJ, Slutsky AS, et al:Mechanical ventilation and acute renal fail-ure. Crit Care Med 2005; 33:1408–1415
8. Esteban A, Alia I, Gordo F, et al: Prospectiverandomized trial comparing pressure-con-trolled ventilation and volume-controlledventilation in ARDS. For the Spanish LungFailure Collaborative Group. Chest 2000;117:1690–1696
9. Ventilation with lower tidal volumes as com-pared with traditional tidal volumes for acutelung injury and the acute respiratory distresssyndrome. The Acute Respiratory DistressSyndrome Network. N Engl J Med 2000; 342:1301–1308
10. Brower RG, Lanken PN, MacIntyre N, et al:Higher versus lower positive end-expiratorypressures in patients with the acute respira-tory distress syndrome. N Engl J Med 2004;351:327–336
11. Moran JL, Bersten AD, Solomon PJ: Meta-analysis of controlled trials of ventilator ther-apy in acute lung injury and acute respira-tory distress syndrome: An alternativeperspective. Intensive Care Med 2005; 31:227–235
12. Anand IS, Chandrashekhar Y, Ferrari R, et al:Pathogenesis of congestive state in chronicobstructive pulmonary disease. Studies ofbody water and sodium, renal function, he-modynamics, and plasma hormones duringedema and after recovery. Circulation 1992;86:12–21
13. Cheng IW, Eisner MD, Thompson BT, et al:Acute effects of tidal volume strategy on he-modynamics, fluid balance, and sedation inacute lung injury. Crit Care Med 2005; 33:63–70
14. Gurkan OU, O’Donnell C, Brower R, et al:Differential effects of mechanical ventilatorystrategy on lung injury and systemic organinflammation in mice. Am J Physiol LungCell Mol Physiol 2003; 285:L710–L718
15. Imai Y, Parodo J, Kajikawa O, et al: Injuriousmechanical ventilation and end-organ epi-thelial cell apoptosis and organ dysfunctionin an experimental model of acute respira-tory distress syndrome. JAMA 2003; 289:2104–2112
16. Ranieri VM, Suter PM, Tortorella C, et al:Effect of mechanical ventilation on inflam-matory mediators in patients with acute re-spiratory distress syndrome: A randomizedcontrolled trial. JAMA 1999; 282:54–61
1461Crit Care Med 2005 Vol. 33, No. 6
Plasma platelet-activating factor acetylhydrolase is a dynamicvariable in critical illness: In the end, is change good for you?*
I n this issue of Critical CareMedicine, Dr. Claus and col-leagues (1) report retrospectivemeasurements of activity of an en-
zyme, platelet-activating factor acetylhy-drolase (PAF AH), in serial plasma sam-ples from consecutive patientshospitalized in a surgical intensive careunit, most of whom developed consensuscriteria for a septic syndrome during ad-mission. What insights does the reportprovide regarding the biology of criticalillness and its therapeutic manipulation?
The extracellular or plasma form ofPAF AH is an endogenous blood lipasethat has been called a “signal terminator”because it hydrolyzes PAF and certainstructurally related PAF-like lipids gener-ated by oxidant attack on membranephospholipid precursors (2–4). PAF andPAF-like lipids bind to a receptor onplatelets, myeloid leukocytes, and someother cells, leading to multiple functionaland phenotypic responses (4); PAF AHprevents these responses by convertingthe phospholipid ligands to products thatare no longer recognized by the PAF re-ceptor (2, 3). Thus PAF and PAF-like lip-ids, the PAF receptor, and PAF AH con-stitute a cell signaling system with bothactivating and terminating limbs (4).That PAF AH evolved as a constituent ofthe blood of normal humans stronglysuggests that the PAF signaling systemhas physiologic roles. There is, however,also substantial preclinical and clinicalevidence that signaling through the PAFreceptor mediates injurious inflamma-tory and prothrombotic responses in sep-tic syndromes, acute lung injury, andother critical illnesses (4). A multiple-
center phase IIb trial of recombinantplasma PAF AH (rPAF AH) yielded pro-vocative evidence that it can improvemortality rates in severe sepsis (5). Sub-sequently, however, a larger phase IIItrial was stopped because of lack of effi-cacy (6), raising the possibility that stud-ies of PAF AH in critical illness were at anend (7). Nevertheless, an analysis of thephase III study concluded that additionaltrials are warranted based on variables inthe patient population compared withthose in the phase IIb study and in thecontext of other evaluations of therapeu-tic modulators of inflammation in sepsis(8). One critical variable appears to bedifferences in the risk of mortality, whichinfluence the efficacy of anti-inflamma-tory and antithrombotic interventions(8). Dr. Claus and colleagues now con-clude that another variable may be thelevel of endogenous PAF-AH activity (1),which was not reported in the earlierclinical trials (5, 6). In the simplest anal-ysis, administration of rPAF AH might beexpected to be more useful in patientswith low activity, rather than those inwhich it is normal or high. The measure-ments reported by Dr. Claus and col-leagues suggest that this may be a mov-ing target, however, because plasma PAFAH activity is a dynamic variable in crit-ically ill patients.
Endogenous plasma PAF AH activitywas depressed in most patients at thetime of intensive care unit admission (1).This is not a new finding: Previous re-ports in small groups of European andAustralian subjects indicate that PAF AHactivity is variably and, in some patients,dramatically reduced in sepsis, poten-tially establishing an imbalance betweenthe proinflammatory PAF and PAF-likelipids and the signal-terminating en-zyme. This was a rationale for the phaseIIb study (5). The new data solidify thisobservation in European subjects (1). Thefactors that depress endogenous PAF AHactivity are not yet clear. Inhibited syn-thesis and oxidative inactivation of PAFAH are leading possibilities (2–4). Be-
cause of the issue of inactivation, mea-surement of activity patterned on a stan-dard assay in the field (9) rather thanmeasurement of the PAF AH protein con-centration by enzyme-linked immu-nosorbent assay or some other methodwas a reasonable choice in the currentstudy (1), although assays of both to de-termine changes in specific activity willbe valuable in the future.
A second key finding in the currentstudy is that endogenous plasma PAF AHactivity increases over time in critically illpatients in general and patients with sep-tic syndromes in particular. This has notbeen previously documented, althoughan earlier study demonstrated dynamicchanges in the alveolar fluid of patientswith acute lung injury (10). In addition,measurements of plasma PAF AH activityin murine models of sepsis demonstratethat it is acutely depressed and then vari-ably rebounds (Gomes RN, et al., unpub-lished data). An increase in extracellularPAF AH activity over time suggests thatthis is a response to injury or inflamma-tory insults and is consistent with theidea that PAF AH is a regulated compo-nent of the PAF signaling system (4).Macrophages are a critical source ofplasma PAF AH, and macrophage differ-entiation and stimulation by agoniststhat include PAF itself drive its synthesisand secretion in vitro (2–4). In the cur-rent study, endogenous PAF AH activitycorrelated with some, but not all, indexesof systemic inflammation and with neop-terin, a macrophage marker (1)—consis-tent with the possibility that macrophageactivation and/or expansion contributedto dynamic alterations. The authors notethat there was considerable variation inserial activity measurements in individ-ual patients and that the activities on thefirst and last intensive care unit days werenot always the lowest and highest values(1), a finding not illustrated in detail butone that is consistent with our studies ofsubjects with acute lung injury (D. Staf-forini, unpublished data). The factors thatcontribute are yet to be defined and may
*See also p. 1416.Key Words: platelet-activating factor acetylhydro-
involve genetic background, hormonalstatus, low-density lipoprotein and high-density lipoprotein levels, the patient’sinflammatory state before critical illness,and, potentially, premorbid variablessuch as smoking (2, 3). Intensive careunit practices including nutritional man-agement (1), blood product replacement,glucose and insulin regimens, and ma-nipulations to prevent adrenal insuffi-ciency in critically ill patients could alsoconceivably influence endogenousplasma PAF AH levels based on what iscurrently known. These and other fea-tures contribute to subgroup heterogene-ity (11) and should be considered in thefuture.
It should come as no surprise thatendogenous plasma PAF AH activitychanges in critically ill study subjects(1)—almost nothing stays the same inthese patients. But is change good foryou? On the one hand, compensatory in-creases in PAF AH activity may be amechanism that interrupts injurious sig-nals by PAF and PAF-like lipids and ame-liorates inflammatory and thrombotic in-jury in sepsis and related syndromes (4,11). Recent experiments in which rPAFAH was examined in murine models ofsepsis (Gomes RN, et al., unpublisheddata) support this possibility as do otherobservations in the field (3, 4, 8, 11). Onthe other hand, there is also evidencethat cellular activation via the PAF recep-tor modulates inflammatory responses incomplex ways (3, 4, 12–14) and can pro-vide “off signals” under some conditions(13, 14). Therefore, timing and rates ofchange of PAF AH activity in specific ex-tracellular compartments, whether byendogenous synthesis or exogenous re-placement, may be critical variables inaddition to absolute levels. An additionalfacet of the current study also raisesquestions. Survivors without organ fail-ure had higher plasma activity than didthose who died, whereas the pattern was
reversed in patients with severe sepsisand septic shock (1). This suggests thatincreased activity may not always begood. One possibility is that synthesis andsecretion of extracellular PAF AH are amarker of inflammatory stimulation andseverity in some phases of critical illness,but it is also potentially more compli-cated than that. Intracellular isoforms ofPAF AH exist and are found in liver, kid-ney, and brain (2)—tissues involved inseptic complications and multiple organfailure. It is possible that not all of theactivity measured in the blood of patientswith severe sepsis and septic shock (1)came from the secreted, extracellularform of PAF AH—the resident enzyme ofnormal plasma—but also included intra-cellular activity that leaked from injuredor dying cells. One unavoidable conclu-sion from the current analysis is thatmuch remains unknown about this inter-esting group of enzymes in critical ill-ness. We are perhaps not at the end of thestory (7) but instead at the beginning (3,4, 8).
Guy A. Zimmerman, MDDepartment of Internal Medicine
and Program in HumanMolecular Biology andGenetics
University of UtahSalt Lake City, UT
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