Thrombolytics for occluded catheters* A for tb...Monturo CA, Dickerson RN, Mullen JL: Efﬁ-cacy of thrombolytic therapy for occlusion of long-term catheters. JPEN J Parenter En-teral

Editorials

Thrombolytics for occluded catheters*

Access to central veins is criticalin the modern era of patientcare. Approximately a quarterof central venous access de-

vices, however, become obstructed andmust be removed unless they can be re-opened (1). The obstruction can becaused by abutment of the catheter tipagainst the vein wall or by a kink in thetubing, but more than half of the time,the problem is a small blood clot (1).Although all central venous access de-vices accumulate a thin coat of fibrin,this remains clinically silent unless it ex-tends to block the catheter tip and acts asa one-way valve that permits infusion butnot withdrawal (2, 3). If a catheter is notadequately flushed, blood can diffuse intoits lumen and form an intraluminal clotthat blocks both infusion and withdrawalthrough the catheter.

In 1980, Hurtubise et al. (4) first re-ported success in remedying this problemwith instillations of thrombolytic agents.They primarily used streptokinase, butsoon urokinase became the dominantdrug for this purpose until it was tempo-rarily removed from the market in 1999(5–8). Then alteplase filled the void (8–11). In this issue of Critical Care Medi-cine, Dr. Svoboda and colleagues (12) re-port a very large, multiple-centerexperience using another thrombolyticagent, recombinant urokinase (r-uroki-nase), to treat obstructed catheters. Theirregimen proved to be very effective andsafe.

Whether r-urokinase offers any advan-tage over its predecessors in lysing cath-eter-obstructing blood clots, however, isnot clear. In the only study comparingtwo thrombolytic agents for restoringcatheter patency, alteplase proved to besuperior to urokinase (8). Although theurokinase in that trial was not recombi-nant, it is likely that r-urokinase would

have given the same result because itsmechanism of action is the same as thatof the native enzyme (13).

The study by Dr. Svoboda and col-leagues (12), however, was unusual intwo respects. First, one third of the cath-eters treated were “totally” occluded,which meant that fluid could neither bewithdrawn nor infused through them.When infusion is blocked, instilling in-traluminal drug becomes problematic. Inthe large studies establishing the efficacyof alteplase for catheter clearance, cathe-ters were excluded if infusion was diffi-cult (9–11). Simply increasing the infu-sion pressure is not the answer because ofthe risk of rupturing the catheter. How-ever, Dr. Svoboda and colleagues (12)were able to infuse enough r-urokinaseinto all but one catheter to clear theobstruction in 76% of those that weretotally obstructed, the same level of suc-cess achieved with catheters with onlywithdrawal occlusion. This was appar-ently accomplished with three-way stop-cocks by using one syringe to create neg-ative intraluminal pressure that was thenused to draw r-urokinase into the lumensfrom a second syringe.

The study by Dr. Svoboda and col-leagues (12) also measured the minimaldwell times necessary for r-urokinase toclear the catheters. In previous studies,the success of treatment was often nottested until at least 30 mins after instil-lation of the drug, although 77% of thecentral venous access devices in the re-port by Hurtubise et al. (4) reopened witha mean dwell time of only 22 mins (5,7–12). In the study by Dr. Svoboda andcolleagues (12), 79% of the treated cath-eters opened with a median dwell time of15 mins.

Although there were no restrictionson the age of the occlusions in the studyby Dr. Svoboda and colleagues (12), thereis also no information provided about thisvariable, which is relevant because asclots age they tend to become resistant tothrombolytic drugs. It seems, however,that most of the obstructions had devel-oped relatively recently. Fifty-six percentof the central venous access devices are

described as nontunneled percutaneoustypes (Table 3), which suggests that theywere intended for relatively short-termuse and therefore that their obstructionshad likely been present for only a fewdays.

Because r-urokinase is currently notmarketed, it is not an option for clini-cians faced with treating occluded centralvenous access devices. However, there isevery reason to believe that alteplase,which is currently formulated for thisindication, could achieve the same suc-cess rates, particularly if it were appliedto totally obstructed catheters with thetechnique used by Dr. Svoboda and col-leagues (12). The study by Dr. Svobodaand colleagues (12) also suggests thatroutinely leaving alteplase to dwell in acatheter for 30–60 mins before testingfor patency is probably much longer thannecessary in many cases.

McDonald K. Horne IIIHematology ServiceDepartment of Laboratory

MedicineW. G. Magnuson Clinical CenterNational Institutes of HealthBethesda, MD

REFERENCES

1. Stephens LC, Haire WD, Kotulak GD: Areclinical signs accurate indicators of thecause of central venous catheter occlusion?JPEN J Parenter Enteral Nutr 1995; 19:75–79

2. Raad II, Luna M, Khalil SAM, et al: Therelationship between the thrombotic and in-fectious complications of central venouscatheters. JAMA 1994; 271:1014–1016

3. Tschirhart JM, Rao MK: Mechanism andmanagement of persistent withdrawal occlu-sion. Am Surg 1988; 54:326–328

4. Hurtubise MR, Bottino JC, Lawson M, et al:Restoring patency of occluded central venouscatheters. Arch Surg 1980; 115:212–213

5. Glynn MFX, Langer B, Jeejeebhoy KN: Ther-apy for thrombotic occlusion of long-termintravenous alimentation catheters. JPEN JParenter Enteral Nutr 1980; 4:387–390

6. Monturo CA, Dickerson RN, Mullen JL: Effi-cacy of thrombolytic therapy for occlusion oflong-term catheters. JPEN J Parenter En-teral Nutr 1990; 14:312–314

7. Wachs T: Urokinase administration in pedi-

*See also p. 1990.Key Words: recombinant urokinase; catheters; al-

teplase; venous accessCopyright © 2004 by the Society of Critical Care

Medicine and Lippincott Williams & Wilkins

DOI: 10.1097/01.CCM.0000142905.76171.B6

2146 Crit Care Med 2004 Vol. 32, No. 10

atric patients with occluded central venouscatheters. J Intraven Nurs 1990; 13:100–102

8. Haire WD, Atkinson JB, Stephens LC, et al:Urokinase versus recombinant tissue plasmin-ogen activator in thrombosed central venouscatheters: A double-blinded, randomized trial.Thromb Haemost 1994; 72:543–547

9. Ponec D, Irwin D, Haire WD, et al: Recom-binant tissue plasminogen activator (alte-plase) for restoration of flow in occludedcentral venous access devices: A double-blindplacebo-controlled trial. The CardiovascularThrombolytic to Open Occluded Lines

(COOL) efficacy trial. J Vasc Interv Radiol2001; 12:951–955

10. Deitcher SR, Fesen MR, Kiproff PM, et al:Safety and efficacy of alteplase for restoringfunction in occluded central venous cathe-ters: Results of the cardiovascular thrombo-lytic to open occluded lines trial. J Clin On-col 2001; 20:317–324

11. Shen V, Li X, Murdock M, et al: Recombinanttissue plasminogen activator (alteplase) forrestoration of function to occluded venouscatheters in pediatric patients. J Pediatr He-matol Oncol 2003; 25:38–45

12. Svoboda P, Barton RP, Barbarash OL, et al:Recombinant urokinase is safe and effec-tive in restoring patency to occluded cen-tral venous access devices: A multiple-center, international trial. Crit Care Med2004; 32:1990 –1996

13. Credo RB, Burke SE, Barker WM, et al:Recombinant urokinase (r-UK): Biochem-istry, pharmacology, and clinical experi-ence. In: New Therapeutic Agents inThrombosis and Thrombolysis. SasaharaAA, Loscalzo J (Eds). New York, MarcelDekker, 1997, pp 513–537

Do not get sick when you are sick: The impact of comorbidconditions*

All clinicians are aware that thepresence of one disease may af-fect the natural history of an-other disease. Immunocom-

promised patients are at increased riskfor infectious complications, and patientswith peripheral vascular occlusive diseaseare at increased risk for wound infec-tions, to name just two clear examples.The hepatorenal syndrome is anotherwell-described clinical entity where un-derlying hepatic disease predisposes tothe development of renal disorders. Thereis less awareness of how a critical illnessmay blunt the host response to an infec-tious challenge. The article by Dr. Vander Poll (1) in this issue of Critical CareMedicine provides some important in-sights into these processes. In this article,the authors demonstrate that acute pan-creatitis reduces the response to acutepneumonia such that the pneumonia isworse, and the pneumonia also makes thepancreatitis more severe. How does thisinteraction take place?

Local complications are relatively easyto understand. A patient with poor limbperfusion who develops an infection can-not deliver sufficient oxygen, nutrients,and inflammatory cells to adequately stopthe initial focus on infection. From astrictly mechanistic point of view, this isnot a challenge to appreciate. Addition-

ally, patients with acute pancreatitis of-ten develop an infection of the necroticparenchyma (2). The mechanisms hereare more complicated and not fully de-fined. In the area of inflammation, thereshould be numerous inflammatory cellsprimed and willing to ingest and kill anyinvading pathogens. However, it has beendocumented that neutrophils at sites ofinflammation are not as effective in clear-ing pathogens as those in the systemiccirculation (3, 4). Additionally, the sys-temic neutrophils fail to chemotax effi-ciently, although this defect occurs later(5). These animal studies have been ver-ified in patients with abdominal abscesses(6). Although there may be a large num-ber of acute inflammatory cells present,they probably do not have the full anti-microbial capacity of their circulatingcounterparts. Additionally, the necroticparenchyma provides a protein-rich envi-ronment for the growth and proliferationof bacteria. Thus, logical explanations ex-ist for the development of local infectiouscomplications.

What about the development of an in-fection distant from the site of the initialtissue injury? What hypothesis may begenerated to explain how a local diseaseprocess sets the stage for subsequent sec-ondary disease? These questions are im-portant clinically, and answers are begin-ning to emerge.

The current communication clearlydocuments that the presence of acutepancreatitis markedly increases the se-verity of the pneumonia. This was dem-onstrated by the increase in the numberof bacteria recovered from the lung, as

well as increased histology scores, lungweights, and neutrophilic infiltration.The mechanisms of how this occurs maybe found in the evidence of increasedinflammation in the pancreatitis/pneu-monia group relative to pancreatitisgroup, or the pneumonia group. In otherwords, the existence of local, comorbidconditions such as pancreatitis increasedinflammation and decreased the ability torespond to infectious challenge. This is avery good beginning to understandingthe interactions of the immune system,the inflammatory response, and con-trolled infections.

In the past, investigators have docu-mented that peripheral blood cells ob-tained from critically ill patients (thosewith severe sepsis) do not respond as wellas those from normal individuals interms of the ability to generate a cytokineresponse to an appropriate stimulus (7,8). Thus, a possible explanation for thepresent observations is that the circulat-ing cells fail to respond to the pulmonaryinfection. This may occur through che-mokine receptor desensitization. Withdesensitization, prior exposure to thechemokines impairs the neutrophil’sability to respond to a second exposure ofthe chemokine (9). This explanation isunlikely for the present observationssince, in the pancreatitis-only group, cir-culating levels of chemokines were notelevated. Additionally, global immuno-suppression is not an adequate explana-tion since the pancreatitis/pneumoniagroup had the strongest inflammatory re-sponse. Although these data are good be-ginning, unanswered questions remain.

*See also p. 1997.Key Words: immunocompromise; infectious com-

plications; acute pancreatitis; acute pneumoniaCopyright © 2004 by the Society of Critical Care


DOI: 10.1097/01.CCM.0000142943.99322.BE

2147Crit Care Med 2004 Vol. 32, No. 10

Another interesting aspect of thepresent investigations is the lack of local-ization of the inflammatory response. Pre-vious publications have documented thatpulmonary exposure to an infectious chal-lenge that results in pneumonia produceslocal levels, but not systemic levels, of in-flammatory mediators (10). It was pre-sumed that there would only be evidence ofsystemic inflammation when there was sig-nificant damage to the lung to allow escapeof the inflammatory mediators through theinjured endothelial cell tight junctions intothe circulation. However, the present arti-cle shows that, in the pneumonia-onlygroup, there was still significant systemicinflammation as demonstrated by the ele-vated levels of interleukin-6 and the che-mokines. The discrepancy between thesetwo publications might lie in the differencebetween the “two-hit” model in the presentarticle and the single-hit model in the pre-vious report.

Thus, the data are clear: Getting sickwhen you are already sick is not good. Thisis an area where animal models are under-developed. These models have been de-scribed as “two-hit” or “two-event” models(11). In the past, mouse models of infec-tious disease have only been evaluated inhealthy, normal, young animals. This failsto recognize the clinical scenario in whichinfectious complications frequently devel-oped in patients who were neither previ-ously healthy nor particularly young. This

is an emerging area of research where eval-uation of the inflammatory response to in-fection is conducted in an animal that has acomorbid or preexisting condition. As thisarticle clearly shows, the inflammatory re-sponse is very different when there is acomorbid condition. This will be an excit-ing area to watch, and the research com-munity should look forward to the results.In the meantime, try to stay healthy beforeyou get sick.

Daniel G. Remick, MDDepartment of PathologyUniversity of Michigan Medical

SchoolAnn Arbor, MI

REFERENCES

1. van Westerloo DJ, Schultz MJ, Bruno MJ, etal: Acute pancreatitis in mice impairs bacte-rial clearance from the lungs, whereas con-current pneumonia prolongs the course ofpancreatitis. Crit Care Med 2004; 32:1997–2001

2. Rau B, Baumgart K, Paszkowski AS, et al:Clinical relevance of caspase-1 activatedcytokines in acute pancreatitis: High cor-relation of serum interleukin-18 with pan-creatic necrosis and systemic complica-tions. Crit Care Med 2001; 29:1556 –1562

3. Kenny PA, Spencer LK, McDonald PJ, et al:Functional activity of individual abscessneutrophils from mice. Bactericidal capac-ity of neutrophils in rabbits with experi-

mental acute and chronic abscesses. InfectImmun 1990; 58:4004 – 4010

4. Bamberger DM, Herndon BL: Bactericidalcapacity of neutrophils in rabbits with exper-imental acute and chronic abscesses. J InfectDis 1990; 162:186–192

5. Lineaweaver W, Soucy D, Howard R: Murineneutrophil migration during the course of anintra- abdominal abscess. Arch Surg 1986;121:797–799

6. Solomkin JS, Bauman MP, Nelson RD, et al:Neutrophils dysfunction during the course ofintra-abdominal infection. Ann Surg 1981;194:9–17

7. Flach R, Majetschak M, Heukamp T, et al:Relation of ex vivo stimulated blood cytokinesynthesis to post-traumatic sepsis. Cytokine1999; 11:173–178

8. Ertel W, Kremer JP, Kenney J, et al: Down-regulation of proinflammatory cytokine re-lease in whole blood from septic patients.Blood 1995; 85:1341–1347

9. Wiekowski MT, Chen SC, Zalamea P, et al:Disruption of neutrophil migration in a con-ditional transgenic model: Evidence forCXCR2 desensitization in vivo. J Immunol2001; 167:7102–7110

10. Nelson S, Bagby GJ, Bainton BG, et al: Com-partmentalization of intraalveolar and sys-temic lipopolysaccharide-induced tumor ne-crosis factor and the pulmonaryinflammatory response. J Infect Dis 1989;159:189–194

11. Nemzek JA, Call DR, Ebong SJ, et al: Im-munopathology of a two-hit murine modelof acid aspiration lung injury. Am J PhysiolLung Cell Mol Physiol 2000; 278:L512–L520

Which patient with a do-not-intubate order is a candidate fornoninvasive ventilation?*

Noninvasive positive-pressureventilation (NPPV), first de-veloped as a way to defer en-dotracheal intubation, has

established its role as the primary ap-proach for ventilatory support in manyclinical settings. For example, in acuteexacerbation of chronic obstructive pul-

monary disease, NPPV, in adjunct withmedical care before severe acidosis oc-curs, will reduce endotracheal intuba-tion, treatment failure, and mortality (1).In acute cardiogenic pulmonary edema,asthma, and acute hypoxemic respiratoryfailure, first-line NPPV also shows prom-ising results (2–4). To avoid complicationand discomfort from endotracheal in-tubation, the use of NPPV has furtherexpanded into more controversial situ-ations, including peri-extubation respi-ratory failure and do-not-intubate(DNI) orders.

Preliminary studies of NPPV in peri-extubation respiratory failure are encour-aging; however, a recent large random-

ized controlled study demonstrated thatNPPV does not reduce reintubation andmay increase mortality (5). In this issueof Critical Care Medicine, Dr. Levy andcolleagues (6) report on a study usingNPPV for patients with DNI orders, someof whom had a do-not-resuscitate (DNR)order. The largest of its kind, this study isthe first to provide predictors of hospitalsurvival, using simple bedside character-istics in DNI patients. Nonetheless as anonrandomized study, it does not testwhether NPPV will compare favorablywith medical treatment or continuouspositive airway pressure. The lack oflong-term outcomes (previously reportedas poor (7)) and data on comfort, quality

*See also p. 2002.Key Words: noninvasive ventilation; complication; end-

of-life; resuscitation; do-not-intubate; do-not-resuscitateThe authors have nothing to disclose.Copyright © 2004 by the Society of Critical Care


DOI: 10.1097/01.CCM.0000142903.66336.E6


of life, or patient satisfaction further castsdoubt on the merit of this therapy.

Dr. Levy and colleagues found that theoverall survival is 43% from their experi-enced centers, although better resultsmay be expected among patients withcongestive heart failure and chronic ob-structive pulmonary disease who have astrong cough or are awake. However, forwhom are these predictors useful?Should any patient with DNI receiveNPPV if favorable predictors are present?In my view, first, it is the patients’ treat-ment goals—not their prognoses, nottheir diagnoses, not their characteris-tics—that should govern the use of non-invasive ventilation.

If the goal is to maximize the chanceof survival, we must provide the care thatserves this goal best: full resuscitation.Partial resuscitation with NPPV—with-out proceeding to endotracheal intuba-tion when it fails—should be discour-aged; this is suboptimal, also violatingour ethical obligation of nonmaleficence(8). At best, NPPV alone will give a resus-citative efficacy equal to initial trachealintubation. For this goal, in fact, a DNIorder should be discontinued. Then,NPPV may be used to avoid tracheal in-tubation and the predictors identified byDr. Levy and colleagues provided to aiddecision. We must know, however, thatNPPV is not for the patients with hemo-dynamic instabilities, inability to protectairway, or lack of co-operation. Lack ofexperienced staffs is also a relative con-traindication. The patients should be in-formed that most patients with DNI or-ders who survive one episode ofrespiratory failure will face another orother life-threatening event soon. Muchtime could be spent in the hospital—as aso-called revolving-door patient—if thepatient survives (7).

On the other hand, if the goal is toavoid discomfort, to survive without try-ing to maximize the chance of surviving,NPPV should not be offered. In these pa-tients, a DNR order, if not alreadypresent, should be recommended becauseit serves the goal best. For those whobelieve that NPPV will provide comfort,they should be told that “noninvasive”ventilation is not noninvasive. In fact, itmay cause great suffering.

Problems often arise from the positivepressure and its delivering devices, press-ing on the face, causing redness, pain,and irritation. Aided by analgesic and se-dation, the instrument may continue topress until skin necrosis develops over

the nose or mouth (9). The blowing aircauses dryness in the nose and throat,and the patients often feel pain in theirear or sinus because of the air pressure.In fact, rupturing of bilateral tympanicmembranes can happen (10). The pres-sure often distends the esophagus andstomach. Esophageal rupture has beenreported (11). Gastric distention causingileus and pain occurs in up to 50% ofpatients. Unfortunate patients may de-velop a ballooning of the stomach (Fig. 1)(12). This misery, treated inappropriately,can progress to an abdominal compart-ment syndrome with cardiovascular col-lapse (13).

In addition to the direct insults fromthe machine, collateral damages are sub-stantial. The patient needs close monitor-ing and frequent arterial blood gas, mea-sured either from an arterial line or byfrequent painful punctures. Besides,alarms from devices in the unit, in uni-son with the ones from his or her ma-chine, plus the noises from certain NPPVinstruments can reach 100 decibels, in-terfering with sleep or rest (14). Air leaksaround the mask often blow into the pa-tients’ eyes; irritation and tearing arecommon, and only more air will flowinside to maintain the pressure when itleaks, perpetuating the ordeal. The dis-

tress extends to family members, seeingtheir loved one struggling while fullyawake. In addition, how we fix these prob-lems can be troublesome, often making ithard to eat or talk—or finalize affairs.Inadequate cooperation will lead to seda-tion; gastric distention will result in na-sogastric tube placement. In fact, if airleak results from the patient gasping forair during nasal application, we may tellthe patient to keep his or her mouth shut(15).

What about those who still prefer todo things in moderation, those who arewilling to bear with the NPPV (but notendotracheal intubation) and get achance of brief survival to finalize affairs?Disappointingly, in the fight for life, thereis no benign middle ground. In my opin-ion, this strategy is not a moderatechoice, but a mediocre choice: not pro-ducing maximal benefit yet associatedwith great risk.

Perhaps, patients who wish to finalizetheir affairs should be advised that at thistime in their lives, there are no moreburdens to bear, no more affairs to final-ize, no more fights to pursue. Let themknow that the most important thing is tobe at peace with themselves. Also, themyth about morphine should be dis-pelled: low-dose morphine to relieve

Figure 1. Ballooning of the stomach. Reproduced with permission (12).


breathlessness will not cause excessivedrowsiness—it will allow interaction withfamily members. Oxygen will further re-lieve the sensation by its direct stimula-tion of the trigeminal nerve. A privateroom with loved ones at the bedside willenhance a sense of control—a dignity.With the patients’ unswerving goals andwith our therapy tailored toward theirgoals, we can effectively serve these se-riously ill patients. When chancescome, we may have the privilege of as-sisting them through the valley ofdeath, making it a heartwarming, a sat-isfying experience.

Tawee Tanvetyanon, MDDivision of Hematology/OncologyLoyola University Chicago Stritch

School of MedicineMaywood, IL

REFERENCES

1. Plant PK, Owen JL, Elliott MW: Early use ofnon-invasive ventilation for acute exacerba-tions of chronic obstructive pulmonary dis-ease on general respiratory wards: A multi-centre randomised controlled trial. Lancet2000; 355:1931–1935

2. Masip J, Betbese AJ, Paez J, et al: Non-invasive pressure support ventilation versusconventional oxygen therapy in acute cardio-genic pulmonary oedema: A randomisedtrial. Lancet 2000; 356:2126–2132

3. Soroksky A, Stav D, Shpirer I: A pilot pro-spective, randomized, placebo-controlledtrial of bilevel positive airway pressure inacute asthmatic attack. Chest 2003; 123:1018–1025

4. Antonelli M, Conti G, Rocco M, et al: A com-parison of noninvasive positive-pressure ven-tilation and conventional mechanical venti-lation in patients with acute respiratoryfailure. N Engl J Med 1998; 339:429–435

5. Esteban A, Frutos-Vivar F, Ferguson ND, etal: Noninvasive positive-pressure ventilationfor respiratory failure after extubation.N Engl J Med 2004; 350:2452–2460

6. Levy M, Tanios MA, Nelson D, et al: Out-comes of patients with do-not-intubate or-ders treated with noninvasive ventilation. CriCare Med 2004; 32:2002–2007

7. Chu CM, Chan VL, Wong IW, et al: Noninva-sive ventilation in patients with acute hyper-capnic exacerbation of chronic obstructivepulmonary disease who refused endotrachealintubation. Crit Care Med 2004; 32:372–377

8. Berger JT: Ethical challenges of partial do-not-resuscitate (DNR) orders: Placing DNRorders in the context of a life-threatening

conditions care plan. Arch Intern Med 2003;163:2270–2275

9. Smurthwaite GJ, Ford P: Skin necrosis fol-lowing continuous positive airway pressurewith a face mask. Anaesthesia 1993; 48:147–148

10. Weaver LK, Fairfax WR, Greenway L: Bilat-eral otorrhagia associated with continuouspositive airway pressure. Chest 1988; 93:878–879

11. Van de Louw A, Brocas E, Boiteau R, et al:Esophageal perforation associated with non-invasive ventilation. Chest 2002; 122:1857–1858

12. Yamada S, Nishimiya J, Kurokawa K, et al:Bilevel nasal positive airway pressure andballooning of the stomach. Chest 2001; 119:1965–1966

13. De Keulenaer BL, De Backer A, Schepens DR,et al: Abdominal compartment syndrome re-lated to noninvasive ventilation. IntensiveCare Med 2003; 29:1177–1181; Epub 2003May 22

14. Cavaliere F, Conti G, Costa R, et al: Noiseexposure during noninvasive ventilation witha helmet, a nasal mask, and a facial mask.Intensive Care Med 2004 Jun 8 [Epub aheadof print]

15. Hill NS. Noninvasive ventilation for chronicobstructive pulmonary disease. Respir Care2004; 49:72–87

Eliminating catheter-related bloodstream infections: Fairy tale ornew reality?*

I n this issue of Critical Care Med-icine, Dr. Berenholtz and col-leagues (1) from Johns HopkinsUniversity School of Medicine de-

scribe their success using a stepwise, me-thodical, protocolized approach in de-creasing catheter-related bloodstreaminfection (CRBSI) in the surgical inten-sive care unit. Results were impressiveover the 5-yr study period, during whichCRBSI was decreased from 11.3/1000

catheter days in the first quarter to0/1000 catheter days in the 20th and lastquarter. With deserved pride and somefanfare, they footnote no additionalCRBSI for 9 months after the study wascompleted.

Think about that! Zero incidence ofCRBSI. CRBSI has been a bane of acutecare medicine for half a century. Whatmanner of pixie dust must these clini-cians be scattering upon their patients toachieve zero CRBSIs? How was this featachieved in a venerable, albeit resource-intensive and well-financed, academicmedical center? Are we not in Camelot? Isthis not a fairy tale? More about this tofollow, but first, what has been the recenthistory of the science of preventingCRBSI?

Early reports (2, 3) describing the ex-tensive use of central venous catheters(CVC) to facilitate the treatment or resus-citation of patients first surfaced afterWorld War II; but the insertion of CVC

mainly escalated in the 1960s and 1970swith the evolution of intensive care med-icine and the introduction of hyperali-mentation (4, 5). More than 5 millionCVCs are inserted in the United Stateseach year, with the incidence of infec-tious complications ranging between 5%and 26% (6). Attributable mortality fromCRBSI may be as low as 3%, but there isno disagreement as to the significance ofmorbidity, increased length of stay, andinflated cost (7). As a consequence, guide-lines for the prevention of CRBSI havebeen issued (8) and the thrust of researchin recent years has focused on strategiesthat enhance infection control methodol-ogy and practice. These measures haveincluded standardized educational effortsdirected toward CVC insertionists (9) andthe preference of chlorhexidine antisepsisas a means of reducing CRBSI by nearly50% compared with povidone-iodine(10). However, the greatest glitz has beenreserved for antimicrobially coated CVC,

*See also p. 2014.Key Words: catheter-related bloodstream infection;

protocols; continuous quality improvement; outcomes;process of care

The author has nothing to disclose.Address requests for reprints to: Stanley A. Nas-

raway, Jr, MD, FCCM, Department of Surgery, Tufts-NewEngland Medical Center, 750 Washington Street, Box4630, Boston, MA 02111. E-mail: [email protected]

Copyright © 2004 by the Society of Critical CareMedicine and Lippincott Williams & Wilkins

DOI: 10.1097/01.CCM.0000142907.52351.1E


which are effective at decreasing CRBSIand very costly (11, 12). For example,acquisition cost of a standard-issue triple-lumen catheter at Tufts-New EnglandMedical Center is $22; the cost of anantimicrobially coated triple-lumen cath-eter is approximately $75. Because theCRBSI rate in our surgical intensive careunit is just 2.6/1000 central catheterdays, which is one-half the nationalbenchmark of 5.2/1000 central catheterdays for surgical intensive care units (13),we have not been convinced of the costeffectiveness in implementing the high-technology solution of antimicrobiallycoated catheters. Interestingly, guide-lines issued by the Centers for DiseaseControl and Prevention give a lukewarmrecommendation for these catheters,which should be employed only after fail-ure of a comprehensive approach at de-creasing CRBSI (8).

The investigators from Johns Hopkinssignificantly decreased CRBSI using alow-technology, stepwise, comprehensivestrategy (1). This strategy included thefollowing: a) standardized education ofstaff; b) essential grouping of necessaryingredients for a CVC into a single loca-tion by use of a vascular line cart; c)discontinuation of no longer necessaryCVC by regularly inquiring as to the needthrough use of a daily goals sheet; d)implementing a catheter-insertionchecklist for assurance of sterile tech-nique; and e) empowering the bedsidenurse to halt the CVC procedure when asterile technique was observed to havebeen violated. This is no pixie dust. Theseclinicians used neither supernaturalmagic nor even glamorous high-technol-ogy solutions. The result achieved bythese clinicians is simply an enchantingmix of hard work, low technology, andmost especially the tenacious applicationof the protocol approach to achieve con-tinuous quality improvement. It may wellbe that the process of changing care wasas important, or even more important,than any of the actual steps used in theirmulti-faceted approach.

The early notions of quality improve-ment originated with the American in-dustrial scientists, Walter Shewart andEdward Deming, in the first half of the20th century (14). They introduced theconcept of “variation reduction.” The useof protocols in intensive care medicine,by comparison, is a belated phenomenonbut is rapidly spreading (15, 16). Success-ful examples in the intensive care arenaof an algorithmic, standardized approach

to decrease patient morbidity and mortal-ity abound and include weaning from me-chanical ventilation (17), use of intensiveinsulin for strict euglycemia (18), contin-uous sedation (19), and early resuscita-tion of patients with severe sepsis (20).

The benefits of the protocol approachare as follows.

1. The application of evidence-based“best practice”

2. The standardization of care

3. Standardized care decreases vari-ability

4. Decreased variation reduces errorand complications

5. Fewer complications lead to im-proved patient outcomes

6. Less error and better patient out-come lead to decreased costs

The gains that result come not frombest practice alone but from the con-stancy of practice that leads to a decreasein errors, improved effectiveness, and thereduction in uncontrolled variables. Theconstruction of protocols requires thatone engage intuitive metrics and expeditemission-critical convergence of the avail-able talents and resources in the ICU.

Dr. Berenholtz and colleagues take theeradication of CRBSI to near perfection,shrewdly using a combination of redun-dancies, prompts, education, assessment,and reassessment. Striving for near per-fection is also not new. Industry giants,including Motorola and General Electric,have refined advanced iterations of qual-ity improvement into the concept of SixSigma. The Six Sigma process uses dataand rigorous statistical analysis to iden-tify “defects” in a process, to reduce vari-ability, and to get as close to zero defectsas possible. Dr. Berenholtz et al. pro-claimed sustained performance improve-ments, with a CRBSI rate of just 0.54/1000 catheter line days in the ensuing 16months after the study period. There areprecious few documented examples ofnear perfect care, particularly over an ex-tended period of time, in the annals ofcritical care medicine. Their example,methods, and degree of achievement area model for all critical care clinicians.

Clinicians should be forewarned, asprolonged improvements in care aremeasured more in years than in meremonths. The protocol approach is notwithout flaws. In our own experiencewith protocols, we have observed a phe-nomenon that we call “protocol fatigue.”

Protocol fatigue develops when adher-ence to a protocol is found to dwindleover time, because of new staff, newtrainees, erosion of knowledge, and per-haps changes in a given patient popula-tion. Recognition of protocol fatigue, bestaccomplished through periodic measure-ment with a database such as ProjectImpact (21), requires protocol revisionsto incorporate new scientific advances,renewed energy, and reinvigoration to in-crease efficiencies. It would be instructiveto follow the Johns Hopkins surgical in-tensive care unit CRBSI incidence overthe next 5–10 yrs, as a measure of genu-ine protocol endurance.

The iterative, protocol approach takesenormous dedication and effort on thepart of critical care clinicians. However,in our experience, and as shown in theexample herein by the Johns Hopkins in-vestigators, sustained and meaningfulimprovements in patient care can beachieved with hard work and commit-ment.

Pixie dust is not necessary.Stanley A. Nasraway, Jr, MD, FCCM

Department of SurgeryTufts-New England Medical

CenterTufts University School of

MedicineBoston, MA

REFERENCES

1. Berenholtz SM, Pronovost PJ, Lipsett PA, etal: Eliminating catheter-related bloodstreaminfections in the intensive care unit. CritCare Med 2004; 32:2014–2020

2. Duffy BJ: Clinical use of polyethylene tubingfor intravenous therapy: Report of 72 cases.Ann Surg 1949; 130:929–936

3. Keeri-Szanto M: The subclavian vein, a con-stant intravenous injection site. Arch Surg1956; 72:179–181

4. English ICW, Frew RM, Pigott JG, et al: Per-cutaneous catheterization of the internaljugular vein. Anaesthesia 1969; 24:521–531

5. Wilmore DW, Dudrick SJ: Safe long-termvenous catheterization. Arch Surg 1969; 98:256–258

6. McGee DC, Gould MK: Preventing complica-tions of central venous catheterization.N Engl J Med 2003; 348:1123–1133

7. Mermel LA: Prevention of intravascular cath-eter-related infections. Ann Intern Med 2000;132:391–402

8. O’Grady NP, Alexander M, Dellinger EP, et al:Guidelines for the prevention of intravascu-lar catheter-related infections. MMWRRecom Rep 2002; 51(RR-10):1–29

9. Sherertz RJ, Ely EW, Westbrook DM, et al:Education of physicians-in-training can de-


crease the risk of vascular catheter infection.Ann Intern Med 2000; 132:641–648

10. Chaiyakunapruk N, Veenstra DL, Lipsky BA,et al: Ann Intern Med 2002;136:792–801

11. Wenzel RP, Edmond MB: The evolving technol-ogy of venous access. N Engl J Med 1999; 340:48–49

12. Russell LM, Weinstein RA: Antimicrobial-coatedcentral venous catheters: Icing on the cake or thestaff of life? Crit Care Med 1998; 26:195–196

13. National Nosocomial Infections Surveillance(NNIS) System Report, Data Summary from Jan-uary 1992 through June 2003, issued August2003. Am J Infect Control 2003; 31:481–498

14. Deming WE: Out of the Crisis. Cambridge,Massachusetts Institute of Technology, 1986

15. Holcomb BW, Wheeler AP, Ely EW: Newways to reduce unnecessary variation andimprove outcomes in the intensive careunit. Curr Opinion in Crit Care 2001;7:304 –311

16. Nasraway SA, Jacobi J, Murray MJ, et al:Sedation, analgesia and neuromuscularblockade of the critically ill adult: Revisedclinical practice guidelines for 2002. CritCare Med 2002; 30:117–118

17. Ely EW, Baker AM, Dunagan DP, et al: Effect onthe duration of mechanical ventilation of identi-fying patients capable of breathing spontane-ously. N Engl J Med 1996; 335:1864–1869

18. Van den Berghe G, Wouters P, Bouillon R, etal: Outcome benefit of intensive insulin ther-

apy in the critically ill: Insulin dose versusglycemic control. Crit Care Med 2003; 31:359

19. 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

20. Rivers E, Nguyen B, Havstad S, et al: Earlygoal-directed treatment of severe sepsisand septic shock. N Engl J Med 2001; 345:1368

21. Cook SF, Visscher WA, Hobbs CL, et al:Project IMPACT: Results from a pilot validitystudy of a new observational database. CritCare Med 2002; 30:2765–2770

Targeting leukocyte trafficking in the treatment of severe trauma*

I n this issue of Critical CareMedicine, Dr. Seekamp and col-leagues (1) report on an ambitiousphase II trial investigating the ef-

fect of L-selectin blockade on outcomesafter severe trauma. Targeting this adhe-sion molecule is an attractive choice, forit governs one of the earliest steps inleukocyte trafficking. Under physiologicconditions, neutrophil delivery to a site ofinflammation involves a series of leuko-cyte-endothelial interactions each medi-ated by a separate set of adhesion mole-cules. Rolling, the first step of leukocytetrafficking, is mediated by L-selectin.This molecule is constitutively expressedon the surface of most leukocytes. Roll-ing results in the activation of the leuko-cyte with up-regulation of surface inte-grins and shedding of L-selection. Thisincrease in surface integrins induces afirm stationary bond (adherence) be-tween the leukocyte and endothelial cell.The leukocyte then transmigrates intothe interstitial compartment along a che-moattractant gradient toward the site ofinjury or infection.

In states of systemic inflammationsuch as severe trauma and sepsis, thisorderly procession of leukocyte traffick-ing is often disturbed. The potent antimi-crobial armamentarium possessed by

neutrophils can be unleashed on host en-dothelium. Indeed, neutrophils have beenimplicated in the pathogenesis of micro-vascular leakage and end-organ injuryleading to multiple organ dysfunctionsyndrome. Furthermore, severe systemicinflammation interferes with effectiveleukocyte trafficking (2, 3), potentially in-creasing the susceptibility to secondaryinfections. L-selectin appears at thecrossroads of both of these potential com-plications.

L-selectin is shed from the leukocytesurface in severe trauma (4) and septic (2)patients, resulting in increased levels of sol-uble L-selectin in plasma. Animal studieshave demonstrated that high soluble L-selectin levels interfere with leukocyte de-livery to inflamed sites (5) and attenuateinflammation-mediated vascular perme-ability (6). Therefore, elevated soluble L-selectin appears to be a protective mecha-nism to limit neutrophil-mediated end-organ injury. In support of this theory,several preliminary human studies havedemonstrated an association between lowL-selectin levels and acute lung injury fol-lowing trauma or sepsis. Donnelly et al. (7)demonstrated an increased risk of acuterespiratory distress syndrome in septic andtrauma patients with low soluble L-selectinlevels. Previously published in this journal,Rainer et al. (8) documented an elevatedrate of acute lung injury in trauma patientswith high surface/soluble L-selectin ratios.Low soluble L-selectin levels were alsofound to be predictive for sepsis mortalityin a longitudinal study by Seidelin et al. (9).

Several large animal studies in themid 1990s attempted to take advantage ofthe early role that L-selectin plays in leu-kocyte trafficking and neutrophil-medi-ated inflammatory injury, with mixed re-sults (10–13). These and other studieslaid the groundwork for the currentstudy. Dr. Seekamp and colleagues (1)present the results of a well-organized,multinational, phase II trial designed toassess the safety (primary objective) andclinical efficacy (secondary objective) ofan anti-L-selectin antibody in severelytraumatized patients. Clinical efficacywas assessed by the quantified Goris mul-tiple organ failure score. A total of 84patients with severe trauma (Injury Se-verity Score �25) from 14 institutions inthree European countries were randomlyallocated placebo or three different singledoses of the L-selectin antibody aseli-zumab (HuDregg-55). With regard to ef-ficacy of this study drug, no trends orsignificant difference in Goris multipleorgan failure score, mortality rate, lengthof intensive care unit stay, time on ven-tilator, or total hospitalization was wit-nessed. Sample size was calculated solelyto be able to detect a 3-point difference inmedian Goris multiple organ failurescore. The study was thus not adequatelypowered to address these other, clinicallysignificant, outcomes. It would be inter-esting to know if the authors plan toproceed with a phase III trial given thesenegative findings, and if so how they willaddress the sample size issue and whichend point will be used. Unfortunately,these issues are left out of the discussion.

*See also p. 2021.Key Words: L-selectin; trauma; multiple organ dys-

function syndrome; leukocyte recruitment; antibodyCopyright © 2004 by the Society of Critical Care


DOI: 10.1097/01.CCM.0000142705.99637.94


There was a dose-dependent (but notsignificant) trend for increased infectiouscomplications and leukopenia with aseli-zumab administration. In the attempt tolimit immune-mediated end-organ injuryby diminishing the migratory capabilitiesof neutrophils, it not unexpected to see areduction in the anti-microbial functionof these inflammatory cells. However, asthe authors acknowledge, the slight in-crease in infection (mostly urinary tractinfections) with aselizumab is probablynot clinically significant. Pulmonary neu-trophil sequestration is well documentedin states of systemic inflammation andcan lead to a diminished circulating poolof leukocytes. However, how L-selectinblockade resulted in increased rates ofleukopenia is less clear. Pulmonary neu-trophil sequestration is thought to be pri-marily a mechanical process, indepen-dent of adhesion molecules, as thedecreased deformability of activated neu-trophils results in physical trapping ofthese cells within the vast pulmonarycapillary network. Regardless, the num-ber of patients with leukopenia in eachgroup was too small to definitively deter-mine the clinical consequences of thisfinding.

The rationale for L-selectin blockadefor the prevention of inflammation-mediated end-organ injury is based onstrong biological evidence from both an-imal and preliminary human studies thatabounds in the literature. However, it isimportant for the authors to demonstratein this present study that the desired bio-chemical effect on the neutrophil popu-lation indeed occurs with aselizumab.The authors do report that the maximumsaturation of neutrophil binding sites washigh (89%) for all patients receivingaselizumab. However, this finding maynot be due solely to L-selectin blockadebut also to increased L-selectin sheddingin these patients. Neutrophil activationand L-selectin shedding due to surfaceL-selectin cross-linking with L-selectinantibodies such as that used in thispresent trial (HuDregg 55) are well de-scribed (14). Therefore, the authors’ find-ings may be due to a decrease in overallsurface L-selectin rather than L-selectin

blockade. In turn, this could result inincreased soluble L-selectin levels in pa-tients receiving aselizumab. Unfortu-nately, the authors did not assess thelevel of soluble L-selectin at any timepoint in this study. Although this maynot alter the safety and efficacy out-comes, it may facilitate the identificationof addressable problems with this nega-tive study. Furthermore, an assessmentof the biological effect, namely reducedneutrophil delivery, would have greatlystrengthened the study and providedvaluable information with which to pro-ceed to a phase III trial. Determination ofneutrophil content of bronchoalveolar la-vage fluid could have readily providedthis data.

Overall, the authors are to commendedfor undertaking an ambitious trial intrauma patients targeting leukocyte traf-ficking ability. Although it is essentially anegative trial, much clinical data can bederived from this study for the planning ofa phase III trial. However, in proceedingtoward future antiselectin or other adhe-sion molecule trials, it is of vital impor-tance to consider the dual nature of theactivated neutrophil in states of systemicinflammation. Limiting the deleterious sys-temic effects of activated leukocytes is anappealing target for therapy. However, de-creased neutrophil recruitment to remotesites may also negatively affect host suscep-tibility to infectious pathogens. Therefore,improved outcome from severe trauma pa-tients hinges on manipulating a fine bal-ance between diminishing leukocyte-mediated end-organ injury yet maintainingeffective leukocyte-dependent host defense.

Lorenzo E. Ferri, MD, FRCS(C)Division of Thoracic SurgeryUniversity of TorontoToronto, Canada

REFERENCES

1. Seekamp A, van Griensven M, Dhondt E, etal: The effect of anti-L-selectin (aselizumab)in multiply traumatized patients—Results ofa phase II clinical trial. Crit Care Med 2004;32:2021–2028

2. Ahmed NA, McGill S, Yee J, et al: Mecha-nisms for the diminished neutrophil exuda-tion to secondary inflammatory sites in in-

fected patients with a systemic inflammatoryresponse (sepsis). Crit Care Med 1999; 27:2459–68

3. Ferri LE, Pascual J, Seely AJ, et al: Intra-abdominal sepsis attenuates local inflamma-tion-mediated increases in microvascularpermeability at remote sites in mice in vivo.Surgery 2004; 135:187–195

4. Maekawa K, Futami S, Nishida M, et al: Ef-fects of trauma and sepsis on soluble L-selectin and cell surface expression of L-selectin and CD11b. J Trauma 1998; 44:460–468

5. Ferri LE, Swartz D, Christou NV: SolubleL-selectin at levels present in septic patientsdiminishes leukocyte-endothelial cell inter-actions in mice in vivo: A mechanism fordecreased leukocyte delivery to remote sitesin sepsis. Crit Care Med 2001; 29:117–22

6. Ferri LE, Pascual J, Seely AJ, et al: SolubleL-selectin attenuates tumor necrosis factor-alpha-mediated leukocyte adherence and vas-cular permeability: A protective role for ele-vated soluble L-selectin in sepsis. Crit CareMed 2002; 30:1842–1847

7. Donnelly SC, Haslett C, Dransfield I, et al:Role of selectins in development of adultrespiratory distress syndrome. Lancet 1994;344:215–219

8. Rainer TH, Lam NY, Chan TY, et al: Earlyrole of neutrophil L-selectin in posttrau-matic acute lung injury. Crit Care Med 2000;28:2766–2772

9. Seidelin JB, Nielsen OH, Strom J: SolubleL-selectin levels predict survival in sepsis.Intensive Care Med 2002; 28:1613–1618

10. Ramamoorthy C, Sasaki SS, Su DL, et al:CD18 adhesion blockade decreases bacterialclearance and neutrophil recruitment afterintrapulmonary E. coli, but not after S. au-reus. J Leukoc Biol 1997; 61:167–172

11. Carraway MS, Welty-Wolf KE, Kantrow SP,et al: Antibody to E- and L-selectin does notprevent lung injury or mortality in septicbaboons. Am J Respir Crit Care Med 1998;157:938–949

12. Schlag G, Redl HR, Till GO, et al: Anti-L-selectin antibody treatment of hemorrhagic-traumatic shock in baboons. Crit Care Med1999; 27:1900–1907

13. Ridings PC, Bloomfield GL, Holloway S, et al:Sepsis-induced acute lung injury is attenu-ated by selectin blockade following the onsetof sepsis. Arch Surg 1995; 130:1199–1208

14. Tsang YT, Neelamegham S, Hu Y, et al: Syn-ergy between L-selectin signaling and che-motactic activation during neutrophil adhe-sion and transmigration. J Immunol 1997;159:4566–4577


Albumin versus crystalloid solutions for the critically ill andinjured*

Albumin in solution, a heart-shaped molecule, has multi-ple functions as buildingblocks. It serves as a carrier

for fatty acids and other water-insolublemetabolites, as a binding site for hor-mones and drugs to facilitate transportof vital substrates, and as the primarycolloid of plasma by which it controlsthe balance between colloid osmoticand hydrosystolic pressure in capillaryexchange vessels. A critical deficit inthe plasma concentrations of albumin,as in liver disease or congenital analbu-minemia, is associated with clinicaledema. Almost 80% of Canadian physi-cians who were polled in the province ofOntario recently prescribed colloids forthe management of critically ill pa-tients (1). Nevertheless, a vigorous de-bate continues regarding the therapeu-tic benefit of infused albumin solutionsor, for that matter, colloidal fluids moregenerally in contrast to crystalloid andespecially electrolyte solutions for fluidmanagement of critically ill and injuredpatients.

Systematic reviews of outcomesbased on meta-analyses of randomized,controlled trials have produced directlyconflicting results with respect to mor-tality. In this issue of Critical CareMedicine, Dr. Vincent and his collabo-rators (2) again sought to establish theclinical benefits of albumin solutionsbut sought a criterion other than mor-tality, namely, complication rates.From an initial review of 484 potentialreports, the authors relied on 71 ran-domized trials for their meta-analysis,including almost 3,800 patients. Theyconcluded from this analysis of an im-

pressively large number of patients whowere resuscitated with albumin that thecombination of albumin and crystalloidfluids reduced the incidence of compli-cations compared with non–albumin-containing parenteral fluids.

In 1998, it was the Cochrane InjuriesGroup Albumin Reviewers (3) who pub-lished a systematic review to establishwhether the administration of humanalbumin or plasma protein fraction af-fected mortality compared with crystal-loid solutions in critically ill patients.Their findings were based on 30 ran-domized trials, including 1,419 pa-tients, fewer than one-half the numberincluded in the study by Vincent andcolleagues. The Cochrane group re-ported that the relative risk of death forpatients defined as hypovolemic wassubstantially greater with albumin thanwith crystalloid, a relative risk of 1.46.The risk alarmed the profession becauseit projected one extra death for every 17critically ill patients treated with albu-min or plasma protein fraction. Themortality was even greater in patientswith burns with a relative risk that wasapproximately two and one-half timesgreater. The results were widely re-ported to the public in the electronicand print media, and the use of albumindeclined steeply (4). Meta-analyses dohave the potential of resulting in majorchanges in clinical practices!

In 1999, another meta-analysis byChoi et al. (5), which included 17 studieson 814 patients, failed to support the Co-chrane study. These investigators foundno difference in the total group whencolloid and crystalloid solutions werecompared, neither with respect to mor-tality nor with the incidence of pulmo-nary edema. Yet, this study also providedevidence that there may be a mortalitybenefit of crystalloid solutions for pa-tients after traumatic injuries.

The most recent meta-analysis, whichpreceded the meta-analysis of Vincent et al.,was by Wilkes et al. in 2001 (6). It included

55 trials on 3,500 patients. This systematicreview also focused on mortality. Onceagain, there was no overall difference.

The preponderance of clinical stud-ies understandably enrolled a diversityof critically ill and injured patientswithout specific reference to the under-lying disease states, the severity of ill-ness or injury, the magnitude of con-current interventions includingsurgical operations, blood transfusions,and concurrent drugs and fluids, andthe length of hospitalization. The datawere focused on whether colloid orcrystalloid fluid was infused but not forthe amounts administered. Impor-tantly, subgroup analyses were typicallypost hoc and, therefore, suspect (7).Crossovers and potential publicationprejudice against negative data furthercomplicated these efforts (8). It is ap-parent that a huge number of uncon-trolled variables constrained the inter-pretation of outcomes and ultimatelyfor each of the meta-analyses.

In the absence of concurrence on out-comes based on mortality, we compli-ment Dr. Vincent and his associates fordefining an alternative measurement ofvalue, namely, complication or adverseevent rates. They found that the fre-quency of complications was significantlylower in albumin-treated patients. Al-though this new endpoint of efficacy oreffectiveness is quite appropriate, it alsois suspect. Even their conscientious effortto maintain objectivity did not allow forsecure categorization. The study was bydefinition retrospective and nonquantita-tive. It sought to classify complications inpatients with diverse disease states, indiverse organs and systems, and at di-verse stages in the clinical course. Iatro-genic complications independent of theunderlying disease states were likely to beof moment. It is these variables that areagain likely to explain the inconsistenciesof outcomes, whether based on morbidityor on mortality. These considerations,notwithstanding, however, the majorityof studies, again project a trend favoring

*See also p. 2029.Key Words: albumin; colloid fluid; crystalloid fluid;

meta-analyses; fluid resuscitation; trauma; hypovole-mia

The authors have nothing to disclose.Copyright © 2004 by the Society of Critical Care


DOI: 10.1097/01.CCM.0000142901.20873.4F


crystalloid over albumin for patients withtraumatic injuries who are likely to bemore uniformly categorized.

These are the limitations of cur-rently published randomized, con-trolled trials that constitute the data-bases of meta-analyses. Yet, meta-analyses may be the only guide thatclinicians have in the absence of moreconventional and well-controlled largescale multiple-centered studies inwhich criteria for entry of patients arenarrowly defined and complied with.The most recently published multiple-centered study by the SAFE Study In-vestigators (9) more closely fulfills thisgoal. It was sponsored by the Australianand New Zealand Intensive Care SocietyClinical Trials Group and was immu-nized from commercial bias. The SAFEStudy included almost 7,000 criticallyill patients. In the opinion of the un-dersigned, it trumps all previous stud-ies that address one of the most funda-mental and contentious issues incritical care medicine. The protocol ofthe study was disarmingly simple indesign, and the study was remarkablywell organized and controlled. A pass-word protected, internet-based systemsecured unbiased randomization andassignment. Prompt implementationwas facilitated by overcoming earlierethical constraints, in that the investi-gators did not have to delay treatmentfor informed consent by adopting thedelayed option consent. Innovativepackaging precluded clinicians fromdistinguishing between albumin andcrystalloid fluids before, during, and af-ter fluid administration. The reportedoutcomes were persuasive (9). Mortalitydid not differ significantly between pa-tients assigned to either the albumin orthe crystalloid (saline) group. Second-ary endpoints, in part, comparable with

the complications analyzed by Dr. Vin-cent and colleagues, including the du-ration of mechanical ventilation, theincidence of renal failure, and thelength of intensive care unit and hospi-tal stay, did not differ. Again, there wasa trend suggesting that albumin hadadverse effects when administered topatients after traumatic injuries.

What are we to conclude? First, forthe majority of critically ill and injuredpatients, there is no secure evidence ofbenefit of colloid, including albuminover crystalloid solutions. Yet, as sug-gested by the analysis of Vincent andcolleagues, it is almost certain that se-lective pathophysiologic states may bebenefited by one fluid over another. Inthe instance of traumatic injuries andperhaps elective surgical operations,the trend favoring crystalloids, al-though incomplete, is consistent overthe horizon of major meta-analyses andthe independent multiple-centeredSAFE trial. This contrasts with patientswith major medical complications,such as hepatorenal failure, severe hy-poproteinemia with edema, or majorinfectious complications, for whom col-loid, including albumin, may ultimatelyprove to be more beneficial.

It is, therefore, appropriate, in the opin-ion of the undersigned, to encourage addi-tional and well-designed randomized mul-tiple-centered studies but on patients whoare enrolled with more narrowly defineddisease states and specific organ dysfunc-tions to confirm or reject special indica-tions for or against albumin (7). Until then,we interpret the current evidence as incon-clusive. Excepting traumatic injuries, wewould hesitate to recommend one fluidover another under the very large umbrellaof “critically ill” patients. This is a conclu-sion to which we have been led by theevidence herein reviewed, admittedly revis-

ing our yesteryear allegiance to colloid flu-ids, including albumin and hydroxyethylstarches (10, 11).

Max Harry Weil, MD, PhD,ScD (Hon), FCCM

Wanchun Tang, MD, FCCMInstitute of Critical Care MedicinePalm Springs, CA

REFERENCES

1. Miletin MS, Stewart TE, Norton PG: Influ-ences on physicians’ choices of intravenouscolloids. Intensive Care Med 2002; 28:917–924

2. Vincent JL, Navickis RJ, Wilkes MM: Morbid-ity in hospitalized patients receiving humanalbumin: A meta-analysis of randomized con-trolled trials. Crit Care Med 2004; 32:2029–2038

3. Cochrane Injuries Group Albumin Review-ers: Human albumin administration in crit-ically ill patients: Systematic review of ran-domized controlled trials. Br Med J 1998;317:235–240

4. Robert I, Bunn F: Egg on their faces: Thestory of human albumin. Eval Health Prof2002; 25:130–130

5. Choi PT, Yip G, Quinonez LG, et al: Crystal-loids vs. colloids in fluid resuscitation: A sys-temic review. Crit Care Med 1999; 27:200–210

6. Wilkes MM, Navickis RJ: Patient survival af-ter human albumin administration: A meta-analysis of randomized, controlled trials. AnnIntern Med 2001; 135:149–164

7. Hebert PC, Cook DJ, Wells G, et al: Thedesign of randomized clinical trials in criti-cally ill patients. Chest 2002; 121:1290–1300

8. Olson CM, Rennie D, Cook D, et al: Publica-tion bias in editorial decision making. JAMA2002; 287:2825–2828

9. Cook D: Is albumin safe? N Engl J Med 2004;350:2294–2296

10. Stein L, Beraud JJ, Morissette M, et al: Pul-monary edema during volume infusion. Cir-culation 1975; 52:483–489

11. Weil MH, Henning RJ, Puri VK: Colloid on-cotic pressure: Clinical significance. CritCare Med 1979; 7:113–116


The deceptive complexity of “simple” proning*

F requently reorienting and re-adjusting body position are de-fining mammalian character-istics. During health,

matching of ventilation to perfusion inthe face of these positional variations isaccomplished by intricate adaptive mech-anisms that include the “passive” influ-ences of structure and gravity and themore “active” regulators of ventilationand perfusion (1). In addition to gravity,distortions of the lung required by oblig-atory shape matching of lung to chestcage alter the distribution of local pleuralpressures. The resulting modifications oftranspulmonary pressures influence localalveolar stretch, ventilation gradient, andvascular resistance. Acting indepen-dently, gravity also affects blood flow—atleast in part—via the classic (if imperfect)“zoning”’ concept first popularized �4decades ago (2–4). Active regulators ofventilation and perfusion include auto-nomic controls, hypoxic vasoconstric-tion, and variations in local PCO2 and pH.

Although these mechanisms of posi-tional ventilation-to-perfusion adaptationapply to most warm-blooded animals,species differ with respect to tolerance tofull inversion of their natural positions.With the exception of certain arborealanimals (e.g., the sloth, opossum, andresting bat) who orient “belly up” in highplaces to protect themselves from preda-tors, the supine position is never main-tained for long. The default body positionis prone, even for our closest primaterelatives (e.g., chimpanzee, orangutan,and mountain gorilla). Apart from allow-ing the potential for immediate mobilityfor feeding, fight, or flight, proning helpsto protect the vulnerable ventral struc-tures from predatory attack. In fact, cer-tain species used in experimentation,such as the sheep, are highly intolerant ofprotracted supine positioning. (Sheep

ranchers understand this well—“sheeptipping” to reestablish a prone orienta-tion is a vital daily activity to prevent lossof livestock unable to “right” themselveson their own.) In the large animal labo-ratory, investigators soon learn thatsheep must be carefully monitored andsupported when studied supine.

Perhaps it is not surprising then, thatin an impressive study of anesthetizedhealthy sheep appearing in this issue ofCritical Care Medicine by Dr. Johanssonand colleagues (5), the authors reportmajor differences in the distributions ofventilation observed in the supine andprone orientations—a point reflected inthe prior work of others. Of more novelinterest is their finding that 10 cm H2Opositive end-expiratory pressure (PEEP)improved the homogeneity of ventilationin prone sheep but merely displaced theheterogeneous distribution of ventilationto a more dependent plane in supine an-imals. Even within a given isogravita-tional tissue plane, the response to PEEPdiffered with position, suggesting thatfactors other than those intrinsic to thestructure of the parenchyma were atwork. These results, which indicate un-expectedly heterogeneous ventilatory re-sponses to PEEP with position change,are qualitatively similar to those reportedpreviously regarding perfusion (6). Al-though the authors exercised admirablerestraint in refraining from speculationas to the possible explanations for theseunexplained positional differences, theinfluence of position on the heart, medi-astinal structures, and lymphatic drain-age patterns comes quickly to mind.

Together with earlier data obtainedfrom normal and lung-injured humans(7, 8), the data of the current studystrongly suggest that proning reduces thegradient of regional transpulmonarypressures in healthy and in acutely in-jured lungs. This is good news whenthere is a need to use relatively highairway pressures to maintain adequategas exchange, as uniformity of transpul-monary pressures allows a more predict-able effect of a single airway pressureprofile applied to the airway opening.More uniform mechanical properties pre-

sumably lessen the potential for raisedairway pressure to cause regional over-distention, adversely redirect blood flow,and predispose to dependent ventilator-induced lung injury.

It is tempting to extrapolate from suchexperimental observations to suggest thatPEEP used in the clinical setting mighthelp maintain recruitment with less po-tential for overdistention and deadspacecreation in the prone position; however,the implications of these laboratory datafor the setting of acute lung injury occur-ring in humans are hardly straightfor-ward. Somewhat in contrast to the datareported by Dr. Johansson and colleagues(5) from healthy lungs, computed tomo-graphic studies in patients with acutelung injury indicate that PEEP applied inthe supine position tends to beneficiallyalter the aeration and ventilation pat-terns, improving the aeration (and pre-sumed ventilation) of dependent lung re-gions (9). Among other importantvariables, the magnitude of such effectswould be expected to depend strongly onthe nature and severity of injury, re-cruitability of the injured lung tissue, lev-els of PEEP and plateau pressure, andchest wall configuration.

One nonbiological feature of positionchange that has received little attention inlaboratory-based and clinical scientific lit-erature could also prove influential in mod-ulating the PEEP response. The firmnessand form of the supporting surface againstwhich the subject rests influence regionalchest wall compliance, modify the shape ofthe thoracic cavity (10), and potentiallymay influence the translocation of bloodbetween the abdominal and chest cagecompartments (11). As in most reports, thestudy by Dr. Johansson and colleagues (5)did not characterize the table contour (e.g.,flat vs. V-shaped), but I think it safe toassume that the surface was rigid, or nearlyso—quite unlike the air-cushioned mat-tresses that typify the modern intensivecare unit. One might also wonder whatimpact the animal’s states of hydration, an-esthesia, and breathing pattern might havemade on the study outcome. The techni-cally demanding methods used to track re-gional ventilation possibly could be influ-

*See also p. 2039.Key Words: ventilation/perfusion; positioning; alve-

olar stretch; ventilation gradient; vascular resistanceCopyright © 2004 by the Society of Critical Care


DOI: 10.1097/01.CCM.0000142944.51482.B5


enced by the selection of a different tidalvolume range or inspiratory flow rate anddelivery profile as well. In short, we mustrespect the potential for interplay amongthe multiple variables that might have ledto the conclusions of this excellent studybefore attempting to generalize them.

Whatever the limitations of such datamight have for clinical applications, theyunderscore the power (and complexity) ofa deceptively simple positional change onphysiologic variables of vital concern tothe practitioner. This type of investiga-tion, which used sophisticated technolo-gies to reexamine a common and “well-understood” bedside intervention, mustbe encouraged if critical care therapeu-tics are to advance.

John J. MariniUniversity of MinnesotaSt. Paul, MN

REFERENCES

1. Nunn JF: Distribution of pulmonary ventilationand perfusion. In: Nunn’s Applied RespiratoryPhysiology. Fourth Edition. 1993, pp 156–197

2. West JB: Regional differences in gas ex-change in the lung of erect man. J ApplPhysiol 1962; 17:893

3. Permutt S, Riley RL: Hemodynamics of col-lapsible vessels with tone: The vascular wa-terfall. J Appl Physiol 1963; 18:924

4. Kaneko K, Milic-Emili ME, Dolovich MB, etal: Regional distribution of ventilation andperfusion as a function of body position.J Appl Physiol 1966; 21:767

5. Johansson MJ, Wiklund A, Flatebø T, et al:Positive end-expiratory pressure affects re-gional redistribution of ventilation differ-ently in prone and supine sheep. Crit CareMed 2004; 32:2039–2044

6. Walther SM, Domino KB, Glenny RW, et al: Pos-itive end expiratory pressure redistributes perfu-sion to dependent lung regions in supine but notin prone lambs. Crit Care Med 1999; 27:37–45

7. Pelosi P, Tubiolo D, Mascheroni D, et al:Effects of the prone position on respiratorymechanics and gas exchange during acutelung injury. Am J Respir Crit Care Med 1998;157:387–393

8. Pelosi P, Croci M, Calappi E, et al: Pronepositioning improves pulmonary function inobese patients during general anesthesia. An-esthes Analg 1996; 83:578–583

9. Gattinoni L, Pelosi P, Crotti S, et al: Effectsof positive end-expiratory pressure on re-gional distribution of tidal volume and re-cruitment in adult respiratory distress syn-drome. Am J Respir Crit Care Med 1995;151:1807–1814

10. Bryan AC: Comments of a devil’s advocate.Am Rev Respir Dis 1974; 110(Suppl):143–144

11. Quintel M, Pelosi P, Caironi P, et al: Anincrease of abdominal pressure increasespulmonary edema in oleic acid-induced lunginjury. Am J Respir Crit Care Med 2004;169:534–541

Through a glass darkly: The brave new world of in silico modeling*

Silicon, the 14th element of theperiodic table, is, after oxygen,the second most common ele-ment on the planet, and the

seventh most abundant element in theuniverse. Its compounds take the form ofsand, rock, and glass; it is also the rawmaterial used to etch the microchips thathave made the computer revolution pos-sible. And, in this incarnation, it has lentits name to a new mode of scientific in-quiry. Where in vivo studies are per-formed in living organisms and in vitrostudies are undertaken using isolatedcells or biological molecules, in silicostudies use the enormous computationalpowers of the computer to mine largedatabases looking for patterns or to inte-grate large amounts of data to modelcomplex phenomena. The uses of thesemodels are diverse, from weather orearthquake forecasting to modeling po-tential terrorist attacks to asserting theplausibility of the Biblical flood. Inevita-

bly, too, they are finding a role in bio-medical research.

In this issue of Critical Care Medicine,Dr. Gary An introduces an innovative insilico approach to the study of criticallyill patients (1). He hypothesizes that anapproach known as “agent-based model-ing” can replicate the interactions be-tween elements of the innate immunesystem and so predict the consequencesof manipulating these in patients withsepsis. It is a bold task. That his initialforays into this uncharted territory arenot completely convincing reflects themagnitude of the challenge and the nov-elty of the approach more than the in-trinsic shortcomings of the exercise. It isinstructive to look at these critically.

The assumption underlying agent-based modeling is that by defining theindividual activities of the components ofa system and using computer algorithmsto model their combined interactions, itis possible to approximate in silico theconsequences of these interactions invivo. Principles of complexity theory sug-gest that when a number of discrete in-fluences interact, they result in a stableemergent system whose properties maynot be immediately apparent from a con-sideration of the individual componentsthemselves (2); in essence, agent-based

modeling reproduces a finite series of in-teractions that result in this emergentorder. It is possible, provided that a rea-sonable number of representative ele-ments are included in the model, that thecharacteristics of the individual variablesare much less important than the aggre-gate consequences of their interactions.However, it is equally plausible that theperformance of the model is critically de-pendent on the specific assumptions of itsinputs, and if this is the case, then thecredibility of the approach hinges on thereliability of the data it uses.

A valid model of in vivo biology,whether a conceptual construct or a com-puter algorithm, presupposes an accuraterepresentation of three separate influ-ences. First, the model must account formost or all of the relevant inputs, consid-ering their identity, their isolated activ-ity, and the magnitude of their effect inresponse to a stimulus. Second, it mustreflect knowledge of the interactions ofeach of these components with other po-tential targets that can modify the out-come. These may be complex. The clini-cal biology of sepsis, for example,encompasses not only the direct effects ofthe microorganism on the host, but alsothe indirect effects of the systemic acti-vation of an inflammatory response, the

*See also p. 2050.The author discloses consultancies with Eisai,

GSK, Edwards, and Medimmune; honoraria from EliLilly and Intrabiotics; and grants from GSK).


DOI: 10.1097/01.CCM.0000142935.34916.B5


anti-inflammatory or procoagulant re-sponse to this response, and the furtherresponse of the host to injury resultingfrom these processes (3). Finally themodel must account for the impact ofother external stimuli (in the critical carecontext, the effects of clinical interven-tion). These, too, are complex and vari-able, shaped by culture, knowledge, expe-rience, prejudice, fatigue, and a host ofother human attributes. Moreover, clini-cal intervention is not stable over time,but rather changes in response to theadoption of new knowledge.

Dr. An has included a number of cellsand soluble mediators in his computermodel; however, the activity of each ofthese is not independent of the others,and many potentially important influ-ences are excluded. For example, acuteendotoxin exposure triggers the expres-sion of �300 genes in neutrophils (4) orendothelial cells (5), whereas sustainedexposure can evoke a state of tolerance(6). Moreover, most of the genes incorpo-rated into his model are those expressedearly following insult, rather than later,and potentially more clinically relevantmediators such as HMGB-1 (7). Hismodel leaves out the potential influenceof the infecting microorganism (8), but atthe same time, proceeds from the opti-mistic assumption that administration ofantibiotics will convert the outcome froma basal lethality of 100% to 38%, andeven more remarkably, from 86% to 37%in patients without infection. The magni-tude of benefit documented in clinicaltrials is much smaller, perhaps of theorder of 10% (9). Conversely, the impact,both positive and negative, of the totalityof other intensive care unit interventionsis not included.

How does one quantify the influenceof any single component of a model sothat its manipulation in silico will faith-fully produce the systemic alterationsthat would occur if they happened invivo? Dr. An draws on narrative reviewsto characterize the biological roles of thecells and mediators he has incorporatedinto his model. The approach emphasizesprevailing generic concepts about the ac-tivity of a given cell or molecule, over thespecific and often contradictory biologi-cal detail that characterizes original sci-entific investigation. Whether the conse-quence of this approach is a balancedpicture of in vivo biology, or simply atautology (the model predicts a conclu-sion because it incorporates the individ-ual assumptions that lead to that conclu-

sion) is difficult to ascertain. Clearly, thereliability of an in silico model hinges onthe methodology used to provide data forthe computer algorithms, whether thosedata are a compilation of interacting bi-ological processes as presented here or,for example, the sequence of base pairsthat comprises the human genome. Howthis is best accomplished and validated isunknown and an important area for fu-ture work.

Dr. An’s model addresses the dynamicsof the innate immune response, postulat-ing that derangements in innate immunityunderlie the systemic inflammatory re-sponse syndrome (SIRS), and its pathologicconsequences, the multiple organ dysfunc-tion syndrome. As an abstraction, this con-cept is well accepted (10). The challenge,however, for both Dr. An and the clinicalresearcher lies in translating an abstractconcept into a set of clinical criteria thatdefine a disease. SIRS is not a disease but aconcept that has been operationalizedthrough a series of nonspecific physiologiccriteria that have no clear pathologic cor-relate (11, 12). Not all patients with tachy-cardia and hypothermia are endotoxemic,and not all patients with elevated circulat-ing levels of tumor necrosis factor manifestleukocytosis or tachypnea. Treatments thatcan ablate SIRS are readily available (�blockers for tachycardia, central cooling forhyperthermia, cyclophosphamide for neu-trophilia, and muscle relaxants for tachy-pnea), but obviously, none of these willreverse the disorder of innate immunitythat is believed to kill patients with sepsis.And, while therapies that target tumor ne-crosis factor have had, at best, only verylimited utility when administered to pa-tients with SIRS (13), they have been muchmore effective when given to patients withinflammatory bowel disease (14) or rheu-matoid arthritis (15). Is this discrepancy afunction of biology or taxonomy? Has Dr.An succeeded in modeling the biology ofsepsis, or simply duplicated the imprecisionof classification that results in heterogene-ity in clinical trials?

Proof in science lies in the ability topredict an outcome; consistency in pre-dictive capacity is tantamount to scien-tific truth. The fact that eclipses of themoon or conjunctions of the planets canbe predicted centuries in advance is com-pelling proof of the Copernican model ofthe solar system, even though scientistswill never be able to observe from afar themovements of the planets around thesun. The role of insulin deficiency in di-abetes is established by the certainty that

administration of insulin will reproduc-ibly lower blood glucose levels and delaydisease progression. In statistical terms,proof is supported by rejecting the nullhypothesis that there is no effect. Dr. An’smodels are consistent with a body of clin-ical trials data in that they fail to demon-strate an effect resulting from manipula-tion of the innate immune response. Butas the science of in silico modelingevolves, it will be important to validatethe concept by showing that it can pre-dict an effect and not simply support thenull hypothesis.

Innovation is important but risky, andthe innovator leaves himself or herselfparticularly vulnerable to the skepticismof those whose ideas are entrenched. Dr.An has opened an important new windowon the study of an immensely complexprocess. We look forward to its evolution.

John C. Marshall, MD, FRCSCDepartment of SurgeryInterdepartmental Division of

Critical Care MedicineUniversity of Toronto

REFERENCES

1. An G: In silico experiment of existing andhypothetical cytokine-directed clinical trialsusing agent-based modeling. Crit Care Med2004; 32:2050–2060

2. Seely AJE, Christou NV: Multiple organ dys-function syndrome: Exploring the paradigmof complex non-linear systems. Crit CareMed 2000; 28:2193–2200

3. Marshall JC: Inflammation, coagulopathy,and the pathogenesis of the multiple organdysfunction syndrome. Crit Care Med 2001;29(Suppl 99):S106

4. Fessler MB, Malcolm KC, Duncan MW, et al:A genomic and proteomic analysis of activa-tion of the human neutrophil by lipopolysac-charide and its mediation by p38 mitogen-activated protein kinase. J Biol Chem 2002;M200755200

5. Zhao B, Bowden RAS, Stavchansky SA, et al:Human endothelial cell response to gram-negative lipopolysaccharide assessed withcDNA microarrays. Am J Physiol Cell Physiol2001; 281:C1587–C1595

6. Cavaillon J-M: The nonspecific nature of en-dotoxin tolerance. Trends Mircobiol 1995;3:320–324

7. Wang H, Bloom O, Zhang M, et al: HMG-1 asa late mediator of endotoxin lethality inmice. Science 1999; 285:248–251

8. Opal SM, Cohen J: Clinical Gram-positivesepsis: Does it fundamentally differ fromGram-negative bacterial sepsis? Crit CareMed 1999; 27:1608–1616

9. MacArthur RD, Miller M, Alberston T, et al:Adequacy of early empiric antibiotic treat-


ment and survival in severe sepsis: Experi-ence from the MONARCS trial. Clin InfectDis 2004; 38:284–288

10. Buchman TG: The community of the self.Nature 2002; 420:246–251

11. Vincent JL: Dear SIRS, I’m sorry to say thatI don’t like you. Crit Care Med 1997; 25:372–374

12. Marshall JC: Rethinking sepsis: From conceptsto syndromes to diseases. Sepsis 1999; 3:5–10

13. Marshall JC: Such stuff as dreams are madeon: Mediator-targeted therapy in sepsis. Na-ture Rev Drug Disc 2003; 2:391–405

14. Targan SR, Hanauer SB, Van Deventer SJH,et al: A short-term study of chimeric mono-clonal antibody cA2 to tumor necrosis factor

� for Crohn’s disease. N Engl J Med 1997;337:1029–1035

15. Lipsky PE, van der Heijde DM, St Clair EW,et al: Infliximab and methotrexate in thetreatment of rheumatoid arthritis. Anti-Tumor Necrosis Factor Trial in RheumatoidArthritis with Concomitant Therapy StudyGroup. N Engl J Med 2000; 343:1594–1602

In vivo, in vitro, in silico. . .*

T his issue of Critical CareMedicine contains reports ontwo projects that model in-flammation and sepsis. One

project, conducted by Gary An (1), ex-plores the aggregate behavior of a modelof the microvasculature at the endotheli-al-blood interface, in which agents repre-senting constituent cells and moleculesinteract according to a simple set of rulesinferred from recent literature. The otherproject, led by Gilles Clermont (2), em-ploys a set of differential equations tosuggest not only why some recent clinicaltrials of anti-inflammatory therapiesfailed, but also how in silico modelingcould inform and refine design of futureimmunomodulator trials.

What is a mathematical model? Theusual definition—a symbolic descriptionof the essential interrelations among allelements of a system—underplays boththe principles of modeling, as well as itsimportance to critical care medicine.Mathematical models are to physiologywhat medical illustrations are to anat-omy. No one would confuse a drawing ofthe heart with the heart itself, yet suchmedical drawings facilitate our under-standing of the organization of the heartprecisely because the illustrator abstracts

and interrelates only key features of theanatomy. A medical illustration is thus apen-and-ink model of the actual anat-omy; importantly, it is a static model.Although the drawing may include ar-rows to suggest flow and dotted lines tosuggest motion, it makes no predictionabout functional change. Drawings andother static models can be verified onlyby inspection.

Mathematical models of physiologyare dynamic. Their purpose is predictivedescription—to suggest what happensover time. As such, mathematical modelsare testable hypotheses. When a mathe-matical model predicts measurable be-havior that emulates the physiology un-der study, one can reasonably infer thatthe mathematical model has, in fact, cap-tured all of the essential interrelations.Conversely, when model and experimentdisagree, something is wrong or missingfrom the model.

Mathematical models should not beconfused with blueprints, either. Blue-prints specify systems that have predict-able behaviors. In both reports, An andClermont et al. describe unexpected, evencounterintuitive, “emergent” behaviorsthat arise from the model specifications.

Dr. An populates his agent-based mod-eling framework with a collection of cells(endothelial cells, neutrophils), receptors(L-selectin, CD 11/18), and mediators (tu-mor necrosis factor, interleukin-1). Theendothelial cells are fixed in space, theother cells can move around or stick,depending on local receptor and mediatorstates. Importantly, there are randomcomponents to the model— cells canmove in one direction, or another. Inter-actions happen most of the time, but notall the time. Despite this stochasticity spec-ified by the model—in fact, because of it—Dr. An’s agent-based model produces be-haviors that correspond to the “two-hit”description of immune-suppressed multi-

ple organ dysfunction syndrome. The “two-hit” phenomenon is not programmed intothe model but rather arises as emergentbehavior from the specifications that gov-ern interaction among the agents.

Dr. Clermont and his colleagues em-ploy deterministic differential equationsin their model but use a cohort of virtualpatients who differ slightly (and plausi-bly!) from one another with respect tobacterial load, bacterial virulence, timingof intervention, and heritable robustnessin the face of stress. Once those (virtual)patient-specific conditions are estab-lished as parameters in the set of differ-ential equations, the outcome for eachpatient is predicted precisely. Just slightvariation in initial conditions and in thetiming of interventions—variation thatmirrors the clinical reality (and contraststhe reproducibility of inbred laboratoryanimals subjected to experimental sep-sis)—is sufficient to produce model be-haviors in which anti-mediator “treat-ments” produce excess “mortality” insilico. This excess mortality in silico wasneither planned nor programmed intothe model any more than excess mortal-ity was anticipated or programmed intothe clinical trials of inflammatory modu-lator therapy. Yet, both in silico and inthe intensive care unit, excess mortalityis a surprising and unwelcome behavior.

No one in the modeling communitywould suggest that mathematical model-ing is a substitute either for animal ex-perimentation or for clinical trials. How-ever, these two reports suggest thatmodeling of critical illness and interven-tion serves at least two purposes. First,any model that predicts behaviors closelycorresponding to experiment and/or clin-ical observation reassure us that themodel has, in fact, captured all of therelevant components and their interac-tions. Second, and perhaps most impor-tant, discordance between the model’s be-

*See also p. 2050.Supported, in part, by research grants from the

National Institute of General Medical Sciences.There are no disclosures relevant to this editorial.

No specific device, product or company is mentionedor can reasonably be inferred from the content of theeditorial. The author has been a consultant to severalpharmaceutical and device companies (including Lilly,Abbott, Ortho Biotech), none of which are known tohave any commercial interest in the development ofmathematical models. The author holds no equity po-sitions in any company that produces or marketsmathematical models or related tools.


DOI: 10.1097/01.CCM.0000142900.95726.7F


havior and anticipated or actual outcomeilluminates those conditions where furtherexperiment should focus. It might be thatthe model is faulty or incomplete. It mightbe that an unexpected behavior emergesfrom both the model and the biologicalsystem. Either way, such focus should beimportant to limiting both excessive use ofexperimental animals, as well as unex-pected adverse events in clinical trials.

Interaction among the clinical, exper-imental and modeling communities ispresently sparse. Without sustained in-teraction, model building and model test-ing in critical care might remain rele-gated to the bottom of clinicians’ list of

priorities and off the modelers’ prioritylist entirely. Fortunately, appropriate fo-rums for building investigative collabora-tions, such as The Society for Complexityin Acute Illness (www.scai-med.org), arebeing formed. The next generation of crit-ical care professionals—those still in train-ing, recently trained, or just thinking aboutcritical care as a career—should not over-look this opportunity for sophisticated re-search that is safe and less expensive thanother avenues of investigation.

Modeling is an art. It is also a science.Done well, modeling enhances the under-standing of our patient’s illnesses and in-forms our care. That is reason enough to

study mathematical models of our pa-tients’ illnesses and of the well-inten-tioned interventions we provide.

Timothy G. Buchman, PhD, MD, FCCMProfessor of SurgeryAnesthesiology and MedicineWashington University in St. Louis

REFERENCES

1. An G: In silico experiments of existing andhypothetical cytokine-directed clinical trialsusing agent-based modeling. Crit Care Med2004; 32:2050–2060

2. Clermont G, Bartels J, Kumar R, et al: In silicodesign of clinical trials: A method coming ofage. Crit Care Med 2004; 32:0000–0000

Do not suction above the cuff*

Salivary secretions are commonin the oropharyngeal cavity ofthe critically ill who requiremechanical ventilation in the

intensive care unit (ICU). The upper air-way secretions also accumulate above theendotracheal tube cuff, allowing for leak-age of these secretions into the lowerairways. These respiratory secretions arecontaminated with “normal” (e.g., Strep-tococcus pneumoniae) and “abnormal”(e.g., Pseudomonas aeruginosa) potentialpathogens. The accumulation of contam-inated secretions above the cuff isthought to increase the risk of microbialmigration into the lower airways and sub-sequent endogenous pneumonia associ-ated with ventilation. Removal of pooledsecretions through suctioning of the sub-glottic region, termed subglottic suction-ing, is thought to reduce pneumonia.This requires the use of a specially de-signed endotracheal tube with a separatedorsal lumen that opens into the subglot-tic region. Subglottic suctioning was firstdescribed in France in 1992, and sincethat time, it has been evaluated in fourrandomized, controlled trials (RCTs) (1–4). The impact of subglottic suctioningon pneumonia and mortality was com-pared with that of a conventional endo-

tracheal tube in 828 patients over the lastdecade (Table 1). Three of the four RCTshave examined subglottic suctioning in amedical/surgical ICU population requir-ing �3 days of mechanical ventilation (1,2, 4), the fourth RCT was limited to post-cardiac surgery patients (3). Two trialsreport a statistically significant reductionin pneumonia in the test group (1, 4), theother two failed to show a difference (2,3). A meta-analysis of the four RCTsshows a relative risk reduction of 0.49(95% confidence interval, 0.39–0.71) inpneumonia. There was no effect on mor-tality, length of treatment in ICU, or du-ration of mechanical ventilation. Onestudy using a decision-model analysissuggests that subglottic suctioning maybe cost effective, despite the expense ofthe special tube (5). Based on these data,influential authorities and opinion lead-ers have recommended subglottic suc-tioning (6, 7).

In this issue of Critical Care Medicine,Dr. Berra and colleagues (8) report thehistologic changes that occur as a resultof subglottic suctioning in an experimen-tal sheep model. The main end point intheir RCT was to assess the safety of thetechnique. Their message is unequivocal:subglottic suctioning is harmful. All ani-mals that received subglottic suctioningshowed macroscopic and microscopic in-jury to the posterior tracheal mucosa atthe level of the suction port. Histologi-cally, the severity of the injury variedfrom erosion, edema, hemorrhage, andinflammation to frank mucosal necrosis

at the level of the evacuation port. Noneof the sheep with the standard endotra-cheal tube showed macroscopic or micro-scopic tracheal lesions, after 3 days ofventilation. This new histologic finding isworrying and challenges the claim thatno adverse patient events were associatedwith the use of the special tube and theadministration of subglottic suctioning(3), but it is in line with a recent FrenchRCT by Girou et al. (9) that reported 40%of patients who received subglottic suc-tioning developed laryngeal edema re-quiring reintubation. This complicationof the normal endotracheal tube has aprevalence of �10% immediately afterextubation (10).

Primary endogenous pneumonias arethe main infectious problem in the ICU,as the prevalence is about 55% (Table 2).Primary endogenous pneumonia due topotential pathogens, both normal and ab-normal, in general occurs within the firstweek of admission to the ICU (11). Pre-viously healthy individuals, includingtrauma and surgical patients, developearly endogenous pneumonias with thenormal potential pathogens such as S.pneumoniae, Haemophilus influenzae,Moraxella catarrhalis, and Staphylococ-cus aureus. Patients with underlyingchronic conditions such as diabetes, al-coholism, and chronic obstructive pul-monary disease and who are referred tothe ICU from home or from other wardsand hospitals may carry abnormal aerobicGram-negative bacilli such as Klebsiella,Acinetobacter, and Pseudomonas species

*See also p. 2071.Key Words: mechanical ventilation; subglottic suc-

tioning; laryngeal edemaCopyright © 2004 by the Society of Critical Care


DOI: 10.1097/01.CCM.0000142902.24268.CC


in their admission flora. This type of pa-tient may develop a primary endogenouspneumonia with abnormal flora. Fortu-nately, most patients recover from theirprimary endogenous pneumonia after in-tensive care treatment including antibi-otic therapy. About one third of ICU ad-missions may develop a late pneumonia,in general, after 1 wk of treatment in theICU. These patients invariably acquire intheir oropharynx abnormal aerobicGram-negative bacilli that are associatedwith the ICU environment. This leads tosecondary carriage and oropharyngealovergrowth, migration, and colonization/infection of the lower airways. This se-quence of events is termed secondary en-dogenous because the pneumonia ispreceded by oropharyngeal carriage. Fi-nally, P. aeruginosa has been described aspossessing an intrinsic tropism to colo-nize lower airways rather than the oro-pharynx when both sites are equally ac-cessible to bacterial entry (12). Thepathogenesis of this type of pneumonia istermed exogenous because the lung isinfected by P. aeruginosa after direct in-oculation without previous carriage. Theprevalence of exogenous lower airway in-fections is about 15%, and this exogenouspneumonia can occur at any time duringtreatment in the ICU.

Exogenous pneumonias are an in-herent limitation of subglottic suction-ing. Surveillance cultures of the oro-pharynx were not obtained in any of thefour RCTs. If the subglottic secretionswere to reflect oropharyngeal flora, twoRCTs (1, 2) report exogenous pneumo-

nias due to P. aeruginosa and Acineto-bacter. In the RCT by Girou et al. (9),eight patients were randomized to re-ceive subglottic suctioning vs. standardcare in ten patients. Oropharyngeal andtracheal secretions were sampled dailyand quantitatively cultured over a pe-riod of 2 wks. Practically all patientshad tracheal aspirates positive for bothnormal and abnormal flora after day 1of ventilation (75% in the test group vs.80% in the control group). There wasno significant difference in the dailybacterial counts of the oropharyngealflora and in the trachea (5.1 log10 col-ony-forming units/mL vs. 6.6 log10 col-ony-forming units/mL in the control)between the two groups of patients. Ap-parently, suctioning of subglottic secre-tions does not prevent potential patho-gens acquired in the oropharynx frommigrating between the cuff of the en-dotracheal tube and the lower airwaymucosa to colonize or infect the lowerairway. Only one RCT allows the iden-tification of the secondary endogenousproblem, as 10 of the 15 pneumonias inthe patients receiving subglottic suc-tioning were of secondary endogenouspathogenesis (2, 11). Thus, the preven-tive method of suctioning also fails tocontrol the second type of late second-ary endogenous pneumonia that, theo-retically, suctioning might have con-trolled. Subglottic suctioning does noteven affect primary endogenous pneu-monias based on the human data byGirou et al. (9), which are in line withthe microbiological data found by Dr.

Berra and colleagues (8) in their sheepmodel. The lower airways of all animalswere colonized/infected when the ani-mals were ventilated with the specialtube in a position similar to patients.

The conclusion is that none of thethree types of pneumonias is controlledby subglottic suctioning. How can thereduction in pneumonia in two RCTs andthe meta-analysis be explained? The dif-ference is due to a reduction in pneumo-nias caused by the normal potentialpathogens S. pneumoniae, S. aureus, andH. influenzae. This is highly likely to bean antibiotic rather than suctioning ef-fect, in that a higher proportion of testpatients are likely to have received ade-quate antimicrobials. This imbalancemay be due to the enrolment into the testgroup of a higher number of trauma andsurgical patients receiving commonlyused antibiotics that cover the three nor-mal bacteria (13). Interestingly, a 3-daycourse of parenteral ceftriaxone was com-pared with subglottic suctioning in anRCT including 57 medical/surgical pa-tients (14). The protective effect of anti-microbials was significantly higher inpreventing primary endogenous pneumo-nias than suctioning. L’histoire se répètein that the transient mortality reductionin patients randomized to bronchoscopyfor diagnosing pneumonia comparedwith the noninvasive approach of trachealaspirate was due to the immediate admin-istration of adequate broad spectrum an-tibiotics in a French RCT including 413patients (15).

Table 1. Subglottic suctioning

Author (ReferenceNo.)

Type ofSuctioning

Type ofPatient

SampleSize

Pneumonia RR(95% Confidence Interval)

Mortality RR(95% Confidence Interval)

Mahul et al. (1) Intermittent Mixed 145 0.46 (0.23 to 0.93) 1.14 (0.62 to 2.07)Valles et al. (2) Continuous Mixed 190 0.56 (0.31 to 1.01) 1.07 (0.70 to 1.65)Kollef et al. (3) Continuous Cardiac 343 0.61 (0.27 to 1.40) 0.86 (0.30 to 2.42)Smulders et al. (4) Intermittent Mixed 150 0.25 (0.07 to 0.85) 1.2 (0.55 to 2.61)

828 0.49 (0.39 to 0.71) 1.1 (0.84 to 1.46)

RR, relative risk; mixed, medical/surgical.

Table 2. Three different types of pneumonia due to “normal” and “abnormal” potentially pathogenic microorganisms (PPM)

Type of Infection PPM Carriage Time CutoffPrevalence,

%

Primary endogenous Normal/abnormal Present in admission flora �1 wk c. 55Secondary endogenous Abnormal Not present in admission flora,

but acquired and carried later�1 wk c. 30

Exogenous Abnormal No carriage at all Anytime throughout thetreatment in intensive care

c. 15


Dr. Berra and colleagues (8) havemade a major contribution to patientcare in exposing an ineffective, costlymethod as unsafe. We predict that moremethods without a positive impact, butexpensive and not free from risk, includ-ing bronchoscopy to diagnose pneumo-nia, will travel along the same path. Theend of suctioning is nigh, and that isgood news for the critically ill.

H. K. F. van SaeneDepartment of Medical

MicrobiologyUniversity of LiverpoolLiverpool, UK

M. AshworthDepartment of HistopathologyAlder Hey HospitalLiverpool, UK

A. J. PetrosPaediatric Intensive Care UnitGreat Ormond Street Children’s

HospitalLondon, UK

M. SanchezDepartment of Intensive CareUniversity Hospital Principe de

AsturiasAlcala de Henares, Spain

M. A. de la CalDepartment of Critical Care

MedicineUniversity Hospital GetafeMadrid, Spain

REFERENCES

1. Mahul P, Auboyer C, Jospe R, et al: Preven-tion of nosocomial pneumonia in intubatedpatients: Respective role of mechanical sub-glottic secretions drainage and stress ulcerprophylaxis. Intensive Care Med 1992; 18:20–25

2. Valles J, Artigas A, Rello J, et al: Continuousaspiration of subglottic secretions in pre-venting ventilator-associated pneumonia.Ann Intern Med 1995; 122:179–186

3. Kollef MH, Skubas NJ, Sundt TM: A random-ized clinical trial of continuous aspiration ofsubglottic secretions in cardiac surgery pa-tients. Chest 1999; 116:1339–1346

4. Smulders K, van der Hoeven H, Weers-Pothoff I, et al: A randomised clinical trial ofintermittent subglottic secretion drainage inpatients receiving mechanical ventilation.Chest 2002; 121:858–862

5. Shorr AF, O’Malley PG: Continuous subglot-tic suctioning for the prevention of ventila-tor-associated pneumonia: Potential eco-nomic implications. Chest 2001; 119:228–235

6. Collard HR, Saint S, Matthay MA: Preventionof ventilator-associated pneumonia: An evi-dence-based systematic review. Ann InternMed 2003; 138:494–501

7. Tablan OC, Anderson LJ, Besser R, et al: Guide-lines for preventing health-care–associatedpneumonia, 2003: Recommendations of CDCand the Healthcare Infection Control PracticesAdvisory Committee. MMWR Recomm Rep2004; 53(RR-3):1–36

8. Berra L, De Marchi L, Panigada, M, et al:Evaluation of continuous aspiration of sub-

glottic secretion in an in vivo study. CritCare Med 2004; 32:2071–2078

9. Girou E, Buu-Hoi A, Stephan F, et al: Airwaycolonisation in long-term mechanically ven-tilated patients: Effect of semirecumbent po-sition and continuous subglottic suctioning.Intensive Care Med 2004; 30:225–233

10. Darmon JY, Rauss A, Dreyfuss D, et al: Eval-uation of risk factors for laryngeal edemaafter tracheal extubation in adults and itsprevention by dexamethasone: A placebo-controlled, double-blind, multicenter study.Anesthesiology 1992; 77:245–251

11. van Saene HKF, de la Cal MA, Petros AJ: Tosuction or not to suction, above the cuff. CritCare Med 2000; 28:596–597

12. Morar P, Singh V, Makura Z, et al: Differingpathways of lower airway colonization andinfection according to mode of ventilation:Endotracheal vs tracheostomy. Arch Otolar-yngol Head Neck Surg 2002; 128:1061–1066

13. Sirvent JM, Torres T, El-Biary M, et al: Pro-tective effect of intravenously administeredcefuroxime against nosocomial pneumoniain patients with structural coma. Am J RespirCrit Care Med 1997; 155:1729–1734

14. Sanchez M, Alvarez-Lerma F, Cerda E, et al:Continuous aspiration of subglottic secre-tions (CASS) compared to a short course ofceftriaxone (SCC) for the prevention of earlyonset pneumonia (EOP) in intubated pa-tients: A randomized multicenter trial. Pre-sented at the 41st Annual ICAAC Meeting,Chicago, 2001, p 433

15. Fagon JY, Chastre J, Wolff M, et al: Invasiveand non-invasive strategies for managementof suspected ventilator-associated pneumo-nia: A randomised trial. Ann Intern Med2000; 132:621–630

Noninvasive interfaces: Should we go to helmets?*

Noninvasive administration ofpositive pressure, in the formof either noninvasive ventila-tion (NIV) using the combi-

nation of pressure support and positiveend-expiratory pressure (PEEP) or con-tinuous positive airway pressure (CPAP),has been shown to improve the outcomesof patients with certain forms of acuterespiratory failure compared with con-

ventional therapy. For example, random-ized trials have demonstrated that NIVusing pressure support significantly re-duces the need for intubation as well ashospital morbidity and mortality ratesand length of stay in patients with acuterespiratory failure due to chronic ob-structive pulmonary disease exacerba-tions (1, 2). Similar findings apply to im-munocompromised patients with acuterespiratory failure (3, 4), and both CPAPalone (5) and NIV (6) rapidly improverespiratory distress and gas exchangewhile reducing the need for intubation inpatients with acute pulmonary edema.

Despite these successes, however,noninvasive positive pressure still runsa substantial failure rate, ranging up to40% in some studies (7). At least part of

this failure rate is attributable to intol-erance of the masks or “interfaces” thatconnect the pressure-generating de-vices to the patient’s upper airway.

Currently, the most commonly usedinterfaces to deliver noninvasive positivepressure to patients with acute respira-tory failure are nasal and oronasal (or fullface) masks. Recent evidence indicatesthat the oronasal mask has a higher ini-tial tolerance rate than the nasal mask,and it has become the preferred initialmask in the acute setting (8). However,the need for this mask to seal over thenose and mouth contributes to mask in-tolerance because of facial discomfort andoccasional ulceration. Therefore, inter-faces that are capable of effectively pro-viding noninvasive positive pressure

*See also p. 2090.Key Words: positive pressure; noninvasive ventila-

tion; positive end-expiratory pressure; continuous pos-itive airway pressure; acute respiratory failure; pulmo-nary edema


DOI: 10.1097/01.CCM.0000142945.20310.E4


without the need to seal around the noseand mouth have the potential of enhanc-ing tolerance rates and thereby increas-ing the success rates of noninvasive pos-itive pressure.

The “helmet” described in the currentissue of Critical Care Medicine by Dr.Taccone and colleagues (9) representsone such approach to interface design.Resembling the diving helmets of yore,the helmet consists of a clear plastic cyl-inder that seals over the upper thorax andshoulders and is held firmly in place bystraps under the axillae. Several studieshave already reported the successful ap-plication of noninvasive positive pressureusing the helmet to treat patients with avariety of forms of acute respiratory fail-ure (10–11). However, one of these stud-ies also raised concerns about CO2 re-breathing with the helmet because of ahigher PaCO2 compared with controls as-sociated with an increased inspired PCO2

(11).Using a lung model and normal sub-

jects, Dr. Taccone and colleagues (9)demonstrated that helmet use is asso-ciated with substantial CO2 rebreathingif CPAP is administered via a standardventilator or at low flush rates withfresh gas. In their mathematical analy-sis, the authors attempted to demon-strate that the CO2 rebreathing behavesas although it is occurring in a “semi-closed environment,” like a room with aventilation system. The mathematicalformula was derived from that for CO2

homeostasis; the partial pressure of CO2

depends on the balance of CO2 produc-tion and CO2 removal. Thus, the resultsare what would be anticipated intu-itively; the higher the flushing rate inthe helmet, the lower the level of CO2.However, the authors have not proventheir hypothesis that the helmet func-tions as a “semiclosed environment” inwhich CO2 rebreathing is independentof mask volume and is “fundamentallydifferent” from traditional interfaces.They tested only two helmet volumesand not a range, and they did not testother interfaces. It seems inconceivablethat other interfaces would not behavesimilarly with respect to the mathemat-ical model; increased flushing ratesshould reduce rebreathing regardless ofthe interface. With standard masks, in-terface volume would be anticipated toaffect rebreathing if it increases dead-space significantly, but even then, re-breathing should be minimized by highflushing rates, as suggested by Fergu-

son and Gilmartin (12). These authorsshowed that during “bilevel” noninva-sive ventilation administered via a stan-dard nasal mask, sufficient expiratorypressure (corresponding to expiratoryflow rate) essentially eliminated re-breathing.

Regardless of whether we accept theauthors’ hypotheses, however, severalimportant points derive from the Tac-cone study. The study highlights theneed to thoroughly evaluate new inter-faces that represent substantial depar-tures in design before they are endorsedfor widespread use. The study alsoclearly demonstrates that the helmetshould not be used to administer CPAPfrom a standard ventilator or at lowflush rates because certain patients,particularly those with high CO2 pro-duction rates, can retain substantialamounts of CO2. The authors’ recom-mendations that the helmet be usedonly with high-flow CPAP systems andthat PCO2 be monitored in some wayduring helmet use are sensible, al-though they have not determined howthe latter should be done. Pendingmore definitive studies, it seems advis-able to check occasional arterial bloodgases during helmet use to ascertainPaCO2 levels.

In addition, although Dr. Taccone andcolleagues (8) did not assess use of thehelmet to deliver pressure support andPEEP from a standard ventilator, theirstudy raises major concerns about theoccurrence of rebreathing during deliv-ery of this form of NIV. Such an approachwould also raise the concern of how tocompensate for the compliance of thehelmet (which is undoubtedly greaterthan that of traditional interfaces) thatcould blunt the rate of pressure deliveryand interfere with patient-ventilator syn-chrony.

Interfaces like the helmet that avoidsealing around the nose and mouth arewelcome additions to our interface arma-mentarium because they offer options topatients who are intolerant of traditionalinterfaces and have the potential of im-proving overall CPAP and NIV successrates. Eventually, these devices are likelyto assume important roles in the nonin-vasive management of such patients withacute respiratory failure. However, stud-ies like that of Dr. Taccone and col-leagues (8) sound a cautionary note. Eachnew interface approach should undergo acareful evaluation so that effects on re-breathing and ventilator performance can

be fully understood before widespread ap-plication.

Nicholas S. Hill, MDPulmonary, Critical Care and

Sleep DivisionTufts-New England Medical

CenterBoston, MA

REFERENCES

1. Brochard L, Mancebo J, Wysocki M, et al:Noninvasive ventilation for acute exacerba-tions of chronic obstructive pulmonary dis-ease. N Engl J Med 1995; 333:817–822

2. Plant PK, Owen JL, Elliott MW: Early use ofnoninvasive ventilation for acute exacerba-tions of chronic obstructive pulmonary dis-ease on general respiratory wards: A multi-center randomized controlled trial. Lancet2000; 355:1931–1935

3. Antonelli M, Conti G, Bufi M, et al: Nonin-vasive ventilation for treatment of acute re-spiratory failure in patients undergoing solidorgan transplantation. JAMA 2000; 283:235–241

4. Hilbert G, Gruson D, Vargas F, et al: Nonin-vasive ventilation in immunosuppressed pa-tients with pulmonary infiltrates, and acuterespiratory failure. N Engl J Med 2001; 344:481–487

5. Bersten AD, Holt AW, Vedig AE, et al: Treat-ment of severe cardiogenic pulmonaryedema with continuous positive airway pres-sure delivered by face mask. N Engl J Med1991; 325:1825–1830

6. Masip J, Betbese AJ, Paez J, et al: Non-invasive pressure support ventilation versusconventional oxygen therapy in acute cardio-genic pulmonary oedema: A randomizedstudy. Lancet 2000; 356:2126–2132

7. Meduri GU, Turner RE, Abou-Shala N, et al:Noninvasive positive pressure ventilation viaface mask. Chest 1996; 109:179–193

8. Kwok H, McCormack J, Cece R, et al: Con-trolled trial of nasal versus oronasal masks inpatients with acute respiratory failure. CritCare Med 2003; 468–473

9. Taccone P, Hess D, Caironi P, et al: Contin-uous positive airway pressure delivered witha “helmet”: Effects on carbon dioxide re-breathing. Crit Care Med 2004; 32:2090–2096

10. Antonelli M, Conti G, Pelosi P, et al: Newtreatment of acute hypoxemic respiratoryfailure: Noninvasive positive support ventila-tion delivered by a helmet—A pilot-con-trolled trial. Crit Care Med 2002; 30:602–608

11. Antonelli M, Pennisi M, Pelosi P, et al: Non-invasive positive pressure ventilation using ahelmet in patients with acute exacerbation ofchronic obstructive pulmonary disease. An-esthesiology 2004; 100:16–24

12. Ferguson GT, Gilmartin M: Co2 rebreath-ing during BiPAP ventilatory assistance.Am J Respir Crit Care Med 1995; 151:1126 –1135


Hypothermia during cardiac arrest: Moving from defenseto offense*

More than 350,000 Ameri-cans die as a result of sud-den cardiac arrest everyyear (approximately 1,000

people every day) (1). About 10–30% oflong-term survivors have permanentbrain damage as a result of global brainischemia (2). Recently, hypothermia hasbeen shown to make a difference. In2002, two randomized, controlled, clini-cal trials demonstrated significantly im-proved outcomes in patients treated withhypothermia (surface cooling) after car-diac arrest (3, 4). Patients were cooled to32–34°C for 12 to 24 hrs. Last year theAdvanced Life Support Task Force of theInternational Liaison Committee on Re-suscitation (ILCOR) recommended cool-ing for unconscious patients after out-of-hospital cardiac arrest from ventricularfibrillation (5).

Cooling can be started before arrest(protection), during arrest (preservation),and after arrest (resuscitation). The de-gree of hypothermia can be mild (34–36°C), moderate (27–32°C), or deep (10–20°C). Induction of hypothermia beforecardiac arrest has been used successfullysince the 1950s to protect the brainagainst global ischemia during cardiacsurgery (6, 7). With prearrest inductionof hypothermia, the lower the tempera-ture, the better the protection. Therapeu-tic hypothermia after cardiac arrest inhumans was explored in the late 1950sbut was essentially abandoned because ofuncertain benefit, slow cooling tech-niques, and side effects such as shivering,arrhythmias, and infection. With postar-rest induction of hypothermia, there is acomplex relationship between timing,depth, and duration such that early onsetof treatment may be combined withmilder hypothermia and shorter dura-

tion, whereas later onset seems to requiredeeper hypothermia and a longer dura-tion to show a benefit. Since the 1980s,induction of hypothermia after return ofspontaneous circulation (resuscitativehypothermia), in various animal modelsusing various strategies, has been associ-ated with improved functional recoveryand reduced cerebral histologic deficits.

In this issue of Critical Care Medicine,Dr. Nozari and colleagues (8) report theresults of a study of preservative hypo-thermia (starting hypothermia during re-suscitation) delivered with venovenousextracorporeal cooling. Twenty-sevendogs were subjected to cardiac arrest andrandomly assigned to one of four groups:1) normothermic controls, 2) moderatehypothermia (27°C) started during resus-citation using venovenous extracorporealcooling, 3) mild hypothermia (34°C)started during resuscitation using veno-venous extracorporeal cooling, and 4)normothermic controls but with veno-venous extracorporeal shunting. Thus,there were 12 normothermic dogs(groups 1 and 4) and 12 hypothermicdogs (groups 2 and 3); three dogs wereexcluded. The primary end points werefunctional outcome (overall performancescore), neurologic function (neurologicdeficit score), and histologic outcome(histologic damage score). The resultsshowed that all 12 normothermic dogsdied except one who survived but re-mained comatose. In contrast, all 12 hy-pothermic dogs not only survived butalso had normal or near normal functionand brain histology. This is impressive.

This study is important for several rea-sons beyond the impressive outcomes.First, although the powerful protectiveeffect of intra-ischemic hypothermia hasbeen known for decades, technical issuesand practicality limited this approach inthe clinical setting of cardiac arrest.There was also an underlying fear thatcooling patients during resuscitationwould somehow hamper and delay returnof spontaneous circulation. In the cur-rent study, the authors have shown that

it is feasible to induce hypothermia dur-ing cardiac arrest, in which it can poten-tially have a greater effect and may becombined with a brief duration. Theremay be additional long-term benefits aswell. Dietrich et al. (9) have demon-strated that intra-ischemic hypothermiamay be more likely to result in perma-nent reduction of neuronal damagerather than simply delaying neuronaldeath. Second and almost equally impor-tant, the authors have reported that mildhypothermia (34°C) was just as good asdeeper levels of hypothermia (27°C). Thishas been reported before (10), but it isworth confirming if only because it seemscounterintuitive. Although moderate hy-pothermia is also generally safe, targetingtemperatures of 34°C is easier. Finally,venovenous extracorporeal cooling, as inthis study, cooled extremely rapidly. Thetime to reach the target temperature of34°C was remarkably only a few minutes.In contrast, surface cooling is slow andcumbersome and takes several hours.New endovascular, counter-current,heat-exchange catheters seem to be faster(11). Venovenous extracorporeal cooling,however, seems to be faster still, albeitless practical. Further studies are neededto determine the quickest, safest, andbest way to cool patients with cardiacarrest.

The late Dr. Peter Safar is credited forthe very idea of cerebral resuscitation atthe same time as cardiopulmonary resus-citation (cardiopulmonary– cerebral re-suscitation). In 1961, Dr. Safar assemblednine steps of cardiopulmonary–cerebralresuscitation beginning with the now fa-miliar ABCs of resuscitation, airway,breathing, and circulation (12). Resusci-tative hypothermia, however, was listedas step H, after stabilization. This studyrepresents another step toward Dr. Sa-far’s vision of cooling patients early dur-ing resuscitation, in a sense moving froma defensive approach (trying to attenuatedamage that has already occurred) to anoffensive approach (trying to prevent thedamage in the first place). Cardiac arrest

*See also p. 2110.Key Words: hypothermia; cardiac arrest; neuropro-

tection; ischemia; resuscitationCopyright © 2004 by the Society of Critical Care


DOI: 10.1097/01.CCM.0000142908.15315.66


can be devastating for patients and fami-lies and frustrating for intensivists whoprovide care. Innovative clinical ap-proaches, such as ultra-early preservativehypothermia and cerebral blood flow pro-motion, are needed to make a break-through.

Michael De Georgia, MDThe Cleveland Clinic FoundationCleveland, OH

REFERENCES

1. Eisenberg MS, Cummins RO, Reynolds-Haertle R, et al: Cardiac arrest and resusci-tation: A tale of 29 cities. Ann Emerg Med1990; 19:179–186

2. Safar P: Cerebral resuscitation after cardiacarrest research: Initiatives and future direc-tions. Ann Emerg Med 1993; 22:324–349

3. 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

4. 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

5. Nolan JP, Morley PT, Vanden Hoek TL, et al:Therapeutic hypothermia after cardiac ar-rest: An advisory statement by the AdvancedLife Support Task Force of the InternationalLiaison Committee on Resuscitation. Circu-lation 2003; 108:118–121

6. Bigelow WG, Callaghan JC, Hopps JA: Gen-eral hypothermia for experimental intracar-diac surgery. Ann Surg 1950; 132:531–539

7. Lewis FJ, Tauffic M: Closure of atrial septaldefect with the aid of hypothermia. Surgery1953; 33:52–59

8. Nozari A, Safar P, Stezoski SW, et al: Mild

hypothermia during prolonged cardiopulmo-nary cerebral resuscitation increases con-scious survival in dogs. Crit Care Med 2004;32:2110–2116

9. 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

10. Weinrauch V, Safar P, Tisherman S, et al:Beneficial effect of mild hypothermia anddetrimental effect of deep hypothermia aftercardiac arrest in dogs. Stroke 1992; 23:1454–1462

11. De Georgia MA, Krieger DW, Abou-Chebl A,et al: Endovascular cooling for acute isch-emic stroke: A pilot, clinical randomizedtrial. Neurology 2004; 63:312–317

12. Safar P, Brown TC, Holtey WJ: Ventilationand circulation with closed-chest cardiacmessage in man. JAMA 1961; 176:574–576


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