Caveats for comparing catheter-associated bloodstream infection rates* R · R educing healthcare-associated infections (HAIs) has become an important and highly pub-licized initiative

Editorials

Caveats for comparing catheter-associated bloodstream infectionrates*

Reducing healthcare-associatedinfections (HAIs) has becomean important and highly pub-licized initiative. HAIs are said

to be among the top ten causes of deathin the United States, accounting for98,987 deaths in 2002 of which 30,665were associated with bloodstream infec-tions (1). In response, at least 17 stateshave established mandates to allow theNational Healthcare Safety Network un-der the aegis of the Center for DiseaseControl and Prevention’s (CDC) Divisionof Healthcare Quality Promotion to col-lect their data on HAI rates. Methods toreduce HAI have largely been directed atimplementing more rigorous and consis-tent infection control measures, decreas-ing use of central venous and urinarycatheters, minimizing the duration ofcatheterization and intubation, and usingcatheters coated with antimicrobials al-though this remains controversial. TheCDC has recently published the firststate-specific HAI rates from January toJune 2009 for the 17 states with NationalHealthcare Safety Network-reporting man-dates (2). These data are tabulated by usinga standardized infection ratio, which is cal-culated as each state’s reported HAIs di-vided by HAIs predicted from pooled na-tional data from 2006 through 2008.Although the CDC cautions that these datashould not to be used to compare HAI ratesamong states, the report notes that 11 ofthe 17 states had standardized infection ra-tios �1, indicating a lower than predictedrate. Several states are also publishing hos-pital-specific rates, often focusing on cen-tral line-associated bloodstream infections(CLABSIs). Thus, comparisons seem inevi-

table. Aside from concerns about the valid-ity of these data (3), there is also uncer-tainty about the reasons for the apparentdecreases in recent years, especially for me-thicillin-resistant Staphylococcus aureusHAIs (4, 5).

The article by Ramos and colleagues(6) in this issue of Critical Care Medicineused data from a 26-bed medical inten-sive care unit (MICU) accrued over 7 yrsin their infection control database to de-termine the relative impact on CLABSIrates of implementing infection controlmeasures with and without using mino-cycline–rifampin-impregnated central ve-nous catheters (M/R CVCs). The authorsreached two potentially important con-clusions: 1) antimicrobial-impregnatedCVCs reduced the CLABSI infection ratebeyond that of infection control measuresalone and 2) rather than the anticipatedincrease in resistance to tetracycline(used as a surrogate for minocycline) andrifampin resulting from repeated expo-sure to the catheters’ coating, resistancedecreased or did not change. In interpret-ing these results, it is important to un-derstand some of the terminology used indefining infection rates associated withCVCs. Paramount among these is the dis-tinction between central line-associatedbloodstream infections (7) and centralline-related bloodstream infections (CRBSIs)(8). Both depend upon identifying a pri-mary bloodstream infection (BSI) definedas one positive blood culture or more forcertain bacteria that cannot be attributed toan infection at any site. A CLABSI is definedas BSI if a CVC was present at the time of orwithin 48 hrs before the defining bloodculture was obtained. There is no require-ment to identify the organism on the cath-eter. This definition was developed for sur-veillance, not for diagnosis. In contrast, aCRBSI requires that the CVC be in place atthe time the positive blood culture wasobtained and a positive quantitative orsemiquantitative culture of the same or-ganism from the catheter tip (8, 9). Slightlydifferent criteria are used for cultures ob-tained via the catheter if it is left in place.

CRBSIs are not included in the NationalHealthcare Safety Network database as aseparate entity, and reporting CRBSI is notpart of statewide mandates. The distinctionbetween CLABSI and CRBSI however is im-portant because the linkage to a CVC as asite of infection is much stronger for aCRBSI than for a CLABSI. Data collectedfor CLABSIs generally do not includewhether the CVC was removed; if so, why;and whether the condition that led to ob-taining a obtain blood culture resolved or ifan infection site was ever found. All of thesedata would be important in strengtheningthe association of the BSI with the CVC.

The study of Ramos and colleagues (6) isunique in that it examined the longitudinalchange in CLABSI over four distinctphases. During each phase, M/R CVCs andmore rigorous standardized infection con-trol procedures were intended either to beused or not used. Phase I during 1998 wasessentially the control period that predatedthe use of M/R CVC or standardized infec-tion control procedures. During phase II,conducted in 1999 and 2000, M/R CVCswere used in 50% of the MICU patients.During phase III, conducted during 2001and 2002, several infection control proce-dures were implemented, including maxi-mum sterile barriers and hand washing,but M/R CVC were not used. Finally, duringphase IV, conducted from 2003 onward,M/R CVCs were again used along with themore rigorous infection control measures.The CLABSI rate decreased in phase II, in-creased during phase III, and then de-creased during phase IV to rates numeri-cally lower than in any other phase. Onelimitation in this study is that it only eval-uated MICU patients. Another is that com-pliance rates for infection control proce-dures during phases III and IV areunknown. Although enforcing these poli-cies is probably easier in an ICU than else-where in a hospital, full compliance is dif-ficult to achieve. Consequently, an ICU is agood arena to test the various interventionsalthough knowing the compliance rateswould be helpful in interpreting the data.In addition, because of the relatively recent

*See also p. 245.Key Words: central line-associated bloodstream

infection; CLABSI; infection rates; bloodstream infec-tions; catheter

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

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

DOI: 10.1097/CCM.0b013e318205c35e

392 Crit Care Med 2011 Vol. 39, No. 2

impetus to shorten the time CVCs are inplace (dwell time), they may have been re-moved sooner in later phases. This seemsunlikely because there were no statisticaldifferences in dwell times over the studyperiod; although the calculation of the req-uisite power to detect such differences isnot provided. It is however possible that therelation of CLABSI to dwell times may havechanged. It also is not clear if CLABSI forCVCs placed within 48 hrs of discharge butdetected after ICU discharge were included,but even if omitted, the numbers of suchpatients are likely to be small. The authorsinterpret these data as showing that M/RCVCs “significantly decrease CLABSI ratesin a manner that is both independent andcomplimentary to the infection controlprocedures.” However, this conclusionseems unwarranted from the data pre-sented because although the decrease inCLABSI from phase I to II was statisticallysignificant, there are no statistical compar-isons among phases II, III, and IV. The pvalue of �.001 in their figure (6) appears toreflect the difference among all of thephases analyzed together but not betweenspecific phases. Thus, it is unclear if nu-merical differences among phases II, III,and IV simply reflect random variations ortrue changes as the authors assert. Unfor-tunately, neither confidence limits nor theactual numbers of CVC days are provided.The latter would permit calculation of con-fidence limits and statistical comparisonsbetween phases. Consequently, from theavailable data there is no way to determinewhether the numerical changes in phasesII, III, and IV differ statistically. Such com-parisons can be made if it is assumed thatthere were exactly 1000 catheter days eachyear but this is unlikely. Nonetheless, anal-ysis using this assumption indicates thatthere are no statistically significant differ-ences among any of the phases (chi-square � 14.17, p � .08). However, this isnot a valid analysis because it is unlikelythat there were exactly 1000 CVC days eachyear or even that the number of days wasthe same every year. Statistical compari-sons of frequencies such as CLABSI ratesdepend upon the number in each groupbeing compared. For example, if the samerates were found for 10,000 catheter days(calculated by multiplying each CLABSIrate by 10), the chi-square would be 141.69and the p value would be �.0001, i.e., tentimes the value for 1000 days. The situationis more complex for other statistical testsused to compare frequencies, especially ifthe numbers are not the same in eachgroup. Thus, regardless of what tests were

used in this study, they cannot be repro-duced unless the catheter days are knownfor each year or at least each phase. There-fore, without further data, it cannot be con-cluded that any of the measures in phasesIII and IV had an impact on CLABSI relativeto phase II. However, this does not negatethe important finding that methicillin-resistant S. aureus and coagulase-negativestaphylococci resistance to either of thecoating antimicrobials (tetracycline wasused as a surrogate for minocycline) didnot increase over the study period. In fact,staphylococcal resistance to tetracyclinedecreased over the 9 yrs of this study withthe exception of S. aureus in the ICU,which remained stable. A similar patternwas found for coagulase-negative staphylo-cocci resistance to rifampin, but oddly, hos-pital-wide resistance to S. aureus did notchange whereas it decreased in the ICU.Nonetheless, the important finding is thatresistance to either of these antimicrobialsdid not increase as might be expected fromrepeated exposure of staphylococcal speciesto the antimicrobial coating on the CVCs.

This study also illustrates some impor-tant limitations in the current recommen-dations for the reporting metric of CLABSIper 1000 catheter days. First, using thetotal catheter days as the denominator forCLABSI as per CDC recommendations im-plies that for a given patient the probabilityof getting a CLABSI is constant over theCVC dwell time. As a hypothetical example,suppose a CLABSI of 2 per 100 catheterdays is found in two hospitals (an improb-ably large number used for illustrative pur-poses). In hospital A, which is a small hos-pital where CVC are used infrequently, aCLABSI occurred in two of five patientseach with dwell time of 20 days. In hospitalB, which is a larger hospital, a CLABSI wasfound in two of 20 patients each with adwell time of 5 days. Although the CLABSIrates are the same in the two hospitals,hospital B might seem preferable becausethe rate per patient is 10% whereas it is40% in hospital B. However, developing aCLASBI within 5 days of placement is morelikely to reflect breaks in infection controlprocedures, whereas absence of a CLASBIfor 20 days may reflect an entirely differentand nonpreventable process. Clearly, dwelltime matters, which implies that the prob-ability per day is not constant. Further-more, if this were not true, there would beno infection control reason to advocateminimizing CVC dwell times. The hypo-thetical data in this example could be help-ful in steering an evaluation toward CVCmaintenance procedures in hospital A and

insertion procedures in hospital B, investiga-tions that might not occur by just comparingCLABSI rates per 1000 days (100 days in thisexample) as the rates were the same in bothhospitals. Of course, this assumes that therisk was identical for all of the patients, whichseems unlikely. However, current CDC strat-ifications do not include potentially impor-tant patient risk factors, e.g., immune sup-pression or diabetes.

A second issue, even assuming that ratesper 1000 catheter days were a valid metric,is that as noted above, statistical compari-sons among rates cannot be made unlessthe total number of catheter days is knownor confidence limits are included in thedata. The latter practice was used by theCDC (2) but not in reporting by individualstates. Confidence limits would permit di-rect comparisons across or within hospitalsas well as with benchmarks. Without suchdata, spurious comparisons are inevitable.A third issue is that CLABSI is a surveil-lance definition, which only inferentiallylinks the CVC as a cause of the BSI. Putdifferently, in essence a CLABSI impliesthat because a source for the BSI could notbe found, it must be related to a CVC evenif it wasn’t present for as long as 48 hrsbefore the positive blood culture. To deter-mine whether this is truly a problem, stud-ies could be conducted in which all cathe-ters were cultured upon removal todetermine whether causality was plausible.Other validation studies are underway butthey are essentially chart reviews (3). Fi-nally, because there are no accepted criteriafor when to obtain blood cultures, the in-cidence of BSI within 48 hrs of the pres-ence of CVC may underestimate CLABSI oreven CRBSI. If a hospital was cynicalenough to set policies that deliberately re-duced the number of blood cultures, itsCLABSI would be underestimated. Al-though this is improbable, criteria arelikely to vary even among physicians in asingle hospital as evidenced by only a 50%compliance during phase II in using M/RCVCs within the single ICU in this study.Even if there were a national policy forobtaining blood cultures, compliancewould still be likely to vary.

None of these putative limitationsshould diminish the importance of track-ing CLABSI rates, which can be especiallyuseful as a quality control measurewithin a hospital or ICU. However, thelimitations in this metric and the mannerin which it is reported should producesome trepidation in making comparisons

393Crit Care Med 2011 Vol. 39, No. 2

both within and between hospitals. Hope-fully, such considerations will stimulatethe development of techniques in analysisthat surmount these difficulties.

Richard Teplick, MDTheodore, AL

REFERENCES

1. Klevens RM, Edwards JR, Richards CL Jr, et al:Estimating health care-associated infectionsand deaths in U.S. hospitals, 2002. PublicHealth Rep 2007; 122:160–166

2. Centers for Disease Control and PreventionNational Healthcare Safety Network: Firststate-specific healthcare-associated infectionssummary data report. 2010; Available at:

http://www.cdc.gov/hai/pdfs/stateplans/SIR_05_25_2010.pdf. Accessed October 27, 2010

3. Thomas A, Cunningham M, Beldavs Z: Protocol forvalidation of mandatory reporting of central line-associated bloodstream infections. Available at:http://www.wrd.state.or.us/OHPPR/docs/HCAIAC/Materials/Binder_Materials/ProtocolforValidationofMandatoryReportingCLABSI.pdf. Accessed Octo-ber 27, 2010

4. Perencevich EN, Diekema DJ: Decline in in-vasive MRSA infection: Where to go fromhere? JAMA 2010; 304:687–689

5. Kallen AJ, Mu Y, Bulens S, et al: Health care-associated invasive MRSA infections,2005–2008. JAMA 2010; 304:641–648

6. Ramos ER, Reitzel R, Jiang Y, et al: Clinicaleffectiveness and risk of emerging resistance as-sociated with prolonged use of antibiotic-

impregnated catheters: More than 0.5 millioncatheter days and 7 years of clinical experience.Crit Care Med 2011; 39:245–251

7. Centers for Disease Control and Prevention:Central Line-Associated Bloodstream Infec-tion (CLABSI) Event. 2010. Available at: http://www.cdc.gov/nhsn/PDFs/pscManual/4PSC_CLABScurrent.pdf. Accessed October 27, 2010

8. Mermel LA, Allon M, Bouza E, et al: Clinicalpractice guidelines for the diagnosis and man-agement of intravascular catheter-related infec-tion: 2009 Update by the Infectious DiseasesSociety of America. Clin Infect Dis 2009; 49:1–45

9. O’Grady NP, Alexander M, Dellinger EP, et al:Guidelines for the prevention of intravascularcatheter-related infections. Morb Mortal WklyRep 2002; 51:1–32

Optimizing sepsis care: Target the process or the patient?*

T he landscape of sepsis care ischanging. The field has histor-ically been dotted with anabundance of failed interven-

tional studies (1) typically focusing on anovel drug targeting a mechanistic aspectof the sepsis cascade applied across abroad range of patients in a multicen-tered study. Renewed interest, height-ened awareness, and early-directed inter-ventions have changed the trajectory forthis seemingly fixed disease process. Thisrevived effort has been prompted not by theuse of a novel medication, but ratherthrough sets of guidelines centralizedaround standardized algorithms recom-mending specific interventions to addressabnormal hemodynamic parameters. Suchguidelines have been created through acombination of available evidence and ex-pert opinion and endorsed by the Instituteof Health Improvement (2).

Recent literature has seen an influx inreports from single and multicentered ef-fectiveness studies of the outcomes andchallenges associated with the implemen-tations of these recommendations (3, 4).

Widely varied in results and impact, a cen-tral message has emerged: compliance withprocess and patient-centered interventionsis challenging and yet consistently resultsin improvement in survival. Recent datafrom the Surviving Sepsis Campaign data-base describing compliance with manage-ment recommendations across 152 centersrepresenting 30 countries showed a de-crease in overall mortality (37% to 30%)associated with improved compliance withthe guidelines, even when the overall com-pliance rate with all aspects of the recom-mendations was only 36% (5).

The study by Schramm et al (6) in thisissue of Critical Care Medicine addressessepsis resuscitation in a novel way with athree-stage, before and after interven-tional trial examining the effect of clini-cal feedback and a treatment team oncompliance with treatment recommenda-tions and associated outcomes. Patientswere identified in the intensive care unitthrough a daily screening process. Thefirst phase of the study was a 12-monthbaseline assessment of compliance rateswith therapy guidelines during a periodof nursing and physician education. Thesecond 9-month phase involved direct au-dit of intensive care unit patients treatedfor septic shock with weekly feedback onguideline compliance provided to theemergency department and intensivecare unit healthcare providers. The third12-month phase used a Sepsis ResponseTeam of physicians, nurses, and ancillarystaff to provide guided diagnostic and

therapeutic interventions based on theresuscitation guidelines.

The authors then took a novel ap-proach and defined the primary outcomeas compliance with the process of care asmodified from the original definitionwithin the resuscitation bundle of theSurviving Sepsis Campaign. The defini-tion of compliance focused on the appro-priate use of an intervention targeting asubthreshold hemodynamic parameterand was not dependent on the ability ofthe patient to reach the parameter target.The compliance rates during each phaseof the study were then compared with theinhospital mortality rate.

The authors reported an increase incompliance (baseline: 13%, weekly feed-back: 38%, Sepsis Response Team: 54%)associated with a decrease in the mortal-ity rate (baseline: 30%, weekly feedback:29%, Sepsis Response Team: 22%) ineach interventional phase of the studywith the largest benefit seen after imple-mentation of the multidisciplinary SepsisResponse Team.

The importance of this study lies in howthe authors approached the question. Cur-rent guidelines are mixed in their assess-ment of goals, including patient-centeredhemodynamic targets and process-basedtherapeutic targets (Table 1). Examples in-clude “Achieving central venous pressure�8” and “Achieving ScvO2 �70%,” whichgroups together two populations of pa-tients: 1) those in whom the parameter wasaddressed but unable to be met as a resultof the high degree of disease severity (eg,

*See also p. 252.Key Words: sepsis; shock; resuscitation; guide-

lines; compliance; critical careDr Arnold received funding from the National In-

stitutes of Health-Loan Repayment Program. Dr. Hol-lenberg has not disclosed any potential conflicts ofinterest.


DOI: 10.1097/CCM.0b013e318205c094


http://www.cdc.gov/hai/pdfs/stateplans/SIR_05_25_2010.pdf

http://www.cdc.gov/hai/pdfs/stateplans/SIR_05_25_2010.pdf

http://www.wrd.state.or.us/OHPPR/docs/HCAIAC/Materials/Binder_Materials/ProtocolforValidationofMandatoryReportingCLABSI.pdf



http://www.cdc.gov/nhsn/PDFs/pscManual/4PSC_CLABScurrent.pdf



central venous pressure �8 despite aggres-sive fluid resuscitation efforts); and 2) thosein whom the parameter was not measuredor unaddressed (eg, no documentation ofcentral venous pressure measurement).This combination limits the ability to iden-tify specific areas for process improvementand illustrates the need to differentiate thehemodynamic target from the presence orabsence of an attempted therapy.

Schramm et al approached this issuethrough a definition of targets defined byaddressing the unstable parameter with aspecific intervention and not dependenton achieving the normalization of thatparameter. The authors defined “appro-priate fluid” by the use of fluid boluses tomaintain central venous pressure �8mm Hg or lactate �2.5 mmol/L andurine output �0.5 mL/kg/min when themean arterial pressure was �65 mm Hgwithout vasopressors. The goal was notdefined by the ability to obtain the hemo-dynamic target of central venous pres-sure �8. Similarly, “appropriate vaso-pressor” was defined by the use ofvasopressors to address a mean arterialpressure of �65 mm Hg after a fluidbolus and not by the ability to obtain thehemodynamic target of mean arterialpressure of �65.

If we continue to combine the twocategories of targets into an overall as-sessment of guideline compliance, ascer-tainment of whether interventions are ef-fective is limited as a result of thelikelihood that the noncompliant cohortwill have a higher disease severity andmortality, making achievement of the pa-rameters less likely and thus leading to afalse association of guideline compliancewith improved outcomes. Such reportshave led to skepticism as to the use ofthese guidelines (7, 8). The current study

by Schramm et al has addressed this con-cern and has shown that in focusing onlyon the process of care and not the abilityto achieve the target, increased compli-ance with the guidelines is associatedwith increased survival.

This study did lack important infor-mation on the therapy received and tim-ing from emergency department presen-tation to intensive care unit transfer andidentification. The goals for achieving thepresent parameters and process measureswere targeted at 6 hrs from recognition ofsevere sepsis once in the intensive careunit. Although the treatment providedand time spent in the emergency depart-ment were not available, there is clearevidence that early identification and ini-tiation of therapy for sepsis can improvemortality and that waiting for intensivecare unit transfer to initiate resuscitationmeasures maybe a loss of opportunity toimprove the outcome (9–12).

Additionally, the authors are to becommended for the use of abnormal lac-tate levels to guide fluid resuscitation butcould have gone farther. The goals in thisstudy defined fluid boluses to achieve ei-ther central venous pressure �8 or lac-tate �2.5, whereas there is evidence forthe serial assessment of lactate indepen-dent of central venous pressure levels.Although these goals are not explicit ineither the Surviving Sepsis Campaign orInstitute of Health Improvement guide-lines, there is textual support that recom-mends supplementing hemodynamic endpoints of resuscitation (eg, mean arterialpressure �65) with markers of tissue per-fusion such as urine output and serumlactate. Previous observational studieshave described the association of lactateclearance (decrease in lactate by �10%)with decreased mortality in sepsis (13–

16). Although lactate clearance has notyet been incorporated as an end point ofresuscitation in current guidelines, it hasbeen shown to be an important andequivalent end point in a multicenteredrandomized controlled trial (17).

Schramm et al have shown a mortalitybenefit through increasing compliancewith the process elements of the resusci-tation guidelines for septic shock and isan important step in better defining themost effective elements. Our hope is thatfuture studies and the next iteration ofrecommendations will follow their exam-ple and differentiate physiological pa-tient-centered end points of resuscitationfrom the presence or absence of an ap-propriate intervention.

Ryan Arnold, MDDepartment of Emergency

MedicineCooper University HospitalUMDNJ-Robert Wood Johnson

Medical School at CamdenCamden, NJ

Steven Hollenberg, MDDepartment of MedicineDivision of CardiologyCooper University HospitalUMDNJ-Robert Wood Johnson

Medical School at CamdenCamden, NJ

REFERENCES

1. Opal SM, Cross AS: Clinical trials for severesepsis. Past failures, and future hopes. InfectDis Clin North Am. 1999; 13:285–297, vii

2. Dellinger RP, Levy MM, Carlet JM, et al:Surviving Sepsis Campaign: Internationalguidelines for management of severe sepsisand septic shock: 2008. Crit Care Med 2008;36:296–327

3. Gao F, Melody T, Daniels DF, et al: Theimpact of compliance with 6-hour and 24-hour sepsis bundles on hospital mortality inpatients with severe sepsis: A prospective ob-servational study. Crit Care 2005;9:R764–R770

4. Kortgen A, Niederprum P, Bauer M: Imple-mentation of an evidence-based ‘standard op-erating procedure’ and outcome in septicshock. Crit Care Med 2006; 34:943–949

5. Levy MM, Dellinger RP, Townsend SR, et al:The Surviving Sepsis Campaign: Results ofan international guideline-based perfor-mance improvement program targeting se-vere sepsis. Crit Care Med 2010; 38:367–374

6. Schramm GE, Kashyap R, Mullon JJ, et al:Septic shock: A multidisciplinary responseteam and weekly feedback to clinicians im-prove the process of care and mortality. CritCare Med 2011; 39:252–258

7. Finfer S: The Surviving Sepsis Campaign:Robust evaluation and high-quality primary

Table 1. Hemodynamic vs. therapeutic targets of resuscitation

Patient-BasedHemodynamic Target

Process-BasedTherapeutic Target

Systemic interventions Measure serum lactateEarly antibiotics within 1-hr recognitionBlood culture before antibioticsConsider rhAPC

Fluid/volume status CVP �8 mm Hg Crystalloid (1000 mL) or colloid (500 mL)fluid bolus over 30 minsUO �0.5 mL/kg/hr

Hemodynamic status MAP �65 mm Hg Norepinephrine or dopamine for MAP �65ScvO2 �70% or Consider vasopressinSvO2 �65% Hydrocortisone for refractory hypotension

Red blood cell transfusion for HCT �30%Inotrope administration for HCT �30%

CVP, central venous pressure; UO, urine output; MAP, mean arterial pressure; ScvO2, centralvenous oxygen saturation; rhAPC, recombinant human activated protein C; HCT � hematocrit.


research is still needed. Crit Care Med 2010;38:683–684

8. Machado FR, Mazza BF: Improving mortalityin sepsis: Analysis of clinical trials. Shock2010;34(Suppl 1):54–58

9. Jones AE, Brown MD, Trzeciak S, et al: Theeffect of a quantitative resuscitation strategyon mortality in patients with sepsis: A meta-analysis. Crit Care Med 2008; 36:2734–2739

10. Trzeciak S, Dellinger RP, Abate NL, et al:Translating research to clinical practice: A1-year experience with implementing earlygoal-directed therapy for septic shock in theemergency department. Chest 2006; 129:225–232

11. Shapiro NI, Howell MD, Talmor D, et al:Implementation and outcomes of the Multi-ple Urgent Sepsis Therapies (MUST) proto-col. Crit Care Med 2006; 34:1025–1032

12. Jones AE, Focht A, Horton JM, et al: Prospec-tive external validation of the clinical effec-tiveness of an emergency department-basedearly goal-directed therapy protocol for se-vere sepsis and septic shock. Chest 2007;132:425–432

13. Nichol AD, Egi M, Pettila V, et al: Relativehyperlactatemia and hospital mortality incritically ill patients: A retrospective multi-centre study. Crit Care 2010; 14:R25

14. Nguyen HB, Rivers EP, Knoblich BP, et al:

Early lactate clearance is associated with im-proved outcome in severe sepsis and septicshock. Crit Care Med 2004; 32:1637–1642

15. Bakker J, Gris P, Coffernils M, et al: Serialblood lactate levels can predict the develop-ment of multiple organ failure following sep-tic shock. Am J Surg 1996; 171:221–226

16. Arnold RC, Shapiro NI, Jones AE, et al: Mul-ticenter study of early lactate clearance as adeterminant of survival in patients with pre-sumed sepsis. Shock 2009; 32:35–39

17. Jones AE, Shapiro NI, Trzeciak S, et al: Lactateclearance vs central venous oxygen saturationas goals of early sepsis therapy: A randomizedclinical trial. JAMA 2010; 303:739–746

Stop filling patients against central venous pressure, please!*

I n this issue of Critical Care Med-icine, Boyd and colleagues (1)present the results of their studyexamining fluid balance during

resuscitation of patients suffering fromseptic shock.

The investigators studied 778 patientsoriginally enrolled in the Vasopressin AndSeptic Shock Trial (2) who had septicshock and who were receiving a mini-mum of 5 �g of noradrenaline perminute. The main objective was to deter-mine whether central venous pressureand fluid balance following resuscitationfor septic shock was associated with mor-tality. The study design was a retrospec-tive review of the use of intravenous flu-ids during the first 4 days of care in theintensive care unit. After correcting forage and Acute Physiology Assessment andChronic Health Evaluation II score, amore positive fluid balance at both 12 hrsand day 4 correlated significantly withincreased mortality. Furthermore, cen-tral venous pressure was found to be anunreliable marker of fluid balance.

Boyd and colleagues (1) present pro-vocative data on a hot topic in intensivecare medicine. The current SurvivingSepsis Guidelines (3) are based on theprotocol first applied by Rivers et a1 (4),

where they aimed to achieve mean arte-rial pressure of �65 mm Hg, central ve-nous pressure of 8–12 mm Hg, urineoutput of �0.5 mL/kg/hr, and a centralvenous oxygen saturation of �70% dur-ing the early phase of resuscitation. Byadministration of antibiotics and a strictadherence to this early goal-directedtherapy protocol, Rivers et al (4) demon-strated a highly favorable outcome.

In this new study, Boyd and colleagues(1) link a negative outcome to those whobecame fluid overloaded. This finding isalso in line with the results from theEuropean survey of critically ill patientswith sepsis, where a positive fluid balancewas found to be associated with increasedmortality (5). Furthermore, positive fluidbalance has also been shown to increasetime spent on mechanical ventilation anda trend toward increased mortality in pa-tients with acute lung injury (6). Theseand other studies highlight the need for acloser monitoring and evaluation of cur-rent practice. How should we monitorpatients suffering from severe sepsis andseptic shock? How should we specificallymonitor fluid balance in septic patientsreceiving early goal-directed therapy, andhow should fluid responsiveness be as-sessed? Current sepsis guidelines focuson targeting an optimum delivery of ox-ygen to the body through preload optimi-zation, initiation of timely and appropri-ate vasopressor and inotropic support (3).For decades central venous pressure hasbeen known to be a poor parameter forfluid balance. Dr. Swan’s group presenteddata on this issue nearly 40 yrs ago (7),and experimental and human studies

have consistently confirmed a very poorcorrelation between central venous pres-sure and preload (8). Although centralvenous pressure is a fairly good estimateof right atrial pressure, it bears little re-lation to right ventricular end-diastolicvolume, right ventricular stroke volume,and left ventricular preload (9). Accord-ingly, fluid resuscitation in septic pa-tients must be guided by other parame-ters than central venous pressure alone,as it might mislead clinicians to eitheroverfill or underfill septic patients (10).Accordingly, the present study shouldurge us to review current guidelines anddiscuss alternatives to central venouspressure as a target parameter for fluidresuscitation.

To date no randomized controlled tri-als have been designed to study dosing ofintravenous fluids in patients sufferingfrom septic shock. The present data werecorrected for age and Acute PhysiologyAssessment and Chronic Health Evalua-tion II score, yet this does not necessarilymean that these patients were equally ill.Two patients with identical Acute Physi-ology Assessment and Chronic HealthEvaluation II scores might respond dif-ferently to fluids. One patient may well bereversed by fluids and the other not.Fluid responsiveness could thus serve asa measure of illness, indirectly reflectingthe degree of inflammation and capillaryleak. Unfortunately, failure to reverseseptic shock with fluids may thus lead usto give even more fluids, leading to fur-ther organ failure and death. The presentstudy links a positive fluid balance andelevated central venous pressure to in-

*See also p. 259.Key Words: septic shock; severe sepsis; fluid re-

suscitation; sepsis guidelinesThe author has not disclosed any potential con-

flicts of interest.Copyright © 2011 by the Society of Critical Care

Medicine and Lippincott Williams & Wilkins

DOI: 10.1097/CCM.0b013e318205c375


creased mortality but did not actuallyshow a causal relationship. This is ofcourse a weakness of retrospective stud-ies. A prospective, randomized study of aliberal vs. restrictive fluid managementstrategy will be required to definitelyprove any causal relationship betweenfluid balance and mortality inpatient withsevere sepsis and septic shock.

In any case, we should continue tomonitor patients and administrate fluidsguided by parameters that can provide uswith accurate information on current he-modynamic and oxygen transport status.Most centers would thus advocate the useof calibrated devices offering intermittentor continuous cardiac index monitoringand monitor oxygen transport data viaarterial and central venous blood gases,as well as performing repeated bedsideclinical assessments. Dynamic responsesto volume challenge by using eitherstroke volume variation or pulse pressurevariation are both highly sensitive andspecific for preload responsiveness in me-chanical ventilated patients, whereas thepassive straight leg test should be used inspontaneously breathing patients (11).However, arrhythmias, spontaneousbreathing efforts, as well as low tidal vol-umes are known to reduce accuracy ofthese two parameters (12). Accordingly,data must be interpreted with these lim-itations in mind. Echocardiographic

methods for assessment of cardiac func-tion and fluid responsiveness provide use-ful complimentary information in thiscontext. However, we should remind our-selves that no single parameter should beevaluated in isolation. Resuscitation fromsevere sepsis and septic shock remains adynamic clinical challenge. Indeed, fluidsdo make a difference and that is why weshould stop filling patients against cen-tral venous pressure.

Lars Marius Ytrebø, MDUniversity Hospital of North

NorwayTromso, Norway

REFERENCES

1. Boyd JH, Forbes J, Nakada T, et al: Fluidresuscitation in septic shock: A positive fluidbalance and elevated central venous pressureare associated with increased mortality. CritCare Med 2011; 39:259–265

2. Russell JA, Walley KR, Singer J, et al: Vaso-pressin versus norepinephrine infusion inpatients with septic shock. N Engl J Med2008; 358:877–887

3. Dellinger RP, Levy MM, Carlet JM, et al:Surviving Sepsis Campaign: internationalguidelines for management of severe sepsisand septic shock: 2008. Intensive Care Med2008; 34:17–60

4. Rivers E, Nguyen B, Havstad S, et al: Earlygoal-directed therapy in the treatment of se-vere sepsis and septic shock. N Engl J Med2001; 345:1368–1377

5. Vincent JL, Sakr Y, Sprung CL, et al: Sepsis

in European intensive care units: Results ofthe SOAP study. Crit Care Med 2006; 34:344–353

6. National Heart, Lung, and Blood InstituteAcute Respiratory Distress Syndrome (ARDS)Clinical Trials Network, Wiedemann HP,Wheeler AP, et al: Comparison of two fluid-management strategies in acute lung injury.N Engl J Med 2006; 354:2564–2575

7. Forrester JS, Diamond G, McHugh TJ, et al:Filling pressures in the right and left sides ofthe heart in acute myocardial infarction. Areappraisal of central-venous-pressure mon-itoring. N Engl J Med 1971; 285:190–193

8. Marik PE, Baram M, Vahid B: Does centralvenous pressure predict fluid responsive-ness? A systematic review of the literatureand the tale of seven mares. Chest 2008;134:172–178

9. Osman D, Ridel C, Ray P, et al: Cardiac fillingpressures are not appropriate to predict he-modynamic response to volume challenge.Crit Care Med 2007; 35:64–68

10. Perel A: Bench-to-bedside review: The initialhemodynamic resuscitation of the septic pa-tient according to Surviving Sepsis Cam-paign guidelines–does one size fit all? CritCare 2008; 12:223

11. Marik PE: Techniques for assessment of in-travascular volume in critically ill patients.J Intensive Care Med 2009; 24:329–337

12. Marik PE, Cavallazzi R, Vasu T, et al: Dy-namic changes in arterial waveform derivedvariables and fluid responsiveness in me-chanically ventilated patients: A systematicreview of the literature. Crit Care Med 2009;37:2642–2647

What is the evidence for glucose control in children undergoingcardiac surgery?*

Critically ill patients commonlydevelop transient, stress-in-duced hyperglycemia, whichhistorically was presumed to

be adaptive and generally not treated.However, triggered in large part by thepublication of the landmark Leuven Uni-versity Hospital adult surgical intensive

care unit trial, which found that the useof insulin to achieve normoglycemia wasassociated with decreased mortality, thetopic has been the focus on substantialinvestigation and debate over the last de-cade (1). Numerous observational studiesin various critically ill adult patient pop-ulations have found associations betweenhyperglycemia and adverse outcomes.Mechanisms of critical illness-relatedglucose toxicity described in adults in-clude proinflammatory effects and immu-noparesis as well as mitochondrial, endo-thelial, and neuronal dysfunction, amongothers (2–4). However, in recent years,the initial enthusiasm for tight glycemiccontrol during critical illness in adults

has been tempered by the fact that twomulticenter adult trials have been termi-nated prematurely for lack of efficacy andsafety concerns related to excessive ratesof hypoglycemia (5, 6). Even more con-cerning were the findings of a third mul-ticenter trial in which patients assignedto tight glycemic control had increasedmortality compared with the controlgroup, in whom the glucose target rangewas 144–180 mg/dL (7). Differences innutritional support, nursing expertise,glucose target ranges, and measurementsystems may explain some of the discrep-ant findings.

Similar to adult data, the majority ofobservational studies in children under-

*See also p. 266.Key Words: pediatrics; intensive care; hyperglyce-

mia; cardiovascular surgery.The author has not disclosed any potential con-



DOI: 10.1097/CCM.0b013e318205c2f1


going cardiac surgery has found an asso-ciation between early postoperative hy-perglycemia and adverse outcomes (8, 9).It is unknown whether similar mecha-nisms of glucose toxicity described inadults are operative in critically ill chil-dren. Of note, intraoperative hyperglyce-mia has not been found to be associatedwith adverse acute or neurodevelopmen-tal outcomes in infants (8, 10). This maybe related to abnormalities in substratedelivery or use under the abnormal per-fusion conditions associated with intra-operative circulatory support and theshort duration of intraoperative expo-sure to high glucose levels—typicallyonly 4 – 6 hrs—relative to the postoper-ative period.

The study by Moga et al (11) in thisissue of Critical Care Medicine providesadditional insight into this issue. In thisretrospective, single-center cohort study,the investigators sought to identify asso-ciations between early postoperative hy-perglycemia and adverse outcomes in 772children undergoing cardiac surgery. Ad-ditional aims were to determine whetherage or the presence of residual cardiaclesions requiring reintervention duringthe same hospitalization modified theseassociations, to characterize the extentand duration of postoperative hyperglyce-mia, and to identify risk factors for thedevelopment of hyperglycemia. The pri-mary outcome measure was a compositevariable that included one or more of thefollowing: death, cardiac arrest, extracor-poreal membrane oxygenation use, infec-tion, renal failure, and liver failure. Priorstudies have purported a causal relation-ship between hyperglycemia and most ofthese end points, thus providing someexternal validity to its use as a primaryend point.

This study design used by Moga et alovercame several deficiencies that weak-ened some of the earlier efforts to explorethis issue. The sample size was relativelylarge, which allowed for meaningful mul-tivariate analyses, subgroup analyses, andidentification of a dose–response rela-tionship. The assessment of glucose lev-els was limited to the first 72 hrs aftersurgery, ensuring that the exposure oc-curred before the outcomes of interest.This study had a number of importantfindings. Prior reports that hyperglyce-mia is common after pediatric cardiacsurgery yet rarely treated with insulinwere reaffirmed. Glucose levels were ele-vated in 90% of study patients on inten-sive care unit admission, yet insulin was

only used in 5%. Younger patients whoreceived intraoperative corticosteroidsand underwent more complex procedureswere at greater risk for developing hyper-glycemia. Patients with significant post-operative hyperglycemia were at greateradjusted odds of reaching the compos-ite morbidity—mortality outcome andseveral secondary outcomes, and theserelationships were dose-dependent. Theincremental risk attributable to hyper-glycemia for reaching the compositemorbidity–mortality outcome was lessin neonates and patients with residualcardiac lesions. These findings are in-teresting in that such patients were athigher risk for developing early postop-erative hyperglycemia as noted previ-ously yet appear to tolerate it for alonger period of time. Of note, in somepatients, the presence of a residual car-diac lesion may not be evident for sev-eral days or longer after the initial op-eration. Thus, the presence of residuallesions cannot practically be used toidentify a subset of patients who couldreceive a modified approach to earlypostoperative tight glycemic control.

Like with all retrospective studies ofthis nature, the associations identified inthe Moga study do not prove causality. Tojustify a change in clinical practice, addi-tional evidence is needed from multipleclinical trials. In the sole pediatric trial ofglycemic control published to date, Vlas-selaers et al (12) randomized 700 criti-cally ill children, 75% of whom were re-covering from cardiac surgery, tointensive insulin therapy in which age-related normal glucose values were tar-geted, or conventional therapy, in whichhyperglycemia was only treated whenglucose levels exceeded 214 mg/dL. Pa-tients assigned to the intensive insulintherapy group had a reduced inflamma-tory state as assessed by C-reactive pro-tein levels, a reduction in intensive careunit length of stay, and a reduction inmortality (3% vs. 6%, p � .038). In thistrial, 25% of children assigned to tightglycemic control experienced at least oneepisode of severe hypoglycemia comparedwith 1% in the control group (12). Thesignificance of hypoglycemia in the set-ting of intensive insulin therapy, al-though concerning, is unknown and war-rants further investigation. It is likelythat continuous glucose monitoring willbecome an important aspect of glycemiccontrol protocols in critically ill patients(13). Two additional ongoing trials willprovide additional evidence regarding the

role of tight glycemic control in criticallyill children. Investigators at two largecardiac programs in the United States arerandomly assigning over 1000 youngchildren to receive either tight glycemiccontrol or usual therapy in the early post-operative period (ClinicalTrials.gov pro-tocol #NCT00443559). A multicenter trialinvolving 1500 children, approximately50% of whom are recovering from car-diac surgery, is also being conducted inthe United Kingdom (14). Data fromthese trials and more large and well-executed observational studies like theone discussed are clearly needed to defineoptimal practice.

John M. Costello, MD, MPHDepartment of PediatricsNorthwestern University

Feinberg School ofMedicine

Regenstein Cardiac Care UnitDivision of CardiologyChildren’s Memorial HospitalChicago, IL

REFERENCES

1. van den Berghe G, Wouters P, Weekers F, etal: Intensive insulin therapy in the criticallyill patients. N Engl J Med 2001; 345:1359–1367

2. Vanhorebeek I, De Vos R, Mesotten D, et al:Protection of hepatocyte mitochondrial ul-trastructure and function by strict blood glu-cose control with insulin in critically ill pa-tients. Lancet 2005; 365:53–59

3. Van den Berghe G, Schoonheydt K, Becx P, etal: Insulin therapy protects the central andperipheral nervous system of intensive carepatients. Neurology 2005; 64:1348–1353

4. Langouche L, Vanhorebeek I, Vlasselaers D,et al: Intensive insulin therapy protects theendothelium of critically ill patients. J ClinInvest 2005; 115:2277–2286

5. Brunkhorst FM, Engel C, Bloos F, et al: In-tensive insulin therapy and pentastarch re-suscitation in severe sepsis. N Engl J Med2008; 358:125–139

6. Preiser JC, Devos P, Ruiz-Santana S, et al: Aprospective randomised multi-centre con-trolled trial on tight glucose control by in-tensive insulin therapy in adult intensivecare units: The Glucontrol study. IntensiveCare Med 2009; 35:1738–1748

7. Finfer S, Chittock DR, Su SY, et al: Intensiveversus conventional glucose control in criti-cally ill patients. N Engl J Med 2009; 360:1283–1297

8. Polito A, Thiagarajan RR, Laussen PC, et al:Association between intraoperative and earlypostoperative glucose levels and adverse out-comes after complex congenital heart sur-gery. Circulation 2008; 118:2235–2242

9. Yates AR, Dyke PC, Taeed R, et al: Hypergly-cemia is a marker for poor outcome in the


postoperative pediatric cardiac patient. Pedi-atr Crit Care Med 2006; 7:351–355

10. de Ferranti S, Gauvreau K, Hickey PR, et al:Intraoperative hyperglycemia during infantcardiac surgery is not associated with adverseneurodevelopmental outcomes at 1, 4, and 8years. Anesthesiology 2004; 100:1345–1352

11. Moga M-A, Manlhiot C, Marwali EM, et al:

Hyperglycemia after pediatric cardiac sur-gery: Impact of age and residual lesions. CritCare Med 2011; 39:266–272

12. Vlasselaers D, Milants I, Desmet L, et al:Intensive insulin therapy for patients in pae-diatric intensive care: A prospective, random-ised controlled study. Lancet 2009; 373:547–556

13. Piper HG, Alexander JL, Shukla A, et al: Real-time continuous glucose monitoring in pe-diatric patients during and after cardiac sur-gery. Pediatrics 2006; 118:1176–1184

14. Macrae D, Pappachan J, Grieve R, et al: Con-trol of hyperglycaemia in paediatric intensivecare (CHiP): Study protocol. BMC Pediatr2010; 10:5

Regional anticoagulation with citrate: Expanding its indications*

Regional anticoagulation withcitrate is increasingly recog-nized as an alternative to hep-arin in critically ill patients

treated with continuous renal replace-ment therapy (1). Citrate reduces hemor-rhage and improves patency, clearancerates, and biocompatibility of hemofilters(2–5). For anticoagulation, citrate is in-fused prefilter into the extracorporeal cir-cuit. Citrate achieves its anticoagulatoryeffect by chelating ionized calcium. Anionized calcium concentration of �0.4mmol/L within the extracorporeal circuitis sufficient to maintain a good antico-agulatory effect. This is generallyachieved by a blood citrate concentrationof approximately 4 mmol of citrate perliter blood (2, 3).

However, the use of citrate as an an-ticoagulant has its limitations. Substan-tial amounts of the infused citrate enterthe systemic circulation and have to bemetabolized. In the physiologic situation,citrate gets rapidly metabolized to bicar-bonate mainly in the liver and to a lesserextent also in the muscles and other tis-sues (6). In patients with a disturbed liverfunction, citrate may accumulate, henceleading to citrate toxicity (7–9). Circulat-ing citrate ions will bind to calcium ionsin circulating blood with a consecutivedrop of the systemic ionized calcium. Inthis circumstance, total calcium concen-tration remains constant or increases, de-pending on the amount of calcium in-fused to correct the decrease in ionizedcalcium levels. In parallel, metabolic ac-

idosis may occur due to a less effectivemetabolization of citrate to bicarbonate.Metabolic acidosis may be enhanced bythe accumulation of free citrate ions lead-ing to metabolic acidosis with increasedanion gap (7).

Although citrate is increasingly usedfor regional anticoagulation in criticallyill patients on renal replacement therapy,data regarding the metabolism, risk, andperceptibility of citrate accumulation inliver failure patients are rare. Impairedcitrate metabolism has been described inpatients with acute liver failure (8, 9) andduring the anhepatic phase of liver trans-plantation (10, 11). Kramer et al (12)found a decreased total-body clearanceafter a 2-hr infusion of citrate in livercirrhosis compared with noncirrhotic pa-tients. Systemic citrate clearance rateswere 710 mL/min for noncirrhotic and340 mL/min for cirrhotic patients (p �.02). Citrate baseline and peak concentra-tions as well as area under the curve andelimination half-life time were also in-creased in these patients. Apsner et al (8)described even lower clearance rates inpatients with acute liver failure.

It is well accepted that systemic clear-ance of citrate is not predictable withstandard laboratory parameters (9, 12,13). As a consequence attempts have beenmade to define a good surrogate markerfor an impaired citrate metabolism. Inthis regard an increase in the total cal-cium to systemic ionized calcium ratiohas been found to be a good indicator forcitrate accumulation (9, 12, 13). Thisusually goes parallel with an unusuallyhigh calcium supplementation require-ment to maintain a normal systemic ion-ized calcium value.

Citrate anticoagulation is theoreticallyvery attractive for patients with hepaticfailure because it effectively reduces thesubstantial risk of bleeding associatedwith heparin anticoagulation for extra-

corporeal therapies in these patients. Incirrhotic patients, the use of heparin ad-ditionally is hampered by low concentra-tions of antithrombin III, which fre-quently leads to a coincidence ofextracorporeal clotting and clinical bleed-ing (14). However, clinicians often refrainfrom using regional citrate anticoagula-tion in these patients in fear of citratetoxicity. In this issue of Critical CareMedicine, Faybik and colleagues (15)present a prospective observational trialin 20 acute liver failure patients receivingregional anticoagulation with citrate dur-ing liver support provided by a molecularadsorbent recirculation system (MARS).All patients had a high Model for End-Stage Liver Disease score indicative foran advanced liver disease. The aim of thestudy was to evaluate the feasibility andsafety of the procedure as well as its ef-fects on electrolyte and acid-base balance.The median duration of MARS treatmentwas 20 hrs. Each patient received a me-dian of three MARS treatments. The in-terval in between MARS session rangedbetween 2 and 4 hrs. Regional citrateanticoagulation of the extracorporeal cir-cuit was provided by 4% trisodium citratesolution with a median infusion rate of3.1 mmol/L blood flow. System patencywas excellent and reached nearly 100% inthis study. Only two MARS treatments(2%) were prematurely discontinued dueto filter clotting and gastrointestinalbleeding, respectively. In contrast to this,a previously published study from thesame group observed a significantlyhigher clotting incidence when using sys-temic unfractioned heparin in combina-tion with prostaglandin I2 for anticoagu-lation of the MARS system (16). Regionalanticoagulation with citrate was well tol-erated in all liver failure patients. Al-though an increase in the total to sys-temic ionized calcium ratio was observed,critical levels were not achieved. No clin-

*See also p. 273.Key Words: regional anticoagulation with citrate;

liver failure; molecular adsorbent recirculation systemThe author has not disclosed any potential con-



DOI: 10.1097/CCM.0b013e318205c500


ical signs related to hypocalcemia or hy-percalcemia were observed. Acid-base sta-tus during the treatments was wellmaintained with a slight alkalinization ofthe blood. No further side effects wereobserved. The authors concluded that re-gional anticoagulation with citrate is asafe and feasible method to maintain ad-equate circuit lifespan without increasingthe risk of hemorrhagic complications inpatients with liver failure supported byMARS.

This study is an essential contribu-tion toward a broader implementationof regional citrate anticoagulation incontinuous renal replacement therapyand MARS. It very nicely shows thatliver failure does not represent a strongcontraindication for use of citrate. Nev-ertheless, a prudent approach is man-datory. Regional anticoagulation withcitrate remains a challenge. A very closemonitoring of the calcium householdand the acid-base status in patients withadvanced liver failure is strongly recom-mended to detect prematurely patientswith citrate accumulation. Further stud-ies, including more patients are neededto expand our knowledge on this field ofacute medicine.

Stanislao Morgera, MDDepartment of NephrologyUniversity Hospital ChariteCampus MitteBerlin, Germany

REFERENCES

1. Mehta RL, McDonald BR, Aguilar MM, et al:Regional citrate anticoagulation for continu-ous arteriovenous hemodialysis in criticallyill patients. Kidney Int 1990; 38:976–981

2. Hetzel GR, Schmitz M, Wissing H, et al:Regional citrate versus systemic heparin foranticoagulation in critically ill patients oncontinuous venovenous haemofiltration: Aprospective randomized multicentre trial.Nephrol Dial Transplant 2010; In Press

3. Morgera S, Schneider M, Slowinski T, et al: Asafe citrate anticoagulation protocol withvariable treatment efficacy and excellent con-trol of the acid-base status. Crit Care Med2009; 37:2018–2024

4. Bohler J, Schollmeyer P, Dressel B, et al:Reduction of granulocyte activation duringhemodialysis with regional citrate anticoag-ulation: Dissociation of complement activa-tion and neutropenia from neutrophil de-granulation. J Am Soc Nephrol 1996;7:234–241

5. Bos JC, Grooteman MP, van Houte AJ, et al:Low polymorphonuclear cell degranulationduring citrate anticoagulation: A comparisonbetween citrate and heparin dialysis. NephrolDial Transplant 1997; 12:1387–1393

6. Wexler IB, Pincus JB, Natelson S, et al: Thefate of citrate in erythroblastic infantstreated with exchange transfusion. J Clin In-vest 1949; 28:474–481

7. Nowak MA, Campbell TE: Profound hypercal-cemia in continuous veno-venous hemofil-tration dialysis with trisodium citrate antico-agulation and hepatic failure. Clin Chem1997; 43:412–413

8. Apsner R, Schwarzenhofer M, Derfler K, et al:

Impairment of citrate metabolism in acutehepatic failure. Wien Klin Wochenschr 1997;109:123–127

9. Meier-Kriesche HU, Gitomer J, Finkel K, etal: Increased total to ionized calcium ratioduring continuous venovenous hemodialysiswith regional citrate anticoagulation. CritCare Med 2001; 29:748–752

10. Diaz J, Acosta F, Parrilla P, et al: Citrateintoxication and blood concentration of ion-ized calcium in liver transplantation. Trans-plant Proc 1994; 26:3669–3670

11. Marquez J, Martin D, Virji MA, et al: Cardio-vascular depression secondary to ionic hy-pocalcemia during hepatic transplantation inhumans. Anesthesiology 1986; 65:457–461

12. Kramer L, Bauer E, Joukhadar C, et al: Ci-trate pharmacokinetics and metabolism incirrhotic and noncirrhotic critically ill pa-tients. Crit Care Med 2003; 31:2450–2455

13. Hetzel GR, Taskaya G, Sucker C, et al: Citrateplasma levels in patients under regional an-ticoagulation in continuous venovenous he-mofiltration. Am J Kidney Dis 2006; 48:806–811

14. Wilkinson AH, Ash SR, Nissenson AR: Hemo-diabsorption in treatment of hepatic failure.J Transpl Coord 1998; 1:43–50

15. Faybik P, Hetz H, Mitterer G, et al: Regionalcitrate anticoagulation in patients with liverfailure supported by a molecular adsorbentrecirculating system. Crit Care Med 2011;39:273–279

16. Faybik P, Bacher A, Kozek-Langenecker SA,et al: Molecular adsorbent recirculating sys-tem and hemostasis in patients at high riskof bleeding: An observational study. Crit Care2006; 10:R24

Resolving issues of consent and oversight: One step closer to terrafirma in deceased organ donor research*

I t is well known that the nation’sneed for organ transplantation faroutstrips the organ supply. Simi-larly disconcerting but perhaps a

less well-known fact is that the number ofdonors, both living and deceased, have

reached a plateau in the past 4–5 yrs in theUnited States. Furthermore, during thesame period, the proportion of extendedcriteria donors (cardiac death and older do-nors) has steadily increased, partly ac-counting for the marginal increase in kid-ney graft survival over a decade (89 –91% between 1998 to 2007; data fromOPTN/SRTR Annual Report 2009, http://www.unos.org, accessed November 6,2010). In addition, approximately 16 –19% and 9–11% of recovered kidneys andlivers, respectively, are deemed unsuit-able for transplantation, figures that havenot decreased during the past 5 yrs (datafrom www.unos.org, accessed November6, 2010). Thus, improving the quality of

deceased donor organs has a real potential tocontribute to improved transplant outcomesand, therefore, must become an importantagenda for research. New donor interventionstested under rigorous standards of prospec-tive randomized trials comprise an importantphalanx in this thrust.

However, a review of donor manage-ment research reveals several obstacles thatneed redress. These include but are notlimited to 1) increased funding by the Na-tional Institutes of Health and other fund-ing agencies; 2) resolving issues of in-formed consent in both donors andrecipients; 3) a streamlining of the regula-tory/oversight process (1–3); and 4) bring-ing the numerous stakeholders together.

*See also p. 280.Key Words: deceased donors; organ quality; trans-

plant outcomes; informed consent; research oversight;randomized clinical trials

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


DOI: 10.1097/CCM.0b013e318206b0eb


It is against this backdrop that the re-port of Rey et al (1) in this issue of theJournal is pertinent. The authors, who areexperts in the field of ethics and clinicaltrials, especially pertaining to transplanta-tion, deserve credit for serving as catalystsin the nascent area of research oversightand informed consent in deceased donormanagement research. We agree with thekey principles espoused by the authors. Ob-taining recipient consent before enrollingdonors in large, multicentered research stud-ies is not only impractical, but in some in-stances such as with studies involving kidneyrecipients impossible. Apart from practicality,the sound ethical arguments espoused by theauthors in this and other publications (3, 4)are cogent and lay the foundation for exemp-tion of obtaining informed consent from therecipients. How and when should recipientsbe informed of the potential or actual receiptof organs from donors enrolled in researchstudies? As discussed by Rey et al (1), thiscould occur either at the time of listing orsoon after transplantation. On the otherhand, in single-institution, small, single or-gan-specific studies in which the recipientsare clearly known well before the interven-tion, it may be appropriate to require in-formed consent from recipients. However,such instances are likely to be few.

With reference to donor consent, theauthors muster very clear and convincingarguments in favor of having either first-person or next of kin/legal guardian con-sent as is the case for organ donation. Sim-ilar arguments have been formulatedearlier by them and others (3, 5, 6). Giventhe stress the donor families are under, theconsent document must be succinct.Whether consent is obtained as an integralpart of consent for organ donation and re-lated research or is protocol-specific would

be context-dependent and is best left open,at least for now. However, our personalexperience with a local ongoing studywould indicate that next of kin are morelikely to agree to specific protocols aimed atimproving organ quality when comparedwith consent for general research. Consentby telephone should be permissible. This isimportant because in quite a few instances,the next of kin are not in geographic prox-imity to the donor hospital and may not beavailable when the research team arrives.

In the regulatory arena, several prob-lems exist as enunciated by the authors.Importantly, they stem from the currentexclusion of deceased donors as human re-search subjects under the current Com-mon Rule. Certainly, the regulatory frame-work proposed by the authors that involvesa system of hierarchy within the OrganProcurement and Transplantation Net-work, which at a grass root level wouldinvolve local organ procurement organiza-tion, is very valid. It would render the over-sight process more uniform. Although weagree that Institutional Review Boards indonor hospitals often do not wish to beinvolved, several of the Institutional ReviewBoards of investigators’ institutions (in-cluding ours) have taken a very active rolein the oversight process and may be greatlyreluctant to cede such authority. Anotheralternative might be oversight by other or-ganizations such as the Western Institu-tional Review Board. Many academic Insti-tutional Review Boards in this countrycurrently work in concert with such enti-ties. Irrespective of who performs the over-sight, having a uniform process is very vi-tal. In any oversight algorithm, the organprocurement organization should serve asa lynchpin given their vantage position onmany fronts such as rapport with donor

families and community members, under-standing of the research, and interactionwith transplant professionals not only atthe local, but at the national level.

Finally, along the lines of Organ Dona-tion Breakthrough Collaborative bringingtogether all the stakeholders involved suchas organ procurement organizations, trans-plant physicians, intensivists, critical carenurses, ethicists, Institutional ReviewBoard personnel, and patient communityrepresentatives, perhaps under the auspicesof the Health Resources and Services Admin-istration, is also very likely to further promotedeceased donor management research.

Cesar Mora-Esteves, MDBaburao Koneru, MD

Department of SurgeryNew Jersey Medical SchoolNewark, NJ

REFERENCES

1. Rey MM, Ware LB, Matthay MA, et al: In-formed consent in research to improve thenumber and quality of deceased donor organs.Crit Care Med 2011; 39:280–283

2. Feng S: Donor intervention and organ preser-vation: Where is the science and what are theobstacles? Am J Transplant 2010; 10:1155–1162

3. Pentz RD, Cohen CB, DeVita MA, et al:Ethics guidelines for research with the re-cently dead. Nat Med 2005; 11:1145–1149

4. Halpern SD, Shaked A, Hasz RD, et al: Inform-ing candidates for solid-organ transplantationabout donor risk factors. N Engl J Med 2008;358:2832–2837

5. Wicclair MR, DeVita M: Oversight of researchinvolving the dead. Kennedy Inst Ethics J2004; 14:143–164

6. Tomasini F: Research on the recently dead: Anhistorical and ethical examination. B Med Bull2008; 85:7–16


Stroke volume variation: From applied physiology to improvedoutcomes*

I n this issue, Loupec et al (1) putanother brick in the wall of clini-cal studies demonstrating that leftventricular stroke volume varia-

tion (SVV) induced by mechanical venti-lation is an accurate predictor of fluidresponsiveness. They used pulse pressurevariation (PPV) and pulse oximetry vari-ations to quantify SVV. Although themethod Loupec et al (1) used to increasepreload was not standardized (they mixed500-mL colloid boluses with passive legraising maneuvers) and despite the factthey assessed fluid responsiveness withan operator-dependent technique (echo-cardiography), they observed amazing re-sults for PPV; the cutoff value of 10% wasable to discriminate between respondersand nonresponders to preload increasewith a specificity of 95% and a sensitivityof 100%! A good performance was alsoreported for pulse oximetry variation.

The question today is no longer to knowif SVV and its surrogates predict fluid re-sponsiveness (the answer was yes in �25clinical studies!) (2) but how, when, andwhy we should assess and use SVV.

How Can We Assess SVV?

First, SVV can be assessed using echo-cardiography Doppler (3). A transthoracicor transgastric view of the heart allowsvisualization of the left ventricular out-flow track and the measurement of itsdiameter. Then, Doppler allows the mea-

surement of blood velocity at the verysame location. The product of the veloc-ity time integral by the outflow track areagives an estimate of stroke volume. Suc-cessive measurements of stroke volumeover at least one mechanical breath allowthe determination of SVV. Although thismethod is useful for research and/orwhen an echocardiography is performed,obviously it cannot be used to guide fluidtherapy in routine clinical practice.

In patients with an arterial line, the sys-tolic pressure variation and PPV have beenproposed as surrogates for SVV. The pulsepressure being directly proportional tostroke volume, PPV has been shown to besuperior to systolic pressure variation topredict fluid responsiveness (4).

New methods allow the beat-to-beatcomputation of stroke volume from arte-rial pressure curves and the automaticcalculation of SVV over a short period oftime. Several studies have shown thatthey are also very accurate to assess SVVand to predict fluid responsiveness (3, 5).

More recently, noninvasive methodshave also been proposed to assess SVVfrom a pulse oximetry waveform. Al-though appealing, these new approacheshave yielded conflicting results so far (5,6). It has been suggested that pulse oxim-etry waveform variations are influencedby sympathetic oscillations in skin micro-circulation (6). They also depend on thesite of measurement (finger, forehead, orearlobe) (7). Whether pulse oximetrywaveform variations can be used as a sur-rogate for SVV in hypotensive patientsand/or in patients with peripheral vaso-constriction also remains to be deter-mined. Of note, Loupec et al (1) wereunable to assess pulse oximetry variationin five patients with peripheral hypoper-fusion (who were excluded from thestudy) and the majority of the remainingstudy population had a normal bloodpressure. They also report a significantcorrelation between the perfusion index(a marker of peripheral perfusion) andthe difference between the invasive PPVand the noninvasive pulse oximetry vari-

ation, suggesting that pulse oximetryvariation is less accurate when the pe-ripheral circulation is shut down.

When Can We Use SVV?

There are several limitations to theuse of SVV. They have been described indetail elsewhere (2) and are summarizedhere as “SOS.” The first S stands forSmall tidal volume and Spontaneousbreathing activity; the O stands for Openchest. In these conditions, changes in in-trathoracic pressure are usually too smallto induce significant changes in venousreturn. As a result, false-negative (smallSVV in fluid responders) may be ob-served. The second S stands for Sustainedcardiac arrhythmia because SVV reflectsaltered cardiac filling times rather thanthe effects of mechanical ventilation inthis setting. Recent software has beendeveloped to handle multiple prematurecontractions and has been validated inanimals (8), but atrial fibrillation still re-mains an issue.

In critically ill patients, mechanicalventilation and sedation are the enemiesso they are stopped as soon as possible.Small tidal volumes are also recom-mended to prevent ventilator-inducedlung injury. The prevalence of cardiacarrhythmia is approximately 12% (9). Forthese reasons, SVV cannot be used inmany intensive care unit patients. In pa-tients undergoing surgery, Maguire et al(10) have recently studied the prevalenceof SVV limitations. A total of 7508 of the12,308 patients (61%) who had under-gone surgery in 2009 at University ofCalifornia Irvine, Orange, CA, had limita-tions to the use of SVV, mainly because ofregional anesthesia and low tidal volume.

Is SVV Useful to ImproveOutcome?

Ensuring high-risk surgical patientsare on the plateau of the Frank-Starlingcurve is useful to prevent both hypo- andhypervolemia and ultimately to improvepostoperative outcome (11). SVV is a

*See also p. 294.Key Words: stroke volume variation; pulse pres-

sure variation; plethysmographic variation index; fluidresponsiveness; fluid optimization; high-risk surgery;postoperative outcome

Dr. Michard is a director at Edwards Lifesciences;he is also co-inventor on patent US 2007179386(method to detect automatically and correct for limi-tations to the use of stroke volume variation, pulsepressure variation, or pulse oximetry variation) and onpatent US 2010137828 (closed loop systems integrat-ing stroke volume variation, pulse pressure variation,or pulse oximetry variation as input parameters).


DOI: 10.1097/CCM.0b013e318205c0a6


marker of the position on the Frank-Starling curve; when SVV is high, thepatient’s heart is operating on the steepportion of the curve, and when SVV islow, it has reached the plateau of thecurve. In the absence of limitations, SVVcan therefore replace stroke volumemonitoring to bring patients toward theplateau of the Frank-Starling curve (Fig.1). Koff et al (12) have recently comparedthe outcome of two groups of patientsundergoing high-risk surgery. The groupin whom PPV was �13% during surgeryhad a better outcome than the othergroup (PPV �13%). Lopes et al (13) werethe first to test prospectively the effects ofminimizing PPV (�10%) during surgeryand they observed a significant reductionin postoperative complications and hos-pital length of stay. These findings havebeen recently confirmed by three ran-domized controlled trials (14 –16) inwhich SVV was monitored continuouslywith the FloTrac/Vigileo system (EdwardsLifesciences, Irvine, CA) and minimizedbelow 10–12% by colloid boluses.

In conclusion, SVV and surrogates aregood predictors of fluid responsiveness.In patients undergoing high-risk surgery,they are useful intraoperatively to titratecolloid administration and ultimately im-prove outcome. They are available todayon virtually all bedside and hemodynamicmonitors, indicating they are already part

of routine clinical practice. Limitationsto the use of SVV and surrogates areobserved in many patients, particularly inintensive care units. They can be by-passed by monitoring online the effects offluid loading (or passive leg raising) onstroke volume using fast response cardiacoutput monitors (17).

Frederic Michard, MD, PhDEdwards LifesciencesNyon, Vaud, Switzerland

REFERENCES

1. Loupec T, Nanadoumgar H, Frasca D, et al:Pleth variability index predicts fluid respon-siveness in critically ill patients. Crit CareMed 2011; 39:294–299

2. Michard F: Changes in arterial pressure dur-ing mechanical ventilation. Anesthesiology2005; 103:419–428

3. Biais M, Nouette-Gaulain K, Roullet S, et al:A comparison of stroke volume variationmeasured by Vigileo/FloTrac system and aor-tic Doppler echocardiography. Anesth Analg2009; 109:466–469

4. Michard F, Boussat S, Chemla D, et al: Rela-tionship between respiratory changes in ar-terial pulse pressure and fluid responsivenessin septic patients with acute circulatory fail-ure. Am J Respir Crit Care Med 2000; 162:134–138

5. Zimmermann M, Feibicke T, Keyl C, et al:Accuracy of stroke volume variation com-pared with Pleth variability index to predictfluid responsiveness in mechanically venti-

lated patients undergoing major surgery.Eur J Anaesthesiol 2010; 27:555–561

6. Landsverk SA, Hoiseth LO, Kvandal P, et al:Poor agreement between respiratory varia-tions in pulse oximetry photoplethysmo-graphic waveform amplitude and pulse pres-sure in intensive care unit patients.Anesthesiology 2008; 109:849–855

7. Shelley KH, Jablonka DH, Awad AA, et al:What is the best site for measuring the effectof ventilation on the pulse oximeter wave-form? Anesth Analg 2006; 103:372–377

8. Cannesson M, Cho M, Hatib F, et al: Predict-ing fluid responsiveness with stroke volumevariation during cardiac arrhythmia. Anes-thesiology 2010; 113:A642

9. Annane D, Sebille V, Duboc B, et al: Inci-dence and prognosis of sustained arrhyth-mias in critically ill patients. Am J RespirCrit Care Med 2008; 178:20–25

10. Maguire S, Rinehart J, Vakharia S, et al:Respiratory variation in pulse pressure andplethysmographic waveforms: Intraoperativeapplicability in a north american academiccenter. Anesth Analg 2010 Oct 26 [E-pubahead of print]

11. Lees N, Hamilton M, Rhodes A: Clinical re-view: Goal-directed therapy in high risk sur-gical patients. Crit Care 2009; 13:231

12. Koff MD, Richard KM, Novak MR, et al: Ele-vated PPV predicts an increased length ofstay and morbidity during high risk abdom-inal surgery. Anesthesiology 2010; 113:A1383

13. Lopes MR, Oliveira MA, Pereira VO, et al:Goal-directed fluid management based onpulse pressure variation monitoring duringhigh-risk surgery: A pilot randomized con-trolled trial. Crit Care 2007; 11:R100

14. Mayer J, Boldt J, Mengistu AM, et al: Goal-directed intraoperative therapy based on au-tocalibrated arterial pressure waveform anal-ysis reduces hospital stay in high-risksurgical patients: A randomized, controlledtrial. Crit Care 2010; 14:R18

15. Benes J, Chytra I, Altmann P, et al: Intraop-erative fluid optimization using stroke vol-ume variation in high risk surgical patients:Results of prospective randomized study.Crit Care 2010; 14:R118

16. Ramsingh D, Gamboa J, Applegate R: Evalu-ation of a goal-directed protocol inlow–moderate risk patients having major ab-dominal surgery. Anesthesiology 2010; 113:A1137

17. Biais M, Vidil L, Sarrabay P, et al: Changes instroke volume induced by passive leg raisingin spontaneously breathing patients: Com-parison between echocardiography and Vigi-leo/FloTrac device. Crit Care 2009; 13:R195

Figure 1. Stroke volume variation (SVV) is a marker of the position on the Frank-Starling curve.Minimizing SVV with the use of colloid solutions is useful to prevent both hypovolemia and hyper-volemia and ultimately to improve the postoperative outcome of patients undergoing high-risksurgery. The green traffic light indicates when colloids should be given. MV, mechanical ventilation.


Stress and cardiopulmonary resuscitation performance*

T he quality of cardiopulmonaryresuscitation (CPR) is an im-portant determinant of out-come in cardiac arrest (1).

Substantial variation exists in the qualityof CPR (2), which may contribute to themarked variation seen in outcomes (3).The majority of studies examining out-comes from cardiac arrest focus on thetechnical aspects of resuscitation such asresponse times, presence/absence of by-stander CPR, and physical and pharma-cologic interventions. More recently theimportance of nontechnical factors suchas team leadership, communication, sit-uational awareness, and task manage-ment has been recognized (4–7).

Managing cardiac arrest is often re-ported as a stressful experience (8). Thisis important because stress can interferewith the performance of technical skillsin critical situations. In the context ofmanaging a cardiac arrest, stress such asthe presence of an emotional familymember or other distractions can impairCPR performance by junior physicians (9)and laypersons (10). In this edition ofCritical Care Medicine, Bjørshol et al (11)examined the effect of socioemotionalstress on the quality of CPR. The authorsconducted a randomized controlled cross-over trial during which paramedic teamswere exposed to a simulated cardiac arrestwith or without exposure to socioemotionalstress. Socioemotional stress took the formof a distressed bystander; challenges to theparamedics’ authority/judgments; presenceof a family photograph; and audible distrac-tion from a television. The authors hypoth-esized that the addition of socioemotionalstress would reduce the quality of CPR. Thesimulation was effective in inducing stresswith paramedics reporting greater mentaldemand, time pressure, effort, and frustra-

tion after the simulation with socioemo-tional stress. However, the addition of so-cioemotional stress did not impairobjective measures of CPR performance(compression quality, ventilation rate, timeto critical interventions) or increase physicaldemands or the sense of achievement.

So why was the paramedics’ perfor-mance unaffected by stress? It is possiblethat the paramedics felt the simulationlacked fidelity and thus were not per-turbed by the behavior of the bystander.This seems unlikely because the para-medics reported the simulation with so-cioemotional stress was more realisticthan the control simulation. It is perhapsmore likely that a combination of CPRprotocols providing step-by-step guid-ance, regular practice, and effective non-technical skills ameliorated the impact ofsocioemotional stress.

CPR protocols provide a standardized,step-by-step framework that healthcareproviders can follow. This reduces uncer-tainty about the sequence of actions andpriorities of care. In a challenging situa-tion, it allows people to revert back tobasic principles and concentrate on theimportant areas of care. The backgroundand experience of the study participantsis important. The paramedics had a me-dian 8 yrs of experience and received reg-ular (three to four times a year) CPRtraining. Regular and repetitive practiceas can be achieved in the patient simula-tion laboratory allows high levels of ex-pertise to be achieved and maintained(12). Such expertise in delivering the“mechanical” aspects of life supportmeans that the clinician is able to devotegreater attention to those aspects thatdemand critical thinking skills.

Recognizing a stressful situation andhaving effective coping strategies are im-portant for managing both the immediatechallenging situation, but also minimiz-ing the risk of longer-term psychologicstress (13). Although the training curric-ulum of the paramedics in this study isnot defined, most paramedic educationalprograms include teaching on nontech-nical skills, particularly situationalawareness and the broader context ofscene management. This is the result of

the fact that the environments withinwhich paramedics operate can be un-safe, chaotic, and unpredictable. Suchteaching will include health- and safety-related factors and managing bystanders,including well-meaning but unhelpful(and possibly harmful) good Samaritanssuch as the doctor within the interven-tion arm of the Bjørshol et al study. Thus,it is likely that the paramedics’ experi-ence and nontechnical skill training facil-itated their ability to identify and managethe increased socioemotional stress of theintervention.

So what key messages can be takenfrom the study by Bjørshol et al? First isthat it is possible for highly trainedhealthcare providers to deliver high-quality CPR. This is most likely to beachieved through regular simulation/CPR refresher training. Second, socio-emotional stress does not need to inter-fere with the quality of CPR.

The challenge that lies for future stud-ies is to define what are the key factorsthat equipped the paramedics with thenecessary tools to effectively manage thepresence of socioemotional stress. In thisway, we will move closer to defining theessential nontechnical skills for the re-suscitation and critical care curriculums.

Mike SmythWest Midlands Ambulance

Service NHS TrustBrierly Hill, UK

Gavin D. PerkinsUniversity of WarwickWarwick Medical SchoolWarwick, UK

REFERENCES

1. Koster RW, Baubin MA, Bossaert LL, et al:European Resuscitation Council Guidelinesfor Resuscitation 2010 Section 2. Adult basiclife support and use of automated externaldefibrillators. Resuscitation 2010; 81:1277–1292

2. Wik L, Kramer-Johansen J, Myklebust H, etal: Quality of cardiopulmonary resuscitationduring out-of-hospital cardiac arrest. JAMA2005; 293:299–304

3. Berdowski J, Berg RA, Tijssen JG, et al:Global incidences of out-of-hospital cardiacarrest and survival rates: Systematic review

*See also p. 300.Key Words: cardiopulmonary resuscitation; stress;

team leadership; nontechnical skills; crisis resourcemanagement; simulation

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


DOI: 10.1097/CCM.0b013e318205c0ca


of 67 prospective studies. Resuscitation2010; 81:1479–1487

4. Andersen PO, Jensen MK, Lippert A, et al:Identifying non-technical skills and barriersfor improvement of teamwork in cardiac ar-rest teams. Resuscitation 2010; 81:695–702

5. Weidman EK, Bell G, Walsh D, et al: Assess-ing the impact of immersive simulation onclinical performance during actual in-hospital cardiac arrest with CPR-sensingtechnology: A randomized feasibility study.Resuscitation 2010; 81:1556–1561

6. Soar J, Mancini ME, Bhanji F, et al: Part 12:Education, implementation, and teams: 2010International Consensus on Cardiopulmo-nary Resuscitation and Emergency Cardio-vascular Care Science with treatment recom-

mendations. Resuscitation 2010; 81:e288–e330

7. Hunziker S, Buhlmann C, Tschan F, et al:Brief leadership instructions improve cardio-pulmonary resuscitation in a high-fidelitysimulation: A randomized controlled trial.Crit Care Med 2010; 38:1086–1091

8. Hayes CW, Rhee A, Detsky ME, et al: Resi-dents feel unprepared and unsupervised asleaders of cardiac arrest teams in teachinghospitals: A survey of internal medicine res-idents. Crit Care Med 2007; 35:1668–1672

9. Fernandez R, Compton S, Jones KA, et al:The presence of a family witness impactsphysician performance during simulatedmedical codes. Crit Care Med 2009; 37:1956–1960

10. Overgard KI, Bjorkli CA, Bjorshol C, et al:Abstract P104: Socio-emotional stressors in-crease ventilation rate during advanced car-dial life support in a manikin model. Circu-lation. 2008; 118:S-1468

11. Bjørshol CA, Myklebust H, Nilsen KL, et al:Effect of socioemotional stress on the qual-ity of cardiopulmonary resuscitation dur-ing advanced life support in a randomizedmanikin study. Crit Care Med 2011; 39:300 –304

12. Perkins GD: Simulation in resuscitationtraining. Resuscitation 2007; 73:202–211

13. Larsson J, Sanner M: Doing a good job andgetting something good out of it: On stressand well-being in anaesthesia. Br J Anaesth2010; 105:34–37

Blood urea nitrogen beyond estimation of renal function*

After the validation and applica-tion of the Risk, Injury, Fail-ure, Loss of kidney function,End-stage renal disease criteria

and the Acute Kidney Injury Network cri-teria in various settings, acute kidney in-jury has been accepted as an independentrisk factor for intensive care unit (ICU)mortality. Furthermore, several studieshave shown that the severity of acutekidney injury, mainly evaluated by serumcreatinine (sCr) levels, is associated withoutcomes. Although blood urea nitrogen(BUN) is used as a parameter to evaluaterenal function, elevations in BUN levelare, often but not always, due to a de-crease in glomerular filtration rate(GFR). Some factors enhance urea pro-duction, such as gastrointestinal bleed-ing, corticosteroid therapy, and a high-protein diet. In conditions of decreaseintravascular effective volume and de-compensated heart failure, increases inBUN are not proportional to the rise insCr level and fall in GFR.

In this issue of Critical Care Medicine,Beier and colleagues (1) examined therelationship between BUN and long-termmortality in critically ill patients. Theyanalyzed data from �28,000 patients in

20 ICUs who had sCr within the normalrange, 0.8 to 1.3 mg/dL. After multivari-able adjustments for confounders andother factors influencing BUN elevation,they demonstrated that in patients withBUN �40 mg/dl, this parameter was asignificant predictor for short- and long-term mortality in their cohort. The studyshows the potential clinical value for BUNas a prognostic marker for mortality in-dependent of sCr and explores the possi-ble mechanism of the association of BUNand mortality. There are a few points thatdeserve to be further discussed before wecan translate these findings for clinicalpractice.

There are some fundamental issueswith the assessment of renal function bysCr that should be mentioned, becausethe normal range of sCr may include pa-tients with renal dysfunction. Although asingle measurement of sCr is used todiagnose acute kidney injury, sCr has alow sensitivity and specificity as a markerof renal function in ICU patients (2, 3).Many characteristics other than renalfunction, such as age, muscle mass, cat-abolic rate, and race, influence creatinineconcentration. In addition, the sCr leveldepends not only on renal eliminationbut also on creatinine generation and vol-ume of distribution (4). Given the expo-nential relation of sCr and the GFR, sig-nificant decreases in GFR are reflected assmall increases in sCr in the early phasesof injury. In the critically ill patients, anon-steady-state condition and the posi-tive cumulative fluid balance enhancesthe insensitivity of sCr as a parameter of

renal dysfunction (5). Hoste et al (2)showed that in a group of recently admit-ted ICU patients with normal sCr, the1-hr urinary creatinine clearance re-vealed values lower than 80 mL/min/1.73m2 in 46.2% of the patients. These datasuggest that sCr is not a reliable tool todetect moderate renal dysfunction in crit-ically ill patients.

As well as assessing the degree of renalfunction, the BUN/creatinine ratio alsohas been used for many years to help todifferentiate between prerenal and renalazotemia, as BUN can increase indepen-dently from sCr in situations character-ized by decreased glomerular perfusionpressure. In heart failure, the distinct im-pact of BUN and sCr on outcomes hasalready been studied (6, 7). These studiesevaluating the association of elevations inBUN independently of sCr levels on out-comes demonstrated that these two pa-rameters are not only an indication of theseverity of renal dysfunction but also areflection of two distinct pathologic pro-cesses (8). The activation of renin–angiotensin–aldosterone system andsympathetic nervous system are respon-sible for decreasing the glomerular per-fusion pressure and GFR. The incrementin vasopressin levels up-regulates auqa-porin-2 expression and increases waterresorption. Urea, in contrast to sCr, is notsecreted but reabsorbed by the renal tu-bules. The increased resorption of so-dium and water, rather than the reducedGFR, enhances resorption of urea andincreases BUN levels. Thus, BUN levelsand BUN/creatinine ratio could be a more

*See also p. 305.Key Words: acute kidney injury; outcomes; mor-

tality; blood urea nitrogen; serum creatinine; diagnosisThe author has not disclosed any potential con-



DOI: 10.1097/CCM.0b013e318205c33a


effective way to assess circulatory volumethan GFR, which is regulated by the pres-sure difference between glomerular affer-ent and efferent arterioles (9). In heartfailure and possibly in other settingswhere underfilling is part of the physio-pathologic process, the rise in BUNgreater than any fall in GFR is a markerof the neurohumoral axis activation (10).

Another factor associated with eleva-tions in BUN independent of creatinine isthe extent of the metabolic state associ-ated with critical illness. The release ofpro- and anti-inflammatory and oxidativestress mediators into the systemic circu-lation and insulin resistance are both fre-quently observed in ICU patients. The re-sult of these processes is the increasedcatabolism of structural proteins, withincreased amino acid turnover and nega-tive nitrogen balance. The association ofpersistent hypercatabolism in critical ill-ness and decreased immune function hasbeen addressed in experimental and clin-ical studies (11, 12). Beier and colleagues(1) found that high BUN was associatedwith the risk of blood culture positivity.This observation may reflect the de-creased immune function related to theextent of catabolism across their cohortand strengthens the association of in-creased BUN and mortality.

Although we still must consider thelimitations of sCr to estimate the renalfunction, especially in ICU patients, BUN

could indeed represent a prognostic fac-tor beyond its role in the estimation ofrenal function. BUN may be a surrogatemarker for neurohormonal activation inunderfilling states and a marker of in-creased catabolism and related immunedysfunction in critically ill patients. Al-though more studies should further ad-vance these concepts, Beier and col-leagues (1) shed light on the differentialrole of BUN and creatinine in predictingoutcomes.

Etienne Macedo, MDSchool of MedicineUniversity of Sao PauloSao Paulo, Brazil

REFERENCES

1. Beier K, Eppanapally S, Bazick HS, et al:Elevation of blood urea nitrogen is predictiveof long-term mortality in critically ill pa-tients independent of “normal” creatinine.Crit Care Med 2011; 39:305–313

2. Hoste EA, Damen J, Vanholder RC, et al:Assessment of renal function in recentlyadmitted critically ill patients with normalserum creatinine. Nephrol Dial Transplant2005; 20:747–753

3. Bouchard J, Macedo E, Soroko S, et al: Com-parison of methods for estimating glomeru-lar filtration rate in critically ill patients withacute kidney injury. Nephrol Dial Transplant2010; 25:102–107

4. Moran SM, Myers BD: Course of acute renalfailure studied by a model of creatinine ki-netics. Kidney Int 1985; 27:928–937

5. Macedo E, Bouchard J, Soroko SH, et al:Fluid accumulation, recognition and stagingof acute kidney injury in critically-ill pa-tients. Crit Care 2010; 14:R82

6. Aronson D, Mittleman MA, Burger AJ: El-evated blood urea nitrogen level as a pre-dictor of mortality in patients admitted fordecompensated heart failure. Am J Med2004; 116:466 – 473

7. Cauthen CA, Lipinski MJ, Abbate A, et al:Relation of blood urea nitrogen to long-termmortality in patients with heart failure. Am JCardiol 2008; 101:1643–1647

8. Schrier RW: Blood urea nitrogen and serumcreatinine: Not married in heart failure. CircHeart Fail 2008; 1:2–5

9. Lin HJ, Chao CL, Chien KL, et al: Elevatedblood urea nitrogen-to-creatinine ratio in-creased the risk of hospitalization and all-cause death in patients with chronic heartfailure. Clin Res Cardiol 2009; 98:487–492

10. Klein L, Massie BM, Leimberger JD, et al:Admission or changes in renal function dur-ing hospitalization for worsening heart fail-ure predict postdischarge survival: Resultsfrom the Outcomes of a Prospective Trial ofIntravenous Milrinone for Exacerbations ofChronic Heart Failure (OPTIME-CHF). CircHeart Fail 2008; 1:25–33

11. Casaer MP, Mesotten D, Schetz MR: Bench-to-bedside review: Metabolism and nutrition.Crit Care 2008; 12:222

12. Heyland DK, Novak F, Drover JW, et al:Should immunonutrition become routine incritically ill patients? A systematic review ofthe evidence. JAMA 2001; 286:944–953

The Frog Prince of calcium homeostasis*

T he contribution by Egi andcolleagues (1) in this issue ofCritical Care Medicine pro-vides an opportunity to briefly

review how far we have traveled fromstudies on frogs to our current under-standing of altered calcium homeostasisin our intensive care unit (ICU) patients.The physician-scientist Luigi Galvani firstdescribed “animal electric fluid” in 1791

as a unique property of living tissues thatallowed a frog’s leg to contract in re-sponse to contact with metal (2). A phys-icist colleague, Alessandro Volta, believedthat “metallic electricity” produced by aninteraction between two different metalswas responsible for the muscle contrac-tion (2). Sidney Ringer (of Ringer’s lac-tate fame) later showed that Na, K, andCa ions are essential for the contractionof the frog heart (3). Hodgkin et al (4)and Fatt and Katz (5) completed this cir-cle of knowledge by revealing that the Na,K, and Ca ions carried the animal/metallic electricity through their respec-tive ion channels by using the squid giantaxon and crustacean skeletal muscle.Subsequent studies in a variety of animalspecies uncovered the central role played

by Ca in intracellular signaling processes(6). A combination of exquisitely con-trolled spatial and temporal subcellularlocalizations of intracellular ionized freeCa (iCa) regulates such diverse but essen-tial processes as muscle contraction, neu-rohumoral secretion, and apoptotic celldeath. Minute changes in the subcellularconcentrations of iCa can have profoundphysiologic and pathophysiologic conse-quences. Considerable metabolic effort isexerted to assure that iCa concentrationsare optimally maintained in specified ex-tracellular and intracellular compart-ments in accordance with the originaldescription of “adaptive physiologic” ho-meostasis by Cannon (7). Therefore,small changes in iCa observed in the ICUsetting could contribute to or be the con-

*See also p. 314.Key Words: cell signaling; calcium; homeostasis;

critical careThe authors have not disclosed any potential con-



DOI: 10.1097/CCM.0b013e318205c34d


sequences of “maladaptive pathophysio-logic” attempts to maintain homeostasis,as later described by Selye (8).

We now routinely use automated de-vices to very accurately measure concen-trations of iCa and other electrolytes inour patients’ blood. It is interesting tonote that homeostatic mechanisms main-tain concentrations of these ions in anextremely narrow range when comparedto macromolecules such as proteins andlipids. Circulating iCa are tightly main-tained in equilibrium with calciumbound to plasma proteins (primarily al-bumin), phosphates, and citrates by acombination of dietary ingestion, renalexcretion, and bone resorption–princi-pally under the modulation of parathy-roid hormone and vitamin D (9). Physio-logic and pathophysiologic shifts in thedistribution of iCa among and withinthese compartments can be detected clin-ically by the application of simple auto-mated technologies.

Previous studies have provided evi-dence of such derangements in calciumhomeostasis among critically ill patients(10, 11). Whitted et al (11) recently pro-posed that elevated catecholamines dur-ing critical illness cause a shift of calciumfrom the circulating pool to intracellularcompartments of various tissues. This“relative” hypocalcemia results in in-creased parathyroid hormone via a ho-meostatic negative feedback loop. In-creased circulating catecholamines andparathyroid hormone further facilitateintracellular Ca overload. MitochondrialCa overload induces oxidative stress,opening of the permeability transitionpore, and apoptotic cell death. Thus, adecrease in circulating iCa concentra-tions likely reflects a redistribution of Cainto cellular compartments and not anabsolute decrease in total body iCa.Therefore, providing additional paren-teral Ca would be analogous to addingsodium to treat dilutional hyponatremiaas a result of inappropriate levels of anti-diuretic hormone (syndrome of inappro-priate antidiuretic hormone secretion).This hypothesis is supported by data inwhich calcium administration increasedmortality in two different animal modelsof sepsis (12, 13).

These clinical and basic data provide aconfusing picture as to the optimal man-agement of hypocalcemia in the ICU set-ting. A key missing piece of this puzzle isthe answer to the question of whether iCa

levels independently predict poor out-come. An affirmative answer for hypocal-cemia would suggest a potentially life-saving role for replacement therapy inthe ICU. Such an easy implementationstrategy would justify investment in amajor multicentered clinical trial. On theother hand, failure to demonstrate an in-dependent effect of hypocalcemia wouldsuggest that simple replacement therapywill not improve outcome. Sufficientnumbers of patients with adequate statis-tical analyses have been lacking to resolvethis compelling issue. A recent authori-tative Cochrane review of the literatureon this subject, entitled “Parenteral cal-cium for intensive care unit patients,”concluded that “there is no clear evidencethat parenteral calcium supplementationimpacts the outcome of critically ill pa-tients” (14). Thus, criteria for clinicalequipoise appear to have been met toconduct a clinical trial to determinewhether calcium supplementation wouldbenefit hypocalcemic patients in the ICU.

Now enters the substantial contribu-tion of Egi and colleagues (1) in this issueof Critical Care Medicine. They report theresults of their very carefully designedand conducted retrospective multicen-tered study of a large heterogeneous crit-ically ill population to assess the relation-ship between serum iCa levels and ICUand in-hospital mortality. Initial univari-ate analyses confirmed previous reportsof an unfavorable outcome in patientswith lower iCa levels. However, multivar-iate analyses, adjusting for other factorsinfluencing mortality, showed that onlyextreme abnormalities of ionized Ca areindependent predictors of mortality. ICUand hospital mortality trends were drivenby very low iCa values of less then 0.8mmol/L and 0.9 mmol/L, respectively. Sim-ilarly, hospital and ICU mortalities wereshown to be primarily dependent on pa-tients with very high iCa levels (�1.4mmol/L). The authors suggest that abnor-malities of iCa concentrations representphysiologic derangements and are likely amarker of illness severity, rather than inde-pendently contribute to mortality.

The implications of the work of Egiand colleagues (1) are both obvious andprofound. First of all, even relativelysmall changes in iCa levels are an impor-tant and consistent indication of poorprognosis in the ICU setting. Secondly,efforts to “fine tune” iCa levels to remainwithin the normal range are unlikely toyield improved outcomes for the vast ma-jority of critically ill patients. And finally,

efforts to understand the biological basisof altered Ca homeostasis in the ICU aremore likely to yield useful clinically rel-evant insights than attempts to simplytreat numbers. We need not look anyfurther than studies into the basic mech-anisms responsible for hyponatremia incongestive heart failure patients who ledto the neurohumoral hypothesis underly-ing our current management of chronicheart failure (15). Disappointing “nega-tive” results of recent clinical trials re-minds us of the veracity of the old adagethat you have to “kiss a lot of frogs [basicexperiments] before you find your prince[successful clinical trial]!”

Sarah Hadique, MDChet Khamare, MDMitchell S. Finkel, MD

West Virginia UniversityCardiology

Morgantown, WV

REFERENCES

1. Egi M, Kim I, Nichol A, et al: Ionized calciumconcentration and outcome in critical illness. CritCare Med 2011; 39:314–321

2. Pera M: The Ambiguous Frog: The Galvani-Volta Controversy on Animal Electricity.Princeton, NJ, Princeton University Press,1992

3. Ringer S: Concerning the influence exertedby each of the constituents of the blood onthe contraction of the ventricle. J Physiol1882; 3:380–393

4. Hodgkin AL, Huxley AF, Katz B: Measure-ment of current-voltage relations in themembrane of the giant axon of Loligo.J Physiol 1952; 115:424–448

5. Fatt P, Katz B: The electrical properties ofcrustacean muscle fibres. J Physiol 1953;120:171–204

6. Bootman MD, Berridge MJ, Roderick HL:Calcium signalling: More messengers, morechannels, more complexity. Curr Biol 2002;12:R563–R565

7. Cannon WB: The Wisdom of the Body. NewYork, NY, W.W. Norton, 1932

8. Selye H: The general adaptation syndromeand the diseases of adaptation. J Clin Endo-crinol Metab 1946; 6:117–230

9. Chattopadhyay N, Brown EM: Role of cal-cium-sensing receptor in mineral ion me-tabolism and inherited disorders of calci-um-sensing. Mol Genet Metab 2006; 89:189 –202

10. Zivin JR, Gooley T, Zager RA, et al: Hypocal-cemia: A pervasive metabolic abnormality inthe critically ill. Am J Kidney Dis 2001; 37:689–698

11. Whitted AD, Stanifer JW, Dube P, et al: Adyshomeostasis of electrolytes and trace ele-


ments in acute stressor states: Impact on theheart. Am J Med Sci 2010; 340:48–53

12. Zaloga GP, Sager A, Black KW, et al: Lowdose calcium administration increases mor-tality during septic peritonitis in rats. CircShock 1992; 37:226–229

13. Malcolm DS, Zaloga GP, Holaday JW: Cal-cium administration increases the mortalityof endotoxic shock in rats. Crit Care Med1989; 17:900–903

14. Forsythe RM, Wessel CB, Billiar TR, et al:Parenteral calcium for intensive care unit

patients. Cochrane Database Syst Rev 2008Oct 8:CD006163

15. Packer M, Medina N, Yushak M: Correctionof dilutional hyponatremia in severe chronicheart failure by converting-enzyme inhibi-tion. Ann Intern Med 1984; 100:782–789

Translating the PIRO staging system concept into clinical practice:Where do we go from here?*

Sepsis has been defined as theclinical syndrome resultingfrom a dysmodulated inflam-matory reaction to the pres-

ence of infection (1). Over the last de-cades, this notion has been used to defineentry criteria in clinical trials and to sup-port the rationale to test adjuvant andimmunomodulatory therapeutic inter-ventions in septic patients. However, it iswell known that virtually all clinical stud-ies testing such interventions failed todemonstrate improvements in patients’outcomes and the results of the very fewstudies exhibiting benefits are being rig-orously questioned (2, 3). This may beascribed to the fact that the diagnosis ofsepsis encompasses both a very heteroge-neous group of diseases caused by a myr-iad of microorganisms in different ana-tomic sites and a mix of patients withdistinctive clinical and biologic behav-iors. All of the mentioned argumentsprompted investigators to work on thedevelopment of a staging system thatcould improve risk assessment and pre-dict response to therapy. With this aim, inthe 2001 International Sepsis DefinitionsConference, the PIRO concept was forgedas a hypothetical framework for stagingsepsis through the perspective of Predispo-sition (that is, predisposing factors and pre-morbid conditions), the nature and charac-teristics related to the underlying Infection,host Response, and Organ dysfunctions (1).However, 7 yrs after the report of the re-vised criteria and definitions for sepsis,

studies evaluating the PIRO concept arestill scarce and currently provide limiteddata to allow the translation of the conceptinto practice (4–7).

In the current issue of the CriticalCare Medicine, Howell et al (8) have ap-plied the PIRO concept to derive a modelfor risk stratification in patients with sus-pected infection admitted to the emer-gency departments of two tertiary careinstitutions. In this valuable contribu-tion, the authors identified 17 easilyavailable clinical and laboratory variablesto develop a composite score to predictinhospital mortality. The main strengthsof the present study are the inclusion of alarge number of patients with a widerange of disease severity evaluated at thevery beginning of their clinical courseand the performance of internal and ex-ternal validations in temporally distinctlarge cohorts. However, some caution isstill needed regarding the generalizationof the study results. First, patients wereincluded based on the suspicion of infec-tion and information on the final dia-gnoses was not obtained. Therefore, it isnot possible to rule out that patients withnoninfectious complications have beenenrolled. Second, as expected for nonin-tensive care unit patients with suspectedinfections admitted to emergency depart-ments, the observed hospital mortalityrates were relatively low in the three co-horts (3.9–6.3%). Despite both good dis-crimination and calibration, concerns onpossible overfitting could be raised be-cause there were 83 deaths in the deriva-tion cohort and 17 covariates were in-cluded into the final model. However,such concerns were certainly minimizedwith the performance of subsequent val-idations. Finally, because �10% of pa-tients had predicted mortality rates �15–25%, additional validations of theproposed model in more severe patients,

particularly those with severe sepsis andseptic shock, will be certainly needed.

Despite the improvement in the cur-rent knowledge on the PIRO concept, webelieve that the methodologic approachused in the available studies evaluatingthe PIRO concept, including the presentone, is similar to those used in the devel-opment of traditional prognostic scores(4–8). Although selecting candidate vari-ables according to each of the PIRO do-mains is a most likely way to better ori-entate the identification of outcomepredictors in patients with sepsis, thiscould also be a limitation. It is widelyacknowledged that translating the hypo-thetical concept of PIRO into clinicalpractice remains a complex task. Never-theless, if we want to go beyond riskstratification, we have to resist the temp-tation to develop models that look muchmore like traditional prognostic scoresand develop models allowing an en-hanced way of phenotyping patients ac-cording to the PIRO concept. Actually, tomove forward applying this new concept,we should choose new methodologic ap-proaches. There is enough evidence fromthe literature that clinical scores are in-appropriate for risk stratification on anindividual basis and should not be usedeither as a criterion for patient enroll-ment into clinical trials or for treatmentdecisions (9). In addition, because sepsisis a dynamic process, the development ofdatabases for future studies should takeinto account this notion for all PIRO do-mains. The assessment of patterns ofvariation in organ dysfunctions (10) andbiomarkers is useful to assess individualoutcomes in sepsis (11). Biomarkers canalso be useful to help identify patientsmost likely to benefit or experiencingharm with an intervention. Such an ap-proach has been proposed in the contextof theragnostics (12). The PIRO concept

*See also p. 322.Key Words: infection; outcome; PIRO staging sys-

tem; sepsis; theragnosticsDr. Soares is supported in part by individual re-

search grant from CNPq. The remaining authors havenot disclosed any potential conflicts of interest.


DOI: 10.1097/CCM.0b013e3181f17a04


was conceived taking into considerationthe use of TNM classification to stratifypatients with solid tumors. Again we canlearn with oncologists again on somesuccessful experiences using theragnos-tics. This involved the expansion of TNMstaging to include molecular and geneticpatterns to guide specific therapeutic in-terventions. Successful examples are nowbeing applied as standard of care forbreast and lung cancer among others.Examples of possible directions using aPIRO-based rationale are available in re-cent studies in which sequential changesin inflammatory markers can be surro-gates of response to therapy (13) and mayhelp guide optimal duration of antibiotictherapy (14). Nonetheless, a preliminaryand methodologically different empiricclinical application of the PIRO conceptdates from more than two decades. In the1980s, patients with AIDS and severePneumocystis jirovecci pneumonia weredemonstrated to benefit from the use ofcorticosteroids. Then, decades before thePIRO concept emerged, patients with aT-cell type immunodeficiency (Predispo-sition), with P. jirovecci, the same infec-tious microorganism (Infection), pre-senting with hypoxemia (Response) andrespiratory failure (Organ dysfunction),were considered eligible to receive an ad-junctive therapy. Finally, the Infectiondomain should necessarily be explored inmore detail in future studies, particularlywith respect to information on microbialpathogenesis and host–pathogen interac-tions (15). The study of Howell et al isalso timely in reminding us to acknowl-edge the PIRO concept as a work inprogress rather than a model to be im-mediately adopted. The understanding ofsepsis as a nonlinear biologic system willrequire improved study designs, use of

new statistical and mathematical model-ing, and extensive clinical investigationfor its validation.

Marcio Soares, MD, PhDIntensive Care UnitHospital de Cancer-I, Instituto

Nacional de CancerRio de Janeiro, Brazil; andPrograma de Pos-Graduacao

em OncologiaInstituto Nacional de CancerRio de Janeiro, Brazil

Thiago Lisboa, MDIntensive Care UnitHospital de ClínicasUniversidade Federal do Rio

Grande do SulPorto Alegre, Brazil

Jorge I. F. Salluh, MD, PhDIntensive Care UnitHospital de Cancer-I, Instituto

Nacional de CancerRio de Janeiro, Brazil; andPrograma de Pos-Graduacao

em OncologiaInstituto Nacional de CancerRio de Janeiro, Brazil

REFERENCES

1. Levy MM, Fink MP, Marshall JC, et al: 2001SCCM/ESICM/ACCP/ATS/SIS InternationalSepsis Definitions Conference. Crit Care Med2003; 31:1250–1256

2. Russell JA: Management of sepsis. N EnglJ Med 2006; 355:1699–1713

3. Carlet J: Prescribing indications based onsuccessful clinical trials in sepsis: A diffi-cult exercise. Crit Care Med 2006; 34:525–529

4. Rubulotta F, Marshall JC, Ramsay G, et al:Predisposition, insult/infection, response,and organ dysfunction: A new model for stag-ing severe sepsis. Crit Care Med 2009; 37:1329–1335

5. Rello J, Rodriguez A, Lisboa T, et al:

PIRO score for community-acquired pne-umonia: A new prediction rule for asse-ssment of severity in intensive care unitpatients with community-acquired pne-umonia. Crit Care Med 2009; 37:456 –462

6. Lisboa T, Diaz E, Sa-Borges M, et al: Theventilator-associated pneumonia PIRO score:A tool for predicting ICU mortality and health-care resources use in ventilator-associatedpneumonia. Chest 2008; 134:1208–1216

7. Moreno RP, Metnitz B, Adler L, et al: Sepsismortality prediction based on predisposition,infection and response. Intensive Care Med2008; 34:496–504

8. Howell MD, Talmor D, Schuetz P, et al: Proofof principle: The Predisposition, Infection,Response, Organ Failure sepsis staging sys-tem. Crit Care Med 2011; 39:322–327

9. Vincent JL, Opal SM, Marshall JC: Ten rea-sons why we should NOT use severity scoresas entry criteria for clinical trials or in ourtreatment decisions. Crit Care Med 2010; 38:283–287

10. Levy MM, Macias WL, Vincent JL, et al: Earlychanges in organ function predict eventualsurvival in severe sepsis. Crit Care Med 2005;33:2194–2201

11. Povoa P: Serum markers in community-acquired pneumonia and ventilator-associ-ated pneumonia. Curr Opin Infect Dis 2008;21:157–162

12. Pene F, Courtine E, Cariou A, et al: Towardtheragnostics. Crit Care Med 2009;37(Suppl):S50–S58

13. Rivers EP, Kruse JA, Jacobsen G, et al: Theinfluence of early hemodynamic optimiza-tion on biomarker patterns of severe sepsisand septic shock. Crit Care Med 2007; 35:2016–2024

14. Schuetz P, Christ-Crain M, Thomann R, et al:Effect of procalcitonin-based guidelines vsstandard guidelines on antibiotic use inlower respiratory tract infections: The Pro-HOSP randomized controlled trial. JAMA2009; 302:1059–1066

15. van der Poll T, Opal SM: Host–pathogen in-teractions in sepsis. Lancet Infect Dis 2008;8:32–43


Niacin as a novel therapy for septic shock?*

Niacin (nicotinic acid, vitaminB3) is a water-soluble, color-less solid that has been ex-tensively used in the man-

agement of dyslipidemia and coronaryheart disease (1–3). Niacin is a precursorof nicotinamide adenine dinucleotideand, hence, increases cellular concentra-tions of nicotinamide adenine dinucle-otide. Niacin upregulates the expressionof glucose-6-phosphate dehydrogenase,which is the rate-limiting enzyme in thepentose phosphate pathway and the mainsource of cellular-reduced nicotinamideadenine dinucleotide phosphate (4). In-creased levels of nicotinamide adeninedinucleotide phosphate reduce cellularlevels of reactive oxygen species by eitherregulating reactive oxygen species-forming oxidases or by maintaining anti-oxidant enzymes such as reduced gluta-thione and catalase. Furthermore,increased levels of nicotinamide adeninedinucleotide phosphate have been shownto downregulate low-density lipoproteinoxidation and oxidation-sensitive inflam-matory processes involved in atheroscle-rosis. These effects have been attributedto niacin possessing potent antioxidantand anti-inflammatory properties (4).

A number of recent studies have in-vestigated the anti-inflammatory proper-ties of niacin. In particular, niacin hasbeen reported to suppress vascular in-flammation by reducing tumor necrosisfactor-�-induced vascular cell adhesionmolecule-1 expression and monocytechemoattractant protein-1 secretion incultured human aortic endothelial cells(4). Furthermore, niacin also attenuatesthe amount of proinflammatory cyto-kines found in the bronchoalveolar lavagefluid obtained from mice subjected to 1)bleomycin-induced lung injury (5); and2) the formation of proinflammatory

cytokines in rats with chronic renal fail-ure (6). Both of these studies have attrib-uted the anti-inflammatory effects of ni-acin to a reduction in the activation ofnuclear factor-�B (NF-�B). NF-�B is atranscription factor that plays an impor-tant role in regulating the transcriptionof a number of genes, especially thoseinvolved in the production of mediatorsinvolved in local and systemic inflamma-tion. Activation of NF-�B requires thephosphorylation of its physiological in-hibitors, the I�Bs (especially I�B-�), atspecific serine residues. This subse-quently leads to the proteolytic degrada-tion of the I�Bs and, hence, allows thetranslocation of a NF-�B subunit (p65)into the nucleus, where it regulates genetranscription.

Numerous agents have been shown toinhibit NF-�B in experimental models ofsepsis. These agents include syntheticcompounds such as glycogen synthase ki-nase-3� inhibitors (7), peroxisome prolif-erator-activated receptor agonists includ-ing peroxisome proliferator-activatedreceptor-� (8), peroxisome proliferator-activated receptor-�/� (9), and peroxi-some proliferator-activated receptor-agonists (10). Furthermore, several nat-ural compounds such as turmeric-derived curcumin (11) or flower- andplant-derived sesquiterpene lactones havealso been reported to inhibit NF-�B inexperimental models of sepsis (12, 13).

In this issue of Critical Care Medicine,Kwon and colleagues have investigatedthe effects (and potential side effects) ofniacin in a rodent model of endotoxin-induced acute lung injury (14). Specifi-cally, they discovered that the adminis-tration of niacin attenuated the mortality(monitored for 72 hrs) caused by intrave-nous injection of lipopolysaccharide(LPS, 10 mg/kg) in a dose-related fashion(niacin was given 10 min after LPS at 360mg/kg or 1180 mg/kg). The reduction inlung injury (measured as acute lung in-jury score and histology at 6 hrs afterLPS) afforded by niacin was associatedwith prevention of the degradation ofI�B� in the cytosol of lungs of animalssubjected to endotoxemia. In addition, ni-acin caused a small, but significant, re-

duction in NF-�B-p65 to DNA binding.The apparent inhibition of the activationof NF-�B by niacin also resulted in anattenuation of the LPS-induced forma-tion of the proinflammatory cytokines tu-mor necrosis factor-� and interleukin-6(measured as mRNA expression in thelung and protein levels in the serum).Endotoxemia resulted in falls in the levelsof nicotinamide adenine dinucleotide,nicotinamide adenine dinucleotide phos-phate, and glutathione, all of which wereprevented by the highest dose of niacinused. Based on these findings, the au-thors conclude that high-dose niacin re-duces the acute lung injury and may re-duce survival in sepsis. In future studies,it would be helpful to provide furtherevidence that niacin does indeed attenu-ate any lung dysfunction (which presum-ably is the consequence of the acute lunginjury documented by the authors)caused by endotoxemia or sepsis by eval-uating respiratory mechanics and bloodgases.

When evaluating the relative impor-tance of any new intervention in experi-mental models of septic shock, one islikely to consider both the magnitude ofthe observed beneficial effect of any givendrug as well as the clinical relevance ofthe animal model used. Kwon and col-leagues have demonstrated in their arti-cle that the highest dose of niacin used(1180 mg/kg) improved survival in anLPS model from 26% to 61% at 72 hrs.To verify the clinical importance of thisfinding, further studies are essential thatconfirm such beneficial effects in a modelthat uses a focus on infection (eg, cecalligation and puncture) in the presence offluid resuscitation and antibiotic therapy(9). When using a cecal ligation andpuncture model, one may also wish toelucidate whether niacin is still effectivewhen given as a late, therapeutic inter-vention (eg, 6–24 hrs after cecal ligationand puncture) or whether, like in thestudy reported here, a very early inter-vention (10 mins after LPS) is essential toenable niacin to be effective. Clearly, thedose of niacin of �1 g/kg is very high andmay well cause significant side effects.Even much lower doses of niacin are

*See also p. 328.Key Words: niacin; sepsis; endotoxemia; lipopoly-

saccharide; NF-�B; lung inflammation; survivalThe authors have not disclosed any potential con-



DOI: 10.1097/CCM.0b013e318205c05e


liver-toxic (15) in normal animals and,hence, it is essential to ensure that niacin(at any dose used) does not significantlyaggravate the degree of liver injury anddysfunction associated with severe sepsis.In addition, high doses of any drug mayhave off-target effects that may not onlylimit the interpretation of the proposedmechanism of action, but also its clinicaluse resulting from side effects. Thus, asignificant amount of further preclinicalstudies using clinically relevant thera-peutic strategies in a clinically relevantmodel is essential to evaluate the relativeimportance of the findings reported byKwon and colleagues in this issue of Crit-ical Care Medicine.

Amar Kapoor, PhDChristoph Thiemermann, MD,

PhD, FMedSciWilliam Harvey Research

InstituteQueen Mary UniversityLondon, UK

REFERENCES

1. Meyers CD, Kamanna VS, Kashyap ML: Nia-cin therapy in atherosclerosis. Curr OpinLipidol 2004; 15:659–665

2. van der Hoorn JW, de Haan W, Berbee JF, et al:Niacin increases HDL by reducing hepatic ex-

pression and plasma levels of cholesteryl estertransfer protein in APOE*3Leiden.CETP mice.Arterioscler Thromb Vasc Biol 2008; 28:2016–2022

3. Green PS, Vaisar T, Pennathur S, et al:Combined statin and niacin therapy re-models the high-density lipoprotein pro-teome. Circulation 2008; 118:1259 –1267

4. Ganji SH, Qin S, Zhang L, et al: Niacininhibits vascular oxidative stress, redox-sensitive genes, and monocyte adhesion tohuman aortic endothelial cells. Atheroscle-rosis 2009; 202:68 –75

5. Gurujeyalakshmi G, Wang Y, Giri SN: Tau-rine and niacin block lung injury and fibrosisby down-regulating bleomycin-induced acti-vation of transcription nuclear factor-kappaBin mice. J Pharmacol Exp Ther 2000; 293:82–90

6. Cho KH, Kim HJ, Rodriguez-Iturbe B, et al:Niacin ameliorates oxidative stress, inflam-mation, proteinuria, and hypertension in ratswith chronic renal failure. Am J Physiol Re-nal Physiol 2009; 297:F106–113

7. Dugo L, Collin M, Allen DA, et al: GSK-3betainhibitors attenuate the organ injury/dysfunction caused by endotoxemia in therat. Crit Care Med 2005; 33:1903–1912

8. Jozefowicz E, Brisson H, Rozenberg S, etal: Activation of peroxisome proliferator-activated receptor-alpha by fenofibrate pre-vents myocardial dysfunction during endo-toxemia in rats. Crit Care Med 2007; 35:856 – 863

9. Kapoor A, Shintani Y, Collino M, et al: Pro-tective role of peroxisome proliferator-activated receptor-{beta}/{delta} in septicshock. Am J Respir Crit Care Med 2010 Aug6 [Epub ahead of print]

10. Zingarelli B, Sheehan M, Hake PW, et al:Peroxisome proliferator activator receptor-gamma ligands, 15-deoxy-delta(12,14)-prostaglandin J2 and ciglitazone, reduce sys-temic inflammation in polymicrobial sepsisby modulation of signal transduction path-ways. J Immunol 2003; 171:6827–6837

11. Poylin V, Fareed MU, O’Neal P, et al: TheNF-kappaB inhibitor curcumin blocks sepsis-induced muscle proteolysis. Mediators In-flamm 2008;2008:317851

12. Sheehan M, Wong HR, Hake PW, et al: Pro-tective effects of isohelenin, an inhibitor ofnuclear factor kappaB, in endotoxic shock inrats. J Endotoxin Res 2002; 8:99–107

13. Sheehan M, Wong HR, Hake PW, et al: Par-thenolide, an inhibitor of the nuclear factor-kappaB pathway, ameliorates cardiovascularderangement and outcome in endotoxicshock in rodents. Mol Pharmacol 2002; 61:953–963

14. Kwon WY, Suh GJ, Kim KS, et al: Niacinattenuates lung inflammation and improvessurvival during sepsis by downregulating thenuclear factor-kB pathway. Crit Care Med2011; 39:328–334

15. Guyton JR, Bays HE: Safety considerationswith niacin therapy. Am J Cardiol. 2007; 99:22C–31C

Ultrasound and abdominal compartment syndrome: Can we castthe other tools aside yet?*

Abdominal compartment syn-drome is a topic drawing in-creasing attention during thelast several years, as more phy-

sicians become aware of its frequency andassociated morbidity/mortality (1). Muchlike a compartment syndrome in a patient’sleg, rising internal pressures have an ad-verse impact on tissue perfusion within aclosed space. Renal blood flow is particu-

larly impacted, even at modest levels ofintra-abdominal hypertension (IAH) (2).Once full abdominal compartment syn-drome has developed, multiple organs areat risk and emergent surgical decompres-sion is often required (3). This procedureleads to a host of potential complications aswould be expected with an open abdomenand the stress of a surgical intervention ona critically ill patient.

Although the current standard of IAHdetection is bladder pressure measure-ment, this technique is generally under-used (4, 5). Despite a relatively easy processthat involves inserting a sensor into theubiquitous urinary catheter, other tech-niques clearly need to be developed for IAHdetection. Unfortunately, initiation of blad-der pressure measurement often dependson clinical suspicion, which depends on thephysical examination (6). Evaluation of ab-

dominal compartment syndrome is not theonly area physical examination has failedclinicians. In fact, physical examination in-accuracy is one of the driving forces behindthe spread of point-of-care ultrasound inthe intensive care unit. Several previousreports have described the use of ultra-sound in the diagnosis of IAH and abdom-inal compartment syndrome and animalmodels have been studied (7–9). The renalartery Resistive Index has been investigatedin abdominal compartment syndrome be-fore. The Resistive Index is effectively ameasure of the resistance to blood flowthrough arteries and studying it makes in-herent sense. Kirkpatrick and colleagues(9) showed a linear Resistive Index re-sponse to increasing IAH. The researchersalso confirmed the potential for early IAHdetection, before any clinical symptoms areobvious. However, they wisely cautioned

*See also p. 344.Key Words: point-of-care ultrasound; abdominal

compartment syndrome; intra-abdominal hyperten-sion; critical care ultrasound; intensive care unit; renalultrasound



DOI: 10.1097/CCM.0b013e318205c305


that scanning laboratory animals and ac-tual sick patients in an intensive care unitare two vastly different tasks. In addition,the authors used a top-of-the-line ultra-sound device not found in most intensivecare units.

Point-of-care ultrasound, althoughhardly ubiquitous, is growing tremen-dously in critical care clinical practice (10).Specific clinical applications such as lungultrasound are spreading rapidly and havebeen well studied. One of the most fre-quently used ultrasound applications in thecritical care setting is focused cardiac eval-uation, including the inferior vena cava(IVC) (11–13). Evaluation of the IVC allowsfor estimation of a patient’s central venouspressure, intravascular volume status, andresponses to fluid resuscitation or diuresis.The IVC is an excellent target because it iseasily seen through the liver in many pa-tients and can be imaged from several an-gles or approaches. In addition, it is rela-tively easy to teach novice ultrasound usershow to find the IVC along with the portalvein. One of the strengths of the study byCavaliere et al (14) is that multiple vesselsin the human abdomen were evaluated forassociation with IAH and thus provide sev-eral targets for interrogation. In most pa-tients, at least one should be accessible toultrasound. The authors brought togetherthe potential for a multifaceted approach,including renal artery Resistive Index esti-mation, portal vein, and IVC shape mea-surements. In addition, they showed posi-tive pressure ventilation still leaves optionsfor ultrasound monitoring. The equipmentneeded to visualize the IVC and portal veindoes not have to be top tier nor expensive.In fact, entry level or basic equipment canbe used to visualize the IVC and portal veinswith good success.

A potential future strategy may in-clude serial evaluations of patients at riskfor IAH such as those receiving aggres-sive fluid resuscitation. This would beimportant because baseline IVC shapeand diameter have some variability. Manyof these patients are also at risk for de-veloping deep venous thrombosis, pneu-monia, pulmonary edema, and heart fail-ure. All of these entities can be rapidlydiagnosed, at the patient’s bedside, withthe same ultrasound machine and probethat is used to screen for IVC changes. Asthe physical examination during roundsis slowly replaced by rapid focused

screening with point-of-care ultrasound,such a scenario could become reality.Think this is science fiction or perhapsfantasy? All of these applications havebeen well documented, are accurate inclinicians’ hands, and currently practicedin intensive care units around the world.

Several cautionary thoughts come tomind, however. The human subjectsstudied by Cavaliere et al were all healthyvolunteers. None were significantly obeseand were unlikely to have been edema-tous. Although the potential for early de-tection and amelioration of IAH is real,how often practice and outcome will re-ally be changed based on an ultrasoundexamination is still an open question. Inaddition, if other steps fail and the onlyoption of IAH resolution is laparotomy,how easy will it be to convince a surgeonto open a patient’s perfectly intact abdo-men when no other signs of organ failureor physiological derangements arepresent? Future research is critical andmust be well designed to study multipleultrasound parameters for detection ofIAH in actual patients as well as the im-pact on early intervention and outcome.Another large pothole in the road, that isslowly being filled, is education. It is sim-ple for clinical ultrasound experts to per-form these techniques. However, re-searchers such as Kirkpatrick andcolleagues have uncommon levels of ul-trasound expertise and years of experi-ence. In this study, the authors used anexperienced radiologist to limit variabil-ity. Eventually, however, this is an appli-cation for the common physician in thesmall intensive care unit as well as theacademician in the state-of-the-art facil-ity. Repeat bedside ultrasound measure-ments do not lend themselves well tooverloaded radiology laboratories. Tocross this bridge will take time, educa-tion, and more research into the actualclinical benefit of a very intriguing andpromising technique.

Michael Blaivas, MDDepartment of Emergency

MedicineNorthside Hospital ForsythCumming, GA

REFERENCES

1. An G, West MA: Abdominal compartmentsyndrome: A concise clinical review. CritCare Med 2008; 36:1304–1310

2. Wiebe S, Kellenberger CJ, Khoury A, et al:Early Doppler changes in a renal transplantpatient secondary to abdominal compart-ment syndrome. Pediatr Radiol 2004; 34:432–434

3. De Waele JJ, Hoste EA, Malbrain ML: Decom-pressive laparotomy for abdominal compart-ment syndrome—A critical analysis. CritCare 2006; 10:R51

4. Cheatham ML, Malbrain ML, Kirkpatrick A,et al: Results from the International Confer-ence of Experts on Intra-abdominal Hyper-tension and Abdominal Compartment Syn-drome. II. Recommendations. Intensive CareMed 2007; 33:951–962

5. Malbrain ML, Cheatham ML, Kirkpatrick A,et al: Abdominal compartment syndrome: It’stime to pay attention! Intensive Care Med2006; 32:1912–1914

6. Kirkpatrick AW, Brenneman FD, McLean R,et al: Is clinical examination an accurate in-dicator of raised intra-abdominal pressure incritically injured patients? Can J Surg 2000;43:207–211

7. Mahjoub Y, Plantefeve G: Cardiac ultrasoundand abdominal compartment syndrome. ActaClin Belg Suppl 2007; 1:183–189

8. Umgelter A, Reindl W, Franzen M, et al:Renal resistive index and renal function be-fore and after paracentesis in patients withhepatorenal syndrome and tense ascites. In-tensive Care Med 2009; 35:152–156

9. Kirkpatrick AW, Colistro R, Laupland KB, etal: Renal arterial resistive index response tointraabdominal hypertension in a porcinemodel. Crit Care Med 2007; 35:207–213

10. Mayo PH, Beaulieu Y, Doelken P, et al: Amer-ican College of Chest Physicians/La Societede Reanimation de Langue Francaise state-ment on competence in critical care ultra-sonography. Chest 2009; 135:1050–1060

11. Stawicki SP, Braslow BM, Panebianco NL, etal: Intensivist use of hand-carried ultra-sonography to measure IVC collapsibility inestimating intravascular volume status: Cor-relations with CVP. J Am Coll Surg 2009;209:55–61

12. Gunst M, Ghaemmaghami V, Sperry J, et al:Accuracy of cardiac function and volume sta-tus estimates using the bedside echocardio-graphic assessment in trauma/critical care.J Trauma 2008; 65:509–516

13. Lyon M, Blaivas M, Brannam L: Sonographicmeasurement of the inferior vena cava as amarker of blood loss. Am J Emerg Med 2005;23:45–50

14. Cavaliere F, Cina A, Biasucci D, et al: Sono-graphic assessment of abdominal vein di-mensional and hemodynamic changes in-duced in human volunteers by a model ofabdominal hypertension. Crit Care Med2011; 39:344–348


Matrix metalloproteinases: From tadpole tails to critical illness*

I n 1962, Gross and LaPiere (1) pub-lished their seminal observationsthat proteolytic activity was neces-sary for the tadpole to reabsorb its

tail. Through an elegant series of experi-ments, they correctly surmised that pro-teinases contribute to the balance betweentissue breakdown and synthesis during nor-mal growth and development. The family ofproteinases Gross and LaPiere discoveredwould later be given the moniker “matrixmetalloproteinases” (MMPs) and, to date,28 members have been characterized. In-terestingly, we now recognize that MMPactivity is not only involved in normal mor-phogenesis, but also a wide variety of pa-thologies.

Increased activity of MMPs, or an im-balance between MMPs and their endog-enous inhibitors (tissue inhibitors ofMMPs), has been implicated in a varietyof chronic diseases, including atheroscle-rosis, heart failure, and cancer. In the lastdecade, a similar imbalance has also beenimplicated in relatively acute processessuch as cardiac ischemia reperfusion in-jury, pre-eclampsia, and thrombosis (2).Through these studies it has become ap-parent that MMPs are not merely “for thematrix,” but can also cleave a variety ofnonmatrix substrates, including cyto-kines, chemokines, vasoactive peptides,and other proteinases. In the arena ofcritical care, increased MMP activity hasbeen demonstrated in preclinical modelsof septic shock, and furthermore, inhibi-tion of MMPs has proven to be protectivein these models (3–5). Interestingly, arecent multicenter prospective observa-tional study demonstrated an increase incirculating MMP-10 and a decrease in tis-sue inhibitor of MMP-1 in patients withseptic shock compared with healthy con-trols (6). To date, however, no clinical

trial has investigated MMP inhibition incritically ill patients.

In this issue of Critical Care Medicine,Neto-Neves et al (7) implicate MMPs inyet another acute pathologic process,acute pulmonary embolism. Using a largeanimal model (dogs), an autologousblood clot was delivered to the rightatrium to induce pulmonary embolism.They investigated the role of MMPs inthis model by pretreating animals witheither doxycycline (a nonspecific MMP in-hibitor) or saline vehicle. MMP inhibitionimproved hemodynamics after embolismas seen by a reduction in pulmonary vas-cular resistance and a more modest de-crease in mean pulmonary artery pres-sure. This hemodynamic protection wasassociated with reduced cardiomyocytedamage (ie, decreased levels of circulat-ing troponin I) and a diminished inflam-matory response (ie, tissue accumulationof neutrophils).

This study is particularly novel withrespect to several findings. First, the au-thors have demonstrated an associationbetween pulmonary embolism and in-creased MMP proteolytic activity withinthe right ventricle. This was shown byconventional gel-based zymography aswell as an in situ zymography techniquethat demonstrates the overall net balancebetween these proteinases and their en-dogenous inhibitors. Second, the in-crease in myocardial MMP activity wasassociated with an increase in circulatingtroponin I, a standard biomarker of myo-cardial damage. Third, the authors havedemonstrated that MMP inhibition canameliorate right heart dysfunction afterpulmonary embolism.

The demonstrated association be-tween MMPs and troponin I in acute pul-monary embolism is particularly intrigu-ing. MMPs have been colocalized to anumber of intracellular domains, includ-ing the contractile apparatus of myocar-dial cells (8). Inappropriate intracellularactivation of MMPs occurs during cardiac–ischemia reperfusion injury and causesdirect cleavage of troponin I and myosinlight chain (8, 9). Although not directlydemonstrated in the study by Neto-Neveset al, these previous studies would sug-

gest that a similar intracellular activationof MMPs may be occurring in the rightventricle after pulmonary embolism. Thisactivation could lead to direct cleavage oftroponin I, resulting in cardiac dysfunc-tion and a measurable increase in circu-lating troponin I.

Equally as interesting was the effective-ness of doxycycline in this model. Doxycy-cline is most commonly known for its an-tibiotic effects; however, it has also beenused as an MMP inhibitor for over twodecades. This anti-MMP effect is completelyindependent of its antimicrobial activity,and it is based on doxycycline’s ability tochelate and inactivate the divalent zinc cat-ion in the proteolytic core of MMPs (10). Alltetracycline antibiotics have this abilitywith doxycycline and minocycline beingpotent inhibitors even occurring at suban-timicrobial doses. Although several MMPinhibitors have been tested (for a variety ofdiseases), to date, only doxycycline hasproven robust enough to be approved bythe Food and Drug Administration. Doxy-cycline has been successfully used for itsanti-MMP effects in periodontal inflamma-tion as a twice-daily 20-mg formulation.Thus, a generic, inexpensive, and well-established drug was used by Neto-Neves etal in their study to investigate MMPs inpulmonary embolism. This will be of par-ticular relevance if a translational clinicaltrial is planned in the future.

Despite these novel findings, a num-ber of important limitations of this studyshould be recognized. Most conspicu-ously, the pretreatment protocol of thestudy limits its applicability to real clini-cal phenomena. A rescue protocol wouldhave more accurately depicted the clini-cal scenario faced by most intensivists.Second, the authors do not address themechanism by which MMPs are activatedin pulmonary embolism. Extrapolatingfrom studies of septic shock or cardiacischemia reperfusion injury, it could besuggested that inflammatory mediatorsactivate MMPs after pulmonary embo-lism; however, this remains to be re-solved. Third, the use of doxycycline, al-though advantageous for the reasonsdescribed, also clouds conclusions fromthe study because it is a nonspecific MMP

*See also p. 349.Key Words: matrix metalloproteinases; pulmonary

embolism; septic shock; troponin IThe author has not disclosed any potential con-



DOI: 10.1097/CCM.0b013e318205c327


inhibitor and likely affects other inflam-matory pathways. Thus, other MMP in-hibitors need to be tested in models ofpulmonary embolism in the future. Fi-nally, although increased troponin I deg-radation is associated with pulmonaryembolism, it is unclear whether this is adirect result of MMP activity or merely adownstream signal of injury.

In conclusion, although MMP activityis clearly increased after acute pulmonaryembolism, additional studies will be re-quired to delineate the precise role ofMMPs in this pathology. Although MMPinhibition holds great potential, furtherinvestigations will be crucial before con-sidering a clinical trial of MMP inhibitorsin the critically ill population.

Manoj M. Lalu, MD, PhDDepartment of AnesthesiologyThe Ottawa HospitalOttawa, Ontario, Canada

REFERENCES

1. Gross J, Lapiere CM: Collagenolytic activityin amphibian tissues: A tissue culture as-say. Proc Nat Acad Sci U S A 1962;481014 – 481022

2. Kandasamy AD, Chow AK, Ali MA, et al: Ma-trix metalloproteinase-2 and myocardial oxi-dative stress injury: Beyond the matrix. Car-diovasc Res 2010; 85:413–423

3. Cena JJ, Lalu MM, Cho WJ, et al: Inhibitionof matrix metalloproteinase activity in vivoprotects against vascular hyporeactivity inendotoxemia. Am J Physiol Heart CircPhysiol 2010; 298:H45–H51

4. Maitra SR, Bhaduri S, Valane PD, et al: Inhi-bition of matrix metalloproteinases by chem-ically modified tetracyclines in sepsis. Shock2003; 20:280–285

5. Steinberg J, Halter J, Schiller HJ, et al: Met-alloproteinase inhibition reduces lung injuryand improves survival after cecal ligation andpuncture in rats. J Surg Res 2003; 111:185–195

6. Lorente L, Martin MM, Labarta L, et al: Ma-

trix metalloproteinase-9, -10, and tissue in-hibitor of matrix metalloproteinases-1 bloodlevels as biomarkers of severity and mortalityin sepsis. Crit Care 2009; 13:R158

7. Neto-Neves EM, Dias-Junior CA, Rizzi E, etal: Metalloproteinase inhibition protectsagainst cardiomyocyte injury during experi-mental acute pulmonary thromboembolism.Crit Care Med 2011; 39:349–356

8. Sawicki G, Leon H, Sawicka J, et al: Degra-dation of myosin light chain in isolated rathearts subjected to ischemia–reperfusion in-jury: A new intracellular target for matrixmetalloproteinase-2. Circulation 2005; 112:544–552

9. Cheung PY, Sawicki G, Wozniak M, et al:Matrix metalloproteinase-2 contributes toischemia–reperfusion injury in the heart.Circulation 2000; 101:1833–1839

10. Griffin MO, Fricovsky E, Ceballos G, et al:Tetracyclines: A pleitropic family of com-pounds with promising therapeutic proper-ties. Review of the literature. Am J PhysiolCell Physiol 2010; 299:C539–C548

ALI: Acute lung injury, or arginine–vasopressin limitsinflammation, or both?*

Acute lung injury (ALI) still isone of the major clinical chal-lenges for intensivists world-wide. Researchers all over the

world studied and still study differentstrategies to reduce mortality of patientswith ALI.

Basically, there are two approaches toimprove outcome: a mechanical or tech-nical approach on the one hand and apharmacologic approach on the other.

In the last decades, research some-what concentrated on the mechanical ortechnical approach: extracorporeal mem-brane oxygenation, extracorporeal CO2

removal, and especially less invasivestrategies of mechanical ventilation (re-duced peak airway pressure, open lungconcept, and limited tidal volume) helpedto significantly improve the outcome of

ALI (1–4). Furthermore, the understand-ing of mechanically induced pulmonarydamage through mechanical ventilationhelped to prevent ALI and/or acute respira-tory distress syndrome, thereby improvingthe outcome of critically ill patients.

The pharmacologic approach stoodsomewhat behind the mechanical ap-proach. Administration of surfactant is apromising therapeutic option for treatinginfants with ALI or acute respiratory dis-tress syndrome but did not achieve accep-tance for adults (5). The idea behind thistherapeutic concept was to achieve an im-provement in pulmonary mechanics. Thisapproach, although pharmacologic, basi-cally aimed at mechanics. The same holdstrue for partial liquid ventilation (6).

When it comes to pharmacologic ma-nipulation of the underlying pathophysi-ology of ALI, the obtained results aresomewhat disappointing (7). Nitric oxidehas been identified as a key mediator notonly in sepsis, but also in ALI. Nitricoxide is a potent vasodilator and, as such,it also contributes to redistribution ofblood flow not only in the systemic cir-culation, but also in the lungs, thus re-ducing the efficacy of hypoxic pulmonary

vasoconstriction with subsequent in-crease in intrapulmonary shunt. Al-though the inhalation of nitric oxide withconsecutive reduction of ventilation–perfusion mismatch led to an improve-ment in oxygenation, after all, it failed toimprove outcome (8). The systemic inhi-bition or reduction of nitric oxide synthe-sis may exert beneficial effects, because itreduces the oxidative stress to the pulmo-nary tissue, thus improving gas ex-change.

The investigational Intensive CareUnit under the direction of Dan Trabermimics, as suggested by its name, clinicalconditions seen everyday on intensivecare units all over the world. No wonderthat research published by this group isof high clinical value. Especially in thefields of sepsis and ALI, Traber and hiscolleagues (9) have set landmarks formore than two decades by now. In thecurrent issue of Critical Care Medicine,this group presents their latest researchfocusing on the effects of low-dose argin-ine–vasopressin (AVP) on ovine ALI.Mimicking clinical conditions, treatmentwas initiated 1 hr after inhalation injuryrather than directly after inhalation in-

*See also p. 357.Key Words: arginine vasopressin; acute lung injury;

acute respiratory distress syndrome; inflammation;sepsis; nitric oxide; vasoconstriction



DOI: 10.1097/CCM.0b013e318205c0b9


jury. At that time, inflammation alreadyis on its way, leading to pulmonary andcardiovascular deterioration. Traber andcolleagues investigated the effects of AVPon systemic circulation in hyperdynamicsepsis (10, 11), and AVP found its way asa therapeutic agent for the treatment ofseptic shock (12). The use of AVP in ALI,however, has not been investigated so far.The presented study nicely demonstratesthat AVP as a continuous low-dose infu-sion initiated 1 hr after inhalation injuryimproves pulmonary gas exchange andstabilizes systemic and pulmonary hemo-dynamics in an ovine model of ALI. Fur-thermore, the presented data suggestthat this effect is related to an anti-inflammatory effect as shown by de-creased levels of nitrates and nitrites. Be-cause AVP is an extremely potentvasoconstrictor, the authors adminis-tered AVP as a continuous infusion at avery low dose only. That way, they pre-vented excessive vasoconstriction, whichcould lead to a reduction in cardiac out-put with subsequent reduction in oxygendelivery, which may have outweighed thehere achieved improvement in pulmo-nary function.

Although the mechanical approach toprevent and treat pulmonary damage inventilated patients has found its way to(hopefully) all intensive care units world-

wide, the presented study may serve as abasis for an adjunctive pharmacologic ap-proach to further improve outcome inpatients with ALI. Clinical studies areneeded to demonstrate whether low-doseAVP in combination with lung-protectiveventilation may serve to further lowermortality in patients with ALI.

Michael Booke, MD, PhD, MHBADepartment of Anesthesiology

and Intensive CareMedicine

Kliniken des Main-Taunus-Kreis

Teaching Hospital of theJohann-Wolfgang-GoetheUniversity

Frankfurt, Germany

REFERENCES

1. Zapol WM, Snider MT, Schneider RC: Extra-corporeal membrane oxygenation for acuterespiratory failure. Anesthesiology 1977; 46:272–285

2. Gattinoni L, Agostoni A, Pesenti A, et al:Treatment of acute respiratory failure withlow-frequency positive pressure ventilationand extracorporeal removal of CO2. Lancet1980; 2:292–294

3. Petrucci N, Iacovelli W: Ventilation withlower tidal volumes versus traditional tidalvolumes in adults for acute lung injury andacute respiratory distress syndrome. Co-chrane Database Syst Rev 2003; 3:CD003844

4. Randolph AG: Management of acute lung in-jury and acute respiratory distress syndrome inchildren. Crit Care Med 2009; 37:3191–3192

5. Lachmann B: Open lung in ARDS. MinervaAnesthesiol 2002; 68:637–642

6. Davies MW, Fraser JF: Partial liquid ventila-tion for preventing death and morbidity inadults with acute lung injury and acute re-spiratory distress syndrome. Cochrane Data-base Syst Rev 2004; 18:CD003707

7. Adhikari N, Burns KE, Meade MO: Pharma-cological therapies for adults with acute lunginjury and acute respiratory distress syn-drome. Cochrane Database Syst Rev 2004;18:CD004477

8. Afshari A, Brok J, Møller AM, et al: Inhalednitric oxide for acute respiratory distress syn-drome (ARDS) and acute lung injury in chil-dren and adults. Cochrane Database SystRev 2010; 7:CD002787

9. Westphal M, Rehberg S, Maybauer MO, et al:Cardiopulmonary effects of low-dose argi-nine vasopressin in ovine acute lung injury.Crit Care Med 2011; 39:357–363

10. Ertmer C, Bone HG, Morelli A, et al: Meth-ylprednisolone reverses vasopressin hypore-sponsiveness in ovine endotoxemia. Shock2007; 27:281–288

11. Maybauer MO, Traber DL, Maybauer DM:Catecholamines, vasopressin and markers ofacute liver injury in septic shock. Shock2009; 31:222–223

12. Dellinger RP, Levy MM, Carlet JM, et al: Sur-viving sepsis campaign: International guide-lines for management of severe sepsis and sep-tic shock. Crit Care Med 2008; 36:296–327

Pushing the envelope*

T om Wolfe popularized theterm “pushing the envelope”in his 1979 classic, The RightStuff (1). Based on mathemat-

ical terminology for the boundary ofcurves, the term described test pilots’ ef-forts to extend the limits of aircraft andhuman capability past the previous edgeof function and has since become a partof the popular lexicon. This term epito-mizes the efforts of innovators to demon-

strate efficacy and to expand the bound-aries of therapeutic use of extracorporealsupport for respiratory failure.

Extracorporeal membrane oxygen-ation (ECMO) was first used for treat-ment in neonatal respiratory failure (2),and its subsequent development set stan-dards for the rapid diffusion of new tech-nology into clinical practice (3). Use ofECMO in neonates is now well supportedby demonstrated benefit from a 1996 ran-domized clinical trial (4), even as its usehas decreased, attributable to therapiessuch as inhaled nitric oxide. Intensivistssubsequently sought to expand the role ofECMO for both adult and pediatric criti-cally ill patients. A recent randomizedclinical trial has suggested that a man-agement approach for severe adult respi-ratory failure that includes ECMO couldimprove survival (5). In pediatrics, ef-

forts to perform a randomized clinicaltrial fell short, as a result of both im-proved outcomes in pediatric acutelung injury and of the difficulty in ob-taining adequate numbers of severely illchildren for study entry (6). However,one might suggest that the combinedevidence of the neonatal and adultECMO trials could “sandwich” the pe-diatric population regarding potentialoutcome benefit.

Although definitive evidence of benefitfor pediatric respiratory failure may awaitthe elusive randomized clinical trial, wedo have a large body of experience tomine from the Extracorporeal Life Sup-port Organization Registry. The registryis the largest international ECMO data-base, containing data on �40,000 neo-nates, children, and adults receiving ex-tracorporeal support for cardiac and

*See also p. 364.Key Words: pediatric respiratory failure; extracor-

poreal membrane oxygenation; ECMO; pediatric lunginjury; venovenous ECMO.



DOI: 10.1097/CCM.0b013e318205c316


respiratory failure from �160 centersworldwide since 1986.

Zabrocki et al (7) in this issue provide along-needed updated Extracorporeal LifeSupport Organization Registry analysis ofpatients receiving ECMO for pediatric re-spiratory failure. The authors report thelargest collective experience to date on theuse of ECMO for acute respiratory failure in�3200 children (31 days to 18 yrs old)during a 14-yr period from 1993 to 2007.The authors not only describe outcomedata with ECMO support, but provide awindow into efforts at pushing the envelopeof typical ECMO use. The review highlightsthree growing trends in ECMO supportthat have pushed this envelope: increaseduse of ECMO with comorbidities, increaseduse of venovenous support, and use ofECMO after increasingly more prolongedventilation periods.

The most intriguing trend reported isthe increased use of ECMO, and improvedsurvival, in children with comorbiditiesonce considered exclusions from consid-eration. Overall ECMO survival remainedessentially unchanged over the reportedtime period. However, the severity of ill-ness of patients being cannulated, as ev-idenced by associated comorbidities, sig-nificantly increased over the 15-yr periodfrom 19% to 47% of all patients annually.Indeed, increasing reports have describedrelatively successful experience withECMO use in a variety of conditions suchas cancer (8) and severe sepsis (9) withprimary respiratory failure that werepreviously thought to be contraindica-tions to ECMO. Given the consistencyin survival rates, the authors infer thatECMO is being successfully offered toincreasingly complex patients. Addi-tionally, when including only patientswith no underlying comorbidities, an-nual survival increased from 57% to72% over the period. Together, thesefindings suggest that ECMO outcomesare improving globally in both the “tra-ditional” respiratory failure ECMO pa-tient and the “newer” ECMO patientwith comorbidities.

A second trend noted was the in-creased use of the venovenous cannula-tion approach for pediatric ECMO sup-port. Past standard approaches to ECMOin children have used a venoarterial tech-nique, in which return of oxygenatedblood from the ECMO circuit is achievedthrough a catheter placed in a centralarterial vessel, typically the carotid ar-tery. In addition to the clear concernabout required carotid artery ligation and

potential systemic emboli, venoarterialsupport presents a variety of other poten-tial negative effects that can be avoidedwith venous cannulation alone (10).Venovenous use increased from 35% to46% annually and double-lumen veno-venous catheters from 1% to 19%. Moreimportantly, the authors report thatvenovenous ECMO cannulation (66 –70%) was associated with improved sur-vival compared with venoarterial(51%). Although venoarterial choicemight have indicated a specific need forcardiovascular support and greater acu-ity of illness, its use in respiratory fail-ure more likely reflects institutional ex-perience and choice.

The authors identify a third impor-tant trend of children undergoing moreprolonged mechanical ventilation be-fore ECMO cannulation. Previous stud-ies have supported poor outcomes withinstitution of ECMO in patients venti-lated over 7 days, and standard recom-mendations have suggested that ECMOsupport should not be initiated after 10days in the pediatric patient (11). Incontrast, the authors found that patientsurvival was essentially unchanged at56 – 61% with up to 14 days of mechan-ical ventilation before ECMO cannula-tion, after which survival was decreasedto 38%. Of note, the overall median pre-ECMO ventilator course was only 3.1days, and pre-ECMO ventilator days weresignificantly lower, by almost a day, insurvivors. Thus, evidence still suggeststhat for the best outcomes considerationof ECMO support should be made as earlyas possible in the course of children fail-ing traditional ventilation.

The limitations of review of the Extra-corporeal Life Support Organization Reg-istry data are well described. The Registryis voluntary and surely is not inclusive ofall international ECMO cases. The Regis-try also lacks robust estimates of pre-ECMO illness severity. Future inclusionof such severity of illness data in theregistry would be beneficial to allow moredirect comparison of patients receivingECMO to patients with similar illness se-verity not receiving ECMO. However, ab-sent a randomized clinical trial, the cur-rent study uses the best available datafrom our largest extracorporeal databaseto identify predictors of mortality and ac-ceptable comorbidities as well as to guidedecisions of timing and optimal cannula-tion for ECMO in pediatric respiratoryfailure. Pushing the envelope in innova-tive ways has defined the development

and diffusion of ECMO. This study pro-vides valuable information for physiciansconsidering ECMO for children failingstandard respiratory support approaches.

James D. Fortenberry, FAAP,FCCM

Children’s Healthcare ofAtlanta

Department of PediatricCritical Care

Emory University School ofMedicine

Atlanta, GA

REFERENCES

1. Wolfe T: The Right Stuff. New York, NY,Farrar, Strauss and Giroux, 1979

2. Bartlett RH, Andrews AF, Toomasian JM, etal: Extracorporeal membrane oxygenationfor newborn respiratory failure: Forty-fivecases. Surgery 1982; 92:425–433

3. National Institute of Child Health and Devel-opment: Report of the Workshop on Diffu-sion of Extracorporeal Membrane Oxygen-ation Technology, January 1993

4. UK Collaborative ECMO Trial Group: UK col-laborative randomized trial of neonatal extra-corporeal membrane oxygenation. Lancet1996; 348:75–82

5. Peek GJ, Mugford M, Tiruvoipati R, et al:Efficacy and economic assessment of conven-tional ventilatory support versus extracorpo-real membrane oxygenation for severe adultrespiratory failure (CESAR): A multicentrerandomized controlled trial. Lancet 2009;374:1351–1363

6. Fackler J, Bohn D, Green T, et al: ECMO forARDS: Stopping a RCT. Abstr. Am J RespirCrit Care Med 1997; 155:A504

7. Zabrocki LA, Brogan TV, Statler KD, et al:Extracorporeal membrane oxygenation forpediatric respiratory failure: Survival andpredictors of mortality. Crit Care Med 2011;39:364–370

8. Gow KW, Heiss KF, Wulkan ML, et al: Extra-corporeal life support of children with ma-lignancy and respiratory or cardiac failure:The ELSO Registry experience. Crit CareMed 2009; 37:1308–1316

9. Maclaren G, Butt W, Best D, et al: Extracor-poreal membrane oxygenation for refractoryseptic shock in children: One institution’sexperience. Pediatr Crit Care Med 2007;8:447–451

10. Fortenberry JD, Pettignano R, Dykes F:Venovenous extracorporeal support: Princi-ples and practice. In: Extracorporeal Cardio-pulmonary Support in Critical Care. ThirdEdition. Van Meurs K, Lally K, Peek G, et al(Eds). Ann Arbor, MI, Extracorporeal LifeSupport Organization, 2005, pp 85–105

11. Conrad SA, Dalton HJ: Extracorporeal lifesupport. In: Rogers Textbook of Pediatric In-tensive Care. Fourth Edition. Nichols DG(Ed). Philadelphia, PA, Lippincott Williams &Wilkins, 2008, p 554


Is it time to replace L-arginine in severe sepsis?*

L-arginine has been considereda semi-essential amino acidsince the 1950s, when Roseand Snyderman described that

L-arginine was not essential for growthand maintenance of nitrogen homeosta-sis (1, 2). However, more recently it hasbeen postulated that in acute catabolicstates like sepsis, trauma, and surgery,this amino acid may become “condition-ally” essential (3, 4).

In healthy individuals, L-arginine isderived from both exogenous and endog-enous sources. Dietary (exogenous)sources undergo intestinal conversion tocitrulline, which is converted back to L-arginine by the kidneys followed bybloodstream release; then the liver argi-nase metabolizes L-arginine into orni-thine, which provides substracts for cellgrowth, collagen synthesis, and woundhealing. This de novo synthesis accountsfor 10% to 15% of L-arginine sources,whereas diet contributes to 20% to 25%;protein breakdown remains the major en-dogenous source of this amino acid (5).L-Arginine is utilized for the synthesis ofcreatine (muscle tissue) and for the pro-duction of the three nitric oxide syn-thases (NOSs) (inducible NOS, neuronalNOS, and endothelial NOS), which arethe main sources of NO. NO is not onlycritical for the maintenance of the hemo-dynamic state in both healthy and dis-eased humans, but also one of the mostimportant endogenous mediators in sep-sis-induced shock (6). Additionally, thereare many immunologic effects that canbe modified by L-arginine and associatedwith antimicrobial properties, such as theenhancement of macrophage phagocyticactivity and reactive oxygen species byneutrophils, as well as the improvementof Th1/Th2 responses and cell-mediatedimmunity (7).

What happens with the L-arginine me-tabolism during sepsis? L-Arginine avail-ability becomes impaired due to severalfactors: lower de novo L-arginine produc-tion (e.g., decreased food intake, de-creased gut absorption, and decreasedcitrulline gut production); increased L-arginine consumption (e.g., increased ar-ginase and NO production, increased pro-tein need) (3, 8). Also, proinflammatorycytokines (e.g., interleukin-1, tumor necro-sis factor-�, and interferon-) increase theproduction of inducible nitric oxide syn-thase (leading to L-arginine depletion) andanti-inflammatory cytokines (e.g., interleu-kin-4, interleukin-10, interleukin-13, andtransforming growth factor-�) induce argi-nase expression (also leading to L-argininedepletion), whereas endotoxin may induceboth inducible nitric oxide synthase andarginase activity (8).

In this edition of Critical Care Medi-cine, Davis and Anstey (9) bring a refresh-ing analysis of all available evidence withrespect to the levels of L-arginine in hu-mans with sepsis. Study methods werepredefined; a clear-cut diagnosis of sepsisand the plasma L-arginine concentrationwere required, and the L-arginine mea-surements had to be done in the absenceof any specific amino acid supplement.Also, a specific study quality score wasdesigned for his meta-analysis, the ran-dom-effects model by DerSimonian andLaird was used for all analyses, and achecklist according to the meta-analysisof observational studies in epidemiologyguidelines was provided as an appendix.The quantitative analysis included 10studies and a total of 341 patients. Theauthors main analysis showed that com-pared with controls, patients with sepsishad a significant 41% relative decrease inL-arginine levels, more specifically, theL-arginine concentration decreased by33.9 �mol/L (95% confidence interval41.2 to 26.6; p � .0001; I2 � 70%).When only the high-quality studies werepooled, the heterogeneity had a dramaticdecrease and the L-arginine level was fur-ther reduced in patients with sepsis(42.5 �mol/L [95% confidence interval47.9 to 37.2]; p � .001; I2 � 0%). Allresults remained similar, independent of

type of controls, that is, nonseptic ill pa-tients or healthy individuals. Interest-ingly, out of the four studies that did notshow lower L-arginine levels, three didnot provide information about the time ofblood collection; because L-arginine lev-els tend to return to normal in 2 to 4days, it is possible that the delay in bloodcollection could have corroborated thesenegative results. Another important ap-proach the authors took was to evaluatestudies that included trauma and surgeryseparately, because patients with sepsismay have concomitant or recent episodesof surgery or trauma. Hence, their meta-analyses clearly focused on sepsis, whichhas not been done before to my knowl-edge. Limitations of this study includedhigher degree of heterogeneity (high I2),some poor-quality studies (studies withsepsis associated to surgery and trauma),and potential publication bias that is dif-ficult to rule out based on the size of thereview and low power of statistical tests.The authors concluded that “given thatplasma L-arginine concentrations areclearly decreased in humans with sepsis,the issue of exogenous arginine adminis-tration in sepsis should be revisited.”

Is now the prime time to evaluate L-arginine replacement in patients withsepsis? Many preclinical studies evaluatedthe role of L-arginine in mice, rats,guinea pigs, rabbits, pigs, sheep, and dogs(7). In a study on bacteremic sheep, L-arginine infusion caused a significant de-crease in blood pressure, systemic vascu-lar resistance index, and oxygen deliveryindex (10). In another study on a canineseptic shock model (11), L-arginine infu-sion was associated with significant wors-ening in shock status and renal and liverfunctions, and a significant increase inmortality. Human studies have shownconflicting results, ranging from benefitsto no differences to harm (7). Of concern,a randomized clinical trial that evaluatedthe effects of L-arginine in patients withacute myocardial infarction (a conditionwith a strong biological rationale for theuse of L-arginine supplementation) (12),no vascular or cardiac benefits could bedetected, and postinfarction mortalitywas significantly higher with L-arginine

*See also p. 380.Key Word: sepsis; L-arginineThe author has not disclosed any potential con-



DOI: 10.1097/CCM.0b013e318205c386


compared with controls. Similarly, manypossible reasons could explain worse out-comes in patients with sepsis; for exam-ple, if L-arginine replacement increasesthe production of vascular and cardiacNO, then both vascular resistance andcardiac output could be negatively af-fected, leading to worsening shock andhigher mortality. Also, increased NO pro-duction could lead to excessive formationof peroxynitrite radicals, culminating inmore mitochondrial dysfunction leadingto worsening organ failure. However, thephysiologic and/or pathologic conse-quences of L-arginine replacement in hu-mans with sepsis remain to be elucidated.

In conclusion, Davis and Anstey (9)are to be congratulated for their elucidat-ing work, which clarifies an old questionand brings more certainty to the fact thatsepsis is in fact an L-arginine deficiencystate. That does not mean that we shouldrush to the conclusion that replacementis the next course to take (this was notthe goal of this study). I say that not onlybecause L-arginine levels rapidly returnto normal without any exogenous re-placement in many patients with sepsis,but also because the consequent increasein NO production from L-arginine re-placement may bring more harmful vas-cular and cardiac effects to these already

critically ill patients. I believe that if thenatural history of L-arginine metabolismis thoroughly and systematically evalu-ated in a large sepsis clinical trial (e.g.,daily sequential L-arginine levels– con-trolling for enteric and intravenous nu-trition–as well as the levels of NO and itsinhibitor asymmetric dimethylarginine,which antagonizes L-arginine utilization,and their relationship to severity of ill-ness, organ failure progression, and mor-tality outcomes), we would be able tofurther elucidate at least three importantissues: More robust biological rationalefor (or against) L-arginine replacement,more precise timing of replacement, andmore specific sepsis patient population(e.g., age, hemodynamic status, and se-verity of illness) who would have the bestrisk/benefit profile from it.

Andre C. Kalil, MDUniversity of Nebraska Medical

CenterOmaha, NE

REFERENCES

1. Snyderman SE, Boyer A, Holt Jr LE: Thearginine requirement of the infant. AMA JDis Child 1959; 97:192–195

2. Carcillo JA: Does arginine become a “near”essential amino acid during sepsis? Crit CareMed 2003; 31:657–659

3. Luiking YC, Poeze M, Dejong CH, et al: Sep-

sis: An arginine deficiency state? Crit CareMed 2004; 32:2135–2145

4. Bronte V, Zanovello P: Regulation of im-mune responses by L-arginine metabolism.Nat Rev Immunol 2005; 5:641–654

5. Wu G, Morris SM Jr: Arginine metabolism:Nitric oxide and beyond. Biochem J 1998;336:1–17

6. Ma P, Danner RL: The many faces of sepsis-induced vascular failure. Crit Care Med 2002;30:947–949

7. Kalil AC, Danner RL: L-Arginine supplemen-tation in sepsis: Beneficial or harmful? CurrOpin Crit Care 2006; 12:303–308

8. Popovic PJ, Zeh HJ III, Ochoa JB: Arginineand immunity. J Nutr 2007; 137(Suppl 2):1681S–1686S

9. Davis JS, Anstey NM: Is plasma arginine con-centration decreased in patients with sepsis?A systematic review and meta-analysis. CritCare Med 2011; 39:380–385

10. Lorente JA, Delgado MA, Tejedor C, et al:Modulation of systemic hemodynamics byexogenous L-arginine in normal and bacte-remic sheep. Crit Care Med 1999; 27:2474–2479

11. Kalil AC, Sevransky JE, Myers DE, et al: Pre-clinical trial of L-arginine monotherapyalone or with N-acetylcysteine in septicshock. Crit Care Med 2006; 34:2719–2728

12. Schulman SP, Becker LC, Kass DA, et al:L-arginine therapy in acute myocardial in-farction: The Vascular Interaction With Agein Myocardial Infarction (VINTAGE MI) ran-domized clinical trial. JAMA 2006; 295:58–64

Does albumin fluid resuscitation in sepsis save lives?*

Colloids have been the subjectof many systematic reviews inthe past 25 yrs, frequently try-ing to discern the superiority

of one fluid type over another for subsetsof patients in which large clinical trialshave not been conducted. The contro-versy between colloids and crystalloidsexists for a good reason. Intrinsic patientheterogeneity makes it impossible to testevery fluid regimen in every patient pop-

ulation. There is not a consensus and it isimpossible to even keep a tally of howmany meta-analyses favored colloids andhow many favored crystalloids. In thecurrent issue of Critical Care Medicine,the most recent meta-analysis specificallyasks if albumin use may be beneficial forthe subset of critically ill patients withsepsis (1). In this article, the authors an-alyzed 17 studies that randomized 1977patients to receive albumin or other flu-ids and concluded that albumin fluid re-suscitation is associated with a lowermortality rate in sepsis patients com-pared with other fluid types. The magni-tude of mortality reduction (an odds ratioof 0.82) would be clinically significant ifreal and just reaches the level of statisti-cal significance.

Albumin entered the clinical world ofmedicine in World War II and has been

administered for innumerable indicationssince that time. Physiology and biochem-istry have taught us that colloid osmoticpressure is important; at the very least, itinfluences fluid flux between tissues andalters protein synthesis (2). Because al-bumin accounts for approximately 75%of colloid osmotic pressure, many clini-cians have believed that prescription ofalbumin is appropriate to maintain ho-meostasis, particularly in critically ill pa-tients. More recently, we have learnedabout the contribution of albumin fortransport and inactivation of various hor-mones, enzymes, and even drugs. Per-haps most interestingly, including instudies of critical illness such as sepsis, isthe effect of albumin on oxidative stress,recognizing it as the most abundant ex-tracellular antioxidant in the humanbody (3–5).

*See also p. 386.Key Words: albumin; meta-analysis; sepsis; col-

loid; fluid resuscitationDr. Martin received a provision of the study drug

for a clinical trial by Baxter Healthcare. Dr. Han has notdisclosed any potential conflicts of interest.


DOI: 10.1097/CCM.0b013e318206b0ff


Sepsis triggers a myriad of inflamma-tory pathways producing free radicals andsevere oxidative stress, leaky endothelialjunctions, and stimulation of the coagu-lation pathway (6). The persistent sys-temic inflammatory state of sepsis createsendothelial and other cellular dysfunc-tion, which can lead to multiple organfailure (7). Fluid resuscitation is a cor-nerstone of strategies to improve tissuefunction and prevent organ dysfunction.

There are several potentially relevantdistinguishing features of colloids and al-bumin specifically. Albumin selectivelyinhibits vascular cell adhesion mole-cule-1, which blocks endothelial activa-tion and leukocyte–endothelial commu-nication to decrease the inflammatoryresponse in human aortic endothelialcells (8). Albumin is reported to decreasevascular permeability and maintainplasma redox homeostasis, (2, 9), and theantioxidant properties of albumin maysignificantly abrogate respiratory organdysfunction (3). From a clinical perspec-tive, albumin supports colloid osmoticpressure and regulates fluid shifts be-tween the extra- and intravascular space(6) and sepsis resuscitation is as much as36% faster with albumin than with crys-talloids (10, 11). Albumin administrationhas been shown to increase hemody-namic stability in patients with acutelung injury while also improving oxygen-ation (12). The mechanisms underlyingclinical and physiological benefits of al-bumin remain uncertain and may be re-lated to either colligative or noncolliga-tive properties of albumin (4, 13).

With all these wonderful effects of al-bumin, it is hard not to be convinced thatalbumin is the superior choice for fluidresuscitation in sepsis. Viewing the bio-chemical profile of albumin in light of thepathophysiology of sepsis creates biolog-ical plausibility, that albumin may havecolligative or noncolligative propertiesthat are important in sepsis fluid resus-citation. The fact that the treatment ef-fect was similar in magnitude to that inthe sepsis subset of the Saline versus Al-bumin Fluid Evaluation (SAFE) study isnot surprising (relative risk 0.87, ad-justed odds ratio 0.71), (14) because thesize of that study contributes substan-tially to these results. Additional supportcomes from the data, in which dilute al-

bumin solutions appear superior to con-centrated solutions, as one might predictfor patients needing fluid resuscitation.The fact that a different colloid, synthetichetastarch, causes kidney injury whenused for fluid resuscitation in patientswith sepsis does not diminish the argu-ment because of large differences be-tween fluids (15). Importantly, however,not all studies in this meta-analysis fa-vored albumin, and recent concern aboutthe veracity of some included studies mayinfluence the direction and magnitude ofthe reported results.

How do we interpret this study, know-ing that meta-analyses are imperfect pre-dictors of true treatment effects such thatthey fail to accurately predict the resultsof subsequent large clinical trials on av-erage 35% of the time and perhaps asoften as 64% of the time? (16) Becauseclinicians seek to provide the best care fortheir patients, and fluid administration isamong the most common interventionsin critically ill patients, we will continueto seek information that best informs ourfluid choices. It is appealing to think thatalbumin saves lives in sepsis resuscita-tion, but as clinicians, we would like tofeel confident that any data are convinc-ing for a cause-and-effect relationship be-tween the fluid chosen and an importantclinical outcome. For an important pop-ulation such as sepsis, we must wait forprospective clinical trials to provide a bet-ter level of evidence regarding the opti-mal fluid resuscitation in sepsis.

Jenny Han, MDDivision of Pulmonary, Allergy

and Critical CareEmory University School of

MedicineGrady Memorial HospitalAtlanta, GA

Greg S. Martin, MD, MScDepartment of MedicineDivision of Pulmonary, Allergy

and Critical CareEmory University School of

MedicineAtlanta, GA

REFERENCES

1. Delaney AP, Dan A, McCafferey J, et al: Therole of albumin as a resuscitation fluid forpatients with sepsis: A systematic review and

meta-analysis. Crit Care Med 2010; 39:386–391

2. Quinlan GJ, Martin GS, Evans TW: Albumin:Biochemical properties and therapeutic po-tential. Hepatology 2005; 41:1211–1219

3. Quinlan GJ, Margarson MP, Mumby S, et al:Administration of albumin to patients withsepsis syndrome: A possible beneficial role inplasma thiol repletion. Clin Sci (Lond) 1998;95:459–465

4. Powers KA, Kapus A, Khadaroo RG, et al:Twenty-five percent albumin prevents lunginjury following shock/resuscitation. CritCare Med 2003; 31:2355–2363

5. Martin GS, Matthay MA, ATS Colloid Consen-sus Working Group: Evidence-based colloiduse in the critically ill: American ThoracicSociety Consensus Statement. Am J RespirCrit Care Med 2004; 170:1247–1259

6. Bone RC: The pathogenesis of sepsis. AnnIntern Med 1991; 115:457–469

7. Martin GS, Lewis CA: Fluid management inshock. Semin Respir Crit Care Med 2004;25:683–694

8. Zhang WJ, Frei B: Albumin selectively inhibitsTNFa-induced expression of vascular cell adhe-sion molecule-1 in human aortic endothelialcells. Cardiovasc Res 2002; 55:820–829

9. Quinlan GJ, Mumby S, Martin G, et al: Albu-min influences total plasma antioxidant ca-pacity favorably in patients with acute lunginjury. Crit Care Med 2004; 32:755–759

10. Shoemaker WC, Schluchter M, Hopkins JA,et al: Comparison of the relative effectivenessof colloids and crystalloids in emergency re-suscitation. Am J Surg 1981; 142:73–84

11. Ernest D, Belzberg AS, Dodek PM: Distribu-tion of normal saline and 5% albumin infu-sions in septic patients. Crit Care Med 1999;27:46–50

12. Martin GS, Moss M, Wheeler AP, et al: Arandomized controlled trial of furosemidewith or without albumin in hypoproteinemicacute lung injury patients. Crit Care Med2005; 33:1681–1687

13. Martin GS, Bernard GR: Improved oxygen-ation in acute lung injury: Albumin gain orfluid loss? Crit Care Med 2003; 31:1886–1887

14. SAFE study investigators: Impact of albumincompared to saline on organ function andmortality of patients with severe sepsis. In-tensive Care Med 2010 Oct 6 [Epub ahead ofprint]

15. Brunkhorst FM, Engel C, Bloos F, et al: In-tensive insulin therapy and pentastarch re-suscitation in severe sepsis. N Engl J Med2008; 358:125–139

16. LeLorier J, Gregoire G, Benhaddad A, et al:Discrepancies between meta-analyses andsubsequent large randomized, controlled tri-als. N Engl J Med 1997; 337:536–542


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